Factor VIII-bypassing activity of bovine tissue factor using the canine hemophilic model.

PubMed Central

O'Brien, D P; Giles, A R; Tate, K M; Vehar, G A

1988-01-01

The bleeding disorder of hemophilia A currently treated by replacement therapy of the missing coagulation factor, factor VIII, is frequently complicated by the development of neutralizing antibodies. The therapeutic potential of attenuated forms of the lipid-associated glycoprotein tissue factor, a known initiator of coagulation, was investigated as a factor VIII-by-passing activity. The protein moiety of tissue factor (Apo-TF) was partially purified and exhibited minimal procoagulant activity before relipidation in vitro. In pilot studies, Apo-TF injection into rabbits previously anticoagulated with an antibody to factor VIII was found to have a procoagulant effect. The efficacy of the material was further demonstrated when injection of Apo-TF in hemophilic dogs resulted in a normalization of the cuticle bleeding time. Little or no change in the blood parameters associated with disseminated intravascular coagulation was observed at lower doses, although mild to moderate effects were seen at higher doses. These data suggest a novel role for Apo-TF preparations as a potential therapeutic agent for hemophiliacs with antibodies to factor VIII once the potential thrombogenicity of such materials is evaluated. Images PMID:3134399

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.

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.

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.

Development of freeze-dried albumin-free formulation of recombinant factor VIII SQ.

PubMed

Osterberg, T; Fatouros, A; Mikaelsson, M

1997-07-01

To develop a stable freeze-dried formulation of recombinant factor VIII-SQ (r-VIII SQ) without the addition of albumin. Different formulations were evaluated for their protective effect during sterile filtration, freeze-thawing, freeze-drying, reconstitution and long term storage. Factor VIII activity (VIII:C), visual inspection, clarity, solubility, moisture content and soluble aggregates and/ or fragments were assayed. A combination of non-crystallising excipients (L-histidine and sucrose), a non-ionic surfactant (polysorbate 80) and a crystalline bulking agent (sodium chloride) was found to preserve the factor VIII activity during formulation, freeze-drying and storage. Calcium chloride was included to prevent dissociation of the heavy and light chains of r-VIII SQ. Sodium chloride was chosen as the primary bulking agent since the concentration of sodium chloride necessary for dissolution of r-VIII SQ in the buffer will inhibit the crystallization of many potential cake formers. It was found that L-histidine, besides functioning as a buffer, also protected r-VIII SQ during freeze-drying and storage. A pH close to 7 was found to be optimal. Some potential macromolecular stabilisers, PEG 4000, Haes-steril and Haemaccel, were evaluated but they did not improve the recovery of VIII:C. The freeze-dried formulation was stable for at least two years at 7 degrees C and for at least one year at 25 degrees C. The reconstituted solution was stable for at least 100 hours at 25 degrees C. The albumin-free formulation resulted in consistently high recovery of VIII:C, very low aggregate formation and good storage stability. The stability of the reconstituted solution makes the formulation suitable for continuous administration via infusion pump. The formulation strategy described here may also be useful for other proteins which require a high ionic strength.

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.

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

Acquired high titre factor VIII inhibitor with underlying polyarteritis nodosa.

PubMed

Snowden, J A; Hutchings, M; Spearing, R; Patton, W N

1997-05-01

We here present the case of a 70-year-old woman referred to our unit for investigation of bleeding. Investigations confirmed a high titre acquired Factor VIII inhibitor. In association there was relapse of systemic illness associated with anti-neutrophil cytoplasmic antibodies (atypical pattern) for which she had been treated five years previously. Immunosuppression was attempted, but it failed to have an impact both on the inhibitor titre and on the underlying disorder. The patient died from multi-organ failure and massive chest hemorrhage. Post-mortem showed necrotizing vasculitis of medium sized vessels at several sites, including the kidney, consistent with a diagnosis of polyarteritis nodosa. Although it is well recognised that Factor VIII inhibitors are found in conjunction with autoimmune disorders, this case is significant in that it is the first associated with histologically proven polyarteritis nodosa type vasculitis. The case illustrates the difficulties in the investigation and management of patients with acquired high titre Factor VIII inhibitors.

Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

PubMed

Rodgers, Susan; Duncan, Elizabeth

2017-01-01

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

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

[Long distance-PCR for detection of factor VIII gene inversion in patients with severe hemophilia A].

PubMed

Ding, Pei-Fang; Sun, Wei-Sheng; Wang, Qin-You; Liu, De-Chun; Zhang, Xue-Qin; Teng, Bin; Shen, Fa-Kui

2003-08-01

The aim of current study was to detect intron 22 inversion of factor VIII gene in severe hemophilia A (HA) patients and screen the carriers of the gene inversion. Fifty-five cases of severe HA were involved and factor VIII gene inversion was detected and identified by long distance-PCR (LD-PCR) and 0.6% agarose gel electrophoresis. The 11 kb and 12 kb bands indicate the factor VIII gene inversion and non-inversion, respectively. Occurring of both 11 kb and 12 kb bands indicates a carrier of the inversion. The results showed that factor VIII gene inversion existed in 22 out of 55 cases, which accounted for about 40% of total detected patients. Five carriers of factor VIII gene inversion were diagnosed from the members in 15 families. In conclusion, LD-PCR assay is a simple, rapid and accurate method for detection of factor VIII gene inversion, and this approach is helpful in screening, carrier testing, and prenatal diagnosis of severe hemophilia A.

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.

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

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.

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.

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.

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

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.

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.

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.

Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome.

PubMed

Fang, B S; Sneller, M C; Straus, S E; Frenkel, L; Dale, J K; Rick, M E

2000-07-01

The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII. ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc.

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.

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.

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.

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.

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.

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

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.

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

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

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.

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.

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

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.

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.

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

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 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.

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

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.

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

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.

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

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.

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.

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.

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

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.

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

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.

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

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...

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.

[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.

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...

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

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.

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.

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

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).

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.

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

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.

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.

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.

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.

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.

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

PubMed Central

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

2012-01-01

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

[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.

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

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 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.

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

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

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.

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

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 * * * **************************************************************************

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…

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.

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...

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

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.

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...

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...

Preclinical evaluation of a new, stabilized neurotensin(8--13) pseudopeptide radiolabeled with (99m)tc.

PubMed

García-Garayoa, Elisa; Bläuenstein, Peter; Bruehlmeier, Matthias; Blanc, Alain; Iterbeke, Koen; Conrath, Peter; Tourwé, Dirk; Schubiger, P August

2002-03-01

The rapid degradation of neurotensin (NT) limits its clinical use in cancer imaging and therapy. Thus, a new NT(8--13) pseudopeptide, NT-VIII, was synthesized. Some changes were introduced in the sequence of NT(8--13) to stabilize the molecule against enzymatic degradation: Arg(8) was N-methylated, and Lys and Tle replaced Arg(9) and Ile(12), respectively. Finally, (NalphaHis)Ac was coupled to the N-terminus for (99m)Tc(CO)(3) labeling. This peptide was characterized both in vitro and in vivo. The new analog was labeled with (99m)Tc(CO)(3). Its metabolic stability was analyzed both in human plasma and in HT-29 cells. Binding properties, receptor downregulation, and internalization were tested with HT-29 cells. Biodistribution was evaluated in nude mice with HT-29 xenografts. (99m)Tc(CO)(3)NT-VIII showed a high stability in plasma, where most of the peptide remained intact after 24 h of incubation at 37 degreesC. However, the degradation in HT-29 cells was more rapid (46% of intact (99m)Tc(CO)(3)NT-VIII after 24 h at 37 degreesC). Binding to NT1 receptors (NTR1) was saturable and specific. Scatchard analysis showed a high affinity for (99m)Tc(CO)(3)NT-VIII, with a dissociation constant similar to (125)I-NT (1.8 vs. 1.6 nmol/L). After interacting with NTR1, (99m)Tc(CO)(3)NT-VIII was rapidly internalized, with more than 90% internalized after 30 min. It also distributed and cleared rapidly in nude mice bearing HT-29 xenografts. The highest rates of accumulation were found in kidney and tumor at all time points tested. Tumor uptake was highly specific because it could be blocked by coinjection with a high dose of (NalphaHis)Ac-NT(8--13). Tumors were clearly visualized in scintigraphy images. The changes that were introduced stabilized the molecule against enzymatic degradation without affecting binding properties. Moreover, the increase in stability enhanced tumor uptake, making this derivative a promising candidate for clinical use.

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.

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.

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.

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

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.

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

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

Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection.

PubMed

Rondina, Matthew T; Tatsumi, Kohei; Bastarache, Julie A; Mackman, Nigel

2016-07-01

To identify plasma biomarkers that can be early predictors of mortality in critically ill patients with primary influenza A/H1N1. A prospective, multicenter, case-cohort pilot study. Three academic ICUs. Fifteen patients with primary influenza A/H1N1 that included seven survivors and eight nonsurvivors. For comparison, age- and gender-matched healthy controls (n = 27) were also studied. Plasma was prepared from whole blood drawn on ICU admission in patients with influenza (ICU day 1). Microvesicle tissue factor activity, thrombin-antithrombin complexes, and D-dimers were measured as procoagulant markers and markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples in a subset of 12 patients with influenza using the Luminex Multi-Analyte Profiling system (Luminex Corporation, DeSoto, TX). Patients were followed up for the primary outcome of 28-day mortality. The average admission Acute Physiology and Chronic Health Evaluation II score of the patients was 25.5 ± 9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n = 8/15). Patients with influenza had dysregulated indices of coagulation and inflammation compared with controls. Among the markers of activation of coagulation measured on ICU day 1, only increased microvesicle tissue factor activity was significantly associated with subsequent influenza-related mortality (5.6 ± 1.2 pg/mL in nonsurvivors vs 1.8 ± 0.8 pg/mL in survivors; p < 0.05). Interleukin-8 was significantly higher in nonsurvivors compared with survivors (71.8 ± 29.1 pg/mL, n = 5 vs 17.3 ± 3.7 pg/mL, n = 7; p < 0.05). In addition, microvesicle tissue factor activity and interleukin-8 levels were significantly and positively correlated (r = 0.60; p = 0.003). Other cytokines, thrombin-antithrombin complexes, and D-dimer were not different between nonsurvivors and survivors and did not correlate with illness severity or mortality. This study identifies an association

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.

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.

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.

Risk factors associated with highly pathogenic avian influenza subtype H5N8 outbreaks on broiler duck farms in South Korea.

PubMed

Kim, W-H; An, J-U; Kim, J; Moon, O-K; Bae, S H; Bender, J B; Cho, S

2018-04-19

Highly Pathogenic Avian Influenza (HPAI) subtype H5N8 outbreaks occurred in poultry farms in South Korea in 2014 resulting in significant damage to the poultry industry. Between 2014 and 2016, the pandemic disease caused significant economic loss and social disruption. To evaluate the risk factors for HPAI infection in broiler duck farms, we conducted a retrospective case-control study on broiler duck farms. Forty-three farms with confirmed laboratories on premises were selected as the case group, and 43 HPAI-negative farms were designated as the control group. Control farms were matched based on farm location and were within a 3-km radius from the case premises. Spatial and environmental factors were characterized by site visit and plotted through a geographic information system (GIS). Univariable and multivariable logistic regression models were developed to assess possible risk factors associated with HPAI broiler duck farm infection. Four final variables were identified as risk factors in a final multivariable logistic model: "Farms with ≥7 flocks" (odds ratio [OR] = 6.99, 95% confidence interval [CI] 1.34-37.04), "Farm owner with ≥15 years of raising poultry career" (OR = 7.91, 95% CI 1.69-37.14), "Presence of any poultry farms located within 500 m of the farm" (OR = 6.30, 95% CI 1.08-36.93) and "Not using a faecal removal service" (OR = 27.78, 95% CI 3.89-198.80). This highlights that the HPAI H5N8 outbreaks in South Korea were associated with farm owner education, number of flocks and facilities and farm biosecurity. Awareness of these factors may help to reduce the spread of HPAI H5N8 across broiler duck farms in Korea during epidemics. Greater understanding of the risk factors for H5N8 may improve farm vulnerability to HPAI and other subtypes and help to establish policies to prevent re-occurrence. These findings are relevant to global prevention recommendations and intervention protocols. © 2018 Blackwell Verlag GmbH.

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.

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

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.

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.

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...

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.

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...

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.

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

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

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.

p- to n-type conductivity transition in 1.0 eV GaInNAs solar cells controlled by the V/III ratio

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

Langer, Fabian, E-mail: fabian.langer@physik.uni-wuerzburg.de; Perl, Svenja; Kamp, Martin

2015-02-09

In this work, we report a p- to n-type conductivity transition of GaInNAs (1.0 eV bandgap) layers in p-i-n dilute nitride solar cells continuously controlled by the V/III ratio during growth. Near the transition region, we were able to produce GaInNAs layers with very low effective electrically active doping concentrations resulting in wide depleted areas. We obtained internal quantum efficiencies (IQEs) up to 85% at 0.2 eV above the bandgap. However, the high IQE comes along with an increased dark current density resulting in a decreased open circuit voltage of about 0.2 V. This indicates the formation of non-radiant defect centers related tomore » the p-type to n-type transition. Rapid-thermal annealing of the solar cells on the one hand helps to anneal some of these defects but on the other hand increases the effective doping concentrations.« less

Factoring 51 and 85 with 8 qubits

PubMed Central

Geller, Michael R.; Zhou, Zhongyuan

2013-01-01

We construct simplified quantum circuits for Shor's order-finding algorithm for composites N given by products of the Fermat primes 3, 5, 17, 257, and 65537. Such composites, including the previously studied case of 15, as well as 51, 85, 771, 1285, 4369, … have the simplifying property that the order of a modulo N for every base a coprime to N is a power of 2, significantly reducing the usual phase estimation precision requirement. Prime factorization of 51 and 85 can be demonstrated with only 8 qubits and a modular exponentiation circuit consisting of no more than four CNOT gates. PMID:24162074

Factoring 51 and 85 with 8 qubits.

PubMed

Geller, Michael R; Zhou, Zhongyuan

2013-10-28

We construct simplified quantum circuits for Shor's order-finding algorithm for composites N given by products of the Fermat primes 3, 5, 17, 257, and 65537. Such composites, including the previously studied case of 15, as well as 51, 85, 771, 1285, 4369, … have the simplifying property that the order of a modulo N for every base a coprime to N is a power of 2, significantly reducing the usual phase estimation precision requirement. Prime factorization of 51 and 85 can be demonstrated with only 8 qubits and a modular exponentiation circuit consisting of no more than four CNOT gates.

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.

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.

Broad NE 8 lambda 774 emission from quasars in the HST-FOS snapshot survey (ABSNAP)

NASA Technical Reports Server (NTRS)

Hamann, Fred; Zuo, Lin; Tytler, David

1995-01-01

We discuss the strength and frequency of broad Ne VIII lambda 774 emission from quasars measured in the Hubble Space Telescope Faint Object Spectrograph (HST-FOS) snapshot survey (Absnap). Five sources in the survey have suitable redshifts (0.86 less than or equal to Z(sub em) less than or equal to 1.31), signal-to-noise ratios and no Lyman limit absorptions. Three of the five sources have a strong broad emission line near 774 A (rest), and the remaining two sources have a less securely measured line near this wavelength. We identify these lines with Ne VIII lambda 774 based on the measured wavelengths and theoretical estimates of various line fluxes (Hamann et al. 1995a). Secure Ne VIII detections occur in both radio-loud and radio-quiet sources. We tentatively conclude that broad Ne VIII lambda 774 emission is common in quasars, with typical strengths between approximately 25% and approximately 200% of O VI lambda 1034. These Ne VIII lambda 774 measurements imply that the broad emission line regions have a much hotter and more highly ionized component than previously recognized. They also suggest that quasar continua have substantial ionizing flux out to energies greater than 207 eV (greater than 15.2 ryd, lambda less than 60 A). Photoionization calculations using standard incident spectra indicate that the Ne VIII emission requires ionization parameters U greater than or = 5, total column densities N(sub H) greater than or = 10(sub 22)/sq cm and covering factors greater than or = 25%. The temperatures could be as high as approximately 10(exp 5) K. If the gas is instead collisionally ionized, strong Ne VIII would imply equilibrium temperatures in the range approximately 400,000 less than or approximately = T(sub e) less than or approximately = 10(exp 6) K. In either case, the highly ionized Ne VIII emission regions would appear as X-ray 'warm absorbers' if they lie along our line of sight to the X-ray continuum source.

Crystal structure and optical property of complex perovskite oxynitrides ALi0.2Nb0.8O2.8N0.2, ANa0.2Nb0.8O2.8N0.2, and AMg0.2Nb0.8O2.6N0.4 (A = Sr, Ba)

NASA Astrophysics Data System (ADS)

Moon, Keon Ho; Avdeev, Maxim; Kim, Young-Il

2017-10-01

Oxynitride type complex perovskites AM0.2Nb0.8O3-xNx (A = Sr, Ba; M = Li, Na, Mg) were newly synthesized by the solid state diffusion of Li+, Na+, or Mg2+ into the layered oxide, A5Nb4O15, with concurrent O/N substitution. Neutron and synchrotron X-ray Rietveld refinement showed that SrLi0.2Nb0.8O2.8N0.2, SrNa0.2Nb0.8O2.8N0.2, and SrMg0.2Nb0.8O2.6N0.4 had body-centered tetragonal symmetry (I4/mcm), while those with A = Ba had simple cubic symmetry (Pm 3 ̅ m). In the tetragonal Sr-compounds, the nitrogen atoms were localized on the c-axial 4a site. However, the octahedral cations, M/Nb (M = Li, Na, Mg) were distributed randomly in all six compounds. The lattice volume of AM0.2Nb0.8O3-xNx was dependent on various factors including the type of A and the electronegativity of M. Compared to the simple perovskites, ANbO2N (A = Sr, Ba), AM0.2Nb0.8O3-xNx had wider band gaps (1.76-2.15 eV for A = Sr and 1.65-2.10 eV for A = Ba), but significantly lower sub-gap absorption.

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

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

Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs.

PubMed

Park, Chul-Yong; Kim, Jungeun; Kweon, Jiyeon; Son, Jeong Sang; Lee, Jae Souk; Yoo, Jeong-Eun; Cho, Sung-Rae; Kim, Jong-Hoon; Kim, Jin-Soo; Kim, Dong-Wook

2014-06-24

Hemophilia A, one of the most common genetic bleeding disorders, is caused by various mutations in the blood coagulation factor VIII (F8) gene. Among the genotypes that result in hemophilia A, two different types of chromosomal inversions that involve a portion of the F8 gene are most frequent, accounting for almost half of all severe hemophilia A cases. In this study, we used a transcription activator-like effector nuclease (TALEN) pair to invert a 140-kbp chromosomal segment that spans the portion of the F8 gene in human induced pluripotent stem cells (iPSCs) to create a hemophilia A model cell line. In addition, we reverted the inverted segment back to its normal orientation in the hemophilia model iPSCs using the same TALEN pair. Importantly, we detected the F8 mRNA in cells derived from the reverted iPSCs lines, but not in those derived from the clones with the inverted segment. Thus, we showed that TALENs can be used both for creating disease models associated with chromosomal rearrangements in iPSCs and for correcting genetic defects caused by chromosomal inversions. This strategy provides an iPSC-based novel therapeutic option for the treatment of hemophilia A and other genetic diseases caused by chromosomal inversions.

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.

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

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.

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

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.

7 CFR 3565.8 - Civil rights compliance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 15 2013-01-01 2013-01-01 false Civil rights compliance. 3565.8 Section 3565.8... AGRICULTURE GUARANTEED RURAL RENTAL HOUSING PROGRAM General Provisions § 3565.8 Civil rights compliance. (a... requirements of title VIII of the Civil Rights Act of 1968, as amended (the Fair Housing Act), are liable for...

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.

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.

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.

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.

A DFT investigation on geometry and chemical bonding of isoelectronic Si8N6V-, Si8N6Cr, and Si8N6Mn+ clusters

NASA Astrophysics Data System (ADS)

Tam, Nguyen Minh; Pham, Hung Tan; Cuong, Ngo Tuan; Tung, Nguyen Thanh

2017-10-01

The geometric feature and chemical bonding of isoelectronic systems Si8N6Mq (M = V, Cr, Mn and q = -1, 0, 1, respectively) are investigated by means of density-functional-theory calculations. The encapsulated form is found for all ground-state structures, where the metal atom locates at the central site of the hollow Si8N6 cage. The Si8N6 cage is established by adding two Si atoms to a distorted Si6N6 prism, which is a combination of Si4N2 and Si2N4 strings. Chemical bonding of Si8N6Mq systems is explored by using the electron localization indicator and theory of atom in molecule, revealing the vital role of metal center in stabilizing the clusters.

Experimental and theoretical investigation of three-dimensional nitrogen-doped aluminum clusters AI 8N - and AI 8N

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

Wang, Leiming; Huang, Wei; Wang, Lai S.

The structure and electronic properties of the Al 8N - and Al 8N clusters were investigated by combined photoelectron spectroscopy and ab initio studies. Congested photoelectron spectra were observed and experimental evidence was obtained for the presence of multiple isomers for Al 8N - Global minimum searches revealed several structures for Al 8N - with close energies. The calculated vertical detachment energies of the two lowest-lying isomers, which are of C 2v and C s symmetry, respectively, were shown to agree well with the experimental data. Unlike the three-dimensional structures of Al 6N - and Al 7N -, in whichmore » the dopant N atom has a high coordination number of 6,the dopant N atom in the two low-lying isomers of Al 8N - has a lower coordination number of 4 and 5, respectively. The competition between the Al–Al and Al–N interactions are shown to determine the global minimum structures of the doped aluminum clusters and results in the structural diversity for both Al 8N - and Al8N. © 2009 American Institute of Physics« 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.

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.

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 . ...

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.

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

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...

5 CFR 8.2 - Appointment of United States citizens.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Appointment of United States citizens. 8... APPOINTMENTS TO OVERSEAS POSITIONS (RULE VIII) § 8.2 Appointment of United States citizens. United States... appointments for United States citizens recruited within the continental limits of the United States whenever...

5 CFR 8.2 - Appointment of United States citizens.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Appointment of United States citizens. 8... APPOINTMENTS TO OVERSEAS POSITIONS (RULE VIII) § 8.2 Appointment of United States citizens. United States... appointments for United States citizens recruited within the continental limits of the United States whenever...

5 CFR 8.2 - Appointment of United States citizens.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Appointment of United States citizens. 8... APPOINTMENTS TO OVERSEAS POSITIONS (RULE VIII) § 8.2 Appointment of United States citizens. United States... appointments for United States citizens recruited within the continental limits of the United States whenever...

5 CFR 8.2 - Appointment of United States citizens.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Appointment of United States citizens. 8... APPOINTMENTS TO OVERSEAS POSITIONS (RULE VIII) § 8.2 Appointment of United States citizens. United States... appointments for United States citizens recruited within the continental limits of the United States whenever...

39 CFR 255.8 - Access to postal facilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... with the National Historic Preservation Act of 1966, 16 U.S.C. 470 et seq.; (vii) The availability of other options to foster service accessibility; and (viii) Any other factor that is relevant and...

Influence of stress in GaN crystals grown by HVPE on MOCVD-GaN/6H-SiC substrate

PubMed Central

Zhang, Lei; Yu, Jiaoxian; Hao, Xiaopeng; Wu, Yongzhong; Dai, Yuanbin; Shao, Yongliang; Zhang, Haodong; Tian, Yuan

2014-01-01

GaN crystals without cracks were successfully grown on a MOCVD-GaN/6H-SiC (MGS) substrate with a low V/III ratio of 20 at initial growth. With a high V/III ratio of 80 at initial growth, opaque GaN polycrystals were obtained. The structural analysis and optical characterization reveal that stress has a great influence on the growth of the epitaxial films. An atomic level model is used to explain these phenomena during crystal growth. It is found that atomic mobility is retarded by compressive stress and enhanced by tensile stress. PMID:24569601

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...

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.

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

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.

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…

Enhancement of CD8+ T-cell memory by removal of a vaccinia virus nuclear factor-κB inhibitor

PubMed Central

Ren, Hongwei; Ferguson, Brian J; de Motes, Carlos Maluquer; Sumner, Rebecca P; Harman, Laura E R; Smith, Geoffrey L

2015-01-01

Factors influencing T-cell responses are important for vaccine development but are incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the development of both effector and memory CD8+ T cells and this correlates with its inhibition of nuclear factor-κB (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-κB resulted in increased central and memory CD8+ T-cell populations, increased CD8+ T-cell cytotoxicity and lower virus titres after challenge. Furthermore, CD8+ memory T-cell function was increased following infection with vN1.I6E, with more interferon-γ production and greater protection against VACV infection following passive transfer to naive mice, compared with CD8+ T cells from mice infected with wild-type virus (vN1.WT). This demonstrates the importance of NF-κB activation within infected cells for long-term CD8+ T-cell memory and vaccine efficacy. Further, it provides a rationale for deleting N1 from VACV vectors to enhance CD8+ T-cell immunogenicity, while simultaneously reducing virulence to improve vaccine safety. PMID:25382035

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.

An intronic mutation c.6430-3C>G in the F8 gene causes splicing efficiency and premature termination in hemophilia A.

PubMed

Xia, Zunjing; Lin, Jie; Lu, Lingping; Kim, Chol; Yu, Ping; Qi, Ming

2018-06-01

: Hemophilia A is a bleeding disorder caused by coagulation factor VIII protein deficiency or dysfunction, which is classified into severe, moderate, and mild according to factor clotting activity. An overwhelming majority of missense and nonsense mutations occur in exons of F8 gene, whereas mutations in introns can also be pathogenic. This study aimed to investigate the effect of an intronic mutation, c.6430-3C>G (IVS22-3C>G), on pre-mRNA splicing of the F8 gene. We applied DNA and cDNA sequencing in a Chinese boy with hemophilia A to search if any pathogenic mutation in the F8 gene. Functional analysis was performed to investigate the effect of an intronic mutation at the transcriptional level. Human Splicing Finder and PyMol were also used to predict its effect. We found the mutation c.6430-3C>G (IVS22-3C>G) in the F8 gene in the affected boy, with his mother being a carrier. cDNA from the mother and pSPL3 splicing assay showed that the mutation IVS22-3C>G results in a two-nucleotide AG inclusion at the 3' end of intron 22 and leads to a truncated coagulation factor VIII protein, with partial loss of the C1 domain and complete loss of the C2 domain. The in-silico tool predicted that the mutation induces altered pre-mRNA splicing by using a cryptic acceptor site in intron 22. The IVS22-3C>G mutation was confirmed to affect pre-mRNA splicing and produce a truncated protein, which reduces the stability of binding between the F8 protein and von Willebrand factor carrier protein due to the loss of an interaction domain.

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…

Defect structure of high temperature hydride vapor phase epitaxy-grown epitaxial (0 0 0 1) AlN/sapphire using growth mode modification process

NASA Astrophysics Data System (ADS)

Su, Xujun; Zhang, Jicai; Huang, Jun; Zhang, Jinping; Wang, Jianfeng; Xu, Ke

2017-06-01

Defect structures were investigated by transmission electron microscopy for AlN/sapphire (0 0 0 1) epilayers grown by high temperature hydride vapor phase epitaxy using a growth mode modification process. The defect structures, including threading dislocations, inversion domains, and voids, were analyzed by diffraction contrast, high-resolution imaging, and convergent beam diffraction. AlN film growth was initiated at 1450 °C with high V/III ratio for 8 min. This was followed by low V/III ratio growth for 12 min. The near-interfacial region shows a high density of threading dislocations and inversion domains. Most of these dislocations have Burgers vector b = 1/3〈1 1 2 0〉 and were reduced with the formation of dislocation loops. In the middle range 400 nm < h < 2 μm, dislocations gradually aggregated and reduced to ∼109 cm-2. The inversion domains have a shuttle-like shape with staggered boundaries that deviate by ∼ ±5° from the c axis. Above 2 μm thickness, the film consists of isolated threading dislocations with a total density of 8 × 108 cm-2. Most of threading dislocations are either pure edge or mixed dislocations. The threading dislocation reduction in these films is associated with dislocation loops formation and dislocation aggregation-interaction during island growth with high V/III ratio.

Dependence of N-polar GaN rod morphology on growth parameters during selective area growth by MOVPE

NASA Astrophysics Data System (ADS)

Li, Shunfeng; Wang, Xue; Mohajerani, Matin Sadat; Fündling, Sönke; Erenburg, Milena; Wei, Jiandong; Wehmann, Hergo-Heinrich; Waag, Andreas; Mandl, Martin; Bergbauer, Werner; Strassburg, Martin

2013-02-01

Selective area growth of GaN rods by metalorganic vapor phase epitaxy has attracted great interest due to its novel applications in optoelectronic and photonics. In this work, we will present the dependence of GaN rod morphology on various growth parameters i.e. growth temperature, H2/N2 carrier gas concentration, V/III ratio, total carrier gas flow and reactor pressure. It is found that higher growth temperature helps to increase the aspect ratio of the rods, but reduces the height homogeneity. Furthermore, H2/N2 carrier gas concentration is found to be a critical factor to obtain vertical rod growth. Pure nitrogen carrier gas leads to irregular growth of GaN structure, while an increase of hydrogen carrier gas results in vertical GaN rod growth. Higher hydrogen carrier gas concentration also reduces the diameter and enhances the aspect of the GaN rods. Besides, increase of V/III ratio causes reduction of the aspect ratio of N-polar GaN rods, which could be explained by the relatively lower growth rate on (000-1) N-polar top surface when supplying more ammonia. In addition, an increase of the total carrier gas flow leads to a decrease in the diameter and the average volume of GaN rods. These phenomena are tentatively explained by the change of partial pressure of the source materials and boundary layer thickness in the reactor. Finally, it is shown that the average volume of the N-polar GaN rods keeps a similar value for a reactor pressure PR of 66 and 125 mbar, while an incomplete filling of the pattern opening is observed with PR of 250 mbar. Room temperature photoluminescence spectrum of the rods is also briefly discussed.

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.

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...

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

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.

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

PubMed

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

2016-02-01

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

Thermoelectric and transport properties of sintered n-type K{sub 8}Ba{sub 16}Ga{sub 40}Sn{sub 96} with type-II clathrate structure

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

Koda, Shota; Kishimoto, Kengo, E-mail: kkishi@yamaguchi-u.ac.jp; Asada, Hironori

This clathrate had a maximum dimensionless figure-of-merit, ZT, of 0.93 at 637 K, which was slightly higher than that of 0.83 for the sintered type-VIII clathrate Ba{sub 8}Ga{sub 16}Sn{sub 30}. We investigated the high-temperature thermoelectric properties, transport properties, electronic structures, and thermal stabilities of the clathrates. The type-II clathrate was found to be superior to the type-VIII clathrate as a thermoelectric material; it had a high thermal stability and melting point, 859 K, high mobility, 141 cm{sup 2}V{sup −1}s{sup −1} at 300 K, because of its low inertial mass, and low high-temperature lattice thermal conductivity, approximately 4 mW cm{sup −1}K{sup −1}, resulting frommore » a larger unit cell and weaker bipolar thermal conduction. We discuss these properties in terms of the electronic structure and the differences between the two types of clathrate.« less

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.

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).

15 CFR Supplement No. 8 to Part 742 - Self-Classification Report for Encryption Items

Code of Federal Regulations, 2011 CFR

2011-01-01

... forensics (v) Cryptographic accelerator (vi) Data backup and recovery (vii) Database (viii) Disk/drive... (MAN) (xxii) Modem (xxiii) Network convergence or infrastructure n.e.s. (xxiv) Network forensics (xxv...

15 CFR Supplement No. 8 to Part 742 - Self-Classification Report for Encryption Items

Code of Federal Regulations, 2014 CFR

2014-01-01

... forensics (v) Cryptographic accelerator (vi) Data backup and recovery (vii) Database (viii) Disk/drive... (MAN) (xxii) Modem (xxiii) Network convergence or infrastructure n.e.s. (xxiv) Network forensics (xxv...

15 CFR Supplement No. 8 to Part 742 - Self-Classification Report for Encryption Items

Code of Federal Regulations, 2013 CFR

2013-01-01

... forensics (v) Cryptographic accelerator (vi) Data backup and recovery (vii) Database (viii) Disk/drive... (MAN) (xxii) Modem (xxiii) Network convergence or infrastructure n.e.s. (xxiv) Network forensics (xxv...

15 CFR Supplement No. 8 to Part 742 - Self-Classification Report for Encryption Items

Code of Federal Regulations, 2012 CFR

2012-01-01

... forensics (v) Cryptographic accelerator (vi) Data backup and recovery (vii) Database (viii) Disk/drive... (MAN) (xxii) Modem (xxiii) Network convergence or infrastructure n.e.s. (xxiv) Network forensics (xxv...

Rational synthesis of high nuclearity Mo/Fe/S clusters: the reductive coupling approach in the convenient synthesis of (Cl(4)-cat)(2)Mo(2)Fe(6)S(8)(PR(3))(6) [R = Et, (n)Pr, (n)Bu] and the new [(Cl(4)-cat)(2)Mo(2)Fe(2)S(3)O(PEt(3))(3)Cl]-1/2(Fe(PEt(3))(2)(MeCN)(4)) and (Cl(4)-cat)(2)Mo(2)Fe(3)S(5)(PEt(3))(5) clusters.

PubMed

Han, J; Koutmos, M; Ahmad, S A; Coucouvanis, D

2001-11-05

A general method for the synthesis of high nuclearity Mo/Fe/S clusters is presented and involves the reductive coupling of the (Et(4)N)(2)[(Cl(4)-cat)MoOFeS(2)Cl(2)] (I) and (Et(4)N)(2)[Fe(2)S(2)Cl(4)] (II) clusters. The reaction of I and II with Fe(PR(3))(2)Cl(2) or sodium salts of noncoordinating anions such as NaPF(6) or NaBPh(4) in the presence of PR(3) (R = Et, (n)Pr, or (n)Bu) affords (Cl(4)-cat)(2)Mo(2)Fe(6)S(8)(PR(3))(6) [R = Et (IIIa), (n)Pr (IIIb), (n)Bu (IIIc)], Fe(6)S(6)(PEt(3))(4)Cl(2) (IV) and (PF(6))[Fe(6)S(8)(P(n)Pr(3))(6)] (V) as byproducts. The isolation of (Et(4)N)[Fe(PEt(3))Cl(3)] (VI), NaCl, and SPEt(3) supports a reductive coupling mechanism. Cluster IV and V also have been synthesized by the reductive self-coupling of compound II. The reductive coupling reaction between I and II by PEt(3) and NaPF(6) in a 1:1 ratio produces the (Et(4)N)(2)[(Cl(4)-cat)Mo(L)Fe(3)S(4)Cl(3)] clusters [L = MeCN (VIIa), THF (VIIb)]. The hitherto unknown [(Cl(4)-cat)(2)Mo(2)Fe(2)S(3)O(PEt(3))(3)Cl](+) cluster (VIII) has been isolated as the 2:1 salt of the (Fe(PEt(3))(2)(MeCN)(4))(2+) cation after the reductive self-coupling reaction of I in the presence of Fe(PEt(3))(2)Cl(2). Cluster VIII crystallizes in the monoclinic space group P2(1)/c with a = 11.098(3) A, b = 22.827(6) A, c = 25.855(6) A, beta = 91.680(4) degrees, and Z = 4. The formal oxidation states of metal atoms in VIII have been assigned as Mo(III), Mo(IV), Fe(II), and Fe(III) on the basis of zero-field Mössbauer spectra. The Fe(PEt(3))(2)(MeCN)(4) cation of VIII is also synthesized independently, isolated as the BPh(4)(-) salt (IX), and has been structurally characterized. The reductive coupling of compound I also affords in low yield the new (Cl(4)-cat)(2)Mo(2)Fe(3)S(5)(PEt(3))(5) cluster (X) as a byproduct. Cluster X crystallizes in the monoclinic space group P2(1)/n with a = 14.811(3) A, b = 22.188(4) A, c = 21.864(4) A, beta = 100.124(3) degrees, and Z = 4 and the structure shows very short Mo

Identification of the antigenic determinants of factors 8, 9, and 34 of genus Candida.

PubMed

Kobayashi, H; Oyamada, H; Suzuki, A; Shibata, N; Suzuki, S; Okawa, Y

1996-10-21

We investigated the antigenic determinants of factors 8, 9, and 34 of the genus Candida among pathogenic yeasts by enzyme-linked immunosorbent assay (ELISA) using mannans of Saccharomyces cerevisiae wild type and mutant types, mnn 1-mnn 4 and mnn 2. Results of ELISA including antisera against the antigenic factors of genus Candida (Candida Check, latron; FAbs) indicated that these three types of mannan distinctly react with FAbs 34, 8 and 9, respectively. To identify the recognition sites of these FAbs, we compared the ability of various oligosaccharides to inhibit the binding of the mannans to FAbs. The results indicated that FAb 34 preferentially recognizes linear side chains containing a non-reducing terminal alpha-1,3-linked mannose residue, Man(alpha)1 --> 3Man(alpha)1 --> (2Man(alpha)1 --> )n(2Man) (n > or = 0), and that one of the recognition sites of FAb 9 is linear alpha-1,6-linked oligomannosyl series, Man(alpha)1 --> (6Man(alpha)1 --> )n(6Man) (n > or = 2). On the other hand, the recognition site of FAb 8 apparently consisted of two alpha-1,2-linked oligomannosyl side chains and an alpha-1,6-linked mannose residue that originated from the mannan backbone, Man(alpha)1 --> 2Man(alpha)1 --> 2(Man(alpha)1 -->2Man(alpha)1 --> 6)Man.

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.

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...

N-(ferrocenecarbonyl)-N'-(quinolin-8-yl)thiourea.

PubMed

Yang, Jia-Xiang; Tian, Yu-Peng; Liu, Qing-Liang; Xie, Yong-Shu; Fun, Hoong-Kun; Chantrapromma, Suchada; Razak, Ibrahim Abdul

2002-01-01

In the title compound, [Fe(C5H5)(C16H12N3OS)], the 8-aminoquinoline and acylthiourea moieties are almost planar. There are two perpendicular arrangements of the molecules in the crystal with slightly different conformations. The two cyclopentadienyl rings in each molecule are parallel and eclipsed.

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.

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.

MOVPE growth of nitrogen- and aluminum-polar AlN on 4H-SiC

NASA Astrophysics Data System (ADS)

Lemettinen, J.; Okumura, H.; Kim, I.; Rudzinski, M.; Grzonka, J.; Palacios, T.; Suihkonen, S.

2018-04-01

We present a comprehensive study on metal-organic vapor phase epitaxy growth of N-polar and Al -polar AlN on 4H-SiC with 4° miscut using constant growth parameters. At a high temperature of 1165 °C, N-polar AlN layers had high crystalline quality whereas the Al-polar AlN surfaces had a high density of etch pits. For N-polar AlN, the V/III ratio below 1000 forms hexagonal hillocks, while the V/III ratio over 1000 yields step bunching without the hillocks. 1-μm-thick N-polar AlN layer grown in optimal conditions exhibited FWHMs of 307, 330 and 337 arcsec for (0 0 2), (1 0 2) and (2 0 1) reflections, respectively.

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.

Avian influenza virus with Hemagglutinin-Neuraminidase combination H8N8, isolated in Russia

USDA-ARS?s Scientific Manuscript database

This study reports the genome sequence of an avian influenza virus (AIV) subtype H8N8 isolated in Russia. The genome analysis shows that all genes belong to AIV Eurasian lineages. The PB2 gene was similar to a Mongolian low pathogenic (LP) AIV H7N1 and a Chinese high pathogenic (HP) AIV H5N2....

15N nuclear magnetic resonance studies on the tautomerism of 8-hydroxy-2'-deoxyguanosine, 8-hydroxyguanosine, and other C8-substituted guanine nucleosides.

PubMed

Cho, B P; Kadlubar, F F; Culp, S J; Evans, F E

1990-01-01

The favored tautomeric and ionic structures were examined for the oxidative DNA damage adduct 8-hydroxy-2'-deoxyguanosine and its RNA analogue 8-hydroxyguanosine by 15N NMR spectroscopy. In addition, 15N chemical shifts and coupling constants from 13 different guanine nucleosides, including a wide variety of C8 substitutions (OH, SH, Br, OCH2C6H5, OCH3, SCH3, and SO2CH3), have been analyzed with respect to their tautomeric structures. A -98.5-Hz proton-nitrogen coupling constant observed for the N7 resonance of 8-hydroxyguanosine in dimethyl sulfoxide was evidence for 8-keto substitution, which is contrary to the structure implied by the generally used nomenclature. The pH dependence of 15N NMR spectra of 8-hydroxyguanosine in aqueous solution showed downfield shifts of the N1 and N7 resonances that were greater than 50 ppm, which indicated the conversion from a neutral 6,8-diketo to a 6-enolate-8-keto (pKa1 = 8.6) and finally to a 6,8-dienolate structure (pKa2 = 11.7). There was no evidence of an 8-enol substituent in the absence of ionization. It is proposed that the syn conformation of these oxidized bases in duplex DNA and RNA can be further stabilized by abnormal hydrogen bonding or mispairing that involves N7-H. The combined data show that 15N NMR is a sensitive probe to examine tautomerism of the guanine ring system. The analysis indicates that the change from a single to a double bond for the C8 substituent, and the accompanying removal of the normal double bond between N7 and C8 on the imidazole ring system, has no detectable effect on the tautomerism at the N1-O6 site of the pyrimidine ring system for both the 8-keto and 8-thio substitutions. In addition, large differences in electronegativity of the C8 substituents do not alter the N1-O6 tautomerism.

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.

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.

Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel small molecule Hypoxia Inducible Factor-1 (HIF-1) pathway inhibitors and anti-cancer agents

PubMed Central

Mun, Jiyoung; Jabbar, Adnan Abdul; Devi, Narra Sarojini; Yin, Shaoman; Wang, Yingzhe; Tan, Chalet; Culver, Deborah; Snyder, James P.; Van Meir, Erwin G.; Goodman, Mark M.

2013-01-01

The Hypoxia Inducible Factor (HIF) pathway is an attractive target for cancer as it controls tumor adaptation to growth under hypoxia and mediates chemo- and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, as a novel small molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; logP7.4: 3.7). Here we describe the synthesis of twelve N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental logP7.4 values of 8 of the 12 new analogs ranged from 1.2 ∼ 3.1. Aqueous solubilities of 3 analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g. a solubility improvement of ∼9,000-fold. The pharmacological optimization had minimal impact on drug efficacy as the compounds retained IC50 values at or below 5 μM in our HIF-dependent reporter assay. PMID:22746274

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

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.

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

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.

Vacuum-assisted closure therapy increases local interleukin-8 and vascular endothelial growth factor levels in traumatic wounds.

PubMed

Labler, Ludwig; Rancan, Mario; Mica, Ladislav; Härter, Luc; Mihic-Probst, Daniela; Keel, Marius

2009-03-01

Clinical observations are suggesting accelerated granulation tissue formation in traumatic wounds treated with vacuum-assisted closure (VAC). Aim of this study was to determine the impact of VAC therapy versus alternative Epigard application on local inflammation and neovascularization in traumatic soft tissue wounds. Thirty-two patients with traumatic wounds requiring temporary coverage (VAC n = 16; Epigard n = 16) were included. At each change of dressing, samples of wound fluid and serum were collected (n = 80). The cytokines interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), and fibroblast growth factor-2 were measured by ELISA. Wound biopsies were examined histologically for inflammatory cells and degree of neovascularization present. All cytokines were found to be elevated in wound fluids during both VAC and Epigard treatment, whereas serum concentrations were negligible or not detectable. In wound fluids, significantly higher IL-8 (p < 0.001) and VEGF (p < 0.05) levels were detected during VAC therapy. Furthermore, histologic examination revealed increased neovascularization (p < 0.05) illustrated by CD31 and von Willebrand factor immunohistochemistry in wound biopsies of VAC treatment. In addition, there was an accumulation of neutrophils as well as an augmented expression of VEGF (p < 0.005) in VAC wound biopsies. This study suggests that VAC therapy of traumatic wounds leads to increased local IL-8 and VEGF concentrations, which may trigger accumulation of neutrophils and angiogenesis and thus, accelerate neovascularization.

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 ( ...

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.

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

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.

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.

An Alternative σ Factor, σ8, Controls Avermectin Production and Multiple Stress Responses in Streptomyces avermitilis.

PubMed

Sun, Di; Wang, Qian; Chen, Zhi; Li, Jilun; Wen, Ying

2017-01-01

Alternative σ factors in bacteria redirect RNA polymerase to recognize alternative promoters, thereby facilitating coordinated gene expression necessary for adaptive responses. The gene sig8 ( sav_741 ) in Streptomyces avermitilis encodes an alternative σ factor, σ 8 , highly homologous to σ B in Streptomyces coelicolor . Studies reported here demonstrate that σ 8 is an important regulator of both avermectin production and stress responses in S. avermitilis . σ 8 inhibited avermectin production by indirectly repressing expression of cluster-situated activator gene aveR , and by directly initiating transcription of its downstream gene sav_742 , which encodes a direct repressor of ave structural genes. σ 8 had no effect on cell growth or morphological differentiation under normal growth conditions. Growth of a sig8- deletion mutant was less than that of wild-type strain on YMS plates following treatment with heat, H 2 O 2 , diamide, NaCl, or KCl. sig8 transcription was strongly induced by these environmental stresses, indicating response by σ 8 itself. A series of σ 8 -dependent genes responsive to heat, oxidative and osmotic stress were identified by EMSAs, qRT-PCR and in vitro transcription experiments. These findings indicate that σ 8 plays an important role in mediating protective responses to various stress conditions by activating transcription of its target genes. Six σ 8 -binding promoter sequences were determined and consensus binding sequence BGVNVH-N 15 -GSNNHH (B: C, T or G, V: A, C or G, S: C or G, H: A, C or T, N: any nucleotide) was identified, leading to prediction of the σ 8 regulon. The list consists of 940 putative σ 8 target genes, assignable to 17 functional groups, suggesting the wide range of cellular functions controlled by σ 8 in S. avermitilis .

Overview on Pendeo-Epitaxy of GaN-Based Heterostructures for Novel Devices Applications

DTIC Science & Technology

2006-11-01

pendeo-epitaxy uses the metal organic chemical vapor deposition (MOCVD) technique that commonly requires ammonia (NH3) and trimethyl gallium ( TMG ...lateral growth rate and the crystallography of the side walls of the pendeo-epitaxial GaN are the growth temperature, the ammonia to TMG flow rate...pressure of 100 Torr and V:III ratio of 2600. It is known that the ammonia to TMG (V:III) molar flow rate ratio plays a major role for the lateral to

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.

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

Follicular localization of growth differentiation factor 8 and its receptors in normal and polycystic ovary syndrome ovaries.

PubMed

Lin, Ting-Ting; Chang, Hsun-Ming; Hu, Xiao-Ling; Leung, Peter C K; Zhu, Yi-Min

2018-05-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and its etiology has not been characterized. Growth differentiation factor 8 (GDF8) is a member of the transforming growth factor-β superfamily that plays a critical role in the regulation of ovarian functions. However, the expression pattern of GDF8 in the human ovary is not yet clear. This study examined the cellular distribution of GDF8 and its putative cellular receptors (ACVR2A, ACVR2B, and ALK5) in a series of normal (n = 34) and PCOS ovaries (n = 14). The immunostaining of GDF8, ACVR2A, ACVR2B, and ALK5 was detected in the oocytes regardless of the developmental stage. All these proteins were localized in antral follicles in normal and PCOS ovaries, and the expression of these proteins increased with increasing follicle diameter. A significantly higher expression of GDF8 was detected in the granulosa cells than in the matched theca cells (TCs). These proteins were also localized in the luteal cells of the corpus luteum. Granulosa cells and TCs of large antral follicles in PCOS ovaries display a higher expression of these proteins. The higher expression levels of GDF8 and its functional receptors (ACVR2A, ACVR2B, and ALK5) in antral follicles of PCOS ovaries than those in normal ovaries suggest the possible involvement of dysregulated GDF8 in the pathogenesis of PCOS.

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

Transformation of hydrazinium azide to molecular N8 at 40 GPa

NASA Astrophysics Data System (ADS)

Duwal, Sakun; Ryu, Young-Jay; Kim, Minseob; Yoo, Choong-Shik; Bang, Sora; Kim, Kyungtae; Hur, Nam Hwi

2018-04-01

Hydrazinium azide (HA) has been investigated at high pressures to 68 GPa using confocal micro-Raman spectroscopy and synchrotron powder x-ray diffraction. The results show that HA undergoes structural phase transitions from solid HA-I to HA-II at 13 GPa, associated with the strengthening of hydrogen bonding, and then to N8 at 40 GPa. The transformation of HA to recently predicted N8 (N≡N+—N-—N=N—-N—+N≡N) is evident by the emergence of new peaks at 2384 cm-1, 1665 cm-1, and 1165 cm-1, arising from the terminal N≡N stretching, the central N=N stretching, and the N—N stretching, respectively. However, upon decompression, N8 decomposes to ɛ-N2 below 25 GPa, but the remnant can be seen as low as 3 GPa.

Genesis of Influenza A(H5N8) Viruses

PubMed Central

El-Shesheny, Rabeh; Barman, Subrata; Feeroz, Mohammed M.; Hasan, M. Kamrul; Jones-Engel, Lisa; Franks, John; Turner, Jasmine; Seiler, Patrick; Walker, David; Friedman, Kimberly; Kercher, Lisa; Begum, Sajeda; Akhtar, Sharmin; Datta, Ashis Kumar; Krauss, Scott; Kayali, Ghazi; McKenzie, Pamela; Webby, Richard J.

2017-01-01

Highly pathogenic avian influenza A(H5N8) clade 2.3.4.4 virus emerged in 2016 and spread to Russia, Europe, and Africa. Our analysis of viruses from domestic ducks at Tanguar haor, Bangladesh, showed genetic similarities with other viruses from wild birds in central Asia, suggesting their potential role in the genesis of A(H5N8). PMID:28609260

Genesis of Influenza A(H5N8) Viruses.

PubMed

El-Shesheny, Rabeh; Barman, Subrata; Feeroz, Mohammed M; Hasan, M Kamrul; Jones-Engel, Lisa; Franks, John; Turner, Jasmine; Seiler, Patrick; Walker, David; Friedman, Kimberly; Kercher, Lisa; Begum, Sajeda; Akhtar, Sharmin; Datta, Ashis Kumar; Krauss, Scott; Kayali, Ghazi; McKenzie, Pamela; Webby, Richard J; Webster, Robert G

2017-08-01

Highly pathogenic avian influenza A(H5N8) clade 2.3.4.4 virus emerged in 2016 and spread to Russia, Europe, and Africa. Our analysis of viruses from domestic ducks at Tanguar haor, Bangladesh, showed genetic similarities with other viruses from wild birds in central Asia, suggesting their potential role in the genesis of A(H5N8).

40 CFR Appendix Viii to Part 261 - Hazardous Constituents

Code of Federal Regulations, 2013 CFR

2013-07-01

... L-Phenylalanine, 4-[bis(2-chloroethyl)aminol]- 148-82-3 U150 Mercury Same 7439-97-6 U151 Mercury... 1327-53-3 P012 Auramine Benzenamine, 4,4′-carbonimidoylbis[N,N-dimethyl 492-80-8 U014 Azaserine L...,3,6-trideoxy-alpha-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-, (8S...

40 CFR Appendix Viii to Part 261 - Hazardous Constituents

Code of Federal Regulations, 2012 CFR

2012-07-01

... L-Phenylalanine, 4-[bis(2-chloroethyl)aminol]- 148-82-3 U150 Mercury Same 7439-97-6 U151 Mercury... 1327-53-3 P012 Auramine Benzenamine, 4,4′-carbonimidoylbis[N,N-dimethyl 492-80-8 U014 Azaserine L...,3,6-trideoxy-alpha-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-, (8S...

40 CFR Appendix Viii to Part 261 - Hazardous Constituents

Code of Federal Regulations, 2014 CFR

2014-07-01

... L-Phenylalanine, 4-[bis(2-chloroethyl)aminol]- 148-82-3 U150 Mercury Same 7439-97-6 U151 Mercury... 1327-53-3 P012 Auramine Benzenamine, 4,4′-carbonimidoylbis[N,N-dimethyl 492-80-8 U014 Azaserine L...,3,6-trideoxy-alpha-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-, (8S...

Infrared photodissociation spectroscopy of M(N2)n(+) (M = Y, La, Ce; n = 7-8) in the gas phase.

PubMed

Xie, Hua; Shi, Lei; Xing, Xiaopeng; Tang, Zichao

2016-02-14

M(N2)n(+) (M = Y, La, Ce; n = 7-8) complexes have been studied by infrared photodissociation (IRPD) spectroscopy and density functional theory (DFT) calculations. The experimental results indicate that the N-N stretching vibrational frequencies are red-shifted from the gas-phase N2 value. The π back-donation is found to be a main contributor in these systems. IRPD spectra and DFT calculations reveal the coexistence of two isomers in the seven-coordinate M(N2)7(+) and eight-coordinate M(N2)8(+) complexes, respectively. The present studies on these metal-nitrogen complexes shed light on the interactions and coordinations toward N2 with transition and lanthanide metals.

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

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...

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.

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...

1,2,3-triazolate-bridged tetradecametallic transition metal clusters [M14(L)6O6(OMe)18X6] (M=FeIII, CrIII and VIII/IV) and related compounds: ground-state spins ranging from S=0 to S=25 and spin-enhanced magnetocaloric effect.

PubMed

Shaw, Rachel; Laye, Rebecca H; Jones, Leigh F; Low, David M; Talbot-Eeckelaers, Caytie; Wei, Qiang; Milios, Constantinos J; Teat, Simon; Helliwell, Madeleine; Raftery, James; Evangelisti, Marco; Affronte, Marco; Collison, David; Brechin, Euan K; McInnes, Eric J L

2007-06-11

We report the synthesis, by solvothermal methods, of the tetradecametallic cluster complexes [M14(L)6O6(OMe)18Cl6] (M=FeIII, CrIII) and [V14(L)6O6(OMe)18Cl6-xOx] (L=anion of 1,2,3-triazole or derivative). Crystal structure data are reported for the {M14} complexes [Fe14(C2H2N3)6O6(OMe)18Cl6], [Cr14(bta)6O6(OMe)18Cl6] (btaH=benzotriazole), [V14O6(Me2bta)6(OMe)18Cl6-xOx] [Me2btaH=5,6-Me2-benzotriazole; eight metal sites are VIII, the remainder are disordered between {VIII-Cl}2+ and {VIV=O}2+] and for the distorted [FeIII14O9(OH)(OMe)8(bta)7(MeOH)5(H2O)Cl8] structure that results from non-solvothermal synthetic methods, highlighting the importance of temperature regime in cluster synthesis. Magnetic studies reveal the {Fe14} complexes to have ground state electronic spins of S8 and 3.4 K for L=bta- and H2C2N3-, respectively). The huge spins of the {Fe14} complexes lead to very large magnetocaloric effects (MCE)-the largest known for any material below 10 K-which is further enhanced by spin frustration within the molecules due to the competing antiferromagnetic interactions. The largest MCE is found for [Fe14(C2H2N3)6O6(OMe)18Cl6] with an isothermal magnetic entropy change -DeltaSm of 20.3 J kg-1 K-1 at 6 K for an applied magnetic field change of 0-7 T.

Demethylation of 5,n-di-tert-butyl-8,n-dimethoxy[2.n]metacyclophane-1-ynes with BBr3 to afford novel [n]benzofuranophanes

NASA Astrophysics Data System (ADS)

Akther, Thamina; Islam, Md Monarul; Matsumoto, Taisuke; Tanaka, Junji; Feng, Xing; Redshaw, Carl; Yamato, Takehiko

2016-10-01

Novel [n]benzofuranophanes (n = 8 & 10) 2a-b have been prepared by successive intramolecular cyclization from 5,19-di-tert-butyl-8,22-dimethoxy[n]metacyclophane-1-yne (syn-1a-b) by treatment with BBr3 in CH2Cl2 at room temperature for 8h. [2.n]Benzofuranophanes 2a-b were also obtained by treatment of 1,2-di-endo-bromo-5,19-di-tert-butyl-8,22-dimethoxy[n]metacyclophane (meso-3a-b) with BBr3 in CH2Cl2 by using the same reaction conditions. 1H NMR spectra of 2a-b reveals the formation of intramolecular hydrogen bonding between hydroxyl proton with the oxygen of the furan moiety and X-ray analysis shows that the lengths between H (OH) and O (furan) are 1.981 and 1.823 Å̊, respectively. The conformation of [8]benzofuranophane 2a in solution is rigid with restricted rotation around the diaryl linkage rather than [10]benzofuranophane 2b because of weak intramolecular hydrogen bonding and the short length of the cross-linking chain.

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...

Cholecystokinin-8 induces brain-derived neurotrophic factor expression in noradrenergic neuronal cells.

PubMed

Hwang, Cheol Kyu; Kim, Do Kyung; Chun, Hong Sung

2013-08-01

The sulfated cholecystokinin octapeptide (CCK-8S) is one of the most abundant CCK fragment in the brain, but the effects of CCK-8S on locus coeruleus (LC) noradrenergic (NA) neuronal cells activity have not been studied. In this study, we investigated the effects of CCK-8S on the expression of brain-derived neurotrophic factor (BDNF) in LC NA neuronal cell line, LC3541. Results showed that CCK-8S (10 nM) elevates BDNF levels time-dependently and by 1.82-fold after 4h of incubation. In addition, pretreatment with CCK-8S reversed H₂O₂ (100 μM)-mediated down-regulation of BDNF expression, and effectively suppressed H₂O₂-induced caspase-3 activation. Furthermore, CCK-8S markedly induced expression of neuronal survival markers, such as extracellular signal-regulated kinase 1/2 (ERK 1/2), Akt/protein kinase B (PKB), Bcl-2, and peroxisome proliferators-activated receptor gamma coactivator-1α (PGC-1α). Pharmacological inhibitors of ERK 1/2, Akt/PKB, and protein kinase A (PKA) reversed CCK-8S-mediated BDNF induction in LC3541 cells. These results suggest the first evidence that CCK-8S can protect noradrenergic neurons and enhance the expression of BDNF via ERK 1/2-Akt/PKB-PKA-dependent pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nitrous oxide nitrification and denitrification 15N enrichment factors from Amazon forest soils.

PubMed

Pérez, Tibisay; Garcia-Montiel, Diana; Trumbore, Susan; Tyler, Stanley; de Camargo, Plínio; Moreira, Marcelo; Piccolo, Marisa; Cerri, Carlos

2006-12-01

The isotopic signatures of 15N and 18O in N2O emitted from tropical soils vary both spatially and temporally, leading to large uncertainty in the overall tropical source signature and thereby limiting the utility of isotopes in constraining the global N2O budget. Determining the reasons for spatial and temporal variations in isotope signatures requires that we know the isotope enrichment factors for nitrification and denitrification, the two processes that produce N2O in soils. We have devised a method for measuring these enrichment factors using soil incubation experiments and report results from this method for three rain forest soils collected in the Brazilian Amazon: soil with differing sand and clay content from the Tapajos National Forest (TNF) near Santarém, Pará, and Nova Vida Farm, Rondônia. The 15N enrichment factors for nitrification and denitrification differ with soil texture and site: -111 per thousand +/- 12 per thousand and -31 per thousand +/- 11 per thousand for a clay-rich Oxisol (TNF), -102 per thousand +/- 5 per thousand and -45 per thousand +/- 5 per thousand for a sandier Ultisol (TNF), and -10.4 per thousand +/- 3.5 per thousand (enrichment factor for denitrification) for another Ultisol (Nova Vida) soil, respectively. We also show that the isotopomer site preference (delta15Nalpha - delta15Nbeta, where alpha indicates the central nitrogen atom and beta the terminal nitrogen atom in N2O) may allow differentiation between processes of production and consumption of N2O and can potentially be used to determine the contributions of nitrification and denitrification. The site preferences for nitrification and denitrification from the TNF-Ultisol incubated soils are: 4.2 per thousand +/- 8.4 per thousand and 31.6 per thousand +/- 8.1 per thousand, respectively. Thus, nitrifying and denitrifying bacteria populations under the conditions of our study exhibit significantly different 15N site preference fingerprints. Our data set strongly suggests

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...

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.

Challenges Facing ZnO and GaN: Facts and Myths. Held in Glen Allen, Virginia on 18-19 October 2007

DTIC Science & Technology

2007-10-01

115 4 VIII.4.3.1. Improving dopant solubility........................................................... 115 VIII.4.3.2. Designing shallow defect...possible (e.g., ZnMgO grown at AFRL-Hanscom). intentional doping •Boron and aluminum only suspected n-type dopants detected (red) •Nitrogen...and sodium as only possible p-type dopants detected (blue) •The major impurity consistently present is silicon (from the quartz ampoule) •Elements

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...

7Li(15N, 14C)8Be reaction at 81 MeV and 14C + 8Be interaction versus that of 13C + 8Be

NASA Astrophysics Data System (ADS)

Rudchik, A. T.; Rudchik, A. A.; Muravynets, L. M.; Kemper, K. W.; Rusek, K.; Koshchy, E. I.; Piasecki, E.; Trzcinska, A.; Pirnak, Val. M.; Ponkratenko, O. A.; Strojek, I.; Stolarz, A.; Plujko, V. A.; Sakuta, S. B.; Siudak, R.; Ilyin, A. P.; Stepanenko, Yu. M.; Shyrma, Yu. O.; Uleshchenko, V. V.

2018-03-01

Angular distributions of the 7Li(15N, 14C)8Be reaction were measured at the energy Elab(15N) = 81 MeV. Data for transfer to the ground and first two excited states in 8Be were acquired as well as to the 14C ground and excited states. The reaction data were analyzed within the coupled-reaction-channels (CRC) method. The required 15N + 7Li entrance channel potential was taken from the 15N + 7Li elastic scattering. The 14C + 8Be potential was found by fitting Woods-Saxon form potentials to those generated by double folded real and imaginary potentials in the region of interaction. These generated potentials were then used in the CRC calculations. Proton transfer dominants this reaction, including to the excited states of 8Be. The reaction dependence on the exit channel potential was examined by using the 13C + 8Be potential previously deduced from the 9Be(12C, 13C)8Be reaction and 14C + 8Be from the 13C(9Be, 8Be)14C reaction.

ASTRONAUT LOVELL, JAMES A., JR. - APOLLO VIII (GUIDANCE & NAVIGATION [G&N])

NASA Image and Video Library

1969-05-25

S69-35099 (21-27 Dec. 1968) --- Astronaut James A. Lovell Jr., Apollo 8 command module pilot, is seen at the Apollo 8 Spacecraft Command Module's Guidance and Navigation station during the Apollo 8 lunar orbit mission. This picture was taken from 16mm motion picture film.

The R-matrix investigation of 8Li(α, n)11B reaction below 6 MeV

NASA Astrophysics Data System (ADS)

Kilic, Ali Ihsan; Muecher, Dennis; Garret, Paul; Svensson, Carl

2017-09-01

The investigation of cross sections for the 8Li(α, n)11B reaction has important impact for both primordial nucleosynthesis in the inhomogeneous models as well as constraining the physical conditions characterizing the r-process. However, there are large discrepancies existing between inclusive and exclusive measurements of the cross section below 3 MeV. The R-Matrix technique is a powerful tool for the analysis of the nuclear data for the purpose of extracting level information of compound nucleus 12B and extrapolation of the astrophysical S-Factor to Gamow energies. We have applied the R-matrix calculations for the 8Li(α, n)11B reaction and will present results for both the reaction rates and the partial S-factor. Combining the direct reaction contribution with the results from our R-matrix calculations, we can well describe the experimental data from the inclusive measurements. However, new experiments are needed in order to understand the role of neutron detection close to the threshold, for which we describe our experimental plans at ISAC, TRIUMF, using the newly developed DESCANT array.

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.

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...

Separation of flavonoids from Millettia griffithii with high-performance counter-current chromatography guided by anti-inflammatory activity.

PubMed

Tang, Huan; Wu, Bo; Chen, Kai; Pei, Heying; Wu, Wenshuang; Ma, Liang; Peng, Aihua; Ye, Haoyu; Chen, Lijuan

2015-02-01

Millettia griffithii is a unique Chinese plant located in the southern part of Yunnan Province. Up to now, there is no report about its phytochemical or related bioactivity research. In our previous study, the n-hexane crude extract of Millettia griffithii revealed significant anti-inflammatory activity at 100 μg/mL, inspiring us to explore the anti-inflammatory constituents. Four fractions (I, II, III, and A) were fractionated from n-hexane crude extract by high-performance counter-current chromatography with solvent system composed of n-hexane/ethyl acetate/methanol/water (8:9:8:9, v/v) and then were investigated for the potent anti-inflammatory activity. Fraction A, with the most potent inhibitory activity was further separated to give another four fractions (IV, V, VI, and B) with solvent system composed of n-hexane/ethyl acetate/methanol/water (8:4:8:4, v/v). Compound V and fraction B exhibited remarkable anti-inflammatory activity with nitric oxide inhibitory rate of 80 and 65%, which was worth further fractionation. Then, three fractions (VII, VIII, and IX) were separated from fraction B with a solvent system composed of n-hexane/ethyl acetate/methanol/water (8:1:8:1, v/v), with compound VIII demonstrating the most potent inhibitory activity (80%). Finally, the IC50 values of compound V and VIII were tested as 38.2 and 14.9 μM. The structures were identified by electrospray ionization mass spectrometry and(1)H and (13)C NMR spectroscopy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Divergences and boundary modes in $$ \\mathcal{N}=8 $$ supergravity

DOE PAGES

Larsen, Finn; Lisbao, Pedro

2016-01-07

We reconsider the one loop divergence ofmore » $$ \\mathcal{N}=8 $$ supergravity in four dimensions. We compute the finite effective potential of $$ \\mathcal{N}=8 $$ anti-deSitter supergravity and interpret it as logarithmic running of the cosmological constant. We show that quantum inequivalence between fields that are classically dual is due to boundary modes in AdS 4. In conclusion, the boundary modes are important in global AdS 4 but not in thermal AdS 4 since these geometries have different Euler characteristic.« less

Documentation of Production: Allied Medical Publication 8(B), Volume 2, Medical Planning Guide of NBC Battle Casualties (Biological)

DTIC Science & Technology

2006-06-01

causing Venezuelan Equine Encephalitis (VEE). Dose Range Signs/Symptoms of Illness Category Number (organisms) Typical Description Abbreviation 1...98 Table VIII-8. Number of Infected Personnel after a Venezuelean equine encephalitis (VEE) Attack...tactical scenario, agent (anthrax, botulinum neurotoxin, plague, tularemia, Staphylococcal enterotoxin B, Q fever, Venezuelan Equine Encephalitis

High-Temperature Growth of GaN and Al x Ga1- x N via Ammonia-Based Metalorganic Molecular-Beam Epitaxy

NASA Astrophysics Data System (ADS)

Billingsley, Daniel; Henderson, Walter; Doolittle, W. Alan

2010-05-01

The effect of high-temperature growth on the crystalline quality and surface morphology of GaN and Al x Ga1- x N grown by ammonia-based metalorganic molecular-beam epitaxy (NH3-MOMBE) has been investigated as a means of producing atomically smooth films suitable for device structures. The effects of V/III ratio on the growth rate and surface morphology are described herein. The crystalline quality of both GaN and AlGaN was found to mimic that of the GaN templates, with (002) x-ray diffraction (XRD) full-widths at half- maximum (FWHMs) of ~350 arcsec. Nitrogen-rich growth conditions have been found to provide optimal surface morphologies with a root-mean-square (RMS) roughness of ~0.8 nm, yet excessive N-rich environments have been found to reduce the growth rate and result in the formation of faceted surface pitting. AlGaN exhibits a decreased growth rate, as compared with GaN, due to increased N recombination as a result of the increased pyrolysis of NH3 in the presence of Al. AlGaN films grown directly on GaN templates exhibited Pendellösung x-ray fringes, indicating an abrupt interface and a planar AlGaN film. AlGaN films grown for this study resulted in an optimal RMS roughness of ~0.85 nm with visible atomic steps.

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...

Cross-protective efficacies of highly-pathogenic avian influenza H5N1 vaccines against a recent H5N8 virus.

PubMed

Park, Su-Jin; Si, Young-Jae; Kim, Jihye; Song, Min-Suk; Kim, Se-Mi; Kim, Eun-Ha; Kwon, Hyeok-Il; Kim, Young-Il; Lee, Ok-Jun; Shin, Ok Sarah; Kim, Chul-Joong; Shin, Eui-Cheol; Choi, Young Ki

2016-11-01

To investigate cross-protective vaccine efficacy of highly-pathogenic avian influenza H5N1 viruses against a recent HPAI H5N8 virus, we immunized C57BL/6 mice and ferrets with three alum-adjuvanted inactivated whole H5N1 vaccines developed through reverse-genetics (Rg): [Vietnam/1194/04xPR8 (clade 1), Korea/W149/06xPR8 (clade 2.2), and Korea/ES223N/03xPR8 (clade 2.5)]. Although relatively low cross-reactivities (10-40 HI titer) were observed against heterologous H5N8 virus, immunized animals were 100% protected from challenge with the 20 mLD50 of H5N8 virus, with the exception of mice vaccinated with 3.5μg of Rg Vietnam/1194/04xPR8. Of note, the Rg Korea/ES223N/03xPR8 vaccine provided not only effective protection, but also markedly inhibited viral replication in the lungs and nasal swabs of vaccine recipients within five days of HPAI H5N8 virus challenge. Further, we demonstrated that antibody-dependent cell-mediated cytotoxicity (ADCC) of an antibody-coated target cell by cytotoxic effector cells also plays a role in the heterologous protection of H5N1 vaccines against H5N8 challenge. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Experimental infection of dogs with highly pathogenic avian influenza virus (H5N8).

PubMed

Yuk, Seong-Su; Lee, Dong-Hun; Park, Jae-Keun; Tseren-Ochir, Erdene-Ochir; Kwon, Jung-Hoon; Noh, Jin-Yong; Song, Chang-Seon

2017-08-31

During the highly pathogenic avian influenza (HPAI) H5N8 virus outbreak in Korea, a dog in layer farm contaminated by H5N8 was reported seropositive for HPAI H5N8. To investigate the possibility of adaptation and transmission of HPAI H5N8 to dogs, we experimentally inoculated dogs with H5N8. Viral genes were weakly detected in nasal swabs and seroconversions in inoculated and contact dogs. Although the H5N8 virus did not induced severe clinical signs to dogs, the results suggest that surveillance of farm dogs should continue as a species in which the avian influenza virus may acquire infectivity to mammals through frequent contact with the virus.

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.

8. Historic American Buildings Survey W. N. Manning, Photographer, June ...

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

8. Historic American Buildings Survey W. N. Manning, Photographer, June 13, 1935. MANTEL AND DOOR IN N.E. BED ROOM, UPSTAIRS - Beeland-Stanley House, 218 East Commerce Street, Greenville, Butler County, AL

Thermodynamic analysis of vapor-phase epitaxial growth of GaAsN on Ge

NASA Astrophysics Data System (ADS)

Kawano, Jun; Kangawa, Yoshihiro; Ito, Tomonori; Kakimoto, Koichi; Koukitu, Akinori

2012-03-01

In this paper, we use thermodynamic analysis to determine how the nitrogen (N) ratio in the source gases affects the solid composition of coherently grown GaAs1-xNx(x˜0.03). The source gases for Ga, As, and N are trimethylgallium ((CH3)3Ga), arsine (AsH3), and ammonia (NH3), respectively. The growth occurs on a Ge substrate, and the analysis includes the stress from the substrate-crystal lattice mismatch. Calculation results indicate that to have just a few percent N incorporation into the grown solid, the V/III ratio in the source gases should be several thousands and the input-gas partial-pressure ratio NH3/(NH3+AsH3) should exceed 0.99. We also find that the lattice mismatch stress from the Ge substrate increases the V/III source-gas ratio required for stable growth, whereas an increase in input Ga partial pressure ratio has the opposite effect.

17 CFR 274.10 - Form N-8A, for notification of registration.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Form N-8A, for notification of... (CONTINUED) FORMS PRESCRIBED UNDER THE INVESTMENT COMPANY ACT OF 1940 Registration Statements § 274.10 Form N...: For Federal Register citations affecting Form N-8A, see the List of CFR Sections Affected, which...

17 CFR 274.10 - Form N-8A, for notification of registration.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Form N-8A, for notification of... (CONTINUED) FORMS PRESCRIBED UNDER THE INVESTMENT COMPANY ACT OF 1940 Registration Statements § 274.10 Form N...: For Federal Register citations affecting Form N-8A, see the List of CFR Sections Affected, which...

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.

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

N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

PubMed Central

Iborra, Salvador; Ramos, Manuel; Arana, David M.; Lázaro, Silvia; Aguilar, Francisco; Santos, Eugenio; López, Daniel

2013-01-01

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate. PMID:23776078

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.

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.

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.

Highly pathogenic avian H5N8 influenza viruses: should we be concerned?

PubMed

Tate, M D

2018-01-01

Avian influenza A viruses pose a constant threat to global human health as sporadic infections continue to occur with associated high mortality rates. To date, a number of avian influenza virus subtypes have infected humans, including H5N1, H7N9, H9N2 and H7N7. The majority of 'bird flu' cases are thought to have arisen from direct contact with infected poultry, particularly in live markets in Asia. 1 While human cases of the H5N8 subtype have not been documented as yet, there is the potential that H5N8 viruses could acquire mutations which favour infection of human cells. There is also the possibility that novel viruses with a tropism for human cells could be generated if H5N8 should reassasort with other circulating avian viruses, such as those of the H5N1 subtype. The emergence of a novel H5N8 virus with the capability of infecting humans could have drastic consequences to global health.

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.

Supersymmetric Janus solutions of dyonic ISO(7)-gauged N = 8 supergravity

NASA Astrophysics Data System (ADS)

Suh, Minwoo

2018-04-01

We study supersymmetric Janus solutions of dyonic ISO(7)-gauged N = 8 supergravity. We mostly find Janus solutions flowing to 3d N = 8 SYM phase which is the worldvolume theory on D2-branes and non-conformal. There are also solutions flowing from the critical points which are dual to 3d SCFTs from deformations of the D2-brane theory.

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...

33 CFR 110.8 - Lake Champlain, N.Y. and Vt.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Lake Champlain, N.Y. and Vt. 110... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.8 Lake Champlain, N.Y. and Vt. (a) Ticonderoga, N.Y. An area shoreward of a line bearing 312° from Ticonderoga Light to the southeast corner of the...

41 CFR 101-8.706-2 - Reasonable factors other than age.

Code of Federal Regulations, 2013 CFR

2013-07-01

... than age. 101-8.706-2 Section 101-8.706-2 Public Contracts and Property Management Federal Property... RECEIVING FEDERAL FINANCIAL ASSISTANCE 8.7-Discrimination Prohibited on the Basis of Age § 101-8.706-2 Reasonable factors other than age. (a) A recipient is permitted to take an action, otherwise prohibited by...

41 CFR 101-8.706-2 - Reasonable factors other than age.

Code of Federal Regulations, 2014 CFR

2014-07-01

... than age. 101-8.706-2 Section 101-8.706-2 Public Contracts and Property Management Federal Property... RECEIVING FEDERAL FINANCIAL ASSISTANCE 8.7-Discrimination Prohibited on the Basis of Age § 101-8.706-2 Reasonable factors other than age. (a) A recipient is permitted to take an action, otherwise prohibited by...

41 CFR 101-8.706-2 - Reasonable factors other than age.

Code of Federal Regulations, 2012 CFR

2012-07-01

... than age. 101-8.706-2 Section 101-8.706-2 Public Contracts and Property Management Federal Property... RECEIVING FEDERAL FINANCIAL ASSISTANCE 8.7-Discrimination Prohibited on the Basis of Age § 101-8.706-2 Reasonable factors other than age. (a) A recipient is permitted to take an action, otherwise prohibited by...

41 CFR 101-8.706-2 - Reasonable factors other than age.

Code of Federal Regulations, 2010 CFR

2010-07-01

... than age. 101-8.706-2 Section 101-8.706-2 Public Contracts and Property Management Federal Property... RECEIVING FEDERAL FINANCIAL ASSISTANCE 8.7-Discrimination Prohibited on the Basis of Age § 101-8.706-2 Reasonable factors other than age. (a) A recipient is permitted to take an action, otherwise prohibited by...

41 CFR 101-8.706-2 - Reasonable factors other than age.

Code of Federal Regulations, 2011 CFR

2011-07-01

... than age. 101-8.706-2 Section 101-8.706-2 Public Contracts and Property Management Federal Property... RECEIVING FEDERAL FINANCIAL ASSISTANCE 8.7-Discrimination Prohibited on the Basis of Age § 101-8.706-2 Reasonable factors other than age. (a) A recipient is permitted to take an action, otherwise prohibited by...

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.

JPRS Report. Science & Technology: China.

DTIC Science & Technology

1989-05-16

Nine aminothiazo peniciliate derivatives were synthesized and their antibacterial activities were tested. The following is the basic structure of the...Ph)tCNNH, » (PhhCN, NHr / S\\/ v 6—APA \\ 4 -N VIII Or XCOOCHPh, Route of Synthesis In Vitro Antibacterial Activities of Compound VIIi_8...Lactam Antibiotics. VII. Effect on Antibacterial Activity of the Oxime O-Substituents with Various Functional Groups in the 7 3-(Z-2-(2-Amino-4

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...

17 CFR 239.15 - Form N-1 for open-end management investment companies registered on Form N-8A.

Code of Federal Regulations, 2010 CFR

2010-04-01

... management investment companies registered on Form N-8A. 239.15 Section 239.15 Commodity and Securities... Registration Statements § 239.15 Form N-1 for open-end management investment companies registered on Form N-8A...-end management investment companies that are separate accounts of insurance companies as defined by...

[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.

76 FR 12390 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-07

... By-Laws, Article VIII, Section 8.1 (Establishment of Districts) and Section 8.2 (Composition of..., Article VIII, Section 2(c) (District Committees and District Business Conduct Committees), amended...\\ See FINRA Regulation By-Laws, Article VIII, Section 8.1 (Establishment of Districts) and Section 8.2...

Influenza A(H5N8) virus isolation in Russia, 2014.

PubMed

Marchenko, Vasiliy Y; Susloparov, Ivan M; Kolosova, Nataliya P; Goncharova, Nataliya I; Shipovalov, Andrey V; Durymanov, Alexander G; Ilyicheva, Tatyana N; Budatsirenova, Lubov V; Ivanova, Valentina K; Ignatyev, Georgy A; Ershova, Svetlana N; Tulyahova, Valeriya S; Mikheev, Valeriy N; Ryzhikov, Alexander B

2015-11-01

In this study, we report the isolation of influenza A(H5N8) virus from a Eurasian wigeon (Anas penelope) in Sakha Republic of the Russian Far East. The strain A/wigeon/Sakha/1/2014 (H5N8) has been shown to be pathogenic for mammals. It is similar to the strains that caused outbreaks in wild birds and poultry in Southeast Asia and Europe in 2014.

PTSD-8: A Short PTSD Inventory

PubMed Central

Hansen, Maj; Andersen, Tonny Elmose; Armour, Cherie; Elklit, Ask; Palic, Sabina; Mackrill, Thomas

2010-01-01

Traumatic events pose great challenges on mental health services in scarcity of specialist trauma clinicians and services. Simple short screening instruments for detecting adverse psychological responses are needed. Several brief screening instruments have been developed. However, some are limited, especially in relation to reflecting the posttraumatic stress disorder (PTSD) diagnosis. Recently, several studies have challenged pre-existing ideas about PTSD’s latent structure. Factor analytic research currently supports two four factor models. One particular model contains a dysphoria factor which has been associated with depression and anxiety. The symptoms in this factor have been hailed as less specific to PTSD. The scope of this article is therefore to present a short screening instrument, based on this research; Posttraumatic Stress Disorder (PTSD) – 8 items. The PTSD-8 is shown to have good psychometric properties in three independent samples of whiplash patients (n=1710), rape victims (n=305), and disaster victims (n=516). Good test-rest reliability is also shown in a pilot study of young adults from families with alcohol problems (n=56). PMID:21253461

PTSD-8: A Short PTSD Inventory.

PubMed

Hansen, Maj; Andersen, Tonny Elmose; Armour, Cherie; Elklit, Ask; Palic, Sabina; Mackrill, Thomas

2010-09-28

Traumatic events pose great challenges on mental health services in scarcity of specialist trauma clinicians and services. Simple short screening instruments for detecting adverse psychological responses are needed. Several brief screening instruments have been developed. However, some are limited, especially in relation to reflecting the posttraumatic stress disorder (PTSD) diagnosis. Recently, several studies have challenged pre-existing ideas about PTSD's latent structure. Factor analytic research currently supports two four factor models. One particular model contains a dysphoria factor which has been associated with depression and anxiety. The symptoms in this factor have been hailed as less specific to PTSD. The scope of this article is therefore to present a short screening instrument, based on this research; Posttraumatic Stress Disorder (PTSD) - 8 items. The PTSD-8 is shown to have good psychometric properties in three independent samples of whiplash patients (n=1710), rape victims (n=305), and disaster victims (n=516). Good test-rest reliability is also shown in a pilot study of young adults from families with alcohol problems (n=56).

IFN-{gamma} sensitizes MIN6N8 insulinoma cells to TNF-{alpha}-induced apoptosis by inhibiting NF-{kappa}B-mediated XIAP upregulation

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

Kim, Hun Sik; Kim, Sunshin; Lee, Myung-Shik

2005-10-28

Although X-linked inhibitor of apoptosis protein (XIAP) is an important intracellular suppressor of apoptosis in a variety of cell types, its role in cytokine-induced pancreatic {beta}-cell apoptosis remains unclear. Here, we found that: (i) XIAP level was inversely correlated with tumor necrosis factor (TNF)-{alpha}-induced apoptosis in MIN6N8 insulinoma cells; (ii) adenoviral XIAP overexpression abrogated the TNF-{alpha}-induced apoptosis through inhibition of caspase activity; (iii) downregulation of XIAP by antisense oligonucleotide or Smac peptide sensitized MIN6N8 cells to TNF-{alpha}-induced apoptosis; (iv) XIAP expression was induced by TNF-{alpha} through a nuclear factor-{kappa}B (NF-{kappa}B)-dependent pathway, and interferon (IFN)-{gamma} prevented such an induction in amore » manner independent of NF-{kappa}B, which presents a potential mechanism underlying cytotoxic IFN-{gamma}/TNF-{alpha} synergism. Taken together, our results suggest that XIAP is an important modulator of TNF-{alpha}-induced apoptosis of MIN6N8 cells, and XIAP regulation in pancreatic {beta}-cells might play an important role in pancreatic {beta}-cell apoptosis and in the pathogenesis of type 1 diabetes.« less

Expression, purification, and characterization of recombinant human and murine milk fat globule-epidermal growth factor-factor 8.

PubMed

Castellanos, Erick R; Ciferri, Claudio; Phung, Wilson; Sandoval, Wendy; Matsumoto, Marissa L

2016-08-01

Milk fat globule-epidermal growth factor-factor 8 (MFG-E8), as its name suggests, is a major glycoprotein component of milk fat globules secreted by the mammary epithelium. Although its role in milk fat production is unclear, MFG-E8 has been shown to act as a bridge linking apoptotic cells to phagocytes for removal of these dying cells. MFG-E8 is capable of bridging these two very different cell types via interactions through both its epidermal growth factor (EGF)-like domain(s) and its lectin-type C domains. The EGF-like domain interacts with αVβ3 and αVβ5 integrins on the surface of phagocytes, whereas the C domains bind phosphatidylserine found on the surface of apoptotic cells. In an attempt to purify full-length, recombinant MFG-E8 expressed in either insect cells or CHO cells, we find that it is highly aggregated. Systematic truncation of the domain architecture of MFG-E8 indicates that the C domains are mainly responsible for the aggregation propensity. Addition of Triton X-100 to the conditioned cell culture media allowed partial recovery of non-aggregated, full-length MFG-E8. A more comprehensive detergent screen identified CHAPS as a stabilizer of MFG-E8 and allowed purification of a significant portion of non-aggregated, full-length protein. The CHAPS-stabilized recombinant MFG-E8 retained its natural ability to bind both αVβ3 and αVβ5 integrins and phosphatidylserine suggesting that it is properly folded and active. Herein we describe an efficient purification method for production of non-aggregated, full-length MFG-E8. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

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.

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

Crystal Structure of the C-terminal Domain of Splicing Factor Prp8 Carrying Retinitis Pigmentosa Mutants

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

Zhang,L.; Shen, J.; Guarnieri, M.

2007-01-01

Prp8 is a critical pre-mRNA splicing factor. Prp8 is proposed to help form and stabilize the spliceosome catalytic core and to be an important regulator of spliceosome activation. Mutations in human Prp8 (hPrp8) cause a severe form of the genetic disorder retinitis pigmentosa, RP13. Understanding the molecular mechanism of Prp8's function in pre-mRNA splicing and RP13 has been hindered by its large size (over 2000 amino acids) and remarkably low-sequence similarity with other proteins. Here we present the crystal structure of the C-terminal domain (the last 273 residues) of Caenorhabditis elegans Prp8 (cPrp8). The core of the C-terminal domain ismore » an / structure that forms the MPN (Mpr1, Pad1 N-terminal) fold but without Zn{sup 2+} coordination. We propose that the C-terminal domain is a protein interaction domain instead of a Zn{sup 2+}-dependent metalloenzyme as proposed for some MPN proteins. Mapping of RP13 mutants on the Prp8 structure suggests that these residues constitute a binding surface between Prp8 and other partner(s), and the disruption of this interaction provides a plausible molecular mechanism for RP13.« 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.

Elastic scattering of 8He on 4He and 4 n system

NASA Astrophysics Data System (ADS)

Wolski, R.; Sidorchuk, S. I.; Ter-Akopian, G. M.; Fomichev, A. S.; Rodin, A. M.; Stepantsov, S. V.; Mittig, W.; Roussel-Chomaz, P.; Savajols, H.; Alamanos, N.; Auger, F.; Lapoux, V.; Raabe, R.; Tchuvil'sky, Yu. M.; Rusek, K.

2003-07-01

Elastic scattering of a 26A MeV beam of 8He on a gaseous helium target has been studied. In spite of efforts made for the observation of backward angle enhancement only upper limits could be obtained for the elastic scattering cross section at backward angles. The angular distribution of 8He nuclei scattered to CM 20°-80° was was analyzed in terms of a phenomenological Optical Model. Possible contributions from transfer reactions were estimated. The DWBA calculations indicate that the two step 2n transfer is more important than the one step 4n transfer. The transfer reaction d( 8He, 6Li)4n is discussed in terms of possible tests of a four-neutron system.

Acetylation of aromatic cysteine conjugates by recombinant human N-acetyltransferase 8.

PubMed

Deol, Reema; Josephy, P David

2017-03-01

1. The mercapturic acid (MA) pathway is a metabolic route for the processing of glutathione conjugates to MA (N-acetylcysteine conjugates). An N-acetyltransferase enzyme, NAT8, catalyzes the transfer of an acetyl group from acetyl-CoA to the cysteine amino group, producing a MA, which is excreted in the urine. We expressed human NAT8 in HEK293T cells and developed an HPLC-MS method for the quantitation of the S-aryl-substituted cysteine conjugates and their MA. 2. We measured the activity of the enzyme for acetylation of benzyl-, 4-nitrobenzyl-, and 1-menaphthylcysteine substrates. 3. NAT8 catalyzed the acetylation of all three cysteine conjugates with similar Michaelis-Menten kinetics.

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.

Growth condition optimization and mobility enhancement through prolonging the GaN nuclei coalescence process of AlGaN/AlN/GaN structure

NASA Astrophysics Data System (ADS)

He, Xiao-Guang; Zhao, De-Gang; Jiang, De-Sheng; Zhu, Jian-Jun; Chen, Ping; Liu, Zong-Shun; Le, Ling-Cong; Yang, Jing; Li, Xiao-Jing; Zhang, Shu-Ming; Yang, Hui

2015-09-01

AlGaN/AlN/GaN structures are grown by metalorganic vapor phase epitaxy on sapphire substrates. Influences of AlN interlayer thickness, AlGaN barrier thickness, and Al composition on the two-dimensional electron gas (2DEG) performance are investigated. Lowering the V/III ratio and enhancing the reactor pressure at the initial stage of the high-temperature GaN layer growth will prolong the GaN nuclei coalescence process and effectively improve the crystalline quality and the interface morphology, diminishing the interface roughness scattering and improving 2DEG mobility. AlGaN/AlN/GaN structure with 2DEG sheet density of 1.19 × 1013 cm-2, electron mobility of 2101 cm2·V-1·s-1, and square resistance of 249 Ω is obtained. Project support by the National Natural Science Foundation of China (Grant Nos. 61474110, 61377020, 61376089, 61223005, and 61176126), the National Science Fund for Distinguished Young Scholars, China (Grant No. 60925017), the One Hundred Person Project of the Chinese Academy of Sciences, and the Basic Research Project of Jiangsu Province, China (Grant No. BK20130362).

A pure inorganic 1D chain based on {Mo8O28} clusters and Mn(II) ions: [Mn(H2O)2Mo8O28 ] n 6 n -

NASA Astrophysics Data System (ADS)

Zhang, Xiaofen; Yan, Yonghong; Wu, Lizhou; Yu, Chengxin; Dong, Xinbo; Hu, Huaiming; Xue, Ganglin

2016-01-01

A new pure inorganic polymer, (NH4)6n[Mn(H2O)2Mo8O28)]n(H2O)2n(1), has been synthesized and characterized by elemental analyses, IR spectrum, UV-vis absorption spectra, TG-DSC and electrochemical studies. In 1, [Mo8O28]8- anions act as tetradentate ligands and are alternately linked by Mn(H2O)2 2 + ions into a one-dimensional chain structure. It is interesting that 1 represents the first example of pure inorganic-inorganic hybrid based on octamolybdate and transition metal ions. Moreover, it was indicated that 1 had definite catalytic activities on the probe reaction of benzyl alcohol oxidation to benzaldehyde with H2O2.

Experimental infection of mandarin duck with highly pathogenic avian influenza A (H5N8 and H5N1) viruses.

PubMed

Kang, Hyun-Mi; Lee, Eun-Kyoung; Song, Byung-Min; Heo, Gyeong-Beom; Jung, Joojin; Jang, Il; Bae, You-Chan; Jung, Suk Chan; Lee, Youn-Jeong

2017-01-01

A highly pathogenic avian influenza (HPAI) H5N8 virus was first detected in poultry and wild birds in South Korea in January 2014. Here, we determined the pathogenicity and transmissibility of three different clades of H5 viruses in mandarin ducks to examine the potential for wild bird infection. H5N8 (clade 2.3.4.4) replicated more efficiently in the upper and lower respiratory tract of mandarin ducks than two previously identified H5N1 virus clades (clades 2.2 and 2.3.2.1). However, none of the mandarin ducks infected with H5N8 and H5N1 viruses showed severe clinical signs or mortality, and gross lesions were only observed in a few tissues. Viral replication and shedding were greater in H5N8-infected ducks than in H5N1-infected ducks. Recovery of all viruses from control duck in contact with infected ducks indicated that the highly pathogenic H5 viruses spread horizontally through contact. Taken together, these results suggest that H5N8 viruses spread efficiently in mandarin ducks. Further studies of pathogenicity in wild birds are required to examine possible long-distance dissemination via migration routes. Copyright © 2016 Elsevier B.V. All rights reserved.

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. ...

Highly Pathogenic Avian Influenza H5N8 in Germany: Outbreak Investigations.

PubMed

Conraths, F J; Sauter-Louis, C; Globig, A; Dietze, K; Pannwitz, G; Albrecht, K; Höreth-Böntgen, D; Beer, M; Staubach, C; Homeier-Bachmann, T

2016-02-01

Epidemiological outbreak investigations were conducted in highly pathogenic avian influenza virus of the subtype H5N8 (HPAIV H5N8)-affected poultry holdings and a zoo to identify potential routes of entry of the pathogen via water, feedstuffs, animals, people, bedding material, other fomites (equipment, vehicles etc.) and the presence of wild birds near affected holdings. Indirect introduction of HPAIV H5N8 via material contaminated by infected wild bird seems the most reasonable explanation for the observed outbreak series in three commercial holdings in Mecklenburg-Western Pomerania and Lower Saxony, while direct contact to infected wild birds may have led to outbreaks in a zoo in Rostock and in two small free-range holdings in Anklam, Mecklenburg-Western Pomerania. © 2015 Blackwell Verlag GmbH.

Comprehensive growth and characterization study on highly n-doped InGaAs as a contact layer for quantum cascade laser applications

NASA Astrophysics Data System (ADS)

Demir, Ilkay; Altuntas, Ismail; Bulut, Baris; Ezzedini, Maher; Ergun, Yuksel; Elagoz, Sezai

2018-05-01

We present growth and characterization studies of highly n-doped InGaAs epilayers on InP substrate by metal organic vapor phase epitaxy to use as an n-contact layer in quantum cascade laser applications. We have introduced quasi two-dimensional electrons between 10 s pulsed growth n-doped InGaAs epilayers to improve both carrier concentration and mobility of structure by applying pulsed growth and doping methods towards increasing the Si dopant concentration in InGaAs. Additionally, the V/III ratio optimization under fixed group III source flow has been investigated with this new method to understand the effects on both crystalline quality and electrical properties of n-InGaAs epilayers. Finally, we have obtained high crystalline quality of n-InGaAs epilayers grown by 10 s pulsed as a contact layer with 2.8 × 1019 cm‑3 carrier concentration and 1530 cm2 V‑1 s‑1 mobility.

Synthesis and antihyperlipaemic activity of some 2-aminomethyl-3-aryl-5,6,7,8-tetrahydrobenzo(b)/5,6-dimethylthieno++ +(2,3- d) -pyrimidin-4-ones.

PubMed

Gadad, A K; Kapsi, S G; Anegundi, R I; Pattan, S R; Mahajanshetti, C S; Shishoo, C J

1996-10-01

A series of 2-aminomethyl-3-aryl-5,6,7,8-tetrahydrobenzo(b)/5,6-dimethylthieno (2,3-d) pyrimidin-4-ones (IX) were prepared by the displacement reaction between various amines and 2-chloromethyl-3-aryl-5,6, 7,8-tetrahydrobenzo(b)/5, 6-dimethylthieno(2, 3-d) pyrimidin-4-ones (VIII), which are obtained by the cyclization of corresponding chloroacetylamino derivatives (VII) under acidic condition. Compounds VII were obtained by the interaction of VI and chloroacetylchloride in glacial acetic acid. Compounds VIII were converted to corresponding 2-acetoxymethyl derivatives (X) with potassium acetate in glacial acetic acid. Selected compounds were screened for antihyperlipaemic activity in albino rats, whereby most of these compounds were found to be active. The serum cholesterol and triglyceride lowering activities exhibited by compounds 1 and 3 were found to be comparable to that of gemfibrozil. Compounds 1 and 3 were also found to be safe as indicated by their acute toxicity study.

[Assessment of venous thromboembolism risk in hospitalized medical patients. Concordance between PRETEMED guide and the recommendations of the viii conference of the American College of Chest Physicians].

PubMed

Gallardo Jiménez, Patricia; Guijarro Merino, Ricardo; Vallejo Herrera, Verónica; Sánchez Morales, David; Villalobos Sánchez, Aurora; Perelló González-Moreno, Juan Ignacio; Gómez-Huelgas, Ricardo

2012-11-03

The aim of this study is to evaluate the use of venous thromboembolism prophylaxis in hospitalized medical patients using 2 clinical practice guidelines and to analyze the agreement between them. Cross-sectional study of medical services in a third level hospital. We calculated the thromboembolic risk and the thromboprophylaxis adequacy by implementing the recommendations of viii conference of the American College of Chest Physicians (ACCP) and PRETEMED guide as well as their agreement. One hundred and twenty eight patients were included in the study. According to the PRETEMED guide, 34.4% of patients were low risk, 6.3% moderate and 59.4% high, with appropriate prophylaxis in 72.7% of patients (CI95%: 64.4-79.9), 18.8% (CI95%: 12.7-26.2) were undertreated and 8.6% (CI95%: 4.6-14.4) overtreated. According to ACCP recommendations, 50% of patients were low risk and 50% high, with appropriate prophylaxis in 74.2% of patients (CI95%: 66.1-81.2), 10.9% (CI95%: 6.4-17.3) were undertreated and 14.8% (CI95%: 9.4-21.8) overtreated. When PRETEMED risk was classified into low or moderate-high group versus ACCP risk low or high, the grade of concordance between both guides was 0.68 (CI95%: 0.56-0.81). When PRETEMED risk was classified into low-moderate or high group versus ACCP risk low or high, the grade of concordance between both guides was 0.81 (CI95%: 0.71-0.91). About a quarter of hospitalized medical patients did not receive adequate prophylaxis, showing an important room for improvement. PRETEMED guide and ACCP recommendations differ in risk assessment mainly because PRETEMED guide overestimates the risk of venous thromboembolism since it includes more risk factors. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer.

PubMed

Zammit, C; Coope, R; Gomm, J J; Shousha, S; Johnston, C L; Coombes, R C

2002-04-08

Fibroblast growth factor 8 can transform NIH3T3 cells and its expression has been found to be associated with breast and prostate cancer. Following our finding that fibroblast growth factor 8 mRNA expression is increased in breast cancer, we have undertaken an immunohistochemistry study of fibroblast growth factor 8 expression in a series of human breast tissues and other normal tissues. Our findings confirm increased expression of fibroblast growth factor 8 in malignant breast tissue but also show significant fibroblast growth factor 8 expression in non-malignant breast epithelial cells. No significant difference in fibroblast growth factor 8 expression was found between different grades of ductal carcinoma, lobular carcinoma and ductal carcinoma in-situ or cancer of different oestrogen receptor, progesterone receptor or nodal status. The highest levels of fibroblast growth factor 8 expression were found in lactating breast tissues and fibroblast growth factor 8 was also detected in human milk. A survey of other normal tissues showed that fibroblast growth factor 8 is expressed in the proliferative cells of the dermis and epithelial cells in colon, ovary fallopian tube and uterus. Fibroblast growth factor 8 appears to be expressed in several organs in man and appears to have an importance in lactation.

The binding interaction of imazapyr with cucurbit[n]uril (n = 6-8): Combined experimental and molecular modeling study

NASA Astrophysics Data System (ADS)

Mokhtar, Maali Saad; Suliman, FakhrEldin O.; Elbashir, Abdalla A.

2018-04-01

The inclusion complexes of imazapyr (IMA) with cucurbit[n]uril, CB[n] (n = 6-8), have been investigated. Fluorescence spectroscopy, MALDI-TOF, and 1HNMR were used to investigate and characterize the inclusion complexation of IMA and CB[n] in solutions. Whereas the solid state complexes have been characterized by Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD). IMA was found to form 1:1 complexes with CB[n] with association constants ranging from 5.80 × 102-2.65 × 103. The guest molecule IMA was found to encapsulate into the larger cavities of CB[7] and CB[8], whereas with CB[6] the molecule remains outside the cavity. Molecular dynamic (MD) simulations were used to follow the inclusion process at an atomistic level to study the mechanism and stability of inclusion. The results obtained showed that inclusion complexes of IMA with both CB[7] and CB[8] are highly stable in aqueous media, but the CB[6] smaller cavity size prohibited the formation of an inclusion complex with IMA. The results clearly show that in addition to hydrophobic effects the presence of hydrogen bonding has added greatly to the stability of these complexes.

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

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

Structure and stability of M6N8 clusters (M = Si, Ge, Sn, Ti).

PubMed

Davydova, Elena I; Timoshkin, Alexey Y; Frenking, Gernot

2010-06-10

The structures and stabilities of the M(6)N(8) clusters (M = Si, Ge, Sn, Ti) have been theoretically studied at DFT and ab initio levels of theory. Two new isomers have been considered: cage-like molecules and propeller-like molecules. It is shown that only for M = Si are both isomers true minima on the potential energy surface. The thermodynamics of the dissociation process (1/6)M(6)N(8) --> (1/3)M(3)N(4) is discussed. For each M(3)N(4) molecule, four structures with different multiplicity are considered. The thermodynamic analysis shows that independently of the multiplicity of M(3)N(4) nitrides all M(6)N(8) clusters are stable in the gas phase in a wide temperature range and could be potential intermediates in chemical vapor deposition of the nitride materials.

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

Dietary n-3 PUFAs augment caspase 8 activation in Staphylococcal aureus enterotoxin B stimulated T-cells

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

Gill, R.

Epidemiological studies have linked consumption of n-3 PUFAs with a variety of beneficial health benefits, particularly with respect to putative anti-inflammatory effects. Unfortunately, many of these results remain somewhat controversial because in most instances there has not been a linkage to specific molecular mechanisms. For instance, dietary exposure to low levels of mercury has been shown to be damaging to neural development, but concomitant ingestion of n-3 PUFAs as occurs during consumption of fish, has been shown to counteract the detrimental effects. As the mechanisms mediating the neurotoxicity of environmental mercury are not fully delineated, it is difficult to conceptualizemore » a testable molecular mechanism explaining how n-3 PUFAs negate its neurotoxic effects. However, environmental exposure to mercury also has been linked to increased autoimmunity. By way of a molecular understanding of this immuno-toxic association, disruption of CD95 signaling is well established as a triggering factor for autoimmunity, and we have previously shown that environmentally relevant in vitro and dietary exposures to mercury interfere with CD95 signaling. In particular we have shown that activation of caspase 8, as well as downstream activation of caspase 3, in response to CD95 agonist stimulation is depressed by mercury. More recently we have shown in vitro that the n-3 PUFA docosahexaenoic acid counteracts the negative effect of mercury on CD95 signaling by restoring caspase activity. We hypothesized that concomitant ingestion of n-3 PUFAs with mercury might be protective from the immuno-toxic effects of mercury, as it is with mercury's neuro-toxic effects, and in the case of immuno-toxicity this would be related to restoration of CD95 signal strength. We now show that dietary ingestion of n-3 PUFAs generally promotes CD95 signaling by upregulating caspase 8 activation. Apart from accounting for the ability of n-3 PUFAs to specifically counteract autoimmune

Screening for Neuraminidase Inhibitor Resistance Markers among Avian Influenza Viruses of the N4, N5, N6, and N8 Neuraminidase Subtypes.

PubMed

Choi, Won-Suk; Jeong, Ju Hwan; Kwon, Jin Jung; Ahn, Su Jeong; Lloren, Khristine Kaith S; Kwon, Hyeok-Il; Chae, Hee Bok; Hwang, Jungwon; Kim, Myung Hee; Kim, Chul-Joong; Webby, Richard J; Govorkova, Elena A; Choi, Young Ki; Baek, Yun Hee; Song, Min-Suk

2018-01-01

Several subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited, and markers of resistance are poorly understood. Previously, we identified unique NAI resistance substitutions in AIVs of the N3, N7, and N9 NA subtypes. Here, we report profiles of NA substitutions that confer NAI resistance in AIVs of the N4, N5, N6, and N8 NA subtypes using gene-fragmented random mutagenesis. We generated libraries of mutant influenza viruses using reverse genetics (RG) and selected resistant variants in the presence of the NAIs oseltamivir carboxylate and zanamivir in MDCK cells. In addition, two substitutions, H274Y and R292K (N2 numbering), were introduced into each NA gene for comparison. We identified 37 amino acid substitutions within the NA gene, 16 of which (4 in N4, 4 in N5, 4 in N6, and 4 in N8) conferred resistance to NAIs (oseltamivir carboxylate, zanamivir, or peramivir) as determined using a fluorescence-based NA inhibition assay. Substitutions conferring NAI resistance were mainly categorized as either novel NA subtype specific (G/N147V/I, A246V, and I427L) or previously reported in other subtypes (E119A/D/V, Q136K, E276D, R292K, and R371K). Our results demonstrate that each NA subtype possesses unique NAI resistance markers, and knowledge of these substitutions in AIVs is important in facilitating antiviral susceptibility monitoring of NAI resistance in AIVs. IMPORTANCE The frequency of human infections with avian influenza viruses (AIVs) has increased in recent years. Despite the availability of vaccines, neuraminidase inhibitors (NAIs), as the only available class of drugs for AIVs in humans, have been constantly used for treatment, leading to the inevitable emergence

8. Historic American Buildings Survey W. N. Manning, Photographer, March ...

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

8. Historic American Buildings Survey W. N. Manning, Photographer, March 7, 1935 MANTEL IN S.E. ROOM UPSTAIRS ALSO SHOWING WINDOW TREATMENT - Rush-Thornton House, U.S. Highway 29, Tuskegee, Macon County, AL

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

8. Historic American Buildings Survey W. N. Manning, Photographer, March ...

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

8. Historic American Buildings Survey W. N. Manning, Photographer, March 13, 1935 ANGLE VIEW, CLOSE-UP OF BIBLE STAND AND LAMP STANDS - Wetumpka Presbyterian Church, West Bridge & North Bridge Streets, Wetumpka, Elmore County, AL

8. Historic American Buildings Survey, N. E. Baldwin, Photographer August ...

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

8. Historic American Buildings Survey, N. E. Baldwin, Photographer August 1940, CONSTRUCTION DETAIL, Gift of New York State Department of Education. - Shaker North Family, Lumber & Grist Mill, Shaker Road, New Lebanon, Columbia County, NY

Cloning of a cancer cell-producing hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 from gastric cancer cells.

PubMed

Iwai, Mineko; Matsuda, Masahiko; Iwai, Yoshiaki

2003-01-01

A cell colony (IM95m) that produces hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) was cloned from gastric cancer cells (IM95 cell line). In culture medium, the highest levels of HGF, VEGF, and IL-8 were about 1.1, 0.9, and 0.17 ng/ml culture medium at 3 d from 10(5) cells. IM95m may be useful in elucidating the role of tumor cells in angiogenesis.

The therapeutic factor inventory-8: Using item response theory to create a brief scale for continuous process monitoring for group psychotherapy.

PubMed

Tasca, Giorgio A; Cabrera, Christine; Kristjansson, Elizabeth; MacNair-Semands, Rebecca; Joyce, Anthony S; Ogrodniczuk, John S

2016-01-01

We tested a very brief version of the 23-item Therapeutic Factors Inventory-Short Form (TFI-S), and describe the use of Item Response Theory (IRT) for the purpose of developing short and reliable scales for group psychotherapy. Group therapy patients (N = 578) completed the TFI-S on one occasion, and their data were used for the IRT analysis. Of those, 304 completed the TFI-S and other measures on more than one occasion to assess sensitivity to change, concurrent, and predictive validity of the brief version. Results suggest that the new TFI-8 is a brief, reliable, and valid measure of a higher-order group therapeutic factor. The TFI-8 may be used for continuous process measurement and feedback to improve the functioning of therapy groups.

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.

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.

Water, socioeconomic factors, and human herpesvirus 8 infection in Ugandan children and their mothers.

PubMed

Mbulaiteye, Sam M; Biggar, Robert J; Pfeiffer, Ruth M; Bakaki, Paul M; Gamache, Christine; Owor, Anchilla M; Katongole-Mbidde, Edward; Ndugwa, Christopher M; Goedert, James J; Whitby, Denise; Engels, Eric A

2005-04-01

Human herpesvirus 8 (HHV-8) infection is common in sub-Saharan Africa, but its distribution is uneven. Transmission occurs during childhood within families by unclear routes. We evaluated 600 Ugandan children with sickle cell disease and their mothers for factors associated with HHV-8 seropositivity in a cross-sectional study. HHV-8 serostatus was determined using an HHV-8 K8.1 glycoprotein enzyme immunoassay. Odds ratios for seropositivity were estimated using logistic regression, and factor analysis was used to identify clustering among socioeconomic variables. One hundred seventeen (21%) of 561 children and 166 (34%) of 485 mothers with definite HHV-8 serostatus were seropositive. For children, seropositivity was associated with age, mother's HHV-8 serostatus (especially for children aged 6 years or younger), lower maternal education level, mother's income, and low-status father's occupation (P < 0.05 for all). Using communal standpipe or using surface water sources were both associated with seropositivity (OR 2.70, 95% CI 0.80-9.06 and 4.02, 95% CI 1.18-13.7, respectively) as compared to using private tap water. These associations remained, albeit attenuated, after adjusting for maternal education and child's age (P = 0.08). In factor analysis, low scores on environmental and family factors, which captured household and parental characteristics, respectively, were positively associated with seropositivity (P(trend) < 0.05 for both). For mothers, HHV-8 seropositivity was significantly associated with water source and maternal income. HHV-8 infection in Ugandan children was associated with lower socioeconomic status and using surface water. Households with limited access to water may have less hygienic practices that increase risk for HHV-8 infection.

H5N8 Highly Pathogenic Avian Influenza in the Republic of Korea: Epidemiology During the First Wave, from January Through July 2014.

PubMed

Yoon, Hachung; Moon, Oun-Kyong; Jeong, Wooseog; Choi, Jida; Kang, Young-Myong; Ahn, Hyo-Young; Kim, Jee-Hye; Yoo, Dae-Sung; Kwon, Young-Jin; Chang, Woo-Seok; Kim, Myeong-Soo; Kim, Do-Soon; Kim, Yong-Sang; Joo, Yi-Seok

2015-04-01

This study describes the outbreaks of H5N8 highly pathogenic avian influenza (HPAI) in Korea during the first wave, from January 16, 2014 through July 25, 2014. Its purpose is to provide a better understanding of the epidemiology of H5N8 HPAI. Information on the outbreak farms and HPAI positive wild birds was provided by the Animal and Plant Quarantine Agency. The epidemiological investigation sheets for the outbreak farms were examined. During the 7-month outbreak period (January-July 2014), H5N8 HPAI was confirmed in 212 poultry farms, 38 specimens from wild birds (stools, birds found dead or captured). Ducks were the most frequently infected poultry species (159 outbreak farms, 75.0%), and poultry in 67 (31.6%) outbreak farms was asymptomatic. As in the previous four H5N1 epidemics of HPAI that occurred in Korea, this epidemic of H5N8 proved to be associated with migratory birds. Poultry farms in Korea can hardly be free from the risk of HPAI introduced via migratory birds. The best way to overcome this geographical factor is to reinforce biosecurity to prevent exposure of farms, related people, and poultry to the pathogen.

8. Historic American Buildings Survey, N. E. Baldwin, Photographer November ...

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

8. Historic American Buildings Survey, N. E. Baldwin, Photographer November 1939, CUPBOARDS IN GUESTS' DINING ROOM, Gift of New York State Department of Education. - Shaker North Family, Dwelling House, Shaker Road, New Lebanon, Columbia County, NY

Evaluation of Meal, Ready-to-Eat 8 at Market Square 2

DTIC Science & Technology

1988-09-01

the MRE were elicited from soldiers in a questionnaire that was administered at the completion of one field study (2). Analysis of this questionnaire...of the cakes , and hot sauce is in four menus. The MRE VIII is still packaged the same way as previous versions. On the average the MRE VIII provides...included the brownie and beef stew which were the two lowest rated items and the nut cakes which got variable ratings depending on type (see Table 4

17 CFR 239.14 - Form N-2 for closed end management investment companies registered on Form N-8A.

Code of Federal Regulations, 2010 CFR

2010-04-01

... management investment companies registered on Form N-8A. 239.14 Section 239.14 Commodity and Securities... Registration Statements § 239.14 Form N-2 for closed end management investment companies registered on Form N... closed end management investment companies registered under the Investment Company Act of 1940 on form N...

33 CFR 110.8 - Lake Champlain, N.Y. and Vt.

Code of Federal Regulations, 2011 CFR

2011-07-01

... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.8 Lake Champlain, N.Y. and Vt. (a) Ticonderoga...°14′05″ W. Note: The anchoring of vessels and placement of temporary moorings in the anchorage area...

33 CFR 110.8 - Lake Champlain, N.Y. and Vt.

Code of Federal Regulations, 2012 CFR

2012-07-01

... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.8 Lake Champlain, N.Y. and Vt. (a) Ticonderoga...°14′05″ W. Note: The anchoring of vessels and placement of temporary moorings in the anchorage area...

33 CFR 110.8 - Lake Champlain, N.Y. and Vt.

Code of Federal Regulations, 2013 CFR

2013-07-01

... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.8 Lake Champlain, N.Y. and Vt. (a) Ticonderoga...°14′05″ W. Note: The anchoring of vessels and placement of temporary moorings in the anchorage area...

33 CFR 110.8 - Lake Champlain, N.Y. and Vt.

Code of Federal Regulations, 2014 CFR

2014-07-01

... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.8 Lake Champlain, N.Y. and Vt. (a) Ticonderoga...°14′05″ W. Note: The anchoring of vessels and placement of temporary moorings in the anchorage area...

Distribution of AAV8 particles in cell lysates and culture media changes with time and is dependent on the recombinant vector

PubMed Central

Piras, Bryan A; Drury, Jason E; Morton, Christopher L; Spence, Yunyu; Lockey, Timothy D; Nathwani, Amit C; Davidoff, Andrew M; Meagher, Michael M

2016-01-01

With clinical trials ongoing, efficient clinical production of adeno-associated virus (AAV) to treat large numbers of patients remains a challenge. We compared distribution of AAV8 packaged with Factor VIII (FVIII) in cell culture media and lysates on days 3, 5, 6, and 7 post-transfection and found increasing viral production through day 6, with the proportion of viral particles in the media increasing from 76% at day 3 to 94% by day 7. Compared to FVIII, AAV8 packaged with Factor IX and Protective Protein/Cathepsin A vectors demonstrated a greater shift from lysate towards media from day 3 to 6, implying that particle distribution is dependent on recombinant vector. Larger-scale productions showed that the ratio of full-to-empty AAV particles is similar in media and lysate, and that AAV harvested on day 6 post-transfection provides equivalent function in mice compared to AAV harvested on day 3. This demonstrates that AAV8 production can be optimized by prolonging the duration of culture post-transfection, and simplified by allowing harvest of media only, with disposal of cells that contain 10% or less of total vector yield. Additionally, the difference in particle distribution with different expression cassettes implies a recombinant vector-dependent processing mechanism which should be taken into account during process development. PMID:27069949

New, simplified, interpolation method for estimation of microscopic nuclear masses based on the p-factor, P = N/sub P/N/sub N//(N/sub p/+N/sub n/)

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

Haustein, P.E.; Brenner, D.S.; Casten, R.F.

1987-12-10

A new semi-empirical method, based on the use of the P-factor (P = N/sub p/N/sub n//(N/sub p/+N/sub n/)), is shown to simplify significantly the systematics of atomic masses. Its uses is illustrated for actinide nuclei where complicated patterns of mass systematics seen in traditional plots versus Z, N, or isospin are consolidated and transformed into linear ones extending over long isotopic and isotonic sequences. The linearization of the systematics by this procedure provides a simple basis for mass prediction. For many unmeasured nuclei beyond the known mass surface, the P-factor method operates by interpolation among data for known nuclei rathermore » than by extrapolation, as is common in other mass models.« less