Two distinct forms of Factor VIII coagulant protein in human plasma. Cleavage by thrombin, and differences in coagulant activity and association with von Willebrand factor.

PubMed Central

Weinstein, M J; Chute, L E

1984-01-01

We have characterized Factor VIII coagulant protein, present in normal human plasma, that reacts with a specific human 125I-labeled anti-human VIII:C antigen Fab antibody fragment. Two major Factor VIII coagulant antigen populations were present. The first, approximately 85% of the total antigen, was bound to von Willebrand factor and when tested in a standard one-stage assay had Factor VIII coagulant activity. The second antigenic population, eluting near fibrinogen when plasma was gel filtered, was not bound to von Willebrand protein, did not have Factor VIII coagulant activity unless activated, but did block anti-VIII:C Fab neutralization of clotting activity. The two antigenic populations were separable by cryoprecipitation and agarose gel electrophoresis. Although the two antigenic populations differed in their Factor VIII coagulant activity and in their binding to von Willebrand factor, the principal member of both populations is of mol wt 2.4 X 10(5). Both antigens, when proteolyzed by thrombin, were quickly converted to a 1 X 10(5)-mol wt form in association with the appearance of VIII:C activity. The 1 X 10(5)-mol wt antigen was further slowly degraded to an 8 X 10(4)-mol wt form while Factor VIII coagulant activity declined. These results demonstrate the presence of an inactive Factor VIII coagulant protein in plasma, not associated with von Willebrand factor, that can react with thrombin to yield Factor VIII coagulant activity. Images PMID:6421875

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

PubMed Central

1992-01-01

Generation of coagulation factor Xa by the intrinsic pathway protease complex is essential for normal activation of the coagulation cascade in vivo. Monocytes and platelets provide membrane sites for assembly of components of this protease complex, factors IXa and VIII. Under biologically relevant conditions, expression of functional activity by this complex is associated with activation of factor VIII to VIIIa. In the present studies, autocatalytic regulatory pathways operating on monocyte and platelet membranes were investigated by comparing the cofactor function of thrombin-activated factor VIII to that of factor Xa-activated factor VIII. Reciprocal functional titrations with purified human factor VIII and factor IXa were performed at fixed concentrations of human monocytes, CaCl2, factor X, and either factor IXa or factor VIII. Factor VIII was preactivated with either thrombin or factor Xa, and reactions were initiated by addition of factor X. Rates of factor X activation were measured using chromogenic substrate specific for factor Xa. The K1/2 values, i.e., concentration of factor VIIIa at which rates were half maximal, were 0.96 nM with thrombin- activated factor VIII and 1.1 nM with factor Xa-activated factor VIII. These values are close to factor VIII concentration in plasma. The Vsat, i.e., rates at saturating concentrations of factor VIII, were 33.3 and 13.6 nM factor Xa/min, respectively. The K1/2 and Vsat values obtained in titrations with factor IXa were not significantly different from those obtained with factor VIII. In titrations with factor X, the values of Michaelis-Menten coefficients (Km) were 31.7 nM with thrombin- activated factor VIII, and 14.2 nM with factor Xa-activated factor VIII. Maximal rates were 23.4 and 4.9 nM factor Xa/min, respectively. The apparent catalytic efficiency was similar with either form of factor VIIIa. Kinetic profiles obtained with platelets as a source of membrane were comparable to those obtained with monocytes. These kinetic profiles are consistent with a 1:1 stoichiometry for the functional interaction between cofactor and enzyme on the surface of monocytes and platelets. Taken together, these results indicate that autocatalytic pathways connecting the extrinsic, intrinsic, and common coagulation pathways can operate efficiently on the monocyte membrane. PMID:1613461

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.

Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

PubMed

Rodgers, Susan; Duncan, Elizabeth

2017-01-01

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

Successful Pregnancy in a Patient with Combined Deficiency of Factor V and Factor VIII.

PubMed

El Adib, Ahmed Ghassan; Majdi, Farah; Dilai, Mohamed Othmane; Asmouki, Hamid; Bassir, Ahlam; Harou, Karam; Soumani, Abderraouf; Younous, Said; Mahmal, Lahoucine

2014-01-01

Inherited combined factor V and factor VIII deficiency (F5F8D) is autosomal recessive transmission disorder. Epistaxis, postsurgical bleeding, and menorrhagia are the most common symptoms. The risk of miscarriage and placental abruption is consequent. We report a case of successful pregnancy in a patient with F5F8D. 20-year-old woman, born of consanguineous parents, third gestate, first parity, two miscarriages, admitted for child birth of a spontaneous pregnancy estimated at 38 weeks and was diagnosed with F5F8D. At admission, patient was hemodynamically stable, with good obstetric conditions. The biologic results showed low levels of PT (52%), factor V (7%), and factor VIII (5%), and the activated partial thromboplastin time was prolonged (68,6%). Parturient was admitted in intensive care unit, maternal and fetal monitoring was performed. Fresh frozen plasma (FFP) and factor VIII concentrates were perfused at the induction of labor. Analgesia used fentanyl titration. The delivery gave birth to a newborn male, with Apgar 10/10 and 3000 g. The puerperium was simple without any important bleeding. Laboratory tests for the newborn were acceptable. Little literature is available on this subject and there are no guidelines available concerning pregnancy; we chose to prescribe a combination of factor VIII concentrate and FFP in pre-, per- and postpartum. The same protocol was successfully used in a patient before dental extraction and prostatectomy. Vaginal delivery is possible, as our case. Management by multidisciplinary team is recommended.

The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion

PubMed Central

Lozier, Jay N.; Dutra, Amalia; Pak, Evgenia; Zhou, Nan; Zheng, Zhili; Nichols, Timothy C.; Bellinger, Dwight A.; Read, Marjorie; Morgan, Richard A.

2002-01-01

In the Chapel Hill colony of factor VIII-deficient dogs, abnormal sequence (ch8, for canine hemophilia 8, GenBank no. AF361485) follows exons 1–22 in the factor VIII transcript in place of exons 23–26. The canine hemophilia 8 locus (ch8) sequence was found in a 140-kb normal dog genomic DNA bacterial artificial chromosome (BAC) clone that was completely outside the factor VIII gene, but not in BAC clones containing the factor VIII gene. The BAC clone that contained ch8 also contained a homologue of F8A (factor 8 associated) sequence, which participates in a common inversion that causes severe hemophilia A in humans. Fluorescence in situ hybridization analysis indicated that exons 1–26 normally proceed sequentially from telomere to centromere at Xq28, and ch8 is telomeric to the factor VIII gene. The appearance of an “upstream” genomic sequence element (ch8) at the end of the aberrant factor VIII transcript suggested that an inversion of genomic DNA replaced factor VIII exons 22–26 with ch8. The F8A sequence appeared also in overlapping normal BAC clones containing factor VIII sequence. We hypothesized that homologous recombination between copies of canine F8A inside and outside the factor VIII gene had occurred, as in human hemophilia A. High-resolution fluorescent in situ hybridization on hemophilia A dog DNA revealed a pattern consistent with this inversion mechanism. We also identified a HindIII restriction fragment length polymorphism of F8A fragments that distinguished hemophilia A, carrier, and normal dogs' DNA. The Chapel Hill hemophilia A dog colony therefore replicates the factor VIII gene inversion commonly seen in humans with severe hemophilia A. PMID:12242334

Analysis of contaminants in factor VIII preparations administered to patients with hemophilia.

PubMed Central

Rock, G. A.; Farrah, G.; Rozon, G.; Smiley, R. K.; Cole, R.; Villeneuve, D.; Tittley, P.

1983-01-01

Cryoprecipitate and the more purified factor VIII concentrates are all heterogeneous preparations that contain not only a high concentration of factor VIII but also various other materials, some of which might be injurious, causing liver damage after long-term exposure. The efficiency of three standard cryoprecipitate filters, two microaggregate filters and the appropriate factor VIII concentrate filters in reducing the amount of particulate matter delivered to the patient was assessed. Filtration of cryoprecipitate through the standard filters removed less than 20% of the contaminating microaggregates and very few of the large number of intact platelets, although the total dose of factor VIII was delivered. Microaggregate filters were no better in reducing the platelet contamination, although the total number of particles delivered was halved. However, 25% of the factor VIII was retained in the bed volume of the filter. The concentrate preparations also contained significant amounts of particulate matter that was unrelated to factor VIII and was not removed following filtration through the designated filter. These findings indicate that a new filter should be developed for administration of factor VIII concentrate that would remove the particulate matter while delivering all of the factor VIII to the patient. Images FIG. 1 FIG. 2 FIG. 3 FIG. 5 PMID:6401585

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

PubMed

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

2014-11-01

In forensic autopsies it is important to determine the age of early vital skin wounds as accurate as possible. In addition to inflammation, coagulation is also induced in vital wounds. Analysis of blood coagulation markers in wound hemorrhage could therefore be an important additional discriminating factor in wound age determination. The aim of this study was to develop a wound age probability scoring system, based on the immunohistochemical expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage. Tissue samples of (A) non injured control skin (n=383), and samples of mechanically induced skin injuries of known wound age, (B) injuries inflicted shortly before death (up to a few minutes old) (n=382), and (C) injuries inflicted 15-30 min before death (n=42) were obtained at autopsy in order to validate wound age estimation. Tissue slides were stained for Fibronectin, CD62p and Factor VIII and were subsequently scored for staining intensity (IHC score) in wound hemorrhage (1=minor, 2=moderate, 3=strong positive). Finally, probability scores of these markers were calculated. In at most 14% of the non-injured control samples, hemorrhage was found, with mean±standard deviation IHC scores of 0.1±0.4, 0.2±0.4 and 0.2±0.5 for Fibronectin, CD62p, and Factor VIII, respectively. Expression of these markers significantly increased to mean IHC scores 1.4±0.8 (Fibronectin), 1.2±0.6 (CD62p), and 1.6±0.8 (Factor VIII) in wounds inflicted shortly before death (few minutes old) and to 2.6±0.5 (Fibronectin), 2.5±0.6 (CD62p), and 2.8±0.4 (Factor VIII) in 15-30 min old wounds. The probabilities that a wound was non vital in case of an IH score 0 were 87%, 88% and 90% for Fibronectin, CD62p, and Factor VIII, respectively. In case of an IHC score 1 or 2, the probabilities that a wound was a few minutes old were 82/90%, 82/83% and 72/93%. Finally, in case of an IHC score 3, the probabilities that a wound was 15-30 min old were 65%, 76% and 55%. Based on the expression of Fibronectin, CD62p and Factor VIII in wound hemorrhage, we developed a probability scoring system that can be used in forensic autopsies to improve wound age estimation in early skin injuries. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Impact on hepatic estrogen-sensitive proteins by a 1-year contraceptive vaginal ring delivering Nestorone® and ethinyl estradiol.

PubMed

Archer, D F; Thomas, M A; Conard, J; Merkatz, R B; Creasy, G W; Roberts, K; Plagianos, M; Blithe, D; Sitruk-Ware, R

2016-01-01

Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE). A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. NES/EE CVR for up to 13cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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

2003-08-01

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

Activity of blood coagulation and fibrinolysis during and after hydroxyethyl starch (HES) colloidal volume replacement.

PubMed

Omar, M N; Shouk, T A; Khaleq, M A

1999-06-01

To examine the effect of medium molecular weight hydroxyethyl starch on protein C levels and the changes in the activation state of blood platelets, coagulation and fibrinolyis during and after 5 day of its infusion. Fifty male patients (mean age: 47 years, range 45-50 years) who required prostatectomy for benign prostatic hyperplasia were divided into two equal groups. One group was given 15 mL/kg body weight (mean volume 1000 mL +/- 100 mL) of 6% hydroxyethyl starch (HES) 200/0.5, the other received an equal volume of 5% human albumin during the operation. Blood samples were collected immediately before infusion (baseline values) and at 20, 40, 60, 90, 240, and 480 min after the infusion started then daily for the next 5 days postoperatively. Hematocrit, factor VIII:C, thrombin-antithrombin III complex; the anticoagulant protein C levels; the fibrinolytic parameters tissue type plasminogen activator (t-PA), and the fibrinolytic product D-Dimer and the platelet aggregation activity were measured. The data obtained did not detect any significant differences between HES and human albumin in the plasma levels of thrombin-antithrombin III complex, protein C, tissue-type plasminogen activator and the fibrin split products D-Dimer. Factor VIII:C and platelet aggregation were significantly lower in the hydroxyethyl starch group in comparison with albumin. Baseline values were attained postoperatively for factor VIII:C and platelet aggregation by the first and fifth days, respectively. The lowering effect of medium molecular weight hydroxyethyl starch on factor VIII:C would not be attributed to increased proteolytic activity of protein C on this coagulation cofactor because there is a nonsignificant change in protein C levels.

The effect of prothrombotic blood abnormalities on risk of deep vein thrombosis in users of hormone replacement therapy: a prospective case-control study.

PubMed

Douketis, Jim D; Julian, Jim A; Crowther, Mark A; Kearon, Clive; Bates, Shannon M; Barone, Marisa; Piovella, Franco; Middeldorp, Saskia; Prandoni, Paolo; Johnston, Marilyn; Costantini, Lorrie; Ginsberg, Jeffrey S

2011-01-01

Few studies have assessed the effect of prothrombotic blood abnormalities on the risk of deep vein thrombosis (DVT) with hormone replacement therapy (HRT). We studied postmenopausal women with suspected DVT in whom HRT use and prothrombotic blood abnormalities were sought. Cases had unprovoked DVT and controls had no DVT and without DVT risk factors. The risk of DVT was determined in women with and without prothrombotic abnormalities. A total of 510 postmenopausal women with suspected DVT were assessed; 57 cases and 283 controls were identified. Compared to HRT, nonusers without the factor V Leiden mutation, the risk of DVT was increased in estrogen-progestin HRT users (odds ratio [OR], 3.2; 95% confidence interval [CI]: 1.2-8.6) and in nonusers with the factor V Leiden mutation (OR, 5.3; 1.9-15.4) and appears multiplied in users of estrogen-progestin HRT with the factor V Leiden mutation (OR, 17.1; 3.7-78). Compared to HRT, nonusers with normal factor VIII, the risk of DVT was increased in estrogen-progestin HRT users with normal factor VIII (OR, 2.8; 1.0-7.9) and in HRT nonusers with the highest factor VIII quartile (OR, 6.0; 2.1-17), and appears to be multiplied in women who are users of estrogen-progestin HRT with the highest factor VIII quartile (OR, 17.0; 3.6-80). In postmenopausal women who are estrogen-progestin HRT users, the presence of the factor V Leiden mutation or an elevated factor VIII level appears to have a multiplicative effect on their overall risk of DVT, increasing it 17-fold compared to women without these blood abnormalities who are HRT nonusers.

Genetic engineering for haemophilia A.

PubMed

Gan, Shu Uin; Kon, Oi Lian; Calne, Roy Y

2006-10-01

At first sight, haemophilia A would appear to be an ideal candidate for treatment by gene therapy. There is a single gene defect; cells in different parts of the body, but especially the liver, produce Factor VIII, and only 5% of normal levels of Factor VIII are necessary to prevent the serious symptoms of bleeding. This review attempts to outline the status of gene therapy at present and efforts that have been made to overcome the difficulties and remaining problems that require solving. Undoubtedly, success will be achieved, but it is likely that considerably more work will be necessary before experimental models can be introduced into the clinic with any likelihood of success. The most successful results in animals that may have clinical application were from introducing the Factor VIII gene to newborn animals before antibodies are produced, presumably inducing a state of tolerance.

Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine

PubMed Central

Novakovic, Valerie A.; Shi, Jialan; Rasmussen, Jan; Pipe, Steven W.

2015-01-01

Thrombin-stimulated platelets expose very little phosphatidylserine (PS) but express binding sites for factor VIII (fVIII), casting doubt on the role of exposed PS as the determinant of binding sites. We previously reported that fVIII binding sites are increased three- to sixfold when soluble fibrin (SF) binds the αIIbβ3 integrin. This study focuses on the hypothesis that platelet-bound SF is the major source of fVIII binding sites. Less than 10% of fVIII was displaced from thrombin-stimulated platelets by lactadherin, a PS-binding protein, and an fVIII mutant defective in PS-dependent binding retained platelet affinity. Therefore, PS is not the determinant of most binding sites. FVIII bound immobilized SF and paralleled platelet binding in affinity, dependence on separation from von Willebrand factor, and mediation by the C2 domain. SF also enhanced activity of fVIII in the factor Xase complex by two- to fourfold. Monoclonal antibody (mAb) ESH8, against the fVIII C2 domain, inhibited binding of fVIII to SF and platelets but not to PS-containing vesicles. Similarly, mAb ESH4 against the C2 domain, inhibited >90% of platelet-dependent fVIII activity vs 35% of vesicle-supported activity. These results imply that platelet-bound SF is a component of functional fVIII binding sites. PMID:26162408

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.

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

PubMed

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

1996-06-01

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

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

Parvinen, M.; Soeder, O.M.; Mali, P.

Levels of rat testicular interleukin-1-like factor (tIL-1) have been shown to correlate with DNA synthetic activity during the cycle of the rat seminiferous epithelium, suggesting its role as a spermatogonial or meiotic growth factor. To explore this further, a new in vitro model system was developed. Rat seminiferous tubule segments from stages I, V, VIIa, and VIII-IX of the cycle were isolated by transillumination-assisted microdissection, cultured in chemically defined serum-free medium supplemented with human recombinant IL-1 {alpha}, and labeled with (3H)thymidine. During incubation, spontaneous progression of spermatogenesis was noted. Inactive stage VIIa tubule segments differentiated to stage VIII and initiatedmore » DNA synthesis, and concomitantly started to secrete IL-1-like factor. DNA synthesis of stages VIII-IX ceased through differentiation of spermatocytes to leptotene-zygotene (stages XII-XIII of the cycle). IL-1 {alpha} stimulated DNA synthesis significantly in spermatogonia of stage I. Meiotic DNA synthesis at stage VIIa was stimulated (48 h/34 C) and maintained at stages VIII-IX (48 h/34 C). IL-1 {alpha} seems to act as a regulator of spermatogenic DNA synthesis in both mitotic and meiotic phases. It has mainly stimulating and maintaining effects, but it may also be inhibitory under certain conditions.« less

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

PubMed Central

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

2016-01-01

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

Role of carbohydrate in multimeric structure of factor VIII/von Willebrand factor protein.

PubMed Central

Gralnick, H R; Williams, S B; Rick, M E

1983-01-01

The carbohydrate moiety of the factor VIII/von Willebrand (vW) factor protein is important in the expression of vW factor activity and the intravascular survival of the protein. Studies of normal human factor VIII/vW factor protein indicate that there is a requirement of a full complement of penultimate galactose for the maintenance of a normal multimeric structure. Release of penultimate galactose by beta-galactosidase or modification by galactose oxidase results in loss of the largest molecular weight multimers and increased numbers of intermediate and smaller multimers. In contrast, terminal galactose on the factor VIII/vW factor protein does not appear to play a significant role in the maintenance of the multimer organization. The abnormalities in multimeric structure and molecular size were demonstrated by NaDodSO4/polyacrylamide/agarose gel electrophoresis, NaDodSO4/glyoxyl-agarose electrophoresis, and sucrose density ultracentrifugation. These studies indicate that the penultimate galactose plays a role in the maintenance of the largest multimers of the factor VIII/vW factor protein. This may explain why, in some patients with variant forms of vW disease, a carbohydrate abnormality also may affect the multimeric structure of the plasma factor VIII/vW factor protein. Images PMID:6601805

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

Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation

PubMed Central

Meeks, Shannon L.; Healey, John F.; Parker, Ernest T.; Barrow, Rachel T.

2007-01-01

The diversity of factor VIII (fVIII) C2 domain antibody epitopes was investigated by competition enzyme-linked immunosorbent assay (ELISA) using a panel of 56 antibodies. The overlap patterns produced 5 groups of monoclonal antibodies (MAbs), designated A, AB, B, BC, and C, and yielded a set of 18 distinct epitopes. Group-specific loss of antigenicity was associated with mutations at the Met2199/Phe2200 phospholipid binding β-hairpin (group AB MAbs) and at Lys2227 (group BC MAbs), which allowed orientation of the epitope structure as a continuum that covers one face of the C2 β-sandwich. MAbs from groups A, AB, and B inhibit the binding of fVIIIa to phospholipid membranes. Group BC was the most common group and displayed the highest specific fVIII inhibitor activities. MAbs in this group are type II inhibitors that inhibit the activation of fVIII by either thrombin or factor Xa and poorly inhibit the binding of fVIII to phospholipid membranes or von Willebrand factor (VWF). Group BC MAbs are epitopically and mechanistically distinct from the extensively studied group C MAb, ESH8. These results reveal the structural and functional complexity of the anti-C2 domain antibody response and indicate that interference with fVIII activation is a major attribute of the inhibitor landscape. PMID:17848617

B-domain deleted recombinant factor VIII formulation and stability.

PubMed

Osterberg, T; Fatouros, A; Neidhardt, E; Warne, N; Mikaelsson, M

2001-04-01

B-domain deleted recombinant factor VIII (BDDrFVIII) is a deletion form of human coagulation factor VIII. A lyophilized formulation of highly purified BDDrFVIII has been developed that does not require the use of blood-derived products such as human serum albumin (HSA). By avoiding the use of blood-derived products, the BDDrFVIII formulation minimizes the risk of transmitting blood-borne pathogens that may be present in plasma-derived factor VIII or in other recombinant factor VIII products that contain HSA in their formulation. Upon reconstitution with saline (4 mL), the composition of the reconstituted product (62.5 to 250 IU/mL BDDrFVIII) is 18 mg/mL sodium chloride, 3.0 mg/mL sucrose, 1.5 mg/mL L-histidine, 0.25 mg/mL calcium chloride dihydrate, and 0.1 mg/mL polysorbate 80. The optimal combination of these excipients in the lyophilized BDDrFVIII formulation provides long-term stability, as measured by a variety of analytical methods. The formulation preserves factor VIII activity of lyophilized BDDrFVIII during storage for at least 24 months at 8 degrees C, and for up to 6 months at room temperature (25 degrees C). The reconstituted product retains its factor VIII potency for at least 100 hours at 25 degrees C, which would allow it to be continuously administered via an infusion pump, assuming the product is handled under aseptic conditions.

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

PubMed

Osterberg, T; Fatouros, A; Mikaelsson, M

1997-07-01

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

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

PubMed

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

2005-01-01

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

Immunogenicity and immune tolerance coagulation Factors VIII and IX.

PubMed

Rup, B

2003-01-01

Some of the major issues related to the development and control of antibodies that occur during treatment of haemophilia with replacement factors (Factor VIII and Factor IX) are reviewed. Information on analytical issues, immunogenicity, and immune tolerance may be applicable to the study of other therapeutic proteins. Conversely, new information obtained from evaluation of other therapeutic protein products may address issues that remain unresolved for Factor VIII and FIX replacement therapy.

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

PubMed Central

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

1988-01-01

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

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

PubMed

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

2012-07-05

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

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...

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.

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

PubMed

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

1983-01-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed Central

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

2007-01-01

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

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

PubMed

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

2016-08-08

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

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

PubMed

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

2013-07-25

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

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

PubMed

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

2018-01-01

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

Relationships of inflammatory and haemostatic markers with social class: results from a population-based study of older men.

PubMed

Ramsay, Sheena; Lowe, Gordon D O; Whincup, Peter H; Rumley, Ann; Morris, Richard W; Wannamethee, S Goya

2008-04-01

Haemostatic and inflammatory markers have been hypothesised to mediate the relationship of social class and cardiovascular disease (CVD). We investigated whether a range of inflammatory/haemostatic markers are associated with social class independent of chronic diseases and behavioural risk factors in a population-based sample of 2682 British men aged 60-79 without a physician diagnosis of CVD, diabetes or musculoskeletal disease requiring anti-inflammatory medications. Men in lower social classes had higher mean levels of C-reactive protein, fibrinogen, interleukin-6, white blood cell count, von Willebrand factor (vWF), factor VIII, activated protein C (APC) resistance, plasma viscosity, fibrin D-dimer and platelet count, compared to higher social class groups; but not of tissue plasminogen activator antigen, haematocrit or activated partial prothrombin time. After adjustment for behavioural risk factors (smoking, alcohol, physical activity and body mass), the associations of social class with vWF, factor VIII, APC resistance, plasma viscosity, and platelet count though weakened, remained statistically significant, while those of other markers were considerably attenuated. In this study of older men without CVD, the social gradient in inflammatory and haemostatic markers was substantially explained by behavioural risk factors. The effect of socio-economic gradient on the factor VIII-vWF complex, APC resistance, plasma viscosity and platelet count merits further study.

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

PubMed Central

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

2012-01-01

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. PMID:22517903

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

PubMed

Winfield, Laramie S; Brooks, Marjory B

2014-03-15

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

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

PubMed Central

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

2016-01-01

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

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

DOE PAGES

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

2015-11-24

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

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

PubMed

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

2016-10-20

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

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

PubMed

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

2016-10-01

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

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

PubMed

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

2000-07-01

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

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.

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

PubMed

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

2016-08-04

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

Acquired high titre factor VIII inhibitor with underlying polyarteritis nodosa.

PubMed

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

1997-05-01

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

Lupus anticoagulant, anticardiolipin antibodies, and human immunodeficiency virus in haemophilia.

PubMed Central

Cohen, H; Mackie, I J; Anagnostopoulos, N; Savage, G F; Machin, S J

1989-01-01

The prevalence of lupus anticoagulant, using the dilute Russell's viper venom time (DRVT), was determined in 22 patients with mild to severe haemophilia A to see if there was any association with the presence of viral disease. Twelve haemophiliacs (58%) were lupus anticoagulant positive, with a mean patient:control ratio of 1.24 (range 1.15-1.52, normal range 0.84-1.06 which partially corrected with lysed, washed platelets). Nine of these patients were IgG or IgM, or both, anticardiolipin antibody positive and nine were human immunodeficiency virus (HIV) antibody positive, but associations between lupus anticoagulant, anticardiolipin antibodies, and HIV antibody positivity were not significant. Mixing studies of normal plasma and immune depleted factor VIII deficient plasma showed that the DRVT ratio increased when the factor VIII concentration fell below 0.15 IU/ml. There was no significant association between plasma factor VIII concentration and positive DRVT results in haemophiliacs. The addition of porcine factor VIII concentrate produced no correction in eight of the 12 with DRVTs indicative of lupus anticoagulant, suggesting that these were prolonged by antiphospholipid activity. It is concluded that the presence of lupus anticoagulant and anticardiolipin antibodies in haemophiliacs may represent an antiphospholipid response to viraemic challenge, not only to HIV but also to other viral antigens, and that a very low factor VIII concentration may produce a false positive DRVT result. PMID:2500459

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

PubMed

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

2013-07-01

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

Duration of Red Blood Cell Storage Is Associated with Increased Incidence of Deep Vein Thrombosis and in Hospital Mortality in Patients with Traumatic Injuries

DTIC Science & Technology

2009-09-22

Verhoeven AJ: Prolonged maintenance of 2, 3- diphosphoglycerate acid and adenosine triphosphate in red blood cells during storage. Transfusion 2008...ABO blood group geno- type and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 2005, 93(3):468-474. 41. Koch

Bloodcurdling movies and measures of coagulation: Fear Factor crossover trial

PubMed Central

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

2015-01-01

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

Factor VIII-associated antigen in human lymphatic endothelium.

PubMed

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

1987-03-01

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

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

PubMed

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

1996-10-01

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

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

PubMed

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

2016-09-01

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

Haemophilia A: carrier detection and prenatal diagnosis by linkage analysis using DNA polymorphism.

PubMed Central

Tuddenham, E G; Goldman, E; McGraw, A; Kernoff, P B

1987-01-01

Restriction fragment length polymorphisms (RFLPs) within or close to the factor VIII locus are very useful for genetic linkage analysis. Such RFLPs allow a mutant allele to be tracked in a family, segregating haemophilia A even when, as is usually the case, the precise mutation causing failure to synthesise factor VIII is unknown. To date two markers tightly linked to the factor VIII locus have been described, one of which is highly polymorphic and therefore informative in most kindreds. A significant crossover rate, however, does not make diagnosis absolute. Three intragenic RFLPs have been defined, which, taken together, are informative in about 70% of women, providing virtually deterministic genetic diagnosis. PMID:2889753

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

PubMed

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

2017-09-01

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

Diagnosis and management of von Willebrand's syndrome.

PubMed

Rick, M E

1994-05-01

von Willebrand's disease is the most common of the inherited bleeding disorders. It is caused by quantitative and/or qualitative abnormalities of von Willebrand factor, and it usually presents with bleeding from mucosal surfaces. The diagnosis is confirmed by measuring von Willebrand factor activity and antigen levels, factor VIII activity, and performing a multimer analysis of von Willebrand factor. Treatment may require plasma-derived concentrates, but can often be accomplished with DDAVP, a vasopressin analogue that causes transient release of von Willebrand factor from body storage sites.

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

PubMed

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

2017-05-01

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

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

PubMed

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

2006-04-01

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

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

PubMed

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

2012-05-01

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

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

PubMed

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

1986-06-01

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

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

PubMed

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

2015-12-16

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

Von Willebrand's disease: case report and review of literature.

PubMed

Echahdi, Hanae; El Hasbaoui, Brahim; El Khorassani, Mohamed; Agadr, Aomar; Khattab, Mohamed

2017-01-01

Von Willebrand Disease (VWD) is the most common human inherited bleeding disorder due to a defect of Von Willebrand Factor (VWF), which a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels < 50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50IU/dL). Von willebrand factor is a complex multimeric protein with two functions: it forms a bridge between the platelets and areas of vascular damage and it binds to and stabilizes factor VIII, which is necessary for the clotting cascade. By taking a clinical history of bleeding (mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is possible) it is important to think about VWD and to make the appropriate diagnosis. If the VWD is suspected diagnostic tests should include an activated partial thromboplastin time, bleeding time, factor VIII: C Ristocetin cofactor and vWF antigen. Additional testing of ristocetin induced plattlet adhesion (RIPA) the multimeric structure and collagen binding test and genanalysis allow diagnosing the different types of von. Willebrand Disease. The treatment of choice in mild forms is the synthetic agent desmopressin. In patients with severe type 1, type 2B, 2N and type 3 or in people who do not response to desmopressin, the appropriate treatment is a factor VIII concentrate that is rich of VWF. We report a case of infant in 27-month-old boy who had been referred due to haemorrhagic shock. His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to the symptoms, the child was on a normal diet and was thriving appropriately. The child presented one days before his admission trauma to the inner face of the lower lip that caused an external acute bleeding loss. The laboratory data showed unfortunately, the most severe form of Von Willebrand's Disease; Type 3. The management was based on erythrocyte and fresh-frozen plasma (FFP) transfusions with administration of factor VII with good evolution.

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

PubMed

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

2017-07-01

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

Laboratory diagnosis of von Willebrand's disease.

PubMed

Rick, M E

1994-12-01

The diagnosis of von Willebrand's disease is becoming complex as more is understood about the disease. Clinical information and laboratory data are necessary for the diagnosis because of the overlap of normal and abnormal laboratory values. A complete evaluation including von Willebrand factor multimers, ristocetin-induced platelet aggregation, factor VIII activity level, and a template bleeding time is necessary to correctly classify the patient so that optimal treatment may be given.

Effectiveness of Mind Mapping in English Teaching among VIII Standard Students

ERIC Educational Resources Information Center

Hallen, D.; Sangeetha, N.

2015-01-01

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

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

USDA-ARS?s Scientific Manuscript database

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

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

PubMed

Hay, C R M

2013-09-01

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

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

PubMed

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

2017-01-01

Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of platelet-expressed FVIII than are required for therapeutic efficacy in hemophilia A are not associated with a thrombotic predilection. © 2016 International Society on Thrombosis and Haemostasis.

Contact system activation and high thrombin generation in hyperthyroidism.

PubMed

Kim, Namhee; Gu, Ja-Yoon; Yoo, Hyun Ju; Han, Se Eun; Kim, Young Il; Nam-Goong, Il Sung; Kim, Eun Sook; Kim, Hyun Kyung

2017-05-01

Hyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extracellular traps (NET) has emerged as an important trigger of thrombosis, we hypothesized that the contact system is activated along with active NET formation in hyperthyroidism and that their markers correlate with disease severity. In 61 patients with hyperthyroidism and 40 normal controls, the levels of coagulation factors (fibrinogen, and factor VII, VIII, IX, XI and XII), D-dimer, thrombin generation assay (TGA) markers, NET formation markers (histone-DNA complex, double-stranded DNA and neutrophil elastase) and contact system markers (activated factor XII (XIIa), high-molecular-weight kininogen (HMWK), prekallikrein and bradykinin) were measured. Patients with hyperthyroidism showed higher levels of fibrinogen (median (interquartile range), 315 (280-344) vs 262 (223-300), P  = 0.001), D-dimer (103.8 (64.8-151.5) vs 50.7 (37.4-76.0), P  < 0.001), peak thrombin (131.9 (102.2-159.4) vs 31.6 (14.8-83.7), P  < 0.001) and endogenous thrombin potential (649 (538-736) vs 367 (197-1147), P  = 0.021) in TGA with 1 pM tissue factor, neutrophil elastase (1.10 (0.39-2.18) vs 0.23 (0.20-0.35), P  < 0.001), factor XIIa (66.9 (52.8-87.0) vs 73.0 (57.1-86.6), P  < 0.001), HMWK (6.11 (4.95-7.98) vs 3.83 (2.60-5.68), P  < 0.001), prekallikrein (2.15 (1.00-6.36) vs 1.41 (0.63-2.22), P  = 0.026) and bradykinin (152.4 (137.6-180.4) vs 118.3 (97.1-137.9), P  < 0.001) than did normal controls. In age- and sex-adjusted logistic regression analysis, fibrinogen, factor VIII, IX and XIIa, D-dimer, peak thrombin, neutrophil elastase, HMWK and bradykinin showed significant odds ratios representing hyperthyroidism's contribution to coagulation and contact system activation. Free T4 was significantly correlated with factors VIII and IX, D-dimer, double-stranded DNA and bradykinin. This study demonstrated that contact system activation and abundant NET formation occurred in the high thrombin generation state in hyperthyroidism and were correlated with free T4 level. © 2017 European Society of Endocrinology.

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

PubMed

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

1986-11-01

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

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

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

Carlo Parisi; Emanuele Negrenti

2017-02-01

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

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

PubMed Central

1995-01-01

OBJECTIVE: To present current strategies for the treatment of hemophilia and von Willebrand's disease. OPTIONS: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered. VALUES: Minimizing morbidity and maximizing functional status and quality of life were given a high value. BENEFITS, HARMS AND COSTS: Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents. RECOMMENDATIONS: DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.VALIDATION: These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison. SPONSORS: These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. PMID:7600466

Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body.

PubMed

Tamilvanan, Shunmugaperumal; Raja, Natarajan Livingston; Sa, Biswanath; Basu, Sanat Kumar

2010-08-01

Similar to the low molecular weight traditional drugs, biopharmaceuticals are capable of producing not only therapeutic effects but also side effects provided if the dose of these compounds exceeds certain concentration and/or if the exposure duration of these compounds at subtoxic doses is being lengthened. In addition, a major drawback of biopharmaceuticals is the risk of antibody formation. Following the administration of biopharmaceuticals into human body, the formation of antidrug-antibody (ADA) or neutralizing antibody and other general immune system effects (including allergy, anaphylaxis, or serum sickness) are of clinical concern regarding therapeutic efficacy and patient safety. For example, drug-induced neutralizing antibodies to erythropoietin (EPO) result in pure red cell aplasia, whereas drug-induced acquired anti-factor VIII antibodies worsen the pathology associated with hemophilia. Since most of the already developed or under development biopharmaceuticals are to some extent immunogenic, the regulatory agencies insist to conduct potential ADA formation during the drug development process itself. This review encompasses a short overview on the clinical concerns of immunogenicity produced at cellular levels by growth hormone, interferon-alpha, EPO, factor VIII, and factor IX following their parenteral administration into human body. Clinical concerns related to immunogenicity produced by the biosimilar versions of these drugs are also presented wherever possible.

Hemophilia in Sports: A Case Report and Prophylactic Protocol

PubMed Central

Maffet, Mark; Roton, Jimmy

2017-01-01

Objective: To describe a successful prophylactic protocol for managing an athlete with hemophilia playing at a high level of contact sports. Background: Published data show that team physicians are not comfortable either treating athletes with bleeding disorders or allowing them to participate in contact sports. Much of the literature historically has recommended against allowing athletes with bleeding disorders to play sports at all and certainly against playing contact sports. Hemophilia treatment can now include prophylactic injections of recombinant factor VIII to prevent bleeding episodes. Modern treatments hold the promise of allowing athletes with hemophilia to participate in contact sports. Differential Diagnosis: Mild, moderate, or severe hemophilia; von Willebrand disease; other factor deficiencies. Treatment: A treatment protocol was developed that included prophylactic factor VIII injections on a regular basis and when the athlete was injured. Uniqueness: This is the first published case report of an athlete with known hemophilia being successfully treated and participating in National Collegiate Athletic Association collegiate basketball for 2 full seasons. Conclusions: Sports medicine teams can successfully manage an athlete with hemophilia playing a contact sport. PMID:27863189

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

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

Lin,L.

2007-01-01

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

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

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

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

2007-01-01

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

Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976-80: report on behalf of the directors of haemophilia centres in the United Kingdom.

PubMed Central

Rizza, C R; Spooner, R J

1983-01-01

A five year survey of the treatment of patients in the United Kingdom suffering from haemophilia and related disorders was carried out on behalf of the directors of haemophilia centres. The survey showed an increase in the number of patients receiving treatment from the centres, a substantial increase in the total amount of therapeutic materials used, and an increase in the average amount of factor VIII or factor IX used yearly per patient. Home treatment became established for severely affected patients and accounted for roughly half of the total amount of material used. Study of the acquisition of factor VIII or factor IX antibodies (inhibitors) in patients with haemophilia A or haemophilia B showed no increase in antibodies during the survey period, despite the increased use of factor VIII and factor IX concentrates. The occurrence of acute hepatitis in treated patients was also studied and no increased incidence was observed. A near normal median expectation of life in patients with severe haemophilia A was found. PMID:6403138

The rational design of a 'type 88' genetically stable peptide display vector in the filamentous bacteriophage fd.

PubMed

Enshell-Seijffers, D; Smelyanski, L; Gershoni, J M

2001-05-15

Filamentous bacteriophages are particularly efficient for the expression and display of combinatorial random peptides. Two phage proteins are often employed for peptide display: the infectivity protein, PIII, and the major coat protein, PVIII. The use of PVIII typically requires the expression of two pVIII genes: the wild-type and the recombinant pVIII gene, to generate mosaic phages. 'Type 88' vectors contain two pVIII genes in one phage genome. In this study a novel 'type 88' expression vector has been rationally designed and constructed. Two factors were taken into account: the insertion site and the genetic stability of the second pVIII gene. It was found that selective deletion of recombinant genes was encountered when inserts were cloned into either of the two non-coding regions of the phage genome. The deletions were independent of recA yet required a functional F-episome. Transcription was also found to be a positive factor for deletion. Taking the above into account led to the generation of a novel vector, designated fth1, which can be used to express recombinant peptides as pVIII chimeric proteins in mosaic bacteriophages. The fth1 vector is not only genetically stable but also of high copy number and produces high titers of recombinant phages.

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

PubMed

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

2017-04-01

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children < 12 years of age with severe hemophilia A. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

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

PubMed Central

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

2001-01-01

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

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

PubMed

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

2013-01-01

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

Treatment of periodontal disease in a patient with Ehlers-Danlos syndrome. A case report and literature review.

PubMed

Perez, Luis A; Al-Shammari, Khalaf F; Giannobile, William V; Wang, Hom-Lay

2002-05-01

Ehlers-Danlos syndrome (EDS) designates a heterogeneous group of connective tissue disorders characterized by skin elasticity, tissue fragility, and chronic joint pain. Dental findings have been reported with some types of EDS. This case report describes the periodontal findings in a patient with a previously undiagnosed EDS type VIII. Diagnostic aids utilized included microbial testing, histological examination, gingival crevicular fluid (GCF) analysis for the levels of C-telopeptide pyridinoline cross-links (ICTP), and genetic counseling. Periodontal treatment consisted of mechanical debridement and adjunctive antibiotic therapy. Genetic counseling and clinical presentation confirmed the diagnosis of EDS type VIII. Periodontal treatment led to marked clinical improvements and GCF levels of the bone resorptive marker ICTP were significantly reduced. The patient and her siblings are currently pursuing appropriate medical care and genetic counseling. Periodontal involvement may lead to the diagnosis of an underlying systemic condition. Identification of suspected etiological factors of periodontal disease may prove critical for the general well-being of some patients.

Internal quality control of blood products: An experience from a tertiary care hospital blood bank from Southern Pakistan.

PubMed

Sultan, Sadia; Zaheer, Hasan Abbas; Waheed, Usman; Baig, Mohammad Amjad; Rehan, Asma; Irfan, Syed Mohammed

2018-01-01

Internal quality control (IQC) is the backbone of quality assurance program. In blood banking, the quality control of blood products ensures the timely availability of a blood component of high quality with maximum efficacy and minimal risk to potential recipients. The main objective of this study is to analyze the IQC of blood products as an indicator of our blood bank performance. An observational cross-sectional study was conducted at the blood bank of Liaquat National Hospital and Medical College, from January 2014 to December 2015. A total of 100 units of each blood components were arbitrarily chosen during the study. Packed red cell units were evaluated for hematocrit (HCT); random platelet concentrates were evaluated for pH, yield, and culture; fresh frozen plasma (FFP) and cryoprecipitate (CP) were evaluated for unit volume, factor VIII, and fibrinogen concentrations. A total of 400 units were tested for IQC. The mean HCT of packed red cells was 69.5 ± 7.24, and in 98% units, it met the standard (<80% of HCT). The mean platelet yield was 8.8 ± 3.40 × 10 9 /L and pH was ≥6.2 in 98% bags; cultures were negative in 97% of units tested. Mean factor VIII and fibrinogen levels were found to be 84.24 ± 15.01 and 247.17 ± 49.69 for FFP, respectively. For CP, mean factor VIII and fibrinogen level were found to be 178.75 ± 86.30 and 420.7 ± 75.32, respectively. The IQC of blood products at our blood bank is in overall compliance and met recommended international standards. Implementation of standard operating procedures, accomplishment of standard guidelines, proper documentation with regular audit, and staff competencies can improve the quality performance of the transfusion services.

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

PubMed

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

2016-03-01

ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)). One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1). Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive overdosing (OR 1.8, 95% CI 1.3-2.4). Quality of care and cost-effectiveness can be improved by refining of dosing strategies based on individual patient characteristics such as blood group and mode of infusion. © 2015 International Society on Thrombosis and Haemostasis.

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

PubMed

Pabinger-Fasching, Ingrid

2016-05-01

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

Identification of 5g and 6g terms and revised ionization energies in the Yb II 4f/sup 14/nl isoelectronic sequence

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

Sugar, J.; Kaufman, V.

1979-01-01

The 5f-5g transitions in Lu III through Os VIII and the 5f-6g transitions in Hf IV through W VI were identified and used to redetermine the ionization energies of Yb II, Lu III, W VI, Re VII, and Os VIII. Complete line-lists and energy levels are given for the one-electron spectra Hf IV, W VI and Os VIII.

Identifying novel genetic determinants of hemostatic balance.

PubMed

Ginsburg, D

2005-08-01

Incomplete penetrance and variable expressivity confound the diagnosis and therapy of most inherited thrombotic and hemorrhagic disorders. For many of these diseases, some or most of this variability is determined by genetic modifiers distinct from the primary disease gene itself. Clues toward identifying such modifier genes may come from studying rare Mendelian disorders of hemostasis. Examples include identification of the cause of combined factor V and VIII deficiency as mutations in the ER Golgi intermediate compartment proteins LMAN1 and MCFD2. These proteins form a cargo receptor that facilitates the transport of factors V and VIII, and presumably other proteins, from the ER to the Golgi. A similar positional cloning approach identified ADAMTS-13 as the gene responsible for familial TTP. Along with the work of many other groups, these findings identified VWF proteolysis by ADAMTS-13 as a key regulatory pathway for hemostasis. Recent advances in mouse genetics also provide powerful tools for the identification of novel genes contributing to hemostatic balance. Genetic studies of inbred mouse lines with unusually high and unusually low plasma VWF levels identified polymorphic variation in the expression of a glycosyltransferase gene, Galgt2, as an important determinant of plasma VWF levels in the mouse. Ongoing studies in mice genetically engineered to carry the factor V Leiden mutation may similarly identify novel genes contributing to thrombosis risk in humans.

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

PubMed

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

2016-07-01

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

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

PubMed

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

1992-03-01

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

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.

Hyperthyroidism and cerebral venous thrombosis.

PubMed

Mouton, S; Nighoghossian, N; Berruyer, M; Derex, L; Philippeau, F; Cakmak, S; Honnorat, J; Hermier, M; Trouillas, P

2005-01-01

The demonstration of an underlying prothrombotic condition in cerebral venous thrombosis (CVT) may have important practical consequences in terms of prevention. Thyrotoxicosis through a hypercoagulable state may be a predisposing factor for CVT. The authors present the cases of 4 patients who developed CVT and hyperthyroidism. At the acute stage, hyperthyroidism was associated with an increase in factor VIII (FVIII). At follow-up, FVIII level remained increased in 2 patients. Hyperthyroidism may have an impact on FVIII level. Accordingly in patients with hyperthyroidism and neurological symptoms, the diagnosis of CVT should be considered and an exhaustive coagulation screening may be appropriate. (c) 2005 S. Karger AG, Basel.

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

PubMed

Staber, Janice M; Pollpeter, Molly J

2016-01-01

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

Prevalence of nucleic acid sequences specific for human parvoviruses, hepatitis A and hepatitis E viruses in coagulation factor concentrates.

PubMed

Modrow, S; Wenzel, J J; Schimanski, S; Schwarzbeck, J; Rothe, U; Oldenburg, J; Jilg, W; Eis-Hübinger, A M

2011-05-01

Due to their high resistance to inactivation procedures, nonenveloped viruses such as parvovirus B19, human bocavirus (HBoV), human parvovirus 4 (PARV4), hepatitis A (HAV) and hepatitis E virus (HEV) pose a particular threat to blood products. Virus transmission to patients treated with blood products presents an additional burden to disease. We determined the frequency and the amount of nucleic acid specific for nonenveloped viruses in recently manufactured preparations of commercial coagulation factor concentrates. At least three different batches of each of 13 different plasma-derived and recombinant coagulation factor products were tested for the presence and the amount of nucleic acid for parvovirus B19, HBoV, human parvovirus 4, hepatitis A virus and HEV by using quantitative polymerase chain reaction. Whereas none of the recombinant products tested positive for any of these viruses, parvovirus B19 DNA with amounts ranging between 2×10(1) and 1.3×10(3) genome equivalents/ml was detected in five plasma-derived products. In addition to parvovirus B19 genotype 1, genotypes 2 and 3 were observed in two batches of a factor VIII/von-Willebrand factor product. In two products (one factor VIII concentrate and one activated prothrombin complex concentrate), a combination of both genotypes 1 and 2 of parvovirus B19 was detected. The data show that nucleic acids from several relevant nonenveloped viruses are not found at detectable levels in coagulation factor concentrates. In some cases, parvovirus B19 DNA was detectable at low levels. Testing of the plasma pools for the full range of parvovirus genotypes is advocated for ensuring product safety. © 2010 The Author(s). Vox Sanguinis © 2010 International Society of Blood Transfusion.

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

PubMed

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

2015-07-01

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

Are patients with thrombophilia and previous venous thromboembolism at higher risk to arterial thrombosis?

PubMed

Linnemann, Birgit; Schindewolf, Marc; Zgouras, Dimitrios; Erbe, Matthias; Jarosch-Preusche, Marie; Lindhoff-Last, Edelgard

2008-01-01

Whether thrombophilic disorders, which are established risk factors for venous thromboembolism (VTE), also increase the risk of arterial thrombosis is still unknown. We analyzed data from 1081 consecutive patients (649 F/432 M, 16-93 years of age) with previous VTE registered in the MAISTHRO (MAin-ISar-THROmbosis) database with regard to arterial thrombotic events and contributing risk factors. Screening for thrombophilia included testing for factor V Leiden and prothrombin G20210A mutation, antiphospholipid antibodies and activities of factor VIII, protein C, protein S and antithrombin. Of the entire study cohort, 40 patients (3.7%) had a prior myocardial infarction (MI), and 41 (3.8%) suffered a stroke. Other arterial thrombotic events were rare. Elevated factor VIII levels were more prevalent in MI patients than in controls (44.4 vs. 25.9%, p=0.044), but after adjusting for the traditional cardiovascular risk factors, this relationship was no longer significant. We observed a higher rate of lupus anticoagulant in MI patients with an adjusted odds ratio of 3.3 (95%CI 0.84-12.8, p=0.090). No difference in any other tested thrombophilia was observed in patients with MI or stroke relative to those without. The cumulative incidence of arterial thrombotic events in VTE patients is low, and the inherited thrombophilias do not seem to substantially increase the risk of arterial thrombosis.

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

NASA Technical Reports Server (NTRS)

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

1995-01-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the z(sub a) approximately equal z(sub e) absorption system of the z(sub e) = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at z(sub a) = 2.1340 (shifted approximately 1500 km/s from z(sub e) strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other z(sub a) approximately equal z(sub e) absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 10(exp 18)/sq cm in the low-ionization gas to approximately 10(exp 20)/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link z(sub a) approximately equal to z(sub e) systems with X-ray 'wamr absorbers. We show that the Ne VIII absorbing gas would itself produce measurable warm absorption -- characterized by bound-free O VII or O VIII edegs near 0.8 keV -- if the column densities were N(sub H) greater than or approximately equal to 10(exp 21)/sq cm (for solar abundances).

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

NASA Astrophysics Data System (ADS)

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

1995-04-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the za approximately equal ze absorption system of the ze = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at za = 2.1340 (shifted approximately 1500 km/s from ze strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other za approximately equal ze absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 1018/sq cm in the low-ionization gas to approximately 1020/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link za approximately equal to ze systems with X-ray 'wamr absorbers. We show that the Ne VIII absorbing gas would itself produce measurable warm absorption -- characterized by bound-free O VII or O VIII edegs near 0.8 keV -- if the column densities were NH greater than or approximately equal to 1021/sq cm (for solar abundances).

Pelvic adhesion and gonadotropin-releasing hormone analogue: effects of triptorelin acetate depot on coagulation and fibrinolytic activities.

PubMed

Di Nardo, Maria Antonietta; Annunziata, Maria Laura; Ammirabile, Massimiliano; Di Minno, Matteo Nicola Dario; Ruocco, Anna Lilia; De Falco, Marianna; Di Lieto, Andrea

2012-06-01

The study investigated the impact of gonadotropin-releasing hormone analogue (GnRH-a) on coagulation and fibrinolytic activities and its effectiveness in the prevention of pelvic adhesion after myomectomy. Thirty-two infertile women underwent myomectomy followed by adhesion evaluation surgery with a second-look laparoscopy. Before myomectomy, 15 women were treated with triptorelin acetate for 3 months and 17 received no treatment. Plasminogen activator inhibitor (PAI), thrombin activatable fibrinolysis inhibitor (TAFI), protein C (PC), plasminogen, α2-antiplasmin were determined by enzyme-linked immunosorbent assays and the activity of coagulation factors V and VIII by coagulometric methods. Patients treated with GnRH-a showed significant decrease in PAI, TAFI, factors V, and VIII (P < .05) and increased PC (P < .05), but no significant change in plasminogen and α2-antiplasmin levels compared with control group. The incidence, extent, and severity of adhesions were significantly lower in GnRH-a-treated patients compared with control group (P < .05), suggesting a possible critical role of the GnRH-a therapy in preventing postoperative adhesion development.

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

NASA Astrophysics Data System (ADS)

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

2012-04-01

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

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

PubMed

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

2009-09-01

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

Clotting Factor Changes during the First Cycle of Oral Contraceptive Use

PubMed Central

Westhoff, Carolyn L.; Eisenberger, Andrew; Tang, Rosalind; Cremers, Serge; Grossman, Lisa V.; Pike, Malcolm C.

2016-01-01

Objectives The risk of venous thromboembolism (VTE) is highest during the initial months of oral contraceptive (OC) use. We sought to evaluate the extent of hemostatic variable changes during the initial OC cycle and if such changes are related to systemic ethinyl estradiol (EE2) exposure. Study Design Participants provided multiple blood samples during a 21-day OC cycle (30 mcg EE2; 150 mcg levonorgestrel) and after a single dose following a wash-out period. Analytes included D-dimer, factor VIII activity, protein C total antigen and the hepatic proteins corticosteroid- and sex-hormone-binding globulins (CBG and SHBG). EE2 pharmacokinetic analyses related to the 24 hours after the first OC tablet (OC1) and at steady state (OC21). Results Seventeen women completed the study. D-dimer more than doubled by OC6 (p = 0.013) and remained elevated at OC21 (p=0.012). D-dimer levels within women varied widely from day-to-day. Factor VIII increased 27% by OC2 (p < 0.001), but declined to a 9% increase by OC21. Protein C increased only 6%. EE2 steady-state area-under-the-curve ranged from 488 to 1103 pg·h/mL; higher levels were not correlated with greater increases in clotting variables. CBG and SHBG increased significantly, but were not significantly correlated with levels of EE2 or with the hemostatic variables. Conclusions D-dimer increases during the first OC cycle were at least as great as increases seen with longer OC use. These results provide support for the increased VTE risk during initial OC use. The extreme variability in D-dimer levels may be an important component of this risk. PMID:26452328

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

PubMed Central

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

2009-01-01

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

Coagulation Factor Tests

MedlinePlus

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

Early intraoperative blood collection does not affect complete blood counts, von Willebrand factor or factor VIII levels in normal children.

PubMed

Darwish, Hanni; Mundell, Gillianne; Engen, Dale; Lillicrap, David; Silva, Mariana; James, Paula

2011-01-01

Obtaining blood from children for research studies can be difficult, particularly for controls. One solution is to obtain samples during elective surgery; however, consideration must be given to the potential effects of the timing of phlebotomy. Ten children were recruited and phlebotomy was carried out during a preoperative clinic visit and intraoperatively immediately after the induction of anesthesia but before the start of surgery. CBCs, VWF, and FVIII levels were measured at both time points and no significant differences were seen. This negative result may be beneficial to pediatric research by suggesting that early intraoperative blood collection for controls does not affect the results.

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

PubMed

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

2008-09-01

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

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

PubMed Central

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

2017-01-01

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

Appeals court reverses verdict favoring drug companies.

PubMed

1995-06-02

An appeals court reversed a verdict favoring drug companies after the widow of a hemophiliac, whose death was linked to HIV-tainted blood products, sued four pharmaceutical companies to pay damages. The four companies, Alpha Therapeutic Corp., Miles Laboratories Inc., Armour Pharmaceutical Co., and Baxter Travenol Laboratories Inc., provided Factor VIII, a clotting concentrate, to [name removed] [name removed], the plaintiff's husband, from 1972 until his death in 1987. [Name removed]'s wife sued the companies, alleging that the defendants negligently solicited blood plasma from paid donors who had a high risk of having HIV, failed to determine whether any lots of Factor VIII contained plasma from an at-risk donor, failed to warn consumers of possible risks, and failed to heat-treat HIV and other viruses in Factor VIII, despite industry-wide knowledge of the risk of infection. The three-judge panel said the trial judge's decision to avoid ruling on the antigenic stimulation theory, based on insufficient evidence, was improper. In addition, the appeals court said a retrial is necessary because of improper remarks made by Alpha's attorney.

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

PubMed

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

2015-07-03

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

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

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

Preanalytical influence of pneumatic tube delivery system on results of routine biochemistry and haematology analysis.

PubMed

Petit, Morgane; Mine, Louis; Pascreau, Tiffany; Brouzes, Chantal; Majoux, Sandrine; Borgel, Delphine; Beaudeux, Jean-Louis; Lasne, Dominique; Hennequin, Carole

2017-12-01

Pneumatic tube delivery system (PTS) enables to reduce considerably turnaround times. The aim of the study was to assess the influence of the PTS on the quality of routine biochemical and hematological tests in our laboratory. Blood samples from 6 hospitalized patients and 8 healthy volunteers were analyzed. Blood samples were delivered to the laboratory by a PTS and by a human courier. We performed the following analysis: ionized calcium, sodium, potassium, lactate deshydrogenase (LDH), aspartate aminotransferase (ASAT), arterial blood gas, complete blood count and coagulation test as prothrombin time, activated partial thromboplastin time, factors V and VIII. Results were compared between the both method of transport according to the recommendation of the Société française de biologie clinique and the French committee for accreditation (SH-GTA01, norme NF ISO 5275-6). The hemolysis index of plasma was similar between the groups and no morphological differences were found on blood cells. For three samples, when delivered by PTS, LDH levels (two samples) and neutrophil polynuclear count (one sample) were above the recommended guidelines compared to those delivered by courier. Conversely, LDH levels and FVIII were below in two samples delivered by PTS. LDH levels, PNN count or factor VIII can be affected by PTS without the clinical interpretation being modified. We concluded that the PTS can be used to transport blood samples for routine biochemical and hematological analysis in our hospital.

Chronic exposure of interleukin-13 suppress the induction of matrix metalloproteinase-1 by tumour necrosis factor α in normal and scleroderma dermal fibroblasts through protein kinase B/Akt.

PubMed

Brown Lobbins, M L; Shivakumar, B R; Postlethwaite, A E; Hasty, K A

2018-01-01

Peripheral blood mononuclear cells taken from patients with scleroderma express increased levels of interleukin (IL)-13. Moreover, the expression of matrix metalloproteinase-1 (MMP-1) from involved scleroderma skin fibroblasts is refractory to stimulation by tumour necrosis factor (TNF)-α. To elucidate the mechanism(s) involved, we examined the effect of IL-13 on TNF-α-induced MMP-1 expression in normal and scleroderma human dermal fibroblast lines and studied the involvement of serine/threonine kinase B/protein kinase B (Akt) in this response. Dermal fibroblast lines were stimulated with TNF-α in the presence of varying concentrations of IL-13. Total Akt and pAkt were quantitated using Western blot analyses. Fibroblasts were treated with or without Akt inhibitor VIII in the presence of IL-13 followed by TNF-α stimulation. MMP-1 expression was analysed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (anova) or Student's t-test. Upon TNF-α stimulation, normal dermal fibroblasts secrete more MMP-1 than systemic sclerosis (SSc) fibroblasts. This increase in MMP-1 is lost when fibroblasts are co-incubated with IL-13 and TNF-α. IL-13 induced a significant increase in levels of pAkt in dermal fibroblasts, while Akt inhibitor VIII reversed the suppressive effects of IL-13 on the response of cultured fibroblasts to TNF-α, increasing their expression of MMP-1. We show that IL-13 suppresses MMP-1 in TNF-α-stimulated normal and scleroderma dermal fibroblast. Akt inhibitor VIII is able to reverse the suppressive effect of IL-13 on MMP-1 expression and protein synthesis. Our data suggest that IL-13 regulates MMP-1 expression in response to TNF-α through an Akt-mediated pathway and may play a role in fibrotic diseases such as scleroderma. © 2017 British Society for Immunology.

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

PubMed

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

2015-06-01

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

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

PubMed

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

2017-10-01

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

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

PubMed

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

2011-02-24

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

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

PubMed

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

2015-02-01

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

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

PubMed

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

2002-02-01

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

Geochemical controls on vanadium accumulation in fossil fuels

USGS Publications Warehouse

Breit, G.N.; Wanty, R.B.

1989-01-01

High vanadium contents in petroleum and other fossil fuels have been attributed to organic-matter type, organisms, volcanic emanations, diffusion of sea water, and epigenetic enrichment. However, these factors are inadequate to account for the high abundance of vanadium in some fossil fuels and the paucity in others. By examining vanadium deposits in sedimentary rocks with sparse organic matter, constraints are placed on processes controlling vanadium accumulation in organic-rich sediments. Vanadium, as vanadate (V(V)), entered some depositional basins in oxidizing waters from dry, subaerial environments. Upon contact with organic matter in anoxic waters, V(V) is reduced to vanadyl (V(IV)), which can be removed from the water column by adsorption. H2S reduces V(IV) to V(III), which hydrolyzes and precipitates. The lack of V(III) in petroleum suggests that reduction of V(IV) to V(III) is inhibited by organic complexes. In the absence of strong complexing agents, V(III) forms and is incorporated in clay minerals.

Geochemical controls of vanadium accumulation in fossil fuels

USGS Publications Warehouse

Breit, G.N.; Wanty, R.B.

1989-01-01

High vanadium contents in petroleum and other fossil fuels have been attributed to organic-matter type, organisms, volcanic emanations, diffusion of sea water, and epigenetic enrichment. However, these factors are inadequate to account for the high abundance of vanadium in some fossil fuels and the paucity in others. By examining vanadium deposits in sedimentary rocks with sparse organic matter, constraints are placed on processes controlling vanadium accumulation in organic-rich sediments. Vanadium, as vanadate (V(V)), entered some depositional basins in oxidizing waters from dry, subaerial environments. Upon contact with organic matter in anoxic waters, V(V) is reduced to vanadyl (V(IV)), which can be removed from the water column by adsorption. H2S reduces V(IV) to V(III), which hydrolyzes and precipitates. The lack of V(III) in petroleum suggests that reduction of V(IV) to V(III) is inhibited by organic complexes. In the absence of strong complexing agents, V(III) forms and is incorporated in clay minerals.

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

PubMed

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

2016-05-01

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

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

PubMed Central

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

2016-01-01

In cases of Dengue fever, late hospital admission can lead to treatment delay and even death. In order to improve early disease notification and management, it is essential to investigate the factors affecting the time of admission of Dengue cases. This study determined the factors associated with the time of admission among notified Dengue cases. The study covered the period between 2008 and 2014 in Region VIII, Philippines. The factors assessed were age, sex, hospital sector, hospital level, disease severity based on the 1997 WHO Dengue classification, and period of admission (distinguishing between the 2010 Dengue epidemic and non-epidemic time). We analysed secondary data from the surveillance of notified Dengue cases. We calculated the association through chi-square test, ordinal logistic regression and linear regression at p value < 0.05. The study included 16,357 admitted Dengue cases. The reported cases included a majority of children (70.09%), mild cases of the disease (64.00%), patients from the public sector (69.82%), and non-tertiary hospitals (62.76%). Only 1.40% of cases had a laboratory confirmation. The epidemic period in 2010 comprised 48.68% of all the admitted cases during this period. Late admission was more likely among adults than children (p<0.05). The severe type of the disease was more likely to be admitted late than the mild type (p<0.05). Late admission was also more likely in public hospitals than in private hospitals (p<0.05); and within tertiary level hospitals than non-tertiary hospitals (p<0.05). Late admission was more likely during the non-epidemic period than the 2010 epidemic period (p<0.05). A case fatality rate of 1 or greater was significantly associated with children, severe diseases, tertiary hospitals and public hospitals when admitted late (p<0.05). Data suggests that early admission among child cases was common in Region VIII. This behavior is encouraging, and should be continued. However, further study is needed on the late admission among tertiary, public hospitals and non-epidemic period with reference to the quality of care, patient volume, out of pocket expense, and accessibility We recommend the consistent use of the 2009 WHO Dengue guidelines in order to standardize the admission criteria and time across hospitals. PMID:27780199

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

PubMed

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

2015-10-21

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

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

PubMed

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

2017-09-01

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

Studies of thermostability in Camelus bactrianus (Bactrian camel) single-domain antibody specific for the mutant epidermal-growth-factor receptor expressed by Pichia.

PubMed

Omidfar, Kobra; Rasaee, Mohhamad Javad; Kashanian, Soheila; Paknejad, Malieheh; Bathaie, Zahra

2007-01-01

Camelids have a unique immune system capable of producing heavy-chain antibodies lacking the light chains and CH1 (constant heavy-chain domain 1). It has been shown that, in contrast with conventional antibody fragments, the variable domains of these heavy-chain antibodies are functional at or after exposure to high temperatures. In the present study, the VHH (variable domain of heavy-chain antibody) camel antibody was subcloned into vector Ppiczc and expressed in Pichia pastoris. ORB1-83 VHH antibody recognizes the external domain of the mutant EGFR [EGF (epidermal growth factor) receptor], EGFR VIII. This tumour-specific antigen is ligand-independent, contains a constitutively active tyrosine kinase domain and has been shown to be present in a number of human malignancies. We report here that, although expression from P. pastoris resulted in a significantly increased level of expression of the anti-EGFR VIII VHH antibodies compared with Escherichia coli [Omidfar, Rasaee, Modjtahedi, Forouzandeh, Taghikhani, Bakhtiari, Paknejad and Kashanian (2004) Tumor Biol. 25, 179-187; Omidfar, Rasaee, Modjtahedi, Forouzandeh, Taghikhani and Golmakany (2004) Tumor Biol. 25, 296-305], this antibody selectively bound to the EGFR VIII peptide and reacted specifically with the immunoaffinity-purified antigen from non-small-cell lung cancer. Furthermore, thermal denaturation stability and CD spectra analysis of the Camelus bactrianus (Bactrian camel) VHH and heavy-chain antibodies at different temperature proved reversibility and binding activity after heat denaturation. Our results indicate that the P. pastoris expression system may be useful for the expression of camel single domain antibody and the ability of the expressed protein to reversibly melt without aggregation, allowing it to regain binding activity after heat denaturation.

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib.

PubMed

Lipsky, Andrew H; Farooqui, Mohammed Z H; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U; Herman, Sarah E M; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M; Lozier, Jay N; Wiestner, Adrian

2015-12-01

Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733. Copyright© Ferrata Storti Foundation.

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

PubMed Central

Lipsky, Andrew H.; Farooqui, Mohammed Z.H.; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M.; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U.; Herman, Sarah E. M.; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M.; Lozier, Jay N.; Wiestner, Adrian

2015-01-01

Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733 PMID:26430171

Haemophilia utilization group study - Part Va (HUGS Va): design, methods and baseline data.

PubMed

Zhou, Z-Y; Wu, J; Baker, J; Curtis, R; Forsberg, A; Huszti, H; Koerper, M; Lou, M; Miller, R; Parish, K; Riske, B; Shapiro, A; Ullman, M; Johnson, K

2011-09-01

To describe the study design, procedures and baseline characteristics of the Haemophilia Utilization Group Study - Part Va (HUGS Va), a US multi-center observational study evaluating the cost of care and burden of illness in persons with factor VIII deficiency. Patients with factor VIII level ≤ 30%, age 2-64 years, receiving treatment at one of six federally supported haemophilia treatment centres (HTCs) were enrolled in the study. Participants completed an initial interview including questions on socio-demographical characteristics, health insurance status, co-morbidities, access to care, haemophilia treatment regimen, factor utilization, self-reported joint pain and motion limitation and health-related quality of life. A periodic follow-up survey collected data regarding time lost from usual activities, disability days, health care utilization and outcomes of care. HTC clinicians documented participants' baseline clinical characteristics and pharmacy dispensing records for 2 years. Between July 2005 and July 2007, 329 participants were enrolled. Average age was 9.7 years for children and 33.5 years for adults; two-thirds had severe haemophilia. The distributions of age, marital status, education level and barriers to haemophilia care were relatively consistent across haemophilic severity categories. Differences were found in participants' employment status, insurance status and income. Overall, children with haemophilia had quality of life scores comparable to healthy counterparts. Adults had significantly lower physical functioning than the general US population. As one of the largest economic studies of haemophilia care, HUGS Va will provide detailed information regarding the burden of illness and health care utilization in the US haemophilia A population. © 2011 Blackwell Publishing Ltd.

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

PubMed

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

2018-03-01

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

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.

A Protocol for the Preparation of Cryoprecipitate and Cryo-depleted Plasma for Proteomic Studies.

PubMed

Sparrow, Rosemary L; Simpson, Richard J; Greening, David W

2017-01-01

Cryoprecipitate is a concentrate of high-molecular-weight plasma proteins that precipitate when frozen plasma is slowly thawed at 1-6 °C. The concentrate contains factor VIII (antihemophilic factor), von Willebrand factor (vWF), fibrinogen, factor XIII, fibronectin, and small amounts of other plasma proteins. Clinical grade preparations of cryoprecipitate are mainly used to treat fibrinogen deficiency caused by acute bleeding or functional abnormalities of the fibrinogen protein. In the past, cryoprecipitate was used to treat von Willebrand disease and hemophilia A (factor VIII deficiency), but the availability of more highly purified coagulation factor concentrates or recombinant protein preparations has superseded the use of cryoprecipitate for these coagulopathies. Cryo-depleted plasma ("cryosupernatant") is the plasma supernatant remaining following removal of the cryoprecipitate from frozen-thawed plasma. It contains all the other plasma proteins and clotting factors present in plasma that remain soluble during cold-temperature thawing of the plasma. This protocol describes the clinical-scale preparation of cryoprecipitate and cryo-depleted plasma for proteomic studies.

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

PubMed Central

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

2011-01-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed Central

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

2017-01-01

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

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

NASA Technical Reports Server (NTRS)

Hamann, Fred; Zuo, Lin; Tytler, David

1995-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

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.

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.

A case control study on the structural equation model of the mechanism of coagulation and fibrinolysis imbalance in chronic schistosomiasis.

PubMed

Le, Aiping; Zhang, Lunli; Liu, Wei; Li, Xiaopeng; Ren, Jianwei; Ning, An

2017-02-01

A structural equation model was used for verification with chronic schistosomiasis to investigate the coagulation-anticoagulation system imbalance and to deduce the mechanism of D-dimer (D-D) level elevation in patients with advanced schistosome hepatic disease. We detected the plasma levels of tissue-type fiber plasminogen activator (tPA), urokinase type plasminogen activator (uPA), plasmin-antiplasmin complex (PAP), plasminogen (PLG), antithrombin (AT), plasminogen activator inhibitor 1 (PAI1), D-D, factor VIII: C (FVIII:C), antithrombin-III (AT-III), PLG, protein S (PS), and protein C (PC) in the healthy people as control (69), patients with chronic schistosomiasis (150) or advanced chronic schistosomiasis (90). FVIII, PAP, D-D, tPA, and uPA plasma levels were significantly higher in the chronic group than in the control group and were also significantly higher in the advanced group. However, AT-III, PC, PS, AT, PLG, and PAI1 plasma levels in the advanced and chronic groups were significantly lower than those in the control group. With progression of disease in patients with schistosomiasis japonica, a hypercoagulable state is induced by the coagulation-anticoagulation imbalance, eventually leading to patients with high levels of D-D. Furthermore, we established a structural equation model path of a "chronic schistosomiasis disease stage-(coagulation-anticoagulation-fibrinolysis)-D-D." By using analysis of moment structures (AMOS), it was shown that the chronic schistosomiasis stage was positively related to factor VIII and had negative correlation with AT-III; a good positive correlation with PAP, tPA, and uPA; and a good negative correlation with PLG and PAI1. In addition, our results show that the path coefficient of anticoagulation-fibrinolysis system to the chronic stage of schistosomiasis or D-D levels was significantly higher than that of the coagulation system. In conclusion, the coagulation and fibrinolysis imbalance in patients with chronic schistosomiasis, especially with advanced schistosomiasis, is due to the progression of disease stages.

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

PubMed

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

2018-06-11

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

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

PubMed

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

2016-01-01

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

Factor VIII assay

MedlinePlus

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

Calculating inspector probability of detection using performance demonstration program pass rates

NASA Astrophysics Data System (ADS)

Cumblidge, Stephen; D'Agostino, Amy

2016-02-01

The United States Nuclear Regulatory Commission (NRC) staff has been working since the 1970's to ensure that nondestructive testing performed on nuclear power plants in the United States will provide reasonable assurance of structural integrity of the nuclear power plant components. One tool used by the NRC has been the development and implementation of the American Society of Mechanical Engineers (ASME) Boiler and Pressure Vessel Code Section XI Appendix VIII[1] (Appendix VIII) blind testing requirements for ultrasonic procedures, equipment, and personnel. Some concerns have been raised, over the years, by the relatively low pass rates for the Appendix VIII qualification testing. The NRC staff has applied statistical tools and simulations to determine the expected probability of detection (POD) for ultrasonic examinations under ideal conditions based on the pass rates for the Appendix VIII qualification tests for the ultrasonic testing personnel. This work was primarily performed to answer three questions. First, given a test design and pass rate, what is the expected overall POD for inspectors? Second, can we calculate the probability of detection for flaws of different sizes using this information? Finally, if a previously qualified inspector fails a requalification test, does this call their earlier inspections into question? The calculations have shown that one can expect good performance from inspectors who have passed appendix VIII testing in a laboratory-like environment, and the requalification pass rates show that the inspectors have maintained their skills between tests. While these calculations showed that the PODs for the ultrasonic inspections are very good under laboratory conditions, the field inspections are conducted in a very different environment. The NRC staff has initiated a project to systematically analyze the human factors differences between qualification testing and field examinations. This work will be used to evaluate and prioritize potential human factors issues that may degrade performance in the field.

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

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

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

1988-12-01

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

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

Vanadium proton exchange membrane water electrolyser

NASA Astrophysics Data System (ADS)

Noack, Jens; Roznyatovskaya, Nataliya; Pinkwart, Karsten; Tübke, Jens

2017-05-01

In order to reverse the reactions of vanadium oxygen fuel cells and to regenerate vanadium redox flow battery electrolytes that have been oxidised by atmospheric oxygen, a vanadium proton exchange membrane water electrolyser was set up and investigated. Using an existing cell with a commercial and iridium-based catalyst coated membrane, it was possible to fully reduce V3.5+ and V3+ solutions to V2+ with the formation of oxygen and with coulomb efficiencies of over 96%. The cell achieved a maximum current density of 75 mA/cm2 during this process and was limited by the proximity of the V(III) reduction to the hydrogen evolution reaction. Due to the specific reaction mechanisms of V(IV) and V(III) ions, V(III) solutions were reduced with an energy efficiency of 61%, making this process nearly twice as energy efficient as the reduction of V(IV) to V(III). Polarisation curves and electrochemical impedance spectroscopy were used to further investigate the losses of half-cell reactions and to find ways of further increasing efficiency and performance levels.

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

PubMed

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

2017-05-01

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

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

PubMed

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

2016-10-01

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

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

PubMed Central

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

2016-01-01

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

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2014 CFR

2014-01-01

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

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2011 CFR

2011-01-01

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

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2012 CFR

2012-01-01

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

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2013 CFR

2013-01-01

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

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

Code of Federal Regulations, 2014 CFR

2014-07-01

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

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

Code of Federal Regulations, 2012 CFR

2012-07-01

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

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

Code of Federal Regulations, 2011 CFR

2011-07-01

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

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

Code of Federal Regulations, 2013 CFR

2013-07-01

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

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.

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

PubMed Central

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

2012-01-01

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

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

PubMed

Henrard, S; Hermans, C

2016-05-01

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

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.

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

Code of Federal Regulations, 2010 CFR

2010-04-01

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

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

Code of Federal Regulations, 2011 CFR

2011-04-01

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

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

Code of Federal Regulations, 2013 CFR

2013-04-01

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

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

Code of Federal Regulations, 2014 CFR

2014-04-01

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

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

Code of Federal Regulations, 2012 CFR

2012-04-01

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

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...

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...

Von Willebrand factor, a versatile player in gastrointestinal bleeding in left ventricular assist device recipients?

PubMed

Fischer, Quentin; Huisse, Marie-Geneviève; Voiriot, Guillaume; Caron, Claudine; Lepage, Laurent; Dilly, Marie-Pierre; Nataf, Patrick; Ajzenberg, Nadine; Kirsch, Matthias

2015-01-01

Bleeding originating in the gastrointestinal (GI) tract is one of the most common adverse events after left ventricular assist device (LVAD) implantation. In these patients, GI bleeding appears to be the consequence of altered hemostasis on the one hand and alterations of the GI microvasculature on the other. We report the case of a patient who suffered repeated, severe GI bleeding early after implantation of a HeartMate II continuous-flow LVAD. After failure of conventional treatment strategies, GI bleeding was controlled using repeated transfusions of a purified von Willebrand factor (VWF) concentrate, almost devoid of Factor VIII (Wilfactin, LFB). No episodes of pump thrombosis were noted. Subsequent to VWF transfusions, we observed a progressive normalization of circulating vascular endothelial growth factor levels. Our data raise the possibility that, in addition to its hemostatic properties, transfusions of VWF might have acted as an antiangiogenic factor. © 2014 AABB.

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

Code of Federal Regulations, 2010 CFR

2010-07-01

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

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

Code of Federal Regulations, 2010 CFR

2010-04-01

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

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

Code of Federal Regulations, 2014 CFR

2014-04-01

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

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

Code of Federal Regulations, 2012 CFR

2012-04-01

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

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

Code of Federal Regulations, 2013 CFR

2013-04-01

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

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

Code of Federal Regulations, 2011 CFR

2011-04-01

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

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

PubMed

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

2017-03-01

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg -1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg -1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg -1 ) or every-7-days (60 IU kg -1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds. © 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

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 ...

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...

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

Code of Federal Regulations, 2010 CFR

2010-04-01

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

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

Code of Federal Regulations, 2014 CFR

2014-04-01

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

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

Code of Federal Regulations, 2011 CFR

2011-04-01

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

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

Code of Federal Regulations, 2013 CFR

2013-04-01

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

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

Code of Federal Regulations, 2012 CFR

2012-04-01

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

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

PubMed

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

2017-07-01

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically. © 2017 International Society on Thrombosis and Haemostasis.

Hemostasis biomarkers and incident cognitive impairment: the REGARDS study.

PubMed

Gillett, S R; McClure, L A; Callas, P W; Thacker, E L; Unverzagt, F W; Wadley, V G; Letter, A J; Cushman, M

2018-05-07

Vascular risk factors are associated with cognitive impairment, a condition with substantial public health burden. We hypothesized that hemostasis biomarkers related to vascular disease would be associated with risk of incident cognitive impairment. We performed a nested case control study including 1,082 participants with 3.5 years of follow-up in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of 30,239 black and white Americans ≥45 years old. Participants were free of stroke or cognitive impairment at baseline. Baseline D-dimer, fibrinogen, factor VIII, and protein C were measured in 495 cases who developed cognitive impairment during follow-up (based on abnormal scores on ≥2 of 3 cognitive tests) and 587 controls. Unadjusted ORs for incident cognitive impairment were 1.32 (95% CI 1.02, 1.70) for D-dimer >0.50 μg/mL, 1.83 (CI 1.24, 2.71) for fibrinogen >90 th percentile, 1.63 (CI 1.11, 2.38) for factor VIII >90 th percentile and 1.10 (CI 0.73, 1.65) for protein C < 10 th percentile. There were no differences in associations by race or region. Adjustment for demographic, vascular and health behavior risk factors attenuated these associations. However, having at least 2 elevated biomarkers was associated with incident cognitive impairment, with an adjusted OR 1.73 (CI 1.10, 2.69). Elevated D-dimer, fibrinogen, and factor VIII were not associated with occurrence of cognitive impairment after multivariable adjustment; however, having at least 2 abnormal biomarkers was associated, suggesting the burden of these biomarkers is relevant. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Factoring nonviral gene therapy into a cure for hemophilia A.

PubMed

Gabrovsky, Vanessa; Calos, Michele P

2008-10-01

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

Intraoperative Changes in Blood Coagulation and Thrombelastographic Monitoring in Liver Transplantation

PubMed Central

Kang, Yoo Goo; Martin, Douglas J.; Marquez, Jose; Lewis, Jessica H.; Bontempo, Franklin A.; Shaw, Byers W.; Starzl, Thomas E.; Winter, Peter M.

2010-01-01

The blood coagulation system of 66 consecutive patients undergoing consecutive liver transplantations was monitored by thrombelastograph and analytic coagulation profile. A poor preoperative coagulation state, decrease in levels of coagulation factors, progressive fibrinolysis, and whole blood clot lysis were observed during the preanhepatic and anhepatic stages of surgery. A further general decrease in coagulation factors and platelets, activation of fibrinolysis, and abrupt decrease in levels of factors V and VIII occurred before and with reperfusion of the homograft. Recovery of blood coagulability began 30–60 min after reperfusion of the graft liver, and coagulability had returned toward baseline values 2 hr after reperfusion. A positive correlation was shown between the variables of thrombelastography and those of the coagulation profile. Thrombelastography was shown to be a reliable and rapid monitoring system. Its use was associated with a 33% reduction of blood and fluid infusion volume, whereas blood coagulability was maintained without an increase in the number of blood product donors. PMID:3896028

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

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

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

2017-05-15

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

Current options and new developments in the treatment of haemophilia.

PubMed

Wong, Trisha; Recht, Michael

2011-02-12

Haemophilia A and B are X-linked bleeding disorders due to the inherited deficiency of factor VIII or factor IX, respectively. Of the approximately 1 per 5000-10000 male births affected by haemophilia, 80% are deficient in factor VIII and 20% are deficient in factor IX. Haemophilia is characterized by spontaneous and provoked joint, muscle, gastrointestinal and CNS bleeding leading to major morbidity and even mortality if left untreated or under-treated. The evolution of haemophilia management has been marked by tragedy and triumph over recent decades. Clotting factors and replacement strategies continue to evolve for patients without inhibitors. For patients with an inhibitor, factor replacement for acute bleeding episodes and immune tolerance, immune modulation and extracorporeal methods for inhibitor reduction are the cornerstone of care. In addition, adjuvant therapies such as desmopressin, antifibrinolytics and topical agents also contribute to improved outcomes for patients with and without inhibitors. The future direction of haemophilia care is promising with new longer-acting clotting factors and genetic therapies, including gene transfer and premature termination codon suppressors. With these current and future treatment modalities, the morbidity and mortality rates in patients with haemophilia certainly will continue to improve.

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...

Hemostatic Abnormalities in Multiple Myeloma Patients

PubMed Central

Gogia, Aarti; Sikka, Meera; Sharma, Satender; Rusia, Usha

2018-01-01

Background: Multiple myeloma (MM) is a neoplastic plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow. Diverse hemostatic abnormalities have been reported in patients with myeloma which predispose to bleeding and also thrombosis. Methods: Complete blood count, biochemical parameters and parameters of hemostasis i.e. platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), factor VIII assay results, plasma fibrinogen, D-dimer and lupus anticoagulant, were assessed in 29 MM patients and 30 age matched controls. Results: The most frequent abnormal screening parameter was APTT. Of the six indicative of a bleeding tendency i.e. thrombocytopenia, prolonged PT, APTT, TT, reduced plasma fibrinogen and factor VIII, at least one was abnormal in 8 (27.6%) patients. Of the four prothrombotic markers, lupus anticoagulant, D-dimer, elevated factor VIII and plasma fibrinogen, one or more marker was present in 24 (82.7%). D-dimer was the most common prothrombotic marker, being elevated in 22 (75.9%) patients. One or more laboratory parameter of hemostasis was abnormal in all 29 (100%) patients. Though thrombotic complications are reported to be less frequent as compared to hemorrhagic manifestations, one or more marker of thrombosis was present in 24 (82.7%) patients. Conclusion: This study provided laboratory evidence of hemostatic dysfunction which may be associated with thrombotic or bleeding complications at diagnosis in all MM patients. Hence, screening for these abnormalities at the time of diagnosis should help improved prognosis in such cases. PMID:29373903

Neovascularization of the corpus luteum of rats during the estrus cycle.

PubMed

Tsukada, K; Matsushima, T; Yamanaka, N

1996-06-01

In order to elucidate the chronological morphological changes of the corpus luteum (CL) of rats, as a physiological angiogenesis model, the CL of rat ovaries was studied light microscopically using periodic acid methenamine silver staining (PAM) and immunostaining for type IV collagen, laminin, thrombomodulin (TM), factor VIII related antigen (factor VIII) and alpha-smooth muscle actin (alpha-SMA). The CL was also studied electron microscopically. Female Wistar-Imamichi rats were used, which have a regular 4-day estrous cycle. The histological changes of the CL were observed in 6-hour intervals from 4 h before the ovulation to 28 h post-ovulation during the estrous cycle. Once the basement membrane (BM) of the follicle disintegrated following ovulation, developing capillaries entered into the CL and formed a vascular lumen with a surrounding BM, which showed positive for PAM staining, type IV collagen and laminin. The developing capillaries in the CL showed a weakly positive reaction for TM and factor VIII, but were negative for alpha-SMA. However, the appearance of immature pericytes around the well-developed capillary was obvious with electron microscopy. The study reported here provides detailed descriptions of angiogenesis during luteinization. It is concluded that the angiogenesis of the CL begins at the time of destruction of the BM of the ovarian follicle, and that the capillary BM appears when the capillary forms its lumen. Moreover, it was demonstrated that the capillary does not develop into an arteriole during luteinization.

Dominant von Willebrand disease type 2A groups I and II due to missense mutations in the A2 domain of the von Willebrand factor gene: diagnosis and management.

PubMed

Michiels, Jan Jacques; van Vliet, Huub H D M

2009-01-01

Pertinent findings in patients with von Willebrand disease (VWD) type 2A include prolonged bleeding time (BT), consistently low von Willebrand factor (VWF):ristocetin cofactor activity (RCo)/antigen concentration (Ag) and VWF:collagen binding (CB)/Ag ratios, absence of high, and (depending on severity) intermediate and large VWF multimers, the presence of pronounced triplet structure of individual bands and increased VWF degradation products due to increased proteolysis caused by mutations in the A2 domain of VWF. Two categories of VWD type 2A can be distinguished: group I with severe and group II with mild VWD. A minority of VWD type 2A have mild VWD characterized by near normal to prolonged BT, normal factor VIII coagulant activity and VWF:Ag, low VWF:RCo and VWF:CB, a normal ristocetin-induced platelet aggregation and complete but transient correction of BT and functional VWF parameters to normal levels for only a few hours due to short half-lives for VWF:RCo and CWF:CB. Such transient complete responses to desmopressin (DDAVP) lasting only a few hours may facilitate treatment and prophylaxis of minor bleedings, but may not be able to prevent bleeding during minor and major surgery. Most VWD type 2A patients have pronounced VWD with very low VWF:RCo, prolonged BT, PFA-100 closure times >250 s, and response to DDAVP is only transient, minor, poor or absent, with no correction of the BT despite some increase in VWF:RCo, thus being candidates for factor VIII-VWF concentrate substitution for the acute and prophylactic treatment of bleeding symptoms. Copyright (c) 2009 S. Karger AG, Basel.

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

Class I and II histone deacetylase expression in human chronic periodontitis gingival tissue.

PubMed

Cantley, M D; Dharmapatni, A A S S K; Algate, K; Crotti, T N; Bartold, P M; Haynes, D R

2016-04-01

Histone deacetylase inhibitors (HDACi) are being considered to treat chronic inflammatory diseases at low doses. Currently HDACi that are more specific are being developed to target particular HDACs; therefore, this study aimed to determine levels and distribution of class I and II HDAC in human gingival samples obtained from patients with chronic periodontitis. Gingival biopsies were obtained from patients with and without (mild inflammation, no bone loss) periodontitis. Total RNA was isolated for real-time quantitative polymerase chain reaction to determine expression of HDACs 1-10. Immunohistochemistry was used to determine protein distribution of HDACs 1, 5, 8 and 9. Factor VIII, CD3 and tartrate resistant acid phosphatase (TRAP) were detected in serial sections to identify blood vessels, lymphocytes, pre-osteoclasts and osteoclasts cells respectively. Tumour necrosis factor α (TNF-α) expression was also assessed. mRNA for HDAC 1, 5, 8 and 9 were significantly upregulated in chronic periodontitis gingival tissues compared to non-periodontitis samples (p < 0.05). Significantly higher HDAC 1 protein expression was observed in chronic periodontitis samples (p < 0.05), and was associated with CD3, TRAP and TNF-α-positive cells. HDAC 1, 5, 8 and 9 were expressed strongly by the factor VIII-positive microvasculature in the chronic periodontitis gingival tissues. HDAC 1, 5, 8 and 9 expression was higher in gingival tissues from patients with chronic periodontitis compared to non-periodontitis samples. Results suggest that these HDACs could therefore be targeted with specific acting HDACi. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of risk factors for thrombophilia in patients with cerebral venous thrombosis.

PubMed

Yokuş, Osman; Şahin Balçık, Özlem; Albayrak, Murat; Ceran, Funda; Dağdaş, Simten; Yılmaz, Mesude; Özet, Gülsüm

2010-09-05

The increased risk for thrombosis is known as hypercoagulability or thrombophilia. In our study, we aimed to compare the frequency of the identified defects for thrombophilia in patients with central venous thrombosis and under the age of 50 years, with the findings in the current literature. Forty-three patients (16-50 years old) were retrospectively evaluated. Thrombophilia investigation included determinations of protein C, protein S, antithrombin, and activated protein C resistance, factor V Leiden (FVL), prothrombin 20210A (PT 20210) and methylene tetrahydrofolate reductase (MTHFR) C677T mutations, antiphospholipid antibodies (APA), factor VIII levels, and homocysteine levels. We detected a single thrombophilic defect in 67.4%, two defects in 27.9% and three defects in 4.7% of our patients. The most common thrombophilic defect was mutation in the MTHFR gene (41.8%), and this was followed by the FVL mutation (34.9%). Since the prevalence of individual thrombophilic defects varies in each population, ethnic group and geographical location, screening for thrombophilic defects in patients presenting with cerebral venous thrombosis should primarily investigate the most frequent thrombophilia risk factors.

The unexpected finding of a splenic infarction in a patient with infectious mononucleosis due to Epstein-Barr virus

PubMed Central

Machado, Catarina; Melo Salgado, Joana; Monjardino, Leonor

2015-01-01

The authors present a case of a 24-year-old man with infectious mononucleosis (IM) due to Epstein-Barr virus (EBV). Among his symptoms, he reported abdominal pain in the upper left quadrant. An abdominal ultrasound and CT revealed an extensive splenic infarction. During the acute stage of this disease, the thrombophilic screening revealed reduced free protein S and elevated factor VIII, with normalisation on re-evaluation 6 weeks later. Splenic infarction is a very rare complication of IM due to EBV but should be considered in patients presenting abdominal pain. A hypercoagulability state should be investigated. To our knowledge, this is the first described case of a splenic infarction in a patient with IM due to EBV associated with a transient reduction of protein S and elevation of factor VIII. Thus, this work promotes the importance of including these factors in the thrombophilic screening conducted during the investigation of similar cases. PMID:26607191

The unexpected finding of a splenic infarction in a patient with infectious mononucleosis due to Epstein-Barr virus.

PubMed

Machado, Catarina; Melo Salgado, Joana; Monjardino, Leonor

2015-11-25

The authors present a case of a 24-year-old man with infectious mononucleosis (IM) due to Epstein-Barr virus (EBV). Among his symptoms, he reported abdominal pain in the upper left quadrant. An abdominal ultrasound and CT revealed an extensive splenic infarction. During the acute stage of this disease, the thrombophilic screening revealed reduced free protein S and elevated factor VIII, with normalisation on re-evaluation 6 weeks later. Splenic infarction is a very rare complication of IM due to EBV but should be considered in patients presenting abdominal pain. A hypercoagulability state should be investigated. To our knowledge, this is the first described case of a splenic infarction in a patient with IM due to EBV associated with a transient reduction of protein S and elevation of factor VIII. Thus, this work promotes the importance of including these factors in the thrombophilic screening conducted during the investigation of similar cases. 2015 BMJ Publishing Group Ltd.

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 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2010 CFR

2010-01-01

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

Analysis of the Strategy to Combat Maritime Piracy

DTIC Science & Technology

2009-12-11

26  Contemporary Maritime Piracy: Causative Factors...NSC National Security Council PUC Persons Under Control viii SLOC Sea lines of communication SSA Ships Security Assessment SSP Ships Security Plan...UNCLOS United Nations Convention on the Law of the Sea USD United States Dollar U.S. United States ix ILLUSTRATIONS Page Figure 1.  Factors

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

PubMed

Kitchen, S; Kershaw, G; Tiefenbacher, S

2016-07-01

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

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

PubMed

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

2010-09-21

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

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

NASA Astrophysics Data System (ADS)

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

2016-05-01

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

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

PubMed

Malhotra, Uma; Aboulafia, David M

2016-01-01

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

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

PubMed

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

2017-06-01

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

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

PubMed

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

1987-10-01

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

Effects of hydrotalcite combined with esomeprazole on gastric ulcer healing quality: A clinical observation study.

PubMed

Yang, Rui-Qi; Mao, Hua; Huang, Li-Yun; Su, Pei-Zhu; Lu, Min

2017-02-21

To evaluate the effects of hydrotalcite combined with esomeprazole on gastric ulcer healing quality. Forty-eight patients diagnosed with gastric ulcer between June 2014 and February 2016 were randomly allocated to the combination therapy group or monotherapy group. The former received hydrotalcite combined with esomeprazole, and the latter received esomeprazole alone, for 8 wk. Twenty-four healthy volunteers were recruited and acted as the healthy control group. Endoscopic ulcer healing was observed using white light endoscopy and narrow band imaging magnifying endoscopy. The composition of collagen fibers, amount of collagen deposition, expression of factor VIII and TGF-β1, and hydroxyproline content were analyzed by Masson staining, immunohistochemistry, immunofluorescent imaging and ELISA. Following treatment, changes in the gastric microvascular network were statistically different between the combination therapy group and the monotherapy group ( P < 0.05). There were significant differences ( P < 0.05) in collagen deposition, expression level of Factor VIII and TGF-β1, and hydroxyproline content in the two treatment groups compared with the healthy control group. These parameters in the combination therapy group were significantly higher than in the monotherapy group ( P < 0.05). The ratio of collagen I to collagen III was statistically different among the three groups, and was significantly higher in the combination therapy group than in the monotherapy group ( P < 0.05). Hydrotalcite combined with esomeprazole is superior to esomeprazole alone in improving gastric ulcer healing quality in terms of improving microvascular morphology, degree of structure maturity and function of regenerated mucosa.

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

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.

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

PubMed Central

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

2014-01-01

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

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

Procoagulant imbalance in patients with non-alcoholic fatty liver disease.

PubMed

Tripodi, Armando; Fracanzani, Anna L; Primignani, Massimo; Chantarangkul, Veena; Clerici, Marigrazia; Mannucci, Pier Mannuccio; Peyvandi, Flora; Bertelli, Cristina; Valenti, Luca; Fargion, Silvia

2014-07-01

Non-alcoholic fatty liver disease (NAFLD) is characterized by increased risk of cardiovascular events and liver-fibrosis. Both could be explained by a procoagulant-imbalance that was surmised but never directly demonstrated. We investigated 113 patients with varying histological liver damage [steatosis (n=32), steatohepatitis (n=51), metabolic-cirrhosis (n=30)], 54 with alcoholic/viral-cirrhosis and 179 controls. Plasma was evaluated for levels of pro- and anti-coagulants, and for thrombin-generation assessed as endogenous-thrombin-potential (ETP) with and without thrombomodulin or Protac® as protein C activators. The procoagulant-imbalance was defined as ETP-ratio (with-to-without thrombomodulin) or as Protac®-induced-coagulation-inhibition (PICI%). High ETP-ratios or low PICI% indicate resistance to thrombomodulin or Protac® and hence a procoagulant-imbalance. ETP-ratio increased from controls [0.57 (0.11-0.89)] to steatosis [0.72 (0.33-0.86)] and metabolic-cirrhosis [0.80 (0.57-0.95)], (p<0.001), the latter being comparable to that for alcoholic/viral-cirrhosis [0.80 (0.57-0.95) vs. 0.80 (0.44-0.96)]. Factor VIII (a potent procoagulant for thrombin-generation) increased from steatosis [99% (71-150)] to metabolic-cirrhosis [157% (64-232)], p<0.001. Protein C (a powerful anticoagulant) decreased from steatosis [103% (77-228)] to metabolic-cirrhosis [77 (17-146)], p<0.001. As a consequence, factor VIII-to-protein C ratio increased from steatosis [0.96 (0.36-1.60)] to metabolic-cirrhosis [2.05 (0.81-12.1)], p<0.001 and was correlated with the ETP-ratio (rho=0.543, p<0.001). Similar results were obtained for PICI%. Patients with procoagulant-imbalance detected as ETP-ratio greater or PICI% lower than the median value of controls tended to have a higher risk of metabolic-syndrome, higher intima-media thickness, fibrosis, steatosis or lobular inflammation, all considered clinical manifestations of NAFLD. NAFLD is characterized by a procoagulant-imbalance progressing from the less severe (steatosis) to the most severe form of the disease (metabolic-cirrhosis). This imbalance appears to result from increased factor VIII and reduced protein C and might play a role in the risk of cardiovascular events and liver-fibrosis commonly observed in NAFLD. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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...

Aviation medicine translations : annotated bibliography of recently translated material, VIII.

DOT National Transportation Integrated Search

1973-12-01

An annotated bibliography of translations of foreign-language articles is presented. The 20 listed entries are concerned with studies of cardiology; aviation vestibular testing and vestibular factors in accidents; use of bones of identification of re...

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...

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

NASA Astrophysics Data System (ADS)

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

1999-10-01

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

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

PubMed

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

2016-07-01

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

Transfusion medicine management for reconstructive spinal repair in a patient with von Willebrand's disease and a history of heavy surgical bleeding.

PubMed

Bolan, C D; Rick, M E; Polly, D W

2001-12-01

A case report of a multidisciplinary approach to a second reconstructive back surgery in a patient with von Willebrand's disease, flatback syndrome, and a history of heavy surgical bleeding is presented. To review the perioperative planning and assessment of hemostasis and transfusion medicine management, including administration of Humate P, a Factor VIII preparation with high von Willebrand factor content. Reconstructive spinal procedures may require significant transfusion support even in patients with normal preoperative hemostasis. In addition to the hemostatic problem caused by von Willebrand's disease, the reported patient requested minimal exposure to allogeneic blood products because of hepatitis C infection acquired from previous transfusions. The multidisciplinary team included the patient, hematologist, blood bank medical director, anesthesiologist, and operating surgeon. Preoperative assessment showed a Type 2A von Willebrand's disease variant. A careful planning process included a test infusion of desmopressin and extensive autologous donations of red cells, plasma, and platelets, which were collected before the procedure. Anterior and posterior spine fusions were performed during a 14-hour procedure. Hemostasis and clinical response were excellent. Humate P was administered perioperatively as assessed by the baseline Factor VIII and von Willebrand's disease levels, the plasma volume, the half-life of infused Humate P, and the anticipated risk and tolerance for bleeding. The estimated blood loss was 5 L. Replacement included 9 units of autologous red cells, 6 units of autologous plasma, 2 autologous plateletpheresis collections, a single allogeneic plateletpheresis product, and 17,000 units of Humate P administered over the perioperative period. Using a careful multidisciplinary approach, excellent hemostasis can be achieved with minimal exposure to untreated allogeneic blood products during aggressive spinal surgery in a patient with a clinically significant congenital coagulopathy.

First-principles investigation of vanadium isotope fractionation in solution and during adsorption

NASA Astrophysics Data System (ADS)

Wu, Fei; Qin, Tian; Li, Xuefang; Liu, Yun; Huang, Jen-How; Wu, Zhongqing; Huang, Fang

2015-09-01

Equilibrium fractionation factors of vanadium (V) isotopes among tri- (V(III)), tetra- (V(IV)) and penta-valent (V(V)) inorganic V species in aqueous system and during adsorption of V(V) to goethite are estimated using first-principles calculation. Our results highlight the dependence of V isotope fractionation on valence states and the chemical binding environment. The heavy V isotope (51V) is enriched in the main V species following a sequence of V(III) < V(IV) < V(V). According to our calculations, at 25 °C, the equilibrium isotope fractionation factor between [V5+O2(OH)2]- and [V4+O(H2O)5]2+ (ln ⁡α V (V)- V (IV)) is 3.9‰, and the equilibrium isotope fractionation factor between [V5+O2(OH)2]- and [V3+(OH)3(H2O)3] (ln ⁡α V (V)- V (III)) is 6.4‰. In addition, isotope fractionation between +5 valence species [V5+O2(OH)2]- and [V5+O2(H2O)4]+ is 1.5‰ at 25 °C, which is caused by their different bond lengths and coordination numbers (CN). Theoretical calculations also show that light V isotope (50V) is preferentially adsorbed on the surface of goethite. Our work reveals that V isotopes can be significantly fractionated in the Earth's surface environments due to redox reaction and mineral adsorption, indicating that V isotope data can be used to monitor toxic V(V) attenuation processes through reduction or adsorption in natural water systems. In addition, a simple mass balance model suggests that V isotope composition of seawater might vary with change of ambient oxygen levels. Thus our theoretical investigations imply a promising future for V isotopes as a potential new paleo-redox tracer.

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

Code of Federal Regulations, 2011 CFR

2011-07-01

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

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.

Lepidium meyenii (Maca) reversed the lead acetate induced -- damage on reproductive function in male rats.

PubMed

Rubio, Julio; Riqueros, Marissa I; Gasco, Manuel; Yucra, Sandra; Miranda, Sara; Gonzales, Gustavo F

2006-07-01

Rats were treated with 0, 8, 16 and 24 mg/kg of lead acetate (LA) (i.p.) for 35 days with or without Maca. Maca was co-administrated orally from day 18 to day 35. The lengths of stages of the seminiferous epithelium were assessed by transillumination. Also, sex organ weights, testicular and epididymal sperm count, sperm motility, daily sperm production, sperm transit rate and serum testosterone levels were measured. Lead acetate treatment resulted in a dose-response reduction of lengths of stages VIII and IX-XI, and serum testosterone levels. However, rats treated with 8 and 16 mg/kg but not 24 mg/kg of lead acetate showed a low number of testicular spermatids, low daily sperm production (DSP) and low epididymal sperm count. Administration of Maca to rats treated with lead acetate resulted in higher lengths of stages VIII and IX-XI with respect to lead acetate-treated rats. Moreover, treatment with Maca to lead acetate-treated rats resulted in lengths of stages VIII and IX-XI similar to the control group. Maca administration also reduced the deleterious effect on DSP caused by lead acetate treatment. Maca prevented LA-induced spermatogenic disruption in rats and it may become in a potential treatment of male infertility associated with lead exposure.

Genetics Home Reference: Fuchs endothelial dystrophy

MedlinePlus

... a protein that is part of type VIII collagen. Type VIII collagen is largely found within the cornea, surrounding the endothelial cells. Specifically, type VIII collagen is a major component of a tissue at ...

Methods for detection of haemophilia carriers: a Memorandum*

PubMed Central

1977-01-01

This Memorandum discusses the problems and techniques involved in the detection of carriers of haemophilia A (blood coagulation factor VIII deficiency) and haemophilia B (factor IX deficiency), particularly with a view to its application to genetic counselling. Apart from the personal suffering caused by haemophilia, the proper treatment of haemophiliacs places a great strain on the blood transfusion services, and it is therefore important that potential carriers should have precise information about the consequences of their having children. The Memorandum classifies the types of carrier and describes the laboratory methods used for the assessment of coagulant activity and antigen concentration in blood. Particular emphasis is laid on the establishment of international, national, and laboratory (working) standards for factors VIII and IX and their calibration in international units (IU). This is followed by a detailed account of the statistical analysis of pedigree and laboratory data, which leads to an assessment of the likelihood that a particular person will transmit the haemophilia gene to her children. Finally, the problems and responsibilities involved in genetic counselling are considered. PMID:304395

Homogeneous, anisotropic three-manifolds of topologically massive gravity

NASA Astrophysics Data System (ADS)

Nutku, Y.; Baekler, P.

1989-10-01

We present a new class of exact solutions of Deser, Jackiw, and Templeton's theory (DJT) of topologically massive gravity which consists of homogeneous, anisotropic manifolds. In these solutions the coframe is given by the left-invariant 1-forms of 3-dimensional Lie algebras up to constant scale factors. These factors are fixed in terms of the DJT coupling constant μ which is the constant of proportionality between the Einstein and Cotton tensors in 3-dimensions. Differences between the scale factors result in anisotropy which is a common feature of topologically massive 3-manifolds. We have found that only Bianchi Types VI, VIII, and IX lead to nontrivial solutions. Among these, a Bianchi Type IX, squashed 3-sphere solution of the Euclideanized DJT theory has finite action. Bianchi Type VIII, IX solutions can variously be embedded in the de Sitter/anti-de Sitter space. That is, some DJT 3-manifolds that we shall present here can be regarded as the basic constituent of anti-de Sitter space which is the ground state solution in higher dimensional generalization of Einstein's general relativity.

Homogeneous, anisotropic three-manifolds of topologically massive gravity

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

Nutku, Y.; Baekler, P.

1989-10-01

We present a new class of exact solutions of Deser, Jackiw, and Templeton's theory (DJT) of topologically massive gravity which consists of homogeneous, anisotropic manifolds. In these solutions the coframe is given by the left-invariant 1-forms of 3-dimensional Lie algebras up to constant scale factors. These factors are fixed in terms of the DJT coupling constant {mu}m which is the constant of proportionality between the Einstein and Cotton tensors in 3-dimensions. Differences between the scale factors result in anisotropy which is a common feature of topologically massive 3-manifolds. We have found that only Bianchi Types VI, VIII, and IX leadmore » to nontrivial solutions. Among these, a Bianchi Type IX, squashed 3-sphere solution of the Euclideanized DJT theory has finite action, Bianchi Type VIII, IX solutions can variously be embedded in the de Sitter/anti-de Sitter space. That is, some DJT 3-manifolds that we shall present here can be regarded as the basic constitent of anti-de Sitter space which is the ground state solution in higher dimensional generalizations of Einstein's general relativity. {copyright} 1989 Academic Press, Inc.« less

An immunocytochemical study of the germinal layer vasculature in the developing fetal brain using Ulex europaeus 1 lectin.

PubMed

Gould, S J; Howard, S

1988-10-01

The characteristics of the germinal matrix vasculature were studied in the developing fetal brain using immunocytochemical methods. A preliminary comparative immunocytochemical study was made on six fetal brains to compare endothelial staining by Ulex europaeus I lectin with that of antibody to Factor VIII related antigen. Ulex was found to stain germinal layer vessels better than Factor VIII related antigen. Subsequently, the germinal layers of a further 15 fetal and preterm infant brains ranging from 13 to 35 weeks' gestation were stained with Ulex europaeus I to demonstrate the vasculature. With increasing gestation, there was a gradual increase in vessel density, particularly of capillaries. This was not a uniform process. A plexus of capillaries was prominent immediately beneath the ependyma while the more central parts of the germinal matrix contained fewer, but often larger diameter, vessels. The variation in vessel density which was a feature of the later gestation brains may have implications for local blood flow and may be a factor in haemorrhage at this site.

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

PubMed

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

2013-01-01

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

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

PubMed Central

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

2013-01-01

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

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

PubMed Central

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

2014-01-01

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

[Fitness of workers with particular sensitivity to non-ionizing radiation].

PubMed

Moccaldi, R; Grandi, C

2011-01-01

Chapter IV and V of Title VIII of D.Lgs 81/2008, implementing the Directives 2004/40/EC respectively (protection of workers exposed to electromagnetic fields) and 2006/25/EC (protection of workers exposed to artificial optical radiation), make frequent reference to the workers as "at particular risk" namely those workers who, by their biological or pathological characteristics, lifestyles, multiple exposure to other risk factors, may be more susceptible to the effects of electromagnetic fields or optical radiation. The identification of workers with particular sensitivity is essential for health surveillance, in particular regarding the determination of fitness. The operational guidance on Title VIII of D.Lgs 81/2008 drafted by the Italian Technical Coordination for Safety in the workplace of Regions and Autonomous Provinces (Document No. 1-2009), in collaboration with ISPESL and ISS, includes a preliminary identification of the categories of workers considered most susceptible to the risk from exposure to electromagnetic fields and optical radiation. On the basis of this information the authors identified more focused and structured classes of workers to be considered as "particularly sensitive to risk", it is not only related to a specific wavelength, but based on a comprehensive risk assessment in individual exposure situation, with regard to the exposure levels, any multiple exposures, the possibility of adequate personal protection.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2017-12-01

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

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

PubMed

Franchini, Massimo; Lippi, Giuseppe

2010-11-01

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

Estimation of earthquake effects associated with a great earthquake in the New Madrid seismic zone

USGS Publications Warehouse

Hopper, Margaret G.; Algermissen, Sylvester Theodore; Dobrovolny, Ernest E.

1983-01-01

Estimates have been made of the effects of a large Ms = 8.6, Io = XI earthquake hypothesed to occur anywhere in the New Madrid seismic zone. The estimates are based on the distributions of intensities associated with the earthquakes of 1811-12, 1843 and 1895 although the effects of other historical shocks are also considered. The resulting composite type intensity map for a maximum intensity XI is believed to represent the upper level of shaking likely to occur. Specific intensity maps have been developed for six cities near the epicentral region taking into account the most likely distribution of site response in each city. Intensities found are: IX for Carbondale, IL; VIII and IX for Evansville, IN; VI and VIII for Little Rock, AR; IX and X for Memphis, TN; VIII, IX, and X for Paducah, KY; and VIII and X for Poplar Bluff, MO. On a regional scale, intensities are found to attenuate from the New Madrid seismic zone most rapidly to the west and southwest sides of the zone, most slowly to the northwest along the Mississippi River, on the northeast along the Ohio River, and on the southeast toward Georgia and South Carolina. Intensities attenuate toward the north, east, and south in a more normal fashion. Known liquefaction effects are documented but much more research is needed to define the liquefaction potential.

Adaptation to vestibular disorientation. VIII, "Coriolis" vestibular stimulation and the influence of different visual surrounds.

DOT National Transportation Integrated Search

1967-08-01

Disorientation caused by 'Coriolis' vestibular reactions has been cited frequently as a significant factor in flying safety. In addition, personnel who maintain rotating radar towers may also be adversely affected by 'Coriolis' problems. In the study...

Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage

PubMed Central

Saito, Tatsuya; Mukae, Jyunichi; Nakamura, Yosuke; Inaba, Hiroshi; Nogami, Keiji; Koyama, Takatoshi; Fukutake, Katsuyuki; Yamamoto, Koh

2017-01-01

A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA. PMID:28674365

Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage.

PubMed

Saito, Tatsuya; Mukae, Jyunichi; Nakamura, Yosuke; Inaba, Hiroshi; Nogami, Keiji; Koyama, Takatoshi; Fukutake, Katsuyuki; Yamamoto, Koh

2017-01-01

A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA.

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

DTIC Science & Technology

2004-02-01

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

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

NASA Astrophysics Data System (ADS)

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

2018-05-01

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

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

DOE PAGES

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

2017-05-03

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

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

PubMed Central

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

2017-01-01

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

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

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

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

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

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

NASA Astrophysics Data System (ADS)

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

2009-09-01

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

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

PubMed

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

2009-06-01

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

Clinical and Laboratory Approaches to Hemophilia A

PubMed Central

Mansouritorghabeh, Hassan

2015-01-01

Hemophilia A is a worldwide disorder of coagulation system. It is a male disorder, yet females with hemophilia are rarely seen in communities with high rate of consanguineous marriages. The abnormalities in factor VIII gene transfer as an X-linked pattern in the family, affects as many as one-third of patients who had no family history of abnormality and thus the occurrence of a sporadic mutation could be documented. Hemorrhagic symptoms usually correlate with the plasma level of factor VIII and comprise a wide range of hemorrhagic pictures, including from fatal spontaneous bleeding in the brain to ecchymosis of the skin. The coagulation study needs to differentiate between the two types of hemophilia A and B as well as the categorization of the disease severity. In the developing countries, due to limitations in diagnostic hemostasis facilities and a scant number of experts in the field, it is estimated that noticeable numbers of undiagnosed patients with hemophilia A exist. Occasionally, we encounter undiagnosed cases by general physicians while having hemorrhagic symptoms. The purpose of this review is to recap clinical and diagnostic parameters, pitfalls, and interpretation of coagulation assay in hemophilia A. A literature review was done in PubMed and Scopus medical search engines using the keywords “Hemophilia” and “Haemophilia”. A time limitation for the publication beyond 1995 and publication in the English language were considered. A total of 94 original articles and chapters of books was selected for the current review. Additionally, a comprehensive and up-to-date information on the clinical and laboratory features for the diagnosis of hemophilia is also presented. PMID:25999618

Effects of hydrotalcite combined with esomeprazole on gastric ulcer healing quality: A clinical observation study

PubMed Central

Yang, Rui-Qi; Mao, Hua; Huang, Li-Yun; Su, Pei-Zhu; Lu, Min

2017-01-01

AIM To evaluate the effects of hydrotalcite combined with esomeprazole on gastric ulcer healing quality. METHODS Forty-eight patients diagnosed with gastric ulcer between June 2014 and February 2016 were randomly allocated to the combination therapy group or monotherapy group. The former received hydrotalcite combined with esomeprazole, and the latter received esomeprazole alone, for 8 wk. Twenty-four healthy volunteers were recruited and acted as the healthy control group. Endoscopic ulcer healing was observed using white light endoscopy and narrow band imaging magnifying endoscopy. The composition of collagen fibers, amount of collagen deposition, expression of factor VIII and TGF-β1, and hydroxyproline content were analyzed by Masson staining, immunohistochemistry, immunofluorescent imaging and ELISA. RESULTS Following treatment, changes in the gastric microvascular network were statistically different between the combination therapy group and the monotherapy group (P < 0.05). There were significant differences (P < 0.05) in collagen deposition, expression level of Factor VIII and TGF-β1, and hydroxyproline content in the two treatment groups compared with the healthy control group. These parameters in the combination therapy group were significantly higher than in the monotherapy group (P < 0.05). The ratio of collagen I to collagen III was statistically different among the three groups, and was significantly higher in the combination therapy group than in the monotherapy group (P < 0.05). CONCLUSION Hydrotalcite combined with esomeprazole is superior to esomeprazole alone in improving gastric ulcer healing quality in terms of improving microvascular morphology, degree of structure maturity and function of regenerated mucosa. PMID:28275307

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

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

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

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

2016-09-02

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

Demonstration/Validation of the Snap Sampler Passive Ground Water Sampling Device for Sampling Inorganic Analytes at the Former Pease Air Force Base

DTIC Science & Technology

2009-07-01

viii Unit Conversion Factors...sampler is also an economic alternative for sampling for inorganic analytes. ERDC/CRREL TR-09-12 xii Unit Conversion Factors Multiply By To Obtain...head- space and then covered with two layers of tightly fitting aluminum foil. To dissolve the analytes, the solutions were stirred for approximately

American River Watershed Project, California. Part 1: Main Report. Part 2: Final Supplemental Environmental Impact Statement/Environmental Impact Report. Supplemental Information Report

DTIC Science & Technology

1996-03-01

VII-7 VIII-1 Computer generated rendering of flood detention dam ................ VIII-3 VIII-2 American River Watershed Project Schedule...shows a plan view of the dam and plate 19 shows the dam in section and profile. Figure VIII-1 is a computer generated rendering of the dam. Table VIH-1...Williamson Act render the land ineligible for continued protection under that law, the local sponsor would be responsible for compensating the landowners

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

PubMed

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

2018-06-01

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

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

PubMed

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

2015-06-01

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

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

NASA Astrophysics Data System (ADS)

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

2018-05-01

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

Studies on the effect of ammonia flow rate induced defects in gallium nitride grown by MOCVD

NASA Astrophysics Data System (ADS)

Suresh, S.; Lourdudoss, S.; Landgren, G.; Baskar, K.

2010-10-01

Gallium nitride (GaN) epitaxial layers were grown with different V/III ratios by varying the ammonia (NH 3) flow rate, keeping the flow rate of the other precursor, trimethylgallium (TMG), constant, in an MOCVD system. X-ray rocking curve widths of a (1 0 2) reflection increase with an increase in V/III ratio while the (0 0 2) rocking curve widths decrease. The dislocation density was found to increase with an increase in ammonia flow rate, as determined by hot-wet chemical etching and atomic force microscopy. 77 K photoluminescence studies show near band emission at 3.49 eV and yellow luminescence peaking at 2.2 eV. The yellow luminescence (YL) intensity decreases with an increase in V/III ratio. Positron annihilation spectroscopy studies show that the concentration of Ga-like vacancies increases with an increase in ammonia flow rate. This study confirms that the yellow luminescence in the GaN arises due to deep levels formed by gallium vacancies decorated with oxygen atoms.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-11

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

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

NASA Astrophysics Data System (ADS)

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

2017-06-01

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

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...

40 CFR 194.44 - Engineered barriers.

Code of Federal Regulations, 2013 CFR

2013-07-01

... impact on worker exposure to radiation both during and after incorporation of engineered barriers; (iii... reduced total system costs; (viii) The impact, if any, on other waste disposal programs from the..., after consideration of one or more of the factors in paragraph (c)(1) of this section, the Department...

Upregulation of distinct collagen transcripts in post-surgery scar tissue: a study of conjunctival fibrosis.

PubMed

Seet, Li-Fong; Toh, Li Zhen; Chu, Stephanie W L; Finger, Sharon N; Chua, Jocelyn L L; Wong, Tina T

2017-06-01

Excessive accumulation of collagen is often used to assess the development of fibrosis. This study aims to identify collagen genes that define fibrosis in the conjunctiva following glaucoma filtration surgery (GFS). Using the mouse model of GFS, we have identified collagen transcripts that were upregulated in the fibrotic phase of wound healing via RNA-seq. The collagen transcripts that were increased the most were encoded by Col8a1 , Col11a1 and Col8a2 Further analysis of the Col8a1 , Col11a1 and Col8a2 transcripts revealed their increase by 67-, 54- and 18-fold, respectively, in the fibrotic phase, compared with 12-fold for Col1a1 , the most commonly evaluated collagen gene for fibrosis. However, only type I collagen was significantly upregulated at the protein level in the fibrotic phase. Type VIII and type I collagens colocalized in fibrous structures and in ACTA2-positive pericytes, and appeared to compensate for each other in expression levels. Type XI collagen showed low colocalization with both type VIII and type I collagens but can be found in association with macrophages. Furthermore, we show that both mouse and human conjunctival fibroblasts expressed elevated levels of the most highly expressed collagen genes in response to TGFβ2 treatment. Importantly, conjunctival tissues from individuals whose GF surgeries have failed due to scarring showed 3.60- and 2.78-fold increases in type VIII and I collagen transcripts, respectively, compared with those from individuals with no prior surgeries. These data demonstrate that distinct collagen transcripts are expressed at high levels in the conjunctiva after surgery and their unique expression profiles may imply differential influences on the fibrotic outcome. © 2017. Published by The Company of Biologists Ltd.

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

PubMed

Roberts, Peter L

2014-07-01

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

76 FR 14417 - ``Low Income Levels'' Used for Various Health Professions and Nursing Programs Included in Titles...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-16

... Levels'' Used for Various Health Professions and Nursing Programs Included in Titles III, VII and VIII of... provide health professions and nursing training for individuals from disadvantaged backgrounds. These... INFORMATION: The various health professions and nursing grant and cooperative agreement programs that use the...

77 FR 22790 - ``Low Income Levels'' Used for Various Health Professions and Nursing Programs Included in Titles...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-17

... Levels'' Used for Various Health Professions and Nursing Programs Included in Titles III, VII and VIII of... provide health professions and nursing training for individuals from disadvantaged backgrounds. These... INFORMATION: The various health professions and nursing grant and cooperative agreement programs that use the...

Chinese-Mandarin: Basic Course. Volume VIII: Lessons 80-87.

ERIC Educational Resources Information Center

Defense Language Inst., Monterey, CA.

This is the eighth of 16 volumes of audiolingual classroom instruction in Mandarin Chinese. The course is designed to train native English speakers to Level 3 Foreign Service Institute proficiency in comprehension and speaking, and to Level 2 proficiency in reading and writing Mandarin. Facility in the use and recognition of Chinese characters is…

32 CFR 2003.8 - Records (Article VIII).

Code of Federal Regulations, 2013 CFR

2013-07-01

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

32 CFR 2003.8 - Records (Article VIII).

Code of Federal Regulations, 2014 CFR

2014-07-01

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

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

PubMed

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

2016-11-01

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

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

PubMed

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

2016-02-01

ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a defined genetic background. © 2015 International Society on Thrombosis and Haemostasis.

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

Code of Federal Regulations, 2014 CFR

2014-07-01

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

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

Code of Federal Regulations, 2013 CFR

2013-07-01

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

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

Code of Federal Regulations, 2012 CFR

2012-07-01

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

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

ERIC Educational Resources Information Center

Kamps, Ivo

1996-01-01

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

Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.

PubMed

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

2013-02-01

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

Relative Risks of Thrombosis and Bleeding in Different ABO Blood Groups.

PubMed

Franchini, Massimo; Lippi, Giuseppe

2016-03-01

The ABO blood group system is composed of complex carbohydrate molecules (i.e., the A, B, and H determinants) that are widely expressed on the surface of red blood cells and in a variety of other cell and tissues. Along with their pivotal role in transfusion and transplantation medicine, the ABO antigens participate in many other physiological processes and, in particular, are important determinants of von Willebrand factor and factor VIII circulating plasma levels. The precise influence of the ABO system on hemostasis has led the way to the investigation of a putative implication in the risk of developing cardiovascular disorders. Along with the underlying molecular mechanisms, the current knowledge on the role of ABO blood group antigens in both the thrombotic and hemorrhagic risk will be summarized in this narrative review. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Combating the Military’s Escalating Pharmacy Costs: A Lean Six Sigma Approach

DTIC Science & Technology

2008-12-01

without illustrating anything that can essentially go wrong. Not surprisingly, not everyone shares the belief that Lean Six Sigma is a cure all for cost...or absenteeism ; however, these factors are discussed in the conclusion found in Chapter VIII. The resources are also only available during

75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-14

... Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and (2) labeling of blood and blood components and plasma-derived products, including plasma-derived albumin and products..., the Committee will hear informational presentations related to FDA's geographic donor deferral policy...

A case of Munchausen syndrome with claims of trauma and haemophilia.

PubMed Central

Park, G; Huang, A; Wright, S

1996-01-01

A case of Munchausen syndrome presented with both factitious trauma and factitious haemophilia. He was treated inappropriately with factor VIII concentrate before the history of the presenting complaint could be validated. Clinical suspicion remains the most important aid to diagnosis. Images Figure 1 PMID:8832359

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...

Assessing What Factors Are Driving the Army Civilian Acquisition Multigenerational Workforce Age/Experience Mix

DTIC Science & Technology

2015-05-06

45 viii ix Abstract Generation members are born, start school, enter the workforce, have children , and retire at about the...conformity, patience • Satisfaction is a job well done • Being respected • Prefer job security over entrepreneurship — cautious • Unadventurous

Optimal Placement of Non-Intrusive Waste Heat Recovery Devices in Exhaust Ducts

DTIC Science & Technology

2015-06-01

Reynolds Number and Local Reynolds Number Depression Mixing .............................................................................40  3...57  viii 1.  Counterintuitive Findings Due to Local Reynolds Number Depression ... depression in the secondary recirculation zone enhances heat transfer, and device placement is the dominant factor for maximizing heat transfer in a

77 FR 58849 - Prescription Drug User Fee Act Patient-Focused Drug Development; Public Meeting and Request for...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-24

... the impact of the disease on patients, the spectrum of severity for those who have the disease, the... glomerular diseases. Narcolepsy. Huntington's Disease. Depression. Autism. Peripheral neuropathy.... Cancer and depression. Clotting disorders (e.g., hemophilia A (factor VIII deficiency) and von Willebrand...

Evaluation of sensitivity and specificity of a standardized procedure using different reagents for the detection of lupus anticoagulants. The Working Group on Hemostasis of the Société Française de Biologie Clinique and for the Groupe d'Etudes sur I'Hémostase et la Thrombose.

PubMed

Goudemand, J; Caron, C; De Prost, D; Derlon, A; Borg, J Y; Sampol, J; Sié, P

1997-02-01

This study was designed to test the sensitivity and specificity of a combination of 3 phospholipid-dependent assays performed with various reagents, for the detection of lupus anticoagulant (LA). Plasmas containing an LA (n = 56) or displaying various confounding pathologies [58 intrinsic pathway factor deficiencies, 9 factor VIII inhibitors, 28 plasmas from patients treated with an oral anticoagulant (OAC)] were selected. In a first step, the efficiency of each assay and reagent was assessed using the Receiving Operating Characteristic (ROC) method. Optimal cut-offs providing both sensitivity and specificity > or = 80% were determined. The APTT assay and most of the phospholipid neutralization assays failed to discriminate factor VIII inhibitors from LA. In a second step, using the optimal cut-offs determined above, the results of all the possible combinations of the 3 assays performed with 4 different reagents were analyzed. Thirteen combinations of reagents allowed > or = 80% of plasmas of each category (LA, factor deficiency or OAC) to be correctly classified (3/3 positive test results in LA-containing plasmas and 0/3 positive results in LA-negative samples).

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

PubMed Central

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

2013-01-01

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

Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF.

PubMed

Yatuv, Rivka; Robinson, Micah; Dayan, Inbal; Baru, Moshe

2010-02-01

Improving the pharmacodynamics of protein drugs has the potential to improve the care and the quality of life of patients suffering from a variety of diseases. Four approaches to improve protein drugs are described: PEGylation, amino acid substitution, fusion to carrier proteins and encapsulation. A new platform technology based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip) is then presented. Binding of proteins to PEGLip is non-covalent, highly specific and dependent on an amino acid consensus sequence within the proteins. Association of proteins with PEGLip results in substantial enhancement of the pharmacodynamic properties of proteins following administration. This has been demonstrated in preclinical studies and clinical trials with coagulation factors VIII and VIIa. It has also been demonstrated in preclinical studies with granulocyte colony-stimulating factor. A mechanism is presented that explains the improvements in hemostatic efficacy of PEGLip-formulated coagulation factors VIII and VIIa. The reader will gain an understanding of the advantages and disadvantages of each of the approaches discussed. PEGLip formulation is an important new approach to improve the pharmacodynamics of protein drugs. This approach may be applied to further therapeutic proteins in the future.

Association of Serum Sex Hormones with Hemostatic Factors in Women On and Off Hormone Therapy: The Multiethnic Study of Atherosclerosis.

PubMed

Williams, Marlene S; Cushman, Mary; Ouyang, Pamela; Heckbert, Susan R; Kalyani, Rita Rastogi; Vaidya, Dhanajay

2016-02-01

Hormone therapy (HT) is associated with increased risk of both venous and arterial thrombosis, which are multifactorial in origin. Our objectives were twofold: first, we sought to examine associations between endogenous serum sex hormone levels and biomarkers of thrombosis and/or coagulation in postmenopausal hormone nonusers. Second, we separately studied the associations between serum sex hormone levels and biomarkers of thrombosis and/or coagulation in postmenopausal hormone users considering the fact that pattern of circulating hormones is different in women taking exogenous hormones. We performed a cross-sectional analysis of postmenopausal women enrolled in a large multiethnic community-based cohort study, The Multiethnic Study of Atherosclerosis. We hypothesized that higher levels of estrogen-related sex hormones would be associated with biomarkers of thrombosis, suggesting mechanisms for differences in thrombotic risk from HT. Women (n = 2878) were included if they were postmenopausal and had thrombotic biomarkers (homocysteine, fibrinogen, C-reactive protein [CRP], factor VIII, and d-dimer) and sex hormone levels (total testosterone [T], bioavailable testosterone, sex hormone binding globulin [SHBG], estradiol [E2], and dehydroepiandrosterone [DHEA]) measured. A smaller random sample of 491 women also had von Willebrand factor (vWF), plasminogen activator inhibitor (PAI-1), and tissue factor pathway inhibitor (TFPI) levels measured. We found that elevated levels of estradiol and SHBG in HT users were associated with elevated levels of CRP and lower levels of TFPI, both of which may be related to a prothrombotic milieu in HT users. HT nonusers had far more prothrombotic associations between elevated serum sex hormone levels and thrombotic biomarkers when compared with HT users.

Hemostasis in Overt and Subclinical Hyperthyroidism

PubMed Central

Ordookhani, Arash; Burman, Kenneth D.

2017-01-01

Context There are contradictory results on the effect of hyperthyroidism on hemostasis. Inadequate population-based studies limited their clinical implications, mainly on the risk of venous thromboembolism (VTE). The present review focuses on hemostatic changes in overt and subclinical hyperthyroidism. Methods A systematic literature search was conducted employing MEDLINE database. The following words were used for the search: Hyperthyroidism; thyrotoxicosis; Graves disease; goiter, nodular; hemostasis; blood coagulation factors; blood coagulation disorders; venous thromboembolism; bleeding; fibrinolysis. The articles that were related to hyperthyroidism and hemostasis are used in this manuscript. Results Hyperthyroidism, either overt or subclinical, renders a hypercoagulable state, although there are several studies with contradictory findings in the literature. Hypercoagulability may be caused by an increase in the level of various coagulation factors such as factor (F) VIII, FX, FIX, von Willebrand F (vWF), and fibrinogen, while hypofibrinolysis by changes in coagulation parameters such as a decrease in plasmin and plasmin activator or an increase in α2-antiplasmin, plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor Conclusions Although many reports are in favor of a hypercoagulable state in overt hyperthyroidism but this finding at the biochemical level and its clinical implication, on the occurrence of VTE, has yet to be confirmed. PMID:29201071

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

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

Code of Federal Regulations, 2013 CFR

2013-07-01

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

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

Code of Federal Regulations, 2014 CFR

2014-07-01

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

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

Code of Federal Regulations, 2012 CFR

2012-07-01

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-07

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

Development of GaInP Solar Cells Grown by Hydride Vapor Phase Epitaxy

DOE PAGES

Schulte, Kevin L.; Simon, John; Mangum, John; ...

2017-04-30

We demonstrate the growth of homojunction GaInP solar cells by dynamic hydride vapor phase epitaxy for the first time. Simple unpassivated n-on-p structures grown in an inverted configuration with gold back reflectors were analyzed. Short wavelength performance varied strongly with emitter thickness, since collection in the emitter was limited by the lack of surface passivation. Collection in the base increased strongly with decreasing doping density, in the range 1 x 10 16 - 5 x 10 17 cm -3. Optical modeling indicated that, in our best device, doped ~1 x 10 16 cm -3, almost 94% of photons that passedmore » through the emitter were collected. Modeling also indicated that the majority of collection occurs in the depletion region with this design, suggesting that nonradiative recombination there might limit device performance. In agreement with this observation, the experimental dark J-V curve exhibited an ideality factor near n = 2. Thus, limitation of deep level carrier traps in the material is a path to improved performance. Preliminary experiments indicate that a reduced V/III ratio, which potentially affects the density of these presumed traps, improves cell performance. With reduced V/III ratio, we demonstrate a ~13% efficient GaInP cell measured under the 1-sun AM1.5G spectrum. In conclusion, this cell had an antireflective coating, but no front surface passivation.« less

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.

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

Park, Kwangwook; Kang, Seokjin; Ravindran, Sooraj

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

Improving self-regulated learning junior high school students through computer-based learning

NASA Astrophysics Data System (ADS)

Nurjanah; Dahlan, J. A.

2018-05-01

This study is back grounded by the importance of self-regulated learning as an affective aspect that determines the success of students in learning mathematics. The purpose of this research is to see how the improvement of junior high school students' self-regulated learning through computer based learning is reviewed in whole and school level. This research used a quasi-experimental research method. This is because individual sample subjects are not randomly selected. The research design used is Pretest-and-Posttest Control Group Design. Subjects in this study were students of grade VIII junior high school in Bandung taken from high school (A) and middle school (B). The results of this study showed that the increase of the students' self-regulated learning who obtain learning with computer-based learning is higher than students who obtain conventional learning. School-level factors have a significant effect on increasing of the students' self-regulated learning.

Reassessment of ABO blood group, sex, and age on laboratory parameters used to diagnose von Willebrand disorder: potential influence on the diagnosis vs the potential association with risk of thrombosis.

PubMed

Favaloro, Emmanuel J; Soltani, Soma; McDonald, Jane; Grezchnik, Ella; Easton, Leanne; Favaloro, James W C

2005-12-01

We reassessed the influence of ABO blood group, sex, and age on plasma levels of von Willebrand factor (vWF) antigen, vWF:ristocetin cofactor, vWF:collagen binding assay, and factor VIII coagulant (FVIII:C). Data show that levels of vWF and FVIII:C increase with increasing age (P < .001 for all parameters) and that the ABO blood group influences plasma levels such that O group levels are significantly less than non-O group levels. There was no significant association with sex and Rh status. The selection of normal ranges based on ABO blood groups may influence the clinical diagnosis of von Willebrand disease (vWD) but might not be clinically relevant or help identify people at increased risk of bleeding. Differences in ABO-related ranges were more extensive at the high end of the ranges. This is of particular interest because high levels of vWF and FVIII are associated with thrombosis risk, and an ABO relationship also has been described. O group individuals may or may not be at greater risk for bleeding (they have lower levels of vWF and FVIII:C) and are more likely to be diagnosed with vWD. It also is possible that O group status may be protective for thrombosis.

Control of Air Pollution from Aviation: The Emission Standard Setting Process.

DTIC Science & Technology

1981-01-01

49 VIII-2 ORGANIC EMISSIONS FROM GAS TURBINE ENGINES .......... 64 VIII-3 THE REACTIVITY OF AIRCRAFT COMPARED WITH OTHER EMISSION SOURCES...SETTING PROCESS ............................................... 45 VIII-I GAS TURBINE POLLUTANT FORMATION AND DECOMPO- SITION...144 A-4-3 AIRCRAFT GAS TURBINE POLLUTION CONSIDERATIONS ....... 145 A-4-4 PRIMARY ZONE ENRICHMENT, DELAYED DILUTION, AND AIRBLAST

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-29

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-23

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

77 FR 21142 - Advisory Committee for the Study of Eastern Europe and the Independent States of the Former...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-09

... the Independent States of the Former Soviet Union (Title VIII) The Advisory Committee for the Study of Eastern Europe and the Independent States of the Former Soviet Union (Title VIII) will convene on Thursday... committee deliberation, interested members of the public may make oral statements concerning the Title VIII...

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.

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.

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

PubMed

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

2004-08-05

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

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

PubMed

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

2014-05-01

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

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

PubMed

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

2015-03-01

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

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

NASA Astrophysics Data System (ADS)

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

2015-01-01

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

Report on Teen Cigarette Smoking and Marijuana Use.

ERIC Educational Resources Information Center

Columbia Univ., New York, NY. National Center on Addiction and Substance Abuse.

While other surveys seek to measure the extent of substance abuse in the population, the "CASA National Survey of American Attitudes on Substance Abuse VIII: Teens and Parents" probes substance-abuse risk and identifies factors that increase or diminish the likelihood that teens will abuse tobacco, alcohol or illegal drugs. This year,…

Immunohistochemical and histomorphometric evaluation of vascular distribution in intact canine cranial cruciate ligament.

PubMed

Hayashi, Kei; Bhandal, Jitender; Kim, Sun Young; Rodriguez, Carlos O; Entwistle, Rachel; Naydan, Diane; Kapatkin, Amy; Stover, Susan M

2011-02-01

To (1) describe vascular distribution in the grossly intact canine cranial cruciate ligament (CCL) using immunohistochemical techniques specific to 2 components of blood vessels (factor VIII for endothelial cells, laminin for basement membrane); and (2) compare the vascularity in different areas of interest (craniomedial versus caudolateral bands; core versus epiligamentous regions; and proximal versus middle versus distal portions) in the intact normal canine CCL. In vitro study. Large, mature dogs (n=7) of breeds prone to CCL disease that were euthanatized for nonorthopedic conditions. Intact CCL were collected from fresh canine cadavers free from stifle pathology. CCL tissue was processed for immunohistochemistry and stained for factor VIII and laminin. Vascular density was determined by histomorphometric analysis. Specific vascular staining was sparsely identified throughout the CCL; however, the proximal portion of the CCL appears to have a greater number of vessels than the middle or distal portion of the ligament. The CCL is a hypovascular tissue and its vascular distribution is not homogeneous. © Copyright 2010 by The American College of Veterinary Surgeons.

75 FR 4340 - Notice of New Recreation Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-27

... season. Fees are assessed based on the level of amenities and services provided, cost of operations and... Forest have shown that publics appreciate and enjoy the availability of historic and other type rental...

Targeted exome sequencing identifies novel compound heterozygous mutations in P3H1 in a fetus with osteogenesis imperfecta type VIII.

PubMed

Huang, Yanru; Mei, Libin; Lv, Weigang; Li, Haoxian; Zhang, Rui; Pan, Qian; Tan, Hu; Guo, Jing; Luo, Xiaomei; Chen, Chen; Liang, Desheng; Wu, Lingqian

2017-01-01

Osteogenesis imperfecta (OI) is a highly clinically and genetically heterogeneous group of disorders. It is difficult to identify severe OI in the perinatal period. Here, a Chinese woman with a suspected history of fetal OI was referred to our institution at 19weeks of gestation, due to ultrasound inspection during antenatal screening, which revealed bulbous metaphyses, short humeri, and short thick bent femora in the fetus. Using targeted exome sequencing of 248 genes known to be involved in skeletal system diseases, we identified novel compound heterozygous mutation in the P3H1 gene in the fetus with OI type VIII: c.105_120del (p.D36Rfs*16) and c.2164C>T (p.Q722*). These two mutations were inherited from the father and mother, respectively. The mRNA level of P3H1 wasn't changed suggested that mRNA with this mutation escaped from nonsense-mediated RNA decay. Besides, the level of P3H1 was absence while the CRTAP was mildly decreased. In conclusion, our findings imply this novel compound heterozygous mutation as the molecular pathogenetic in a Chinese fetus with OI type VIII, and demonstrate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia with genetic and clinical heterogeneity, especially for autosomal recessive skeletal disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Lipid profile in oral submucous fibrosis.

PubMed

Mehrotra, Ravi; Pandya, Shruti; Chaudhary, Ajay Kumar; Singh, Himanshu Pratap; Jaiswal, Ritesh Kumar; Singh, Mangal; Gupta, S C; Singh, Mamta

2009-07-24

Changes in lipid profile have long been associated with malignancies as lipids play a key role in maintenance of cell integrity. This study evaluated the alterations in extended lipid profile in untreated patients of oral submucous fibrosis (OSMF) and studied the correlation between lipid levels with tobacco consumption. In this hospital-based study, 65 clinically diagnosed and histopathologically proven patients of OSMF and 42 age and sex matched controls were studied. In these samples serum lipids including: (i) Total cholesterol, (ii) LDL cholesterol (LDLC), (iii) HDL cholesterol (HDLC) (iv) VLDL cholesterol (VLDLC) (v) triglycerides (vi) Apo-A1 (viii) Apo-B and (viii) LPa were analyzed. A significant decrease in plasma total cholesterol, HDLC and Apo-A1 was observed in patients with OSMF as compared to the controls. Thus an inverse relationship between plasma lipid levels and patients was found in OSMF. The lower levels of plasma cholesterol and other lipid constituents in patients might be due to their increased utilization. The findings strongly warrant an in-depth study of alterations in plasma lipid profile in patients with oral precancerous conditions.

76 FR 27375 - Advisory Committee for the Study of Eastern Europe and the Independent States of the Former...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

... the Independent States of the Former Soviet Union (Title VIII) The Advisory Committee for the Study of Eastern Europe and the Independent States of the Former Soviet Union (Title VIII) will convene on Thursday... of the public may make oral statements concerning the Title VIII program in general. This meeting...

A global quantitative survey of hemostatic assessment in postpartum hemorrhage and experience with associated bleeding disorders.

PubMed

James, Andra H; Cooper, David L; Paidas, Michael J

2017-01-01

Coagulopathy may be a serious complicating or contributing factor to postpartum hemorrhage (PPH), and should be promptly recognized to ensure proper bleeding management. This study aims to evaluate the approaches of obstetrician-gynecologists worldwide towards assessing massive PPH caused by underlying bleeding disorders. A quantitative survey was completed by 302 obstetrician-gynecologists from 6 countries (the UK, France, Germany, Italy, Spain, and Japan). The survey included questions on the use of hematologic laboratory studies, interpretation of results, laboratory's role in coagulation assessments, and experience with bleeding disorders. Overall, the most common definitions of "massive" PPH were >2,000 mL (39%) and >1,500 mL (34%) blood loss. The most common criteria for rechecking a "stat" complete blood count and for performing coagulation studies were a drop in blood pressure (73%) and ongoing visible bleeding (78%), respectively. Laboratory coagulation (prothrombin time/activated partial thromboplastin time [PT/aPTT]) and factor VIII/IX assays were performed on-site more often than were mixing studies (laboratory coagulation studies, 93%; factor VIII/IX assays, 63%; mixing studies, 22%). Most commonly consulted sources of additional information were colleagues within one's own specialty (68%) and other specialists (67%). Most respondents had consulted with a hematologist (78%; least, Germany [56%]; greatest, UK [98%]). The most common reason for not consulting was hematologist unavailability (44%). The most commonly reported thresholds for concern with PT and aPTT were 13 to 20 seconds (36%) and 30 to 45 seconds (50%), respectively. Most respondents reported having discovered an underlying bleeding disorder (58%; least, Japan [35%]; greatest, Spain [74%]). Global survey results highlight similarities and differences between countries in how PPH is assessed and varying levels of obstetrician-gynecologist experience with identification of underlying bleeding disorders and engagement of hematology consultants. Opportunities to improve patient management of PPH associated with bleeding disorders include greater familiarity with interpreting PT/aPTT test results and identification of and consistent consultation with hematologists with relevant expertise.

[Effect of the ethanol extracts of starfish Asterias amurensis on the levels of serum IL-4 and IFN-γ in mice].

PubMed

He, Su-hui; Tang, Xiao-lei; Deng, Ye-feng; Chen, Zhang-quan

2011-11-01

To investigate the effect of the ethanol extracts of the starfish Asterias amurensis on the levels of serum IL-4 and IFN-γ in mice. The whole bodies of the starfish were chopped and extracted with ethanol. The ethanol extracts were chromatographed on silica gel column. The separating fractions of the ethanol extracts were intraperitoneally injected into mice, respectively. The levels of serum IL-4 and IFN-γ in mice were detected by ELISA. The ethanol extracts from the starfish were separated through silica gel column chromatography to obtain 8 fractions (I-VIII). The high levels of IL-4 and IFN-γ were produced in serum of the mice injected with fractions III and VIII of the ethanol extracts from the starfish Asterias amurensis. The fractions III and VIIII separated from the ethanol extracts of the starfish Asterias amurensis can stimulate the mice to produce high lelves of IL-4 and IFN-γ, which has the characteristic of natural kill T (NKT) cells activator. It is suggests that there is the active substance that can activate NKT cells in the starfish Asterias amurensis.

Expanding the versatility of phage display I: efficient display of peptide-tags on protein VII of the filamentous phage.

PubMed

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

2011-02-24

Phage display is a platform for selection of specific binding molecules and this is a clear-cut motivation for increasing its performance. Polypeptides are normally displayed as fusions to the major coat protein VIII (pVIII), or the minor coat protein III (pIII). Display on other coat proteins such as pVII allows for display of heterologous peptide sequences on the virions in addition to those displayed on pIII and pVIII. In addition, pVII display is an alternative to pIII or pVIII display. Here we demonstrate how standard pIII or pVIII display phagemids are complemented with a helper phage which supports production of virions that are tagged with octa FLAG, HIS(6) or AviTag on pVII. The periplasmic signal sequence required for pIII and pVIII display, and which has been added to pVII in earlier studies, is omitted altogether. Tagging on pVII is an important and very useful add-on feature to standard pIII and pVII display. Any phagemid bearing a protein of interest on either pIII or pVIII can be tagged with any of the tags depending simply on choice of helper phage. We show in this paper how such tags may be utilized for immobilization and separation as well as purification and detection of monoclonal and polyclonal phage populations.

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.

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.

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

PubMed

Soulier, J P; Prou-Wartelle, O

1975-01-01

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

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

PubMed

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

2017-01-01

Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a critical factor for hemophilia A gene therapy. © 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

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.

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

DOE PAGES

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

2017-01-16

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

Design considerations for optically pumped, UV and XUV lasers in the Be isoelectronic sequence

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

Krishnan, M.; Trebes, J.

1984-09-01

Intense line radiation from plasmas of MnVI, PIX, AlV, AlVIII, AlIX, and AlXI may be used to selectively pump population inversions in plasmas of Be-like CIII, NIV, FVI, NeVII, NaVIII, and MgIX. Quasi-cw lasing is possible on 4p-3d and 4f-3d transitions at wavelengths from 2177 A to 230 A. At the XUV wavelengths, 1 J, 10 ns laser output pulses at 10/sup 8/ W power levels are shown possible with existing discharge technology. Since all six laser ions are in the Be isoelectronic sequence, detailed studies of the optical pumping process at UV wavelengths in CIII would provide scaling parametersmore » for the less accessible XUV wavelengths.« less

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

PubMed

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

1996-01-01

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

Increased thromboplastic potential in diabetes: a multifactorial phenomenon.

PubMed

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

1987-07-01

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

Vulvar epithelioid hemangiosarcoma with solar elastosis in a mare.

PubMed

Gumber, Sanjeev; Baia, Petrisor; Wakamatsu, Nobuko

2011-09-01

A 15-year-old female gray Appaloosa horse was presented with history of a mass over the right dorsal commissure of vulva for the past 7 months. Based on histopathological examination, and positive staining with factor VIII-related antigen, vimentin, and Verhoeff-van Gieson stain, the vulvar mass was diagnosed as hemangiosarcoma with marked solar elastosis.

76 FR 54202 - Honey From Argentina: Preliminary Results of Antidumping Duty New Shipper Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-31

... its responses to sections B and C (BQR and CQR, respectively), and Appendix VIII (customer-specific... ``particular market situation'' questionnaire on June 29, 2011, and, in combination with its U.S. customer... therefore bona fide, the Department considers, inter alia, such factors as: (1) The timing of the sale; (2...

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...

Determining the crystal structure of fibrinogen.

PubMed

Doolittle, R F

2004-05-01

Summary. I have enjoyed reading previous historical sketches that have appeared in Journal of Thrombosis and Haemostasis, and especially those by Ted Tuddenham on factor VIII and Bjorn Dahlback on activated protein C resistance. Like those authors, I have tried to capture some of the excitement-as well as the disappointments-that occurred along the way to a long-term goal.

Improving Military Change Detection Skills in a Virtual Environment: The Effects of Time, Threat Level, and Tutorials

DTIC Science & Technology

2011-09-01

36 b. Designing for Vigilance .............................................. 38 viii c. Landmarks and Spatial Navigation... DESIGNING AND EXECUTING CHANGE DETECTION SCENARIO TRAINING ............................................................................... 153 A...SCENARIO INSTRUCTIONS FOR EDITORS ................................. 153 B. HOW TO DESIGN A CHANGE DETECTION SCENARIO .............. 157 APPENDIX K

40 CFR Appendix Xiii to Part 266 - Mercury Bearing Wastes That May Be Processed in Exempt Mercury Recovery Units

Code of Federal Regulations, 2011 CFR

2011-07-01

... are exempt mercury-bearing materials with less than 500 ppm of 40 CFR Part 261, appendix VIII organic... tank sludge 13. Mercury cell process solids 14. Recoverable levels of mercury contained in soil [59 FR...

40 CFR Appendix Xiii to Part 266 - Mercury Bearing Wastes That May Be Processed in Exempt Mercury Recovery Units

Code of Federal Regulations, 2012 CFR

2012-07-01

... are exempt mercury-bearing materials with less than 500 ppm of 40 CFR Part 261, appendix VIII organic... tank sludge 13. Mercury cell process solids 14. Recoverable levels of mercury contained in soil [59 FR...

40 CFR Appendix Xiii to Part 266 - Mercury Bearing Wastes That May Be Processed in Exempt Mercury Recovery Units

Code of Federal Regulations, 2014 CFR

2014-07-01

... are exempt mercury-bearing materials with less than 500 ppm of 40 CFR Part 261, appendix VIII organic... tank sludge 13. Mercury cell process solids 14. Recoverable levels of mercury contained in soil [59 FR...

40 CFR Appendix Xiii to Part 266 - Mercury Bearing Wastes That May Be Processed in Exempt Mercury Recovery Units

Code of Federal Regulations, 2010 CFR

2010-07-01

... are exempt mercury-bearing materials with less than 500 ppm of 40 CFR Part 261, appendix VIII organic... tank sludge 13. Mercury cell process solids 14. Recoverable levels of mercury contained in soil [59 FR...

40 CFR Appendix Xiii to Part 266 - Mercury Bearing Wastes That May Be Processed in Exempt Mercury Recovery Units

Code of Federal Regulations, 2013 CFR

2013-07-01

... are exempt mercury-bearing materials with less than 500 ppm of 40 CFR Part 261, appendix VIII organic... tank sludge 13. Mercury cell process solids 14. Recoverable levels of mercury contained in soil [59 FR...

Teacher's opinions about learning continuum based on the student's level of competence and specific pedagogical materials on anatomical aspects

NASA Astrophysics Data System (ADS)

Astuti, Laili Dwi; Subali, Bambang

2017-08-01

This research deals with designing learning continuum for developing a curriculum. The objective of this study is to gather the opinion of public junior and high school teachers about Learning Continuum based on Student's Level of Competence and Specific Pedagogical Material on Anatomical Aspects. This is a survey research. The population of the research is natural science teachers at junior high school and biology teacher at senior high school in Yogyakarta Special Region. Data were collected using a questionnaire. Data were analyzed using a descriptive analysis technique. Based on the results of the survey, the teachers opinion are in accordance with the level of the students they teach. Junior high school teachers argued that anatomical aspects were taught in grade VII,VIII, IX and X on the level of C2 (understanding), the high school teacher argued that anatomical aspects were taught in grade VIII, X and XI on the level of C2 (understanding) and C3 (apply). While according to the opinions of primary school teachers about aspects of anatomy resulted from the research of Subali (2016), anatomy is mostly not taught at the elementary school level, only some of the materials that are taught in this school level. Therefore, the results of the survey can be inferred that the opinions of teachers is still based on the existing curriculum.

Cyclic adenosine monophosphate levels and the function of skin microvascular endothelial cells.

PubMed

Tuder, R M; Karasek, M A; Bensch, K G

1990-02-01

The maintenance of the normal epithelioid morphology of human dermal microvascular endothelial cells (MEC) grown in vitro depends strongly on the presence of factors that increase intracellular levels of cyclic AMP. Complete removal of dibutyryl cAMP and isobutylmethylxanthine (IMX) from the growth medium results in a progressive transition from an epithelioid to a spindle-shaped cell line. This transition cannot be reversed by the readdition of dibutyryl cAMP and IMX to the growth medium or by addition of agonists that increase cAMP levels. Spindle-shaped MEC lose the ability to express Factor VIII rAG and DR antigens and to bind peripheral blood mononuclear leukocyte (PBML). Ultrastructural analyses of transitional cells and spindle-shaped cells show decreased numbers of Weibel-Palade bodies in transitional cells and their complete absence in spindle-shaped cells. Interferon-gamma alters several functional properties of both epithelioid and spindle-shaped cells. In the absence of dibutyryl cAMP it accelerates the transition from epithelial to spindle-shaped cells, whereas in the presence of cyclic AMP interferon-gamma increases the binding of PBMLs to both epithelioid and spindle-shaped MEC and the endocytic activity of the endothelial cells. These results suggest that cyclic AMP is an important second messenger in the maintenance of several key functions of microvascular endothelial cells. Factors that influence the levels of this messenger in vivo can be expected to influence the angiogenic and immunologic functions of the microvasculature.

Chandra Discovery of a Tree in the X-Ray Forest toward PKS 2155-304: The Local Filament?

NASA Astrophysics Data System (ADS)

Nicastro, Fabrizio; Zezas, Andreas; Drake, Jeremy; Elvis, Martin; Fiore, Fabrizio; Fruscione, Antonella; Marengo, Massimo; Mathur, Smita; Bianchi, Stefano

2002-07-01

We present the first X-ray detection of resonant absorption from warm/hot local gas either in our Galaxy, or in the intergalactic space surrounding our Galaxy, along the line of sight toward the blazar PKS 2155-304. The Chandra HRCS/LETG spectrum of this z=0.116 source clearly shows, at >=5 σ level, unresolved (FWHM<=800 km s-1 at a 2 σ confidence level) O VII Kα and Ne IX Kα resonant absorption lines at 21.603+0.014-0.024 and 13.448+0.022-0.024 Å (i.e., cz=14+190-330 km s-1 in the rest frame, from the O VII Kα line). O VIII Kα and O VII Kβ from the same system are also detected at a lower significance level (i.e., ~3 σ), while upper limits are set on O VIII Kβ, Ne X Kα, and Ne IX Kβ. The Far Ultraviolet Spectroscopic Explorer spectrum of this source shows complex O VI 2s-->2p absorption at the same redshift as the X-ray system, made by at least two components: one relatively narrow (FWHM=106+/-9 km s-1) and slightly redshifted (cz=36+/-6 km s-1), and one broader (FWHM=158+/-26 km s-1) and blueshifted (cz=-135+/-14 km s-1). We demonstrate that the physical states of the UV and X-ray absorbers are hard to reconcile with a single, purely collisionally ionized, equilibrium plasma. We propose instead that the X-ray and at least the broader and blueshifted UV absorber are produced in a low-density intergalactic plasma, collapsing toward our Galaxy, consistent with the predictions of a warm-hot intergalactic medium from numerical simulations. We find that any reasonable solution requires overabundance of Ne compared to O by a factor of ~2, with respect to the solar value. We propose several scenarios to account for this observation.

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

PubMed

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

2013-06-01

The aim of this study is to assess whether the haemostatic markers D-dimer, factor VIII (FVIII) and von Willebrand factor (VWF) are predictive of non-dipping status in treated hypertensive patients; so, as easy available laboratory data can predict non-dipping pattern and help with the selection of the patients whom circadian blood pressure should be re-examined. Forty treated hypertensive patients with essential hypertension were included in the study. Twenty-four-hour ambulatory blood pressure monitoring was performed in all patients. Daytime and nocturnal average systolic, diastolic and mean blood pressures were calculated. Patients were characterised as "non-dippers" on the basis of a less than 10 % decline in nocturnal blood pressure (BP); either systolic or diastolic or mean (MAP). D-dimer as marker of fibrinolytic function, FVIII activity and VWF antigen as marker of endothelial dysfunction were measured on plasma. The predictive efficiency was analysed by receiver operating characteristic (ROC) curves. Youden index was used for the estimation of the cut-off points and the associated values for sensitivity and 1-specificity. Plasma levels of D-dimer, FVIII and VWF were significantly higher in non-dippers as compared with dippers, irrespective of the classification used (BP index); all P < 0.05. The ROC curves indicated a good diagnostic efficiency for D-dimer (AUC(ROC) = 0.697, 0.715 and 0.774), FVIII (AUC(ROC) = 0.714, 0.692 and 0.755) and VWF (AUC(ROC) = 0.706, 0.740 and 0.708) in distinguishing non-dipping pattern (systolic, diastolic or mean) in the study population; all P < 0.05. Among the three haemostatic markers, D-dimer presents the most satisfactory sensitivity/1-specificity for the differentiation of non-dippers, with a cut-off point >168 ng/ml (sensitivity/1-specificity for systolic BP non-dippers of 0.789/0.381, for diastolic BP non-dippers 0.923/0.444 and for MAP non-dippers 0.875/0.375). In conclusion, D-dimer has a good predictive value for non-dipping pattern and the decision for the 24-h ambulatory blood pressure re-monitoring among dippers could rely on its values.

Effect of temporary cements on the shear bond strength of luting cements

PubMed Central

FIORI-JÚNIOR, Marco; MATSUMOTO, Wilson; SILVA, Raquel Assed Bezerra; PORTO-NETO, Sizenando Toledo; SILVA, Jaciara Miranda Gomes

2010-01-01

Objective The purpose of this study was to evaluate, by shear bond strength (SBS) testing, the influence of different types of temporary cements on the final cementation using conventional and self-etching resin-based luting cements. Material and Methods Forty human teeth divided in two halves were assigned to 8 groups (n=10): I and V (no temporary cementation); II and VI: Ca(OH)2-based cement; III and VII: zinc oxide (ZO)based cement; IV and VIII: ZO-eugenol (ZOE)-based cement. Final cementation was done with RelyX ARC cement (groups I to IV) and RelyX Unicem cement (groups V to VIII). Data were analyzed statistically by ANOVA and Tukey's test at 5% significance level. Results Means were (MPa): I - 3.80 (±1.481); II - 5.24 (±2.297); III - 6.98 (±1.885); IV - 6.54 (±1.459); V - 5.22 (±2.465); VI - 4.48 (±1.705); VII - 6.29 (±2.280); VIII - 2.47 (±2.076). Comparison of the groups that had the same temporary cementation (Groups II and VI; III and VII; IV and VIII) showed statistically significant difference (p<0.001) only between Groups IV and VIII, in which ZOE-based cements were used. The use of either Ca(OH)2 based (Groups II and VI) or ZO-based (Groups III and VII) cements showed no statistically significant difference (p>0.05) for the different luting cements (RelyXTM ARC and RelyXTM Unicem). The groups that had no temporary cementation (Groups I and V) did not differ significantly from each other either (p>0.05). Conclusion When temporary cementation was done with ZO- or ZOE-based cements and final cementation was done with RelyX ARC, there was an increase in the SBS compared to the control. In the groups cemented with RelyX Unicem, however, the use of a ZOE-based temporary cement affected negatively the SBS of the luting agent used for final cementation. PMID:20379679

Separation of whole blood into plasma and red cells by using a hollow-fibre filtration system.

PubMed

Hornsey, V S; McColl, K; Drummond, O; Prowse, C V

2005-08-01

The aim of this study was to assess the separation of whole blood into red cells and plasma by using the Sangofer device, which is a gravity-fed, hollow-fibre system. The components would then be compared with those produced by the use of more elaborate technical equipment. Ten whole-blood units were leucoreduced by using a WBF2 filter and immediately separated into red cells and plasma by using the Sangofer blood-separation device. Red cells were stored in additive solution and tested on days 1 and 42. The plasma was assayed for levels of various coagulation factors and for markers of both coagulation and complement activation. The red-cell parameters were similar to those obtained when routine centrifugation methods were used. The filter did not cause haemolysis. Levels of plasma factor VIII and factor XI were lower than those seen in routinely produced leucoreduced plasma units but there was no evidence of activation of the coagulation and complement systems. The Sangofer device is simple and straightforward to use and eliminates the need for both centrifugation and automated separation steps during the processing of whole blood into red cells and plasma components. Minor changes are required to make the procedure easier to incorporate into routine use.

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

Code of Federal Regulations, 2013 CFR

2013-10-01

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

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

Code of Federal Regulations, 2011 CFR

2011-10-01

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

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

Code of Federal Regulations, 2012 CFR

2012-10-01

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

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

Code of Federal Regulations, 2010 CFR

2010-10-01

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

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

Code of Federal Regulations, 2014 CFR

2014-10-01

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

Resonances and thresholds in the Rydberg-level population of multiply charged ions at solid surfaces

NASA Astrophysics Data System (ADS)

Nedeljković, Lj. D.; Nedeljković, N. N.

1998-12-01

We present a theoretical study of resonances and thresholds, two specific features of Rydberg-state formation of multiply charged ions (Z=6, 7, and 8) escaping a solid surface at intermediate velocities (v~1 a.u.) in the normal emergence geometry. The resonances are recognized in pronounced maxima of the experimentally observed population curves of Ar VIII ions for resonant values of the principal quantum number n=nres=11 and for the angular momentum quantum numbers l=1 and 2. Absence of optical signals in detectors of beam-foil experiments for n>nthr of S VI and Cl VII ions (with l=0, 1, and 2) and Ar VIII for l=0 is interpreted as a threshold phenomenon. An interplay between resonance and threshold effects is established within the framework of quantum dynamics of the low angular momentum Rydberg-state formation, based on a generalization of Demkov-Ostrovskii's charge-exchange model. In the model proposed, the Ar VIII resonances appear as a consequence of electron tunneling in the very vicinity of the ion-surface potential barrier top and at some critical ion-surface distances Rc. The observed thresholds are explained by means of a decay mechanism of ionic Rydberg states formed dominantly above the Fermi level EF of a solid conduction band. The theoretically predicted resonant and threshold values, nres and nthr of the principal quantum number n, as well as the obtained population probabilities Pnl=Pnl(v,Z), are in sufficiently good agreement with all available experimental findings.

Elevated lipoprotein (a) levels are an independent risk factor for retinal vein occlusion.

PubMed

Kuhli-Hattenbach, Claudia; Miesbach, Wolfgang; Lüchtenberg, Marc; Kohnen, Thomas; Hattenbach, Lars-Olof

2017-03-01

To investigate the prevalence of lipoprotein (a) [Lp(a)] and other thrombophilic disorders among retinal vein occlusion (RVO) patients with regard to age and various risk factors. We retrospectively reviewed the medical records of 100 patients with central, hemicentral or branch RVO who had undergone routine thrombophilia screening. Data were compared with 100 controls. Both cohorts were divided into three subgroups (≤45 years, >45-≤60 years or >60 years), depending on the patients' age at the time of the RVO or a previous thromboembolic event. Elevated Lp(a) plasma levels were significantly more prevalent among RVO patients than among controls (p < 0.0001; OR: 4.8). Moreover, we determined age ≤60 years by the time of the first thromboembolic event as a strong predictor of elevated Lp(a) (p = 0.0002). The coincidence of elevated Lp(a) with other coagulation disorders further increased the OR for RVO to 9.3 (95% CI 2.1-41.8). Multivariate analysis revealed the presence of cardiovascular risk factors (OR: 3.1, p = 0.0004), elevated lipoprotein (a) levels (OR: 5.2, p = 0.0001) and increased factor VIII activity (OR: 5.9, p = 0.001) as independent risk factors for the development of RVO among patients. Our results indicate that elevated plasma levels of Lp(a) are associated with the development of RVO. Selective screening of young patients and subjects with a personal or family history of thromboembolism may be helpful in identifying RVO patients with elevated Lp(a). © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Treasure of the Past VIII: Molecular Basis of Flame Inhibition*

PubMed Central

Hastie, J. W.

2001-01-01

The role played by inorganic chemical additives in fire retardancy and flame inhibition is considered. Particular attention is given to the molecular level aspects of commercially important systems containing compounds of antimony, halogens, and phosphorus. The flame inhibiting function of metal containing additives is also discussed. PMID:27500045

MERCURY RISK MANAGEMENT IN LIVESTOCK PONDS ON THE CHEYENNE RIVER SIOUX RESERVATION

EPA Science Inventory

In a prior collaborative 3 year study with the Cheyenne River Sioux Tribe Department of Environmental Protection (CRST DEP), and the Agencies' Environmental Response Team, RegionVIII investigated Hg levels in fish tissues from the Cheyenne River and Lake Oahe in South Dakota. In...

50 CFR 218.181 - Permissible methods of taking.

Code of Federal Regulations, 2010 CFR

2010-10-01

... and the indicated number of times: (1) Level B Harassment: (i) Sperm whale (Physeter macrocephalus)—10...); (vii) Spinner dolphin (S. longirostris)—115 (an average of 23 annually); (viii) Melon-headed whale (Peponocephala electra)—10 (an average of 2 annually); (ix) Short-finned pilot whale (Globicephala macrorhynchus...

50 CFR 218.181 - Permissible methods of taking.

Code of Federal Regulations, 2012 CFR

2012-10-01

... and the indicated number of times: (1) Level B Harassment: (i) Sperm whale (Physeter macrocephalus)—10...); (vii) Spinner dolphin (S. longirostris)—115 (an average of 23 annually); (viii) Melon-headed whale (Peponocephala electra)—10 (an average of 2 annually); (ix) Short-finned pilot whale (Globicephala macrorhynchus...

50 CFR 218.181 - Permissible methods of taking.

Code of Federal Regulations, 2011 CFR

2011-10-01

... and the indicated number of times: (1) Level B Harassment: (i) Sperm whale (Physeter macrocephalus)—10...); (vii) Spinner dolphin (S. longirostris)—115 (an average of 23 annually); (viii) Melon-headed whale (Peponocephala electra)—10 (an average of 2 annually); (ix) Short-finned pilot whale (Globicephala macrorhynchus...

Platelets and hemophilia: A review of the literature.

PubMed

Riedl, Julia; Ay, Cihan; Pabinger, Ingrid

2017-07-01

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

Advances in Gene Therapy for Hemophilia.

PubMed

Nathwani, Amit C; Davidoff, Andrew M; Tuddenham, Edward G D

2017-11-01

Gene therapy provides hope for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene copy to replace the hemophilic patient's own defective gene. Hemophilia may be considered a "low-hanging fruit" for gene therapy because a small increment in blood factor levels (≥2% of normal) significantly improves the bleeding tendency from severe to moderate, eliminating most spontaneous bleeds. After decades of research, the first trial to provide clear evidence of efficiency after gene transfer in patients with hemophilia B using adeno-associated virus vectors was reported by the authors' group in 2011. This has been followed by unprecedented activity in this area, with the commencement of seven new early-phase trials involving >55 patients with hemophilia A or hemophilia B. These studies have, in large part, generated promising clinical data that lay a strong foundation for gene therapy to move forward rapidly to market authorization. This review discusses the data from the authors' studies and emerging results from other gene therapy trials in both hemophilia A and B.

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

Experimental Validation of a Time-Accurate Finite Element Model for Coupled Multibody Dynamics and Liquid Sloshing

DTIC Science & Technology

2007-04-16

velocity of the fluid mesh, P is the relative pressure, xr is the position vector, τ is the deviatoric stress tensor, D is the rate of deformation...corresponds to a slip factor of zero. The slip factor determines how much of the fluid and structure forces are mutually exchanged. Equations 22 and 23...updated from last to first. viii.Average the fluid pressure (This step eliminates the pressure checker-boarding effect and allows use of equal

The Effect of rFVIIa on Pro- and Anti-Inflamatory Cytokines in Serum and Cerebrospinal Fluid in a Swine Model of Traumatic Brain Injury

DTIC Science & Technology

2011-01-01

6) While the rate of ventilator associated pneumonia ( VAP ) has been estimated at between 8% and 28% in non-trauma patients , intubated patients ...Recombinant Factor VIla (rFVIIa) is approved for use in the treatment and prophylaxis of bleeding in patients with Factor VIII and IX deficiencies...injured patients [3). In all of these trials, rFVIIa was administered only in the hospi- tal setting, after identification of either clinically relevant

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

NASA Astrophysics Data System (ADS)

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

2015-10-01

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

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

PubMed Central

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

2002-01-01

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

Acquired Hemophilia A in an advanced age patient of hispanic origin: a case report.

PubMed

Rivera Cora, Nalyssa I; Irizarry Delgado, Freddie; Merle Ramírez, Santa M; Vera Quiñones, Jorge

2017-09-04

Acquired Hemophilia A (AHA) is a rare hematological disorder that exhibits an incidence of approximately 1.5 cases per million patients a year. It is characterized by the development of autoantibodies against circulating Factor VIII coagulation proteins which, in turn, which in turn lead to potentially life-threatening hemorrhagic episodes. The incidence of AHA increases with age; with 80% of the affected patient population encompassing men and women that are 65 years or older. Some of the challenges that are highlighted in managing this disorder relate to the delayed diagnosis of this condition due to the rarity of the latter, the difficulty in establishing reliable hemostasis, and the secondary complications that are found when using immunosuppressive and hemostatic treatments in tandem with the elderly population afflicted with this disease. A 90-year-old female of Hispanic origin presented with a 2-week history of generalized weakness, dizziness, shortness of breath and extensive purpuric formations that involved the left arm towards the lateral aspect of the thorax with the inclusion of a small right lateral neck hematoma formation. Upon initial laboratory screening, a hemoglobin level of 7.9, a hematocrit level of 21.9 and a PTT value of 70.9 were discovered. Despite conventional hemostatic treatment approaches, the patient did not show marked improvement of the laboratory values. Ongoing specialized laboratory reports, combined with the clinical presentation of the patient, led to the diagnosis of Acquired Hemophilia A. Treatment with recombinant porcine Factor VIII was initiated, which led to rapid improvement of clinical symptoms and laboratory values. The patient was discharged with current treatment plan and emergent follow/up with a hematologist was scheduled. Acquired Hemophilia A is an elusive bleeding disorder that has been seldom encountered in the demographics of Puerto Rico. The prompt detection of this diagnosis based on the clinical presentation alone is paramount to prevent the occurrence of grave hemorrhagic episodes. General knowledge and awareness of the treatment options available is key to ameliorate the prognosis of this ailment.

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.

Pheochromocytoma and haemophilia: an unusual combination.

PubMed

Jebasingh, K F; Koshy, T G; Paul, T V; Paul, M J; Abraham, D; Viswabandya, A

2009-02-01

We report pheochromocytoma and haemophilia occurring in a 19-year-old South Indian man. To the best of our knowledge, this case is the first of its kind to be reported in the medical literature. The patient had bilateral adrenal pheochromocytomas with an extradrenal pheochromocytoma on the left side, and was successfully operated on after optimal preoperative blood pressure control and factor VIII support.

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...

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

PubMed

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

2011-02-15

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

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

PubMed

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

2013-11-01

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

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

PubMed

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

2017-03-01

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

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

PubMed

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

1996-03-01

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

Analysis of rhG-CSF-effects on platelets by in vitro bleeding test and transcranial Doppler ultrasound examination.

PubMed

Söhngen, D; Wienen, S; Siebler, M; Boogen, C; Scheid, C; Schulz, A; Kobbe, G; Diehl, V; Heyll, A

1998-12-01

Experimental evidence suggests a stimulatory effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on both platelets and coagulation. RhG-CSF is increasingly used to stimulate healthy volunteer donors for blood stem cell mobilization. We therefore assessed 25 healthy donors receiving rhG-CSF for changes in in vitro bleeding test (IVBT), coagulation parameters and cerebral microembolism by transcranial Doppler (TCD) ultrasound. A significant shortening of IVBT was found on day 4 of rhG-CSF administration together with increased levels of fibrinogen and factor VIII and reduced activities of protein C and protein S. Although these changes are quite small it is possible that they may lead to a hypercoagulable state especially in donors with other risk factors for thromboembolism. However, TCD examination failed to detect any signs of microembolism. We therefore conclude that rhG-CSF leads to significant changes in coagulation parameters, but has no effect on TCD detectable microembolism as a stroke risk factor. However donors receiving rhG-CSF should be examined carefully to detect pre-existing changes in the coagulation system and we would like to suggest a routine thrombophilia screen.

Overexpression of protein kinase C ɛ improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction.

PubMed

He, H; Zhao, Z-H; Han, F-S; Liu, X-H; Wang, R; Zeng, Y-J

2016-01-21

We assessed the effects of protein kinase C ɛ (PKCɛ) for improving stem cell therapy for acute myocardial infarction (AMI). Primary mesenchymal stem cells (MSCs) were harvested from rat bone marrow. PKCɛ-overexpressed MSCs and control MSCs were transplanted into infarct border zones in a rat AMI model. MSCs and PKCɛ distribution and expression of principal proteins involved in PKCɛ signaling through the stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4) axis and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by immunofluorescence and western blot 1 day after transplantation. Echocardiographic measurements and histologic studies were performed at 4 weeks after transplantation, and MSC survival, expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor β (TGFβ), cardiac troponin I (cTnI), von Willebrand factor (vWF), smooth muscle actin (SMA) and factor VIII and apoptosis in infarct border zones were assessed. Rat heart muscles retained more MSCs and SDF-1, CXCR4, PI3K and phosphorylated AKT increased with PKCɛ overexpression 1 day after transplantation. MSC survival and VEGF, bFGF, TGFβ, cTnI, vWF, SMA and factor VIII expression increased in animals with PKCɛ-overexpressed MSCs at 4 weeks after transplantation and cardiac dysfunction and remodeling improved. Infarct size and apoptosis decreased as well. Inhibitory actions of CXCR4 or PI3K partly attenuated the effects of PKCɛ. Activation of PKCɛ may improve retention, survival and differentiation of transplanted MSCs in myocardia. Augmentation of PKCɛ expression may enhance the therapeutic effects of stem cell therapy for AMI.

Collateral Damage to Satellites from an EMP Attack

DTIC Science & Technology

2010-08-01

peak dose is computed in an infinite half plane of silicon. The resulting in- plane stresses in silicon are shown in Figure VI.23. In- plane refers to...achieved by the SLAR coating 81 Figure VIII.6. Ratio of the peak in- plane compressive stress to the maximum compressive stress for the SLAR coating...82 Figure VIII.7. Maximum in- plane compressive stress in a SLAR coating on DMSP/NOAA subjected to the threat events 83 Figure VIII.8. Maximum in

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

PubMed Central

Yang, Yao-Hsu; Chang, Chia-Hao; Chen, Chih-Cheng; Chen, Pau-Chung

2016-01-01

Introduction Rehabilitation plays an important role in the physical health of patients with hemophilia. However, comprehensive information regarding the utilization of rehabilitation for such patients remains scarce. Aim This population-based study aimed to examine the characteristics, trends, and most important factors affecting rehabilitation usage in patients with hemophilia A using a nationwide database in Taiwan. Methods Data from 777 patients with hemophilia A who were registered in the National Health Insurance Research Database between 1998 and 2008 were analyzed using SAS 9.0. Results Musculoskeletal or nervous system-related surgical procedures and clotting factor VIII concentrate costs were identified as factors affecting rehabilitation usage; musculoskeletal or nervous system-related surgical procedures (odds ratio = 3.788; P < 0.001) were the most important predictor of whether a patient with hemophilia A would use rehabilitation services. Joint disorders, arthropathies, bone and cartilage disorders, intracranial hemorrhage, and brain trauma were common diagnoses during rehabilitation use. The costs of physical therapy (physiotherapy) comprised the majority (71.2%) of rehabilitation therapy categories. Increasingly, rehabilitation therapy was performed at physician clinics. The total rehabilitation costs were <0.1% of the total annual medical costs. Conclusion Musculoskeletal or nervous system-related surgical procedures and increased use of clotting factor VIII concentrate affect the rehabilitation utilization of patients with hemophilia A the most. The findings in this study could help clinicians comprehensively understand the rehabilitation utilization of patients with hemophilia A. PMID:27690229

75 FR 21583 - Notice of Proposed New Fee Site; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

... on the level of amenities and services provided, cost of operations and maintenance, market... comment. Funds from fees would be used for the continued operation and maintenance and improvements of..., serving tables, utility tables, information bulletins, fencing, improved roads and a host site. These...

50 CFR 665.815 - Pelagic longline seabird mitigation measures.

Code of Federal Regulations, 2014 CFR

2014-10-01

... rate; (vi) Use completely thawed bait that has been dyed blue to an intensity level specified by a... 1 lb size) containing blue dye on board the vessel; and (viii) Follow the requirements in paragraphs... complete the deployment no later than local sunrise, using only the minimum vessel lights to conform with...

50 CFR 665.815 - Pelagic longline seabird mitigation measures.

Code of Federal Regulations, 2013 CFR

2013-10-01

... rate; (vi) Use completely thawed bait that has been dyed blue to an intensity level specified by a... 1 lb size) containing blue dye on board the vessel; and (viii) Follow the requirements in paragraphs... complete the deployment no later than local sunrise, using only the minimum vessel lights to conform with...

50 CFR 665.815 - Pelagic longline seabird mitigation measures.

Code of Federal Regulations, 2011 CFR

2011-10-01

... rate; (vi) Use completely thawed bait that has been dyed blue to an intensity level specified by a... 1 lb size) containing blue dye on board the vessel; and (viii) Follow the requirements in paragraphs... complete the deployment no later than local sunrise, using only the minimum vessel lights to conform with...

50 CFR 665.815 - Pelagic longline seabird mitigation measures.

Code of Federal Regulations, 2012 CFR

2012-10-01

... rate; (vi) Use completely thawed bait that has been dyed blue to an intensity level specified by a... 1 lb size) containing blue dye on board the vessel; and (viii) Follow the requirements in paragraphs... complete the deployment no later than local sunrise, using only the minimum vessel lights to conform with...

Electronic Principles VIII, 7-12. Military Curriculum Materials for Vocational and Technical Education.

ERIC Educational Resources Information Center

Ohio State Univ., Columbus. National Center for Research in Vocational Education.

This eighth of 10 blocks of student and teacher materials for a secondary/postsecondary level course in electronic principles comprises one of a number of military-developed curriculum packages selected for adaptation to vocational instruction and curriculum development in a civilian setting. Prerequisites are the previous blocks. This block on…

29 CFR 1910.111 - Storage and handling of anhydrous ammonia.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 1,200 gallons water capacity. (viii) Filling density. the percent ratio of the weight of the gas in... ammonia. (xi) Capacity. Total volume of the container in standard U.S. gallons. (xii) DOT specifications... allowable water level to which the container may be filled for test purposes. (vii) With the density of the...

29 CFR 1910.111 - Storage and handling of anhydrous ammonia.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 1,200 gallons water capacity. (viii) Filling density. the percent ratio of the weight of the gas in... ammonia. (xi) Capacity. Total volume of the container in standard U.S. gallons. (xii) DOT specifications... allowable water level to which the container may be filled for test purposes. (vii) With the density of the...

29 CFR 1910.111 - Storage and handling of anhydrous ammonia.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 1,200 gallons water capacity. (viii) Filling density. the percent ratio of the weight of the gas in... ammonia. (xi) Capacity. Total volume of the container in standard U.S. gallons. (xii) DOT specifications... allowable water level to which the container may be filled for test purposes. (vii) With the density of the...

MERCURY CONTAMINATION OF SUBSISTENCE FISHERIES ON TRIBAL LANDS: A PARTNERSHIP OF ORD, REGION 8 AND CHEYENNE RIVER SIOUX RESERVATION

EPA Science Inventory

In a prior collaborative 3 year study with the Cheyenne River Sioux Tribe Department of Environmental Protection (CRST DEP), and the Agencies' Environmental Response Team, RegionVIII investigated Hg levels in fish tissues from the Cheyenne River and Lake Oahe in South Dakota. In...

50 CFR 218.11 - Permissible methods of taking.

Code of Federal Regulations, 2010 CFR

2010-10-01

... annually); (viii) Pilot whales (Globicephala sp.)—100 (an average of 20 annually); (ix) Dwarf or pygmy sperm whales (Kogia sp.)—15 (an average of 3 annually); (x) Beaked whales—100 (an average of 20 annually); (xi) Minke whales (Balaenoptera acutorostrata)—15 (an average of 3 annually). (2) Level A Harassment...

50 CFR 218.11 - Permissible methods of taking.

Code of Federal Regulations, 2011 CFR

2011-10-01

... annually); (viii) Pilot whales (Globicephala sp.)—100 (an average of 20 annually); (ix) Dwarf or pygmy sperm whales (Kogia sp.)—15 (an average of 3 annually); (x) Beaked whales—100 (an average of 20 annually); (xi) Minke whales (Balaenoptera acutorostrata)—15 (an average of 3 annually). (2) Level A Harassment...

50 CFR 218.11 - Permissible methods of taking.

Code of Federal Regulations, 2012 CFR

2012-10-01

... annually); (viii) Pilot whales (Globicephala sp.)—100 (an average of 20 annually); (ix) Dwarf or pygmy sperm whales (Kogia sp.)—15 (an average of 3 annually); (x) Beaked whales—100 (an average of 20 annually); (xi) Minke whales (Balaenoptera acutorostrata)—15 (an average of 3 annually). (2) Level A Harassment...

40 CFR 141.720 - Inactivation toolbox components.

Code of Federal Regulations, 2014 CFR

2014-07-01

... treatment unit process with a measurable disinfectant residual level and a liquid volume. Under this... through reactor validation testing, as described in paragraph (d)(2) of this section. The UV dose values....0 12 11 143 (vii) 3.5 15 15 163 (viii) 4.0 22 22 186 (2) Reactor validation testing. Systems must...

7 CFR 51.3410 - Grades.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Rot; (vi) Insects, worms or larvae; (vii) Soft rot and wet breakdown; and, (viii) Loose sprouts, dirt..., (viii) Loose sprouts, dirt and foreign material. (3) Free from serious damage by any cause. (4) Size...

Factor VIII organisation on nanodiscs with different lipid composition.

PubMed

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

2015-04-01

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

Influence of class I and II HLA alleles on inhibitor development in severe haemophilia A patients from the south of Brazil.

PubMed

De Barros, M F; Herrero, J C M; Sell, A M; De Melo, F C; Braga, M A; Pelissari, C B; Machado, J; De Souza Schiller, S; De Souza Hirle, L; Visentainer, J E L

2012-05-01

Congenital haemophilia A is a chromosome-linked recessive disorder caused by the deficiency or reduction of factor VIII (FVIII) pro-coagulant activity. During treatment, some patients develop alloantibodies (FVIII inhibitors) that neutralize the action of exogenously administered FVIII. Currently, the presence of these inhibitors is the most serious adverse event found in replacement therapy. Some studies have suggested that genetic factors influence the development of the FVIII coagulation inhibitors. To identify the class I and II alleles that may be influencing the formation of inhibitors in severe haemophilic patients. Genotyping of the class I (HLA-A, -B and -C) and class II (HLA-DRB1, -DQA1 and -DQB1) alleles of 122 patients with severe haemophilia A, including 36 who had developed antibodies to factor VIII, was performed. After the comparison of the group without inhibitors and the group with inhibitors, HLA-C*16 [Odds ratio (OR) = 7.73; P = 0.0092] and HLA-DRB1*14 (OR = 4.52; P = 0.0174) were found to be positively associated with the formation of the inhibitors. These results confirm that HLA alleles are involved in inhibitor production and could be used as a tool for recognition of groups at high risk of possible inhibitor development in Southern Brazilian haemophilic patients. © 2011 Blackwell Publishing Ltd.

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

PubMed

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

2015-07-01

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

Venom Protein C activators as diagnostic agents for defects of protein C System.

PubMed

Ramzan, Faiqah; Asmat, Andleeb

2018-06-18

Background Protein C is a vitamin K dependent plasma zymogen. It prevents clotting by inhibiting clotting by inactivating factor V and factor VIII. Protein C activation pathway involves three steps: (i) Activation of protein C; (ii) Inhibition of coagulation through inactivating factor V and VIII by activated protein C and (iii) Inhibition of activated protein C by plasma protease inhibitors specific for this enzyme. Proteinases converts the zymogen Protein C (PC) of vertebrates into activated PC, which has been detected in several snake venoms. Most PC activators have been purified from venom of snake species belonging to the genera of the Agkistrodon complex. Unlike the physiological thrombin-catalyzed PC activation reaction which requires thrombomodulin as a cofactor, most snake venom activators directly convert the zymogen PC into the catalytically active form which can easily be determined by means of coagulation or chromogenic substrate techniques. Conclusion The fast-acting PC activator Protac® from Agkistrodon contortrix (southern copperhead snake) venom has been found to have broad application in diagnostic practice for the determination of disorders in the PC pathway. Recently, screening assays for the PC pathway have been introduced, based on the observation that the PC pathway is probably the most important physiological barrier against thrombosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Tuning the morphology of self-assisted GaP nanowires

NASA Astrophysics Data System (ADS)

Leshchenko, E. D.; Kuyanov, P.; LaPierre, R. R.; Dubrovskii, V. G.

2018-06-01

Patterned arrays of self-assisted GaP nanowires (NWs) were grown on a Si substrate by gas source molecular beam epitaxy using various V/III flux ratios from 1–6, and various pitches from 360–1000 nm. As the V/III flux ratio was increased from 1–6, the NWs showed a change in morphology from outward tapering to straight, and eventually to inward tapering. The morphologies of the self-assisted GaP NWs are well described by a simple kinetic equation for the NW radius versus the position along the NW axis. The most important growth parameter that governs the NW morphology is the V/III flux ratio. Sharpened NWs with a stable radius equal to only 12 nm at a V/III flux of 6 were achieved, demonstrating their suitability for the insertion of quantum dots.

Tuning the morphology of self-assisted GaP nanowires.

PubMed

Leshchenko, E D; Kuyanov, P; LaPierre, R R; Dubrovskii, V G

2018-06-01

Patterned arrays of self-assisted GaP nanowires (NWs) were grown on a Si substrate by gas source molecular beam epitaxy using various V/III flux ratios from 1-6, and various pitches from 360-1000 nm. As the V/III flux ratio was increased from 1-6, the NWs showed a change in morphology from outward tapering to straight, and eventually to inward tapering. The morphologies of the self-assisted GaP NWs are well described by a simple kinetic equation for the NW radius versus the position along the NW axis. The most important growth parameter that governs the NW morphology is the V/III flux ratio. Sharpened NWs with a stable radius equal to only 12 nm at a V/III flux of 6 were achieved, demonstrating their suitability for the insertion of quantum dots.

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

NASA Astrophysics Data System (ADS)

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

2017-10-01

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

Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex.

PubMed

Chang, Weizhong; Barnes, Aileen M; Cabral, Wayne A; Bodurtha, Joann N; Marini, Joan C

2010-01-15

Null mutations in cartilage-associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) cause types VII and VIII OI, respectively, two novel recessive forms of osteogenesis imperfecta (OI) with severe to lethal bone dysplasia and overmodification of the type I collagen helical region. CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue of alpha1(I) and alpha1(II) collagen chains. We investigated the interaction of complex components in fibroblasts from types VII and VIII OI patients. Both CRTAP and P3H1 are absent or reduced on western blots and by immunofluorescence microscopy in cells containing null mutations in either gene. Levels of LEPRE1 or CRTAP transcripts, however, are normal in CRTAP- or LEPRE1-null cells, respectively. Stable transfection of a CRTAP or LEPRE1 expression construct into cells with null mutations for the transfected cDNA restored both CRTAP and P3H1 protein levels. Normalization of collagen helical modification in transfected CRTAP-null cells demonstrated that the restored proteins functioned effectively as a complex. These data indicate that CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex. CyPB levels were unaffected by mutations in either CRTAP or LEPRE1. Proteasomal inhibitors partially rescue P3H1 protein in CRTAP-null cells. In LEPRE1-null cells, secretion of CRTAP is increased compared with control cells and accounts for 15-20% of the decreased CRTAP detected in cells. Thus, mutual stabilization of P3H1 and CRTAP in the ER collagen modification complex is an underlying mechanism for the overlapping phenotype of types VII and VIII OI.

Haemostatic profile of healthy premature small for gestational age neonates.

PubMed

Mitsiakos, George; Giougi, Evaggelia; Chatziioannidis, Ilias; Karagianni, Paraskevi; Papadakis, Emmanouil; Tsakalidis, Christos; Papaioannou, Georgia; Malindretos, Pavlos; Nikolaidis, Nikolaos

2010-08-01

The pathogenetic profile of premature Small for Gestational Age (SGA) neonates is strongly related to their haemostatic equilibrium, which is inadequately understood. To evaluate coagulation and fibrinolysis in premature SGA neonates before intervening with Vitamin K administration. We performed a comparison of coagulation, natural inhibitors and fibrinolysis between SGA and Appropriate for Gestational Age (AGA) infants born prematurely [gestational age (G.A.) <37 weeks]. Study population consisted of 139 preterm newborns, 68 of whom were SGA (25 males and 43 females), while 71 were AGA (37 males and 34 females) that consisted the control group. Blood samples were obtained within 30 minutes following birth and before the administration of vitamin K. Investigation included: PT, INR, APTT, fibrinogen, coagulation factors II, V, VII, VIII, IX, X, XI, XII, von Willebrand factor, protein C and free protein S, antithrombin (AT), APCR, tPA and PAI-1. The independent t-test and the Mann-Whitney U test were used to compare the differences between the values of haemostatic parameters. Premature SGA infants presented significantly lower levels of fibrinogen (p<0.029) and higher levels of VIIIc factor, APCR, tPA and PAI-1 (p<0.041, 0.017, 0.021 and 0.019 respectively). The two groups had similar demographic characteristics (except from birth weight), without significant differences in the values of other haemostatic parameters. Despite the statistically significant differentiation in the levels of fibrinogen, VIIIc factor, APCR, tPA and PAI-1, the rest of haemostatic parameters have similar values between SGA and AGA preterms. (c) 2010 Elsevier Ltd. All rights reserved.

A cross-sectional analysis of cardiovascular disease in the hemophilia population

PubMed Central

Sood, Suman L.; Cheng, Dunlei; Ragni, Margaret; Kessler, Craig M.; Quon, Doris; Shapiro, Amy D.; Key, Nigel S.; Manco-Johnson, Marilyn J.; Cuker, Adam; Kempton, Christine; Wang, Tzu-Fei; Eyster, M. Elaine; Kuriakose, Philip; von Drygalski, Annette; Gill, Joan Cox; Wheeler, Allison; Kouides, Peter; Escobar, Miguel A.; Leissinger, Cindy; Galdzicka, Sarah; Corson, Marshall; Watson, Crystal

2018-01-01

Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population. PMID:29895623

[Plasma fractionation in the world: current status].

PubMed

Burnouf, T

2007-05-01

From 22 to 25 million liters of plasma are fractionated yearly in about 70 fractionation plants, either private or government-owned, mainly located in industrialized countries, and with a capacity ranging from 50000 to three million liters. In an increasingly global environment, the plasma industry has recently gone through a major consolidation phase that has seen mergers and acquisitions, and has led to the closure of a number of small plants in Europe. Currently, some fifteen countries are involved into contract plasma fractionation programs to ensure a supply of plasma-derived medicinal products. The majority of the plasma for fractionation is obtained by automated plasmapheresis, the remaining (recovered plasma) being prepared from whole blood as a by-product of red cell production. Plasma for fractionation should be produced, and controlled following well established procedures to meet the strict quality requirements set by regulatory authorities and fractionators. The plasma fractionation technology still relies heavily on the cold ethanol fractionation process, but has been improved by the introduction of modern chromatographic purification methods, and efficient viral inactivation and removal treatments, ensuring quality and safety to a large portfolio of fractionated plasma products. The safety of these products with regards to the risk of transmission of variant Creutzfeldt-Jakob disease seems to be provided, based on current scientific data, by extensive removal of the infectious agent during certain fractionation steps. The leading plasma product is now the intravenous immunoglobulin G, which has replaced factor VIII and albumin in this role. The supply of plasma products (most specifically coagulation products and immunoglobulin) at an affordable price and in sufficient quantity remains an issue; the problem is particularly acute in developing countries, as the switch to recombinant factor VIII in rich countries has not solved the supply issue and has even led to an increase of the mean price of plasma-derived factor VIII to the developing world. In the last few years, the plasma fractionation industry has improved greatly, and should remain essential in the years to come for the procurement of many essential medicines.

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.

A Rare Presentation of Cranial Polyneuropathy Without Rash Caused by Varicella Zoster Virus

PubMed Central

Tecellioglu, Mehmet; Kamisli, Suat; Erbay, Mehmet Fatih; Kamisli, Ozden; Ozcan, Cemal

2017-01-01

Introduction: Varicella Zoster Virus (VZV) is associated with many disorders of the central and peripheral nervous systems including neuralgia, meningitis, meningoencephalitis, cerebellitis, vasculopathy, myelopathy, Ramsay-Hunt syndrome, and polyneuritis cranialis. Cranial nerves V, VI, VII, VIII, IX, X, XI, and/or XII may be affected. The neurological disorders caused by VZV usually present with rash, but may rarely present without rash. Case report: We herein present a case of polyneuritis cranialis without rash caused by VZV affecting cranial nerves VII, VIII, IX, and X. After excluding other causes of the condition, we diagnosed VZV infection based on VZV DNA in the CSF and an elevated anti-VZV IgG level in serum. The patient responded well to antiviral therapy. Conclusion: VZV infection should be kept in mind during the differential diagnosis of polyneuritis cranialis; it is important to note that VZV re-activation may occur without rash. PMID:28974853

Antineoplastic And Antiviral Properties Of Merocyanine 540

NASA Astrophysics Data System (ADS)

Sieber, Fritz

1989-03-01

Simultaneous exposure to the lipophilic photosensitizer, merocyanine 540, and light in the presence of serum (or certain serum components) and oxygen kills leukemia cells, lymphoma cells, neuroblastoma cells, cell-free enveloped viruses, cell-associated enveloped viruses, and virus-infected cells. The same treatment spares pluripotent hematopoietic stem cells, mature erythrocytes, factor VIII, von Willebrand factor, and probably other blood components. Merocyanine 540-mediated photosensitization is now being evaluated clinically as a means to eliminate residual tumor cells from autologous remission bone marrow grafts and preclinically as a means to inactivate pathogenic viruses in blood products.

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

PubMed Central

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

1988-01-01

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

KSC-08pd1343

NASA Image and Video Library

2008-05-12

CAPE CANAVERAL, Fla. -- A representative of the 301st Rescue Squadron familiarizes participants in the Mode VIII exercise with the HH-60G helicopter that will play a part. The Mode VIII is being conducted at Patrick Air Force Base, Fla. In support of, and with logistical support from, NASA, USSTRATCOM is hosting a major exercise involving Department of Defense, Department of Homeland Security, search and rescue (SAR) forces, including the 45th Space Wing at Patrick Air Force Base, which support space shuttle astronaut bailout contingency operations, known as Mode VIII. This exercise tests SAR capabilities to locate, recover and provide medical treatment for astronauts following a space shuttle launch phase open-ocean bailout. Participants include members of the U.S. Navy, U.S. Coast Guard, U.S. Air Force, and NASA's Kennedy Space Center and Johnson Space Center. This will be the 15th Mode VIII exercise conducted in the past 20 years. Photo credit: NASA/Kim Shiflett

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

NASA Astrophysics Data System (ADS)

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

2018-04-01

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

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

PubMed

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

2004-09-01

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

An economic model of haemophilia in Mexico.

PubMed

Martínez-Murillo, C; Quintana, S; Ambriz, R; Benitez, H; Berges, A; Collazo, J; Esparza, A; Pompa, T; Taboada, C; Zavala, S; Larochelle, M R; Bentkover, J D

2004-01-01

A model was developed to assess the lifetime costs and outcomes associated with haemophilia in Mexico. A retrospective chart review of 182 type A haemophiliacs was conducted for patients aged 0-34 years receiving one of three treatments: (i) cryoprecipitate at clinic; (ii) concentrate at home; or (iii) concentrate at clinic. Patients treated at home experienced 30% less joint damage, used 13-54% less factor VIII, had four times fewer clinic visits, and utilized half as many hospital days than those treated at a clinic. For cryoprecipitate at clinic patients, the annual incidence rates of HCV and HIV were calculated to be 3.6% and 1.4% respectively. The life expectancy for patients receiving cryoprecipitate and those receiving concentrate was estimated to be 49 years and 69 years respectively, with 58% of cryoprecipitate patients predicted to die of AIDS before age 69. Across the lifespan, the average annual cost of care was US$11,677 (MN$110,464) for cryoprecipitate at clinic patients, US$10,104 (M$95,580) for concentrate at home patients and US$18,819 (MN$178,027) for concentrate at clinic patients. Using a 5% discount rate, the incremental lifetime cost per year of life added for treatment with concentrate at home compared with cryoprecipitate at a clinic was US$738 (MN$6981). Rank order stability analysis demonstrated that the model was most sensitive to the cost of fVIII. These results indicate that treatment with concentrate at home compared with cryoprecipitate at a clinic substantially improves clinical outcomes at reduced annual cost levels.

75 FR 65696 - Cost-of-Living Increase and Other Determinations for 2011

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-26

... amount under title VIII of the Act for certain World War II veterans will remain $505.50 in 2011; (3) The... their 2010 levels: (1) The maximum Federal Supplemental Security Income (SSI) monthly benefit amounts for 2011, under title XVI of the Act, will remain $674 for an eligible individual, $1,011 for an...

Careers (A Course of Study). Unit VIII: Budgeting--What to Do With Your Paycheck.

ERIC Educational Resources Information Center

Turley, Kay

Designed to enable special needs students to understand the basics of personal income management, normal living expenses, banking, and comparison shopping, this set of activities on budgeting is the eighth unit in a nine-unit secondary level career course intended to provide handicapped students with the knowledge and tools necessary to succeed in…

Miami-Dade Community College 1984 Institutional Self-Study. Volume VIII: Medical Center Campus Studies.

ERIC Educational Resources Information Center

Miami-Dade Community Coll., FL.

Part of a systematic, in-depth assessment of Miami-Dade Community College's (MDCC's) educational programs, student support systems, and selected campus-level activities, this volume of the college's institutional self-study report examines the impact and effectiveness of the Medical Center Campus. The report contains the results of a campus study…

Water Quality Instructional Resources Information System (IRIS): A Compilation of Abstracts to Water Quality and Water Resources Materials. Supplement VIII.

ERIC Educational Resources Information Center

Ohio State Univ., Columbus, OH. Information Reference Center for Science, Mathematics, and Environmental Education.

Compiled are abstracts and indexes to selected print and non-print materials; related to wastewater treatment and water quality education and instruction, as well as materials related to pesticides, hazardous wastes, and public participation. Sources of abstracted/indexed materials include all levels of government, private concerns, and…

Ultrasonic Inspection and Fatigue Evaluation of Critical Pore Size in Welds.

DTIC Science & Technology

1981-09-01

Boiler and Pressure Vessel Code ) 20...Five porosity levels were produced that parallelled ASME boiler and pressure vessel code specification (Section VIII). Appendix IV of the pressure...Figure 2 shows porosity charts (ASME Boiler and Pressure Vessel Code ) which classify and designate the number and size of pores in any six inch length

7 CFR 1901.203 - Title VIII of the Civil Rights Act of 1968.

Code of Federal Regulations, 2014 CFR

2014-01-01

... background of the dwelling or landlord such as “White private home,” or “all Black subdivision,” may not be... individuals of similar income levels in the housing market area have housing choices available to them..., including minority publications and other minority outlets available in the housing market area. As part of...

7 CFR 1901.203 - Title VIII of the Civil Rights Act of 1968.

Code of Federal Regulations, 2010 CFR

2010-01-01

... background of the dwelling or landlord such as “White private home,” or “all Black subdivision,” may not be... individuals of similar income levels in the housing market area have housing choices available to them..., including minority publications and other minority outlets available in the housing market area. As part of...

7 CFR 1901.203 - Title VIII of the Civil Rights Act of 1968.

Code of Federal Regulations, 2011 CFR

2011-01-01

... background of the dwelling or landlord such as “White private home,” or “all Black subdivision,” may not be... individuals of similar income levels in the housing market area have housing choices available to them..., including minority publications and other minority outlets available in the housing market area. As part of...

7 CFR 1901.203 - Title VIII of the Civil Rights Act of 1968.

Code of Federal Regulations, 2013 CFR

2013-01-01

... background of the dwelling or landlord such as “White private home,” or “all Black subdivision,” may not be... individuals of similar income levels in the housing market area have housing choices available to them..., including minority publications and other minority outlets available in the housing market area. As part of...

7 CFR 1901.203 - Title VIII of the Civil Rights Act of 1968.

Code of Federal Regulations, 2012 CFR

2012-01-01

... background of the dwelling or landlord such as “White private home,” or “all Black subdivision,” may not be... individuals of similar income levels in the housing market area have housing choices available to them..., including minority publications and other minority outlets available in the housing market area. As part of...

78 FR 37667 - Federal Acquisition Regulation; Federal Acquisition Circular 2005-67; Introduction

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-21

...-010 Morgan. Women-owned Small Business Concerns (Interim). VIII Deletion of Report 2013-008 Davis. to... Contracting Integrity, an internal DoD panel, consists of senior-level DoD officials from across DoD working... contractor performance. This final rule is not required to be published for public comment because it only...

78 FR 37698 - Federal Acquisition Regulation; Federal Acquisition Circular 2005-67; Small Entity Compliance Guide

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-21

............ Contracting with 2013-010 Morgan. Women-owned Small Business Concerns (Interim). VIII Deletion of Report 2013... panel, consists of senior-level DoD officials from across DoD working to review progress made by DoD to... ensure that CORs understand their duties and responsibilities to survey contractor performance. This...

Dose-response effects of Lepidium meyenii (Maca) aqueous extract on testicular function and weight of different organs in adult rats.

PubMed

Chung, Francisco; Rubio, Julio; Gonzales, Carla; Gasco, Manuel; Gonzales, Gustavo F

2005-04-08

Lepidium meyenii (Brassicaceae) known as Maca grows exclusively between 4000 and 4500 m over the sea level in the Peruvian central Andes. The dried hypocotyls of Maca are traditionally used as food and for its supposed fertility-enhancing properties. A dose-response study was performed to determine the effect of 7 days oral administration of an aqueous lyophilized extract of Maca at 0.01-5 g/kg (corresponding to 0.022-11 g dry hypocotyls of Maca/kg) on body and different organ weights, stages of the seminiferous tubules, epididymal sperm count and motility, and serum testosterone and estradiol levels in rats. In doses up to 5 g extract/kg, no toxicity was observed. Almost all organ weights were similar in controls and in the Maca extract-treated groups. Seminal vesicles weight was significantly reduced at 0.01 and 0.10 g extract/kg. Maca increased in length of stages VII-VIII of the seminiferous tubules in a dose-response fashion, with highest response at 1.0 g/kg, while caput/corpus epididymal sperm count increased at the 1.0 g dose. Cauda epididymal sperm count, sperm motility, and serum estradiol level were not affected at any of the doses studied. Serum testosterone was lower at 0.10 g extract/kg. Low-seminal vesicle weights correlated with low-serum testosterone levels (R2=0.33; P<0.0001) and low-testosterone/estradiol ratio (R2=0.35; P<0.0001). Increase in epididymal sperm count was related to lengths of stages VII-VIII. Highest effect on stages VII-VIII of the seminiferous tubules was observed at 1.0 g Maca aqueous extract/kg. The present study demonstrated that Maca extract in doses up to 5 g/kg (equivalent to the intake of 770 g hypocotyls in a man of 70 kg) was safe and that higher effect on reproductive parameters was elicited with a dose of 1 g extract/kg corresponding to 2.2 g dry Maca hypocotyls/kg.

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

Code of Federal Regulations, 2012 CFR

2012-04-01

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

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

Code of Federal Regulations, 2013 CFR

2013-04-01

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

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

Code of Federal Regulations, 2010 CFR

2010-04-01

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

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

Code of Federal Regulations, 2014 CFR

2014-04-01

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

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

Code of Federal Regulations, 2011 CFR

2011-04-01

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

Radiative rates for E1, E2, M1, and M2 transitions in the Br-like ions Sr IV, Y V, Zr VI, Nb VII, and Mo VIII

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

Aggarwal, Kanti M., E-mail: K.Aggarwal@qub.ac.uk; Keenan, Francis P.

Energies and lifetimes are reported for the lowest 375 levels of five Br-like ions, namely Sr IV, Y V, Zr VI, Nb VII, and Mo VIII, mostly belonging to the 4s{sup 2}4p{sup 5}, 4s{sup 2}4p{sup 4}4ℓ, 4s4p{sup 6}, 4s{sup 2}4p{sup 4}5ℓ, 4s{sup 2}4p{sup 3}4d{sup 2}, 4s4p{sup 5}4ℓ, and 4s4p{sup 5}5ℓ configurations. Extensive configuration interaction has been included and the general-purpose relativistic atomic structure package (GRASP) has been adopted for the calculations. Additionally, radiative rates are listed among these levels for all E1, E2, M1, and M2 transitions. From a comparison with the measurements, the majority of our energy levels are assessed to be accurate tomore » better than 2%, although discrepancies between theory and experiment for a few are up to 6%. An accuracy assessment of the calculated radiative rates (and lifetimes) is more difficult, because no prior results exist for these ions.« less

An Investigation of the Interatomic Bonding Characteristics of a Ti - 51at.% Al Alloy by X-Ray Diffraction

DTIC Science & Technology

1991-06-01

GROUP SUBGROUP X-ray Diffraction, XRD, TiAI, titanium , aluminum, bonding characteristics, titanium aluminides , Debye-Waller temperature factor...XRD Powder Particles (575X) .............. 47 viii I. INTRODUCTION Titanium aluminides are recognized for their high specific strength, particularly at...bonding characteristics of binary titanium aluminides . Upon the introduction of a third element to the system, a rearrangement of the valence

The Ethnic Factor in the Soviet Armed Forces. The Muslim Dimension

DTIC Science & Technology

1991-01-01

Muslim conscripts into effective soldiers. The types of problems that a Muslim conscript presents for the Soviet military can be narrowed to two categories ... categories : ability and reliability. ETHNICITY AND DEMOGRAPHICS The major Soviet Muslim ethnic groups are creations of the Soviet regime, dating back to...avoid such embarrassments in the future. viii SOVIET MILITARY REFORM The predominantly coercive type of compliance previously used by the Soviet military

Immunohistochemical characterization of hemangiopericytomas and other spindle cell tumors in the dog.

PubMed

Pérez, J; Bautista, M J; Rollón, E; de Lara, F C; Carrasco, L; Martin de las Mulas, J

1996-07-01

The immunohistochemical expression of muscle actin has been studied in 45 canine hemangiopericytomas (CHP) using a monoclonal antibody (HHF35) and formalin-fixed, paraffin-embedded specimens. The distribution of vimentin, desmin, cytokeratins, lysozyme, factor VIII-related antigen, S-100 protein, and glial fibrillary acidic protein was studied both in CHP and in some canine soft-tissue neoplasms (seven fibrosarcomas, seven benign schwannomas, seven benign fibrous histiocytomas, and six leiomyosarcomas) used as controls for differential diagnosis. All CHP and control tumors expressed vimentin. Twenty-three CHP expressed muscle actin, whereas all control tumors analyzed were muscle actin-negative, with the exception of leiomyosarcomas. Among muscle actin- and vimentin-positive CHP, one case could be reclassified as leiomyosarcoma because it was desmin-positive, two cases expressed lysozyme, and nine cases expressed S-100 protein. Among muscle actin-negative and vimentin-positive CHP, seven expressed S-100 protein. In addition, S-100 protein was detected in five schwannomas. All CHP and control tumors analyzed were negative for cytokeratins, factor VIII-related antigen, and glial fibrillary acidic protein. Our results support the hypothesis of a pericytic origin of CHP, and suggest that muscle actin, desmin, vimentin, and lysozyme could be useful for the differential diagnosis of canine spindle cell tumors, but not all these neoplasms can be identified with these tumor tissue markers.

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

PubMed

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

2016-03-01

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

Traumatic Hemarthrosis of the Knee Secondary to Hemophilia A in a Collegiate Soccer Player: A Case Report

PubMed Central

Fiala, Kelly A.; Hoffmann, Sandra J.; Ritenour, Donna M.

2002-01-01

Objective: To present the case of a collegiate soccer player who suffered from a traumatic knee hemarthrosis secondary to hemophilia A. This case presents an opportunity to discuss the participation status of athletes with hemophilia. Background: Hemophilia is a hereditary blood disease characterized by impaired coagulability of the blood. Hemophilia A is the most common of the severe, inherited bleeding disorders. This type, also called classic hemophilia, is due to a deficiency of clotting factor VIII. The athlete with hemophilia A reported pain and loss of function of his knee during a soccer game despite the absence of injury. Differential Diagnosis: Anterior cruciate ligament tear, intra-articular fracture, meniscus tear, capsular tear, hemarthrosis. Treatment: After the injury, the athlete was admitted to the hospital, where his knee joint was aspirated and he was infused with factor VIII. Later, he participated in traditional knee rehabilitation and was returned to play at the discretion of the orthopaedist and the hematologist. Uniqueness: In past participation guidelines, individuals with bleeding disorders were disqualified from athletic participation; however, with advances in medical care, these individuals may be permitted to participate in accordance with the law. Conclusions: Individuals with hemophilia participate in athletics; therefore, team physicians and athletic trainers must be prepared to care for these individuals. PMID:12937588

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

PubMed

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

2017-07-01

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

Lonoctocog Alfa: A Review in Haemophilia A.

PubMed

Al-Salama, Zaina T; Scott, Lesley J

2017-10-01

Lonoctocog alfa (rVIII-SingleChain; Afstyla ® ) is a novel single-chain recombinant factor VIII (FVIII) molecule, with a truncated B-domain and the heavy and light chains covalently linked to form a stable and homogenous drug that binds with high affinity to von Willebrand factor (VWF). Intravenous lonoctocog alfa is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in several countries worldwide. In two pivotal, multicentre trials, lonoctocog alfa was effective in the treatment of bleeding episodes and as prophylaxis, including for perioperative management in adults, adolescents and children. In terms of haemostatic efficacy in controlling bleeding episodes, overall treatment and investigator-assessed success rates were high across all age groups, with the majority of these bleeds controlled with a single injection of lonoctocog alfa. Low median spontaneous, overall and traumatic annualized bleeding rates were evident with prophylactic lonoctocog alfa regimens in both trials. Lonoctocog alfa was generally well-tolerated, with very low rates of injection-site reactions. No previously treated patient experienced an anaphylactic reaction or developed an inhibitor. In conclusion, lonoctocog alfa is an effective and generally well-tolerated alternative to conventional FVIII products for the treatment and prophylaxis of bleeding, including in the surgical setting, in adults, adolescents and children with haemophilia A.

Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

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

Zawawi, M.S.F.; Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005; Dharmapatni, A.A.S.S.K.

2012-10-19

Highlights: Black-Right-Pointing-Pointer Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. Black-Right-Pointing-Pointer Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. Black-Right-Pointing-Pointer FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway inmore » osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcR{gamma}) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin ({beta}3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p < 0.05) reduced the expression of NFATc1, CathK, OSCAR, FcR{gamma}, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p < 0.05) decreased CathK, OSCAR, FcR{gamma}, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.« less

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

PubMed

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

2012-05-22

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

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

PubMed Central

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

2013-01-01

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

The Anopheles (Anopheles) Crucians Subgroup in the United States (Diptera: Culicidae)

DTIC Science & Technology

1976-01-01

without pale spots except at tip; and LA with 3 dark scaled areas (basally, medially, and apically). The pupa has seta * An illustration is...Beadle, 19, Joplin, 13-1X-1942, A. B. Gurney, 1G. New Jersey: Nixon, 23-VIII-1966, P. H. Thompson, 29; 26-VIII-1966, P, H. Thomp- son , 29; 3P-VIII-1966...IV-1943, La Roth, 1G; Z-IV- 1944, L. Roth, 2WL. Myrtle Beach, 31-x-1943, PWL; 27-VI-1944, La Roth, PWL; lO-VII-1944, L. Roth, lWL; 27-VII-1944, 1WL

A general insert label for peptide display on chimeric filamentous bacteriophages.

PubMed

Kaplan, Gilad; Gershoni, Jonathan M

2012-01-01

The foreign insert intended to be displayed via recombinant phage proteins can have a negative effect on protein expression and phage assembly. A typical example is the case of display of peptides longer than 6 amino acid residues on the major coat protein, protein VIII of the filamentous bacteriophages M13 and fd. A solution to this problem has been the use of "two-gene systems" generating chimeric phages that concomitantly express wild-type protein VIII along with recombinant protein VIII. Although the two-gene systems are much more permissive in regard to insert length and composition, some cases can still adversely affect phage assembly. Although these phages genotypically contain the desired DNA of the insert, they appear to be phenotypically wild type. To avoid false-negative results when using chimeric phages in binding studies, it is necessary to confirm that the observed lack of phage recognition is not due to faulty assembly and display of the intended insert. Here we describe a strategy for generating antibodies that specifically recognize recombinant protein VIII regardless of the nature of its foreign insert. These antibodies can be used as a general monitor of the display of recombinant protein VIII into phage particles. Copyright © 2011 Elsevier Inc. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2018-04-01

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

Omental implantation of BOECs in hemophilia dogs results in circulating FVIII antigen and a complex immune response.

PubMed

Ozelo, Margareth C; Vidal, Barbara; Brown, Christine; Notley, Colleen; Hegadorn, Carol; Webster, Sandra; Harpell, Lori; Ahlin, James; Winterborn, Andrew; Handforth, Janine; Arruda, Valder R; Hough, Christine; Lillicrap, David

2014-06-26

Ex vivo gene therapy strategies avoid systemic delivery of viruses thereby mitigating the risk of vector-associated immunogenicity. Previously, we delivered autologous factor VIII (FVIII)-expressing blood outgrowth endothelial cells (BOECs) to hemophilia A mice and showed that these cells remained sequestered within the implanted matrix and provided therapeutic levels of FVIII. Prior to translating this strategy into the canine (c) model of hemophilia A, we increased cFVIII transgene expression by at least 100-fold with the use of the elongation factor 1 alpha (EF1α) promoter and a strong endothelial enhancer element. BOECs isolated from hemophilia A dogs transduced with this lentiviral vector express levels of cFVIII ranging between 1.0 and 1.5 U/mL per 10(6) cells over 24 hours. Autologous BOECs have been implanted into the omentum of 2 normal and 3 hemophilia A dogs. These implanted cells formed new vessels in the omentum. All 3 hemophilia A dogs treated with FVIII-expressing autologous BOECs developed anti-FVIII immunoglobulin G2 antibodies, but in only 2 of the dogs were these antibodies inhibitory. FVIII antigen levels >40% in the absence of FVIII coagulant function were detected in the circulation for up to a year after a single gene therapy treatment, indicating prolonged cellular viability and synthesis of FVIII. © 2014 by The American Society of Hematology.

Budget Impact Analysis of Prolonged Half-Life Recombinant FVIII Therapy for Hemophilia in the United States.

PubMed

McMullen, Suzanne; Buckley, Brieana; Hall, Eric; Kendter, Jon; Johnston, Karissa

2017-01-01

Hemophilia A is a factor VIII deficiency, associated with spontaneous, recurrent bleeding episodes. This may lead to comorbidities such as arthropathy and joint replacement, which contribute to morbidity and increased health care expenditure. Recombinant factor VIII Fc fusion protein (rFVIIIFc), a prolonged half-life factor therapy, requires fewer infusions, resulting in reduced treatment burden. Use a budget impact analysis to assess the potential economic impact of introducing rFVIIIFc to a formulary from the perspective of a private payer in the United States. The budget impact model was developed to estimate the potential economic impact of adding rFVIIIFc to a private payer formulary across a 2-year time period. The eligible patient population consisted of inhibitor-free adults with severe hemophilia A, receiving recombinant-based episodic or prophylaxis treatment regimens. Patients were assumed to switch from conventional recombinant factor treatment to rFVIIIFc. Only medication costs were included in the model. The introduction of rFVIIIFc is estimated to have a budget impact of 1.4% ($0.12 per member per month) across 2 years for a private payer population of 1,000,000 (estimated 19.7 individuals receiving treatment for hemophilia A). The introduction of rFVIIIFc is estimated to prevent 124 bleeds across 2 years at a cost of $1891 per bleed avoided. Hemophilia A is a rare disease with a low prevalence; therefore, the overall cost to society of introducing rFVIIIFc is small. Considerations for comprehensively assessing the budget impact of introducing rFVIIIFc should include episodic and prophylaxis regimens, bleed avoidance, and annual factor consumption required under alternative scenarios. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

77 FR 13317 - Notice Announcing Filing Priority for Preliminary Permit Applications: Lock+ Hydro Friends Fund...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-06

... Applications: Lock+ Hydro Friends Fund VIII; FFP Project 92, LLC; Riverbank Hydro No. 24, LLC On February 28.... 14276-000. 2. Riverbank Hydro No. 24, LLC: Project No. 14280-000. 3. Lock+ Hydro Friends Fund VIII...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-16

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

Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

PubMed

Zeelenberg, Ingrid S; Ostrowski, Matias; Krumeich, Sophie; Bobrie, Angélique; Jancic, Carolina; Boissonnas, Alexandre; Delcayre, Alain; Le Pecq, Jean-Bernard; Combadière, Béhazine; Amigorena, Sebastian; Théry, Clotilde

2008-02-15

Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic cells). The modes of tumor antigen capture by dendritic cells in vivo remain unclear. Here we examine the immunogenicity of the same model antigen secreted by live tumors either in association with membrane vesicles (exosomes) or as a soluble protein. We have artificially addressed the antigen to secreted vesicles by coupling it to the factor VIII-like C1C2 domain of milk fat globule epidermal growth factor-factor VIII (MFG-E8)/lactadherin. We show that murine fibrosarcoma tumor cells that secrete vesicle-bound antigen grow slower than tumors that secrete soluble antigen in immunocompetent, but not in immunodeficient, host mice. This growth difference is due to the induction of a more potent antigen-specific antitumor immune response in vivo by the vesicle-bound than by the soluble antigen. Finally, in vivo secretion of the vesicle-bound antigen either by tumors or by vaccination with naked DNA protects against soluble antigen-secreting tumors. We conclude that the mode of secretion can determine the immunogenicity of tumor antigens and that manipulation of the mode of antigen secretion may be used to optimize antitumor vaccination protocols.

Vedolizumab Treatment for Ulcerative Colitis in an Elderly Multimorbid Patient with Hemophilia A.

PubMed

Schäffler, Holger; Huth, Astrid; Lamprecht, Georg; Anders, Olaf

2017-01-01

The treatment of inflammatory bowel diseases (IBD) can be challenging, especially in elderly multimorbid patients. Since incidence and prevalence rates of IBD are rising steadily, treatment of older patients with relevant and also rare comorbidities will be of increasing relevancy for caregivers. Here we report on a 74-year-old multimorbid patient with severe ulcerative colitis (UC) and hemophilia A. Because of the chronic active disease, therapy with a tumor necrosis factor-α inhibitor was started. He suffered from a severe infectious complication (pneumonia) under therapy with infliximab. The therapy was changed to vedolizumab, with which the patient stayed in long-term clinical and endoscopic remission. Because the patient had a non-ST-segment elevation myocardial infarction in April 2016, he received dual platelet inhibitor therapy with aspirin and clopidogrel. Because of consecutive aspirin intolerance, the therapy was changed to clopidogrel monotherapy. Although the UC was treated appropriately with vedolizumab and the patient was in endoscopic mucosal remission, recurrent bleeding episodes from multiple inflammatory pseudopolyps occurred. The bleeding episodes resolved quickly after immediate treatment with factor VIII (Kogenate®). In conclusion, we describe the first patient in the literature with UC and hemophilia A who stayed in long-term remission under therapy with vedolizumab. From our point of view, vedolizumab can be safely administered in the setting of UC and hemophilia A. Antiplatelet drugs which inhibit primary hemostasis must be used with caution in this setting. Bleeding episodes can be treated safely and effectively with factor VIII (Kogenate®).

Bleeding disorders in pregnant patients with rheumatic diseases.

PubMed

Rick, M E

1989-05-01

Although the bleeding disorders that occur in patients with rheumatic diseases are not different during pregnancy than at other times, their diagnosis and management are often different during pregnancy. In idiopathic thrombocytopenic purpura, for instance, antiplatelet antibodies may cross the placenta and cause life-threatening thrombocytopenia in the fetus while the mother is asymptomatic. Management of this disease has changed significantly in the past 5 years with the use of intravenous gammaglobulin which appears to lessen the degree of fetal as well as maternal thrombocytopenia when administered during the peripartum period. The utilization of plasmapheresis and plasma infusions for patients with thrombotic thrombocytopenic purpura has salvaged both the mother and the fetus in a disease which was fatal in more than 60 per cent of patients prior to their use. The outcome of pregnancy in this patient population has markedly improved with this treatment. The stimulus for the production of factor VIII inhibitors in the postpartum period is still not understood, but guidelines for management have changed, with the increased likelihood of decreasing the antibody and inducing tolerance with regimens including factor VIII, immunosuppressive agents and intravenous gammaglobulin in those patients who require treatment. The diagnosis of von Willebrand's disease during pregnancy is difficult because of the physiologic increase in von Willebrand factor during pregnancy; in this instance family studies may help in the diagnosis of this relatively common, autosomal dominant inherited disorder. Management now includes treatment with desmopressin as well as cryoprecipitate replacement therapy.

VIII Olimpíada Brasileira de Astronomia e Astronáutica

NASA Astrophysics Data System (ADS)

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

2007-07-01

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

Comparative mitochondrial and chloroplast genomics of a genetically distinct form of Sargassum contributing to recent "Golden Tides" in the Western Atlantic.

PubMed

Amaral-Zettler, Linda A; Dragone, Nicholas B; Schell, Jeffrey; Slikas, Beth; Murphy, Leslie G; Morrall, Clare E; Zettler, Erik R

2017-01-01

Over the past 5 years, massive accumulations of holopelagic species of the brown macroalga Sargassum in coastal areas of the Caribbean have created "golden tides" that threaten local biodiversity and trigger economic losses associated with beach deterioration and impact on fisheries and tourism. In 2015, the first report identifying the cause of these extreme events implicated a rare form of the holopelagic species Sargassum natans (form VIII ). However, since the first mention of S. natans VIII in the 1930s, based solely on morphological characters, no molecular data have confirmed this identification. We generated full-length mitogenomes and partial chloroplast genomes of all representative holopelagic Sargassum species, S. fluitans III and S. natans I alongside the putatively rare S. natans VIII , to demonstrate small but consistent differences between S. natans I and VIII (7 bp differences out of the 34,727). Our comparative analyses also revealed that both S. natans I and S. natans VIII share a very close phylogenetic relationship with S. fluitans III (94- and 96-bp differences of 34,727). We designed novel primers that amplified regions of the cox2 and cox3 marker genes with consistent polymorphic sites that enabled differentiation between the two S. natans forms ( I and VIII ) from each other and both from S. fluitans III in over 150 Sargassum samples including those from the 2014 golden tide event. Despite remarkable gene synteny and sequence conservation, the three Sargassum forms differ in morphology, ecology, and distribution patterns, warranting more extensive interrogation of holopelagic Sargassum genomes as a whole.

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

PubMed

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

2018-01-01

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

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

PubMed Central

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

2018-01-01

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

Establishment and characterization of a novel lymphangiosarcoma cell line (MO-LAS) compared with the hemangiosarcoma cell line (ISO-HAS).

PubMed

Masuzawa, Mikio; Masuzawa, Mamiko; Hamada, Yuhko; Arakawa, Nobuko; Mori, Mari; Ishii, Masako; Nishiyama, Shigeo

2012-08-01

The concept of "lymphangiosarcoma" remains obscure. Therefore, we reported a patient with lymphangiosarcoma, resistant to immunotherapy. The patient presented with impressive and discriminative features: clinically an ill-defined edematous lesion with lymphorrhea and pathologically atypical vascular channel formation without extravasation of blood, clearly distinguished from common angiosarcoma with hemorrhage. From this case, a lymphangiosarcoma cell line, MO-LAS, was established and its characteristics were compared with the hemangiosarcoma cell line, ISO-HAS. Flow cytometric analysis revealed that MO-LAS was negative for factor VIII-related antigen, but positive for CD31, D2-40, NZ-1, and vascular endothelial growth factor receptor-3 (VEGFR-3), similar to ISO-HAS. However, MO-LAS expressed a much higher level of homeobox gene PROX1, indicating a lymphatic phenotype, compared with ISO-HAS. Furthermore, MO-LAS showed a much lesser expression of oncogenes and much lower sensitivity against lymphokine-activated killer (LAK) cells. Lymphangiosarcoma may be difficult to recognize by the immune system. Conclusively, the establishment of MO-LAS, a novel angiosarcoma cell line bearing lymphatic characters, strongly suggests the entity of lymphangiosarcoma.

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

PubMed

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

2016-01-01

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

75 FR 74123 - Office of the Commissioner; Cost-of-Living Increase and Other Determinations for 2011; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-30

... 2010. As a result, the following items will remain at their 2010 levels: (1) The maximum Federal... $674 for an eligible individual, $1,011 for an eligible individual with an eligible spouse, and $338 for an essential person; (2) The special benefit amount under title VIII of the Act for certain World...

Measuring Productivity of Depot-Level Aircraft Maintenance in the Air Force Logistics Command.

DTIC Science & Technology

1985-09-01

of Figures...... . . . . . . . . . . . . vi List of Tables . . . . . . . . . ............ vii Abstract . . . ...................... viii I...59 6. DEA Efficiency Values (Third DEA Model) . .... 62 7. DMU 5 Input Efficiencies ................ 64 vi F "-’ List of Tables Table Page I. DEA...Regression Results for 20 Months . . . ..... 68 V. Regression Results for 7 Quarters . . ..... 70 VI . Coefficients of Correlation (Using Quarterly Data

Features of the Information and Communication Technology Application by the Subjects of Special Education

ERIC Educational Resources Information Center

Arhipova, Svetlana Vladimirovna; Sergeeva, Olesya Sergeevna

2015-01-01

The main purpose of this study is to reveal the features of information and communication technologies application by the subjects of education in the conditions of special (correctional) school type VIII, and to identify the level of computer literacy of special education. The study was conducted on the basis of the State Budgetary Special…

14 CFR Appendix A to Part 141 - Recreational Pilot Certification Course

Code of Federal Regulations, 2012 CFR

2012-01-01

... navigation using pilotage with the aid of a magnetic compass; (e) Recognition of critical weather situations...) Ground reference maneuvers; (vii) Navigation; (viii) Slow flight and stalls; (ix) Emergency operations..., and go-arounds; (vi) Performance maneuvers; (vii) Navigation; (viii) Emergency operations; and (ix...

12 CFR 614.4910 - Basic authorities.

Code of Federal Regulations, 2010 CFR

2010-01-01

..., except a bank for cooperatives, with direct lending authority may originate agricultural real estate loans for sale to one or more certified agricultural mortgage marketing facilities under title VIII of... operate as an agricultural mortgage marketing facility under title VIII of the Act, either acting alone or...

26 CFR 1.671-5 - Reporting for widely held fixed investment trusts.

Code of Federal Regulations, 2010 CFR

2010-04-01

... method. (iv) Gross income requirement. (2) Information to be reported by all WHFITs. (i) Trust... interests. (vi) Information regarding bond premium. (vii) Information regarding market discount. (viii... premium. (viii) Other information. (ix) Required statement. (3) Due date and other requirements. (4...

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

PubMed

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

2016-05-26

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

Tabulation of comet observations.

NASA Astrophysics Data System (ADS)

1991-07-01

Concerning comets: 1957 III Arend-Roland, 1957 V Mrkos, 1958 III Burnham, 1959 III Bester-Hoffmeister, 1959 VI Alcock, 1959 VIII P/Giacobini-Zinner, 1960 I P/Wild 1, 1960 II Burnham, 1960 III P/Schaumasse, 1960 VIII P/Finlay, 1961 V Wilson-Hubbard, 1961 VIII Seki, 1962 III Seki-Lines, 1962 VIII Humason, 1963 I Ikeya, 1963 III Alcock, 1963 V Pereyra, 1964 VI Tomita-Gerber-Honda, 1964 VIII Ikeya, 1964 IX Everhart, 1979 X Bradfield, 1980 X P/Stephan-Oterma, 1980 XII Meier, 1980 XIII P/Tuttle, 1981 II Panther, 1982 I Bowell, 1982 IV P/Grigg-Skjellerup, 1982 VII P/d'Arrest, 1986 III P/Halley, 1987 IV Shoemaker, 1987 XII P/Hartley 3, 1987 XIX P/Schwassmann-Wachmann 2, 1987 XXIX Bradfield, 1987 XXX Levy, 1987 XXXII McNaught, 1987 XXXIII P/Borrelly, 1987 XXXVI P/Parker-Hartley, 1987 XXXVII P/Helin- Roman-Alu 1, 1988 III Shoemaker-Holt, 1988 V Liller, 1988 VIII P/Ge-Wang, 1988 XI P/Shoemaker-Holt 2, 1988 XIV P/Tempel 2, 1988 XV Machholz, 1988 XX Yanaka, 1988 XXI Shoemaker, 1988 XXIV Yanaka, 1989 III Shoemaker, 1989 V Shoemaker-Holt-Rodriquez, 1989 VIII P/Pons-Winnecke, 1989 X P/Brorsen-Metcalf, 1989 XI P/Gunn, 1989 XIII P/Lovas 1, 1989 XVIII McKenzie-Russell, 1989 XIX Okazaki-Levy-Rudenko, 1989 XX P/Clark, 1989 XXI Helin-Ronan-Alu, 1989 XXII Aarseth-Brewington, 1989h P/Van Biesbroeck, 1989t P/Wild 2, 1989u P/Kearns-Kwee, 1989c1 Austin, 1989e1 Skorichenko-George, 1990a P/Wild 4, 1990b Černis-Kiuchi-Nakamura, 1990c Levy, 1990e P/Wolf-Harrington, 1990f P/Honda-Mrkos-Pajdušáková, 1990g McNaught-Hughes, 1990i Tsuchiya-Kiuchi, 1990n P/Taylor, 1990ο P/Shoemaker-Levy 1, 1991a P/Metcalf-Brewington, 1991b Arai, 1991c P/Swift-Gehrels, 1991d Shoemaker-Levy, 1991e P/Shoemaker-Levy 3, 1991h P/Takamizawa, 1991j P/Hartley 1, 1991k P/Mrkos, 1991l Helin-Lawrence, 1991n P/Faye, 1991q P/Levy, 1991t P/Hartley 2, P/Encke, P/Schwassmann-Wachmann 1.

Regional lymph node metastases are a strong risk factor for venous thromboembolism: results from the Vienna Cancer and Thrombosis Study

PubMed Central

Dickmann, Boris; Ahlbrecht, Jonas; Ay, Cihan; Dunkler, Daniela; Thaler, Johannes; Scheithauer, Werner; Quehenberger, Peter; Zielinski, Christoph; Pabinger, Ingrid

2013-01-01

Advanced cancer is a risk factor for venous thromboembolism. However, lymph node metastases are usually not considered an established risk factor. In the framework of the prospective, observational Vienna Cancer and Thrombosis Study we investigated the association between local (N0), regional (N1–3), and distant (M1) cancer stages and the occurrence of venous thromboembolism. Furthermore, we were specifically interested in the relationship between stage and biomarkers that have been reported to be associated with venous thromboembolism. We followed 832 patients with solid tumors for a median of 527 days. The study end-point was symptomatic venous thromboembolism. At study inclusion, 241 patients had local, 138 regional, and 453 distant stage cancer. The cumulative probability of venous thromboembolism after 6 months in patients with local, regional and distant stage cancer was 2.1%, 6.5% and 6.0%, respectively (P=0.002). Compared to patients with local stage disease, patients with regional and distant stage disease had a significantly higher risk of venous thromboembolism in multivariable Cox-regression analysis including age, newly diagnosed cancer (versus progression of disease), surgery, radiotherapy, and chemotherapy (regional: HR=3.7, 95% CI: 1.5–9.6; distant: HR=5.4, 95% CI: 2.3–12.9). Furthermore, patients with regional or distant stage disease had significantly higher levels of D-dimer, factor VIII, and platelets, and lower hemoglobin levels than those with local stage disease. These results demonstrate an increased risk of venous thromboembolism in patients with regional disease. Elevated levels of predictive biomarkers in patients with regional disease underpin the results and are in line with the activation of the hemostatic system in the early phase of metastatic dissemination. PMID:23585523

Plasma fractionation issues.

PubMed

Farrugia, Albert; Evers, Theo; Falcou, Pierre-Francois; Burnouf, Thierry; Amorim, Luiz; Thomas, Sylvia

2009-04-01

Procurement and processing of human plasma for fractionation of therapeutic proteins or biological medicines used in clinical practice is a multi-billion dollar international trade. Together the private sector and public sector (non-profit) provide large amounts of safe and effective therapeutic plasma proteins needed worldwide. The principal therapeutic proteins produced by the dichotomous industry include gamma globulins or immunoglobulins (including pathogen-specific hyperimmune globulins, such as hepatitis B immune globulins) albumin, factor VIII and Factor IX concentrates. Viral inactivation, principally by solvent detergent and other processes, has proven highly effective in preventing transmission of enveloped viruses, viz. HBV, HIV, and HCV.

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.

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

NASA Astrophysics Data System (ADS)

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

2018-04-01

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

Deposing the Cool Corona of KPD 0005+5106

NASA Astrophysics Data System (ADS)

Drake, Jeremy J.; Werner, Klaus

2005-06-01

The ROSAT PSPC pulse-height spectrum of the peculiar He-rich hot white dwarf KPD 0005+5106 provided a great surprise when first analyzed by Fleming, Werner, & Barstow. It defied the best non-LTE modeling attempts in terms of photospheric emission from He-dominated atmospheres including C, N, and O and was instead interpreted as the first evidence for a coronal plasma around a white dwarf. We show here that a recent high-resolution Chandra LETGS spectrum has more structure than expected from a thermal bremsstrahlung continuum and lacks the narrow lines of H-like and He-like C expected from a coronal plasma. Moreover, a coronal model requires a total luminosity more than 2 orders of magnitude larger than that of the star itself. Instead, the observed 20-80 Å flux is consistent with photospheric models containing trace amounts of heavier elements such as Fe. The soft X-ray flux is highly sensitive to the adopted metal abundance and provides a metal abundance diagnostic. The weak X-ray emission at 1 keV announced by O'Dwyer and coworkers instead cannot arise from the photosphere and requires alternative explanations. We echo earlier speculation that such emission arises in a shocked wind. Despite the presence of UV-optical O VIII lines from transitions between levels n=7 and 10, no X-ray O VIII Lyα flux is detected. We show that O VIII Lyman photons can be trapped by resonant scattering within the emitting plasma and destroyed by photoelectric absorption.

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

EPA Pesticide Factsheets

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

Gold nanoprobe functionalized with specific fusion protein selection from phage display and its application in rapid, selective and sensitive colorimetric biosensing of Staphylococcus aureus.

PubMed

Liu, Pei; Han, Lei; Wang, Fei; Petrenko, Valery A; Liu, Aihua

2016-08-15

Staphylococcus aureus (S. aureus) is one of the most ubiquitous pathogens in public healthcare worldwide. It holds great insterest in establishing robust analytical method for S. aureus. Herein, we report a S. aureus-specific recognition element, isolated from phage monoclone GQTTLTTS, which was selected from f8/8 landscape phage library against S. aureus in a high-throughput way. By functionalizing cysteamine (CS)-stabilized gold nanoparticles (CS-AuNPs) with S. aureus-specific pVIII fusion protein (fusion-pVIII), a bifunctional nanoprobe (CS-AuNPs@fusion-pVIII) for S. aureus was developed. In this strategy, the CS-AuNPs@fusion-pVIII could be induced to aggregate quickly in the presence of target S. aureus, resulting in a rapid colorimetric response of gold nanoparticles. More importantly, the as-designed probe exhibited excellent selectivity over other bacteria. Thus, the CS-AuNPs@fusion-pVIII could be used as the indicator of target S. aureus. This assay can detect as low as 19CFUmL(-1)S. aureus within 30min. Further, this approach can be applicable to detect S. aureus in real water samples. Due to its sensitivity, specificity and rapidness, this proposed method is promising for on-site testing of S. aureus without using any costly instruments. Copyright © 2016 Elsevier B.V. All rights reserved.

[Ehler-Danlos syndrome type VIII].

PubMed

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

2010-03-01

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

Relationship of pericardial fat with biomarkers of inflammation and hemostasis, and cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Ong, Kwok-Leung; Ding, Jingzhong; McClelland, Robyn L.; Cheung, Bernard M.Y.; Criqui, Michael H.; Barter, Philip J.; Rye, Kerry-Anne; Allison, Matthew A.

2015-01-01

Objective Pericardial fat may increase the risk of cardiovascular disease (CVD) by increasing circulating levels of inflammation and hemostasis biomarkers. We investigated the associations of pericardial fat with inflammation and hemostasis biomarkers, as well as incident CVD events, and whether there are any ethnic differences in these associations. Methods We analyzed results from 6415 participants from the Multi-Ethnic Study of Atherosclerosis who had measurements of pericardial fat volume and circulating levels of C-reactive protein (CRP), fibrinogen, interleukin (IL)-6, factor VIII, D-dimer and plasmin-antiplasmin complex (PAP), and had a mean follow-up period of 9.5 years. Incident CVD event was defined as any adjudicated CVD event. Results After adjusting for confounding factors, pericardial fat volume was positively associated with natural log (ln) of IL-6 levels, but inversely associated with ln D-dimer and ln PAP levels (β=0.067, −0.032, and −0.105 respectively, all P<0.05). Although a larger pericardial fat volume was associated with a higher risk of incident CVD, the association was attenuated to borderline significance after adjusting for traditional cardiovascular risk factors (P=0.050). There was a borderline significant ethnicity interaction (P=0.080), whereby the association between pericardial fat volume and incident CVD was significant in Hispanic Americans, even after further adjusting for biomarkers of inflammation and hemostasis (hazard ratio=1.31 per SD increase, 95% confidence interval 1.09-1.57, P=0.004). Conclusion Pericardial fat was associated with several inflammation and hemostasis biomarkers. The association of pericardial fat with incident CVD events was independent of these biomarkers only among Hispanic Americans. PMID:25682037

Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease.

PubMed

Metjian, A D; Wang, C; Sood, S L; Cuker, A; Peterson, S M; Soucie, J M; Konkle, B A

2009-07-01

Type 3 von Willebrand disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) protein, accompanied by a parallel decrease in VWF function and factor VIII (FVIII) activity. The goal of this study was to describe the population of patients enrolled in the USA Centers for Disease Control Universal Data Collection (UDC) study with type 3 VWD, defined as a VWF:Ag of <10%, and to correlate bleeding symptoms with VWF and FVIII levels. Data on 150 patients were analysed. Almost all patients experienced bleeding episodes (98%) and required blood and/or factor product treatment (92%). While oral mucosal bleeding (the site of first bleed in 54%) was most common, subsequent muscle and joint bleeds were also seen (28%, 45%, respectively), and intracranial haemorrhage occurred in 8% of individuals. Mean age of first bleed was lower in those with either a FVIII < or =5% or a VWF:Ag <1%. Univariate marginal model analysis showed lower levels of FVIII and VWF:Ag both predicted a higher risk of joint bleeding. Longitudinal multivariate analysis found a lower FVIII level (P = 0.03), increasing age (P < 0.0001), history of joint bleeding (P = 0.001), higher body mass index (BMI) (P < 0.0001), and use of home infusion (P = 0.02) were all negatively associated with joint mobility. Low levels of VWF:Ag (P = 0.003) and male sex (P = 0.007) were also negatively associated with joint function. This study documents the strong bleeding phenotype in severe VWD and provides data to help target therapy, including prophylaxis, for patients most at risk of bleeding complications.

A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism.

PubMed

Antoni, G; Morange, P-E; Luo, Y; Saut, N; Burgos, G; Heath, S; Germain, M; Biron-Andreani, C; Schved, J-F; Pernod, G; Galan, P; Zelenika, D; Alessi, M-C; Drouet, L; Visvikis-Siest, S; Wells, P S; Lathrop, M; Emmerich, J; Tregouet, D-A; Gagnon, F

2010-12-01

Factor VIII (FVIII) and von Willebrand factor (VWF) are two known quantitative risk factors for venous thromboembolism (VTE). To identify new loci that could contribute to VTE susceptibility and to modulating FVIII and/or VWF levels. A pedigree linkage analysis was first performed in five extended French-Canadian families, including 253 individuals, to identify genomic regions linked to FVIII or VWF levels. Identified regions were further explored using 'in silico' genome-wide association studies (GWAS) data on VTE (419 patients and 1228 controls), and two independent case-control studies (MARTHA and FARIVE) for VTE, gathering 1166 early-onset patients and 1408 healthy individuals. Single nucleotide polymorphisms (SNPs) associated with VTE risk were further investigated in relation to plasma levels of FVIII and VWF in a cohort of 108 healthy nuclear families. Four main linkage regions were identified, among which the well-characterized ABO locus, the recently identified STAB 2 gene, and a third one, on chromosome 6q13-14, harbouring four non-redundant SNPs, associated with VTE at P < 10(-4) in the GWAS dataset. The association of one of these SNPs, rs9363864, with VTE was further replicated in the MARTHA and FARIVE studies. The rs9363864-AA genotype was associated with a lower risk for VTE (OR = 0.58 [0.42-0.80], P = 0.0005) but mainly in non-carriers of the FV Leiden mutation. This genotype was further found to be associated with the lowest levels of FVIII (P = 0.006) and VWF (P = 0.001). The BAI3 locus where the rs9363864 maps is a new candidate for VTE risk. © 2010 International Society on Thrombosis and Haemostasis.

Pathogenesis of new strains of Newcastle disease virus from Israel and Pakistan

USDA-ARS?s Scientific Manuscript database

In the past few years, Newcastle disease virus (NDV) strains with epizootic characteristics belonging to subgenotypes VIIi and XIIIb emerged in the Middle East and Asia. In this study, 2 NDV strains—1 representative of subgenotype VIIi isolated in Israel (Kvuzat/13) and 1 representative of subgenoty...

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

ERIC Educational Resources Information Center

CAUSE, Boulder, CO.

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

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

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

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

75 FR 34255 - Federal Acquisition Regulation; Federal Acquisition Circular 2005-42; Introduction

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-16

... Designated Country--Taiwan 2009-014 Sakalos. VIII....... Nonavailable Articles 2009-013 Davis. IX... Organization Agreement on Government Procurement. Item VIII--Nonavailable Articles (FAR Case 2009-013) This final rule amends FAR 25.104(a) to add certain items to the list of articles not available from domestic...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-01

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-22

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-13

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

20 CFR 408.101 - What is this part about?

Code of Federal Regulations, 2010 CFR

2010-04-01

....101 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II... in this part 408 (Regulation No. 8 of the Social Security Administration) relate to the provisions of title VIII of the Social Security Act as added by Pub. L. 106-169 enacted December 14, 1999. Title VIII...

The learning continuum based on student's level of competence and specific pedagogical learning material on physiological aspects from teachers's opinions

NASA Astrophysics Data System (ADS)

Hadi, Ria Fitriyani; Subali, Bambang

2017-08-01

The scope of learning continuum at the conceptual knowledge is formulated based on the student's level of competence and specific pedagogical learning material. The purpose of this study is to develop a learning continuum of specific pedagogical material aspects of physiology targeted for students in primary and secondary education. This research was conducted in Province of Yogyakarta Special Region from October 2016 to January 2017. The method used in this study was survey method. The data were collected using questionnaire that had been validated from the aspects of construct validity and experts judgements. Respondents in this study consist of 281 Science/Biology teachers at Public Junior and Senior High Schools in the Province of Yogyakarta Special Region which spread in Yogyakarta city and 4 regencies namely Sleman, Bantul, Kulonprogo, and Gunungkidul. The data were taken using a census. Data were analyzed using a descriptive analysis technique. The results show the learning continuum of physiology based on teachers's opinion from grade VII, VIII, and IX are taught in grade VII, VIII, IX and X on level of C2 (understanding) and the learning continuum of physiology based on teachers's opinion from grade X, XI and XII are taught in grade X and XI on level of C2 (understanding), C3 (applying), and C4 (analyzing) based on teachers's opinions. The conclusion is that many teachers refer to the existing curriculum rather than their own original idea for developing learning continuum.