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

PubMed

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

2017-10-01

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

Acquired factor VII deficiency associated with acute myeloid leukemia.

PubMed

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

2015-04-01

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

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

PubMed

Koizume, Shiro; Miyagi, Yohei

2015-01-01

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

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

PubMed Central

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

1989-01-01

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

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

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

PubMed

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

2010-08-01

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

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

PubMed Central

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

2013-01-01

This case report presents a newly diagnosed congenital factor VII deficiency treated with recombinant activated factor VII (rFVIIa). Congenital factor VII deficiency is a rare autosomal-recessive bleeding disorder that occurs in fewer than 1/500,000 persons. Its presentation can vary from epistaxis to hemarthroses and severe central nervous system bleeding, and correlates poorly with factor VII levels. Our patient had not had a significant hemostatic challenge prior to his presentation and therefore never had any symptomatology suggestive of this disease. He was treated with rFVIIa, and was able to undergo repair of his fractures without bleeding. Case report A 19-year-old African-American male presented to the emergency room after an altercation that resulted in significant trauma. He sustained bilateral mandibular angle fractures and orbital floor fractures, requiring urgent surgical correction. On initial evaluation, he was noted to have a prolonged prothrombin time of 40.1 seconds, with an International Normalized Ratio of 4.0, a normal activated partial thromboplastin time of 29.9 seconds, and a platelet count of 241. After receiving vitamin K and fresh frozen plasma, he was taken to the operating room for a temporary rigid maxillomandibular fixation. A 1:1 mixing study with normal plasma corrected the prothrombin time (decreasing from 40.7 to 14.7 seconds) and a factor VII assay revealed 5% of the normal factor VII level. The patient was diagnosed with congenital factor VII deficiency. Due to his coagulopathy and the extensive surgical correction needed, rFVIIa was administered and surgery was accomplished without hemorrhagic sequelae. Conclusion This case report and review describes a rare congenital disease, the history of rFVIIa use, and its mechanism. rFVIIA use in our patient provided a treatment option that allowed the necessary surgical correction, but further prospective studies on dose optimization would ensure adequate dosing with minimal risk of severe side effects. PMID:23516010

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

PubMed

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

2013-01-01

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

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

PubMed

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

2007-02-01

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

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

PubMed

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

2011-06-01

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

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

PubMed

Naderi, Ali

2015-02-01

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

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

DTIC Science & Technology

2010-07-01

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

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

PubMed

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

2017-06-01

During cesarean delivery in patients with placenta previa, hemorrhaging after removal of the placenta is often challenging. In this condition, the extraordinarily high concentration of tissue factor at the placenta site may constitute a principle of treatment as it activates coagulation very effectively. The presumption, however, is that tissue factor is bound to activated factor VII. We hypothesized that topical application of recombinant activated factor VII at the placenta site reduces bleeding without affecting intravascular coagulation. We included 5 cases with planned cesarean delivery for placenta previa. After removal of the placenta, the surgeon applied a swab soaked in recombinant activated factor VII containing saline (1 mg in 246 mL) to the placenta site for 2 minutes; this treatment was repeated once if the bleeding did not decrease sufficiently. We documented the treatment on video recordings and measured blood loss. Furthermore, we determined hemoglobin concentration, platelet count, international normalized ratio, activated partial thrombin time, fibrinogen (functional), factor VII:clot, and thrombin generation in peripheral blood prior to and 15 minutes after removal of the placenta. We also tested these blood coagulation variables in 5 women with cesarean delivery planned for other reasons. Mann-Whitney test was used for unpaired data. In all 5 cases, the uterotomy was closed under practically dry conditions and the median blood loss was 490 (range 300-800) mL. There were no adverse effects of recombinant activated factor VII and we did not measure factor VII to enter the circulation. Neither did we observe changes in thrombin generation, fibrinogen, activated partial thrombin time, international normalized ratio, and platelet count in the peripheral circulation (all P values >.20). This study indicates that in patients with placenta previa, topical recombinant activated factor VII may diminish bleeding from the placenta site without initiation of systemic coagulation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2013-11-01

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

Serendipitous Discovery of Factor VII Deficiency and the Ensuing Dilemma.

PubMed

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

2018-03-01

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

Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy.

PubMed

Napolitano, Mariasanta; Siragusa, Sergio; Mariani, Guglielmo

2017-03-28

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

Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy

PubMed Central

Napolitano, Mariasanta; Siragusa, Sergio; Mariani, Guglielmo

2017-01-01

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

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

PubMed

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

2018-04-18

Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 μg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses. When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2013-07-01

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

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

PubMed

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

2013-03-01

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

Factor VII deficiency: a single-center experience.

PubMed

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

2012-11-01

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

Prophylactic treatment of hereditary severe factor VII deficiency in pregnancy.

PubMed

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

2017-09-01

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

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

PubMed

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

2017-02-01

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

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2013-11-01

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

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

DTIC Science & Technology

2008-02-01

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

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

PubMed

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

2011-04-09

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

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

PubMed Central

2011-01-01

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

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

PubMed

Bay, Ali; Aktekin, Elif; Erkutlu, Ibrahim

2015-12-01

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

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

PubMed

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

2007-07-01

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

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

PubMed

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

2016-01-01

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

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

PubMed

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

2009-12-15

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

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

PubMed

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

2007-10-01

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

Remarks on KERMA Factors in ACE files

NASA Astrophysics Data System (ADS)

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

2014-04-01

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

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

PubMed

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

2007-01-01

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

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

PubMed

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

2015-05-15

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

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

PubMed

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

2017-10-01

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

Monthly haemostatic factor variability in women and men.

PubMed

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

2014-01-01

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

Stability of prothrombin and factor VII in freeze-dried plasma

PubMed Central

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

1971-01-01

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

30 CFR 750.12 - Permit applications.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 779; (vii) Part 780; (viii) Part 783; (ix) Part 784; and (x) Part 785; (2) The following provisions of... consider the following factors as well as other relevant factors in determining the significance of a... significant deterioration limitations, or other Federal laws for air quality protection. (vii) A description...

Factors Influencing Title VII Bilingual Program Institutionalization.

ERIC Educational Resources Information Center

Lewis, Gerald R.; And Others

1985-01-01

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

Lack of bleeding in patients with severe factor VII deficiency.

PubMed

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

2005-02-01

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

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

PubMed

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

2016-03-01

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

Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders.

PubMed

Croom, Katherine F; McCormack, Paul L

2008-01-01

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

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.

29 CFR 825.107 - Successor in interest coverage.

Code of Federal Regulations, 2010 CFR

2010-07-01

... because it is a “successor in interest” to a covered employer, the factors used under Title VII of the... VII, whether the successor has notice of the employee's claim is not a consideration. Notice may be relevant, however, in determining successor liability for violations of the predecessor. The factors to be...

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

PubMed

Fayek, Ihab Samy

2015-01-01

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

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

PubMed

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

2005-05-01

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

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

PubMed

Okajima, K; Ishii, M

1999-02-01

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

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

PubMed

Yildirim, E; Erol, K; Birdane, A

2014-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2017-09-01

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

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.

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

PubMed

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

2004-01-01

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

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

PubMed

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

2013-12-01

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

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

PubMed

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

2017-09-01

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

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

PubMed

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

2013-01-01

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

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

PubMed

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

2015-12-01

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

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

PubMed

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

2016-01-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2011-04-26

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

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

PubMed

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

2013-08-20

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

77 FR 61753 - Granting of Request for Early Termination of the Waiting Period Under the Premerger Notification...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-11

..., Inc.; Astria Semiconductor Holdings, Inc.; FormFactor, Inc. 20121365 G ABRY Partners VII, L.P.; Source.... 20121303 G Wind Point Partners L.P.; Mistral Equity Partners, LP; Wind Point Partners VII-A, L.P. 20121307... Dillard. 20121364 G Apollo Investment Fund VII, L.P.; Jimmy Sanders Incorporated; Apollo Investment Fund...

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

PubMed

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

2006-11-01

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

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

PubMed

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

1999-04-01

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

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

PubMed

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

2004-01-01

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

Factor VII deficiency

MedlinePlus

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

Decidualized Human Endometrial Stromal Cells Mediate Hemostasis, Angiogenesis, and Abnormal Uterine Bleeding

PubMed Central

Lockwood, Charles J.; Krikun, Graciela; Hickey, Martha; Huang, S. Joseph; Schatz, Frederick

2011-01-01

Factor VII binds trans-membrane tissue factor to initiate hemostasis by forming thrombin. Tissue factor expression is enhanced in decidualized human endometrial stromal cells during the luteal phase. Long-term progestin only contraceptives elicit: 1) abnormal uterine bleeding from fragile vessels at focal bleeding sites, 2) paradoxically high tissue factor expression at bleeding sites; 3) reduced endometrial blood flow promoting local hypoxia and enhancing reactive oxygen species levels; and 4) aberrant angiogenesis reflecting increased stromal cell-expressed vascular endothelial growth factor, decreased Angiopoietin-1 and increased endothelial cell-expressed Angiopoietin-2. Aberrantly high local vascular permeability enhances circulating factor VII to decidualized stromal cell-expressed tissue factor to generate excess thrombin. Hypoxia-thrombin interactions augment expression of vascular endothelial growth factor and interleukin-8 by stromal cells. Thrombin, vascular endothelial growth factor and interlerukin-8 synergis-tically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding. PMID:19208784

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

PubMed

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

2011-10-01

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

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

PubMed

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

2011-06-01

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

Impact of nuclear data on sodium-cooled fast reactor calculations

NASA Astrophysics Data System (ADS)

Aures, Alexander; Bostelmann, Friederike; Zwermann, Winfried; Velkov, Kiril

2016-03-01

Neutron transport and depletion calculations are performed in combination with various nuclear data libraries in order to assess the impact of nuclear data on safety-relevant parameters of sodium-cooled fast reactors. These calculations are supplemented by systematic uncertainty analyses with respect to nuclear data. Analysed quantities are the multiplication factor and nuclide densities as a function of burn-up and the Doppler and Na-void reactivity coefficients at begin of cycle. While ENDF/B-VII.0 / -VII.1 yield rather consistent results, larger discrepancies are observed between the JEFF libraries. While the newest evaluation, JEFF-3.2, agrees with the ENDF/B-VII libraries, the JEFF-3.1.2 library yields significant larger multiplication factors.

42 CFR 57.1507 - Limitations applicable to loan guarantee.

Code of Federal Regulations, 2010 CFR

2010-10-01

... factors consistent with the purpose of part B of title VII of the Act and this subpart. (3) In determining... under part B of title VII of the Act or any other law of the United States, or to the total of such... part B of title VII of the Act. In making such determinations, the Secretary will in each case consider...

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

PubMed

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

2010-11-01

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

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

PubMed Central

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

2011-01-01

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

Optimization of Lyophilized Plasma for Use in Combat Casualties

DTIC Science & Technology

2013-01-21

SD. (Fib: fibrinogen, FII: Factor II, FV: Factor V, FVII : Factor VII, FVIII: Factor VIII, FIX: Factor IX, FX: Factor X, FXI: Factor XI, FXII...coagulation factor activity. Twenty swine were anesthetized and subjected to a validated model of polytrauma and hemorrhagic shock. They were...to assess inflammatory markers. Major Findings: 50%LP had higher electrolyte concentrations, osmolarity, and increased coagulation factor activity

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

PubMed

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

2008-01-01

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

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

PubMed

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

2012-05-01

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

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.

21 CFR 864.7750 - Prothrombin time test.

Code of Federal Regulations, 2010 CFR

2010-04-01

... the detection of possible clotting factor deficiencies in the extrinsic coagulation pathway, which involves the reaction between coagulation factors III and VII, and to monitor patients receiving coumarin...

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

PubMed

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

2017-04-01

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

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

PubMed

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

2015-06-01

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

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

PubMed

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

2013-07-01

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

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

PubMed

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

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

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 50% at D2 compared to the basal levels, and these reductions in plasma activity for both factors were consistent with our RT-PCR findings. In contrast, the plasma activities of the other coagulation factors (fibrinogen, factors V, VII, XIII, and VWF) were not significantly reduced, despite the reduction in the liver mRNA levels. Unlike the other factors, FX showed a temporal increase in its plasma activity, with significant increases (P<0.05) detected at D1. Investigating the coagulation cascade protein profiles during liver regeneration by DH may help to better understand the basic biology of the liver under normal and pathological conditions.

Platelet Glycoprotein lb-1X and Malignancy

DTIC Science & Technology

2011-09-01

Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci...JM, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves...interactions in vitro. (14) The extrinsic pathway of coagulation triggered by factor VII ( FVII ) and tissue factor can be activated in cancer patients. (15

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

ERIC Educational Resources Information Center

Beller, Andrea

1978-01-01

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

46 CFR 134.170 - Operating manual.

Code of Federal Regulations, 2010 CFR

2010-10-01

...; (iii) Wave height; (iv) Wave period; (v) Wind; (vi) Current; (vii) Temperatures; and (viii) Other environmental factors. (4) The heaviest loads allowable on deck. (5) Information on the use of any special cross... (vii) Access to different compartments and decks. (12) A list of shutdown locations for emergencies and...

15 CFR 400.24 - Application for zone.

Code of Federal Regulations, 2010 CFR

2010-01-01

...; (vii) If part of a port facility, a summary of port and transportation services and facilities; if not... from those firms that are considered prime prospects; and (vii) A description of proposed manufacturing and processing operations, if applicable, with information covering the factors described in § 400.31...

Prehospital Blood Transfusion in the En Route Management of Severe Combat Trauma: A Matched Cohort Study

DTIC Science & Technology

2014-09-01

routine use of tranexamic acid and decreased recombinant activated factor VII use repre- sent the effects of opposing trends in the evidence base for...Respiratory rate 19 (15Y24) 20 (16Y26) 0.173** Heart rate 92 (74Y115) 105 (82Y128) 0.041** Tranexamic acid 22 (22.6) 0 (0) U/T Recombinant activated factor VII...Military Applica- tion of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study. Arch Surg. 2012;147(2):113Y119. 6. Penn-Barwell JG

Human Cells as Platform to Produce Gamma-Carboxylated Proteins.

PubMed

de Sousa Bomfim, Aline; de Freitas, Marcela Cristina Corrêa; Covas, Dimas Tadeu; de Sousa Russo, Elisa Maria

2018-01-01

The gamma-carboxylated proteins belong to a family of proteins that depend on vitamin K for normal biosynthesis. The major representative gamma-carboxylated proteins are the coagulation system proteins, for example, factor VII, factor IX, factor X, prothrombin, and proteins C, S, and Z. These molecules have harbored posttranslational modifications, such as glycosylation and gamma-carboxylation, and for this reason they need to be produced in mammalian cell lines. Human cells lines have emerged as the most promising alternative to the production of gamma-carboxylated proteins. In this chapter, the methods to generate human cells as a platform to produce gamma-carboxylated proteins, for example the coagulation factors VII and IX, are presented. From the cell line modification up to the vitamin K adaptation of the produced cells is described in the protocols presented in this chapter.

10 CFR 430.62 - Submission of data.

Code of Federal Regulations, 2010 CFR

2010-01-01

... energy factor expressed in cycles per kilowatt-hour. (vii) Faucets, the maximum water use in gpm (L/min... seasonal energy efficiency ratio and heating seasonal performance factor. For central air conditioning heat pumps whose seasonal energy efficiency ratio and heating seasonal performance factor are based on an...

What a Decade of Experiments Reveals about Factors that Influence the Sense of Presence: Latest Findings

DTIC Science & Technology

2007-05-01

Paper presented at VII Encontro Portugues de Computacao Grafica, Eurographics, Monte de Caparica, Portugal, February. Slater, M., Usoh, M., and Steed...window? An experimental comparison of immersive and non-immersive walkthroughs. Paper presented at VII Encontro Portugues de Computacao Grafica

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

PubMed

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

2008-10-01

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

78 FR 24293 - Pilot Program on NAFTA Trucking Provisions

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-24

... Part 385, Appendix B, Section VII. Parts of the FMCSRs and HMRs having similar characteristics are combined together into six regulatory areas called ``factors.'' The regulatory factors are intended to evaluate the adequacy of a carrier's management controls. M. Passed Phase 1, Factor 1: A ``yes'' in this...

76 FR 56868 - Pilot Project on NAFTA Trucking Provisions

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-14

... part 385, Appendix B, Section VII. Parts of the FMCSRs and HMRs having similar characteristics are combined together into six regulatory areas called ``factors.'' The regulatory factors are intended to evaluate the adequacy of a carrier's management controls. L. Passed Phase 1, Factor 1: A ``yes'' in this...

77 FR 12356 - Pilot Program on NAFTA Trucking Provisions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-29

... part 385, Appendix B, Section VII. Parts of the FMCSRs and HMRs having similar characteristics are combined together into six regulatory areas called ``factors.'' The regulatory factors are intended to evaluate the adequacy of a carrier's management controls. M. Passed Phase 1, Factor 1: A ``yes'' in this...

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

PubMed

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

2013-08-01

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

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

PubMed

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

2012-03-01

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

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

PubMed

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

2015-11-01

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

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

PubMed

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

2005-03-01

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

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

PubMed

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

1994-02-01

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

Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice.

PubMed

Mihara, Masatomo; Aihara, Ken-ichi; Ikeda, Yasumasa; Yoshida, Sumiko; Kinouchi, Mizuho; Kurahashi, Kiyoe; Fujinaka, Yuichi; Akaike, Masashi; Matsumoto, Toshio

2010-02-01

The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. It also reduced adipocyte size and macrophage infiltration into adipose tissue. The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation.

Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.

PubMed

Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E

2017-01-03

Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.

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

PubMed

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

2016-05-01

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

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

ERIC Educational Resources Information Center

Edwards, Charles A.

1974-01-01

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

Implementation Practices of Bilingual Education Programs.

ERIC Educational Resources Information Center

Ortiz, Flora Ida

The ethnographic study investigated the implementation practices of a bilingual education program. A school site containing factors which were determined to be prevalent across Title VII programs was selected from over 300 Title VII sites. In addition, the school also contained a local student population, i.e., no one was bused from elsewhere; two…

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

PubMed

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

2016-12-01

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

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

PubMed

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

2007-02-01

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

76 FR 56272 - Pilot Project on NAFTA Trucking Provisions

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-12

... controls. A list of acute and critical regulations is included in 49 CFR part 385, Appendix B, Section VII... areas called ``factors.'' The regulatory factors are intended to evaluate the adequacy of a carrier's management controls. L. Passed Phase 1, Factor 1: A ``yes'' in this column indicates the carrier has...

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

PubMed

Augustsson, Cecilia; Persson, Egon

2014-11-13

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

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

PubMed

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

2012-02-01

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

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

PubMed

Hedner, Ulla

2006-01-01

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

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

PubMed

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

2009-01-01

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

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

PubMed

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

2016-05-01

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

Effects of the Application of the New Nuclear Data Library ENDF/B to the Criticality Analysis of AP1000

NASA Astrophysics Data System (ADS)

Kuntoro, Iman; Sembiring, T. M.; Susilo, Jati; Deswandri; Sunaryo, G. R.

2018-02-01

Calculations of criticality of the AP1000 core due to the use of new edition of nuclear data library namely ENDF/B-VII and ENDF/B-VII.1 have been done. This work is aimed to know the accuracy of ENDF/B-VII.1 compared to ENDF/B-VII and ENDF/B-VI.8. in determining the criticality parameter of AP1000. Analysis ws imposed to core at cold zero power (CZP) conditions. The calculations have been carried out by means of MCNP computer code for 3 dimension geometry. The results show that criticality parameter namely effective multiplication factor of the AP1000 core are higher than that ones resulted from ENDF/B-VI.8 with relative differences of 0.39% for application of ENDF/B-VII and of 0.34% for application of ENDF/B-VII.1.

Purification and Autoactivation Method for Recombinant Coagulation Factor VII.

PubMed

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

2018-01-01

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

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

PubMed

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

2017-09-01

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

7 CFR 4279.30 - Lenders' functions and responsibilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... sound lending practices, (v) Supervising construction (vi) Distribution of loan funds, (vii) Servicing... the loan processing phase. The lender must analyze all credit factors associated with each proposed loan and apply its professional judgment to determine that the credit factors, considered in...

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.

Longitudinal association of hemostatic factors with risk for cancers of the breast, colorectum, and lung among postmenopausal women.

PubMed

Kabat, Geoffrey C; Salazar, Christian R; Zaslavsky, Oleg; Lane, Dorothy S; Rohan, Thomas E

2016-09-01

The aim of this study was to examine whether hemostatic factors associated with coagulation and inflammation pathways are associated with cancer risk in postmenopausal women. We used data from the Women's Health Initiative study to examine the association of plasma fibrinogen levels, factor VII antigen activity, and factor VII concentration measured at baseline and during follow-up with the risk for cancers of the breast, colorectum, and lung. Among 5287 women who were followed up for a median of 11.4 years, 275 cases of breast cancer, 102 cases of colorectal cancer, and 90 cases of lung cancer were identified. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association of hemostatic factors with each cancer. Hemostatic factors were not associated with breast cancer in either baseline or longitudinal analyses. Baseline hemostatic factors showed weak associations with colorectal cancer; however, no association was seen in longitudinal analyses. Fibrinogen was positively associated with lung cancer in both baseline and longitudinal analyses; the association was seen only in never and former smokers, not in current smokers. We found no evidence of an association between hemostatic factors and breast or colorectal cancer in postmenopausal women. The positive association of fibrinogen levels with lung cancer requires confirmation in larger studies.

VizieR Online Data Catalog: Ba V, Ba VI, and Ba VII oscillator strengths (Rauch+, 2014)

NASA Astrophysics Data System (ADS)

Rauch, T.; Werner, K.; Quinet, P.; Kruk, J. W.

2014-04-01

table1.dat contains calculated HFR oscillator strengths (loggf) and transition probabilities (gA, in 1/s) in Ba V. CF is the cancellation factor as defined by Cowan (1981). In columns 3 and 6, e is written for even and o for odd. table2.dat contains calculated HFR oscillator strengths (loggf) and transition probabilities (gA, in 1/s) in Ba VI. CF is the cancellation factor as defined by Cowan (1981). In columns 3 and 6, e is written for even and o for odd. table3.dat contains calculated HFR oscillator strengths (loggf) and transition probabilities (gA, in 1/s) in Ba VII. CF is the cancellation factor as defined by Cowan (1981). In columns 3 and 6, e is written for even and o for odd. (3 data files).

The use of recombinant factor VIIa (NovoSeven) for treatment of active or impending bleeding in brain injury: broadening the indications.

PubMed

Yusim, Yakov; Perel, Azriel; Berkenstadt, Haim; Attia, Moshe; Knoller, Nachshon; Sidi, Avner

2006-11-01

We report three patients with severe traumatic brain injury, both open and closed, who were treated with recombinant activated factor VII. This treatment was given in a desperate, last-ditch effort to save the life of patient 1, as a preventive or early treatment of a developing hematoma in patient 2, and as treatment of a threatening hematoma in patient 3. One of the three patients survived. During the past few years we have broadened the indications for recombinant activated factor VII and started using it as a preventive measure rather than as a "last line of defense." However, the potential complications of disseminated intravascular coagulation and thrombotic events, as well as the cost-effectiveness in view of the available evidence-based medicine, should be considered.

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

ERIC Educational Resources Information Center

Berman, Paul; And Others

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

42 CFR 66.206 - Grant awards.

Code of Federal Regulations, 2010 CFR

2010-10-01

... other pertinent factors: (i) The scientific, technical, or educational merit of the proposed program...; (vii) The reasonableness of the proposed budget in relation to the proposed program; and (viii) The... of such awards will be made after consideration of such factors as the grantee's progress and...

40 CFR 194.44 - Engineered barriers.

Code of Federal Regulations, 2010 CFR

2010-07-01

... compliance assessment; (vi) Public comments requesting specific engineered barriers; (vii) The increased or..., after consideration of one or more of the factors in paragraph (c)(1) of this section, the Department... without evaluating the remaining factors in paragraph (c)(1) of this section, then any compliance...

25 CFR 700.833 - Civil penalty amounts.

Code of Federal Regulations, 2010 CFR

2010-04-01

... factors. (i) Agreement by the person being assessed a civil penalty to return to the Federal Land Manager...) Demonstration of hardship or inability to pay, provided that this factor shall only be considered when the... under the circumstances. (vii) Determination of other mitigating circumstances appropriate to...

42 CFR 136.351 - Application and selection.

Code of Federal Regulations, 2010 CFR

2010-10-01

... factors: (1) The extent of the unmet health care needs of the urban Indians in the urban center involved..., in the urban center. Factors to be considered in determining relative accessibility include: (i...; (vi) Technical barriers created by State and local health agencies; (vii) Availability of...

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

PubMed

Hedner, Ulla

2015-06-01

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

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

PubMed

He, Jin Peng; Feng, Jie Xiong

2017-10-01

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

Kinetic modeling sheds light on the mode of action of recombinant factor VIIa on thrombin generation.

PubMed

Mitrophanov, Alexander Y; Reifman, Jaques

2011-10-01

The therapeutic potential of a hemostatic agent can be assessed by investigating its effects on the quantitative parameters of thrombin generation. For recombinant activated factor VII (rFVIIa)--a promising hemostasis-inducing biologic--experimental studies addressing its effects on thrombin generation yielded disparate results. To elucidate the inherent ability of rFVIIa to modulate thrombin production, it is necessary to identify rFVIIa-induced effects that are compatible with the available biochemical knowledge about thrombin generation mechanisms. The existing body of knowledge about coagulation biochemistry can be rigorously represented by a computational model that incorporates the known reactions and parameter values constituting the biochemical network. We used a thoroughly validated numerical model to generate activated factor VII (FVIIa) titration curves in the cases of normal blood composition, hemophilia A and B blood, blood lacking factor VII, blood lacking tissue factor pathway inhibitor, and diluted blood. We utilized the generated curves to perform systematic fold-change analyses for five quantitative parameters characterizing thrombin accumulation. The largest fold changes induced by increasing FVIIa concentration were observed for clotting time, thrombin peak time, and maximum slope of the thrombin curve. By contrast, thrombin peak height was much less affected by FVIIa titrations, and the area under the thrombin curve stayed practically unchanged. Comparisons with experimental data demonstrated that the computationally derived patterns can be observed in vitro. rFVIIa modulates thrombin generation primarily by accelerating the process, without significantly affecting the total amount of generated thrombin. Copyright © 2011 Elsevier Ltd. All rights reserved.

36 CFR 296.16 - Civil penalty amounts.

Code of Federal Regulations, 2010 CFR

2010-07-01

... remit the penalty may be based upon any of the following factors: (i) Agreement by the person being... factor shall only be considered when the person being assessed a civil penalty has not been found to have... constitute excessive punishment under the circumstances; (vii) Determination of other mitigating...

Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran.

PubMed

Dorgalaleh, Akbar; Alavi, Sayed Ezatolla Rafiee; Tabibian, Shadi; Soori, Shahrzad; Moradi, Es'hagh; Bamedi, Taregh; Asadi, Mansour; Jalalvand, Masumeh; Shamsizadeh, Morteza

2017-05-01

Rare bleeding disorders (RBDs) are heterogeneous disorders, mostly inherited in an autosomal recessive pattern. Iran is a Mideast country with a high rate of consanguinity that has a high rate of RBDs. In this study, we present prevalence and clinical presentation as well as management and genetic defects of Iranian patients with RBDs. For this study, all relevant publications were searched in Medlin until 2015. Iran has the highest global incidence of factor XIII deficiency. Factor VII deficiency also is common in Iran, while factor II deficiency, with a prevalence of 1 per ∼3 million, is the rarest form of RBDs. Factor activity is available for all RBDs except for factor XIII deficiency, in which clot solubility remains as a diagnostic test. Molecular analysis of Iranian patients with RBDs revealed a few recurrent, common mutations only in patients with factor XIII deficiency, and considerable novel mutations in other RBDs. Clinical manifestations of these patients are variable and patients with factor XIII, factor X and factor VII more commonly presented severe life-threatening bleeding, while patients with combined factor V and factor VIII presented a milder phenotype. Plasma-derived products are the most common therapeutic choice in Iran, used prophylactically or on-demand for the management of these patients. Since Iran has a high rate of RBDs with life-threatening bleeding, molecular studies can be used for carrier detection and, therefore, prevention of the further expansion of these disorders and their fatal consequence.

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

PubMed

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

2012-04-01

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

26 CFR 25.2522(c)-3T - Transfers not exclusively for charitable, etc., purposes in the case of gifts made after July 31...

Code of Federal Regulations, 2010 CFR

2010-04-01

...) and (c)(2)(vii)(a) of this section that guaranteed annuity interests or unitrust interests... uses an individual other than one permitted in paragraphs (c)(2)(vi)(a) and (c)(2)(vii)(a) of this... of years is determined by taking the factor for valuing the annuity or unitrust interest for the...

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

PubMed

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

2010-01-01

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

Isolated acquired factor VII deficiency: review of the literature.

PubMed

Mulliez, Sylvie M N; Devreese, Katrien M J

2016-04-01

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

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

PubMed

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

1998-04-15

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

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

PubMed

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

2016-02-01

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

Inhibitor development after liver transplantation in congenital factor VII deficiency.

PubMed

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

2016-09-01

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

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

PubMed

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

2013-12-01

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

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

77 FR 40938 - Pilot Program on NAFTA Trucking Provisions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-11

... regulations is included in 49 CFR part 385, Appendix B, Section VII. Parts of the FMCSRs and HMRs having similar characteristics are combined together into six regulatory areas called ``factors.'' The regulatory factors are intended to evaluate the adequacy of a carrier's management controls. M. Passed Phase 1...

32 CFR 229.16 - Civil penalty amounts.

Code of Federal Regulations, 2010 CFR

2010-07-01

... and/or a proposal to mitigate or remit the penalty may be based upon any of the following factors: (i... or inability to pay, provided that this factor shall only be considered when the person being...) Determination that the proposed penalty would constitute excessive punishment under the circumstances; (vii...

75 FR 66829 - Determination of Foreign Exchange Swaps and Forwards

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-29

... Commodity Exchange Act (``CEA''), as amended by Title VII of the Dodd-Frank Wall Street Reform and Consumer... the application of the factors that the Secretary must consider in making a determination regarding... Treasury must consider the following factors: \\7\\ Notwithstanding any such determination by the Secretary...

40 CFR 86.1806-04 - On-board diagnostics.

Code of Federal Regulations, 2010 CFR

2010-07-01

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

18 CFR 1312.16 - Civil penalty amounts.

Code of Federal Regulations, 2010 CFR

2010-04-01

... to mitigate or remit the penalty may be based upon any of the following factors: (i) Agreement by the... to pay, provided that this factor shall only be considered when the person being assessed a civil...) Determination that the proposed penalty would constitute excessive punishment under the circumstances; (vii...

Screening Study on Feasibility of Standards of Performance ...

EPA Pesticide Factsheets

... VII ittttl w.xi Itl lln-.virc li .-illy Im 61,1, | ell to I III' ptl.rv'NS wt'l^lil | I linll.1l I"lis il|'|>l I- ^O f.'thl*' I,i fi,,,-l, M M.tir,-.-: ... 3 Industrial Factors K. Factor K is the ...

48 CFR 315.204-5 - Part IV-Representations and instructions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... as using too few.) (3) Examples of topics that form a basis for evaluation factors. Typical examples of topics that form a basis for the development of evaluation factors are listed in the following... special research, test, and other equipment or facilities. (vii) Managerial capability (ability to achieve...

48 CFR 315.204-5 - Part IV-Representations and instructions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... as using too few.) (3) Examples of topics that form a basis for evaluation factors. Typical examples of topics that form a basis for the development of evaluation factors are listed in the following... special research, test, and other equipment or facilities. (vii) Managerial capability (ability to achieve...

48 CFR 315.204-5 - Part IV-Representations and instructions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... as using too few.) (3) Examples of topics that form a basis for evaluation factors. Typical examples of topics that form a basis for the development of evaluation factors are listed in the following... special research, test, and other equipment or facilities. (vii) Managerial capability (ability to achieve...

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

PubMed

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

2017-01-01

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

Recombinant Factor VIIa Reduces Rebleed Hemorrhage Volume in a Swine Aortotomy Model: A Randomized Double-Blinded Study

DTIC Science & Technology

2008-06-01

Bpops,[ a dose of 90 Hg kgj1 will produce serum concentrations of factor VII high enough to reduce hemorrhage by accelerating thrombin production and...interaction is species-specific, and human FVII seems to have only between 5% and 50% activity when exposed to porcine tissue factor (15). The results...Copyright @ 200 by the Shock Society. Unauthorized reproduction of this article is prohibited.8 RECOMBINANT FACTOR VIIA REDUCES REBLEED HEMORRHAGE

Computational Analysis of the Effects of Reduced Temperature on Thrombin Generation: The Contributions of Hypothermia to Coagulopathy

DTIC Science & Technology

2013-09-01

reactions characterize the interactions of factor VII ( FVII ) and factor VIIa (FVIIa) and their complexes with TF and other clotting factors . These...patients), is one of the major factors contributing to coagulopathy of trauma.1–3 Heavy bleeding may result in a decreased blood volume and...tri- phosphate synthesis.4 Transfusion of blood products and resuscitation fluids, which are stored at low temperatures or even in a frozen state

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

PubMed

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

2012-01-01

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

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

PubMed Central

He, Jin Peng; Feng, Jie Xiong

2017-01-01

Abstract Rationale: The main complication of patients with severe hemophilia is recurrent bleeding events that usually affected musculoskeletal contractures. And replacement therapy methods were continuously improved to minimize adverse impacts brought by those complications. However, only several cases reported about the appendectomy for hemophilia A. We report a case of acute appendicitis treated by two-incision laparoscopy in a boy with hemophilia A and coagulation factor VII deficiency for the first time. Patient concerns: An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. Diagnoses: He received a computed tomography (CT) scan which revealed an enlarged appendix, thickened wall and appendiceal fecalith, and had received a conservative anti-bacterial treatment for his acute appendicitis but failed. He was diagnosed with hemophilia A and coagulation factor VII deficiency. Interventions: Two-incision laparoscopic appendectomy was made in success with a careful management of perioperative period. We monitored the clotting factor FVIII level and gave him a replacement therapy. Outcomes: The patient had an uneventful recovery. Lessons: It is important to exclude intraabdominal or retroperitoneal hemorrhage in patients suffering from hemophilia and acute abdominal pain. Pre-operative evaluation of validity of the FVIII replacement therapy is another effective strategy to assess the safety and feasibility of applying an operation procedure. The two-incision laparoscopic appendectomy is an effective treatment for this kind of patients for its minimal trauma and fast recovery characteristics. Our report shows that laparoscopic appendectomy is feasible in a child suffering from hemophilia after adequate blood clotting factor replacement treatment. PMID:29019885

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

PubMed Central

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

2012-01-01

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

48 CFR 42.1104 - Surveillance requirements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... following factors: (i) Contract requirements for reporting production progress and performance. (ii) The... contractor's financial capability. (vii) Any supplementary written instructions from the contracting office...

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

PubMed Central

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

2010-01-01

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

Kinetic Modeling Sheds Light on the Mode of Action of Recombinant Factor VIIa on Thrombin Generation

DTIC Science & Technology

2011-01-01

Regular Article Kinetic modeling sheds light on the mode of action of recombinant factor VIIa on thrombin generation Alexander Y. Mitrophanov...its effects on the quantitative parameters of thrombin generation. For recombinant activated factor VII (rFVIIa) ― a promising hemostasis-inducing...modulate thrombin production , it is necessary to identify rFVIIa-induced effects that are compatible with the available biochemical knowledge about

Defense Analysis: The Decision Process

DTIC Science & Technology

1985-07-01

problems ot resource allocation. Includes chapters on tormulating the problem, the research ettort, evaluation ot alternatives, interpretations of...Economics and Decision Making. He is a graduate of Colgate University (BA, Psychology) and received his Masters degree at the Naval Post Graduate School...Analysis 62 ’, ’The Steps irn Subject iye Aiuslysis 66 " Identify the Factors 66 Discusss the Factors 67 Evaluate Each Factor 67 Summa r y 68 Chapter VII

The effects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors.

PubMed

Archer, D F; Mammen, E F; Grubb, G S

1999-11-01

This study was undertaken to evaluate the effects on hemostatic factors of a low-dose preparation of levonorgestrel and ethinyl estradiol in a 12-cycle study. Thirty healthy women began taking 100 microg levonorgestrel and 20 microg ethinyl estradiol on the first day of the menstrual cycle, continued to take the preparation for the next 21 days, and then took placebo for 7 days. Mean changes in prothrombin time, partial thromboplastin time, and levels of factors VII and X, antithrombin, plasminogen, fibrinogen, protein S, thrombin-antithrombin complexes, and D-dimer were analyzed at baseline and at cycles 3, 6, and 12 with paired Student t tests. Factor X, plasminogen antigen and activity, and D-dimer levels were significantly increased (P

Acidosis and Correction of Acidosis Does Not Affect rFVIIa Function in Swine

DTIC Science & Technology

2012-12-15

and its correction (or normalization of pH) has been suggested before clinical use of rFVIIa [21, 22]. FVII is one of the many coagulation factors ...A or B (deficient in Factor VIII and Factor IX). Mice lacking FVII die in-utero or soon after birth due to vascular and hemostatic defects [23...the activity of recombinant activated Factor VII (rFVIIa) in vitro. However, it is not known if acidosis induced by hemorrhagic shock or infusion of

49 CFR Appendix A to Part 385 - Explanation of Safety Audit Evaluation Criteria

Code of Federal Regulations, 2010 CFR

2010-10-01

... safety management controls in place, is included in Appendix B, VII. List of Acute and Critical... having similar characteristics are combined together into six regulatory areas called “factors.” The regulatory factors, evaluated on the basis of the adequacy of the carrier's safety management controls, are...

78 FR 23557 - Fipronil; Receipt of Application for Emergency Exemptions, Solicitation of Public Comment

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-19

... your concerns and suggest alternatives. vii. Explain your views as clearly as possible, avoiding the... population who, as a result of their location, cultural practices, or other factors, may have atypical or... that an emergency situation exists based upon three factors: A severe increase in cabbage maggot...

40 CFR 35.4065 - How can my group get more than $50,000?

Code of Federal Regulations, 2010 CFR

2010-07-01

... ten factors below must occur: (i) A Remedial Investigation/Feasibility Study (“RI/FS”) costing more...” (ESD); (vii) A legislative or regulatory change results in new site information after EPA awards the... the community require many meetings, copies, etc.; and (x) Any other factor that, in EPA's judgment...

Structural Equation Analysis of the Wechsler Adult Intelligence Scale-Revised in a Normal Elderly Sample.

ERIC Educational Resources Information Center

Burton, D. Bradley; And Others

1994-01-01

A maximum-likelihood confirmatory factor analysis was performed by applying LISREL VII to the Wechsler Adult Intelligence Scale-Revised results of a normal elderly sample of 225 adults. Results indicate that a three-factor model fits best across all sample combinations. A mild gender effect is discussed. (SLD)

The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells

PubMed Central

Probst, Olivia C.; Karayel, Evren; Schida, Nicole; Nimmerfall, Elisabeth; Hehenberger, Elisabeth; Puxbaum, Verena; Mach, Lukas

2013-01-01

The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, the simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor. PMID:23347038

A Method for Visualization of Incoming Adenovirus Chromatin Complexes in Fixed and Living Cells

PubMed Central

Komatsu, Tetsuro; Dacheux, Denis; Kreppel, Florian; Nagata, Kyosuke; Wodrich, Harald

2015-01-01

Inside the adenovirus virion, the genome forms a chromatin-like structure with viral basic core proteins. Core protein VII is the major DNA binding protein and was shown to remain associated with viral genomes upon virus entry even after nuclear delivery. It has been suggested that protein VII plays a regulatory role in viral gene expression and is a functional component of viral chromatin complexes in host cells. As such, protein VII could be used as a maker to track adenoviral chromatin complexes in vivo. In this study, we characterize a new monoclonal antibody against protein VII that stains incoming viral chromatin complexes following nuclear import. Furthermore, we describe the development of a novel imaging system that uses Template Activating Factor-I (TAF-I/SET), a cellular chromatin protein tightly bound to protein VII upon infection. This setup allows us not only to rapidly visualize protein VII foci in fixed cells but also to monitor their movement in living cells. These powerful tools can provide novel insights into the spatio-temporal regulation of incoming adenoviral chromatin complexes. PMID:26332038

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

PubMed

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

2013-09-01

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

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

PubMed

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

1992-01-01

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

High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors.

PubMed

Koizume, Shiro; Ito, Shin; Yoshioka, Yusuke; Kanayama, Tomohiko; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Yamada, Roppei; Ochiya, Takahiro; Ruf, Wolfram; Miyagi, Etsuko; Hirahara, Fumiki; Miyagi, Yohei

2016-01-01

Thromboembolic events occur frequently in ovarian cancer patients. Tissue factor (TF) is often overexpressed in tumours, including ovarian clear-cell carcinoma (CCC), a subtype with a generally poor prognosis. TF-coagulation factor VII (fVII) complexes on the cell surface activate downstream coagulation mechanisms. Moreover, cancer cells secrete extracellular vesicles (EVs), which act as vehicles for TF. We therefore examined the characteristics of EVs produced by ovarian cancer cells of various histological subtypes. CCC cells secreted high levels of TF within EVs, while the high-TF expressing breast cancer cell line MDA-MB-231 shed fewer TF-positive EVs. We also found that CCC tumours with hypoxic tissue areas synthesised TF and fVII in vivo, rendering the blood of xenograft mice bearing these tumours hypercoagulable compared with mice bearing MDA-MB-231 tumours. Incorporation of TF into EVs and secretion of EVs from CCC cells exposed to hypoxia were both dependent on the actin-binding protein, filamin-A (filA). Furthermore, production of these EVs was dependent on different protease-activated receptors (PARs) on the cell surface. These results show that CCC cells could produce large numbers of TF-positive EVs dependent upon filA and PARs. This phenomenon may be the mechanism underlying the increased incidence of venous thromboembolism in ovarian cancer patients.

24 CFR 1000.162 - How will a recipient know that non-dwelling structures assisted under the IHBG program meet the...

Code of Federal Regulations, 2010 CFR

2010-04-01

..., design, features, amenities, performance or other factors. The standards for such structures must be able to support the reasonableness and necessity for these factors and to clearly identify the affordable... change; (vi) Cultural relevance of design; (vii) Size and scope supported by population and need; (viii...

50 CFR 23.70 - How can I trade internationally in American alligator and other crocodilian skins, parts, and...

Code of Federal Regulations, 2010 CFR

2010-10-01

... requirements for skins and parts. (vii) Habitat evaluation. (viii) Information on nuisance alligator management... or hatchlings is allowed, what factors are used to set harvest levels, and whether any alligators are... allowed, what factors are used to set harvest levels, and whether any alligators are returned to the wild...

[Case report. Phenprocoumon (Marcumar, Falithrom) as an unusual reason for coumarin poisoning in a dog].

PubMed

Lutze, G; Römhild, W; Elwert, J; Leppelt, J; Kutschmann, K

2003-01-01

Coumarin poisoning in dogs is not unusual and is in most cases caused by warfarin, a coumarin derivative which is used as a rodenticide. Competitive inhibition of vitamin K with an incomplete synthesis of the coagulation factors II, VII, IX and X can lead to a significant bleeding tendency. We observed a 3-year old male West Highland White Terrier with a reduced general condition and dyspnoea together with a massive haemothorax. Administration of vitamin K1 (3 mg/kg) led to a rapid improvement of the condition. Coagulation analysis revealed a prolonged activated recalcification time (ARCT), prothrombin time (PT) and aPTT with uncharacteristic thrombin time (TT); factor II, VII and X activities were reduced while factor V activity was normal, all of which are characteristic for coumarin poisoning. HPLC did not reveal the presence of warfarin but of phenoprocoumon, a drug used for thromboembolic prophylaxis in humans. This observation has not been described for dogs to date.

Strategic Petroleum Reserve Plan. Distribution Plan for the Strategic Petroleum Reserve. Amendment No. 3. Energy Action DOE No. 5

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

Not Available

Purpose of this Strategic Petroleum Reserve (SPR) Plan Amendment is to provide a Distribution Plan, setting forth the method of drawdown and distribution of the Reserve. Chapter VII of the SPR Plan contained a Distribution Plan which identified and discussed the major objectives, criteria and other factors that will be considered in developing the detailed plan. This Amendment replaces Chapter VII of the SPR Plan in its entirety.

36 CFR 907.12 - Preparation of an environmental assessment.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) Energy requirements and conservation; (vi) Solid waste; (vii) Transportation; (viii) Community facilities and services; (ix) Social and economic; (x) Historic and aesthetic; and (xi) Other relevant factors...

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

PubMed Central

Castaman, Giancarlo

2017-01-01

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

Japanese family with congenital factor VII deficiency.

PubMed

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

2015-10-01

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

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.

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

PubMed

Heinz, Stefan; Braspenning, Joris

2015-01-01

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

Effect of Recombinant FVIIA in Hypothermic, Coagulopathic Pigs with Liver Injuries

DTIC Science & Technology

2005-04-01

1󈨊 190 210 230 250 Time (min) United States Army Institute of Surgical Research 33 FIG 5A. Activated Factor FVII (FVIIa) in pig plasma--as measured by...8217X18)F 18) Pre-Dilution Basal Post-Dilution Basal Experimental stage with reference to liver injury FIG 5B. Activated Factor FVII (rFVIIa...the drug, rcombinant activated Factor VII (rFVIIa) on survival, survival time, blood loss, and disseminated intravascular coagulation (DIC) in

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

PubMed

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

2002-12-01

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

Youth Suicidal Behavior

MedlinePlus

... ii Risk Factors* Mental illness Substance abuse iv Firearms in the household vi Previous suicide attempts viii ... connectedness iii Safe schools v Reduced access to firearms vii Academic achievement ix Self-esteem xi Talking ...

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

PubMed

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

2015-06-01

Factor VII (FVII) deficiency is one of the two congenital coagulation disorders that was not discovered by the description of a new bleeding patient whose clotting pattern did not fit the blood coagulation knowledge of the time (the other is factor XIII deficiency). The existence of an additional factor capable of accelerating the conversion of prothrombin into thrombin was suspected before 1951, the year in which the first family with FVII deficiency was discovered. As several investigators were involved in the discovery of FVII deficiency from both sides of the Atlantic, several different names were tentatively suggested to define this entity, namely stable factor (in contrast with labile factor or FV), cothromboplastin, proconvertin, serum prothrombin conversion accelerator, prothrombin acceleration, and autoprothrombin I. The last term was proposed by those who denied the existence of this new entity, which was instead considered to be a derivate of prothrombin activation, namely autoprothrombin. The description of several families, from all over the world, of the same defect, however clearly demonstrated the singularity of the condition. Factor VII was then proposed to define this protein. In subsequent years, several variants were described with peculiar reactivity toward tissue thromboplastins of different origin. Molecular biology techniques demonstrated several gene mutations, usually missense mutations, often involving exon 8 of the FVII gene. Later studies dealt with the relation of FVII with tissue factor and activated FVII (FVIIa). The evaluation of circulating FVIIa was made possible by the use of a truncated form of tissue factor, which is only sensitive to FVIIa present in the circulation. The development of FVII concentrates, both plasma derived and recombinant, has facilitated therapeutic management of FVII-deficient patients. The use of FVIIa concentrates was noted to be associated with the occasional occurrence of thrombotic events, mainly venous. Total or partial liver transplants have been performed with success in these patients and have "cured" their deficiencies. Prenatal diagnosis has also been performed and recent research involves the development of inhibitors of FVII + tissue factor complex or of FVIIa. This approach, if successful, could provide another antithrombotic therapeutics tool. The story of FVII well summarizes the efforts of both theoretical and clinical approaches in the characterization of a coagulation disorder, that is, among the rare bleeding conditions, most frequently encountered in clinical practice. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Influence of blood lipids on global coagulation test results.

PubMed

Kim, Jung-Ah; Kim, Ji-Eun; Song, Sang Hoon; Kim, Hyun Kyung

2015-01-01

High levels of blood lipids have been associated with high levels of coagulation factors. We investigated whether blood lipids influence the results of global coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA). PT, aPTT, and TGA, along with procoagulant and anticoagulant factors, were measured in 488 normal individuals. Vitamin K status was assessed with prothrombin-induced by vitamin K absence-II (PIVKA-II). The procoagulant factors II, VII, IX, X, and XI and anticoagulant factors protein C and protein S showed significant correlations with triglyceride, and the procoagulant factors II, V, VII, IX, X, XI, and XII and anticoagulant factors antithrombin and protein C correlated with total cholesterol. There were no correlations of blood lipid levels with PIVKA-II levels. Subjects with high triglyceride levels (≥200 mg/dL) showed shorter PT values than those with lower triglyceride levels. However, aPTT value was not changed in terms of blood lipid levels. In both 1 and 5 pM tissue factor-induced TGAs, subjects in the high-triglyceride or high-cholesterol groups (≥240 mg/dL) had high levels of lag time, time-to-peak, and endogenous thrombin potential. Total cholesterol was a significant determinant of PT and TGA values. High blood lipids were related with increased coagulation activity in a normal population. Our findings are expected to help interpret the global coagulation test results in individuals with high lipid levels.

Influence of Blood Lipids on Global Coagulation Test Results

PubMed Central

Kim, Jung-Ah; Kim, Ji-Eun; Song, Sang Hoon

2015-01-01

Background High levels of blood lipids have been associated with high levels of coagulation factors. We investigated whether blood lipids influence the results of global coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA). Methods PT, aPTT, and TGA, along with procoagulant and anticoagulant factors, were measured in 488 normal individuals. Vitamin K status was assessed with prothrombin-induced by vitamin K absence-II (PIVKA-II). Results The procoagulant factors II, VII, IX, X, and XI and anticoagulant factors protein C and protein S showed significant correlations with triglyceride, and the procoagulant factors II, V, VII, IX, X, XI, and XII and anticoagulant factors antithrombin and protein C correlated with total cholesterol. There were no correlations of blood lipid levels with PIVKA-II levels. Subjects with high triglyceride levels (≥200 mg/dL) showed shorter PT values than those with lower triglyceride levels. However, aPTT value was not changed in terms of blood lipid levels. In both 1 and 5 pM tissue factor-induced TGAs, subjects in the high-triglyceride or high-cholesterol groups (≥240 mg/dL) had high levels of lag time, time-to-peak, and endogenous thrombin potential. Total cholesterol was a significant determinant of PT and TGA values. Conclusion High blood lipids were related with increased coagulation activity in a normal population. Our findings are expected to help interpret the global coagulation test results in individuals with high lipid levels. PMID:25553275

The preparation and structure of salty ice VII under pressure

NASA Astrophysics Data System (ADS)

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

2009-05-01

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

The preparation and structure of salty ice VII under pressure.

PubMed

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

2009-05-01

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

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

PubMed

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

2016-09-01

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

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

PubMed

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

2016-06-24

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

The Tenth Circuit View of Title VII Discovery--EEOC v. University of New Mexico, 504 F. 2d 1296 (10th Cir. 1974); Rich v. Martin Marietta Corp., 522 F. 2d 353 (10th Cir. 1975)

ERIC Educational Resources Information Center

Hoeltgen, Kristine A.

1976-01-01

In both these cases the Tenth Circuit continued the trend begun in earlier Title VII cases of giving a liberal interpretation to the scope of discovery. In these decisions the court began to speak more particularly of the factors to be considered in acting on motions to compel discovery. (Author/LBH)

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

PubMed

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

2013-11-01

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

Coagulation factor VII variants resistant to inhibitory antibodies.

PubMed

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

2014-11-01

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

Clustering of haemostatic variables and the effect of high cashew and walnut diets on these variables in metabolic syndrome patients.

PubMed

Pieters, Marlien; Oosthuizen, Welma; Jerling, Johann C; Loots, Du Toit; Mukuddem-Petersen, Janine; Hanekom, Susanna M

2005-09-01

We investigated the effect of a high walnut and cashew diet on haemostatic variables in people with the metabolic syndrome. Factor analysis was used to determine how the haemostatic variables cluster with other components of the metabolic syndrome and multiple regression to determine possible predictors. This randomized, control, parallel, controlled-feeding trial included 68 subjects who complied with the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol criteria. After a 3-week run-in following the control diet, subjects were divided into three groups receiving either walnuts or cashews (20 energy%) or a control diet for 8 weeks. The nut intervention had no significant effect on von Willebrand factor antigen, fibrinogen, factor VII coagulant activity, plasminogen activator inhibitor 1 activity, tissue plasminogen activator activity or thrombin activatable fibrinolysis inhibitor. Statistically, fibrinogen clustered with the body-mass-correlates and acute phase response factors, and factor VII coagulant activity clustered with high-density lipoprotein cholesterol (HDL-C). Tissue plasminogen activator activity, plasminogen activator inhibitor 1 activity and von Willebrand factor antigen clustered into a separate endothelial function factor. HDL-C and markers of obesity were the strongest predictors of the haemostatic variables. We conclude that high walnut and cashew diets did not influence haemostatic factors in this group of metabolic syndrome subjects. The HDL-C increase and weight loss may be the main focus of dietary intervention for the metabolic syndrome. Furthermore, diet composition may have only limited effects if weight loss is not achieved.

Effects of In Vitro Hemodilution, Hypothermia and rFVIIa Addition on Coagulation in Human Blood

DTIC Science & Technology

2012-03-30

primary fluids used by many trauma units and the US Army for pre-hospital resuscitation [17]. HX, a hetastarch-based product in a balanced electro...and has been associated with dilution of coagulation factors and hypothermia. Recombinant activated Factor VII (rFVIIa) has been used, often as a...of rFVIIa results in an enhancement of thrombin generation on the platelet surface at the site of injury independent of the presence of Factor VIII

Intravenous rFVIIa Administered for Hemorrhage Control in Hypothermic Coagulopathic Swine with Grade V Liver Injuries

DTIC Science & Technology

2001-04-01

Hendriks H, Meijer K, Hagenaars A, et al. Recombinant factor VIIa (rFVIIa, NovoSeven) decreases blood loss and blood product requirements during...and John R. Hess, MD, MPH Background: Intravenous adminis- tration of recombinant activated human clotting factor VII (rFVIIa) has been used...onds, fibrinogen was 91 6 20 mg/dL, and platelets were 221 6 57 3 105/mL, with no differences between groups (p > 0.05). Clotting factor levels

A Search for Factors Causing Training Costs to Rise by Examining the U. S. Navy’s AT, AW, and AX Ratings during their First Enlistment Period

DTIC Science & Technology

1986-09-01

HYPOTHESIS TEST .................... 20 III. TIME TO GET RATED TWO FACTOR ANOVA RESULTS ......... 23 IV. TIME TO GET RATED TUKEY’S PAIRED COvfl’PARISON... TEST RESULTS A ............................................ 24 V. TIME TO GET RATED TUKEY’S PAIRED COMPARISON TEST RESULTS B...25 VI. SINGLE FACTOR ANOVA HYPOTHESIS TEST #I............... 27 VII. AT: TIME TO GET RATED ANOVA TEST RESULTS ............. 30

40 CFR 60.2635 - What are the operator training and qualification requirements?

Code of Federal Regulations, 2010 CFR

2010-07-01

...) Combustion controls and monitoring. (v) Operation of air pollution control equipment and factors affecting... devices. (vii) Actions to correct malfunctions or conditions that may lead to malfunction. (viii) Bottom...

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

PubMed

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

2016-06-01

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

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

PubMed

Selin, S; Tejani, A

2006-03-01

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

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

PubMed

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

2012-12-01

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

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

PubMed

Williams, C M

2001-08-01

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

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

PubMed

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

2003-10-01

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

The effectivenes of science domain-based science learning integrated with local potency

NASA Astrophysics Data System (ADS)

Kurniawati, Arifah Putri; Prasetyo, Zuhdan Kun; Wilujeng, Insih; Suryadarma, I. Gusti Putu

2017-08-01

This research aimed to determine the significant effect of science domain-based science learning integrated with local potency toward science process skills. The research method used was a quasi-experimental design with nonequivalent control group design. The population of this research was all students of class VII SMP Negeri 1 Muntilan. The sample of this research was selected through cluster random sampling, namely class VII B as an experiment class (24 students) and class VII C as a control class (24 students). This research used a test instrument that was adapted from Agus Dwianto's research. The aspect of science process skills in this research was observation, classification, interpretation and communication. The analysis of data used the one factor anova at 0,05 significance level and normalized gain score. The significance level result of science process skills with one factor anova is 0,000. It shows that the significance level < alpha (0,05). It means that there was significant effect of science domain-based science learning integrated with local potency toward science learning process skills. The results of analysis show that the normalized gain score are 0,29 (low category) in control class and 0,67 (medium category) in experiment class.

Evaluation of procoagulant tissue factor expression in canine hemangiosarcoma cell lines.

PubMed

Witter, Lauren E; Gruber, Erika J; Lean, Fabian Z X; Stokol, Tracy

2017-01-01

OBJECTIVE To evaluate expression of procoagulant tissue factor (TF) by canine hemangiosarcoma cells in vitro. SAMPLES 4 canine hemangiosarcoma cell lines (SB-HSA [mouse-passaged cutaneous tumor], Emma [primary metastatic brain tumor], and Frog and Dal-1 [primary splenic tumors]) and 1 nonneoplastic canine endothelial cell line (CnAoEC). PROCEDURES TF mRNA and TF antigen expression were evaluated by quantitative real-time PCR assay and flow cytometry, respectively. Thrombin generation was measured in canine plasma and in coagulation factor-replete or specific coagulation factor-deficient human plasma by calibrated automated thrombography. Corn trypsin inhibitor and annexin V were used to examine contributions of contact activation and membrane-bound phosphatidylserine, respectively, to thrombin generation. RESULTS All cell lines expressed TF mRNA and antigen, with significantly greater expression of both products in SB-HSA and Emma cells than in CnAoEC. A greater percentage of SB-HSA cells expressed TF antigen, compared with other hemangiosarcoma cell lines. All hemangiosarcoma cell lines generated significantly more thrombin than did CnAoEC in canine or factor-replete human plasma. Thrombin generation induced by SB-HSA cells was significantly lower in factor VII-deficient plasma than in factor-replete plasma and was abolished in factor X-deficient plasma; residual thrombin generation in factor VII-deficient plasma was abolished by incubation of cells with annexin V. Thrombin generation by SB-HSA cells was unaffected by the addition of corn trypsin inhibitor. CONCLUSIONS AND CLINICAL RELEVANCE Hemangiosarcoma cell lines expressed procoagulant TF in vitro. Further research is needed to determine whether TF can be used as a biomarker for hemostatic dysfunction in dogs with hemangiosarcoma.

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.

20 CFR 1002.198 - What efforts must the employer make to help the employee become qualified for the reemployment...

Code of Federal Regulations, 2010 CFR

2010-04-01

... position does not make him or her unqualified. (2) Whether a task is essential depends on several factors, and these factors include but are not limited to: (i) The employer's judgment as to which functions... experience of past incumbents in the job; and/or (vii) The current work experience of incumbents in similar...

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-11-01

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

Dynamic expression of transcription factor Brn3b during mouse cranial nerve development

PubMed Central

Sajgo, Szilard; Ali, Seid; Popescu, Octavian; Badea, Tudor Constantin

2015-01-01

During development transcription factor combinatorial codes define a large variety of morphologically and physiologically distinct neurons. Such a combinatorial code has been proposed for the differentiation of projection neurons of the somatic and visceral components of cranial nerves. It is possible that individual neuronal cell types are not specified by unique transcription factors, but rather emerge through the intersection of their expression domains. Brn3a, Brn3b and Brn3c, in combination with each other and/or transcription factors of other families, can define subgroups of Retinal Ganglion Cells (RGC), Spiral and Vestibular Ganglia, inner ear and vestibular hair cell neurons in the vestibuloacoustic system, and groups of somatosensory neurons in the Dorsal Root Ganglia (DRG). In the present study we investigated the expression and potential role of the Brn3b transcription factor in cranial nerves and associated nuclei of the brainstem. We report the dynamic expression of Brn3b in the somatosensory component of cranial nerves II, V, VII and VIII and visceromotor nuclei of nerves VII, IX, X, as well as other brainstem nuclei during different stages of development into adult stage. We find that genetically identified Brn3bKO RGC axons show correct but delayed pathfinding during the early stages of embryonic development. However loss of Brn3b does not affect the anatomy of the other cranial nerves normally expressing this transcription factor. PMID:26356988

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...

12 CFR 202.1 - Authority, scope and purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... regulation is issued by the Board of Governors of the Federal Reserve System pursuant to title VII (Equal... prohibits creditor practices that discriminate on the basis of any of these factors. The regulation also...

40 CFR 86.001-25 - Maintenance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... used to determine exhaust, evaporative or refueling emission deterioration factors, as appropriate, is.... (b)(3)(vi)(E)-(b)(3)(vi)(J) [Reserved]. For guidance see § 86.098-25. (b)(3)(vii)-(b)(6)(i)(E...

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

PubMed

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

2015-10-01

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

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

PubMed

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

2018-02-01

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

Engineering of a mammalian O-glycosylation pathway in the yeast Saccharomyces cerevisiae: production of O-fucosylated epidermal growth factor domains.

PubMed

Chigira, Yuko; Oka, Takuji; Okajima, Tetsuya; Jigami, Yoshifumi

2008-04-01

Development of a heterologous system for the production of homogeneous sugar structures has the potential to elucidate structure-function relationships of glycoproteins. In the current study, we used an artificial O-glycosylation pathway to produce an O-fucosylated epidermal growth factor (EGF) domain in Saccharomyces cerevisiae. The in vivo O-fucosylation system was constructed via expression of genes that encode protein O-fucosyltransferase 1 and the EGF domain, along with genes whose protein products convert cytoplasmic GDP-mannose to GDP-fucose. This system allowed identification of an endogenous ability of S. cerevisiae to transport GDP-fucose. Moreover, expression of EGF domain mutants in this system revealed the different contribution of three disulfide bonds to in vivo O-fucosylation. In addition, lectin blotting revealed differences in the ability of fucose-specific lectin to bind the O-fucosylated structure of EGF domains from human factors VII and IX. Further introduction of the human fringe gene into yeast equipped with the in vivo O-fucosylation system facilitated the addition of N-acetylglucosamine to the EGF domain from factor IX but not from factor VII. The results suggest that engineering of an O-fucosylation system in yeast provides a powerful tool for producing proteins with homogenous carbohydrate chains. Such proteins can be used for the analysis of substrate specificity and the production of antibodies that recognize O-glycosylated EGF domains.

The effects of proton radiation on the prothrombin and partial thromboplastin times of irradiated ferrets

PubMed Central

Krigsfeld, Gabriel S.; Sanzari, Jenine K.; Kennedy, Ann R.

2013-01-01

Purpose To determine whether proton radiation affects coagulation. Material and methods Ferrets were exposed to solar particle event-like proton radiation at doses of 0, 25, 100, or 200 centigray (cGy), and dose rates of 50 cGy/minute (high dose rate or HDR) or 50 cGy/hour (low dose rate or LDR). Plasma was isolated from blood collected prior to radiation exposure and at 3–7 h post-radiation. Prothrombin time (PT) assays and activated partial thromboplastin time (aPTT) assays were performed as were mixing studies to determine the coagulation factors involved. Results HDR and LDR exposure led to statistically significant increases in PT values. It was determined that the HDR-induced increase in PT was due to Factor VII, while Factors II, V, and VII contributed to the LDR-induced increase in PT values. Only acute LDR exposure caused an increase in aPTT values, which remained elevated for 48 h post-irradiation (which was the latest time assayed in these studies). Mixing studies revealed that Factor IX contributed to the increased aPTT values. A majority of the animals exposed at the LDR had an International Normalized Ratio approaching or surpassing 2.0. Conclusions PT/aPTT assays resulted in increased clotting times due to different coagulation factors, indicating potential radiation-induced coagulopathy. PMID:22221163

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

PubMed

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

2018-01-01

Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL -1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL -1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk. © 2017 International Society on Thrombosis and Haemostasis.

40 CFR 721.10133 - 2-Propenoic acid, 2-methyl, 2-hydroxyethyl ester, homopolymer.

Code of Federal Regulations, 2010 CFR

2010-07-01

... for Occupational Safety and Health (NIOSH) assigned protection factor (APF) of at least 1,000. A NIOSH... percent), (f), (g)(1)(vii), and (g)(2)(iv). (iii) Industrial, commercial, and consumer activities...

46 CFR 4.05-2 - Incidents involving foreign tank vessels.

Code of Federal Regulations, 2010 CFR

2010-10-01

... discharge, resulting from damage to the vessel or its equipment. The factors you must consider to determine...; (vi) The nature of damage to the vessel; and (vii) Failure or breakdown aboard the vessel, its...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-07

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

29 CFR 1608.11 - Limitations on the application of these guidelines.

Code of Federal Regulations, 2010 CFR

2010-07-01

... AFFIRMATIVE ACTION APPROPRIATE UNDER TITLE VII OF THE CIVIL RIGHTS ACT OF 1964, AS AMENDED § 1608.11... such factors as progress in correcting the conditions disclosed by the self analysis. The currency of...

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

NASA Astrophysics Data System (ADS)

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

1981-05-01

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

Two novel cases of cerebral haemorrhages at the neonatal period associated with inherited factor VII deficiency, one of them revealing a new nonsense mutation (Ser52Stop).

PubMed

Giansily-Blaizot, Muriel; Aguilar-Martinez, Patricia; Briquel, Marie-Elisabeth; d'Oiron, Roseline; De Maistre, Emmanuel; Epelbaum, Serge; Schved, Jean-François

2003-02-01

Factor VII (FVII) is a plasma glycoprotein that plays a key role in the initiation of blood coagulation cascade. Inherited FVII deficiency is a rare autosomal recessive disorder with a wide heterogeneous clinical pattern. The severe form may be associated with intracranial haemorrhages occurring closely to birth with a high mortality rate. In the present article, we report two novel cases of neonatal intracerebral bleeding associated with FVII activity levels below 1% of normal. FVII genotyping investigations revealed particular genotypes including the deleterious Cys135Arg mutation and a novel Ser52Stop nonsense mutation at the homozygous state. Both mutations, through different mechanisms, are expected to be inconsistent with the production of functional FVII. These putative mechanisms are discussed through a review of the literature on phenotypic and genotypic characteristics of cerebral haemorrhages in severe inherited FVII deficiency.

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

PubMed

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

2007-06-01

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

Influence of stearic acid on postprandial lipemia and hemostatic function.

PubMed

Sanders, Thomas A B; Berry, Sarah E E

2005-12-01

It has been suggested that fats rich in stearic acid may result in exaggerated postprandial lipemia and have adverse effects on hemostatic function. The effects of test meals containing different saturated and monounsaturated FA were compared in healthy subjects in a series of studies to investigate this hypothesis. Stearic acid, when present as cocoa butter, resulted in similar postprandial lipemia and factor VII activation compared with a meal containing high-oleic sunflower oil. Stearic acid when presented as shea butter or as randomized stearate-rich TAG resulted in decreased postprandial lipemia and decreased postprandial activation of factor VII. Stearic acid-rich test meals did not result in impaired fibrinolytic activity compared with either a low-fat meal or a meal high in oleate. The difference in responses between the different stearic acid-rich fats appears to be due to varying solid fat contents of the fats at 37 degrees C.

U.S. Army Medical Department Journal, July-September 2004

DTIC Science & Technology

2004-09-01

on the surface of intestinal, lung, and brain cells. The TF protein then converts FVII into an activated form. Activated factor VII then combines...and FIX, which limits generation of thrombin. Platelets are able to increase production of thrombin when increased FVIIa is present. Normally FVII ...hemorrhage in severe neonatal FVII deficiency. Hemophilia. 2000; 6: 50-54. 12. Gilchrist J. Use of recombinant factor VIIa to treat a severe

Sequence and Expression Analyses of Ethylene Response Factors Highly Expressed in Latex Cells from Hevea brasiliensis

PubMed Central

Piyatrakul, Piyanuch; Yang, Meng; Putranto, Riza-Arief; Pirrello, Julien; Dessailly, Florence; Hu, Songnian; Summo, Marilyne; Theeravatanasuk, Kannikar; Leclercq, Julie; Kuswanhadi; Montoro, Pascal

2014-01-01

The AP2/ERF superfamily encodes transcription factors that play a key role in plant development and responses to abiotic and biotic stress. In Hevea brasiliensis, ERF genes have been identified by RNA sequencing. This study set out to validate the number of HbERF genes, and identify ERF genes involved in the regulation of latex cell metabolism. A comprehensive Hevea transcriptome was improved using additional RNA reads from reproductive tissues. Newly assembled contigs were annotated in the Gene Ontology database and were assigned to 3 main categories. The AP2/ERF superfamily is the third most represented compared with other transcription factor families. A comparison with genomic scaffolds led to an estimation of 114 AP2/ERF genes and 1 soloist in Hevea brasiliensis. Based on a phylogenetic analysis, functions were predicted for 26 HbERF genes. A relative transcript abundance analysis was performed by real-time RT-PCR in various tissues. Transcripts of ERFs from group I and VIII were very abundant in all tissues while those of group VII were highly accumulated in latex cells. Seven of the thirty-five ERF expression marker genes were highly expressed in latex. Subcellular localization and transactivation analyses suggested that HbERF-VII candidate genes encoded functional transcription factors. PMID:24971876

Sequence and expression analyses of ethylene response factors highly expressed in latex cells from Hevea brasiliensis.

PubMed

Piyatrakul, Piyanuch; Yang, Meng; Putranto, Riza-Arief; Pirrello, Julien; Dessailly, Florence; Hu, Songnian; Summo, Marilyne; Theeravatanasuk, Kannikar; Leclercq, Julie; Kuswanhadi; Montoro, Pascal

2014-01-01

The AP2/ERF superfamily encodes transcription factors that play a key role in plant development and responses to abiotic and biotic stress. In Hevea brasiliensis, ERF genes have been identified by RNA sequencing. This study set out to validate the number of HbERF genes, and identify ERF genes involved in the regulation of latex cell metabolism. A comprehensive Hevea transcriptome was improved using additional RNA reads from reproductive tissues. Newly assembled contigs were annotated in the Gene Ontology database and were assigned to 3 main categories. The AP2/ERF superfamily is the third most represented compared with other transcription factor families. A comparison with genomic scaffolds led to an estimation of 114 AP2/ERF genes and 1 soloist in Hevea brasiliensis. Based on a phylogenetic analysis, functions were predicted for 26 HbERF genes. A relative transcript abundance analysis was performed by real-time RT-PCR in various tissues. Transcripts of ERFs from group I and VIII were very abundant in all tissues while those of group VII were highly accumulated in latex cells. Seven of the thirty-five ERF expression marker genes were highly expressed in latex. Subcellular localization and transactivation analyses suggested that HbERF-VII candidate genes encoded functional transcription factors.

Photometric and spectral evolution of the symbiotic eclipsing variable V1329 Cygni at a late stage of its nova-like outburst

NASA Astrophysics Data System (ADS)

Arkhipova, V. P.; Esipov, V. F.; Ikonnikova, N. P.; Komissarova, G. V.

2015-03-01

The photoelectric UBV observations of the peculiar symbiotic star V1329 Cyg performed at the Crimean Station of the SAI-MSU during 245 nights over the period 2003-2014 are presented. The star's light curves since 1973 from the Crimean observations are shown. The brightness decline after its outburst over the last 40 years was . The phase color curves at phases 0.2 and 0.8 have maxima. Their qualitative interpretation in terms of the model of interacting winds in symbiotic binary star systems is proposed. The orbital period of the binary system has been redetermined. The spectroscopic observations at the 125-cm telescope of the Crimean Station from 1994 to 2014 have confirmed the change in the system's emission spectrum with orbital phase. The HI, He I, and Fe II line fluxes clearly trace the orbital motion. The Balmer hydrogen lines as well as the continuum at λ6000 and the V-band flux change by a factor of ˜3.5 from minimum to maximum light. The neutral helium lines change by a factor of 5. The high-excitation He II, [FeVII], [Ca VII] lines and the Raman O VI λ6825 line have shown changes in the fluxes by a factor of ˜2-3 weakly correlating with the orbital phase. The equivalent widths of the HI and He I lines are maximal at the star's maximum light and have distinct minima at phases 0.2 and 0.8, while the equivalent widths of the He II, [FeVII], and [CaVII] lines are minimal in the range of phases 0.2-0.8. The question about the location of the permitted and forbidden line emission zones in the binary system V1329 Cyg is discussed. The evolution of the emission spectrum for V1329 Cyg from 1980 to 2014 has been studied on the basis of new and archival data. A gradual decrease in the absolute fluxes of the nebular emission lines has been detected. The [O III] and [Fe VII] lines have weakened significantly. However, the [Fe X] λ6375 Å line has appeared and gradually strengthened, suggesting an increase in the degree of gas ionization in the line formation zone.

42 CFR 57.2003 - Determinations of increased enrollment solely for the program.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) Other Federal programs, such as those set forth in title VII and VIII of the Public Health Service Act... unusual factors, such as: (1) An institution having been newly established or (2) an institution...

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

NASA Astrophysics Data System (ADS)

Ngamsai, Kittima; Arpornwichanop, Amornchai

2015-11-01

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

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2018-06-16

Absence of collagen VII causes blistering of the skin, eyes and many other tissues. This disease is termed dystrophic epidermolysis bullosa (DEB). Corneal fibrosis occurs in up to 41% and vision loss in up to 64% of patients. Standard treatments are supportive and there is no cure. The immune-histologic and morphologic changes in the corneas of the mouse model for this disease have not been described in the literature. Our purpose is to characterize the eyes of these mice to determine if this is an appropriate model for study of human therapeutics. Western blot analysis (WB) and immunohistochemistry (IHC) were performed to assess the relative collagen VII protein levels and its location within the cornea. Additional IHC for inflammatory and fibrotic biomarkers alpha-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), proteinase 3, tenascin C and collagen III were performed. Clinical photographs documenting opacification of the corneas of animals of differing ages were assessed and scored independently by 2 examiners. Histology was then used to investigate morphologic changes. IHC and WB confirmed that these mice are deficient in collagen VII production at the level of the basement membrane when compared with wild-types. IHC showed anomalous deposition of collagen III throughout the stroma. Of the 5 biomarkers tested, TGF-β showed the strongest and most consistently staining. Photographs documented corneal opacities only in mice older than 10 weeks, opacities were not seen in younger animals. Histology showed multiple abnormalities, including epithelial hyperplasia, ulceration, fibrosis, edema, dysplasia, neovascularization and bullae formation. The collagen VII hypomorphic mouse shows reduced collagen VII production at the level of the corneal basement membrane. Corneal changes are similar to pathology seen in humans with this disease. The presence of anomalous stromal collagen III and TGF-β appear to be the most consistent and strongest staining biomarkers in diseased mice. This mouse appears to mimic human corneal disease. It is an appropriate model for testing of therapeutics to treat EB ocular disease. Copyright © 2018. Published by Elsevier Ltd.

Hypoxia induces cancer-associated cAMP/PKA signalling through HIF-mediated transcriptional control of adenylyl cyclases VI and VII.

PubMed

Simko, Veronika; Iuliano, Filippo; Sevcikova, Andrea; Labudova, Martina; Barathova, Monika; Radvak, Peter; Pastorekova, Silvia; Pastorek, Jaromir; Csaderova, Lucia

2017-08-31

Hypoxia is a phenomenon often arising in solid tumours, linked to aggressive malignancy, bad prognosis and resistance to therapy. Hypoxia-inducible factor-1 has been identified as a key mediator of cell and tissue adaptation to hypoxic conditions through transcriptional activation of many genes involved in glucose metabolism and other cancer-related processes, such as angiogenesis, cell survival and cell invasion. Cyclic adenosine 3'5'-monophosphate is one of the most ancient and evolutionarily conserved signalling molecules and the cAMP/PKA signalling pathway plays an important role in cellular adaptation to hypoxia. We have investigated possible new mechanisms behind hypoxic activation of the cAMP/PKA pathway. For the first time, we have shown that hypoxia induces transcriptional up-regulation of the system of adenylyl cyclases, enzymes responsible for cAMP production, in a panel of carcinoma cell lines of various origin. Our data prove functional relevance of the hypoxic increase of adenylyl cyclases VI and VII at least partially mediated by HIF-1 transcription factor. We have identified adenylyl cyclase VI and VII isoforms as mediators of cellular response to hypoxia, which led to the elevation of cAMP levels and enhanced PKA activity, with an impact on cell migration and pH regulation.

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

PubMed

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

2007-01-01

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

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

PubMed

Woehrle, D; Martinez, M; Bolliger, D

2016-10-01

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

Hemostasis in Hypothyroidism and Autoimmune Thyroid Disorders.

PubMed

Ordookhani, Arash; Burman, Kenneth D

2017-04-01

There are contradictory results on the effect of hypothyroidism on the changes in hemostasis. Inadequate population-based studies limited their clinical implications, mainly on the risk of venous thromboembolism (VTE). This paper reviews the studies on laboratory and population-based findings regarding hemostatic changes and risk of VTE in hypothyroidism and autoimmune thyroid disorders. A comprehensive literature search was conducted employing MEDLINE database. The following words were used for the search: Hypothyroidism; thyroiditis, autoimmune; blood coagulation factors; blood coagulation tests; hemostasis, blood coagulation disorders; thyroid hormones; myxedema; venous thromboembolism; fibrinolysis, receptors thyroid hormone. The papers that were related to hypothyroidism and autoimmune thyroid disorder and hemostasis are used in this review. Overt hypothyroidism is more associated with a hypocoagulable state. Decreased platelet count, aggregation and agglutination, von Willebrand factor antigen and activity, several coagulation factors such as factor VIII, IX, XI, VII, and plasminogen activator-1 are detected in overt hypothyrodism. Increased fibrinogen has been detected in subclinical hypothyroidism and autoimmune thyroid disease rendering a tendency towards a hypercoagulability state. Increased factor VII and its activity, and plasminogen activator inhibitor-1 are among several findings contributing to a prothrombotic state in subclinical hypothyroidism. Overt hypothyroidism is associated with a hypocoagulable state and subclinical hypothyroidism and autoimmune thyroid disorders may induce a prothrombotic state. However, there are contradictory findings for the abovementioned thyroid disorders. Prospective studies on the risk of VTE in various levels of hypofunctioning of the thyroid and autoimmune thyroid disorders are warranted.

Hemostasis in Hypothyroidism and Autoimmune Thyroid Disorders

PubMed Central

Ordookhani, Arash; Burman, Kenneth D.

2017-01-01

Context There are contradictory results on the effect of hypothyroidism on the changes in hemostasis. Inadequate population-based studies limited their clinical implications, mainly on the risk of venous thromboembolism (VTE). This paper reviews the studies on laboratory and population-based findings regarding hemostatic changes and risk of VTE in hypothyroidism and autoimmune thyroid disorders. Evidence Acquisition A comprehensive literature search was conducted employing MEDLINE database. The following words were used for the search: Hypothyroidism; thyroiditis, autoimmune; blood coagulation factors; blood coagulation tests; hemostasis, blood coagulation disorders; thyroid hormones; myxedema; venous thromboembolism; fibrinolysis, receptors thyroid hormone. The papers that were related to hypothyroidism and autoimmune thyroid disorder and hemostasis are used in this review. Results Overt hypothyroidism is more associated with a hypocoagulable state. Decreased platelet count, aggregation and agglutination, von Willebrand factor antigen and activity, several coagulation factors such as factor VIII, IX, XI, VII, and plasminogen activator-1 are detected in overt hypothyrodism. Increased fibrinogen has been detected in subclinical hypothyroidism and autoimmune thyroid disease rendering a tendency towards a hypercoagulability state. Increased factor VII and its activity, and plasminogen activator inhibitor-1 are among several findings contributing to a prothrombotic state in subclinical hypothyroidism. Conclusions Overt hypothyroidism is associated with a hypocoagulable state and subclinical hypothyroidism and autoimmune thyroid disorders may induce a prothrombotic state. However, there are contradictory findings for the abovementioned thyroid disorders. Prospective studies on the risk of VTE in various levels of hypofunctioning of the thyroid and autoimmune thyroid disorders are warranted. PMID:29026409

Estimation of the Dose and Dose Rate Effectiveness Factor

NASA Technical Reports Server (NTRS)

Chappell, L.; Cucinotta, F. A.

2013-01-01

Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

Why Johnny Can Read...But Doesn't

ERIC Educational Resources Information Center

Landy, Sarah

1977-01-01

The article analyzes characteristics of readers vs. non-readers and environmental factors which influence reading patterns among Grade VII (age 12-13) students. The study is based on 573 students and includes data on frequency of reading and book subject preferences. (JAB)

Coagulation and oxidative stress plasmatic levels in a type 2 diabetes population.

PubMed

Barillari, Giovanni; Fabbro, Elisabetta; Pasca, Samantha; Bigotto, Enrico

2009-06-01

Type 2 diabetes mellitus (DM2) is a metabolic disorder characterized by relative insulin deficiency, insulin resistance and hyperglycemia. DM2 improperly managed can cause severe complications such as renal failure, blindness or arterial disease. In addition to serious complications due to DM2, in the past 20 years, several studies have demonstrated the association between DM2, insulin resistance and prothrombotic risk. In our study, we wanted to evaluate the correlation between coagulation factor levels, oxidative plasmatic levels and DM2. We considered 20 DM2 patients (65% women and 35% men), 40-65 years of age, who had a BMI between 25 and 40 kg/m2 and followed a diet with or without oral antidiabetic treatment and 20 controls, blood donors, 15 men (75%) and five women (25%), who had a BMI between 25 and 40 kg/m2 and their age was between 40 and 65 years. Plasmatic levels of oxidative stress markers (tumor necrosis factor-alpha, nitrotyrosine, oxidized low-density lipoprotein) and coagulation markers (factors VII, VIII, IX, XI, XII, antithrombin III and fibrinogen) of both populations were analyzed following statistic criteria. The analyzed data of this study related to oxidative stress and coagulation factors proved that the differences observed between diabetic patients and controls were not statistically significant (P < 0.05) for tumor necrosis factor-alpha, nitrotyrosine, oxidized low-density lipoprotein, factor VII and factor XI; conversely for factor VIII, factor IX, factor XII, antithrombin III and fibrinogen, the results gave a difference statistically significant (P < 0.01). In patients with DM2, factor VIII increased from 79 to 103%, factor IX from 88 to 103%, factor XII from 87 to 105% and finally, antithrombin III from 81 to 103%. Different results between literature and our study could be due to fact that the patients considered were in the early stage of diabetes when endothelial damage is absent and vascular complications are not clinically expressed. In this study, it is still shown that DM2 is a multifactor disease and its physiopathologic mechanisms are not completely known today.

Reduction and removal of heptavalent technetium from solution by Escherichia coli.

PubMed

Lloyd, J R; Cole, J A; Macaskie, L E

1997-03-01

Anaerobic, but not aerobic, cultures of Escherichia coli accumulated Tc(VII) and reduced it to a black insoluble precipitate. Tc was the predominant element detected when the precipitate was analyzed by proton-induced X-ray emission. Electron microscopy in combination with energy-dispersive X-ray analysis showed that the site of Tc deposition was intracellular. It is proposed that Tc precipitation was a result of enzymatically mediated reduction of Tc(VII) to an insoluble oxide. Formate was an effective electron donor for Tc(VII) reduction which could be replaced by pyruvate, glucose, or glycerol but not by acetate, lactate, succinate, or ethanol. Mutants defective in the synthesis of the transcription factor FNR, in molybdenum cofactor (molybdopterin guanine dinucleotide [MGD]) synthesis, or in formate dehydrogenase H synthesis were all defective in Tc(VII) reduction, implicating a role for the formate hydrogenlyase complex in Tc(VII) reduction. The following observations confirmed that the hydrogenase III (Hyc) component of formate hydrogenlyase in both essential and sufficient for Tc(VII) reduction: (i) dihydrogen could replace formate as an effective electron donor for Tc(VII) reduction by wild-type bacteria and mutants defective in MGD synthesis; (ii) the inability of fnr mutants to reduce Tc(VII) can be suppressed phenotypically by growth with 250 microM Ni2+ and formate; (iii) Tc(VII) reduction is defective in a hyc mutant; (iv) the ability to reduce Tc(VII) was repressed during anaerobic growth in the presence of nitrate, but this repression was counteracted by the addition of formate to the growth medium; (v) H2, but not formate, was an effective electron donor for a Sel- mutant which is unable to incorporate selenocysteine into any of the three known formate dehydrogenases of E. coli. This appears to be the first report of Hyc functioning as an H2-oxidizing hydrogenase or as a dissimilatory metal ion reductase in enteric bacteria.

Boko Haram: A Systemic and Strategic Analysis

DTIC Science & Technology

2016-06-01

21 5 Example Structural System Model …..……………………………….…………21 6 Interconnections ...…………………………………………………….…………23 vii 7...result from exogenous, endogenous, or structural factors. Endogenous factors exist within the geographical bounds of the system state, but exogenous...of the system, the structural factors are a result of the anarchic nature of the international system. Changes in system states reveal long-term

15 CFR 990.55 - Restoration selection-developing restoration plans.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Foreign Trade (Continued) NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE OIL... involvement of the responsible parties in the assessment; and (vii) A description of monitoring for.... (3) The monitoring component to the Draft Restoration Plan should address such factors as duration...

76 FR 66914 - Amendment of Limitation of Duty- and Quota-Free Imports of Apparel Articles Assembled in...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-28

... eligible fabrics, fabric components, or components knit-to-shape. Title VII of the Tax Relief and Health... Clothing (ATC), and the conversion factors for units of measure into square meter equivalents used by the...

10 CFR 431.422 - Prescriptions of a rule.

Code of Federal Regulations, 2010 CFR

2010-01-01

... costs, benefits, burdens, and reliability of alternative approaches to energy savings or production... factors including: The extent to which the State regulation will increase manufacturing or distribution...)(vii) of this section, and shall be available for public review, except for confidential or proprietary...

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

PubMed

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

2015-06-01

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

Overexpression of Grain Amaranth (Amaranthus hypochondriacus) AhERF or AhDOF Transcription Factors in Arabidopsis thaliana Increases Water Deficit- and Salt-Stress Tolerance, Respectively, via Contrasting Stress-Amelioration Mechanisms

PubMed Central

Massange-Sánchez, Julio A.; Palmeros-Suárez, Paola A.; Espitia-Rangel, Eduardo; Rodríguez-Arévalo, Isaac; Sánchez-Segura, Lino; Martínez-Gallardo, Norma A.; Alatorre-Cobos, Fulgencio; Tiessen, Axel; Délano-Frier, John P.

2016-01-01

Two grain amaranth transcription factor (TF) genes were overexpressed in Arabidopsis plants. The first, coding for a group VII ethylene response factor TF (i.e., AhERF-VII) conferred tolerance to water-deficit stress (WS) in transgenic Arabidopsis without affecting vegetative or reproductive growth. A significantly lower water-loss rate in detached leaves coupled to a reduced stomatal opening in leaves of plants subjected to WS was associated with this trait. WS tolerance was also associated with an increased antioxidant enzyme activity and the accumulation of putative stress-related secondary metabolites. However, microarray and GO data did not indicate an obvious correlation between WS tolerance, stomatal closure, and abscisic acid (ABA)-related signaling. This scenario suggested that stomatal closure during WS in these plants involved ABA-independent mechanisms, possibly involving reactive oxygen species (ROS). WS tolerance may have also involved other protective processes, such as those employed for methyl glyoxal detoxification. The second, coding for a class A and cluster I DNA binding with one finger TF (i.e., AhDof-AI) provided salt-stress (SS) tolerance with no evident fitness penalties. The lack of an obvious development-related phenotype contrasted with microarray and GO data showing an enrichment of categories and genes related to developmental processes, particularly flowering. SS tolerance also correlated with increased superoxide dismutase activity but not with augmented stomatal closure. Additionally, microarray and GO data indicated that, contrary to AhERF-VII, SS tolerance conferred by AhDof-AI in Arabidopsis involved ABA-dependent and ABA-independent stress amelioration mechanisms. PMID:27749893

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

PubMed

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

2016-09-01

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

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

PubMed

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

2013-02-01

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

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

PubMed

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

2009-11-01

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

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

PubMed

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

2011-01-01

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

The Politics of Affirmative Action.

ERIC Educational Resources Information Center

Walters, David

1982-01-01

Reviews legislation and labor policies which have discriminated historically against Blacks as a class and explains how Title VII of the Civil Rights Act of 1964 was intended to redress such generalized discrimination. Discusses political and economic factors that jeopardize already insufficient efforts to enforce equal employment opportunities…

Attrition of Hmong Students in Teacher Education Programs.

ERIC Educational Resources Information Center

Root, Steven; Rudawski, Anthony; Taylor, Matthew; Rochon, Ronald

2003-01-01

A descriptive study addressed student attrition in two Title VII Bilingual Education Career Ladder Programs for Hmong paraprofessionals and traditional-age college students working toward teacher certification in Wisconsin. Surveys showed that dropouts were disproportionately male and nontraditional students; factors included financial problems,…

ADVISORY ON UPDATED METHODOLOGY FOR ESTIMATING CANCER RISKS FROM EXPOSURE TO IONIZING RADIATION

EPA Science Inventory

The National Academy of Sciences (NAS) published the Biological Effects of Ionizing Radiation (BEIR) committee's report (BEIR VII) on risks from ionizing radiation exposures in 2006. The Committee analyzed the most recent epidemiology from the important exposed cohorts and factor...

Crew factors in flight operations VII : psychophysiological responses to overnight cargo operations

DOT National Transportation Integrated Search

1996-02-01

To document the psychophysiological effects of flying overnight cargo operations, 41 B-727 crew members (average age 38 yr) were monitored before, during, and after one of two typical 8-day trip patterns. During daytime layovers, the average sleep ep...

48 CFR 13.106-3 - Award and documentation.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) Supporting the award decision if other than price-related factors were considered in selecting the supplier...) Comparison of the proposed price with prices found reasonable on previous purchases; (iii) Current price... being purchased; (vi) Comparison to an independent Government estimate; or (vii) Any other reasonable...

Chronic sleep deprivation markedly reduces coagulation factor VII expression

PubMed Central

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

2010-01-01

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

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

PubMed

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

2006-11-01

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

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

PubMed

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

2004-05-28

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

Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity.

PubMed

Erem, Cihangir

2006-03-01

Various abnormalities of coagulation and fibrinolysis occur in patients with thyroid diseases, and may range from subclinical laboratory abnormalities to clinically significant disorders of coagulation and, rarely, major haemorrhage or thromboembolism. The influence of subclinical hypothyroidism (SHypo) on haemostasis is controversial, both hypercoagulable and hypocoagulable states have been reported. A hypercoagulable state might be a risk factor for thromboembolic disease in SHypo. On the other hand, subclinical hyperthyroidism (SCHyper) is associated with enhanced cardiovascular risk. In the English literature, there are no studies on changes in coagulation and fibriolytic status in subjects with SCHyper. Therefore, the aim of the present study was to investigate the markers of endogenous coagulation and fibrinolysis, and to evaluate the relationships between serum lipid profile and thyroid hormones and these haemostatic parameters in subclinical thyroid patients. Various haemostatic parameters were investigated in 30 patients with SHypo and 20 patients with SCHyper and compared to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these haemostatic parameters were examined. Compared with the control subjects, only FX activity was significantly increased in patients with SCHyper (P < 0.01). Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in patients with SHypo compared with the control group (P < 0.001 and P < 0.01, respectively). TC levels were significantly higher in patients with SCHyper than in controls (P < 0.05). No differences could be found in coagulation/fibrinolysis parameters between subclinical hypothyroid patients and control subjects. In patients with SCHyper, serum TSH level was positively correlated with FX activity (r: 0.58, P < 0.01) and inversely correlated with PAI-1 (r: -0.55. P < 0.05). Serum TG levels were inversely correlated with plasma activities of factors V, VII, VIII, IX, X and vWF (r: -0.83, P < 0.001; r: -0.68, P < 0.05; r: -0.61, P < 0.05; r: -0.77, P < 0.01; r: -0.63, P < 0.05; r: -0.60, P < 0.05, respectively). Serum TC levels were positively correlated with plasma fibrinogen levels (r: 0.72, P < 0.05). Serum HDL-C levels were positively correlated with protein S activity (r: 0.68, P < 0.05) and negatively correlated with F VII activity (r: -0.69, P < 0.05). Also, in patients with SHypo, serum TG levels were positively correlated with serum TSH levels (r: 0.42, P < 0.05), plasma activities of factors V, VII and X (r: 0.42, P < 0.05; r: 0.54, P < 0.01; r: 0.57, P < 0.01, respectively) and negatively correlated with plasma fibrinogen levels (r: -0.41, P < 0.05). Serum TC levels were positively correlated with factors V and X (r: 0.42, P < 0.05; r: 0.58, P < 0.01, respectively) and negatively correlated with t-PA Ag levels (r: -0.44, P < 0.05). Serum HDL-C levels were inversely correlated with F VII activity (r: -0.48, P < 0.05). Some differences were found in the haemostatic parameters and lipid profile between the subclinical thyroid patients and healthy controls. Increased factor X activity in patients with subclinical hyperthyroidism represent a potential hypercoagulable state, which might augment the already existing risk for atheroscleroic complications. Also, subclinical hypothyroid patients exhibit a more atherogenic lipid profile compared with healthy individuals. Therefore, subclinical hypothyroidism is also associated with an increased risk of cardiovascular disease. However, thyroid hormones may play a role at different levels of the complex haemostatic system in subclinical thyroid disease.

The Plant Cysteine Oxidases from Arabidopsis thaliana are kinetically tailored to act as oxygen sensors.

PubMed

White, Mark D; Kamps, Jos J A G; East, Samuel; Taylor Kearney, Leah J; Flashman, Emily

2018-05-30

Group VII Ethylene Response Factors (ERF-VIIs) regulate transcriptional adaptation to flooding-induced hypoxia in plants. ERF-VII stability is controlled in an O 2 -dependent manner by the Cys/Arg branch of the N-end rule pathway, whereby oxidation of a conserved N-terminal cysteine residue initiates target degradation. This oxidation is catalyzed by Plant Cysteine Oxidases (PCOs) which use O 2 as co-substrate to generate Cys-sulfinic acid. The PCOs directly link O2 availability to ERF-VII stability and anaerobic adaptation leading to the suggestion that they act as plant O 2 sensors. However, their ability to respond to fluctuations in O 2 concentration has not been established. Here, we investigated the steady-state kinetics of Arabidopsis thaliana PCOs 1-5 to ascertain whether their activities are sensitive to O 2 levels. We found that the most catalytically competent isoform is AtPCO4, in terms of both responding to O 2 , and oxidizing At RAP2.2 and 2.12, two of the primary hypoxic response activating ERF-VIIs; these data suggest that AtPCO4 plays a central role in ERF-VII regulation. Furthermore, we found that AtPCO activity is susceptible to decreases in pH and that the hypoxia-inducible AtPCOs 1/2 and the non-inducible AtPCOs 4/5 have discrete AtERF-VII substrate preferences. Pertinently, the AtPCOs had K m app (O 2 ) values in a physiologically relevant range, which should enable them to sensitively react to changes in O 2 availability. This work validates an O 2 -sensing role for the PCOs and suggests that differences in expression pattern, ERF-VII selectivity and catalytic capability may enable the different isoforms to have distinct biological functions. Individual PCOs could therefore be targeted to manipulate ERF-VII levels and improve stress tolerance in plants. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Analysis of Expandability and Modifiability of Computer Configuration Concepts for ATC. Volume I. Distributed Concept.

DTIC Science & Technology

1979-11-01

C-9 TRANSITION CONFIGURATION ........................... C-29 i r Fvii LIST OF TABLES Table Page 2.1-1 PARAMETERS DESCRIBING ATC OPERATION - BASELINE...buffer load from each sensor. Medium Storage (Buffer space for data in and out is largest factor .) II P=K +KR Processing. Where R is the number of... factors to the data from the next scan VII Provides support service Operational Role VIII Dependence Requires data from Preliminary Processing and Target

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

PubMed

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

2016-12-01

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

40 CFR 63.1367 - Recordkeeping requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

...), records of consumption, production, and the rolling average values of the HAP and VOC factors. (3) For... Standards for Hazardous Air Pollutants for Pesticide Active Ingredient Production § 63.1367 Recordkeeping...)(i) through (vii) of this section to document that HAP emissions or HAP loadings (for wastewater) are...

Energy levels and radiative rates for transitions in Fe V, Co VI and Ni VII

NASA Astrophysics Data System (ADS)

Aggarwal, K. M.; Bogdanovich, P.; Keenan, F. P.; Kisielius, R.

2017-03-01

Energy levels, Landé g-factors and radiative lifetimes are reported for the lowest 182 levels of the 3d4, 3d34s and 3d34p configurations of Fe V, Co VI and Ni VII. Additionally, radiative rates (A-values) have been calculated for the E1, E2 and M1 transitions among these levels. The calculations have been performed in a quasi-relativistic approach (QR) with a very large configuration interaction (CI) wavefunction expansion, which has been found to be necessary for these ions. Our calculated energies for all ions are in excellent agreement with the available measurements, for most levels. Discrepancies among various calculations for the radiative rates of E1 transitions in Fe V are up to a factor of two for stronger transitions (f ≥ 0.1), and larger (over an order of magnitude) for weaker ones. The reasons for these discrepancies have been discussed and mainly are due to the differing amount of CI and methodologies adopted. However, there are no appreciable discrepancies in similar data for M1 and E2 transitions, or the g-factors for the levels of Fe V, the only ion for which comparisons are feasible.

30 CFR 250.916 - What are the CVA's primary duties during the design phase?

Code of Federal Regulations, 2010 CFR

2010-07-01

...) Stress analyses; (vi) Material designations; (vii) Soil and foundation conditions; (viii) Safety factors... INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Platforms and... pipeline risers, and riser tensioning systems; (ii) Turrets and turret-and-hull interfaces; (iii...

Differential roles of tissue factor and phosphatidylserine in activation of coagulation.

PubMed

Spronk, Henri M H; ten Cate, Hugo; van der Meijden, Paola E J

2014-05-01

It has been suggested that the main physiological trigger of coagulation, tissue factor, possesses limited procoagulant activity and occurs in an inactive or so-called encrypted state. For the conversion of encrypted into decrypted tissue factor with sufficient procoagulant activity, four distinct models have been proposed: 1; dimer formation, 2; lipid rafts, 3; disulfide bonds, and 4; phosphatidylserine exposure. Pro and cons can be given for each of these mechanisms of tissue factor encryption/decryption, however, it seems most likely that two or more mechanisms act together in activating the procoagulant activity. The exposure of phosphatidylserine in the outer layer of cell membranes supports coagulation through enhanced formation of the tenase (factors IXa, VIIIa and X) and prothrombinase (factors Xa, Va and prothrombin) complexes. The proposed role for phosphatidylserine in decryption of tissue factor could contribute to the correct orientation of the tissue factor - factor VII complex. Overall, the contribution of both tissue factor and phosphatidylserine to coagulation seems distinct with tissue factor being the physiological activator and phosphatidylserine the driving force of propagation of coagulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Equid Herpesvirus Type 1 Activates Platelets

PubMed Central

Stokol, Tracy; Yeo, Wee Ming; Burnett, Deborah; DeAngelis, Nicole; Huang, Teng; Osterrieder, Nikolaus; Catalfamo, James

2015-01-01

Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in clinically infected horses and provides a new mechanism by which viruses activate hemostasis. PMID:25905776

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

PubMed

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

2016-01-01

Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an (18)F-labeled derivative of factor VII. Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-(18)F-fluorobenzoate and purified. The corresponding product, (18)F-FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small-animal PET/CT imaging 1, 2, and 4 h after injection. Ex vivo biodistribution was performed after the last imaging session, and tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by enzyme-linked immunosorbent assay and correlated with the uptake of (18)F-FVIIai in the tumors measured in vivo by PET imaging. The PET images showed high uptake of (18)F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of (18)F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7 %ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of (18)F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P < 0.001). The uptake of (18)F-FVIIai measured in vivo by PET imaging correlated (r = 0.72, P < 0.02) with TF protein level measured ex vivo. (18)F-FVIIai is a promising PET tracer for specific and noninvasive imaging of tumor TF expression. The tracer merits further development and clinical translation, with potential to become a companion diagnostics for emerging TF-targeted therapies. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Evaluation of the 235U prompt fission neutron spectrum including a detailed analysis of experimental data and improved model information

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

Neudecker, Denise; Talou, Patrick; Kahler, Albert Comstock III

We present an evaluation of the 235U prompt fission neutron spectrum (PFNS) induced by thermal to 20-MeV neutrons. Experimental data and associated covariances were analyzed in detail. The incident energy dependence of the PFNS was modeled with an extended Los Alamos model combined with the Hauser-Feshbach and the exciton models. These models describe prompt fission, pre-fission compound nucleus and pre-equilibrium neutron emissions. The evaluated PFNS agree well with the experimental data included in this evaluation, preliminary data of the LANL and LLNL Chi-Nu measurement and recent evaluations by Capote et al. and Rising et al. However, they are softer thanmore » the ENDF/B-VII.1 (VII.1) and JENDL-4.0 PFNS for incident neutron energies up to 2 MeV. Simulated effective multiplication factors k eff of the Godiva and Flattop-25 critical assemblies are further from the measured k eff if the current data are used within VII.1 compared to using only VII.1 data. However, if this work is used with ENDF/B-VIII.0β2 data, simulated values of k eff agree well with the measured ones.« less

Evaluation of the 235U prompt fission neutron spectrum including a detailed analysis of experimental data and improved model information

DOE PAGES

Neudecker, Denise; Talou, Patrick; Kahler, Albert Comstock III; ...

2017-09-13

We present an evaluation of the 235U prompt fission neutron spectrum (PFNS) induced by thermal to 20-MeV neutrons. Experimental data and associated covariances were analyzed in detail. The incident energy dependence of the PFNS was modeled with an extended Los Alamos model combined with the Hauser-Feshbach and the exciton models. These models describe prompt fission, pre-fission compound nucleus and pre-equilibrium neutron emissions. The evaluated PFNS agree well with the experimental data included in this evaluation, preliminary data of the LANL and LLNL Chi-Nu measurement and recent evaluations by Capote et al. and Rising et al. However, they are softer thanmore » the ENDF/B-VII.1 (VII.1) and JENDL-4.0 PFNS for incident neutron energies up to 2 MeV. Simulated effective multiplication factors k eff of the Godiva and Flattop-25 critical assemblies are further from the measured k eff if the current data are used within VII.1 compared to using only VII.1 data. However, if this work is used with ENDF/B-VIII.0β2 data, simulated values of k eff agree well with the measured ones.« less

Evaluation of the 235U prompt fission neutron spectrum including a detailed analysis of experimental data and improved model information

NASA Astrophysics Data System (ADS)

Neudecker, Denise; Talou, Patrick; Kahler, Albert C.; White, Morgan C.; Kawano, Toshihiko

2017-09-01

We present an evaluation of the 235U prompt fission neutron spectrum (PFNS) induced by thermal to 20-MeV neutrons. Experimental data and associated covariances were analyzed in detail. The incident energy dependence of the PFNS was modeled with an extended Los Alamos model combined with the Hauser-Feshbach and the exciton models. These models describe prompt fission, pre-fission compound nucleus and pre-equilibrium neutron emissions. The evaluated PFNS agree well with the experimental data included in this evaluation, preliminary data of the LANL and LLNL Chi-Nu measurement and recent evaluations by Capote et al. and Rising et al. However, they are softer than the ENDF/B-VII.1 (VII.1) and JENDL-4.0 PFNS for incident neutron energies up to 2 MeV. Simulated effective multiplication factors keff of the Godiva and Flattop-25 critical assemblies are further from the measured keff if the current data are used within VII.1 compared to using only VII.1 data. However, if this work is used with ENDF/B-VIII.0β2 data, simulated values of keff agree well with the measured ones.

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.

29 CFR 1604.4 - Discrimination against married women.

Code of Federal Regulations, 2014 CFR

2014-07-01

... DISCRIMINATION BECAUSE OF SEX § 1604.4 Discrimination against married women. (a) The Commission has determined... applicable to married men is a discrimination based on sex prohibited by title VII of the Civil Rights Act... married females, for so long as sex is a factor in the application of the rule, such application involves...

Comparison of Employer Factors in Disability and Other Employment Discrimination Charges

ERIC Educational Resources Information Center

Nazarov, Zafar E.; von Schrader, Sarah

2014-01-01

Purpose: We explore whether certain employer characteristics predict Americans with Disabilities Act (ADA) charges and whether the same characteristics predict receipt of the Age Discrimination in Employment Act and Title VII of the Civil Rights Act charges. Method: We estimate a set of multivariate regressions using the ordinary least squares…

Factors Effecting on Study Habits

ERIC Educational Resources Information Center

Khan, Zebun Nisa

2016-01-01

The present study was undertaken with the objectives to find out the impact of Socio-economic Status as well as sex differences on study habits of class VII students (100) of Government Colleges of Amroha District. The effects of two independent variables on study habits of the aforementioned students were assessed by using two Psychological tests…

Federal Programs Supporting Educational Change, Vol. 2: Factors Affecting Change Agent Projects.

ERIC Educational Resources Information Center

Berman, Paul; Pauly, Edward W.

This second volume in the change-agent series reports the interim results of an exploratory statistical analysis of a survey of a nationwide sample of 293 change-agent projects funded by four federal demonstration programs--Elementary Secondary Education Act (ESEA) Title III, Innovative Projects; ESEA Title VII, Bilingual Projects; Vocational…

77 FR 59610 - Flonicamid; Applications To Add New Food Uses on Previously Registered Pesticide Products

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-28

... entities may include, but are not limited to: Crop production (NAICS code 111). Animal production (NAICS... to illustrate your concerns and suggest alternatives. vii. Explain your views as clearly as possible... factors, may have atypical or disproportionately high and adverse human health impacts or environmental...

7 CFR 4290.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Debentures and/or TCs. (iv) Arranging for the production of Offering Circulars, certificates, and such other... to determine those factors that will minimize or reduce the cost of funding Debentures. (iii) Monitor... the Secretary; (vii) Remain custodian of such other documentation as the Secretary shall direct by...

13 CFR 108.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

Code of Federal Regulations, 2010 CFR

2010-01-01

... periodic sales of Debentures and/or TCs. (iv) Arranging for the production of Offering Circulars... financial markets to determine those factors that will minimize or reduce the cost of funding Debentures... SBA; (vii) Remain custodian of such other documentation as SBA shall direct by written instructions...

13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Participating Securities and/or TCs. (iv) Arranging for the production of the Offering Circular, certificates... markets to determine those factors that will minimize or reduce the cost of funding Debentures or... instructions from SBA; (vii) Remain custodian of such other documentation as SBA shall direct by written...

76 FR 12693 - Notice of an Opportunity To Serve on the Innovation Advisory Board Advising the Department of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-08

... experts, and State and local government officials active in technology-based economic development. DATES...) Barriers to competitiveness in newly emerging business or technology sectors, factors influencing... development and evolution of start-ups, firms, and industries. (vii) The effects of domestic and international...

20 CFR 416.929 - How we evaluate symptoms, including pain.

Code of Federal Regulations, 2012 CFR

2012-04-01

...), and (5), and (d). These include statements or reports from you, your treating or nontreating source... expected to produce your symptoms, such as pain. Your symptoms, such as pain, fatigue, shortness of breath..., standing for 15 to 20 minutes every hour, sleeping on a board, etc.); and (vii) Other factors concerning...

20 CFR 416.929 - How we evaluate symptoms, including pain.

Code of Federal Regulations, 2013 CFR

2013-04-01

...), and (5), and (d). These include statements or reports from you, your treating or nontreating source... expected to produce your symptoms, such as pain. Your symptoms, such as pain, fatigue, shortness of breath..., standing for 15 to 20 minutes every hour, sleeping on a board, etc.); and (vii) Other factors concerning...

20 CFR 416.929 - How we evaluate symptoms, including pain.

Code of Federal Regulations, 2014 CFR

2014-04-01

...), and (5), and (d). These include statements or reports from you, your treating or nontreating source... expected to produce your symptoms, such as pain. Your symptoms, such as pain, fatigue, shortness of breath..., standing for 15 to 20 minutes every hour, sleeping on a board, etc.); and (vii) Other factors concerning...

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

PubMed

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

2015-06-01

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

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

PubMed

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

2011-06-01

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

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

PubMed Central

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

2011-01-01

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

Spall behavior of cast iron with varying microstructures

NASA Astrophysics Data System (ADS)

Plume, Gifford; Rousseau, Carl-Ernst

2014-07-01

The spall strength of cast iron with varying microstructures has been investigated using plate impact at moderate speed. Stress history measurements were made with manganin stress gauges embedded between the back face of the specimen and a low impedance polycarbonate backing. Five separate cast irons were tested. Four of these consisted of gray cast iron with graphite in flake form, with three classified as Type VII A2 and the fourth containing a bimodal distribution of Types VII A4 and VII D8. The fifth casting consisted of ductile cast iron with graphite in nodular form, classified as Type I, size class 5. The spall strength for the Type VII A2 gray cast irons varied between 40 and 370 MPa, and that of the additional gray cast iron, between 410 and 490 MPa. The spall strength of the ductile cast iron fell within the range of 0.94-1.2 GPa. It is shown that the spall strength is linked to the damage level at the spall plane, where an increased level of tensile stress is required to generate higher levels of damage. Post mortem analysis was performed on the recovered samples, revealing the graphite phase to be the primary factor governing the spall fracture of cast irons, where crack nucleation is directly correlated to the debonding of graphite from the metal matrix. The average length of graphite found within a casting is linked to the material's strength, where strength increases as a function of decreasing length. The morphology and mean free path of graphite precipitates further govern the subsequent coalescence of initiated cracks to form a complete fracture plane. In cases where graphite spacing is large, increased energy level is required to complete the fracture process. A secondary factor governing the spall fracture of cast irons has also been linked to the microstructure of the metal matrix, with pearlite yielding higher spall strengths than free ferrite.

Silent Circulation of St. Louis Encephalitis Virus Prior to an Encephalitis Outbreak in Cordoba, Argentina (2005)

PubMed Central

Díaz, Luis Adrian; Albrieu Llinás, Guillermo; Vázquez, Ana; Tenorio, Antonio; Contigiani, Marta Silvia

2012-01-01

St. Louis encephalitis virus is a complex zoonoses. In 2005, 47 laboratory-confirmed and probable clinical cases of SLEV infection were reported in Córdoba, Argentina. Although the causes of 2005 outbreak remain unknown, they might be related not only to virological factors, but also to ecological and environmental conditions. We hypothesized that one of the factors for SLE reemergence in Córdoba, Argentina, was the introduction of a new SLEV genotype (SLEV genotype III), with no previous activity in the area. In order to evaluate this hypothesis we carried out a molecular characterization of SLEV detections from mosquitoes collected between 2001 and 2004 in Córdoba city. A total of 315 mosquito pools (11,002 individuals) including 12 mosquitoes species were analyzed. Overall, 20 pools (8 mosquitoes species) were positive for SLEV. During this study, genotypes II, V and VII were detected. No mosquito pool infected with genotype III was detected before the 2005 outbreak. Genotype V was found every year and in the 8 sampled sites. Genotypes II and VII showed limited temporal and spatial activities. We cannot dismiss the association of genotype II and V as etiological agents during the outbreak. However, the silent circulation of other SLEV strains in Córdoba city before the 2005 outbreak suggests that the introduction of genotype III was an important factor associated to this event. Not mutually exclusive, other factors such as changes in avian hosts and mosquitoes vectors communities, driven by climatic and environmental modifications, should also be taken into consideration in further studies. PMID:22303490

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

PubMed

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

2015-01-01

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

Syndromes, disorders and maternal risk factors associated with neural tube defects (VII).

PubMed

Chen, Chih-Ping

2008-09-01

Neural tube defects (NTDs) may be associated with syndromes, disorders and maternal risk factors. This article provides a comprehensive review of the syndromes, disorders and maternal risk factors associated with NTDs, including DK phocomelia syndrome (von Voss-Cherstvoy syndrome), Siegel-Bartlet syndrome, fetal warfarin syndrome, craniotelencephalic dysplasia, Czeizel-Losonci syndrome, maternal cocaine abuse, Weissenbacher- Zweymller syndrome, parietal foramina (cranium bifidum), Apert syndrome, craniomicromelic syndrome, XXagonadism with multiple dysraphic lesions including omphalocele and NTDs, Fryns microphthalmia syndrome, Gershoni-Baruch syndrome, PHAVER syndrome, periconceptional vitamin B6 deficiency, and autosomal dominant Dandy-Walker malformation with occipital cephalocele. NTDs associated with these syndromes, disorders and maternal risk factors are a rare but important cause of NTDs. The recurrence risk and the preventive effect of maternal folic acid intake in NTDs associated with syndromes, disorders and maternal risk factors may be different from those of nonsyndromic multifactorial NTDs. Perinatal diagnosis of NTDs should alert doctors to the syndromes, disorders and maternal risk factors associated with NTDs, and prompt thorough etiologic investigation and genetic counseling.

In Vitro Effect of Activated Recombinant Factor VII (rFVIIa) on Coagulation Properties of Human Blood at Hypothermic Temperatures

DTIC Science & Technology

2007-11-01

purified soy phosphatides in ellagic acid (Actin FS Activated PTT Reagent, Dade Behring, Marburg, Germany) was added to plasma samples in a 1:1 volume...acetylsali- cylic acid or any other nonsteroidal anti-inflammatory drugs for the 7 days before blood sampling. A smooth cubital venipuncture was

76 FR 54493 - Furfuryl Alcohol From China; Institution of a Five-Year Review Concerning the Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-01

... the use, cost, or availability of major inputs into production); and factors related to the ability to... constitutes a major proportion of the total domestic production of the product. In its original determination... products which the Commission conducts under Title VII of the Act, or in internal audits and investigations...

75 FR 23303 - Chlorinated Isocyanurates From China and Spain

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-03

... output of the Domestic Like Product constitutes a major proportion of the total domestic production of... Commission conducts under Title VII of the Act, or in internal audits and investigations relating to the... various factors specified in section 752(a) of the Act (19 U.S.C. 1675a(a)) including the likely volume of...

16 CFR 305.8 - Submission of data.

Code of Federal Regulations, 2010 CFR

2010-01-01

... input voltage and frequency; (vi) Ballast efficacy factor; and (vii) Type (F40T12, F96T12 or F96T12HO..., heat pumps, furnaces, ceiling fans, and pool heaters) for each basic model in current production..., for each basic model in current production: the brand name; the model numbers for each basic model...

College and Adult Reading VII: The Seventh Yearbook of the North Central Reading Association.

ERIC Educational Resources Information Center

Wark, David M., Ed.

Spanning the annual meetings of the North Central Reading Association from 1971 to 1974, this yearbook presents papers dealing with programs and centers, materials and techniques, a new research field, and in honor of Roger S. Pepper. Papers include: "Attitudinal Factors among Marginal Admission Students" (Roger S. Pepper and John A. Drexler,…

77 FR 24436 - Approval and Promulgation of Air Quality Implementation Plans; Wisconsin; Milwaukee-Racine...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-24

.... How did EPA address missing data? V. Proposed Action VI. What is the effect of this action? VII.... ** Indicates incomplete data due to monitor shut down. IV. How did EPA address missing data? Appendix N of 40... in Milwaukee, where there are missing or incomplete data due to monitor shutdown or other factors...

In Vivo Bleeding Time and In Vitro Thrombelastography Measurements are Better Indicators of Dilutional Hypothermic Coagulopathy Than Prothrombin Time

DTIC Science & Technology

2007-06-01

of increased bruising, hematomas, and oozing from the recent surgical sites, or in massive hemorrhage from silent, pre-existing lesions such as peptic ... ulcers . Severe reduction of the vitamin K-dependent coagulation factors II, VII, IX, and X prolongs both PT and aPTT tests. Treatment with sodium

40 CFR 86.117-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2014 CFR

2014-07-01

...), as measured in paragraph (b)(1) of this section. (v) r=FID response factor to methanol. (vi) PB = Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi) MHC, out = mass of...

40 CFR 86.117-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... this section. (v) r=FID response factor to methanol. (vi) PB=Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi) MHC, out=mass of hydrocarbon exiting the enclosure...

40 CFR 86.117-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... this section. (v) r=FID response factor to methanol. (vi) PB=Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi) MHC, out=mass of hydrocarbon exiting the enclosure...

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

PubMed

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

2003-01-01

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

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

ERIC Educational Resources Information Center

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

1930-01-01

At the request of the Association of Land-Grant Colleges and Universities, the Office of Education undertook a survey of the 69 land-grant colleges and universities, including 17 institutions for Negroes. For more than a half century, these institutions have grown in importance as vital factors in the agricultural, industrial, and educational…

Revised Study Design for Final Phase of the Change Agent Study. Study of Change Agent Programs: A Working Note.

ERIC Educational Resources Information Center

Bass, G.; And Others

The Rand change agent study was designed to determine the factors for successful implementation and continuation of selected federal programs--the Elementary and Secondary Education Act, Title III, Innovation Projects; ESEA Title VII, Bilingual Projects; Vocational Education Part D, Exemplary Programs; and the Right-to-Read program. This report…

Some Thoughts on the Equal Pay Act and Coaching Salaries.

ERIC Educational Resources Information Center

Boring, Phyllis

This paper discusses the Equal Pay Act, Title VII of the Civil Rights Act of 1964, as it applies to women athletic coaches and physical education teachers. The following points are considered: (1) application of the Equal Pay Act; (2) advantage of voluntary compliance with the Equal Pay Act; (3) factors used to measure "equal work"; (4)…

7 CFR 999.300 - Regulation governing importation of raisins.

Code of Federal Regulations, 2010 CFR

2010-01-01

... meet the U.S. Grade C tolerances for those factors; (2) With respect to Muscat raisins—the requirements... under section 8e of the AMA Act of 1937”; and (vii) If the lot fails to meet the import requirements, a...) of this section for use in the production of alcohol, syrup for industrial use, or which does not...

40 CFR 86.1217-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... volume ft3 (m3), as measured in paragraph (b)(1) of this section. (v) r=FID response factor to methanol. (vi) PB=Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi...

40 CFR 86.1217-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... volume ft3 (m3), as measured in paragraph (b)(1) of this section. (v) r=FID response factor to methanol. (vi) PB=Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi...

Racial and Ethnic Tensions in American Communities: Poverty, Inequality, and Discrimination. Volume VII: The Mississippi Delta Report.

ERIC Educational Resources Information Center

Commission on Civil Rights, Washington, DC.

This report examines underlying causes of racial and ethnic tensions in the Mississippi Delta. It is based on sworn testimony from a public hearing, subpoenaed documents received by the U.S. Commission on Civil Rights, and legal research. Data are provided on: equality of economic opportunity (racial factors and economic opportunity, agriculture,…

Evaluation of thrombogenicity of beta-propiolactone/ultraviolet (beta-PL/UV) treated PPSB in chimpanzees

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

Kotitschke, R.; Stephan, W.; Prince, A.M.

1983-05-01

The thrombogenicity of beta-PL/UV-treated PPSB (factor IX concentrate) was evaluated in chimpanzees. PPSB isolated from beta-propiolactone-treated and UV-irradiated plasma was injected into chimpanzees at a dose of approximately 100 units/kg body weight. An FDA licensed PPSB preparation served as the negative control, and a preparation containing activated as well as precursor clotting factors served as the positive control. 15 minutes, 1 h, 4 h, and 24 h after the PPSB application the following parameters were determined in the chimpanzee blood: factors II, VII, IX, X, VIII, fibrinogen, AT III, thrombin coagulase, Quick value, APTT and platelet count. Neither the untreatedmore » control preparation, nor the PPSB isolated from beta-propiolactone-treated and UV-irradiated plasma, showed signs of thrombogenicity in the chimpanzee model. The positive control indicated that the chimpanzee is a suitable model for the thrombogenicity testing of activated clotting factors.« less

Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis

PubMed Central

Altman, Raul; Scazziota, Alejandra Silvia; Herrera, Maria de Lourdes; Gonzalez, Claudio

2006-01-01

Background Platelet activation is crucial in normal hemostasis. Using a clotting system free of external tissue factor, we investigated whether activated Factor VII in combination with platelet agonists increased thrombin generation (TG) in vitro. Methods and results TG was quantified by time parameters: lag time (LT) and time to peak (TTP), and by amount of TG: peak of TG (PTG) and area under thrombin formation curve after 35 minutes (AUC→35min) in plasma from 29 healthy volunteers using the calibrated automated thrombography (CAT) technique. TG parameters were measured at basal conditions and after platelet stimulation by sodium arachidonate (AA), ADP, and collagen (Col). In addition, the effects of recombinant activated FVII (rFVIIa) alone or combined with the other platelet agonists on TG parameters were investigated. We found that LT and TTP were significantly decreased (p < 0.05) and PTG and AUC→35min were significantly increased (p < 0.05) in platelet rich plasma activated with AA, ADP, Col, and rFVIIa compared to non-activated platelet rich plasma from normal subjects (p = 0.01). Furthermore platelet rich plasma activated by the combined effects of rFVIIa plus AA, ADP or Col had significantly reduced LT and TTP and increased AUC→35min (but not PTG) when compared to platelet rich plasma activated with agonists in the absence of rFVIIa. Conclusion Platelets activated by AA, ADP, Col or rFVIIa triggered TG. This effect was increased by combining rFVIIa with other agonists. Our intrinsic coagulation system produced a burst in TG independent of external tissue factor activity an apparent hemostatic effect with little thrombotic capacity. Thus we suggest a modification in the cell-based model of hemostasis. PMID:16630353

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

PubMed

Hawryluk, Gregory W J; Cusimano, Michael D

2006-12-01

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

Large enhancement of functional activity of active site-inhibited factor VIIa due to protein dimerization: insights into mechanism of assembly/disassembly from tissue factor.

PubMed

Stone, Matthew D; Harvey, Stephen B; Martinez, Michael B; Bach, Ronald R; Nelsestuen, Gary L

2005-04-26

Active site-inhibited blood clotting factor VIIa (fVIIai) binds to tissue factor (TF), a cell surface receptor that is exposed upon injury and initiates the blood clotting cascade. FVIIai blocks binding of the corresponding enzyme (fVIIa) or zymogen (fVII) forms of factor VII and inhibits coagulation. Although several studies have suggested that fVIIai may have superior anticoagulation effects in vivo, a challenge for use of fVIIai is cost of production. This study reports the properties of dimeric forms of fVIIai that are cross-linked through their active sites. Dimeric wild-type fVIIai was at least 75-fold more effective than monomeric fVIIai in blocking fVIIa association with TF. The dimer of a mutant fVIIai with higher membrane affinity was 1600-fold more effective. Anticoagulation by any form of fVIIai differed substantially from agents such as heparin and showed a delayed mode of action. Coagulation proceeded normally for the first minutes, and inhibition increased as equilibrium binding was established. It is suggested that association of fVIIa(i) with TF in a collision-dependent reaction gives equal access of inhibitor and enzyme to TF. Assembly was not influenced by the higher affinity and slower dissociation of the dimer. As a result, anticoagulation was delayed until the reaction reached equilibrium. Properties of different dissociation experiments suggested that dissociation of fVIIai from TF occurred by a two-step mechanism. The first step was separation of TF-fVIIa(i) while both proteins remained bound to the membrane, and the second step was dissociation of the fVIIa(i) from the membrane. These results suggest novel actions of fVIIai that distinguish it from most of the anticoagulants that block later steps of the coagulation cascade.

Anticoagulatory and antiinflammatory effects of astaxanthin in diabetic rats.

PubMed

Chan, Kung-Chi; Pen, Pei-Jain; Yin, Mei-Chin

2012-02-01

Astaxanthin at 0.01 or 0.05% of the diet was supplied to diabetic rats for 12 wk. Astaxanthin intake significantly increased its deposit in plasma, and retained glutathione content, reduced the production of reactive oxygen species, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in blood and kidney of diabetic rats (P < 0.05). Astaxanthin treatments also significantly decreased plasma levels of C-reactive protein and von Willebrand factor in diabetic rats (P < 0.05). Astaxanthin intake at 0.05% significantly diminished plasminogen activator inhibitor-1 and factor VII activities, enhanced antithrombin-III and protein C activities in circulation (P < 0.05). These results support that astaxanthin could attenuate diabetes associated coagulatory, oxidative, and inflammatory stress. © 2012 Institute of Food Technologists®

Analysis of the functional consequences of targeted exon deletion in COL7A1 reveals prospects for dystrophic epidermolysis bullosa therapy

PubMed Central

Bornert, Olivier; Kühl, Tobias; Bremer, Jeroen; van den Akker, Peter C; Pasmooij, Anna MG; Nyström, Alexander

2016-01-01

Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB)—a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therapeutic potential of this approach is critically dependent on gene, protein, and disease intrinsic factors. Naturally occurring exon skipping in COL7A1, translating collagen VII, suggests that skipping of exons containing disease-causing mutations may be feasible for the treatment of DEB. However, despite a primarily in-frame arrangement of exons in the COL7A1 gene, no general conclusion of the aptitude of exon skipping for DEB can be drawn, since regulation of collagen VII functionality is complex involving folding, intra- and intermolecular interactions. To directly address this, we deleted two conceptually important exons located at both ends of COL7A1, exon 13, containing recurrent mutations, and exon 105, predicted to impact folding. The resulting recombinantly expressed proteins showed conserved functionality in biochemical and in vitro assays. Injected into DEB mice, the proteins promoted skin stability. By demonstrating functionality of internally deleted collagen VII variants, our study provides support of targeted exon deletion or skipping as a potential therapy to treat a large number of individuals with DEB. PMID:27157667

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

PubMed

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

2018-05-24

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

Uterine atony: definition, prevention, nonsurgical management, and uterine tamponade.

PubMed

Breathnach, Fionnuala; Geary, Michael

2009-04-01

Uterine atony, or failure of the uterus to contract following delivery, is the most common cause of postpartum hemorrhage. This review serves to examine the prevention and treatment of uterine atony, including risk-factor recognition and active management of the third stage of labor. A range of uterotonic agents will be compared for efficacy, safety, and ease of administration. Oxytocin and ergot alkaloids represent the cornerstone of uterotonic therapy, while prostaglandin therapy has been studied more recently as an attractive alternative, particularly for resource-poor settings. Newer supplementary medical therapies, such as recombinant factor VII and hemostatic agents, and adjunctive nonsurgical methods aimed at achieving uterine tamponade will be evaluated.

Postprandial changes in platelet function and coagulation factors after high-fat meals with different fatty acid compositions.

PubMed

Freese, R; Mutanen, M

1995-09-01

To compare the postprandial effects of three oils differing in their fatty acid composition on platelet aggregation and coagulation. The oils studied were low-erucic acid rapeseed oil (RO, oleic acid 54% of fatty acids), sunflower oil (SO, linoleic acid 64% of fatty acids) and butter oil (BO, saturated fatty acids 62% of fatty acids). The postprandial effects of three fat-loads were followed for 5 h. Division of Nutrition, University of Helsinki. Twelve healthy female subjects (aged 23-38 years) were recruited among university students and employees. Postprandial lipaemia was induced by high-fat meals containing fat (RO, SO or BO) 1 g/kg of body weight, skim-milk powder, sugar, strawberries, and water. Each subject ingested each meal in three separate mornings after an overnight fast. The order of the meals was randomised. Blood samples were taken before and 1, 2.5, and 5 h after the test meal. All three test meals similarly affected platelet aggregation in platelet-rich plasma. Aggregation induced by collagen (0.6, 1 and 2.5 micrograms/ml) decreased during the 5-h period after the meals (P = 0.000). ADP-induced aggregation did not change during the follow-up period after any meal (P = 0.105-0.483). All fat loads increased factor VII coagulant activity (F VII:C) (P = 0.000), but in plasma fibrinogen concentration (P = 0.155) or antithrombin III activity (P = 0.278) no postprandial changes were found. These results show that high-fat meals have acute effects on platelet function and F VII:C in healthy women and that these effects are not mediated through the fatty acid composition of the meals.

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

PubMed

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

2017-03-01

Essentials Differences in sensitivity to factor VII (FVII) have been suggested between thromboplastins. FVII-induced International Normalized Ratio (INR) changes differ between commercial reagents. Recombinant human thromboplastins are more sensitive to FVII than tissue-extract thromboplastins. Thromboplastin choice may affect FVII-mediated INR stability. Background Differences regarding sensitivity to factor VII have been suggested for recombinant human and tissue-extract thromboplastins used for International Normalized Ratio (INR) measurement, but the evidence is scarce. Differences in FVII sensitivity are clinically relevant, as they can affect INR stability during treatment with vitamin K antagonists (VKAs). Objectives To determine whether commercial thromboplastins react differently to changes in FVII. Methods We studied the effect of addition of FVII on the INR in plasma by using three tissue-extract (Neoplastin C1+, Hepato Quick, and Thromborel S) and three recombinant human (Recombiplastin 2G, Innovin, and CoaguChek XS) thromboplastins. Three different concentrations of purified human FVII (0.006, 0.012 and 0.062 μg mL -1 plasma), or buffer, were added to five certified pooled plasmas of patients using VKAs (INR of 1.5-3.5). Changes in FVII activity were measured with two bioassays (Neoplastin and Recombiplastin), and relative INR changes were compared between reagents. Results After addition of 0.062 μg mL -1 FVII, FVII activity in the pooled plasmas increased by approximately 20% (Neoplastin) or 32% (Recombiplastin) relative to the activity in pooled normal plasma. All thromboplastins showed dose-dependent INR decreases. The relative INR change in the pooled plasmas significantly differed between the six thromboplastins. No differences were observed among recombinant or tissue-extract thromboplastins. Pooled results indicated that the FVII-induced INR change was greater for recombinant than for tissue-extract thromboplastins. Conclusions Differences regarding FVII sensitivity exist between various thromboplastins used for VKA monitoring. Recombinant human thromboplastins are more sensitive to FVII than tissue-extract thromboplastins. Therefore, thromboplastin choice may affect FVII-mediated INR stability. © 2017 International Society on Thrombosis and Haemostasis.

Can Genetic Analysis of Putative Blood Alzheimer’s Disease Biomarkers Lead to Identification of Susceptibility Loci?

PubMed Central

Huebinger, Ryan M.; Shewale, Shantanu J.; Koenig, Jessica L.; Mitchel, Jeffrey S.; O’Bryant, Sid E.; Waring, Stephen C.; Diaz-Arrastia, Ramon; Chasse, Scott

2015-01-01

Although 24 Alzheimer’s disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10-7. Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated. PMID:26625115

Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

PubMed

Barber, Robert C; Phillips, Nicole R; Tilson, Jeffrey L; Huebinger, Ryan M; Shewale, Shantanu J; Koenig, Jessica L; Mitchel, Jeffrey S; O'Bryant, Sid E; Waring, Stephen C; Diaz-Arrastia, Ramon; Chasse, Scott; Wilhelmsen, Kirk C

2015-01-01

Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

Biological and analytical variations of 16 parameters related to coagulation screening tests and the activity of coagulation factors.

PubMed

Chen, Qian; Shou, Weiling; Wu, Wei; Guo, Ye; Zhang, Yujuan; Huang, Chunmei; Cui, Wei

2015-04-01

To accurately estimate longitudinal changes in individuals, it is important to take into consideration the biological variability of the measurement. The few studies available on the biological variations of coagulation parameters are mostly outdated. We confirmed the published results using modern, fully automated methods. Furthermore, we added data for additional coagulation parameters. At 8:00 am, 12:00 pm, and 4:00 pm on days 1, 3, and 5, venous blood was collected from 31 healthy volunteers. A total of 16 parameters related to coagulation screening tests as well as the activity of coagulation factors were analyzed; these included prothrombin time, fibrinogen (Fbg), activated partial thromboplastin time, thrombin time, international normalized ratio, prothrombin time activity, activated partial thromboplastin time ratio, fibrin(-ogen) degradation products, as well as the activity of factor II, factor V, factor VII, factor VIII, factor IX, and factor X. All intraindividual coefficients of variation (CVI) values for the parameters of the screening tests (except Fbg) were less than 5%. Conversely, the CVI values for the activity of coagulation factors were all greater than 5%. In addition, we calculated the reference change value to determine whether a significant difference exists between two test results from the same individual. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

PubMed Central

Perozo, Francisco; Marcano, Rosmar

2012-01-01

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

17 CFR 240.17i-2 - Notice of intention to be supervised by the Commission as a supervised investment bank holding...

Code of Federal Regulations, 2011 CFR

2011-04-01

... correlations across risk factors, a description of the process used to measure those correlations; (D) A... risk, credit risk, and operational risk made in accordance with § 240.17i-7(a)-(d); (vi) A list of the... and credit risk on those categories of positions pursuant to § 240.17i-7(b) and (c); (vii) A...

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

PubMed

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

2013-02-01

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

Outcome of laparoscopic ovariohysterectomy or ovariectomy in dogs with von Willebrand disease or factor VII deficiency: 20 cases (2012-2014).

PubMed

Keeshen, Thomas P; Case, J Brad; Runge, Jeffrey J; Singh, Ameet; Mayhew, Philipp D; Steffey, Michele A; Culp, William T N

2017-11-01

OBJECTIVE To describe surgical techniques and perioperative management of dogs with von Willebrand disease (VWD) or factor VII (FVII) deficiency undergoing laparoscopic ovariohysterectomy or ovariectomy and evaluate outcomes. DESIGN Retrospective case series. ANIMALS 20 client-owned dogs with VWD (n = 16) or FVII deficiency (4). PROCEDURES Dogs with VWD or FVII deficiency that underwent laparoscopic ovariohysterectomy or ovariectomy between 2012 and 2014 were retrospectively identified via a multi-institutional review of medical records. RESULTS Median expression of von Willebrand factor was 19% (interquartile range, 18% to 30%). All 16 dogs with VWD were Doberman Pinschers, and all were pretreated with desmopressin; 4 also received cryoprecipitate. One of 4 dogs with FVII deficiency received plasma preoperatively, and 1 was treated with desmopressin; 2 dogs received no preoperative treatment. Laparoscopic ovariectomy was performed in 9 dogs with VWD and 2 dogs with FVII deficiency, laparoscopic ovariectomy with gastropexy was performed in 6 dogs with VWD and 1 dog with FVII deficiency, and laparoscopic-assisted ovariohysterectomy was performed in 1 dog with VWD and 1 dog with FVII deficiency. Iatrogenic splenic laceration requiring conversion to laparotomy occurred during trocar insertion in 1 dog with VWD. No postoperative complications, including signs of hemorrhage, were reported for any dogs. CONCLUSIONS AND CLINICAL RELEVANCE Laparoscopic ovariohysterectomy or ovariectomy in dogs with VWD or FVII deficiency pretreated with desmopressin, cryoprecipitate, or plasma transfusions were not associated with clinical signs of hemorrhage, suggesting that minimally invasive ovariohysterectomy or ovariectomy may be considered in female dogs affected with these coagulopathies.

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

PubMed

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

2017-11-01

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

Factor VII deficiency: Unveiling the cellular and molecular mechanisms underlying three model alterations of the enzyme catalytic domain.

PubMed

Chollet, Maria Eugenia; Andersen, Elisabeth; Skarpen, Ellen; Myklebust, Christiane F; Koehler, Christian; Morth, Jens Preben; Chuansumrit, Ampaiwan; Pinotti, Mirko; Bernardi, Francesco; Thiede, Bernd; Sandset, Per Morten; Skretting, Grethe

2018-03-01

Activated factor (F) VII is a vitamin K-dependent glycoprotein that initiates blood coagulation upon interaction with tissue factor. FVII deficiency is the most common of the rare congenital bleeding disorders. While the mutational pattern has been extensively characterized, the pathogenic molecular mechanisms of mutations, particularly at the intracellular level, have been poorly defined. Here, we aimed at elucidating the mechanisms underlying altered FVII biosynthesis in the presence of three mutation types in the catalytic domain: a missense change, a microdeletion and a frameshift/elongation, associated with severe or moderate to severe phenotypes. Using CHO-K1 cells transiently transfected with expression vectors containing the wild-type FVII cDNA (FVIIwt) or harboring the p.I289del, p.G420V or p.A354V-p.P464Hfs mutations, we found that the secretion of the FVII mutants was severely decreased compared to FVIIwt. The synthesis rate of the mutants was slower than the FVIIwt and delayed, and no degradation of the FVII mutants by proteasomes, lysosomes or cysteine proteases was observed. Confocal immunofluorescence microscopy studies showed that FVII variants were localized into the endoplasmic reticulum (ER) but were not detectable within the Golgi apparatus. These findings suggested that a common pathogenic mechanism, possibly a defective folding of the mutant proteins, was triggered by the FVII mutations. The misfolded state led to impaired trafficking of these proteins causing ER retention, which would explain the low to very low FVII plasma levels observed in patients carrying these mutations. Copyright © 2017 Elsevier B.V. All rights reserved.

Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes

PubMed Central

Mathison, Angela; Escande, Carlos; Calvo, Ezequiel; Seo, Seungmae; White, Thomas; Salmonson, Ann; Faubion, William A.; Buttar, Navtej; Iovanna, Juan; Lomberk, Gwen; Chini, Eduardo N.

2015-01-01

We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the −331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11−/− mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11−/− mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11−/− phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator-activated receptor-γ. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11−/− mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes. PMID:26248217

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

Oral and parenteral anticoagulants: new kids on the block.

PubMed

Aditya, S

2012-01-01

Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "'antithrombins." Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.

Model of a ternary complex between activated factor VII, tissue factor and factor IX.

PubMed

Chen, Shu-wen W; Pellequer, Jean-Luc; Schved, Jean-François; Giansily-Blaizot, Muriel

2002-07-01

Upon binding to tissue factor, FVIIa triggers coagulation by activating vitamin K-dependent zymogens, factor IX (FIX) and factor X (FX). To understand recognition mechanisms in the initiation step of the coagulation cascade, we present a three-dimensional model of the ternary complex between FVIIa:TF:FIX. This model was built using a full-space search algorithm in combination with computational graphics. With the known crystallographic complex FVIIa:TF kept fixed, the FIX docking was performed first with FIX Gla-EGF1 domains, followed by the FIX protease/EGF2 domains. Because the FIXa crystal structure lacks electron density for the Gla domain, we constructed a chimeric FIX molecule that contains the Gla-EGF1 domains of FVIIa and the EGF2-protease domains of FIXa. The FVIIa:TF:FIX complex has been extensively challenged against experimental data including site-directed mutagenesis, inhibitory peptide data, haemophilia B database mutations, inhibitor antibodies and a novel exosite binding inhibitor peptide. This FVIIa:TF:FIX complex provides a powerful tool to study the regulation of FVIIa production and presents new avenues for developing therapeutic inhibitory compounds of FVIIa:TF:substrate complex.

Autotransfusion from experimental hemothorax: levels of coagulation factors.

PubMed

Napoli, V M; Symbas, P J; Vroon, D H; Symbas, P N

1987-03-01

The coagulation system was investigated in five dogs undergoing autotransfusion from experimental hemothorax. One fourth of the blood volume was bled into the pleural space, drained, and autotransfused. The hemothorax blood showed: very prolonged PT and PTT; very low platelets and fibrinogen; midly elevated FDP; very low coagulation factors VIII, and V; reduced XII, prothrombin, X, XI, and VII. Partial clotting, mild fibrinolysis, and fibrin deposition over the pulmonary pleura seemed to cause incoagulability of hemothorax blood. Post autotransfusion arterial blood showed: normal PT and PTT; 25% decrease in platelets, and 31% decrease in fibrinogen from baseline values. There was also an overall 20% reduction of fibrinogen from baseline values. There was also an overall 20% reduction of all clotting factors, but their levels remained above 50% activity. It was concluded that autotransfusion from a hemothorax of 25% the blood volume in dogs causes a mild loss of hemostatic components, but does not significantly compromise the clotting mechanism.

Myelofibrosis and acquired hemophilia A: a case report.

PubMed

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

2016-05-07

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

Protein A sepharose immunoadsorption: immunological and haemostatic effects in two cases of acquired haemophilia.

PubMed

Guillet, B; Kriaa, F; Huysse, M G; Proulle, V; George, C; Tchernia, G; D'Oiron, R; Laurian, Y; Charpentier, B; Lambert, T; Dreyfus, M

2001-09-01

Acquired haemophilia is a life-threatening disorder caused by circulating auto-antibodies that inhibit factor VIII coagulant activity (FBIII:C). Immunoadsorption on protein A sepharose (IA-PA) was performed in two bleeding patients with acquired haemophilia: we observed a dramatic and quick decrease in the anti-FVIII:C inhibitor titre leading to a normal, albeit transient, haemostatic status. In one case, IA-PA was the only procedure which succeeded in stopping massive haemorrhage. In the second case, IA-PA reinforced the haemostatic effect of recombinant activated factor VII by increasing the endogenous plasma factor VIII level. The efficacy of IA-PA was sustained with immunosuppressive treatment introduced, respectively, 10 and 15 d before the IA-PA procedures. Our experience with IA-PA suggests that this extracorporeal anti-FVIII:C removal procedure is a valuable therapeutic tool for acquired haemophilia and can alleviate life-threatening haemorrhages.

[Hemorrhage, hemostasis and thrombosis in surgery].

PubMed

Páramo, José A

2009-06-01

Surgery is a leading cause of major hemorrhage as well as of thrombosis unless patients are administered appropriate antithrombotic prophylaxis after their thrombo-hemorrhagic risk has been stratified. Therefore, thorough preoperative evaluation is essential to minimize surgical complications. In cases of incoercible bleeding, drugs such as desmopressin, synthetic antifibrinolytics or recombinant factor VII can be administered. To prevent postoperative thrombosis, low molecular weight heparins or pentasaccharide have been shown to significantly reduce the incidence of thromboembolism.

SupportNet for Frontline Behavioral Health Providers

DTIC Science & Technology

2013-07-01

hired. (Objective 3) d) We have facilitated six, on -site Focus Group meetings at Fort Carson. (Objective 3) (Appendix VII) e) We have reviewed the...Based on these results, the final model with factor loadings and the covariance constrained to be equal across both groups (Model 6; Table 3) was...and 2.17 hours of group clinical supervision per month. On average, they were receiving peer support by discussing the patients with colleagues on

Single Crystal Diffractometry

NASA Astrophysics Data System (ADS)

Arndt, U. W.; Willis, B. T. M.

2009-06-01

Preface; Acknowledgements; Part I. Introduction; Part II. Diffraction Geometry; Part III. The Design of Diffractometers; Part IV. Detectors; Part V. Electronic Circuits; Part VI. The Production of the Primary Beam (X-rays); Part VII. The Production of the Primary Beam (Neutrons); Part VIII. The Background; Part IX. Systematic Errors in Measuring Relative Integrated Intensities; Part X. Procedure for Measuring Integrated Intensities; Part XI. Derivation and Accuracy of Structure Factors; Part XII. Computer Programs and On-line Control; Appendix; References; Index.

Air-to-Air Target Acquisition: Factors and Means of Improvement.

DTIC Science & Technology

1980-03-01

and an atmospheric modelo B t - Bb VISTARAQ C - b derived from input quantities and an B atmospheric model Bt Bb RAE/BAC C B derived from input...seair ’ h task in a !static, fielId. I" Osi c r r, I’lut ion is, dependi- ent upon the angle of’ t hr vi:i x is, -ft wh iih -wilil1y is measured and th

Management of Coagulopathy in the Patients With Multiple Injuries: Results From an International Survey of Clinical Practice

DTIC Science & Technology

2008-10-01

Fresh whole blood D Not available D Trigger: D Treatment protocol: Comment: Adjuvant therapy D Aprotinin D Tranexamic acid D Desmopressin D Ca...that were mentioned included prothrombin complex concentrate (PCC), activated recombinant factor VII (rFVIIa), aprotinin, and tranexamic acid (Fig. 2...of respondents, followed by Ca (53%) and vitamin K (38%), and to a lesser extent tranexamic acid (28%), aprotinin (26%), desmopressin (24%), and

Observation of Solar Wind Charge Exchange Emission From Exospheric Material in and Outside Earth's Magnetosheath 2008 September 25

NASA Technical Reports Server (NTRS)

Snowden, S. L.; Collier, M. R.; Cravens, T.; Kuntz, K. D.; Lepri, S. T.; Robertson, I.; Tomas, L.

2009-01-01

A long XMM-Newton exposure is used to observe solar wind charge exchange (SWCX) emission from exospheric material in and outside Earth's magnetosheath. The light curve of the O vii (0.5-0.62 keV) band is compared with a model for the expected emission, and while the emission is faint and the light curve has considerable scatter, the correlation is significant to better than 99.9%. This result demonstrates the validity of the geocoronal SWCX emission model for predicting a contribution to astrophysical observations to a scale factor of order unity (1.5). In addition, an average value of the SWCX O vii emission from the magnetosheath over the observation of 2.6 +/- 0.5 LU is derived. The results also demonstrate the potential utility of using X-ray observations to study global phenomena of the magnetosheath which currently are only investigated using in situ measurements.

Multicomutation flow system for manganese speciation by solid phase extraction and flame atomic absorption spectrometry

NASA Astrophysics Data System (ADS)

Tobiasz, Anna; Sołtys, Monika; Kurys, Ewa; Domagała, Karolina; Dudek-Adamska, Danuta; Walas, Stanisław

2017-08-01

In the paper an application of solid phase extraction technique for speciation analysis of manganese in water samples with the use of flame atomic absorption spectrometry is presented. Two types of sorbents, activated silica gel and Dowex 1 × 4, were used respectively for simultaneously Mn2 + and MnO42 - retention and preconcentration. The whole procedure was realized in multicomutation flow system. Different conditions like: type and concentration of eluent, sample pH and loading time were tested during the study. Under appropriate conditions, it was possible to obtained enrichment factors of 20 and 16 for Mn(II) and Mn(VII), respectively. Precision of the procedure was close to 4% (measured as relative standard deviation), whereas the detection limit (3σ) was 1.4 μg·L- 1 for Mn(II) and 4.8 μg·L- 1 for Mn(VII).

A search for the millimetre lines of HCN in Comets Wilson 1987 VII and Machholz 1988 XV

NASA Astrophysics Data System (ADS)

Crouvisier, J.; Despois, D.; Bockelee-Morvan, D.; Gerard, E.; Paubert, G.; Johansson, L. E. B.; Ekelund, L.; Winnberg, A.; Ge, W.; Irvine, W. M.; Kinzel, W. M.; Schloerb, F. P.

1990-08-01

The J(1-0) lines of HCN at 89 GHz were searched for in Comet Wilson 1987 VII, with the FCRAO, the SEST and the IRAM radio telescopes between February and June 1987. There was no firm detection, but significant upper limits were obtained, which put severe constraints on the HCN production rate in that comet. A direct comparison with the observations of P/Halley suggests that the HCN abundance relative to water might be smaller in Comet Wilson by at least a factor of two. The J(1-0) and J(3-2) lines of HCN at 89 and 266 GHz were searched for in Comet Machholz 1988 XV when it was close to perihelion at 0.17 AU from the sun. There was no detection. At that moment, the comet was probably no longer active.

A Joint Model for Vitamin K-Dependent Clotting Factors and Anticoagulation Proteins.

PubMed

Ooi, Qing Xi; Wright, Daniel F B; Tait, R Campbell; Isbister, Geoffrey K; Duffull, Stephen B

2017-12-01

Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation. Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis. Nine blood samples were collected from each subject at baseline, and at 1-5, 8, 15 and 29 days after warfarin initiation and assayed for factors II, VII, IX and X, and proteins C and S. Warfarin concentration-time data were not available. The coagulation proteins data were modelled in a stepwise manner using NONMEM ® Version 7.2. In the first stage, each of the coagulation proteins was modelled independently using a kinetic-pharmacodynamic model. In the subsequent step, the six kinetic-pharmacodynamic models were combined into a single joint model. One patient was administered VK and was excluded from the analysis. Each kinetic-pharmacodynamic model consisted of two parts: (1) a common one-compartment pharmacokinetic model with first-order absorption and elimination for warfarin; and (2) an inhibitory E max model linked to a turnover model for coagulation proteins. In the joint model, an unexpected pharmacodynamic lag was identified and the estimated degradation half-life of VK-dependent coagulation proteins were in agreement with previously published values. The model provided an adequate fit to the observed data. The joint model represents the first work to quantify the influence of warfarin on all six VK-dependent coagulation proteins simultaneously. Future work will expand the model to predict the influence of exogenously administered VK on the time course of clotting factor concentrations after warfarin overdose and during perioperative warfarin reversal procedures.

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

PubMed

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

2015-05-01

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

Hemoglobin enhances tissue factor expression on human malignant cells.

PubMed

Siddiqui, F A; Amirkhosravi, A; Amaya, M; Meyer, T; Biggerstaff, J; Desai, H; Francis, J L

2001-04-01

Tissue Factor (TF) is a transmembrane glycoprotein that complexes with factor VII/activated factor VII to initiate blood coagulation. TF may be expressed on the surface of various cells including monocytes and endothelial cells. Over-expression of TF in human tumor cell lines promotes metastasis. We recently showed that hemoglobin (Hb) forms a specific complex with TF purified from human malignant melanoma cells and enhances its procoagulant activity (PCA). To further study this interaction, we examined the effect of Hb on the expression of TF on human malignant (TF+) cells and KG1 myeloid leukemia (TF-) cells. Human melanoma A375 and J82 bladder carcinoma cells, which express TF at moderate and relatively high levels, respectively, were incubated with varying concentrations (0-1.5 mg/ml) of Hb. After washing, cells were analyzed for Hb binding and TF expression using flow cytometry and confocal microscopy. Hb bound to the cells in a concentration-dependent manner, and increased both TF expression and PCA. The human A375 malignant melanoma cells incubated with Hb (1 mg/ml) expressed up to six times more TF antigen than cells without Hb. This increase in TF expression and PCA of intact cells incubated with Hb was significantly inhibited by cycloheximide at a concentration of 10 microg/ml (P < 0.01). An increase in total cellular TF antigen content was demonstrated by specific immunoassay. In contrast, Hb (5 mg/ml) did not induce TF expression and PCA on KG1 cells as determined by flow cytometry and TF (FXAA) activity. We conclude that Hb specifically binds to TF-bearing malignant cells and increases their PCA. This effect seems to be at least partly due to de novo synthesis of TF and increased surface expression. However, the exact mechanism by which Hb binds and upregulates TF expression remains to be determined.

Characterisation of clotting factors, anticoagulant protein activities and viscoelastic analysis in healthy donkeys.

PubMed

Perez-Ecija, A; Mendoza, F J

2017-11-01

Studies have demonstrated differences in commonly measured haemostatic parameters between donkeys and horses. Whether clotting factors, anticoagulant protein activities and thromboelastography parameters also differ between species is still unknown. To characterise haemostatic parameters in healthy donkeys and to compare these with those in horses. Cross-sectional study. Clotting factors (V, VII, VIII, IX, X, XI and XII), and antithrombin III, Protein C and Protein S activities were measured in 80 healthy Andalusian and crossbred donkeys and 40 healthy Andalusian crossbred horses with assays based on human deficient plasmas. Thromboelastography was performed in 34 donkeys using a coagulation and platelet function analyser. Donkeys had shorter activated partial thromboplastin time (mean ± s.d. 33.4 ± 5.2 s vs. 38.8 ± 4.2 s; P<0.001) and higher Factor VII (1825 ± 206 vs. 1513 ± 174; P<0.001), IX (142 ± 41 vs. 114 ± 28; P<0.05) and XI (59.4 ± 14.0 vs. 27.2 ± 6.3; P<0.001) activities, whereas horses showed higher Factor X (130 ± 32 vs. 145 ± 23; P>0.05) and XII (96 ± 21 vs. 108 ± 15; P<0.001) activities. Antithrombin III (204 ± 26 vs. 174 ± 29; P<0.001), Protein C (33.16 ± 10.0 vs. 7.57 ± 1.70; P<0.001) and Protein S (median [interquartile range]: 7.8 [5.8-9.3] vs. 6.2 [5.2-7.0]; P<0.001) activities were higher in donkeys. Activated clot time (175 [159-189]), time to peak (6.5 [5.8-7.8]) and clot formation rate (26.9 [16.9-36.4]) in donkeys were shorter than reported values in horses. Haemostatic pathways could not be fully evaluated in donkeys because some tests are unavailable. Certain fibrinolytic parameters (plasmin, plasminogen, etc.) have not been characterised in donkeys and this may have affected our results. The haemostatic system in donkeys differs from that in horses and extrapolation of reference values between these species is not appropriate. © 2017 EVJ Ltd.

In vitro characterization of high purity factor IX concentrates for the treatment of hemophilia B.

PubMed

Limentani, S A; Gowell, K P; Deitcher, S R

1995-04-01

This study employed sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis and immunoblotting to assess the purity of seven high purity factor IX concentrates: Aimafix (Aima), AlphaNine-SD (Alpha Therapeutic), Factor IX VHP (Biotransfusion), Immunine (Immuno), Mononine (Armour Pharmaceutical), Nanotiv (Kabi Pharmacia), and 9MC (Blood Products Laboratory). The mean specific activity of these products ranged from 68 U factor IX/mg (Aimafix) to 246 U factor IX/mg (Mononine). SDS-PAGE analysis showed that the highest purity product, Mononine, had a single contaminating band under non-reducing conditions. Two additional bands were detected when this product was analyzed under reducing conditions. All other products had multiple contaminating bands that were more apparent under reducing than non-reducing conditions. The immunoblot for factor IX showed a dominant factor IX band for all products. In addition, visible light chain of factor IX was detected for AlphaNine-SD, Factor IX VHP, Immunine, Mononine, Nanotiv, and 9MC, suggesting that the factor IX in these products had undergone partial activation to factor IXa. Another contaminating band was visible at 49,500 for all of the products except 9MC. In addition to this band, high molecular weight contaminants were apparent for some products, most notably AlphaNine-SD. The identity of these bands is unknown. Immunoblotting failed to demonstrate factor VII as a contaminant of any of the high purity products, although factor VIIa could be detected in some lots of Immunine, Nanotiv, and 9MC by a clot-based assay. Factor X contaminated Aimafix, AlphaNine-SD, Factor IX VHP, Immunine, Nanotiv, and 9MC, but activation products of factor X were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Industrial production of clotting factors: Challenges of expression, and choice of host cells.

PubMed

Kumar, Sampath R

2015-07-01

The development of recombinant forms of blood coagulation factors as safer alternatives to plasma derived factors marked a major advance in the treatment of common coagulation disorders. These are complex proteins, mostly enzymes or co-enzymes, involving multiple post-translational modifications, and therefore are difficult to express. This article reviews the nature of the expression challenges for the industrial production of these factors, vis-à-vis the translational and post-translational bottlenecks, as well as the choice of host cell lines for high-fidelity production. For achieving high productivities of vitamin K dependent proteins, which include factors II (prothrombin), VII, IX and X, and protein C, host cell limitation of γ-glutamyl carboxylation is a major bottleneck. Despite progress in addressing this, involvement of yet unidentified protein(s) impedes a complete cell engineering solution. Human factor VIII expresses at very low levels due to limitations at several steps in the protein secretion pathway. Protein and cell engineering, vector improvement and alternate host cells promise improvement in the productivity. Production of Von Willebrand factor is constrained by its large size, complex structure, and the need for extensive glycosylation and disulfide-bonded oligomerization. All the licensed therapeutic factors are produced in CHO, BHK or HEK293 cells. While HEK293 is a recent adoption, BHK cells appear to be disfavored. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effects of long-term diet and omega-3 fatty acid supplementation on coagulation factor VII and serum phospholipids with special emphasis on the R353Q polymorphism of the FVII gene.

PubMed

Lindman, Anja S; Pedersen, Jan I; Hjerkinn, Elsa M; Arnesen, Harald; Veierød, Marit B; Ellingsen, Ingrid; Seljeflot, Ingebjørg

2004-06-01

The aim of the present study was to investigate the effect of long-term diet and very long chain n-3 fatty acids (VLC n-3) intervention on plasma coagulation factor VII (FVII), choline-containing phospholipids (PC) and triglycerides (TG), especially related to the R353Q polymorphism of the FVII gene. The present investigation included 219 subjects from the Diet and Omega-3 Intervention Trial on atherosclerosis (DOIT), a 2x2 factorial designed study in elderly men with long-standing hypercholesterolemia. The subjects were randomly allocated to receive placebo capsules (corn oil) (control), placebo capsules and dietary advice ("Mediterranean type" diet), VLC n-3 capsules, or VLC n-3 capsules and dietary advice combined. The R353Q genotype and the levels of FVIIc, FVIIag, FVIIa, PC, and TG at baseline and after 6 months were determined. Diet intervention was followed by a significant reduction of 5.1% in the levels of FVIIag and 2.4 mU/ml in FVIIa (95% CI -7.4, -2.9, and -3.8, -1.1, respectively) (both p<0.001) compared to the no diet group, independent of genotype. No effects of diet intervention on FVIIc, PC or TG were observed. After VLC n-3 supplementation the TG levels were significantly reduced compared to placebo (p=0.01), whereas all FVII levels and PC remained unchanged. Dietary advice towards a "Mediterranean type" diet, but not VLC n-3 supplementation, was shown to reduce the levels of FVIIag and FVIIa after 6 months, independent of genotype. The results indicate the dietary advice to be more favourable in reducing this risk factor for CVD as compared to specific VLC n-3 supplementation.

Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

PubMed

Takedani, H; Shima, M; Horikoshi, Y; Koyama, T; Fukutake, K; Kuwahara, M; Ishiguro, N

2015-05-01

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries. © 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Chronic dietary fat intake modifies the postprandial response of hemostatic markers to a single fatty test meal.

PubMed

Delgado-Lista, Javier; Lopez-Miranda, Jose; Cortés, Begoña; Perez-Martinez, Pablo; Lozano, Aquiles; Gomez-Luna, Rafael; Gomez, Purificacion; Gomez, Maria Jose; Criado, Juan; Fuentes, Francisco; Perez-Jimenez, Francisco

2008-02-01

Hemostasis is the result of a complex equilibrium between coagulation and fibrinolysis, and the influence of different dietary models on this equilibrium is not entirely known. The objective was to compare the effects of the chronic intake of different dietary models on postprandial hemostasis. In a randomized crossover design, 20 healthy men consumed for 28 d each diets rich in monounsaturated fatty acids (MUFAs), saturated fatty acids (SFAs), and carbohydrates plus n-3 fatty acids (CHO/N3). Fasting and postprandial hemostatic factors (factor VII coagulant activity, plasminogen activator inhibitor-1, tissue-type plasminogen activator, d-dimer, and thromboxane B(2)) were measured; meal tests for the postprandial measures were based on butter, virgin olive oil, and walnuts for the SFA, MUFA, and CHO/N3 diets, respectively. There were no differences in the fasting variables after the dietary periods. After the 3 fatty meals were consumed, we observed an increase in thromboxane B(2) and d-dimer and a reduction in tissue plasminogen activator, irrespective of the dietary model. The MUFA or CHO/N3 meals lowered postprandial concentrations of factor VII coagulant activity, although the reduction was greater after the MUFA-enriched meal. The concentration of plasminogen activator inhibitor-1 was greater after the SFA meal than after the other 2 meals. The administration of a fatty meal induces a postprandial procoagulant tendency, irrespective of the type of fat consumed. However, the use of a dietary model rich in SFA creates a more procoagulant environment than does a model that includes MUFA or CHO/N3 as the source of fatty acids.

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

PubMed Central

2010-01-01

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

How old is old in allegations of age discrimination? The limitations of existing law.

PubMed

Wiener, Richard L; Farnum, Katlyn S

2016-10-01

Under Title VII, courts may give a mixed motive instruction allowing jurors to determine that defendants are liable for discrimination if an illegal factor (here: race, color, religion, sex, or national origin) contributed to an adverse decision. Recently, the Supreme Court held that to conclude that an employer discriminated against a worker because of age, the Age Discrimination in Employment Act, unlike Title VII of the Civil Rights Act of 1964, requires "but for" causality, necessitating jurors to find that age was the determinative factor in an employer's adverse decision regarding that worker. Using a national online sample (N = 392) and 2 study phases, 1 to measure stereotypes, and a second to present experimental manipulations, this study tested whether older worker stereotypes as measured through the lens of the Stereotype Content Model, instruction type (but for vs. mixed motive causality), and plaintiff age influenced mock juror verdicts in an age discrimination case. Decision modeling in Phase 2 with 3 levels of case orientation (i.e., proplaintiff, prodefendant, and neutral) showed that participants relied on multiple factors when making a decision, as opposed to just 1, suggesting that mock jurors favor a mixed model approach to discrimination verdict decisions. In line with previous research, instruction effects showed that mock jurors found in favor of plaintiffs under mixed motive instructions but not under "but for" instructions especially for older plaintiffs (64- and 74-year-old as opposed to 44- and 54-year-old-plaintiffs). Most importantly, in accordance with the Stereotype Content Model theory, competence and warmth stereotypes moderated the instruction effects found for specific judgments. The results of this study show the importance of the type of legal causality required for age discrimination cases. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Early Science with the Large Millimeter Telescope: discovery of the 12CO(1-0) emission line in the ring galaxy VIIZw466

NASA Astrophysics Data System (ADS)

Wong, O. Ivy; Vega, O.; Sánchez-Argüelles, D.; Narayanan, G.; Wall, W. F.; Zwaan, M. A.; Rosa González, D.; Zeballos, M.; Bekki, K.; Mayya, Y. D.; Montaña, A.; Chung, A.

2017-04-01

We report an early science discovery of the 12CO(1-0) emission line in the collisional ring galaxy VII Zw466, using the Redshift Search Receiver instrument on the Large Millimeter Telescope Alfonso Serrano. The apparent molecular-to-atomic gas ratio either places the interstellar medium (ISM) of VII Zw466 in the H I-dominated regime or implies a large quantity of CO-dark molecular gas, given its high star formation rate. The molecular gas densities and star formation rate densities of VII Zw466 are consistent with the standard Kennicutt-Schmidt star formation law even though we find this galaxy to be H2-deficient. The choice of CO-to-H2 conversion factors cannot explain the apparent H2 deficiency in its entirety. Hence, we find that the collisional ring galaxy, VII Zw466, is either largely deficient in both H2 and H I or contains a large mass of CO-dark gas. A low molecular gas fraction could be due to the enhancement of feedback processes from previous episodes of star formation as a result of the star-forming ISM being confined to the ring. We conclude that collisional ring galaxy formation is an extreme form of galaxy interaction that triggers a strong galactic-wide burst of star formation that may provide immediate negative feedback towards subsequent episodes of star formation - resulting in a short-lived star formation history or, at least, the appearance of a molecular gas deficit.

Illustrative Examples of Principal Component Analysis using SPSS-X/FACTOR.

DTIC Science & Technology

1987-06-26

south of the Third #rmv §*ctar. Montoomer. al O ordered LTG J. Lawton Collins. VII Corps commander, to be precared to counterattaci south as soon as the...Ike Plan to Blame Montgomery For ’Bulge’ Defeat?" Article form The Dail Progress, Charlottesville. Virginia. May 2 and 3. 1976, p. 16-17. OOJ. Lawton ...Clausewitz. Carl von. On War. Princeton: Princeton University Press. 1184. Collins. J. Lawton . Lightning Joe. Baton Rouae: Louisiana State University

Astronomical Odds: A Policy Framework for the Cosmic Impact Hazard

DTIC Science & Technology

2004-06-01

171. 52 An early example of an expost approach to NEO interceptor design is Project Icarus, a study effort that recommended a Saturn-V class system...68 vii viii Astronomical Odds: A Policy Framework for the Cosmic Impact Hazard 3.2. "Giggle factor" within USAF study report...the access to the NEO SDT Study model provided by MIT Lincoln Laboratory, with special thanks to Grant Stokes and Jenifer Evans. I am grateful for

Effect of cineole, alpha-pinene, and camphor on survivability of skin flaps

PubMed

İnce, Bilsev; Dadacı, Mehmet; Kılınç, İbrahim; Oltulu, Pembe; Yarar, Serhat; Uyar, Mehmet

2018-06-14

Background/aim: The aim of this study was to determine the specific component of Rosmarinus officinalis (RO) responsible for increased flap survival and how RO displays its efficacy. Materials and methods: Rectangular random-pattern flaps were elevated from the back of each rat. Group I was the control group. In group II 0.1 mL of cineole, in group III 0.1 mL of alpha-pinene, in group IV 0.1 mL of camphor, in group V 0.1 mL each of alpha-pinene and cineole, in group VI 0.1 mL each of alpha-pinene and camphor, in group VII 0.1 mL each of cineole and camphor, and in group VIII, 0.1 mL each of alpha-pinene, cineole, and camphor was orally administered once a day before surgery. The luminal area of the largest blood vessel in the proximal flap was measured. Interleukin-1, tumor necrosis factor alpha, thiobarbituric acid reactive substances, and vascular endothelial growth factor values were measured. Results: The mean percentage of the viable surface area was significantly greater in groups VIII, III, and V. The mean percentage of vessel diameter was significantly greater in groups V, VIII, and VII. Conclusion: We suggest that alpha-pinene and cineole were the components of RO that were responsible for increased flap survival. The most effective of feature of RO was the antiinflammatory effects.

Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

PubMed

Cramer, Thomas J; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M; Mosnier, Laurent O; von Drygalski, Annette

2016-03-01

In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

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

2017-09-01

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

Recombinant Activated Factor VII (Eptacog Alfa Activated, NovoSeven®) in Patients with Rare Congenital Bleeding Disorders. A Systematic Review on its Use in Surgical Procedures.

PubMed

Di Minno, Matteo Nicola Dario; Ambrosino, Pasquale; Myasoedova, Veronika; Amato, Manuela; Ventre, Itala; Tremoli, Elena; Minno, Alessandro Di

2017-01-01

In the absence of definite guidelines in the area, we have carried a systemic review to provide a thorough overview concerning the efficacy and safety of recombinant activated factor VII (rFVIIa, NovoSeven®, Novo Nordisk A/S, Bagsværd, Denmark) in patients with Glanzmann's thrombasthenia (GT) and FVII deficiency, undergoing surgical procedures. PubMed, Web of Science, Scopus and EMBASE databases was employed for the search. Three multicenter registries were identified: the Glanzmann's Thrombasthenia Registry (GTR), the Seven Treatment Evaluation Registry (STER), and a German post-marketing surveillance registry (the WIRK study). In addition, data from 10 case-series and/or single-center experiences have been summarized. We have found that the following; perioperatively, the hemostatic effectiveness of rFVIIa was high in GT patients and in those with FVII deficiency undergoing both minor and major surgical procedures. Moreover, in all studies, rFVIIa was well tolerated. Thus, the current evidence shows an optimal perioperative safety/efficacy profile of rFVIIa in the setting of these rare bleeding disorders, and provides the rationale for further studies aimed at evaluating the optimal perioperative anti-hemorrhagic prophylaxis with rFVIIa in GT and in FVII deficient patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Efficacy and safety of recombinant activated factor vii in major surgical procedures: systematic review and meta-analysis of randomized clinical trials.

PubMed

Ranucci, Marco; Isgrò, Giuseppe; Soro, Giorgio; Conti, Daniela; De Toffol, Barbara

2008-03-01

To investigate the efficacy and safety of recombinant activated factor VII (rFVIIa) treatment in patients undergoing major surgical procedures. Relevant studies were searched in BioMedCentral, CENTRAL, PubMed, and PubMed Central. Only randomized controlled trials on humans undergoing major surgery were included. Efficacy was determined as the rate of patients receiving allogeneic packed red blood cells; safety was assessed in terms of thromboembolic complications and mortality rate. We followed the Cochrane Collaboration method for data extraction and internal validity procedures, as well as the Quality of Reporting of Meta-analyses statement. Seven randomized controlled trials met the inclusion criteria. Treatment with rFVIIa is associated with a reduced risk of receiving allogeneic packed red blood cells (odds ratio, 0.29; 95% confidence interval, 0.10-0.80). In a subgroup analysis, only patients receiving at least 50 mug/kg of rFVIIa had a significant benefit (odds ratio, 0.43; 95% confidence interval, 0.23-0.78). No differences in thromboembolic complications and mortality rates were observed. Treatment with rFVIIa is effective in reducing the rate of patients undergoing transfusion with allogeneic packed red blood cells. However, the cost-benefit ratio is favorable only in patients who need a huge number of packed red blood cell units. No safety concerns arise from the present study.

Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.

PubMed

Strauss, Kevin A; Ferreira, Carlos; Bottiglieri, Teodoro; Zhao, Xueqing; Arning, Erland; Zhang, Shucha; Zeisel, Steven H; Escolar, Maria L; Presnick, Nancy; Puffenberger, Erik G; Vugrek, Oliver; Kovacevic, Lucija; Wagner, Conrad; Mazariegos, George V; Mudd, S Harvey; Soltys, Kyle

2015-01-01

A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A>G, p.Tyr143Cys; c.982T>G, p.Tyr328Asp) presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency. Plasma methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) were markedly elevated and the molar concentration ratio of AdoMet:AdoHcy, believed to regulate a myriad of methyltransferase reactions, was 15% of the control mean. Dietary therapy failed to normalize biochemical markers or alter the AdoMet to AdoHcy molar concentration ratio. At 40 months of age, the proband received a liver segment from a healthy, unrelated living donor. Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52±0.19 to 1.48±0.79 mol:mol (control 4.10±2.11 mol:mol). Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted diet. Average calculated tissue methyltransferase activity increased from 43±26% to 60±22%, accompanied by signs of increased transmethylation in vivo. Factor VII activity increased from 12% to 100%. During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains in gross motor, language, and social skills. Copyright © 2015 Elsevier Inc. All rights reserved.

Massive oral bleeding after full-mouth extraction in a patient with B-cell lymphocytic leukemia/small lymphocytic lymphoma reversed with recombinant activated factor VII.

PubMed

Sprenker, Collin; Omar, Hesham R; Powless, R Andrew; Mangar, Devanand; Camporesi, Enrico

2016-02-01

Full-mouth extraction can be associated with intraoral bleeding, which usually is controlled with local hemostatic measures. Recombinant activated factor VII (rFVIIa) occasionally is used to stop bleeding in a variety of off-label indications, with the main argument curtailing its use being thrombotic events. The authors describe the use of rFVIIa for bleeding after full-mouth extraction in a patient with undiagnosed B-cell lymphocytic leukemia/small lymphocytic lymphoma. A 72-year-old man underwent full-mouth extraction (18 teeth). The next day, the patient experienced massive oral bleeding. The authors administered tranexamic acid, aminocaproic acid, and a total of 12 units of packed red blood cells in addition to local hemostatic measures without control of bleeding. On postoperative day 10, the authors administered 5,000 micrograms of rFVIIa, and within 2 hours oral the bleeding ceased. The authors performed flow cytometry and diagnosed B-cell lymphocytic leukemia/small lymphocytic lymphoma. Unexplained massive oral bleeding despite adequate local hemostatic measures should prompt further investigations for underlying bleeding or coagulation disorders. The authors describe the successful use of rFVIIa in massive oral bleeding. Further studies are mandatory to study the effectiveness of this drug for this off-label indication. Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.

Nuclear data libraries assessment for modelling a small fluoride salt-cooled, high-temperature reactor

NASA Astrophysics Data System (ADS)

Mohamed, Hassan; Lindley, Benjamin; Parks, Geoffrey

2017-01-01

Nuclear data consists of measured or evaluated probabilities of various fundamental physical interactions involving the nuclei of atoms and their properties. Most fluoride salt-cooled high-temperature reactor (FHR) studies that were reviewed do not give detailed information on the data libraries used in their assessments. Therefore, the main objective of this data libraries comparison study is to investigate whether there are any significant discrepancies between main data libraries, namely ENDF/B-VII, JEFF-3.1 and JEF-2.2. Knowing the discrepancies, especially its magnitude, is important and relevant for readers as to whether further cautions are necessary for any future verification or validation processes when modelling an FHR. The study is performed using AMEC's reactor physics software tool, WIMS. The WIMS calculation is simply a 2-D infinite lattice of fuel assembly calculation. The comparison between the data libraries in terms of infinite multiplication factor, kinf and pin power map are presented. Results show that the discrepancy between JEFF-3.1 and ENDF/B-VII libraries is reasonably small but increases as the fuel depletes due to the data libraries uncertainties that are accumulated at each burnup step. Additionally, there are large discrepancies between JEF-2.2 and ENDF/B-VII because of the inadequacy of the JEF-2.2 library.

CONSULTATION ON UPDATED METHODOLOGY FOR ...

EPA Pesticide Factsheets

The National Academy of Sciences (NAS) expects to publish the Biological Effects of Ionizing Radiation (BEIR) committee's report (BEIR VII) on risks from ionizing radiation exposures in calendar year 2005. The committee is expected to have analyzed the most recent epidemiology from the important exposed cohorts and to have factored in any changes resulting from the updated analysis of dosimetry for the Japanese atomic bomb survivors. To the extent practical, the Committee will also consider any relevant radiobiological data, including those from the Department of Energy's low dose effects research program. Based on their evaluation of relevant information, the Committee is then expected to propose a set of models for estimating risks from low-dose ionizing radiation. ORIA will review the BEIR VII report and consider revisions to the Agency's methodology for estimating cancer risks from exposure to ionizing radiation in light of this report and other relevant information. This will be the subject of the Consultation. This project supports a major risk management initiative to improve the basis on which radiation risk decisions are made. This project, funded by several Federal Agencies, reflects an attempt to characterize risks where there are substantial uncertainties. The outcome will improve our ability to assess risks well into the future and will strengthen EPAs overall capability for assessing and managing radiation risks. the BEIR VII report is funde

Effects of exposure to factor concentrates containing donations from identified AIDS patients

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

Jason, J.; Holman, R.C.; Dixon, G.

1986-10-03

The authors recipients of eight lots of factors VII and IX voluntarily withdrawn from distribution because one donor was known to have subsequently developed the acquired immunodeficiency syndrome with a nonexposed cohort matched by age, sex, and factor use. The factor VIII recipient cohorts did not differ in prevalence of antibody to human immunodeficiency virus (HIV), T-cell subset numbers, T-helper to T-suppressor ratios, or immunogloubulin levels. Exposed individuals had higher levels of immune complexes by C1q binding and staphylococcal binding assays and lower responses to phytohemagglutinin and concanavalin A. However, only the staphylococcal binding assay values were outside the normalmore » range for our laboratory. Factor IX recipient cohorts did not differ in HIV antibody prevalence or any immune tests. Although exposed and nonexposed individuals did not differ from each other in a clinically meaningful fashion at initial testing, both the exposed and nonexposed cohorts had high rats of HIV seroprevalence. Market withdrawals were clearly insufficient means of limiting the spread of HIV in hemophilic patients; however, the currently available methods of donor screening and viral inactivation of blood products will prevent continued exposed within this population.« less

[A Jehovah's Witness child with hemophilia B and factor IX inhibitors undergoing scoliosis surgery].

PubMed

Chau, Anthony; Wu, John; Ansermino, Mark; Tredwell, Stephen; Purdy, Robert

2008-01-01

To describe the successful perioperative hemostatic management of a Jehovah's Witness patient with hemophilia B and anaphylactic inhibitors to factor IX, undergoing scoliosis surgery. A 14 (1/2)-yr-old boy with severe hemophilia B who had a history of anaphylactic inhibitors to factor IX was scheduled to undergo corrective scoliosis surgery. He was initially started on epoetin alfa and iron supplementation to maximize preoperative red cell mass. Additionally, he was placed on a desensitization protocol of recombinant coagulation factor IX (rFIX) and was then treated with activated recombinant coagulation factor VII (rFVIIa) during the postoperative period. Tranexamic acid was given concomitantly. The intraoperative blood loss was approximately 350 mL. The nadir hemoglobin concentration was 111 g.L(-1) on postoperative days one and two. On postoperative day 11, the patient was stable and discharged home with a hemoglobin of 138 g.L(-1). He did not require blood transfusion and no adverse events were observed. The use of rFIX, rFVIIa, erythropoetin, iron, and tranexamic acid before, during and after scoliosis surgery may be a viable and safe option for hemophilia patients with inhibitors, who refuse blood products.

Antithrombotic Effect of Antisense Factor XI Oligonucleotide Treatment in Primates

PubMed Central

Crosby, Jeffrey R.; Marzec, Ulla; Revenko, Alexey S.; Zhao, Chenguang; Gao, Dacao; Matafonov, Anton; Gailani, David; MacLeod, A. Robert; Tucker, Erik I.; Gruber, Andras; Hanson, Stephen R.; Monia, Brett P.

2013-01-01

Objective During coagulation, factor IX (FIX) is activated by two distinct mechanisms mediated by the active proteases of either factors VII (FVIIa) or XI (FXIa). Both coagulation factors may contribute to thrombosis; factor XI, however, plays only a limited role in the arrest of bleeding. Therefore, therapeutic targeting of FXI may produce an antithrombotic effect with relatively low hemostatic risk. Approach and Results We have reported that reducing FXI levels with FXI antisense oligonucleotides (ASOs) produces antithrombotic activity in mice, and that administration of FXI ASOs to primates decreases circulating FXI levels and activity in a dose- and time-dependent manner. Here we evaluated the relationship between FXI plasma levels and thrombogenicity in an established baboon model of thrombosis and hemostasis. In previous studies with this model, antibody-induced inhibition of FXI produced potent antithrombotic effects. In the present report, ASO-mediated reduction of FXI plasma levels by ≥50% resulted in a demonstrable and sustained antithrombotic effect without an increased risk of bleeding. Conclusion These results indicate that reducing FXI levels using ASOs is a promising alternative to direct FXI inhibition, and that targeting FXI may be potentially safer than conventional antithrombotic therapies that can markedly impair primary hemostasis. PMID:23559626

Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms.

PubMed

Self, Timothy H; Oliphant, Carrie S; Reaves, Anne B; Richardson, Amy M; Sands, Christopher W

2015-01-01

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Atomic Approaches to Defect Thermochemistry

DTIC Science & Technology

1992-04-30

from the enthalpy of melting of ison with real experiments by a factor of Au to be 29 meV. (We have checked that the 2.1x10 3; the time scale of the...Diffusion and to Map Vacancy Concentrations at a Fixed Time V. Studies of Electroluminescent Flat-Panel Display Devices VI. Defect Characterization VII...kT), where n = ND - NA is the doping density, about the same time that P. Mei et al. published the first experimental report of this effect (Appl. Phys

Classrooms of the Future. A Thirty-Three Act Play with an Ever-Changing Cast; Out of the Spotlight; Selected Acts; The Perils and Promises of Technological Literacy: Three Case Studies; The Producers, the Critics, and the Glitch Factor.

ERIC Educational Resources Information Center

Landsberger, Joe; Krey, Cynthia L.; Moorhead, Alice

2001-01-01

This special section on the history and creators of COTF VII describe the process for creating a conference on technology in education using the example of the Minnesota-based Classrooms of the Future Symposia presented by colleges and universities in the Twin Cities area. Highlights include the role of technology in instruction; promotional…

Classical strongly coupled quark-gluon plasma. VII. Energy loss

NASA Astrophysics Data System (ADS)

Cho, Sungtae; Zahed, Ismail

2010-12-01

We use linear response analysis and the fluctuation-dissipation theorem to derive the energy loss of a heavy quark in the SU(2) classical Coulomb plasma in terms of the l=1 monopole and nonstatic structure factor. The result is valid for all Coulomb couplings Γ=V/K, the ratio of the mean potential to kinetic energy. We use the Liouville equation in the collisionless limit to assess the SU(2) nonstatic structure factor. We find the energy loss to be strongly dependent on Γ. In the liquid phase with Γ≈4, the energy loss is mostly metallic and soundless with neither a Cerenkov nor a Mach cone. Our analytical results compare favorably with the SU(2) molecular dynamics simulations at large momentum and for heavy quark masses.

Vesical Artery Embolization in Haemorrhagic Cystitis in Children

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

García-Gámez, Andrés, E-mail: agargamez@gmail.com; Bermúdez Bencerrey, Patricia, E-mail: PBERMUDE@clinic.ub.es; Brio-Sanagustin, Sonia, E-mail: sbrio@santpau.cat

Haemorrhagic cystitis is an uncommon and, in its severe form, potentially life-threatening complication of haematopoietic stem cell transplantation or cancer therapy in children. The severe form involves macroscopic haematuria with blood clots, urinary obstruction and/or renal impairment. There are many therapeutic options to treat acute haemorrhage, but only recombinant factor VII has a high level of clinical evidence in children. Supraselective vesical artery embolization (SVAE) is an increasingly used therapeutic procedure for controlling haemorrhage in adults, but is less commonly used in children. This might be due to several factors, such as the invasive nature of the procedure, lack ofmore » appropriate medical experience and possible long-term side effects. We present three cases of children successfully treated by means of effective SVAE.« less

Coincidences between O VI and O VII Lines: Insights from High-resolution Simulations of the Warm-hot Intergalactic Medium

NASA Astrophysics Data System (ADS)

Cen, Renyue

2012-07-01

With high-resolution (0.46 h -1 kpc), large-scale, adaptive mesh-refinement Eulerian cosmological hydrodynamic simulations we compute properties of O VI and O VII absorbers from the warm-hot intergalactic medium (WHIM) at z = 0. Our new simulations are in broad agreement with previous simulations with ~40% of the intergalactic medium being in the WHIM. Our simulations are in agreement with observed properties of O VI absorbers with respect to the line incidence rate and Doppler-width-column-density relation. It is found that the amount of gas in the WHIM below and above 106 K is roughly equal. Strong O VI absorbers are found to be predominantly collisionally ionized. It is found that (61%, 57%, 39%) of O VI absorbers of log N(O VI) cm2 = (12.5-13, 13-14, > 14) have T < 105 K. Cross correlations between galaxies and strong [N(O VI) > 1014 cm-2] O VI absorbers on ~100-300 kpc scales are suggested as a potential differentiator between collisional ionization and photoionization models. Quantitative prediction is made for the presence of broad and shallow O VI lines that are largely missed by current observations but will be detectable by Cosmic Origins Spectrograph observations. The reported 3σ upper limit on the mean column density of coincidental O VII lines at the location of detected O VI lines by Yao et al. is above our predicted value by a factor of 2.5-4. The claimed observational detection of O VII lines by Nicastro et al., if true, is 2σ above what our simulations predict.

Where Are the Baryons? III. Nonequilibrium Effects and Observables

NASA Astrophysics Data System (ADS)

Cen, Renyue; Fang, Taotao

2006-10-01

A significant fraction (40%-50%) of baryons at the present epoch are predicted to be shock-heated to the warm-hot intergalactic medium (WHIM) by our previous numerical simulations. Here we recompute the evolution of the WHIM with several major improvements: (1) galactic superwind feedback processes from galaxy and star formation are explicitly included; (2) major metal species (O V to O IX) are computed explicitly in a nonequilibrium way; and (3) mass and spatial dynamic ranges are larger by factors of 8 and 2, respectively, than in our previous simulations. We find the following: (1) Nonequilibrium calculations produce significantly different results than do ionization equilibrium calculations. (2) The abundance of O VI absorption lines based on nonequilibrium simulations with galactic superwinds is in remarkably good agreement with the latest observations, strongly validating our model, while the predicted abundances for O VII and O VIII absorption lines appear to be lower than the still very uncertain observations. The expected abundances for O VI (as well as Lyα), O VII, and O VIII absorption systems are in the range 50-100 per unit redshift at equivalent width EW=1 km s-1, decreasing to 10-20 per unit redshift at EW=10 km s-1, to one to three lines for O VII and O VIII and negligible for O VI at EW>100 km s-1. (3) Emission lines, primarily O VI and Lyα in the UV and O VII and O VIII in soft X-rays, are potentially observable by future missions, and different lines provide complementary probes of the WHIM in the temperature-density-metallicity phase space. The number of emission lines per unit redshift that may be detectable by planned UV and soft X-ray missions are of order 0.1-1.

Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study.

PubMed

Guren, Tormod Kyrre; Thomsen, Maria; Kure, Elin H; Sorbye, Halfdan; Glimelius, Bengt; Pfeiffer, Per; Österlund, Pia; Sigurdsson, Fridbjörn; Lothe, Inger Marie Bowitz; Dalsgaard, Astrid Marie; Skovlund, Eva; Christoffersen, Thoralf; Tveit, Kjell Magne

2017-05-09

The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis. A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations. Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy. Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

Precision measurement of the 238 Pu ( n , γ ) cross section

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

Chyzh, A.; Wu, C. Y.; Kwan, E.

2013-10-14

Here, the neutron-capture cross section for 238Pu was measured by using the detector for advanced neutron-capture experiments (DANCE) array, which is a highly segmented and highly efficient 4π γ-ray calorimeter. The neutron-capture events were recognized by the total γ-ray energy deposited in DANCE, which is equal to the reaction Q value plus the incident neutron energy. The absolute neutron-capture cross section was derived as a function of incident neutron energy from thermal to about 30 keV. The measured cross section for incident neutron energy below 18 eV was performed for the first time by using the direct method and doesmore » not support the most recently adopted changes in endf/b-vii.1 where the neutron-capture cross section was lowered by as much as a factor of ~3 in the neighborhood of 0.3 eV from those evaluated in ENDF/B-VII.0.« less

ADVISORY ON UPDATED METHODOLOGY FOR ...

EPA Pesticide Factsheets

The National Academy of Sciences (NAS) published the Biological Effects of Ionizing Radiation (BEIR) committee's report (BEIR VII) on risks from ionizing radiation exposures in 2006. The Committee analyzed the most recent epidemiology from the important exposed cohorts and factored in changes resulting from the updated analysis of dosimetry for the Japanese atomic bomb survivors. To the extent practical, the Committee also considered relevant radiobiological data, including that from the Department of Energy's low dose effects research program. Based on the review of this information, the Committee proposed a set of models for estimating risks from low-dose ionizing radiation. ORIA then prepared a white paper revising the Agency's methodology for estimating cancer risks from exposure to ionizing radiation in light of this report and other relevant information. This is the first product to be developed as a result of the BEIR VII report. We requested that the SAB conduct an advisory during the development of this methodology. The second product to be prepared will be a revised version of the document,

Role of the 2 adenine (g.11293_11294insAA) insertion polymorphism in the 3' untranslated region of the factor VII (FVII) gene: molecular characterization of a patient with severe FVII deficiency.

PubMed

Peyvandi, F; Garagiola, I; Palla, R; Marziliano, N; Mannucci, P M

2005-11-01

Polymorphic variants in the gene encoding factor VII (F7) affect the plasma levels of this coagulation protein and modify the clinical phenotype of FVII deficiency in some patients. In this study we report the in vitro functional analysis of a novel polymorphic variant located in the 3' untranslated region of F7: g.11293_11294insAA. To determine whether this variant regulates FVII expression, we initially compared an expression vector containing FVII cDNA with g.11293_11294insAA with the FVII wild-type (WT) construct. The kinetics of mRNA production showed that the insertion decreases the steady-state FVII mRNA levels. To assess whether the insertion influences the phenotype of FVII-deficient patients, we evaluated its effect on the expression of FVII in a patient with severe FVII deficiency (undetectable FVII activity and antigen) carrying two additional homozygous missense variations (p.Arg277Cys and p.Arg353Gln). The two substitutions alone reduced the expression of FVII activity and antigen in vitro, but with the insertion polymorphism in our expression vector the patient's phenotype of undetectable plasma FVII was recapitulated. The insertion polymorphism in the 3' untranslated region of F7 is another modifier of FVII expression that might explain the poor genotype-phenotype correlation in some FVII-deficient patients. Copyright 2005 Wiley-Liss, Inc.

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

PubMed

Jen, Howard; Shew, Stephen

2008-12-01

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

Recombinant activated factor VII (NovoSeven): addition to replacement therapy in acute, uncontrolled and life-threatening bleeding.

PubMed

Mayo, A; Misgav, M; Kluger, Y; Geenberg, R; Pauzner, D; Klausner, J; Ben-Tal, O

2004-07-01

Recombinant activated factor VII (rFVIIa, NovoSeven) has been used off-label for various conditions. A protocol for its use in acute, uncontrolled life-threatening bleeding, was devised and employed. A haematologist/transfusion specialist was assigned as a member of the team. The clinical data were reviewed and summarized. A scoring system for the assessment and monitoring of coagulopathy was employed. Each parameter of prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet number and fibrinogen level was allocated points according to the degree of abnormality. Three scoring levels emerged. Between April 2001 and April 2003, 13 patients received rFVIIa for acute, uncontrolled life-threatening bleeding. Nine of 13 patients remained alive for 15 days or longer after rFVIIa infusion. All patients who experienced a reduction or cessation of bleeding after rFVIIa infusion, also had a lower coagulopathy score after replacement therapy, prior to rFVIIa infusion, compared with their score at rFVIIa request. There was a reduction in the average use of blood products after rFVIIa infusion. The coagulopathy score was statistically predictive of response to rFVIIa and survival. In an area where very little data exists, we report the usefulness of rFVIIa. We propose that transfusion replacement should aim to correct coagulopathy before infusion of rFVIIa and that a haematologist/transfusion specialist should be involved in the management of these patients. A prognostically significant coagulopathy scoring system is offered.

Nuclear Data Needs for the Neutronic Design of MYRRHA Fast Spectrum Research Reactor

NASA Astrophysics Data System (ADS)

Stankovskiy, A.; Malambu, E.; Van den Eynde, G.; Díez, C. J.

2014-04-01

A global sensitivity analysis of effective neutron multiplication factor to the change of nuclear data library has been performed. It revealed that the test version of JEFF-3.2 neutron-induced evaluated data library produces closer results to ENDF/B-VII.1 than JEFF-3.1.2 does. The analysis of contributions of individual evaluations into keff sensitivity resulted in the priority list of nuclides, uncertainties on cross sections and fission neutron multiplicities of which have to be improved by setting up dedicated differential and integral experiments.

The Automated DC Parameter Testing of GaAs MESFETs Using the Singer Automatic Integrated Circuit Test System.

DTIC Science & Technology

1980-09-01

Timing Diagram Showing Relationship of Control Signals to Phase Clocks 219 70 Sample MESFET Used to Obtain Error Factors 231 x LIST OF TABLES TABLE PAGE...each chi,,, tested ear Leio within the fixture. This means that -:acij vii to e testd must be diced from the wafer. Some sicans urine - ,ut si - nals of...dy anhc testing of GaA; MEVET_’.’ . It would therefore be necess-ry to add a storage buffer between the tri-state fubber and the measurinv instrument

Recombinant activated factor VII in the treatment of bleeds and for the prevention of surgery-related bleeding in congenital haemophilia with inhibitors.

PubMed

Santagostino, Elena; Escobar, Miguel; Ozelo, Margareth; Solimeno, Luigi; Arkhammar, Per; Lee, Hye Youn; Rosu, Gabriela; Giangrande, Paul

2015-06-01

The availability of recombinant activated factor VII (rFVIIa, eptacog alfa activated) has greatly advanced the care of patients with haemophilia A or B who have developed inhibitors against the infused replacement factor. Recombinant FVIIa is licensed for the on-demand treatment of bleeding episodes and the prevention of bleeding in surgery or invasive procedures in patients with congenital haemophilia with inhibitors. This article attempts to review in detail the extensive evidence of rFVIIa in congenital haemophilia patients with inhibitors. Patients with acute bleeding episodes are best treated on demand at home, to achieve the short- and long-term benefits of rapid bleed control. Key prospective studies have shown that rFVIIa achieves consistently high efficacy rates in the management of acute (including joint) bleeds in inhibitor patients in the home treatment setting. Substantial post-approval data from key registries also support the on-demand efficacy profile of rFVIIa established by the prospective clinical trials. The availability of rFVIIa has allowed major surgery to become a reality for inhibitor patients. Studies in key surgery, including orthopaedic procedures, have found that rFVIIa provides consistently high efficacy rates. Importantly, the wealth of data does not raise any unexpected safety concerns surrounding rFVIIa use; this is likely because rFVIIa is a recombinant product with a localised mechanism of action at the site of vascular injury. In summary, rFVIIa is established as an effective and well-tolerated first-line treatment for on-demand bleeding control and bleed prevention during minor and major (including elective orthopaedic) surgery in inhibitor patients. Use of rFVIIa has been a major step towards narrowing the gap in outcomes between inhibitor patients and non-inhibitor patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Observed Limits on Charge Exchange Contributions to the Diffuse X-Ray Background

NASA Astrophysics Data System (ADS)

Crowder, S. G.; Barger, K. A.; Brandl, D. E.; Eckart, M. E.; Galeazzi, M.; Kelley, R. L.; Kilbourne, C. A.; McCammon, D.; Pfendner, C. G.; Porter, F. S.; Rocks, L.; Szymkowiak, A. E.; Teplin, I. M.

2012-10-01

We present a high-resolution spectrum of the diffuse X-ray background from 0.1 to 1 keV for a ~1 sr region of the sky centered at l = 90°, b = +60° using a 36 pixel array of microcalorimeters flown on a sounding rocket. With an energy resolution of 11 eV FWHM below 1 keV, the spectrum's observed line ratios help separate charge exchange contributions originating within the heliosphere from thermal emission of hot gas in the interstellar medium. The X-ray sensitivity below 1 keV was reduced by about a factor of four from contamination that occurred early in the flight, limiting the significance of the results. The observed centroid of helium-like O VII is 568+2 - 3 eV at 90% confidence. Since the centroid expected for thermal emission is 568.4 eV and for charge exchange is 564.2 eV, thermal emission appears to dominate for this line complex. The dominance of thermal emission is consistent with much of the high-latitude O VII emission originating in 2-3 × 106 K gas in the Galactic halo. On the other hand, the observed ratio of C VI Lyγ to Lyα is 0.3 ± 0.2. The expected ratios are 0.04 for thermal emission and 0.24 for charge exchange, indicating that charge exchange must contribute strongly to this line and therefore potentially to the rest of the ROSAT R12 band usually associated with 106 K emission from the Local Hot Bubble. The limited statistics of this experiment and systematic uncertainties due to the contamination require only >32% thermal emission for O VII and >20% from charge exchange for C VI at the 90% confidence level. An experimental gold coating on the silicon substrate of the array greatly reduced extraneous signals induced on nearby pixels from cosmic rays passing through the substrate, reducing the triggered event rate by a factor of 15 from a previous flight of the instrument.

Observed Limits on Charge Exchange Contributions to the Diffuse X-Ray Background

NASA Technical Reports Server (NTRS)

Crowder, S. G.; Barger, K. A.; Brandl, D. E.; Eckart, M. E.; Galeazzi, M.; Kelley, R. L.; Kilbourne, C. A.; McCammon, D.; Pfendner, C. G.; Porter, F. S.;

Binge drinking as a risk factor for violence among secondary school students in a nationally representative sample in Puerto Rico.

PubMed

Reyes-Pulliza, Juan Carlos; Rodríguez-Figueroa, Linnette; Moscoso-Álvarez, Margarita R; Colón, Héctor; Cotto-Negrón, Coral; Rivera, Laura; Irizarry-Pérez, Marisela

2015-03-01

The objective of this study was to determine the association between binge drinking and violence in a representative sample of secondary-school students in Puerto Rico. Consulta Juvenil VII (a biennial survey of school-aged youths in Puerto Rico) has a representative sample of adolescent students in Puerto Rico. A multi-stage stratified cluster sampling design was used. The sampling frame of Consulta Juvenil VII includes all the public and private schools registered with the Department of Education and the Council of General Education in Puerto Rico. The study utilizes a self-administered questionnaire that was translated and adapted from the "Student Survey of Risk and Protective Factors and Prevalence of Alcohol, Tobacco, and Other Drug Use". "Binge drinking" was defined as having 5 or more alcoholic drinks in a row during the 30 days preceding the survey. Almost 20% of the sample members reported that at least 1 instance of binge drinking had taken place during the 2 weeks prior to the survey (17.7%). After controlling for gender, age, school level, the type of system, and the parents' educational levels, the odds of a given binge drinker reporting violent behaviors were 5 times greater than the odds among non-binge drinkers (OR: 5.6; 95% CI: 4.7-6.7). The study shows an association between binge drinking and violence in Puerto Rican adolescents, indicating that Hispanic youths who abuse alcohol may be at increased risk of violence. These findings suggest that violence prevention programs should be integrated with substance use prevention programs. [PR Health

Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease.

PubMed

Günther, A; Mosavi, P; Ruppert, C; Heinemann, S; Temmesfeld, B; Velcovsky, H G; Morr, H; Grimminger, F; Walmrath, D; Seeger, W

2000-06-01

Bronchoalveolar lavage fluids (BALF) from patients with hypersensitivity pneumonitis (HP; n = 35), idiopathic pulmonary fibrosis (IPF, n = 41) and sarcoidosis (SARC, n = 48) were investigated for alterations in the alveolar hemostatic balance. Healthy individuals (n = 21) served as Controls. Procoagulant activity (PCA), tissue factor (TF) activity and F VII activity were assessed by means of specific recalcification assays. The overall fibrinolytic activity (FA) was measured using the (125)I-labeled fibrin plate assay. Fibrinopeptide A (FP-A), D-Dimer, plasminogen activators (PA) of the urokinase (u-PA) or tissue type (t-PA), PA-inhibitor I (PAI-1) and alpha2-antiplasmin (alpha2-AP) were determined by ELISA technique. As compared to Controls, all groups with interstitial lung disease (ILD) displayed an increase in BALF PCA by approximately one order of magnitude, and this was ascribed to enhanced TF activity by >98%. Accordingly, F VII-activity was increased in all ILD groups, and elevated FP-A levels were noted. There was no significant difference in procoagulant activities between the different ILD entities, but the increase in TF was significantly correlated with deterioration of lung compliance. Overall fibrinolytic activity did not significantly differ between ILD entities and Controls, although some reduction in IPF subjects was observed. Nevertheless, changes in the profile of the different pro- and antifibrinolytic compounds were noted. U-PA, but not t-PA levels were significantly reduced in all ILD groups. alpha2-AP was markedly elevated throughout, whereas PAI-1 levels were lowered. As a balance of

Cost-Effectiveness Analysis of Biogeneric Recombinant Activated Factor VII (AryoSeven™) and Activated Prothrombin Complex Concentrates (FEIBA™) to Treat Hemophilia A Patients with Inhibitors in Iran.

PubMed

Golestani, Mina; Eshghi, Peyman; Rasekh, Hamid Reza; Cheraghali, Abdoll Majid; Salamzadeh, Jamshid; Naderi, Majid; Managhchi, Mohammad Reza; Hoorfar, Hamid; Toogeh, Gholam Reza; Imani, Ali; Khodayari, Mohammad Taghi; Habibpanah, Behnaz; Hantooshzadeh, Razieh

2016-01-01

Nowadays, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC) are used to treat bleeding episodes in the Hemophilia patients with inhibitors. AryoSeven® is an Iranian biogeneric rFVIIa with homogeneity of efficacy and the nature to NovoSeven in a comparative trial. The current clinical trial aimed to evaluate the cost-effectiveness of FEIBA and AryoSeven® by Decision Analytic Model according to the Iranian healthcare system. An open label, multi-center, cross-over clinical trial was designed. Patients were categorized into 3 groups based on their prior tendency to one or none of the products. To determine the premium therapeutic strategy, the Incremental cost-effectiveness ratio (ICER) was calculated. Protocol F led to more treatment success in group F than the other groups (P= 0.03). Also, there was a significant statistical difference between the mean of effectiveness scores in the groups using protocol F (P = 0.01). The effectiveness of protocol F and A were 89% and 72%, respectively. ICER cost US$ to manage an episode of bleeding to get one more unit of effectiveness using FEIBA VS. AryoSeven. Although the results showed that AryoSeven was more cost-effective compared to FEIBA, the two strategies were undominated. In other words, both medicines can be applied in the first line of the treatment if the cost of FEIBA was reduced. The present clinical trial was registered at IRCT website, under ID No.2013020612380N1.

Factor VII assay performance: an analysis of the North American Specialized Coagulation Laboratory Association proficiency testing results.

PubMed

Zantek, N D; Hsu, P; Refaai, M A; Ledford-Kraemer, M; Meijer, P; Van Cott, E M

2013-06-01

The performance of factor VII (FVII) assays currently used by clinical laboratories was examined in North American Specialized Coagulation Laboratory Association (NASCOLA) proficiency tests. Data from 12 surveys conducted between 2008 and 2010, involving 20 unique specimens plus four repeat-tested specimens, were analyzed. The number of laboratories per survey was 49-54 with a total of 1224 responses. Numerous reagent/instrument combinations were used. For FVII > 80 or <40 U/dL, 99.5% of results (859/863) were correctly classified by laboratories as normal/abnormal. Classification of specimens with 40-73 U/dL FVII was heterogeneous. Interlaboratory precision was better for normal specimens (coefficient of variation (CV) 10.7%) than for FVII<20 U/dL (CV 33.1%), with a mean CV of 17.2% per specimen. Intralaboratory precision for repeated specimens demonstrated no significant difference between the paired survey results (mean absolute difference 2.5-5.0 U/dL). For specimens with FVII >50 U/dL, among commonly used methods, one thromboplastin and one calibrator produced results 5-6 U/dL higher and another thromboplastin and calibrator produced results 5-6 U/dL lower than all other methods, and human thromboplastin differed from rabbit by +7.6 U/dL. Preliminary evidence suggests these differences could be due to the calibrator. For FVII <50 U/dL, differences among the commonly used reagents and calibrators were generally not significant. © 2013 Blackwell Publishing Ltd.

Impact on postoperative bleeding and cost of recombinant activated factor VII in patients undergoing heart transplantation.

PubMed

Hollis, Allison L; Lowery, Ashleigh V; Pajoumand, Mehrnaz; Pham, Si M; Slejko, Julia F; Tanaka, Kenichi A; Mazzeffi, Michael

2016-01-01

Cardiac transplantation can be complicated by refractory hemorrhage particularly in cases where explantation of a ventricular assist device is necessary. Recombinant activated factor VII (rFVIIa) has been used to treat refractory bleeding in cardiac surgery patients, but little information is available on its efficacy or cost in heart transplant patients. Patients who had orthotopic heart transplantation between January 2009 and December 2014 at a single center were reviewed. Postoperative bleeding and the total costs of hemostatic therapies were compared between patients who received rFVIIa and those who did not. Propensity scores were created and used to control for the likelihood of receiving rFVIIa in order to reduce bias in our risk estimates. Seventy-six patients underwent heart transplantation during the study period. Twenty-one patients (27.6%) received rFVIIa for refractory intraoperative bleeding. There was no difference in postoperative red blood cell transfusion, chest tube output, or surgical re-exploration between patients who received rFVIIa and those who did not, even after adjusting with the propensity score (P = 0.94, P = 0.60, and P = 0.10, respectively). The total cost for hemostatic therapies was significantly higher in the rFVIIa group (median $10,819 vs. $1,985; P < 0.0001). Subgroup analysis of patients who underwent redo-sternotomy with left ventricular assist device explantation did not show any benefit for rFVIIa either. In this relatively small cohort, rFVIIa use was not associated with decreased postoperative bleeding in patients undergoing heart transplantation; however, it led to significantly higher cost.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011.

PubMed

Brown, S A; Barnes, C; Curtin, J; Dunkley, S; Ockelford, P; Phillips, J; Rowell, J; Smith, M; Tran, H

2012-11-01

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus-based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90-120 μg/kg is the favoured starting dose in most settings. Initial dosing using 90-180 μg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2-hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors. © 2012 The Authors; Internal Medicine Journal © 2012 Royal Australasian College of Physicians.

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

PubMed

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

2016-10-01

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

Size versus electronic factors in transition metal carbide and TCP phase stability

NASA Astrophysics Data System (ADS)

Pettifor, D. G.; Seiser, B.; Margine, E. R.; Kolmogorov, A. N.; Drautz, R.

2013-09-01

The contributions of atomic size and electronic factors to the structural stability of transition metal carbides and topologically close-packed (TCP) phases are investigated. The hard-sphere model that has been used by Cottrell to rationalize the occurrence of the octahedral and trigonal local coordination polyhedra within the transition metal carbides is shown to have limitations in TiC since density functional theory (DFT) predicts that the second most metastable phase closest to the B1 (NaCl) ground state takes the B? (BN) structure type with 5-atom local coordination polyhedra with very short Ti-C bond lengths. The importance of electronic factors in the TCP phases is demonstrated by DFT predictions that the A15, ? and ? phases are stabilized between groups VI and VII of the elemental transition metals, whereas the ? and Laves phases are destabilized. The origin of this difference is related to the bimodal shape parameter of the electronic density of states by using the bond-order potential expansion of the structural energy within a canonical tight-binding model. The importance of the size factor in the TCP phases is illustrated by the DFT heats of formation for the binary systems Mo-Re, Mo-Ru, Nb-Re and Nb-Ru which show that the ? and Laves phases become more and more stable compared to A15, ? and ? as the size factor increases from Mo-Re through to Nb-Ru.

NUSTAR AND XMM-Newton Observations of the Neutron Star X-Ray Binary 1RXS J180408.9-34205

NASA Astrophysics Data System (ADS)

Ludlam, Renee; Miller, Jon M.; Cackett, Edward; Fabian, Andrew C.; Bachetti, Matteo; Parker, Michael; Tomsick, John; Barret, Didier; Natalucci, Lorenzo; Rana, Vikram; Harrison, Fiona

2016-04-01

We report on observations of the neutron star (NS) residing in the low-mass X-ray binary 1RXS J180408.9-34205 taken 2015 March by NuSTAR and XMM-Newton while the source was in the hard spectral state. We findmultiple reflection features (Fe Kα detected with NuSTAR N VII, O VII, and O VIII detected in the RGS) fromdifferent ionization zones. Through joint fits using the self consistent relativistic reflection model RELXILL,we determine the inner radius to be 6.6(+13.2,-0.6) Rg. We find the inclination of the system to be between 18-29 degrees.If the disk is truncated at a radius greater than the innermost stable circular orbit (ISCO), then the position at which the inner disk terminates likely corresponds to the magnetospheric radius. For a spin parameter of a = 0, we estimate a conservative upper limit on the strength of the magnetic field to be B ≤ (0.9 - 3.0) × 109 G at the magnetic poles depending on the choice of conversion factor between spherical and disk accretion.

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

PubMed

Citak, Demirhan; Tuzen, Mustafa; Soylak, Mustafa

2010-01-15

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

Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion

DOE PAGES

Rosenberg, Oren S.; Dovala, Dustin; Li, Xueming; ...

2015-04-09

We report that Mycobacterium tuberculosis and Staphylococcus aureus secrete virulence factors via type VII protein secretion (T7S), a system that intriguingly requires all of its secretion substrates for activity. To gain insights into T7S function, we used structural approaches to guide studies of the putative translocase EccC, a unique enzyme with three ATPase domains, and its secretion substrate EsxB. The crystal structure of EccC revealed that the ATPase domains are joined by linker/pocket interactions that modulate its enzymatic activity. EsxB binds via its signal sequence to an empty pocket on the C-terminal ATPase domain, which is accompanied by an increasemore » in ATPase activity. Surprisingly, substrate binding does not activate EccC allosterically but, rather, by stimulating its multimerization. Thus, the EsxB substrate is also an integral T7S component, illuminating a mechanism that helps to explain interdependence of substrates, and suggests a model in which binding of substrates modulates their coordinate release from the bacterium.« less

Impact of New Nuclear Data Libraries on Small Sized Long Life CANDLE HTGR Design Parameters

NASA Astrophysics Data System (ADS)

Liem, Peng Hong; Hartanto, Donny; Tran, Hoai Nam

2017-01-01

The impact of new evaluated nuclear data libraries (JENDL-4.0, ENDF/B-VII.0 and JEFF-3.1) on the core characteristics of small-sized long-life CANDLE High Temperature Gas-Cooled Reactors (HTGRs) with uranium and thorium fuel cycles was investigated. The most important parameters of the CANDLE core characteristics investigated here covered (1) infinite multiplication factor of the fresh fuel containing burnable poison, (2) the effective multiplication factor of the equilibrium core, (3) the moving velocity of the burning region, (4) the attained discharge burnup, and (5) the maximum power density. The reference case was taken from the current JENDL-3.3 results. For the uranium fuel cycle, the impact of the new libraries was small, while significant impact was found for thorium fuel cycle. The findings indicated the needs of more accurate nuclear data libraries for nuclides involved in thorium fuel cycle in the future.

Multiple APOBEC3 Restriction Factors for HIV-1 and One Vif to Rule Them All

PubMed Central

Desimmie, Belete A.; Delviks-Frankenberry, Krista A.; Burdick, Ryan; Qi, Dongfei; Izumi, Taisuke; Pathak, Vinay K.

2013-01-01

Several members of the APOBEC3 family of cellular restriction factors provide intrinsic immunity to the host against viral infection. Specifically, APOBEC3DE, APOBEC3F, APOBEC3G, and APOBEC3H haplotypes II, V, and VII provide protection against HIV-1Δvif through hypermutation of the viral genome, inhibition of reverse transcription, and inhibition of viral DNA integration into the host genome. HIV-1 counteracts APOBEC3 proteins by encoding the viral protein Vif, which contains distinct domains that specifically interact with these APOBEC3 proteins to ensure their proteasomal degradation, allowing virus replication to proceed. Here, we review our current understanding of APOBEC3 structure, editing and non-editing mechanisms of APOBEC3-mediated restriction, Vif-APOBEC3 interactions that trigger APOBEC3 degradation, and the contribution of APOBEC3 proteins to restriction and control of HIV-1 replication in infected patients. PMID:24189052

Immunomodulatory activity of various fractions derived from Physalis angulata L extract.

PubMed

Lin, Y S; Chiang, H C; Kan, W S; Hone, E; Shih, S J; Won, M H

1992-01-01

The immunomodulatory effects of Physalis angulata L. extract fraction VII (PA-VII), PA-VII-A, PA-VII-B and PA-VII-C were investigated in this study. The results showed that PA-VII and PA-VII-C strongly enhanced blastogenesis response, PA-VII-B had moderate activity, and PA-VII-A exerted only slight effect on cell proliferation. A synergistic effect was observed when the suboptimal dosage of phytohemagglutinin (PHA) or lipopolysaccharide (LPS) was added to the culture. Furthermore, PA-VII and PA-VII-C possessed stimulatory activity on B cells and less effect on T cells. The antibody responses were also augmented by PA-VII, PA-VII-B and PA-VII-C, but not by PA-VII-A. The enhancement of antibody response could be observed both in BALB/c and C3H/HeJ mice.

Coagulation Testing in the Core Laboratory.

PubMed

Winter, William E; Flax, Sherri D; Harris, Neil S

2017-11-08

Primary hemostasis begins with endothelial injury. VWF, produced by endothelial cells, binds to platelets and links them to subendothelial collagen. Platelet-derived ADP and thromboxane activate non-adhered platelets via their GPIIb/IIIa receptors, allowing these platelets to participate in platelet aggregation. Secondary hemostasis is initiated with the binding of factor VII to extravascular tissue factor (TF). Factors II, VII, IX and X are vitamin K-dependent factors. The role of vitamin K is to assist in the addition of gamma carboxylate groups to glutamic acids in the "GLA" domains of these factors.In vitro the intrinsic pathway is initiated when fresh whole blood is placed in a glass tube. The negative charge of the glass initiates the "contact pathway" where FXII is activated and then FXIa cleaves FIX to FIXa. The extrinsic pathway is triggered when tissue factor, phospholipid and calcium are added to plasma anticoagulated with citrate. In vitro, FVII is activated to FVIIa, and TF-FVIIa preferentially converts FX to FXa activating the common pathway.The prothrombin time is commonly used to monitor warfarin anticoagulant therapy. To correct for differences in reagent and instrument, the international normalized ratio was developed to improve standardization of PT reporting globally. The activated partial thromboplastin time (aPTT) is used to evaluate the intrinsic and common pathways of coagulation. The aPTT is useful clinically as a screening test for inherited and acquired factor deficiencies as well as to monitor unfractionated heparin therapy although the anti-Xa assay is now the preferred measure of the effects of unfractionated heparin. The Clauss assay is the most commonly performed fibrinogen assay and uses diluted plasma where clotting is initiated with a high concentration of reagent thrombin.The mixing study assists in the assessment of an abnormally prolonged PT or aPTT. An equal volume of citrated patient plasma is mixed with normal pooled plasma and the PT or aPTT are repeated on the 1:1 mix. Factor activity assays are most commonly performed as a one-stage assay. The patient's citrated plasma is diluted and mixed 1-to-1 with a single factor-deficient substrate plasma. A PT or aPTT is performed on the above mix, depending on the factor being tested.Factor inhibitors are antibodies that are most commonly diagnosed in male patients with severe hemophilia A (FVIII deficiency) where they are induced by factor replacement therapy.Factor inhibitors can also appear in the form of spontaneous autoantibodies in both male and female individuals who were previously well. This is an autoimmune condition called "acquired hemophilia."Most coagulation laboratories can measure the plasma concentration of VWF protein (VWF antigen) by an immunoturbidimetric technique. Testing the functional activity of VWF, utilizes the drug ristocetin.The state of multimerization of VWF is important and is assessed by electrophoresis on agarose gels. Type 2a and 2b VWD are associated with the lack of intermediate- and high molecular weight multimers.The antiphospholipid syndrome (APLS) is an acquired autoimmune phenomenon associated with an increased incidence of both venous and arterial thromboses, as well as fetal loss. Typically, there is a paradoxical prolongation of the aPTT in the absence of any clinical features of bleeding. This is the so-called "lupus anticoagulant (LA) effect." The laboratory definition of the APLS requires the presence of either a "lupus anticoagulant" or a persistent titer of antiphospholipid antibodies.There are now 2 broad classes of direct-acting oral anticoagulants (DOACs): [1] The oral direct thrombin inhibitors (DTIs) such as dabigatran; and [2] The oral direct factor Xa inhibitors such as rivaroxaban and apixaban. The PT and aPTT are variably affected by the DOACs and are generally unhelpful in monitoring their concentrations. Most importantly, a normal PT or aPTT does NOT exclude the presence of any of the DOACs. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Population Inversion and Gain Measurements for Soft X-Ray Laser Development in a Magnetically Confined Plasma Column.

DTIC Science & Technology

1985-09-01

initial conditions for gas target and solid targets. (2) As in (a) but for the Li-like ions CIV, OVI, FVII , NeVIII, AtXI, and SiXII. r,," (3) To...directions indicated an enhancement of CVI 182A line intensity in the axial direction, and population inversion for Li-like CIV, OVI, FVII and NeVII ions12...lines (particularly OVI 173 A line) increased by a factor of 2-3 in comparison to our earlier data.12 Most of the measurements of line intensities

Suzaku Reveals Helium-burning Products in the X-Ray-emitting Planetary Nebula BD +30 3639

NASA Astrophysics Data System (ADS)

Murashima, M.; Kokubun, M.; Makishima, K.; Kotoku, J.; Murakami, H.; Matsushita, K.; Hayashida, K.; Arnaud, K.; Hamaguchi, K.; Matsumoto, H.

2006-08-01

BD +30 3639, the brightest planetary nebula at X-ray energies, was observed with Suzaku, an X-ray observatory launched on 2005 July 10. Using the X-ray Imaging Spectrometer, the K lines from C VI, O VII, and O VIII were resolved for the first time, and the C/O, N/O, and Ne/O abundance ratios were determined. The C/O and Ne/O abundance ratios exceed the solar value by factors of at least 30 and 5, respectively. These results indicate that the X-rays are emitted mainly by helium-shell-burning products.

Finding Uncertainties that Cause the Age Dependence of Dose Limits to Be Immature

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.

2007-01-01

Space radiation permissible exposure limits (PEL) are intended to set acceptable levels of cancer risks, and avoid any clinical significant non-cancer effects. The 1989 recommendation of the National Council of Radiation Protection and Measurements (NCRP) recommended a strong age dependence of dose limits that departed drastically from the then mature 1970 dose limits recommendations from the National Academy of Science, which were independent of age. In 2000, the NCRP recommended revised limits that showed a similar trend of risk with age to the 1989 report. In this model, the cancer risk per Sv varies by more than 2-fold for ages between 30- and 50-yr. Therefore for galactic cosmic rays exposure, astronaut age has a larger influence on risk then radiation shielding mass or material composition, vehicle propulsion method, or position in the solar cycle. For considering the control of mission costs and resources, the possibility of using astronaut age as a trade variable in mission design could be considered. However, the uncertainties in describing the age dependence on risk have not been fully explored. We discuss biological factors that influence the age dependence of radiation risks, including susceptibility, expression and latency, and radiation quality. These factors depend not only on the individual s age, but also their genetic sensitivity and interaction with other environmental factors. Epidemiological data is limited in describing the age dependence on risk. The 2005, BEIR VII report recommends an age dependence for cancer risk attributable solely to the life-table disagreeing strongly with the NCRP model. However, BEIR VII also noted the limited power of human data for concomitantly describing both age and age after exposure dependences of cancer risks. Many experimental studies have shown that high LET radiation (e.g., high charge and energy (HZE) nuclei and neutrons) display reduced latency compared to low LET radiation, suggesting distinct biological factors are important. We discuss potential molecular mechanisms that would influence the age dependence of radiation risks. A probability distribution function for the uncertainties in age-dependence of risk models is described and predictions for Mars missions discussed. Our report suggests that theoretical considerations based on new experimental studies are needed to ensure the correct age dependence in space radiation risk models and the resulting Astronaut PEL.

Anxiety and depression in patients three months after myocardial infarction: Association with markers of coagulation and the relevance of age.

PubMed

Geiser, Franziska; Urbach, Anne Sarah; Harbrecht, Ursula; Conrad, Rupert; Pötzsch, Bernd; Amann, Nele; Kiesewetter, Katharina; Sieke, Alexandra; Wolffs, Kyra; Skowasch, Dirk

2017-08-01

Anxiety and depression are associated with an activation of coagulation and an impairment of fibrinolysis, which may contribute to the increased cardiovascular risk associated with the two disorders. However, very few studies have examined the impact of psychological distress on coagulation factors in coronary artery disease patients. The aim of this study was to assess the correlation between anxiety/depression and factors of coagulation and fibrinolysis in patients who had suffered an acute MI three months prior. In 148 patients, anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS) shortly after MI and three months later. At the second time of assessment, plasma levels of fibrinogen, factor VII, factor VIII, von Willebrand factor, prothrombin-fragment 1 and 2, tissue-plasminogen-activator, plasminogen activator inhibitor-1, D-dimer, and homocysteine were measured. In 32% of the patients, elevated levels of anxiety and depression were found three months after a MI. Multiple regression analyses showed that coagulation and fibrinolysis markers were not significantly associated with HADS anxiety and depression scores. We found that age, gender, BMI, and smoking status were significant predictors for haemostasis factors. A higher age was associated with a higher coagulability but lower anxiety levels. We measured parameters of coagulation and fibrinolysis in patients three months after MI and found no predictive value of HADS anxiety and depression scores shortly after MI or at the time of blood sampling. The effects of age on the relationship between anxiety and haemostasis should be further investigated. Copyright © 2017 Elsevier Inc. All rights reserved.

Source apportionment revisited for long-term measurements of fine aerosol trace elements at two locations in southern Norway

NASA Astrophysics Data System (ADS)

Maenhaut, Willy

2018-02-01

Five-year-long (1991-1996) aerosol trace element data sets for the fine (PM2) size fraction from the sites of Birkenes and Skreådalen in southern Norway were reanalysed by US EPA positive matrix factorization PMF5 in order to assess the sources and their contribution to the PM2 aerosol. The data sets contained the concentrations of the particulate mass (PM), black carbon (BC) and 21 elements in over 700 samples for each of the two sites. The PM was obtained from weighing with a microbalance and BC was determined with a light reflectance technique. The data for the elements were obtained by a combination of particle-induced X-ray emission and instrumental neutron activation analysis. Eight source factors were retained for each site, i.e., (i) secondary sulfate, which accounted for around 40% of the average measured PM2 mass, (ii) wood burning, with BC, K, Zn and As, which accounted for about 17%, (iii) an iodine factor (with also Br and Se), which is probably related to a marine biogenic source and was responsible for about 6.5%, (iv) aged sea salt with Na, Mg, Cl and Ca, but heavily depleted in Cl; (v) a crustal factor containing Al, Si, Ca, Ti and Fe; (vi) a heavy oil burning factor with V and Ni in a ratio of 3-4; (vii) a general pollution factor (with Cu, Zn, As, Se, Sb and Pb), and (viii) an almost pure manganese factor, which is attributed to Mn and FeMn industries in southern Norway. The results were substantially different from those of an earlier PMF analysis, in which use was made of PMF2.

Spectrophotometry of VIIZW421 and IIZW67 - s0 Galaxies Dominated by Young Stars

NASA Astrophysics Data System (ADS)

Sparke, L. S.; Kormendy, J.; Spinrad, H.

1980-02-01

We investigate the stellar content of two SO galaxies whose spectra show deep Balmer absorption lines but little emission. Continuum colors and the Faber-Burstein (Mg)0 index show that the blue light is dominated by young stars. In VII Zw 421 there is a radial population gradient; the nucleus has relatively more young stars than the lens. An approximate spectral synthesis confirms the need for young (rather than metal-poor) stars to produce sufficiently strong Balmer lines. In VII Zw 421 the best synthesis implies that 45Th of the nuclear light at 5000 Å comes from stars close to A1 V in type. In the lens, the young-star contribution is smaller by a factor of 2-3. Also, in the nucleus only, the observed Na D lines are much stronger than in our model. This suggests a connection with the young component and supports Faber and Burstein's conclusion that abnormally strong Na D absorption is sometimes interstellar. Thus VII Zw 421 and II Zw 67 are similar to NGC 5102, the nearest SO galaxy dominated by young stars. The present SO's provide important constraints on any interpretation of the young component. At - 19.9 and -21.5 absolute B mag (H0 = 50 km s-1 1 Mpc-1), they are unusually luminous for their early-type spectra. They are also unusually compact, which may provide them with gravitational potential wells deep enough to retain gas despite processes which remove gas from other early-type galaxies.

High-Fat Diet Increased Renal and Hepatic Oxidative Stress Induced by Vanadium of Wistar Rat.

PubMed

Wang, J P; Cui, R Y; Zhang, K Y; Ding, X M; Luo, Y H; Bai, S P; Zeng, Q F; Xuan, Y; Su, Z W

2016-04-01

The study was conducted to assess the effect of vanadium (V) in high-fat diet on the liver and kidney of rats in a 5-week trial. Seventy-two female Wistar rats (BW = 95 ± 5 g) were randomly allotted into eight groups. Groups I, II, III, and IV obtained low-fat diet containing 0, 3, 15, and 30 mg/kg V, and V, VI, VII, and VIII groups received the respective vanadium doses with high-fat diet, respectively. There were lesions in the liver and kidney of V, VI, VII, and VIII groups, granular degeneration and vacuolar degeneration were observed in the renal tubular and glomerulus epithelial cells, and hepatocytes showed granular degeneration and vacuolar degeneration. Supplemented high-fat diet with vanadium was shown to decrease (P < 0.05) activities of superoxide dismutase, total antioxidant capacity, glutathione-S transferase, and NAD(P)H/quinone oxidoreductase 1 (NQO1) and increase malondialdehyde content in the liver and kidney. The relative expression of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and NQO1 mRNA was downregulated by V addition and high-fat diet, and the effect of V was more pronounced in high-fat diet (interaction, P < 0.05), with VIII group having the lowest mRNA expression of Nrf-2 and NQO1 in the liver and kidney. In conclusion, it suggested that dietary vanadium ranging from 15 to 30 mg/kg could lead to oxidative damage and vanadium accumulation in the liver and kidney, which caused renal and hepatic toxicity. The high-fat diet enhanced vanadium-induced hepatic and renal damage, and the mechanism was related to the modulation of the hepatic and renal mRNA expression of Nrf-2 and NQO1.

The molecular basis of low activity levels of coagulation factor VII: a Brazilian cohort.

PubMed

Rabelo, F Y; Jardim, L L; Landau, M B; Gadelha, T; Corrêa, M F B; Pereira, I F M; Rezende, S M

2015-09-01

Inherited factor VII (FVII) deficiency is the most common among the rare bleeding disorders. It is transmitted as an autosomal recessive inheritance, due to mutations in the FVII gene (F7). Molecular studies of FVII deficiency are rare in non-Caucasian populations. The aim of the study was to evaluate the molecular basis behind low levels of FVII activity (FVII:C) levels in a cohort of Brazilian patients. A total of 34 patients with low FVII levels were clinically evaluated and submitted to laboratory tests, among these, prothrombin time and FVII:C, with different thromboplastins. All exons and intron/exon boundaries of F7 were amplified and sequenced. A total of 14 genetic alterations were identified, of which six were described previously, c.1091G>A, c.1151C>T, c.-323_-313insCCTATATCCT, c.285G>A, c.525C>T, c.1238G>A and eight (54.0%) and eight were new, c.128G>A, c.252C>T, c.348G>A, c.417G>A, c.426G>A, c.745_747delGTG, c.843G>A and c.805+52C>T. In addition to the mutation c.1091G>A, known as FVII Padua, the mutation c.1151C>T also presented discrepant FVII:C levels when tested with human and rabbit brain thromboplastin. There was no association between phenotype and genotype. Most of the identified genetic alterations found were polymorphisms. Low levels of FVII:C in this population were mostly related to polymorphisms in F7 and associated with a mild clinical phenotype. Mutation c.1151C>T was associated with discrepant levels of FVII:C using different thromboplastins, such as reported with FVII Padua. © 2015 John Wiley & Sons Ltd.

A novel missense mutation close to the charge-stabilizing system in a patient with congenital factor VII deficiency.

PubMed

Jiang, Minghua; Wang, Zhaoyue; Yu, Ziqiang; Bai, Xia; Su, Jian; Cao, Lijuan; Zhang, Wei; Ruan, Changgeng

2011-06-01

Congenital factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder. Its clinical manifestation and mutational spectrum are highly variable. The purpose of this study was to identify and characterize the mutation causing the FVII deficiency in a Chinese patient and his family. The FVII gene was analyzed by genomic DNA sequencing, and the FVII levels in patient's plasma were measured with an enzyme-linked immunoabsorbent assay (ELISA) and one-stage prothrombin time based method. In addition, the FVII-Phe190 mutant identified in the pedigree was expressed in the HEK293 cells, and the subcellular localization experiments in the Chinese hamster ovary (CHO) cells were performed. The patient had a prolonged prothrombin time and low levels of both FVII antigen and activity, and two heterozygous mutations were identified in F7 gene (NG-009262.1): a g.15975 G>A in the splice receptor site of intron 6 and a novel g.16750 C>T in exon 8 resulting in Ser190 to Phe190 replacement. In expression experiments, the reduced antigen and activity levels of FVII-Phe190 in the culture medium were found, whereas an ELISA and Western blotting analysis of FVII revealed that mutant FVII-Phe190 was synthesized in the cells as the wild-type FVII-Ser190. And FVII-Phe190 was found in endoplasmic reticulum and Golgi apparatus. Compound heterozygous mutations in F7 gene should be responsible for the FVII deficiency in this patient. The FVII-Phe190 can normally be synthesized and transported from endoplasmic reticulum to Golgi apparatus, but degraded or inefficiently secreted.

Expression and fast preparation of biologically active recombinant human coagulation factor VII in CHO-K1 cells.

PubMed

Xiao, W; Li, C Q; Xiao, X P; Lin, F Z

2013-12-16

Human coagulation factor VII (FVII) plays an important role in the blood coagulation process and exists in micro amounts in human plasma; therefore, any attempt at the large-scale production of FVII in significant quantities is challenging. The purpose of this study was to express and obtain biologically active recombinant FVII (rFVII) from Chinese hamster ovary K1 (CHO-K1) cells. The full-length FVII cDNA was isolated from a HepG2 cell line and then subcloned in pcDNA3.1 to construct an expression vector, pcDNA-FVII. CHO-K1 cells were transfected with 1 µg pcDNA-FVII. The cell line that stably expressed secretory FVII was screened using 900 µg/mL G418. The FVII copy number in CHO-K1 cells was detected by quantitative polymerase chain reaction (qPCR). The rFVII was purified in ligand affinity chromatography medium. The purified protein was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis. The biological activity of the purified FVII protein was determined by a prothrombin time assay. Three cell lines that permanently expressed rFVII were screened. The qPCR results demonstrated that each CHO-K1 cell harbored two FVII DNA copies. The SDS-PAGE and Western blot analysis showed that the purified protein was about 50 kDa. The purity of the target protein was 95%. The prothrombin time assay indicated that the FVII-specific activity of rFVII was 2573 ± 75 IU/mg. This method enabled the fast preparation of high-purity rFVII from CHO-K1 cells, and the purified protein had good biological activity.

Recombinant activated factor VII in the treatment of non-haemophilia patients: physician under-reporting of thromboembolic adverse events.

PubMed

Hsia, C C; Zurawska, J H; Tong, M Z Y; Eckert, K; McAlister, V C; Chin-Yee, I H

2009-02-01

The objective of this study was to determine if clinically important thromboembolic adverse events (TAEs) because of recombinant activated factor VII (rFVIIa) administration are being under-reported. rFVIIa is a potent haemostatic agent with a short half-life of 2.6 h that is increasingly used in 'off-label' situations. Retrospective review of 94 patients who received rFVIIa during 1 January 2003 to 30 June 2007 was carried out at a tertiary care centre. Sixty-nine patients, 32 females and 37 males, mean age 55 years (18-84 years), satisfied study criteria of off-label usage. This was a high-risk population with 33 (48%) deaths. A mean dose of 8.2 mg (2.4-19.2 mg) was administered in two average divided doses. Thirty-six potential TAEs were identified in 29 patients, and of these, 12 patients had TAEs deemed to be rFVIIa related and were identified on average 8.8 days after exposure to rFVIIa. Forty-eight (70%) physician questionnaires were completed; however, no TAEs were reported in these questionnaires or on chart review. Potential clinically significant TAEs are being under-reported by treating physicians. Until further evidence, we suggest the urgent need to develop consensus recommendations for utilization and required follow up to monitor the safety of rFVIIa and that at a minimum, all use of rFVIIa should be regulated through a gate-keeping mechanism that ensures adherence to these policies. Furthermore, prospective registries and trials are necessary to evaluate the efficacy and safety of rFVIIa in off-label settings.

Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium.

PubMed

Peng, Lin; Yu, Xiao; Li, Chengyuan; Cai, Yanfei; Chen, Yun; He, Yang; Yang, Jianfeng; Jin, Jian; Li, Huazhong

2016-04-01

Signal peptides play an important role in directing and efficiently transporting secretory proteins to their proper locations in the endoplasmic reticulum of mammalian cells. The aim of this study was to enhance the expression of recombinant coagulation factor VII (rFVII) in CHO cells by optimizing the signal peptides and type of fed-batch culture medium used. Five sub-clones (O2, I3, H3, G2 and M3) with different signal peptide were selected by western blot (WB) analysis and used for suspension culture. We compared rFVII expression levels of 5 sub-clones and found that the highest rFVII expression level was obtained with the IgK signal peptide instead of Ori, the native signal peptide of rFVII. The high protein expression of rFVII with signal peptide IgK was mirrored by a high transcription level during suspension culture. After analyzing culture and feed media, the combination of M4 and F4 media yielded the highest rFVII expression of 20 mg/L during a 10-day suspension culture. After analyzing cell density and cell cycle, CHO cells feeding by F4 had a similar percentage of cells in G0/G1 and a higher cell density compared to F2 and F3. This may be the reason for high rFVII expression in M4+F4. In summary, rFVII expression was successfully enhanced by optimizing the signal peptide and fed-batch medium used in CHO suspension culture. Our data may be used to improve the production of other therapeutic proteins in fed-batch culture.

Differences in N-glycosylation of recombinant human coagulation factor VII derived from BHK, CHO, and HEK293 cells.

PubMed

Böhm, Ernst; Seyfried, Birgit K; Dockal, Michael; Graninger, Michael; Hasslacher, Meinhard; Neurath, Marianne; Konetschny, Christian; Matthiessen, Peter; Mitterer, Artur; Scheiflinger, Friedrich

2015-09-18

BACKGROUND & Recombinant factor VII (rFVII), the precursor molecule for recombinant activated FVII (rFVIIa), is, due to its need for complex post translational modifications, produced in mammalian cells. To evaluate the suitability of a human cell line in order to produce rFVII with post-translational modifications as close as possible to pdFVII, we compared the biochemical properties of rFVII synthesized in human embryonic kidney-derived (HEK)293 cells (HEK293rFVII) with those of rFVII expressed in Chinese hamster ovary (CHO, CHOrFVII) and baby hamster kidney (BHK, BHKrFVII) cells, and also with those of plasma derived FVII (pdFVII), using various analytical methods. rFVII was purified from selected production clones derived from BHK, CHO, and HEK293 cells after stable transfection, and rFVII isolates were analyzed for protein activity, impurities and post-translational modifications. RESULTS & The analytical results showed no apparent gross differences between the various FVII proteins, except in their N-linked glycosylation pattern. Most N-glycans found on rFVII produced in HEK293 cells were not detected on rFVII from CHO and BHK cells, or, somewhat unexpectedly, on pdFVII; all other protein features were similar. HEK293rFVII glycans were mainly characterized by a higher structural variety and a lower degree of terminal sialylation, and a high amount of terminal N-acetyl galactosamines (GalNAc). All HEK293rFVII oligosaccharides contained one or more fucoses (Fuc), as well as hybrid and high mannose (Man) structures. From all rFVII isolates investigated, CHOrFVII contained the highest degree of sialylation and no terminal GalNAc, and CHO cells were therefore assumed to be the best option for the production of rFVII.

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

PubMed

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

2006-11-01

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

Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs

PubMed Central

Zhang, Jun; Groff, Robert F.; Chen, Xiao-Han; Browne, Kevin D.; Huang, Jason; Schwartz, Eric D.; Meaney, David F.; Johnson, Victoria E.; Stein, Sherman C.; Rojkjaer, Rasmus; Smith, Douglas H.

2012-01-01

Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI. PMID:18291370

Intake of phenol-rich virgin olive oil improves the postprandial prothrombotic profile in hypercholesterolemic patients.

PubMed

Ruano, Juan; López-Miranda, José; de la Torre, Rafael; Delgado-Lista, Javier; Fernández, Javier; Caballero, Javier; Covas, María Isabel; Jiménez, Yolanda; Pérez-Martínez, Pablo; Marín, Carmen; Fuentes, Francisco; Pérez-Jiménez, Francisco

2007-08-01

Oxidative stress associated with postprandial lipemia contributes to endothelial dysfunction, which shifts hemostasis to a more thrombogenic state. We investigated whether a high concentration of phenols in olive oil can partly reverse this phenomenon. Twenty-one hypercholesterolemic volunteers received 2 breakfasts rich in olive oils with different phenolic contents (80 or 400 ppm) according to a randomized, sequential crossover design. Plasma concentrations of lipid fractions, factor VII antigen (FVIIag), activated factor VII (FVIIa), and plasminogen activator inhibitor-1 (PAI-1) activity were measured at baseline and postprandially. Concentrations of FVIIa increased less (P = 0.018) and plasma PAI-1 activity decreased more (P = 0.021) 2 h after the high-phenol meal than after the low-phenol meal. FVIIa concentrations 120 min after intake of the olive oil with a high phenol content correlated positively with fasting plasma triacylglycerols (P = 0.001), area under the curve (AUC) of triacylglycerols (P = 0.001), and AUC of nonesterified fatty acids (P = 0.024) and negatively with hydroxytyrosol plasma concentrations at 60 min (P = 0.039) and fasting HDL-cholesterol concentrations (P = 0.005). PAI-1 positively correlated with homeostasis model assessment of insulin resistance (P = 0.005) and fasting triacylglycerols (P = 0.025) and inversely with adiponectin (P = 0.026). In a multivariate analysis, the AUCs of nonesterified fatty acids (R(2) = 0.467; beta: 0.787; SE: 0.02; P < 0.001) and adiponectin (R(2) = 0.232; beta: -1.594; SE: 0.629; P < 0.05) were the strongest predictors of plasma FVIIa and PAI-1, respectively. A virgin olive oil with a high content of phenolic compounds changes the postprandial hemostatic profile to a less thrombogenic state.

Differential permeability of the blood-testis barrier during reinitiation of spermatogenesis in adult male rats.

PubMed

Haverfield, Jenna T; Meachem, Sarah J; Nicholls, Peter K; Rainczuk, Katarzyna E; Simpson, Evan R; Stanton, Peter G

2014-03-01

The blood-testis barrier (BTB) sequesters meiotic spermatocytes and differentiating spermatids away from the vascular environment. We aimed to assess whether meiosis and postmeiotic differentiation could occur when the BTB is permeable. Using a model of meiotic suppression and reinitiation, BTB function was assessed using permeability tracers of small, medium, and large (0.6-, 70-, and 150-kDa) sizes to emulate blood- and lymphatic-borne factors that could cross the BTB. Adult rats (n = 9/group) received the GnRH antagonist acyline (10 wk) to suppress gonadotropins, followed by testosterone (24cm Silastic implant), for 2, 4, 7, 10, 15, and 35 days. In acyline-suppressed testes, all tracers permeated the seminiferous epithelium. As spermatocytes up to diplotene stage XIII reappeared, both the 0.6- and 70-kDa tracers, but not 150 kDa, permeated around these cells. Intriguingly, the 0.6- and 70-kDa tracers were excluded from pachytene spermatocytes at stages VII and VIII but not in subsequent stages. The BTB became progressively impermeable to the 0.6- and 70-kDa tracers as stages IV-VII round spermatids reappeared in the epithelium. This coincided with the appearance of the tight junction protein, claudin-12, in Sertoli cells and at the BTB. We conclude that meiosis can occur when the BTB is permeable to factors up to 70 kDa during the reinitiation of spermatogenesis. Moreover, BTB closure corresponds with the presence of particular pachytene spermatocytes and round spermatids. This research has implications for understanding the effects of BTB dynamics in normal spermatogenesis and also potentially in states where spermatogenesis is suppressed, such as male hormonal contraception or infertility.

Intra-patient variability of thromboelastographic parameters following in vivo and ex vivo administration of recombinant activated factor VII in haemophilia patients. A multi-centre, randomised trial.

PubMed

Kenet, G; Stenmo, C B; Blemings, A; Wegert, W; Goudemand, J; Krause, M; Schramm, W; Kirchmaier, C; Martinowitz, U

2010-02-01

Thromboelastography methods have been used to predict or monitor treatment of haemophilia patients with recombinant activated factor VII (rFVIIa). However, neither of the two thromboelastographic methods (ROTEM and TEG) has as yet been validated. This multi-centre, randomised trial compared both methods in terms of intra- and inter- patient variability following in vivo and ex vivo rFVIIa administration to haemophilia A and B patients with and without inhibitors. Patients ((3)16 years old) received the same intravenous rFVIIa dose (45, 90 or 180 microg/kg) twice, 1-12 weeks apart. Blood samples were collected pre-dose and 15, 60, 120 and 240 minutes post-dose for ROTEM and TEG analysis. Pre-dose samples were also spiked ex vivo with rFVIIa (0.6, 1.2 or 2.4 microg/ml), to correspond to the three in vivo doses. Twenty-six haemophilia A and four haemophilia B patients were enrolled. A significant treatment effect was observed with in vivo rFVIIa (p<0.05) with more pronounced effects in inhibitor (n=14) versus non-inhibitor (n=16) patients. There was a strong positive correlation between ROTEM and TEG parameters. Intra- and inter-patient variation was large for all thromboelastography parameters at all time points and rFVIIa doses. Intra-patient variation was generally lower for non-inhibitor than inhibitor patients, and lower following ex vivo spiking versus in vivo rFVIIa administration. In conclusion, there was a clear effect of rFVIIa on all thromboelastography parameters, but the large intra- and inter-patient variability following in vivo rFVIIa administration renders the use of our method unsuitable for dose-response prediction for haemophilia patients in the clinical setting.

Hemorrhage under veno-venous extracorporeal membrane oxygenation in acute respiratory distress syndrome patients: a retrospective data analysis

PubMed Central

Muders, Thomas; Theuerkauf, Nils; Spitzhüttl, Juliane; Schellhaas, Torsten; Schewe, Jens-Christian; Guenther, Ulf; Wrigge, Hermann; Putensen, Christian

2017-01-01

Background Despite being still invasive and challenging, technical improvement has resulted in broader and more frequent application of extracorporeal membrane oxygenation (ECMO), to prevent hypoxemia and to reduce invasiveness of mechanical ventilation (MV). Heparin-coated ECMO-circuits are currently standard of care, in addition to heparin based anticoagulation (AC) regimen guided by activated clotting time (ACT) or activated partial thromboplastin time (aPTT). Despite these advances, a reliable prediction of hemorrhage is difficult and the risk of hemorrhagic complication remains unfortunately high. We hypothesized, that there are coagulation parameters that are indices for a higher risk of hemorrhage under veno-venous (VV)-ECMO therapy. Methods Data from 36 patients with severe respiratory failure treated with VV-ECMO at a University Hospital intensive care unit (ICU) were analyzed retrospectively. Patients were separated into two groups based on severity of hemorrhagic complications and transfusion requirements. The following data were collected: demographics, hemodynamic data, coagulation samples, transfusion requirements, change of ECMO-circuit during treatment and adverse effects, including hemorrhage and thrombosis. Results In this study 74 hemorrhagic events were observed, one third of which were severe. Patients suffering from severe hemorrhage had a lower survival rate on VV-ECMO (43% vs. 91%; P=0.002) and in ICU (36% vs. 86%; P=0.002). SAPS II, factor VII and X were different between mild and severe hemorrhage group. Conclusions Severe hemorrhage under VV-ECMO is associated with higher mortality. Only factor VII and X differed between groups. Further clinical studies are required to determine the timing of initiation and targets for AC therapies during VV-ECMO. PMID:29312706

Health economics of treating haemophilia A with inhibitors.

PubMed

Knight, C

2005-11-01

Haemophilia is a rare, inherited blood disorder in which blood clotting is impaired such that patients suffer from excessive internal and external bleeding. At present there is no cure for haemophilia A and patients require expensive, life-long treatment involving clotting factor replacement therapy. Treatment costs are perceived to be higher for patients who have developed inhibitory antibodies to factor VIII, the standard therapy for haemophilia A. However, initial cost analyses suggest that clotting factor therapy with alternative haemostatic agents, such as recombinant activated factor VII or activated prothrombin complex concentrate, is no more expensive for the majority of haemophilia A patients with inhibitors than for those without inhibitors. With the availability of effective alternative haemostatic agents, orthopaedic surgery for haemophilia A patients with inhibitors is now a clinical option, and initial cost analyses suggest this may be a cost-effective treatment strategy for patients with inhibitors whose quality of life (QoL) is severely impaired by joint arthropathy. In an era of finite healthcare resourcing it is important to determine whether new treatments justify higher unit costs compared with standard therapies and whether such higher costs are justified from an individual perspective in terms of improved QoL, and from a societal perspective in terms of improved productivity and reduced overall healthcare costs. This paper examines current data on the health economics of treating haemophilia A patients with inhibitors, focusing on the overall costs of clotting factor replacement therapy and the cost consequences of joint replacement.

Rediscovering the wound haematoma as a site of haemostasis during major arterial haemorrhage

PubMed Central

White, N.J.; Mehic, E.; Wang, X.; Chien, D.; Lim, E.; St. John, A.E.; Stern, S.A.; Mourad, P.D.; Rieger, M.; Fries, D.; Martinowitz, U.

2015-01-01

Background Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical haemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial haemostasis, or how these commonly-used treatments might influence haemostasis. Objectives (1) Use a swine model of femoral artery bleeding to understand the perivascular haemostatic response to contained arterial haemorrhage. (2) Directly confirm the association between hemodynamics and bleeding velocity. (3) Observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach. Methods Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery haemorrhage was also used to demonstrate feasibility of local delivery of an activated clotting factor. Results In this model, clots formed slowly within the peri-wound hematoma , but eventually containing the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated Factor VII into the injured artery nearby the site of major internal haemorrhage in the pelvis and axillae was feasible. Conclusions We rediscover that clot formation within the peri-wound haematoma is an integral component of haemostasis and a feasible target for treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach. PMID:26414624

Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage.

PubMed

Switzer, Jeffrey A; Rocker, Jody; Mohorn, Phillip; Waller, Jennifer L; Hughes, Douglas; Bruno, Askiel; Nichols, Fenwick T; Hess, David C; Natarajan, Kavita; Fagan, Susan C

2012-09-01

The effectiveness of prothrombin complex concentrate (PCC) products available in the United States that contain low levels of factor VII (3-factor PCC) has not been tested. The purpose of this study was to review our experience with 3-factor PCC (Profilnine) in the setting of warfarin-associated intracranial hemorrhage (wICH). In November 2007, we implemented a protocol for reversal of anticoagulation in wICH using Profilnine. Additional treatment with fresh-frozen plasma was at the discretion of the treating physician. Medical records of all patients receiving PCC for wICH between November 1, 2007, and December 7, 2011 were reviewed. Correction of the international normalized rate (INR) was defined as an INR <1.4. Seventy wICH patients were treated with Profilnine, including 46 (66%) with intraparenchymal hemorrhage, 22 (31%) with subdural hemorrhage, and 2 (3%) with subarachnoid hemorrhage. Mean INR was reduced from 3.36 to 1.96, and in 44 (62.9%) patients the INR corrected to <1.4. Baseline INR ≥3.0 decreased the likelihood of INR correction. Concomitant administration of fresh-frozen plasma (mean, 2.6 U) did not increase the likelihood of INR correction. Seven (10%) patients had serious adverse events during their hospital course, including 2 sudden deaths from suspected pulmonary embolism. Reversal of coagulopathy in wICH with Profilnine was incomplete and associated with serious adverse events. In the absence of available 4-factor PCC, options for urgent reversal of anticoagulation in wICH remain limited.

Estimation of effective dose and lifetime attributable risk from multiple head CT scans in ventriculoperitoneal shunted children.

PubMed

Aw-Zoretic, J; Seth, D; Katzman, G; Sammet, S

2014-10-01

The purpose of this review is to determine the averaged effective dose and lifetime attributable risk factor from multiple head computed tomography (CT) dose data on children with ventriculoperitoneal shunts (VPS). A total of 422 paediatric head CT exams were found between October 2008 and January 2011 and retrospectively reviewed. The CT dose data was weighted with the latest IRCP 103 conversion factor to obtain the effective dose per study and the averaged effective dose was calculated. Estimates of the lifetime attributable risk were also calculated from the averaged effective dose using a conversion factor from the latest BEIR VII report. Our study found the highest effective doses in neonates and the lowest effective doses were observed in the 10-18 years age group. We estimated a 0.007% potential increase risk in neonates and 0.001% potential increased risk in teenagers over the base risk. Multiple head CTs in children equates to a slight potential increase risk in lifetime attributable risk over the baseline risk for cancer, slightly higher in neonates relative to teenagers. The potential risks versus clinical benefit must be assessed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia.

PubMed

Reshetnikov, Evgeny; Zarudskaya, Oksana; Polonikov, Alexey; Bushueva, Olga; Orlova, Valentina; Krikun, Evgeny; Dvornyk, Volodymyr; Churnosov, Mikhail

2017-07-01

The aim of this study was to examine the role of hereditary thrombophilia in the development of fetal growth retardation (FGR) in the population of Central Russia. The case-control study sample included 497 women in the third trimester of pregnancy recruited during 2009-2013. The participants were enrolled into two groups: patients with FGR (n = 250) and controls without FGR (n = 247). The participants were genotyped for four genetic markers of hereditary thrombophilia: factor V Leiden (G > A FV, rs6025), prothrombin (G > A FII, rs1799963), factor VII (G > A FVII, rs6046), and fibrinogen (G > A FI, rs1800790). The genetic factors for an increased risk of FGR were allele G of rs6046 (odds ratio [OR] = 2.34) and genotype GG of rs6046 (OR = 2.64), whereas genotype GA of rs6046 had the protective value (OR = 0.42). A combination of alleles G of rs1799963, A of rs6046, and G of rs1800790 (OR = 0.31) reduces the risk of FGR. Polymorphism rs6046 of the FVII gene is associated with the development of FGR. © 2017 Japan Society of Obstetrics and Gynecology.

Effect of circulating tissue factor on hypercoagulability in type 2 diabetes mellitus studied by rheometry and dielectric blood coagulometry.

PubMed

Uchimura, Isao; Kaibara, Makoto; Nagasawa, Masayuki; Hayashi, Yoshihito

2016-01-01

Hypercoagulability in type 2 diabetes mellitus (T2DM) patients increases their risk of cardiovascular diseases. The aim of this work was to investigate the hypercoagulation mechanism in T2DM patients in terms of circulating tissue factor (TF). Whole blood coagulation tests by damped oscillation rheometry and dielectric blood coagulometry (DBCM) were performed. The average coagulation time was significantly shorter for T2DM patients than for healthy controls. In vitro addition of either anti-TF or anti-activated factor VII (FVIIa) antibody to hypercoagulable blood samples prolonged coagulation times for one group of patients, while coagulation times remained short for another group. The levels of circulating TF were estimated in the former group by measuring the coagulation times for blood samples from healthy subjects with addition of various concentrations of TF and comparing them with the coagulation times for the group. The results indicated that the levels of circulating TF were on the order of subpicomolar at most. Circulating TF is at least partially responsible for a hypercoagulable group of T2DM patients, while an abnormality in the intrinsic coagulation pathway probably occurs in the other group.

Alternatives to allogeneic platelet transfusion.

PubMed

Desborough, Michael J R; Smethurst, Peter A; Estcourt, Lise J; Stanworth, Simon J

2016-11-01

Allogeneic platelet transfusions are widely used for the prevention and treatment of bleeding in thrombocytopenia. Recent evidence suggests platelet transfusions have limited efficacy and are associated with uncertain immunomodulatory risks and concerns about viral or bacterial transmission. Alternatives to transfusion are a well-recognised tenet of Patient Blood Management, but there has been less focus on different strategies to reduce bleeding risk by comparison to platelet transfusion. Direct alternatives to platelet transfusion include agents to stimulate endogenous platelet production (thrombopoietin mimetics), optimising platelet adhesion to endothelium by treating anaemia or increasing von Willebrand factor levels (desmopressin), increasing formation of cross-linked fibrinogen (activated recombinant factor VII, fibrinogen concentrate or recombinant factor XIII), decreasing fibrinolysis (tranexamic acid or epsilon aminocaproic acid) or using artificial or modified platelets (cryopreserved platelets, lyophilised platelets, haemostatic particles, liposomes, engineered nanoparticles or infusible platelet membranes). The evidence base to support the use of these alternatives is variable, but an area of active research. Much of the current randomised controlled trial focus is on evaluation of the use of thrombopoietin mimetics and anti-fibrinolytics. It is also recognised that one alternative strategy to platelet transfusion is choosing not to transfuse at all. © 2016 John Wiley & Sons Ltd.

Low plasma FVII:C and activated FVII as predictive markers for overt disseminated intravascular coagulation.

PubMed

Lertthammakiat, Surapong; Anantasit, Nattachai; Anurathapan, Usanarat; Sirachainan, Nongnuch; Kadegasem, Praguywan; Chuansumrit, Ampaiwan

2017-07-26

In sepsis, binding of factor VII (FVII:C) and activated factor VII (FVIIa) with tissue factor is the key step of coagulation resulting in disseminated intravascular coagulation (DIC). We conducted a prospective cohort study among 47 septic patients, aged 8 months to 18.8 years. They were initially divided into three groups of no DIC (n=27), non-overt DIC (n=14) and overt DIC (n=6). Blood samples were collected at 0, 24 and 48 hours (h) after the onset of sepsis. At the onset of sepsis, FVII:C tended to be lower in the non-overt DIC [median 57 % (interquartile range [IQR] 41-80)] and overt DIC groups [33 % (23-52)] than that in the no DIC group [65 % (44-87)]. Whereas FVIIa tended to be lower in the overt DIC group [1.29 % (0.50-4.19)] than those in the non-overt DIC [3.01 % (1.01-5.24)] and no DIC groups [2.49 % (1.14-3.13)]. At 24 h, FVII:C was significantly lower in the non-overt DIC [57 % (41-101)] and overt DIC groups [31 % (28-49)] than that in the no DIC group [83 % (70-102)]. While FVIIa was significantly lower in the overt DIC group [2.15 % (0.86-3.96)] than that in the no DIC group [3.83 % (2.90-5.46)]. Using FVII:C <65 % or FVIIa <3 % at 24 h among patients without hepatic dysfunction to determine overt DIC at 24 h, the sensitivity was 83.9 % and 77.4 %, respectively, and the specificity was both 83.3 %. Patients with low FVII:C and low FVIIa at 24 h after the onset of sepsis had a 20.8-fold (95 % confidence interval [CI], 2.0-213.0, p=0.010) and 14.4-fold (95 %CI, 1.5-142.4, p=0.023) chance of overt DIC.

First Detection of Krypton and Xenon in a White Dwarf

NASA Astrophysics Data System (ADS)

Werner, Klaus; Rauch, Thomas; Ringat, Ellen; Kruk, Jeffrey W.

2012-07-01

We report on the first detection of the noble gases krypton (Z = 36) and xenon (54) in a white dwarf. About 20 Kr VI- VII and Xe VI- VII lines were discovered in the ultraviolet spectrum of the hot DO-type white dwarf RE 0503-289. The observations, performed with the Far Ultraviolet Spectroscopic Explorer, also reveal highly ionized photospheric lines from other trans-iron group elements, namely Ga (31), Ge (32), As (33), Se (34), Mo (42), Sn (50), Te (52), and I (53), from which gallium and molybdenum are new discoveries in white dwarfs, too. For Kr and Xe, we performed an NLTE analysis and derived mass fractions of log Kr = -4.3 ± 0.5 and log Xe = -4.2 ± 0.6, corresponding to an enrichment by factors of 450 and 3800, respectively, relative to the Sun. The origin of the large overabundances is unclear. We discuss the roles of neutron-capture nucleosynthesis in the precursor star and radiation-driven diffusion. It is possible that diffusion is insignificant and that the observed metal abundances constrain the evolutionary history of the star. Its hydrogen deficiency may be the consequence of a late helium-shell flash or a binary white dwarf merger.

A molecular dynamic investigation for shock induced phase transition of water

NASA Astrophysics Data System (ADS)

Mitra, Nilanjan; Neogi, Anupam

2015-06-01

Atomistic equilibrium molecular dynamics (EMD) was carried out to investigate shock induced phase transition of bulk liquid water. Multi-scale shock technique (MSST) was utilized to investigate low (US = 2 . 5km /s) to strong (US = 6 . 5km /s) intensity shock response on an extended flexible three point model up to 100 ns. The thermodynamic pathway of phase transition from liquid water to ice VII was investigated using temporal variation of thermodynamic state variables, power spectrum analyses of O-H bond vibration along with temporal evolution of pair correlation function between O-O, O-H and H-H atoms. Static structure factor along with pair-distribution function extended up to 20 Å was calculated and compared against the ideal ice VII to get information regarding long range ordering. Bragg reflection at different crystal planes were evaluated to investigate percentage of crystallinity of the shocked sample. Specific questions answered in this work involves: What is the exact time frame after the passage of shock at certain intensity in which nucleation of solid phase can be observed? Is it a complete or partial phase transition? Are external nucleators essential for this transformation? What is the percentage of crystallinity of the nucleated phase?

Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism.

PubMed

Solomonson, Matthew; Setiaputra, Dheva; Makepeace, Karl A T; Lameignere, Emilie; Petrotchenko, Evgeniy V; Conrady, Deborah G; Bergeron, Julien R; Vuckovic, Marija; DiMaio, Frank; Borchers, Christoph H; Yip, Calvin K; Strynadka, Natalie C J

2015-03-03

Mycobacterium tuberculosis (Mtb) uses the ESX-1 type VII secretion system to export virulence proteins across its lipid-rich cell wall, which helps permeabilize the host's macrophage phagosomal membrane, facilitating the escape and cell-to-cell spread of Mtb. ESX-1 membranolytic activity depends on a set of specialized secreted Esp proteins, the structure and specific roles of which are not currently understood. Here, we report the X-ray and electron microscopic structures of the ESX-1-secreted EspB. We demonstrate that EspB adopts a PE/PPE-like fold that mediates oligomerization with apparent heptameric symmetry, generating a barrel-shaped structure with a central pore that we propose contributes to the macrophage killing functions of EspB. Our structural data also reveal unexpected direct interactions between the EspB bipartite secretion signal sequence elements that form a unified aromatic surface. These findings provide insight into how specialized proteins encoded within the ESX-1 locus are targeted for secretion, and for the first time indicate an oligomerization-dependent role for Esp virulence factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

PubMed Central

Huffman, Jennifer E.; de Vries, Paul S.; Morrison, Alanna C.; Sabater-Lleal, Maria; Kacprowski, Tim; Auer, Paul L.; Brody, Jennifer A.; Chasman, Daniel I.; Chen, Ming-Huei; Guo, Xiuqing; Lin, Li-An; Marioni, Riccardo E.; Müller-Nurasyid, Martina; Yanek, Lisa R.; Pankratz, Nathan; Grove, Megan L.; de Maat, Moniek P. M.; Cushman, Mary; Wiggins, Kerri L.; Qi, Lihong; Sennblad, Bengt; Harris, Sarah E.; Polasek, Ozren; Riess, Helene; Rivadeneira, Fernando; Rose, Lynda M.; Goel, Anuj; Taylor, Kent D.; Teumer, Alexander; Uitterlinden, André G.; Vaidya, Dhananjay; Yao, Jie; Tang, Weihong; Levy, Daniel; Waldenberger, Melanie; Becker, Diane M.; Folsom, Aaron R.; Giulianini, Franco; Greinacher, Andreas; Hofman, Albert; Huang, Chiang-Ching; Kooperberg, Charles; Silveira, Angela; Starr, John M.; Strauch, Konstantin; Strawbridge, Rona J.; Wright, Alan F.; McKnight, Barbara; Franco, Oscar H.; Zakai, Neil; Mathias, Rasika A.; Psaty, Bruce M.; Ridker, Paul M.; Tofler, Geoffrey H.; Völker, Uwe; Watkins, Hugh; Fornage, Myriam; Hamsten, Anders; Deary, Ian J.; Boerwinkle, Eric; Koenig, Wolfgang; Rotter, Jerome I.; Hayward, Caroline; Dehghan, Abbas; Reiner, Alex P.; O’Donnell, Christopher J.

2015-01-01

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76 000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways. PMID:26105150

Current use of factor concentrates in pediatric cardiac anesthesia.

PubMed

Guzzetta, Nina A; Williams, Glyn D

2017-07-01

Excessive bleeding following pediatric cardiopulmonary bypass is associated with increased morbidity and mortality, both from the effects of hemorrhage and the therapies employed to achieve hemostasis. Neonates and infants are especially at risk because their coagulation systems are immature, surgeries are often complex, and cardiopulmonary bypass technologies are inappropriately matched to patient size and physiology. Consequently, these young children receive substantial amounts of adult-derived blood products to restore adequate hemostasis. Adult and pediatric data demonstrate associations between blood product transfusions and adverse patient outcomes. Thus, efforts to limit bleeding after pediatric cardiopulmonary bypass and minimize allogeneic blood product exposure are warranted. The off-label use of factor concentrates, such as fibrinogen concentrate, recombinant activated factor VII, and prothrombin complex concentrates, is increasing as these hemostatic agents appear to offer several advantages over conventional blood products. However, recognizing that these agents have the potential for both benefit and harm, well-designed studies are needed to enhance our knowledge and to determine the optimal use of these agents. In this review, our primary objective was to examine the evidence regarding the use of factor concentrates to treat bleeding after pediatric CPB and identify where further research is required. PubMed, MEDLINE/OVID, The Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched to identify existing studies. © 2017 John Wiley & Sons Ltd.

Suzaku Reveals He-burning Products in the X-ray Emitting Planetary Nebula BD +30deg 3639

NASA Technical Reports Server (NTRS)

Murashima, M.; Kokubun, M.; Makishima, K.; Kotoku, J.; Murakami, H.; Matsushita, K.; Hayashida, K.; Hamaguchi, K.; Matsumoto, H.

2004-01-01

BD +30deg 3639, the brightest planetary nebula at X-ray energies, was observed with Suzaku, an X-ray observatory launched on 2005 July 10. Using the X-ray Imaging Spectrometer, the K-lines from C VI, O VII, and O VIII were resolved for the first time, and C/O, N/O, and Ne/O abundance ratios determined. The C/O abundance ratio exceeds the solar value by nearly two orders of magnitude, and that of Ne/O by at least a factor of 5. These results indicate that the X-rays are emitted mainly by helium shell-burning products.

Neutron Thermal Cross Sections, Westcott Factors, Resonance Integrals, Maxwellian Averaged Cross Sections and Astrophysical Reaction Rates Calculated from the ENDF/B-VII.1, JEFF-3.1.2, JENDL-4.0, ROSFOND-2010, CENDL-3.1 and EAF-2010 Evaluated Data Libraries

NASA Astrophysics Data System (ADS)

Pritychenko, B.; Mughabghab, S. F.

2012-12-01

We present calculations of neutron thermal cross sections, Westcott factors, resonance integrals, Maxwellian-averaged cross sections and astrophysical reaction rates for 843 ENDF materials using data from the major evaluated nuclear libraries and European activation file. Extensive analysis of newly-evaluated neutron reaction cross sections, neutron covariances, and improvements in data processing techniques motivated us to calculate nuclear industry and neutron physics quantities, produce s-process Maxwellian-averaged cross sections and astrophysical reaction rates, systematically calculate uncertainties, and provide additional insights on currently available neutron-induced reaction data. Nuclear reaction calculations are discussed and new results are presented. Due to space limitations, the present paper contains only calculated Maxwellian-averaged cross sections and their uncertainties. The complete data sets for all results are published in the Brookhaven National Laboratory report.

Recombinant factor VIIa in major abdominal surgery and liver transplantation.

PubMed

da Silva Viana, J

2006-04-01

The author reviewed the literature regarding recombinant activated Factor VII (rFVIIa) in major abdominal surgery and liver transplantation and concluded that, on the basis of evidence-based medicine, there is no evidence to support an extensive use of rFVIIa. Nevertheless, various case reports suggest the usefulness of rFVIIa to treat life-threatening bleeding after failure of conventional therapies. It appears that there is a consensus that rFVIIa can be used with good results as a rescue therapy in extremely severe situations. Economic cost and potential thrombosis risk remain arguments against more widespread use of rFVIIa. Doses from 5 to 120 kg/kg in each administration have been reported without clear evidence to support a specific protocol. Efficacy of 15 to 20 kg/kg in surgical settings has been reported, but higher doses are more frequently used. The majority of the reviewed investigators accepted the use of rFVIIa after or simultaneously with the use of aprotinin; no data refute the safety of this association.

29 CFR 1608.1 - Statement of purpose.

Code of Federal Regulations, 2010 CFR

2010-07-01

... upon the principles of title VII. Any uncertainty as to the meaning and application of title VII in... Commission believes that it is now necessary to clarify and harmonize the principles of title VII in order to... who comply with the principles of title VII. (b) Purposes of title VII. Congress enacted title VII in...

Evaluation of procoagulant tissue factor expression in canine hemangiosarcoma cell lines

PubMed Central

Witter, Lauren E.; Gruber, Erika J.; Lean, Fabian Z. X.; Stokol, Tracy

2017-01-01

OBJECTIVE To evaluate expression of procoagulant tissue factor (TF) by canine hemangiosarcoma cells in vitro. SAMPLES 4 canine hemangiosarcoma cell lines (SB-HSA [mouse-passaged cutaneous tumor], Emma [primary metastatic brain tumor], and Frog and Dal-1 [primary splenic tumors]) and 1 nonneoplastic canine endothelial cell line (CnAoEC). PROCEDURES TF mRNA and TF antigen expression were evaluated by quantitative real-time PCR assay and flow cytometry, respectively. Thrombin generation was measured in canine plasma and in coagulation factor–replete or specific coagulation factor–deficient human plasma by calibrated automated thrombography. Corn trypsin inhibitor and annexin V were used to examine contributions of contact activation and membrane-bound phosphatidylserine, respectively, to thrombin generation. RESULTS All cell lines expressed TF mRNA and antigen, with significantly greater expression of both products in SB-HSA and Emma cells than in CnAoEC. A greater percentage of SB-HSA cells expressed TF antigen, compared with other hemangiosarcoma cell lines. All hemangiosarcoma cell lines generated significantly more thrombin than did CnAoEC in canine or factor-replete human plasma. Thrombin generation induced by SB-HSA cells was significantly lower in factor VII-deficient plasma than in factor-replete plasma and was abolished in factor X–deficient plasma; residual thrombin generation in FVII-deficient plasma was abolished by incubation of cells with annexin V. Thrombin generation by SB-HSA cells was unaffected by the addition of corn trypsin inhibitor. CONCLUSIONS AND CLINICAL RELEVANCE Hemangiosarcoma cell lines expressed procoagulant TF in vitro. Further research is needed to determine whether TF can be used as a biomarker for hemostatic dysfunction in dogs with hemangiosarcoma. PMID:28029283

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

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

Komatsu, Tetsuro; Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575; Will, Hans

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions asmore » well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. - Highlights: • Host nuclear antiviral factors were analyzed upon adenovirus genome delivery. • Interferon treatments fail to permit PML nuclear bodies to target adenoviral genomes. • Neither Sp100A nor B targets adenoviral genomes despite potentially opposite roles. • The nuclear DNA sensor IFI16 does not target incoming adenoviral genomes. • PHF13/SPOC1 targets neither incoming adenoviral genomes nor genome-bound protein VII.« less

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

PubMed Central

van Beers, Eduard J.; Schaap, Marianne C.L.; Berckmans, René J.; Nieuwland, Rienk; Sturk, Augueste; van Doormaal, Frederiek F.; Meijers, Joost C.M.; Biemond, Bart J.

2009-01-01

Background Sickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived microparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease. Design and Methods In the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease. Results The majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived microparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=−0.58, p<0.001) and lactate dehydrogenase (r=0.59, p<0.001), von Willebrand factor as a marker of platelet/endothelial activation (r=0.44, p<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52, p<0.001 and r=0.59, p<0.001, respectively) as markers of fibrinolysis and coagulation activation. Thrombin generation depended on the total number of microparticles (r=0.63, p<0.001). Anti-human factor XI inhibited thrombin generation by about 50% (p<0.001), whereas anti-human factor VII was ineffective (p>0.05). The extent of factor XI inhibition was associated with erythrocyte-derived microparticles (r=0.50, p=0.023). Conclusions We conclude that the procoagulant state in sickle cell disease is partially explained by the factor XI-dependent procoagulant properties of circulating erythrocyte-derived microparticles. PMID:19815831

Effects of porosity distribution and porosity volume fraction on the electromechanical properties of 3-3 piezoelectric foams

NASA Astrophysics Data System (ADS)

Nguyen, B. V.; Challagulla, K. S.; Venkatesh, T. A.; Hadjiloizi, D. A.; Georgiades, A. V.

2016-12-01

Unit-cell based finite element models are developed to completely characterize the role of porosity distribution and porosity volume fraction in determining the elastic, dielectric and piezoelectric properties as well as relevant figures of merit of 3-3 type piezoelectric foam structures. Eight classes of foam structures which represent structures with different types and degrees of uniformity of porosity distribution are identified; a Base structure (Class I), two H-type foam structures (Classes II, and III), a Cross-type foam structure (Class IV) and four Line-type foam structures (Classes V, VI, VII, and VIII). Three geometric factors that influence the electromechanical properties are identified: (i) the number of pores per face, pore size and the distance between the pores; (ii) pore orientation with respect to poling direction; (iii) the overall symmetry of the pore distribution with respect to the center of the face of the unit cell. To assess the suitability of these structures for such applications as hydrophones, bone implants, medical imaging and diagnostic devices, five figures of merit are determined via the developed finite element model; the piezoelectric coupling constant (K t ), the acoustic impedance (Z), the piezoelectric charge coefficient (d h ), the hydrostatic voltage coefficient (g h ), and the hydrostatic figure of merit (d h g h ). At high material volume fractions, foams with non-uniform Line-type porosity (Classes V and VII) where the pores are preferentially distributed perpendicular to poling direction, are found to exhibit the best combination of desirable piezoelectric figures of merit. For example, at about 50% volume fraction, the d h , g h , and d h g h figures of merit are 55%, 1600% and 2500% higher, respectively, for Classes V and VII of Line-like foam structures compared with the Base structure.

OVII and Temperature Limits on the Local Hot Bubble

NASA Astrophysics Data System (ADS)

Pirtle, Robert; Petre, N.; McCammon, D.; Morgan, K.; Sauter, P.; Clavadetscher, K.; Fujimoto, R.; Hagihara, T.; Masui, K.; Mitsuda, K.; Takei, Y.; Wang, Q. D.; Yamasaki, N. Y.; Yao, Y.; Yoshino, T.

2013-01-01

The observed ¼-keV (ROSAT R12 band) X-ray background originates largely in a region of hot ionized gas roughly 100 pc in extent surrounding the Sun known as the Local Hot Bubble (LHB). The observed flux is quite uniform at low latitudes (|b| < 30°), but there a several large areas at intermediate and high latitudes that are enhanced by factors of 2 - 3. Charge exchange between highly charged ions in the Solar wind and interstellar neutral H and He moving through interplanetary space might provide a very roughly isotropic contribution about equal to the low- latitude flux (Koutroumpa et al. 2008), but cannot produce the enhancements. Correlations with the interstellar absorbing column show that some of these bright regions are apparently due to clumps of hot gas in the Galactic halo, while many of them show no correlation and must be due to extensions of the LHB (Kuntz & Snowden 2000, Bellm & Vaillancourt 2005). Global fits of simple plasma emission spectra give temperatures near 1.0 x 106 K for both LHB and halo emission, but the possibility of a substantial contamination by charge exchange could distort this result in unknown ways. Thermal excitation of O VII is strongly temperature dependent in this range, so we have tried to correlate O VII fluxes measured with Suzaku with variations in ¼-keV intensity from the ROSAT R12 band map to determine the temperature. We take eleven O VII intensity measurements from Yoshino et al. (2009), one from Masui et al. (2009), and an additional eighteen from archival Suzaku pointings and correlate these with the R12 band local and halo intensities as separated by Kunzt & Snowden (2000). The lack of detectable correlation in both cases strongly limits any O VII production by the material producing the enhancements, and upper limits to the temperatures are set. This work was supported in part by the National Science Foundation's REU program through NSF Award AST-1004881 and by NASA grant NNX09AF09G. *present address: Department of Physics, Lewis & Clark College, Portland, OR. This work was supported in part by the National Science Foundation's REU program through NSF Award AST-1004881.

Multivariate statistical analysis to characterize/discriminate between anthropogenic and geogenic trace elements occurrence in the Campania Plain, Southern Italy.

PubMed

Busico, Gianluigi; Cuoco, Emilio; Kazakis, Nerantzis; Colombani, Nicolò; Mastrocicco, Micòl; Tedesco, Dario; Voudouris, Konstantinos

2018-03-01

Shallow aquifers are the most accessible reservoirs of potable groundwater; nevertheless, they are also prone to various sources of pollution and it is usually difficult to distinguish between human and natural sources at the watershed scale. The area chosen for this study (the Campania Plain) is characterized by high spatial heterogeneities both in geochemical features and in hydraulic properties. Groundwater mineralization is driven by many processes such as, geothermal activity, weathering of volcanic products and intense human activities. In such a landscape, multivariate statistical analysis has been used to differentiate among the main hydrochemical processes occurring in the area, using three different approaches of factor analysis: (i) major elements, (ii) trace elements, (iii) both major and trace elements. The elaboration of the factor analysis approaches has revealed seven distinct hydrogeochemical processes: i) Salinization (Cl - , Na + ); ii) Carbonate rocks dissolution; iii) Anthropogenic inputs (NO 3 - , SO 4 2- , U, V); iv) Reducing conditions (Fe 2+ , Mn 2+ ); v) Heavy metals contamination (Cr and Ni); vi) Geothermal fluids influence (Li + ); and vii) Volcanic products contribution (As, Rb). Results from this study highlight the need to separately apply factor analysis when a large data set of trace elements is available. In fact, the impact of geothermal fluids in the shallow aquifer was identified from the application of the factor analysis using only trace elements. This study also reveals that the factor analysis of major and trace elements can differentiate between anthropogenic and geogenic sources of pollution in intensively exploited aquifers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage.

PubMed

White, N J; Mehic, E; Wang, X; Chien, D; Lim, E; St John, A E; Stern, S A; Mourad, P D; Rieger, M; Fries, D; Martinowitz, U

2015-12-01

Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis. (i) To use a swine model of femoral artery bleeding to understand the perivascular hemostatic response to contained arterial hemorrhage. (ii) To directly confirm the association between hemodynamics and bleeding velocity. (iii) To observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach. Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery hemorrhage was also used to demonstrate the feasibility of local delivery of an activated clotting factor. In this model, clots formed slowly within the peri-wound hematoma, but eventually contained the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated factor VII into the injured artery near the site of major internal hemorrhage in the pelvis and axillae was feasible. We rediscovered that clot formation within the peri-wound hematoma is an integral component of hemostasis and a feasible target for the treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach. © 2015 International Society on Thrombosis and Haemostasis.

PET Imaging of Tissue Factor in Pancreatic Cancer Using 64Cu-Labeled Active Site-Inhibited Factor VII.

PubMed

Nielsen, Carsten H; Jeppesen, Troels E; Kristensen, Lotte K; Jensen, Mette M; El Ali, Henrik H; Madsen, Jacob; Wiinberg, Bo; Petersen, Lars C; Kjaer, Andreas

2016-07-01

Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53%-89% of all pancreatic adenocarcinomas, and the expression level of TF has in clinical studies correlated with advanced stage, increased microvessel density, metastasis, and poor overall survival. Imaging of TF expression is of clinical relevance as a prognostic biomarker and as a companion diagnostic for TF-directed therapies currently under clinical development. Factor VII (FVII) is the natural ligand to TF. The purpose of this study was to investigate the possibility of using active site-inhibited FVII (FVIIai) labeled with (64)Cu for PET imaging of TF expression. FVIIai was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with (64)Cu ((64)Cu-NOTA-FVIIai). Longitudinal in vivo PET imaging was performed at 1, 4, 15, and 36 h after injection of (64)Cu-NOTA-FVIIai in mice with pancreatic adenocarcinomas (BxPC-3). The specificity of TF imaging with (64)Cu-NOTA-FVIIai was investigated in subcutaneous pancreatic tumor models with different levels of TF expression and in a competition experiment. In addition, imaging of orthotopic pancreatic tumors was performed using (64)Cu-NOTA-FVIIai and PET/MRI. In vivo imaging data were supported by ex vivo biodistribution, flow cytometry, and immunohistochemistry. Longitudinal PET imaging with (64)Cu-NOTA-FVIIai showed a tumor uptake of 2.3 ± 0.2, 3.7 ± 0.3, 3.4 ± 0.3, and 2.4 ± 0.3 percentage injected dose per gram at 1, 4, 15, and 36 h after injection, respectively. An increase in tumor-to-normal-tissue contrast was observed over the imaging time course. Competition with unlabeled FVIIai significantly (P < 0.001) reduced the tumor uptake. The tumor uptake observed in models with different TF expression levels was significantly different from each other (P < 0.001) and was in agreement with the TF level evaluated by TF immunohistochemistry staining. Orthotopic tumors were clearly visible on the PET/MR images, and the uptake of (64)Cu-NOTA-FVIIai was colocalized with viable tumor tissue. (64)Cu-NOTA-FVIIai is well suited for PET imaging of tumor TF expression, and imaging is capable of distinguishing the TF expression level of various pancreatic tumor models. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Opposite effects of Agrimonia pilosa Ledeb aqueous extracts on blood coagulation function

PubMed Central

Yuan, Wufeng; Jiang, Lei; Wang, Huan

2017-01-01

Background Agrimonia pilosa Ledeb (APL) has showed anticoagulant and antithrombotic activities in some studies, whereas its actual effects on blood coagulation are still unclear. This study was designed to observe the in vitro effects of APL aqueous extracts on blood coagulation, as well as to investigate the underlying mechanisms. Methods Studies were divided into four groups: 0, 4, 20, and 80 g/L of APL aqueous extracts mixed with plasma or whole blood samples. Clotting time of whole blood, plasma coagulation tests, activities of plasma coagulation factors, plasma calcium ion, platelet aggregation test, and platelet fibrinogen receptor as well as the blood viscosity were measured. Results It was observed that the APL aqueous extracts in 4 g/L significantly prolonged the whole blood clotting time and activated partial thromboplastin time, shortened prothrombin time, decreased activities of coagulation factor VIII, IX and XI, and levels of platelet aggregation and fibrinogen receptor expression. However, coagulation factor VII activity, and blood viscosity were increased after the extracts treatment. And the effects of APL extracts were in a concentration-dependent manner (0–80 g/L). Conclusions The results suggest that APL aqueous extracts have a total anticoagulant activity, whereas they exhibit opposite effects of greater anticoagulant activity than pro-coagulant activity. PMID:28480193

Fine particulate pollution in the Nanjing northern suburb during summer: composition and sources.

PubMed

An, Junlin; Duan, Qing; Wang, Honglei; Miao, Qing; Shao, Ping; Wang, Jian; Zou, Jianan

2015-09-01

To understand the chemical composition characteristic of pollution in a northern suburb of Nanjing, particle samples were collected by two Andersen cascade impactors from May to July 2013. The positive matrix factorization version 3 (EPA-PMF 3.0) was applied to identify the source contribution of PM2.1 concentrations in the study area. Source categories were determined based on the chemical component abundances in the source profiles. Overall, results indicated that seven factors were obtained. The factors are identified as follows: (I) secondary aerosol, characterized by high concentrations of NH4 (+), NO3 (-), and SO4 (2-), accounting for 20.22 %; (II) metallurgical aerosol, characterized by high concentrations of Pb, Cd, and Zn, accounting for 6.71 %; (III) road dust, characterized by high concentrations of Mg, Ca, Na, Al, and Ba, accounting for 11.85 %; (IV) biomass burning, characterized by high concentrations of K(+), Na(+), Cl(-), and K, accounting for 10.17 %; (V) residual oil, characterized by high concentrations of V and Cr, accounting for 16.63 %; (VI) iron and steel industry, characterized by high concentrations of Mn and Fe, accounting for 9.48 %; and (VII) vehicle exhaust, characterized by high concentrations of organic carbon (OC), Mo, elemental carbon (EC) and K, accounting for 24.94 %.

Strength training in the elderly: effects on risk factors for age-related diseases.

PubMed

Hurley, B F; Roth, S M

2000-10-01

Strength training (ST) is considered a promising intervention for reversing the loss of muscle function and the deterioration of muscle structure that is associated with advanced age. This reversal is thought to result in improvements in functional abilities and health status in the elderly by increasing muscle mass, strength and power and by increasing bone mineral density (BMD). In the past couple of decades, many studies have examined the effects of ST on risk factors for age-related diseases or disabilities. Collectively, these studies indicate that ST in the elderly: (i) is an effective intervention against sarcopenia because it produces substantial increases in the strength, mass, power and quality of skeletal muscle; (ii) can increase endurance performance; (iii) normalises blood pressure in those with high normal values; (iv) reduces insulin resistance; (v) decreases both total and intra-abdominal fat; (vi) increases resting metabolic rate in older men; (vii) prevents the loss of BMD with age; (viii) reduces risk factors for falls; and (ix) may reduce pain and improve function in those with osteoarthritis in the knee region. However, contrary to popular belief, ST does not increase maximal oxygen uptake beyond normal variations, improve lipoprotein or lipid profiles, or improve flexibility in the elderly.

DNA aptamer affinity ligands for highly selective purification of human plasma-related proteins from multiple sources.

PubMed

Forier, Cynthia; Boschetti, Egisto; Ouhammouch, Mohamed; Cibiel, Agnès; Ducongé, Frédéric; Nogré, Michel; Tellier, Michel; Bataille, Damien; Bihoreau, Nicolas; Santambien, Patrick; Chtourou, Sami; Perret, Gérald

2017-03-17

Nucleic acid aptamers are promising ligands for analytical and preparative-scale affinity chromatography applications. However, a full industrial exploitation requires that aptamer-grafted chromatography media provide a number of high technical standards that remained largely untested. Ideally, they should exhibit relatively high binding capacity associated to a very high degree of specificity. In addition, they must be highly resistant to harsh cleaning/sanitization conditions, as well as to prolonged and repeated exposure to biological environment. Here, we present practical examples of aptamer affinity chromatography for the purification of three human therapeutic proteins from various sources: Factor VII, Factor H and Factor IX. In a single chromatographic step, three DNA aptamer ligands enabled the efficient purification of their target protein, with an unprecedented degree of selectivity (from 0.5% to 98% of purity in one step). Furthermore, these aptamers demonstrated a high stability under harsh sanitization conditions (100h soaking in 1M NaOH). These results pave the way toward a wider adoption of aptamer-based affinity ligands in the industrial-scale purification of not only plasma-derived proteins but also of any other protein in general. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Plasminogen activator inhibitor-1 4G/5G promoter polymorphism and coagulation factor VII Arg353-->Gln polymorphism in Korean patients with coronary artery disease.

PubMed Central

Song, J.; Yoon, Y. M.; Jung, H. J.; Hong, S. H.; Park, H.; Kim, J. Q.

2000-01-01

An increased risk for arterial thrombosis is associated with high plasma levels of coagulation and fibrinolytic factors such as PAI-1 and FVII. In this study, the 4G/5G polymorphism in the promoter of PAI-1 gene and Arg353-->Gln polymorphism in the FVII gene were analysed in 139 normal adults and 158 patients with coronary artery disease (CAD), and their association with plasma lipid traits was investigated. There were no significant differences in the allele frequencies of PAI-1 and FVII polymorphisms between control and patient groups. The allelic distributions of both polymorphisms in Koreans were similar to those in Japanese but significantly different from those in Caucasians. In the CAD group, the 4G homozygotes of PAI-1 polymorphism showed significantly higher levels of total (p=0.0250) and LDL cholesterol (p=0.0335) with individuals having other genotypes. However, FVII polymorphism showed no association with lipid levels. In conclusion, the 4G/5G PAI-1 promoter polymorphism and Arg353-->Gln FVII polymorphism are not major genetic risk factors for CAD in Koreans. However, 4G allele of PAI-1 polymorphism revealed to be associated with the levels of cholesterol, especially LDL cholesterol levels in CAD patients. PMID:10803689

Effect of circulating tissue factor on hypercoagulability in type 2 diabetes mellitus studied by rheometry and dielectric blood coagulometry

PubMed Central

Uchimura, Isao; Kaibara, Makoto; Nagasawa, Masayuki; Hayashi, Yoshihito

2016-01-01

Background: Hypercoagulability in type 2 diabetes mellitus (T2DM) patients increases their risk of cardiovascular diseases. Objective: The aim of this work was to investigate the hypercoagulation mechanism in T2DM patients in terms of circulating tissue factor (TF). Methods: Whole blood coagulation tests by damped oscillation rheometry and dielectric blood coagulometry (DBCM) were performed. Results: The average coagulation time was significantly shorter for T2DM patients than for healthy controls. In vitro addition of either anti-TF or anti-activated factor VII (FVIIa) antibody to hypercoagulable blood samples prolonged coagulation times for one group of patients, while coagulation times remained short for another group. The levels of circulating TF were estimated in the former group by measuring the coagulation times for blood samples from healthy subjects with addition of various concentrations of TF and comparing them with the coagulation times for the group. The results indicated that the levels of circulating TF were on the order of subpicomolar at most. Conclusions: Circulating TF is at least partially responsible for a hypercoagulable group of T2DM patients, while an abnormality in the intrinsic coagulation pathway probably occurs in the other group. PMID:27858671

Simultaneous expression of tissue factor and tissue factor pathway inhibitor by human monocytes. A potential mechanism for localized control of blood coagulation

PubMed Central

1994-01-01

Cells of monocytic lineage can initiate extravascular fibrin deposition via expression of blood coagulation mediators. This report is about experiments on three mechanisms with the potential to modulate monocyte- initiated coagulation. Monocyte procoagulant activity was examined as a function of lipid cofactor, protein cofactor, and specific inhibitor expression during short-term culture in vitro. Lipid cofactor activity was measured as the initial rate of factor X activation by intrinsic- pathway components, the assembly of which depends on this cofactor. Lipid cofactor activity levels changed by < 30% during 48-h culture. Protein cofactor, i.e., tissue factor (TF) antigen was measured by enzyme immunoassay. It increased from 461 pg/ml to a maximum value of 3,550 pg/ml at 24 h and remained at 70% of this value. Specific TF activity, measured as factor VII-dependent factor X activation rate, decreased from 54 to 18 nM FXa/min between 24 and 48 h. TF activity did not correlate well with either lipid cofactor or TF protein levels. In contrast, the decrease in TF activity coincided in time with maximal expression of tissue factor pathway inhibitor (TFPI) mRNA, which was determined using reverse transcriptase polymerase chain reaction (RT- PCR), and with maximal TFPI protein levels measured by immunoassay. The number of mRNA copies coding for TFPI and TF in freshly isolated blood monocytes were 46 and 20 copies/cells, respectively. These values increased to 220 and 63 copies/cell during short-term cell culture in the presence of endotoxin. Results demonstrate concomitant expression by monocytes of genes coding for both the essential protein cofactor and the specific inhibitor of the extrinsic coagulation pathway. Together with functional and antigenic analyses, they also imply that the initiation of blood clotting by extravascular monocyte/macrophages can be modulated locally by TFPI independently of plasma sources of the inhibitor. PMID:8195712

19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

Code of Federal Regulations, 2010 CFR

2010-04-01

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

19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

Code of Federal Regulations, 2014 CFR

2014-04-01

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

19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

Code of Federal Regulations, 2011 CFR

2011-04-01

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

19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

Code of Federal Regulations, 2013 CFR

2013-04-01

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

19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

Code of Federal Regulations, 2012 CFR

2012-04-01

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

Milestones: A Directory of Human Engineering Laboratories Publications, 1953 - 1968

DTIC Science & Technology

1969-04-01

rates. ’Track ing E ’rro r Nleasullenient OAt i’cinltieu ot Invest igating ’Ta.nk Guinner’ Tracking I’. rior TMN 2l)0-02, Une I. 1". N1 . MVCIuty re thiS...inl Skuot Ii Vii’t Nam (1.1() j . N1 . II. Kv’ysc r (Ui) A 1xittt ni ofl Nyvaliont chloo’c is ~ctl, d fori South V ictiialinic t .roopls. 11 Is a ssilill...of Human Factors Studies of N1 113 and a New Concept Armoredx Squad Carrier, (ancl), Jun 1962 Corona 11-17 Tcý(Aicatl Notes NO. Title Auttior 5 A

Analysis of 238Pu and 56Fe Evaluated Data for Use in MYRRHA

NASA Astrophysics Data System (ADS)

Díez, C. J.; Cabellos, O.; Martínez, J. S.; Stankovskiy, A.; Van den Eynde, G.; Schillebeeckx, P.; Heyse, J.

2014-04-01

A sensitivity analysis on the multiplication factor, keff, to the cross section data has been carried out for the MYRRHA critical configuration in order to show the most relevant reactions. With these results, a further analysis on the 238Pu and 56Fe cross sections has been performed, comparing the evaluations provided in the JEFF-3.1.2 and ENDF/B-VII.1 libraries for these nuclides. Then, the effect in MYRRHA of the differences between evaluations are analysed, presenting the source of the differences. With these results, recommendations for the 56Fe and 238Pu evaluations are suggested. These calculations have been performed with SCALE6.1 and MCNPX-2.7e.

VII. The history of physical activity and academic performance research: informing the future.

PubMed

Castelli, Darla M; Centeio, Erin E; Hwang, Jungyun; Barcelona, Jeanne M; Glowacki, Elizabeth M; Calvert, Hannah G; Nicksic, Hildi M

2014-12-01

The study of physical activity, physical fitness, and academic performance research are reviewed from a historical perspective, by providing an overview of existing publications focused on children and adolescents. Using rigorous inclusion criteria, the studies were quantified and qualified using both meta-analytic and descriptive evaluations analyses, first by time-period and then as an overall summary, particularly focusing on secular trends and future directions. This review is timely because the body of literature is growing exponentially, resulting in the emergence of new terminology, methodologies, and identification of mediating and moderating factors. Implications and recommendations for future research are summarized. © 2014 The Society for Research in Child Development, Inc.

Extracting the sovereigns’ CDS market hierarchy: A correlation-filtering approach

NASA Astrophysics Data System (ADS)

León, Carlos; Leiton, Karen; Pérez, Jhonatan

2014-12-01

This paper employs correlation-into-distance mapping techniques and a minimal spanning tree-based correlation-filtering methodology on 36 sovereign CDS spread time-series in order to identify the sovereigns’ informational hierarchy. The resulting hierarchy (i) concurs with sovereigns’ eigenvector centrality; (ii) confirms the importance of geographical and credit rating clustering; (iii) identifies Russia, Turkey and Brazil as regional benchmarks; (iv) reveals the idiosyncratic nature of Japan and United States; (v) confirms that a small set of common factors affects the system; (vi) suggests that lower-medium grade rated sovereigns are the most influential, but also the most prone to contagion; and (vii) suggests the existence of a “Latin American common factor”.

Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay.

PubMed

Amiral, Jean; Vissac, Anne Marie; Seghatchian, Jerard

2017-12-01

Activated Protein C Resistance is mainly associated to a factor V mutation (RQ506), which induces a deficient inactivation of activated factor V by activated protein C, and is associated to an increased risk of venous and arterial thrombosis in affected individuals, caused by the prolonged activated factor V survival. Its prevalence is mainly in Caucasians (about 5%), and this mutation is absent in Africans and Asians. Presence of Factor V-Leiden is usually evidenced with clotting methods, using a two-step APTT assay performed without or with APC: prolongation of blood coagulation time is decreased if this factor is present. The R506Q Factor V-Leiden mutation is now usually characterized using molecular biology, and this technique tends to become the first intention assay for characterization of patients. Both techniques are qualitative, and allow classifying tested individuals as heterozygotes or homozygotes for the mutation, when present. A new quantitative assay for Factor V-Leiden, using a one-step clotting method, has been developed, and designed with highly purified human coagulation proteins. Clotting is triggered with human Factor Xa, in presence of calcium and phospholipids (mixture which favours APC action over clotting process). Diluted tested plasma, is supplemented with a clotting mixture containing human fibrinogen, prothrombin, and protein S at a constant concentration. APC is added, and clotting is initiated with calcium. Calibration is performed with a pool of plasmas from patients carrying the R506Q Factor V mutation, and its mixtures with normal plasma. Homozygous patients have clotting times of about <40sec; heterozygous patients have clotting times of about 40-60sec and normal individuals yield clotting times >70sec. Factor V-Leiden concentration is usually >75% in homozygous patients, 30-60% in heterozygous patients and below 5% in normal. The assay is insensitive to clotting factor deficiencies (II, VII, VIII: C, IX, X), dicoumarol or heparin therapies, and has no interference with lupus anticoagulant (LA). This new assay for Factor V-Leiden can be easily used in any coagulation laboratory, is performed as a single test, and is quantitative. This assay has a high robustness, is accurate and presents a good intra- (<3%) and inter-assay (<5%) variability. It contributes solving most of the laboratory issues faced when testing factor V-Leiden. Quantitation of Factor V-L could contribute to a better assessment of thrombotic risk in affected patients, as this complication is first associated to and caused by the presence of a defined amount of FVa. Copyright © 2017 Elsevier Ltd. All rights reserved.

First Detection of Krypton and Xenon in a White Dwarf

NASA Technical Reports Server (NTRS)

Werner, Klaus; Rauch, Thomas; Ringat, Ellen; Kruk, Jeffrey W.

2012-01-01

We report on the first detection of the noble gases krypton (Z = 36) and xenon (54) in a white dwarf. About 20 KrVI-VII and Xe VI-VII lines were discovered in the ultraviolet spectrum of the hot DO-type white dwarf RE 0503-289. The observations, performed with the Far Ultraviolet Spectroscopic Explorer, also reveal highly ionized photospheric lines from other trans-iron group elements, namely Ga (31), Ge (32), As (33), Se (34), Mo (42), Sn (50), Te (52), and I (53), from which gallium and molybdenum are new discoveries in white dwarfs, too. For Kr and Xe, we performed an NLTE analysis and derived mass fractions of log Kr = -4.3 plus or minus 0.5 and log Xe = -4.2 plus or minus 0.6, corresponding to an enrichment by factors of 450 and 3800, respectively, relative to the Sun. The origin of the large overabundances is unclear. We discuss the roles of neutron-capture nucleosynthesis in the-precursor star and radiation-driven diffusion. It is possible that diffusion is insignificant and thaI the observed metal abundances constrain the evolutionary history of the star. Its hydrogen deficiency may be the consequence of a late helium-shell nash or a binary white dwarf merger.

Developmental control of hypoxia during bud burst in grapevine.

PubMed

Meitha, Karlia; Agudelo-Romero, Patricia; Signorelli, Santiago; Gibbs, Daniel J; Considine, John A; Foyer, Christine H; Considine, Michael J

2018-05-01

Dormant or quiescent buds of woody perennials are often dense and in the case of grapevine (Vitis vinifera L.) have a low tissue oxygen status. The precise timing of the decision to resume growth is difficult to predict, but once committed, the increase in tissue oxygen status is rapid and developmentally regulated. Here, we show that more than a third of the grapevine homologues of widely conserved hypoxia-responsive genes and nearly a fifth of all grapevine genes possessing a plant hypoxia-responsive promoter element were differentially regulated during bud burst, in apparent harmony with resumption of meristem identity and cell-cycle gene regulation. We then investigated the molecular and biochemical properties of the grapevine ERF-VII homologues, which in other species are oxygen labile and function in transcriptional regulation of hypoxia-responsive genes. Each of the 3 VvERF-VIIs were substrates for oxygen-dependent proteolysis in vitro, as a function of the N-terminal cysteine. Collectively, these data support an important developmental function of oxygen-dependent signalling in determining the timing and effective coordination bud burst in grapevine. In addition, novel regulators, including GASA-, TCP-, MYB3R-, PLT-, and WUS-like transcription factors, were identified as hallmarks of the orderly and functional resumption of growth following quiescence in buds. © 2018 John Wiley & Sons Ltd.

The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women.

PubMed

Stephenson, Kenna; Neuenschwander, Pierre F; Kurdowska, Anna K

2013-01-01

Menopause impacts 25 million women world wide each year, and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030. Menopause has been associated with symptoms of hot flashes, night sweats, dysphoric mood, sleep disturbance, and conditions of cardiovascular disease, depression, osteoporosis, osteoarthritis, depression, dementia, and frailty. Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women's Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors. Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile, yet long-term studies of this treatment model are lacking. The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol, estradiol, progesterone, DHEA, and testosterone on cardiovascular biomarkers, hemostatic, inflammatory, immune signaling factors; quality-of-life measures; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care. A prospective, cohort, closed-label study received approval from the Human Subjects Committee. Recruitment from outpatient clinics at an academic medical center and the community at large resulted in three hundred women giving signed consent. Seventy-five women who met strict inclusion/exclusion criteria were enrolled. Baseline hormone evaluation was performed along with baseline experimental measures. Following this, women received compounded transdermal bioidentical hormone therapy of BiEst (80%Estriol/20%Estradiol), and/or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women. The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic, ischemic, or neuronal injury. Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of androgens of DHEA and Testosterone if indicated. Experimental subjects were monitored for 36 months. Baseline, 2-month, and annual values were obtained for: blood pressure, body mass index, fasting glucose, Homeostasis Metabolic Assessment of Insulin Resistance (HOMA-IR), fasting triglycerides, total Factor VII, Factor VIII, fibrinogen, Antithrombin III, Plasminogen Activator Inhibitor1(PAL-1), C-reactive protein (CRP), Interleukin-6 (IL-6), Matrix Metalloproteinase-9 (MMP-9), Tumor Necrosis Factor-alpha (TNF), Insulin-like Growth Factor (IGF-1), and sex steroid levels. Psychosocial measures included: Greene Climacteric Scale, Visual Analog Pain Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Holmes Rahe Stress Scale, Job Strain, and Home Strain. Health outcome measures included the number of prescribed medications used, number of co-morbidities, and endometrial thickness in postmenopausal women with intact uteri. Subjects receiving compounded transdermal bioidentical hormone therapy showed significant favorable changes in: Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, Insulin-Like Growth Factor 1, and health outcomes of co-morbidities and a number of prescribed medications. Antithrombin III levels were significantly decreased at 36 months. All other measures did not exhibit significant effects. Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes were favorably impacted, despite very high life stress, and home and work strain in study subjects. The therapy did not adversely alter the net prothrombotic potential, and there were no associated adverse events. This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in populations with high perceived stress and a history of stressful life events prior to, or during the menopausal transition.

Differential functional readthrough over homozygous nonsense mutations contributes to the bleeding phenotype in coagulation factor VII deficiency.

PubMed

Branchini, A; Ferrarese, M; Lombardi, S; Mari, R; Bernardi, F; Pinotti, M

2016-10-01

Essentials Potentially null homozygous Factor(F)7 nonsense mutations are associated to variable bleeding symptoms. Readthrough of p.Ser112X (life-threatening) and p.Cys132X (moderate) stop codons was investigated. Readthrough-mediated insertion of wild-type or tolerated residues produce functional proteins. Functional readthrough over homozygous F7 nonsense mutations contributes to the bleeding phenotype. Background Whereas the rare homozygous nonsense mutations causing factor (F)VII deficiency may predict null conditions that are almost completely incompatible with life, they are associated with appreciable differences in hemorrhagic symptoms. The misrecognition of premature stop codons (readthrough) may account for variable levels of functional full-length proteins. Objectives To experimentally evaluate the basal and drug-induced levels of FVII resulting from the homozygous p.Cys132X and p.Ser112X nonsense mutations that are associated with moderate (132X) or life-threatening (112X) symptoms, and that are predicted to undergo readthrough with (132X) or without (112X) production of wild-type FVII. Methods We transiently expressed recombinant FVII (rFVII) nonsense and missense variants in human embryonic kidney 293 cells, and evaluated secreted FVII protein and functional levels by ELISA, activated FX generation, and coagulation assays. Results The levels of functional FVII produced by p.Cys132X and p.Ser112X mutants (rFVII-132X, 1.1% ± 0.2% of wild-type rFVII; rFVII-112X, 0.5% ± 0.1% of wild-type rFVII) were compatible with the occurrence of spontaneous readthrough, which was magnified by the addition of G418 - up to 12% of the wild-type value for the rFVII-132X nonsense variant. The predicted missense variants arising from readthrough abolished (rFVII-132Trp/Arg) or reduced (rFVII-112Trp/Cys/Arg, 22-45% of wild-type levels) secretion and function. These data suggest that the appreciable rescue of p.Cys132X function was driven by reinsertion of the wild-type residue, whereas the minimal p.Ser112X function was explained by missense changes permitting FVII secretion and function. Conclusions The extent of functional readthrough might explain differences in the bleeding phenotype of patients homozygous for F7 nonsense mutations, and prevent null conditions even for the most readthrough-unfavorable mutations. © 2016 International Society on Thrombosis and Haemostasis.

One amino acid in mouse activated factor VII defines its endothelial protein C receptor (EPCR) binding and modulates its EPCR-dependent hemostatic activity in vivo.

PubMed

Pavani, G; Zintner, S M; Ivanciu, L; Small, J C; Stafford, K A; Szeto, J H; Margaritis, P

2017-03-01

Essentials The lack of factor (F) VIIa-endothelial protein C receptor (EPCR) binding in mice is unresolved. A single substitution of Leu4 to Phe in mouse FVIIa (mFVIIa) enables its interaction with EPCR. mFVIIa with a Phe4 shows EPCR binding-dependent enhanced hemostatic function in vivo vs. mFVIIa. Defining the FVIIa-EPCR interaction in mice allows for further investigating its biology in vivo. Background Human activated factor VII (hFVIIa), which is used in hemophilia treatment, binds to the endothelial protein C (PC) receptor (EPCR) with unclear hemostatic consequences. Interestingly, mice lack the activated FVII (FVIIa)-EPCR interaction. Therefore, to investigate the hemostatic consequences of this interaction in hemophilia, we previously engineered a mouse FVIIa (mFVIIa) molecule that bound mouse EPCR (mEPCR) by using three substitutions from mouse PC (mPC), i.e. Leu4→Phe, Leu8→Met, and Trp9→Arg. The resulting molecule, mFVIIa-FMR, modeled the EPCR-binding properties of hFVIIa and showed enhanced hemostatic capacity in hemophilic mice versus mFVIIa. These data implied a role of EPCR in the action of hFVIIa in hemophilia treatment. However, the substitutions in mFVIIa-FMR only broadly defined the sequence determinants for its mEPCR interaction and enhanced function in vivo. Objectives To determine the individual contributions of mPC Phe4, Met8 and Arg9 to the in vitro/in vivo properties of mFVIIa-FMR. Methods The mEPCR-binding properties of single amino acid variants of mFVIIa or mPC at position 4, 8 or 9 were investigated. Results and conclusions Phe4 in mFVIIa or mPC was solely critical for interaction with mEPCR. In hemophilic mice, administration of mFVIIa harboring a Phe4 resulted in a 1.9-2.5-fold increased hemostatic capacity versus mFVIIa that was EPCR binding-dependent. This recapitulated previous observations made with triple-mutant mFVIIa-FMR. As Leu8 is crucial for hFVIIa-EPCR binding, we describe the sequence divergence of this interaction in mice, now allowing its further characterization in vivo. We also illustrate that modulation of the EPCR-FVIIa interaction may lead to improved FVIIa therapeutics. © 2016 International Society on Thrombosis and Haemostasis.

A quantitative systems pharmacology model of blood coagulation network describes in vivo biomarker changes in non-bleeding subjects.

PubMed

Lee, D; Nayak, S; Martin, S W; Heatherington, A C; Vicini, P; Hua, F

2016-12-01

Essentials Baseline coagulation activity can be detected in non-bleeding state by in vivo biomarker levels. A detailed mathematical model of coagulation was developed to describe the non-bleeding state. Optimized model described in vivo biomarkers with recombinant activated factor VII treatment. Sensitivity analysis predicted prothrombin fragment 1 + 2 and D-dimer are regulated differently. Background Prothrombin fragment 1 + 2 (F 1 + 2 ), thrombin-antithrombin III complex (TAT) and D-dimer can be detected in plasma from non-bleeding hemostatically normal subjects or hemophilic patients. They are often used as safety or pharmacodynamic biomarkers for hemostatis-modulating therapies in the clinic, and provide insights into in vivo coagulation activity. Objectives To develop a quantitative systems pharmacology (QSP) model of the blood coagulation network to describe in vivo biomarkers, including F 1 + 2 , TAT, and D-dimer, under non-bleeding conditions. Methods The QSP model included intrinsic and extrinsic coagulation pathways, platelet activation state-dependent kinetics, and a two-compartment pharmacokinetics model for recombinant activated factor VII (rFVIIa). Literature data on F 1 + 2 and D-dimer at baseline and changes with rFVIIa treatment were used for parameter optimization. Multiparametric sensitivity analysis (MPSA) was used to understand key proteins that regulate F 1 + 2 , TAT and D-dimer levels. Results The model was able to describe tissue factor (TF)-dependent baseline levels of F 1 + 2 , TAT and D-dimer in a non-bleeding state, and their increases in hemostatically normal subjects and hemophilic patients treated with different doses of rFVIIa. The amount of TF required is predicted to be very low in a non-bleeding state. The model also predicts that these biomarker levels will be similar in hemostatically normal subjects and hemophilic patients. MPSA revealed that F 1 + 2 and TAT levels are highly correlated, and that D-dimer is more sensitive to the perturbation of coagulation protein concentrations. Conclusions A QSP model for non-bleeding baseline coagulation activity was established with data from clinically relevant in vivo biomarkers at baseline and changes in response to rFVIIa treatment. This model will provide future mechanistic insights into this system. © 2016 International Society on Thrombosis and Haemostasis.

Diagnostic Error of a Patient with Combined Inherited Factor VII and Factor X Deficiency due to Accidental Ingestion of a Diphacinone Rodenticide.

PubMed

Li, Min; Jin, Yanhui; Wang, Mingshan; Xie, Yaosheng; Ding, Hongxiang

2016-11-01

To explore the characteristics of laboratory examination and confirm the diagnosis of a patient with combined inherited FVII and FX deficiency after he ingested diphacinone rodenticide accidentally. The coagulant parameter screening tests and coagulation factor activities were tested many times in the patient due to accidental ingestion of a diphacinone rodenticide. After the patient was treated for more than one year, gene analysis of correlated coagulation factors was analyzed in the patient and other family members by DNA direct sequencing. 106 persons were selected as controls from routine health examinations. After the patient was admitted to hospital, routine coagulation screening tests revealed the prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) and low levels of vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) activity, which was 102.4 seconds, 88.5 seconds, 7%, 3%, 8%, and 2%, respectively. During more than one year of treatment, the value of PT and APTT still showed significantly prolonged activity and FVII and FX activity levels were about 5%. While FII and FIX activity levels were in the normal range after 12 weeks of treatment. Two homozygous mutations, g.11267C>T of F7 gene resulting in the substitution Arg277Cys and g.28139G>T of F10 gene leading to the substitution Val384Phe, were identified in the patient. The patient's parents and sister was heterozygous for Arg277Cys and Val384Phe mutations. FVII and FX antigen levels in the patient were 7% and 30%, respectively. There were many similarities in the characteristics of laboratory examination between combined inherited FVII and FX deficiency and acquired vitamin K deficiency. The best way to identify them was gene analysis.

Increased production of functional recombinant human clotting factor IX by baby hamster kidney cells engineered to overexpress VKORC1, the vitamin K 2,3-epoxide-reducing enzyme of the vitamin K cycle.

PubMed

Wajih, Nadeem; Hutson, Susan M; Owen, John; Wallin, Reidar

2005-09-09

Some recombinant vitamin K-dependent blood coagulation factors (factors VII, IX, and protein C) have become valuable pharmaceuticals in the treatment of bleeding complications and sepsis. Because of their vitamin K-dependent post-translational modification, their synthesis by eukaryotic cells is essential. The eukaryotic cell harbors a vitamin K-dependent gamma-carboxylation system that converts the proteins to gamma-carboxyglutamic acid-containing proteins. However, the system in eukaryotic cells has limited capacity, and cell lines overexpressing vitamin K-dependent clotting factors produce only a fraction of the recombinant proteins as fully gamma-carboxylated, physiologically competent proteins. In this work we have used recombinant human factor IX (r-hFIX)-producing baby hamster kidney (BHK) cells, engineered to stably overexpress various components of the gamma-carboxylation system of the cell, to determine whether increased production of functional r-hFIX can be accomplished. All BHK cell lines secreted r-hFIX into serum-free medium. Overexpression of gamma-carboxylase is shown to inhibit production of functional r-hFIX. On the other hand, cells overexpressing VKORC1, the reduced vitamin K cofactor-producing enzyme of the vitamin K-dependent gamma-carboxylation system, produced 2.9-fold more functional r-hFIX than control BHK cells. The data are consistent with the notion that VKORC1 is the rate-limiting step in the system and is a key regulatory protein in synthesis of active vitamin K-dependent proteins. The data suggest that overexpression of VKORC1 can be utilized for increased cellular production of recombinant vitamin K-dependent proteins.

Psychosocial Factors Are Associated With Blood Pressure Progression Among African Americans in the Jackson Heart Study

PubMed Central

Sims, Mario; Higginbotham, John C.; Crowther, Martha R.; Wyatt, Sharon B.; Musani, Solomon K.; Payne, Thomas J.; Fox, Ervin R.; Parton, Jason M.

2016-01-01

BACKGROUND Research that examines the associations of psychosocial factors with incident hypertension among African Americans (AA) is limited. Using Jackson Heart Study (JHS) data, we examined associations of negative affect and stress with incident hypertension and blood pressure (BP) progression among AA. METHODS Our sample consisted of 1,656 normotensive participants at baseline (2000–2004) (mean age 47±12; 61% women). We investigated associations of negative affect (cynical distrust, anger-in, anger-out, and depressive symptoms) and stress (perceived stress, weekly stress inventory (WSI)-event, WSI-impact, and major life events) with BP progression (an increase by one BP stage as defined by JNC VII) and incident hypertension by examination 2 (2005–2008). Poisson regression analysis was utilized to examine the prevalence ratios (PRs; 95% confidence interval (CI)) of BP tracking and incident hypertension with psychosocial factors, adjusting for baseline age, sex, socioeconomic status (SES), and hypertension risk factors. RESULTS Fifty-six percentage of the sample (922 cases) had BP progression from 2005 to 2008. After adjustment for age, sex, and SES, a high anger-out score was associated with a 20% increased risk of BP progression compared to a low anger-out score (PR 1.20; 95% CI 1.05–1.36). High depressive symptoms score was associated with BP progression in the age, sex, and SES-adjusted model (PR 1.14; 95% CI 1.00–1.30). High WSI-event scores were associated with BP progression in the fully adjusted model (PR 1.21; 95% CI 1.04–1.40). We did not observe significant associations with any of the psychosocial measures and incident hypertension. CONCLUSIONS Psychosocial factors were associated with BP progression, with the strongest evidence for number of stressful events that occurred. PMID:26964661

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

PubMed

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

2014-05-01

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

F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency. Results from a genotype-phenotype study.

PubMed

Quintavalle, Gabriele; Riccardi, Federica; Rivolta, Gianna Franca; Martorana, Davide; Di Perna, Caterina; Percesepe, Antonio; Tagliaferri, Annarita

2017-08-01

Congenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. It was the objective of this study to identify genetic defects and to evaluate their relationships with phenotype in a large cohort of patients with FVII:C<50 %. One hundred twenty-three probands were genotyped for F7 mutations and three polymorphic variants and classified according to recently published clinical scores. Forty out of 123 patients (33 %) were symptomatic (43 bleedings). A severe bleeding tendency was observed only in patients with FVII:C<0.10 %. Epistaxis (11 %) and menorrhagia (32 % of females in fertile age) were the most frequent bleedings. Molecular analysis detected 48 mutations, 20 not reported in the F7 international databases. Most mutations (62 %) were missense, large deletions were 6.2 %. Compound heterozygotes/homozygotes for mutations presented lower FVII:C levels compared to the other classes (Chi 2 =43.709, p<0,001). The polymorphisms distribution was significantly different among the three F7 genotypic groups (Chi 2 =72.289, p<0,001). The presence of truncating mutations was associated with lowest FVII:C levels (Chi 2 =21.351, p=0.002). This study confirms the clinical and molecular variability of the disease and the type of symptoms. It shows a good correlation between the type of F7 mutation and/or polymorphisms and FVII:C levels, without a direct link between FVII:C and bleeding tendency. The results suggest that large deletions are underestimated and that they represent a common mechanism of F7 gene inactivation which should always be investigated in the diagnostic testing for FVII deficiency.

Long-term Spectral Evolution of Tidal Disruption Candidates Selected by Strong Coronal Lines

NASA Astrophysics Data System (ADS)

Yang, Chen-Wei; Wang, Ting-Gui; Ferland, Gary; Yuan, Weimin; Zhou, Hong-Yan; Jiang, Peng

2013-09-01

We present results of follow-up optical spectroscopic Multi-Mirror Telescope (MMT) observations of seven rare, extreme coronal line-emitting galaxies reported by Wang et al. Large variations in coronal lines are found in four objects, making them strong candidates for tidal disruption events (TDEs). For the four TDE candidates, all the coronal lines with ionization states higher than [Fe VII] disappear within 5-9 yr. The [Fe VII] line faded by a factor of about five in one object (J0952+2143) within 4 yr, whereas the line emerged in another two objects that previously did not show the line. A strong increment in the [O III] flux is observed, shifting the line ratios toward the loci of active galactic nuclei on the BPT diagram. Surprisingly, we detect a non-canonical [O III] λ5007/[O III] λ4959 ratio of ~= 2 in two objects, indicating a large column density of O2 + and thus probably optically thick gas. This result also requires a very large ionization parameter and a relatively soft ionizing spectral energy distribution (e.g., a blackbody with T < 5 × 104 K). Our observations can be explained as the echoing of a strong ultraviolet to soft X-ray flare caused by TDEs on molecular clouds in the inner parsecs of the galactic nuclei. Reanalyzing the Sloan Digital Sky Survey spectra reveals double-peaked or strongly blue-shouldered broad lines in three of the objects, which disappeared in the MMT spectra of two objects and faded by a factor of 10 in 8 yr in the remaining object with a decrease in both the line width and centroid offset. We interpret these broad lines as arising from decelerating biconical outflows. Our results demonstrate that the signatures of echoing can persist for as long as 10 yr and can be used to probe the gas environment in quiescent galactic nuclei.

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

PubMed Central

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

2013-01-01

Background Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Methods Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Results Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Conclusions Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach. PMID:22551846

Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations.

PubMed

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

2012-06-01

Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16-43 μg/kg) rFVIIa given 51 minutes (42-67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p=0.05; international normalized ratio, 0.8 versus 1.2; p<0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p=0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Treatment of refractory bleeding after cardiac operations with low-dose recombinant activated factor VII (NovoSeven): a propensity score analysis.

PubMed

Gelsomino, Sandro; Lorusso, Roberto; Romagnoli, Stefano; Bevilacqua, Sergio; De Cicco, Giuseppe; Billè, Giuseppe; Stefàno, Pierluigi; Gensini, Gian Franco

2008-01-01

Recombinant activated factor VII (rFVIIa) has been increasingly used to stop life-threatening bleeding following cardiac operations. Nonetheless, the issue of dosing, given the expense and potential for thrombotic complications, is still of major concern. We report our experience with small-dose rFVIIa in patients with refractory bleeding after cardiac surgery. From September 2005 to June 2007, 40 patients (mean age 70.1+/-9.2 years, 52.5 males) received a low dose of rFVIIa (median: 18 microg/kg, interquartile range: 9-16 microg/kg) for refractory bleeding after cardiac surgery. Forty propensity score-based greedy matched controls were compared to the study group. Low dose of rFVIIa significantly reduced the 24-h blood loss: 1610 ml [ 1285-1800 ml] versus 3171 ml [2725-3760 ml] in the study and control groups, respectively (p<0.001). Thus, hourly bleeding was 51.1 ml [34.7-65.4 ml] in patients receiving rFVIIa and 196.2 ml/h [142.1-202.9 ml] in controls (p<0.001). Furthermore, patients receiving rFVIIa showed a lower length of stay in the intensive care unit (p<0.001) and shorter mechanical ventilation time (p<0.001). In addition, the use of rFVIIa was associated with reduction of transfusion requirements of red blood cells, fresh frozen plasma and platelets (all, p<0.001). Finally, treated patients showed improved hemostasis with rapid normalization of coagulation variables (partial thromboplastin time, international normalized ratio, platelet count, p<0.001). In contrast, activated prothrombin time and fibrinogen did not differ between groups (p=ns). No thromboembolic-related event was detected in our cohort. In our experience low-dose rFVIIa was associated with reduced blood loss, improvement of coagulation variables and decreased need for transfusions. Our findings need to be confirmed by further larger studies.