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Sample records for therapeutic factor viii

  1. Factor VIII assay

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003678.htm Factor VIII assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  2. Blood coagulation factor VIII

    Indian Academy of Sciences (India)

    Factor VIII (FVIII) functions as a co-factor in the blood coagulation cascade for the proteolytic activation of factor X by factor IXa. Deficiency of FVIII causes hemophilia A, the most commonly inherited bleeding disorder. This review highlights current knowledge on selected aspects of FVIII in which both the scientist and the ...

  3. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a

    NARCIS (Netherlands)

    C.L. Eckhardt (Corien); A.S. van Velzen (Alice); M.A.D. Peters (Marjolein); J. Astermark (Jan); P.P. Brons; G. Castaman (Giancarlo); M.H. Cnossen (Marjon); N. Dors (N.); C. Escuriola-Ettingshausen (Carmen); K. Hamulyák (K.); D.P. Hart (Daniel); C.R.M. Hay (Charles R.); S. Haya (Saturnino); W.L. van Heerde; C. Hermans (Cédric); M. Holmström (Margareta); V. Jimenez-Yuste (Victor); R.D. Keenan (Russell); R. Klamroth (Robert); B.A.P. Laros-Van Gorkom (Britta); F.W.G. Leebeek (Frank); R. Liesner (Ri); A. Mäkipernaa (Anne); C. Male (Christoph); E.P. Mauser-Bunschoten (Eveline); M.G. Mazzucconi (Maria); S. McRae (Simon); K. Meijer (K.); M. Mitchell (Michael); M. Morfini (Massimo); M.R. Nijziel (Marten); J. Oldenburg (Jan); K. Peerlinck; P. Petrini (Pia); H. Platokouki (Helena); S.E. Reitter-Pfoertner (Sylvia); E. Santagostino (Elena); P. Schinco (Piercarla); F.J.W. Smiers (Frans); K.D. Siegmund (Kimberly); A. Tagliaferri (Annarita); T.T. Yee (Thynn); P.W. Kamphuisen (Pieter Willem); J.G. van der Bom (Anske); K. Fijnvandraat

    2013-01-01

    textabstractNeutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into

  4. Progress toward inducing immunologic tolerance to factor VIII

    OpenAIRE

    Scott, David W.; Pratt, Kathleen P.; Miao, Carol H.

    2013-01-01

    A major problem in treating hemophilia A patients with therapeutic factor VIII (FVIII) is that 20% to 30% of these patients produce neutralizing anti-FVIII antibodies. These antibodies block (inhibit) the procoagulant function of FVIII and thus are termed “inhibitors.” The currently accepted clinical method to attempt to eliminate inhibitors is immune tolerance induction (ITI) via a protocol requiring intensive FVIII treatment until inhibitor titers drop. Although often successful, ITI is ext...

  5. Factoring in Factor VIII With Acute Ischemic Stroke.

    Science.gov (United States)

    Siegler, James E; Samai, Alyana; Albright, Karen C; Boehme, Amelia K; Martin-Schild, Sheryl

    2015-10-01

    There is growing research interest into the etiologies of cryptogenic stroke, in particular as it relates to hypercoagulable states. An elevation in serum levels of the procoagulant factor VIII is recognized as one such culprit of occult cerebral infarctions. It is the objective of the present review to summarize the molecular role of factor VIII in thrombogenesis and its clinical use in the diagnosis and prognosis of acute ischemic stroke. We also discuss the utility of screening for serum factor VIII levels among patients at risk for, or those who have experienced, ischemic stroke. © The Author(s) 2015.

  6. The influence of prophylactic factor VIII in severe hemophilia A

    Science.gov (United States)

    Gissel, Matthew; Whelihan, Matthew F; Ferris, Lauren A; Mann, Kenneth G; Rivard, Georges E; Brummel-Ziedins, Kathleen E

    2013-01-01

    Introduction Hemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Aim To evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe hemophilia utilizing both empirical and computational models. Methods We investigated twenty-five clinically severe hemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. Results Due to prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from hemophilia A. The combination of each individual's coagulation factors (outside of fVIII) determine each individual's baseline thrombin potential and may affect bleeding risk. PMID:21899664

  7. Development and characterization of recombinant ovine coagulation factor VIII.

    Directory of Open Access Journals (Sweden)

    Philip M Zakas

    Full Text Available Animal models of the bleeding disorder, hemophilia A, have been an integral component of the biopharmaceutical development process and have facilitated the development of recombinant coagulation factor VIII (fVIII products capable of restoring median survival of persons with hemophilia A to that of the general population. However, there remain several limitations to recombinant fVIII as a biotherapeutic, including invasiveness of intravenous infusion, short half-life, immunogenicity, and lack of availability to the majority of the world's population. The recently described ovine model of hemophilia A is the largest and most accurate phenocopy. Affected sheep die prematurely due to bleeding-related pathogenesis and display robust adaptive humoral immunity to non-ovine fVIII. Herein, we describe the development and characterization of recombinant ovine fVIII (ofVIII to support further the utility of the ovine hemophilia A model. Full-length and B-domain deleted (BDD ofVIII cDNAs were generated and demonstrated to facilitate greater biosynthetic rates than their human fVIII counterparts while both BDD constructs showed greater expression rates than the same-species full-length versions. A top recombinant BDD ofVIII producing baby hamster kidney clone was identified and used to biosynthesize raw material for purification and biochemical characterization. Highly purified recombinant BDD ofVIII preparations possess a specific activity nearly 2-fold higher than recombinant BDD human fVIII and display a differential glycosylation pattern. However, binding to the carrier protein, von Willebrand factor, which is critical for stability of fVIII in circulation, is indistinguishable. Decay of thrombin-activated ofVIIIa is 2-fold slower than human fVIII indicating greater intrinsic stability. Furthermore, intravenous administration of ofVIII effectively reverses the bleeding phenotype in the murine model of hemophilia A. Recombinant ofVIII should facilitate

  8. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

    Science.gov (United States)

    Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

    2017-12-28

    Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with

  9. Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

    Directory of Open Access Journals (Sweden)

    Nicholas B. Abt

    2014-01-01

    Full Text Available Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient’s plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered.

  10. Acquired high titre factor VIII inhibitor with underlying polyarteritis nodosa.

    Science.gov (United States)

    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.

  11. Factor VIII-associated antigen in human lymphatic endothelium.

    Science.gov (United States)

    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.

  12. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin

    International Nuclear Information System (INIS)

    Hill-Eubanks, D.C.; Parker, C.G.; Lollar, P.

    1989-01-01

    Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO 4 /PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated 125 I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociate the complex and heavy-chain cleavage to activate the cofactor function

  13. Characterization of five partial deletions of the factor VIII gene

    International Nuclear Information System (INIS)

    Youssoufian, H.; Antonarakis, S.E.; Aronis, S.; Tsiftis, G.; Phillips, D.G.; Kazazian, H.H. Jr.

    1987-01-01

    Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, the authors have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes

  14. Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

    Science.gov (United States)

    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.

  15. Acquired factor VIII inhibitor syndrome: A rare cause of hematuria

    Directory of Open Access Journals (Sweden)

    Muthuvel Seral Kannan

    2015-01-01

    Full Text Available A 50-year-old woman presented with gross hematuria for 1 month. Clinical examinations, laboratory investigations, ultrasound and contrast computed tomography were normal, except anemia. Cystoscopy revealed bloody efflux from the right side. Retrograde pyelogram showed filling defect in the renal pelvis and biopsy was inconclusive. Renal angiogram was normal. She developed ecchymosis on the right thigh and arm with elevated activated partial thromboplastin time. The partial thromboplastin time correction study and Bethesda study confirmed the presence of acquired factor VIII inhibitor (acquired hemophilia. With flexible ureterorenoscopy, the mass in the renal pelvis was removed and its histopathology revealed clotted blood. The patient was subsequently managed with steroids and Factor eight inhibitor bypass activity.

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

    Science.gov (United States)

    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.

  17. Factor VIII and von Willebrand factor co-delivery by endothelial cells

    NARCIS (Netherlands)

    Bouwens, E.A.M.|info:eu-repo/dai/nl/314061894

    2011-01-01

    A defect in coagulation factor VIII (FVIII) results in the inherited bleeding disorder hemophilia A. Current treatment of hemophilia A is hampered by the need of frequent administration of costly FVIII products. Therefore gene therapy is an attractive alternative for protein replacement to treat

  18. Crystal Structure of Human Factor VIII: Implications for the Formation of the Factor IXa-Factor VIIIa Complex

    Energy Technology Data Exchange (ETDEWEB)

    Ngo, J.C.; Huang, M.; Roth, D.A.; Furie, B.C.; Furie, B. (Wyeth); (MBL)

    2008-06-03

    Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca{sup 2+} and two Cu{sup 2+} ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.

  19. Crystal Structure of Human Factor VIII: Implications for the Formation of the Factor IXa-Factor VIIIa Complex

    Energy Technology Data Exchange (ETDEWEB)

    Chi Ki Ngo,J.; Huang, M.; Roth, D.; Furie, B.; Furie, B.

    2008-01-01

    Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca(2+) and two Cu(2+) ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.

  20. Diagnostic accuracy study of a factor VIII ELISA for detection of factor VIII antibodies in congenital and acquired haemophilia A.

    Science.gov (United States)

    Batty, Paul; Moore, Gary W; Platton, Sean; Maloney, James C; Palmer, Ben; Bowles, Louise; Pasi, K John; Rangarajan, Savita; Hart, Daniel P

    2015-10-01

    Antibody formation to factor VIII (FVIII) remains the greatest clinical and diagnostic challenge to the haemophilia-treating physician. Current guidance for testing for inhibitory FVIII antibodies (inhibitors) recommends the functional Nijmegen-Bethesda assay (NBA). A FVIII ELISA offers a complementary, immunological approach for FVIII antibody testing. It was the aim of this study to retrospectively evaluate the performance of a FVIII ELISA (index) for detection of FVIII antibodies, compared with the NBA (reference). All samples sent for routine FVIII antibody testing at two haemophilia Comprehensive Care Centres, were tested in parallel using the NBA and a solid-phase, indirect FVIII ELISA kit (Immucor). A total of 497 samples from 239 patients (severe haemophilia A=140, non-severe haemophilia A=85, acquired haemophilia A=14) were available for analysis. Sixty-three samples tested positive by the NBA (prevalence 12.7%, 95% confidence interval [CI], 9.9-15.9 %), with a median inhibitor titre of 1.2 BU/ml (range 0.7-978.0). The FVIII ELISA demonstrated a specificity of 94.0% (95%CI, 91.3-96.0), sensitivity of 77.8% (95%CI, 65.5-87.3), negative predictive value of 96.7% (95%CI, 94.5-98.2), positive predictive value 65.3% (95%CI, 53.5-76.0), negative likelihood ratio 0.2 (95%CI, 0.1-0.4), positive likelihood ratio 13.0 (95%CI, 8.7-19.3) and a diagnostic odds ratio of 54.9 (95%CI, 27.0-112.0). Strong positive correlation (r=0.77, pNBA (log adjusted) and FVIII ELISA optical density. In conclusion, FVIII ELISA offers a simple, specific, surveillance method enabling batch testing of non-urgent samples for the presence of FVIII antibodies.

  1. The F309S mutation increases factor VIII secretion in human cell line

    Directory of Open Access Journals (Sweden)

    Daianne Maciely Carvalho Fantacini

    2016-06-01

    Full Text Available ABSTRACT OBJECTIVES: The capacity of a human cell line to secrete recombinant factor VIII with a F309S point mutation was investigated, as was the effect of the addition of chemical chaperones (betaine and sodium-4-phenylbutyrate on the secretion of factor VIII. METHODS: This work used a vector with a F309S mutation in the A1 domain to investigate FVIII production in the HEK 293 human cell line. Factor VIII activity was measured by chromogenic assay. Furthermore, the effects of chemical drugs on the culture were evaluated. RESULTS: The addition of the F309S mutation to a previously described FVIII variant increased FVIII secretion by 4.5 fold. Moreover, the addition of betaine or sodium-4-phenylbutyrate increased the secretion rate of FVIIIΔB proteins in HEK 293 cells, but the same effect was not seen for FVIIIΔB-F309S indicating that all the recombinant protein produced had been efficiently secreted. CONCLUSION: Bioengineering factor VIII expressed in human cells may lead to an efficient production of recombinant factor VIII and contribute toward low-cost coagulation factor replacement therapy for hemophilia A. FVIII-F309S produced in human cells can be effective in vivo.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

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

    NARCIS (Netherlands)

    van den Biggelaar, M.; Bouwens, E.A.M.; Kootstra, N.A.; Hebbel, R.P.; Voorberg, J.; Mertens, K.

    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

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

    NARCIS (Netherlands)

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

    2009-01-01

    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

  6. Analysis of mutations in the entire coding sequence of the factor VIII gene

    Energy Technology Data Exchange (ETDEWEB)

    Bidichadani, S.I.; Lanyon, W.G.; Connor, J.M. [Glascow Univ. (United Kingdom)] [and others

    1994-09-01

    Hemophilia A is a common X-linked recessive disorder of bleeding caused by deleterious mutations in the gene for clotting factor VIII. The large size of the factor VIII gene, the high frequency of de novo mutations and its tissue-specific expression complicate the detection of mutations. We have used a combination of RT-PCR of ectopic factor VIII transcripts and genomic DNA-PCRs to amplify the entire essential sequence of the factor VIII gene. This is followed by chemical mismatch cleavage analysis and direct sequencing in order to facilitate a comprehensive search for mutations. We describe the characterization of nine potentially pathogenic mutations, six of which are novel. In each case, a correlation of the genotype with the observed phenotype is presented. In order to evaluate the pathogenicity of the five missense mutations detected, we have analyzed them for evolutionary sequence conservation and for their involvement of sequence motifs catalogued in the PROSITE database of protein sites and patterns.

  7. Idiopathic factor VIII inhibitor autoantibody in a man presented after accident.

    NARCIS (Netherlands)

    Mansouritorghabeh, H.; Lak, M.; Heerde, W.L. van

    2009-01-01

    Acquired hemophilia A is a rare but severe autoimmune bleeding disorder caused by autoantibodies against factor VIII activity and is a potentially life-threatening hemorrhagic disorder. The incidence of acquired hemophilia A has been estimated as 1.48 cases per million per year. The overall rate of

  8. In vivo recovery and safety of human factor VIII product AAFACT in patients with haemophilia A

    NARCIS (Netherlands)

    Vossebeld, P. J. M.; Tissing, M. H.; van den Berg, H. M.; Leebeek, F. W. G.; de Goede-Bolder, A.; Novakova, I. R. O.; Gerrits, W. B. J.; Peters, M.; Koopman, M. M. W.; Faber, A.; Hiemstra, H.; Grob, P.; Strengers, P. F. W.

    2003-01-01

    AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance

  9. Safety and Efficacy of BAY 94-9027, a Prolonged-Half-Life Factor VIII

    DEFF Research Database (Denmark)

    Reding, M T; Ng, H J; Poulsen, Lone Hvitfeldt

    2017-01-01

    BACKGROUND: BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) 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 PATIEN...

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  12. Specific membrane binding of factor VIII is mediated by O-phospho-L-serine, a moiety of phosphatidylserine.

    Science.gov (United States)

    Gilbert, G E; Drinkwater, D

    1993-09-21

    Phosphatidylserine, a negatively charged lipid, is exposed on the platelet membrane following cell stimulation, correlating with the expression of factor VIII receptors. We have explored the importance of the negative electrostatic potential of phosphatidylserine vs chemical moieties of phosphatidylserine for specific membrane binding of factor VIII. Fluorescein-labeled factor VIII bound to membranes containing 15% phosphatidic acid, a negatively charged phospholipid, with low affinity compared to phosphatidylserine-containing membranes. Binding was not specific as it was inhibited by other proteins in plasma. Factor VIII bound to membranes containing 10% phosphatidylserine in spite of a varying net charge provided by 0-15% stearylamine, a positively charged lipid. The soluble phosphatidylserine moiety, O-phospho-L-serine, inhibited factor VIII binding to phosphatidylserine-containing membranes with a Ki of 20 mM, but the stereoisomer, O-phospho-D-serine, was 5-fold less effective. Furthermore, binding of factor VIII to membranes containing synthetic phosphatidyl-D-serine was 5-fold less than binding to membranes containing phosphatidyl-L-serine. Membranes containing synthetic phosphatidyl-L-homoserine, differing from phosphatidylserine by a single methylene, supported high-affinity binding, but it was not specific as factor VIII was displaced by other plasma proteins. O-Phospho-L-serine also inhibited the binding of factor VIII to platelet-derived microparticles with a Ki of 20 mM, and the stereoisomer was 4-fold less effective. These results indicate that membrane binding of factor VIII is mediated by a stereoselective recognition O-phospho-L-serine of phosphatidylserine and that negative electrostatic potential is of lesser importance.

  13. Haemophilia A: Database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene

    Energy Technology Data Exchange (ETDEWEB)

    Tuddenham, E.G.D. (Clinical Research Centre, Harrow (United Kingdom)); Cooper, D.N. (Thrombosis Research Inst., London (United Kingdom)); Gitschier, J. (Univ. of California, San Francisco (United States)); Higuchi, M.; Kazazian, H.H.; Antonarakis, S.E. (Johns Hopkins Univ., Baltimore (United States)); Hoyer, L.W. (American Red Cross, Rockville (United States)); Yoshioka, A. (Nara Medical Coll., Kashihara City (Japan)); Peake, I.R. (Royal Hallamshire Hospital, Sheffield (United Kingdom)); Schwaab, R. (Inst. fuer Klinische Biochemie der Univ. Bonn (West Germany)); Lavergne, J.M. (Hopital de Bicetre (France)); Giannelli, F. (Guy' s Hospital, London (United Kingdom))

    1991-09-25

    Mutations at the factor VIII gene locus causing Haemophilia A have now been identified in many patients from a many ethnic groups. Earlier studies used biased methods which detected repetitive mutations at a few CG dinucleotides. More recently rapid gene scanning methods have uncovered an extreme diversity of mutations. Over 80 different point mutations, 6 insertions, 7 small deletions, and 60 large deletions have been characterized. Repetitive mutation has been proved for at least 16 CpG sites. All nonsense mutations cause severe disease. Most missense mutations appear to cause instability of the protein, but some are associated with production of dysfunctional factor VIII molecules, thereby localizing functionally critical regions of the cofactor. Variable phenotype has been observed in association with three of the latter class of genotype. This catalogue of gene lesions in Haemophilia A will be updated annually.

  14. Detection of Intracellular Factor VIII Protein in Peripheral Blood Mononuclear Cells by Flow Cytometry

    Directory of Open Access Journals (Sweden)

    Gouri Shankar Pandey

    2013-01-01

    Full Text Available Flow cytometry is widely used in cancer research for diagnosis, detection of minimal residual disease, as well as immune monitoring and profiling following immunotherapy. Detection of specific host proteins for diagnosis predominantly uses quantitative PCR and western blotting assays. In this study, we optimized a flow cytometry-based detection assay for Factor VIII protein in peripheral blood mononuclear cells (PBMCs. An indirect intracellular staining (ICS method was standardized using monoclonal antibodies to different domains of human Factor VIII protein. The FVIII protein expression level was estimated by calculating the mean and median fluorescence intensities (MFI values for each monoclonal antibody. ICS staining of transiently transfected cell lines supported the method's specificity. Intracellular FVIII protein expression was also detected by the monoclonal antibodies used in the study in PBMCs of five blood donors. In summary, our data suggest that intracellular FVIII detection in PBMCs of hemophilia A patients can be a rapid and reliable method to detect intracellular FVIII levels.

  15. Construction of a mouse model of factor VIII deficiency by gene targeting

    Energy Technology Data Exchange (ETDEWEB)

    Bi, L.; Lawler, A.; Gearhart, J. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others

    1994-09-01

    To develop a small animal model of hemophilia A for gene therapy experiments, we set out to construct a mouse model for factor VIII deficiency by gene targeting. First, we screened a mouse liver cDNA library using a human FVIII cDNA probe. We cloned a 2.6 Kb partial mouse factor VIII cDNA which extends from 800 base pairs of the 3{prime} end of exon 14 to the 5{prime} end of exon 26. A mouse genomic library made from strain 129 was then screened to obtain genomic fragments covering the exons desired for homologous recombination. Two genomic clones were obtained, and one covering exon 15 through 22 was used for gene targeting. To make gene targeting constructs, a 5.8 Kb genomic DNA fragment covering exons 15 to 19 of the mouse FVIII gene was subcloned, and the neo expression cassette was inserted into exons 16 and 17 separately by different strategies. These two constructs were named MFVIIIC-16 and MFVIIIC-17. The constructs were linearized and transfected into strain 129 mouse ES cells by electroporation. Factor VIII gene-knockout ES cell lines were selected by G-418 and screened by genomic Southern blots. Eight exon 16 targeted cell lines and five exon 17 targeted cell lines were obtained. Three cell lines from each construct were injected into blastocysts and surgically transferred into foster mothers. Multiple chimeric mice with 70-90% hair color derived from the ES-cell genotype were seen with both constructs. Germ line transmission of the ES-cell genotype has been obtained for the MFVIIIC-16 construct, and multiple hemophilia A carrier females have been identified. Factor VIII-deficient males will be conceived soon.

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

    OpenAIRE

    Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Nichols, Timothy C.; 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 fu...

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

    Science.gov (United States)

    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 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.

  18. Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms.

    Science.gov (United States)

    Albánez, S; Ogiwara, K; Michels, A; Hopman, W; Grabell, J; James, P; Lillicrap, D

    2016-05-01

    Essentials von Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms. Background The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (β = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (β = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (β = -0.15; 95% CI, -0.25, -0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly

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

    Science.gov (United States)

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

    2017-06-01

    Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for  85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

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

    Science.gov (United States)

    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

  1. Human Factor in Therapeutic Relationship

    Directory of Open Access Journals (Sweden)

    Ramazan Akdogan

    2011-03-01

    Full Text Available herapeutic relationship is a professional relationship that has been structured based on theoretical props. This relationship is a complicated, wide and unique relationship which develops between two people, where both sides' personality and attitudes inevitably interfere. Therapist-client relationship experienced through transference and counter transference, especially in psychodynamic approaches, is accepted as the main aspect of therapeutic process. However, the approaches without dynamic/deterministic tendency also take therapist-client relationship into account seriously and stress uniqueness of interaction between two people. Being a person and a human naturally sometimes may negatively influence the relationship between the therapist and client and result in a relationship going out of the theoretical frame at times. As effective components of a therapeutic process, the factors that stem from being human include the unique personalities of the therapist and the client, their values and their attitude either made consciously or subconsciously. Literature has shown that the human-related factors are too effective to be denied in therapeutic relationship process. Ethical and theoretical knowledge can be inefficient to prevent the negative effects of these factors in therapeutic process at which point a deep insight and supervision would have a critical role in continuing an acceptable therapeutic relationship. This review is focused on the reflection of some therapeutic factors resulting from being human and development of counter transference onto the therapeutic process.

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

    Science.gov (United States)

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

    2005-01-01

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

  3. The 1.7 Å X-ray crystal structure of the porcine factor VIII C2 domain and binding analysis to anti-human C2 domain antibodies and phospholipid surfaces.

    Directory of Open Access Journals (Sweden)

    Caileen M Brison

    Full Text Available The factor VIII C2 domain is essential for binding to activated platelet surfaces as well as the cofactor activity of factor VIII in blood coagulation. Inhibitory antibodies against the C2 domain commonly develop following factor VIII replacement therapy for hemophilia A patients, or they may spontaneously arise in cases of acquired hemophilia. Porcine factor VIII is an effective therapeutic for hemophilia patients with inhibitor due to its low cross-reactivity; however, the molecular basis for this behavior is poorly understood. In this study, the X-ray crystal structure of the porcine factor VIII C2 domain was determined, and superposition of the human and porcine C2 domains demonstrates that most surface-exposed differences cluster on the face harboring the "non-classical" antibody epitopes. Furthermore, antibody-binding results illustrate that the "classical" 3E6 antibody can bind both the human and porcine C2 domains, although the inhibitory titer to human factor VIII is 41 Bethesda Units (BU/mg IgG versus 0.8 BU/mg IgG to porcine factor VIII, while the non-classical G99 antibody does not bind to the porcine C2 domain nor inhibit porcine factor VIII activity. Further structural analysis of differences between the electrostatic surface potentials suggest that the C2 domain binds to the negatively charged phospholipid surfaces of activated platelets primarily through the 3E6 epitope region. In contrast, the G99 face, which contains residue 2227, should be distal to the membrane surface. Phospholipid binding assays indicate that both porcine and human factor VIII C2 domains bind with comparable affinities, and the human K2227A and K2227E mutants bind to phospholipid surfaces with similar affinities as well. Lastly, the G99 IgG bound to PS-immobilized factor VIII C2 domain with an apparent dissociation constant of 15.5 nM, whereas 3E6 antibody binding to PS-bound C2 domain was not observed.

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

    Science.gov (United States)

    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.

  5. Analysis of inversions in the factor VIII gene in Spanish hemophilia A patients and families

    Energy Technology Data Exchange (ETDEWEB)

    Domenech, M.; Tizzano, E.; Baiget, M. [Hospital de Sant Pau, Barcelona (Spain); Altisent, C. [Hospital Vall d`Hebron, Barcelona (Spain)

    1994-09-01

    Intron 22 is the largest intron of the factor VIII gene and contains a CpG island from which two additional transcripts originate. One of these transcripts corresponds to the F8A gene which have telomeric extragenic copies in the X chromosome. An inversion involving homologous recombination between the intragenic and the distal or proximal copies of the F8A gene has been recently described as a common cause of severe hemophilia A (HA). We analyzed intron 22 rearrangements in 195 HA patients (123 familial and 72 sporadic cases). According to factor VIII levels, our sample was classified as severe in 114 cases, moderate in 29 cases and mild in 52 cases. An intron 22 (F8A) probe was hybridized to Southern blots of BcII digested DNA obtained from peripheral blood. A clear pattern of altered bands identifies distal or proximal inversions. We detected an abnormal pattern identifying an inversion in 49 (25%) of the analyzed cases. 43% of severe HA patients (49 cases) showed an inversion. As expected, no inversion was found in the moderate and mild group of patients. We found a high proportion (78%) of the distal rearrangement. From 49 identified inversions, 33 were found in familial cases (27%), while the remaining 15 were detected in sporadic patients (22%) in support that this mutational event occurs with a similar frequency in familial or sporadic cases. In addition, we detected a significant tendency of distal inversion to occur more frequently in familial cases than in sporadic cases. Inhibitor development to factor VIII was documented in approximately 1/3 of the patients with inversion. The identification of such a frequent molecular event in severe hemophilia A patients has been applied in our families to carrier and prenatal diagnosis, to determine the origin of the mutation in the sporadic cases and to detect the presence of germinal mosaicism.

  6. Hemophilia as a defect of the tissue factor pathway of blood coagulation: Effect of factors VIII and IX on factor X activation in a continuous-flow reactor

    International Nuclear Information System (INIS)

    Repke, D.; Gemmell, C.H.; Guha, A.; Turitto, V.T.; Nemerson, Y.; Broze, G.J. Jr.

    1990-01-01

    The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a wall shear rate of 57, 300, or 1130 sec -1 . The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2 endash-to 3 endash fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  9. Assessing patients' and caregivers' perspectives on stability of factor VIII products for haemophilia A

    DEFF Research Database (Denmark)

    DiBenedetti, D B; Coles, T M; Sharma, T

    2014-01-01

    Haemophilia A is a rare inherited bleeding disorder characterized by an inability of the blood to clot normally. Patients can experience spontaneous or trauma-induced joint and soft tissue bleeding and must keep coagulation factor VIII (FVIII) accessible at all times; thus, FVIII product storage...... challenges with storing FVIII products, especially storage away from home. More than half preferred storing FVIII products at room temperature vs. in the refrigerator for long periods of time. FVIII product accessibility, usage and storage affect disease management. Results support the need for more...... convenient and accessible FVIII products for patients in daily life and while travelling. In addition, the use of social media has potential value in recruiting this population....

  10. Milk fat globule-epidermal growth factor-factor VIII attenuates sepsis-induced acute kidney injury.

    Science.gov (United States)

    Cen, Cindy; Aziz, Monowar; Yang, Weng-Lang; Zhou, Mian; Nicastro, Jeffrey M; Coppa, Gene F; Wang, Ping

    2017-06-01

    Acute kidney injury (AKI) is most commonly caused by sepsis in critically ill patients, and it is associated with high morbidity and mortality. The pathophysiology of sepsis-induced AKI is generally accepted to include direct inflammatory injury, endothelial cell dysfunction, and apoptosis. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in the enhancement of apoptotic cell clearance and regulation of inflammation. We hypothesize that administration of recombinant mouse MFG-E8 (rmMFG-E8) can protect mice from kidney injuries caused by sepsis. Sepsis was induced in 8-wk-old male C57BL/6 mice by cecal ligation and puncture (CLP). rmMFG-E8 or phosphate-buffered saline (vehicle) was injected intravenously at a dosage of 20 μg/kg body weight at time of CLP (n = 5-8 mice per group). After 20 h, serum and renal tissue were harvested for various analyses. The renal injury markers blood urea nitrogen (BUN) and creatinine were determined by enzymatic and chemical reactions, respectively. The gene expression analysis was carried out by real-time quantitative polymerase chain reaction. At 20 h after CLP, serum levels of BUN and creatinine were both significantly increased in the vehicle group compared with the sham group, whereas the mice treated with rmMFG-E8 had a significant reduction in BUN and creatinine levels by 28% and 24.1%, respectively (BUN: 197.7 ± 23.6 versus 142.3 ± 20.7 mg/dL; creatinine: 0.83 ± 0.12 versus 0.63 ± 0.06 mg/dL; P sepsis through inhibiting the production of proinflammatory cytokines and chemokine, as well as through the activation of endothelial cells. Thus, MFG-E8 may have a therapeutic potential for treating AKI induced by sepsis. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Analysis of factor VIII gene inversions in 164 unrelated hemophilia A families

    Energy Technology Data Exchange (ETDEWEB)

    Vnencak-Jones, L.; Phillips, J.A. III; Janco, R.L. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)] [and others

    1994-09-01

    Hemophilia A is an X-linked recessive disease with variable phenotype and both heterogeneous and wide spread mutations in the factor VIII (F8) gene. As a result, diagnostic carrier or prenatal testing often relies upon laborious DNA linkage analysis. Recently, inversion mutations resulting from an intrachromosomal recombination between DNA sequences in one of two A genes {approximately}500 kb upstream from the F8 gene and a homologous A gene in intron 22 of the F8 gene were identified and found in 45% of severe hemophiliacs. We have analyzed banked DNA collected since 1986 from affected males or obligate carrier females representing 164 unrelated hemophilia A families. The disease was sporadic in 37%, familial in 54% and in 10% of families incomplete information was given. A unique deletion was identified in 1/164, a normal pattern was observed in 110/164 (67%), and 53/164 (32%) families had inversion mutations with 43/53 (81%) involving the distal A gene (R3 pattern) and 10/53 (19%) involving the proximal A gene (R2 pattern). While 19% of all rearrangements were R2, in 35 families with severe disease (< 1% VIII:C activity) all 16 rearrangements seen were R3. In 18 families with the R3 pattern and known activities, 16 (89%) had levels < 1%, with the remaining 2 families having {le} 2.4% activity. Further, 18 referrals specifically noted the production of inhibitors and 8/18 (45%) had the R3 pattern. Our findings demonstrate that the R3 inversion mutation patterns is (1) only seen with VIII:C activity levels of {le} 2.4%, (2) seen in 46% of families with severe hemophilia, (3) seen in 45% of hemophiliacs known to have inhibitors, (4) not correlated with sporadic or familial disease and (5) not in disequilibrium with the Bcl I or Taq I intron 18 or ST14 polymorphisms. Finally, in families positive for an inversion mutation, direct testing offers a highly accurate and less expensive alternative to DNA linkage analysis.

  12. Factor VIII S373L: mutation at P1' site confers thrombin cleavage resistance, causing mild haemophilia A.

    Science.gov (United States)

    Johnson, D J; Pemberton, S; Acquila, M; Mori, P G; Tuddenham, E G; O'Brien, D P

    1994-04-01

    A novel CRM+ mutation, factor VIII position 373 serine to leucine substitution (FVIII 373-Leu) was identified during a survey of Factor VIII (FVIII) mutations. We have purified the variant protein from the patient's plasma in order to allow further characterisation of the molecule. The CRM+ plasma contained 120% Factor VIII antigen (FVIII:Ag) and 6% Factor VIII coagulant activity (FVIII:C). After purification the mutant FVIII was subjected to thrombin proteolysis, and was thereby activated 5.6-fold compared with 7-fold for wild type molecule. Subsequently, spontaneous inactivation of the mutant was much slower than noted for wild type FVIII. Western blot analysis using monoclonal antibodies demonstrated that thrombin cleavage of FVIII 373-Leu at positions 740 and 1689 were normal but that cleavage at position 372 was completely absent. Crystallographic coordinates of the active site of thrombin complexed to fibrinopeptide A were used to explore possible mechanistic reasons for the failure of thrombin to cleave the mutant FVIII at position 372. Steric hindrance between the mutant side chain and the side chain of the P1 residue was apparent. We conclude that the functional defect of FVIII 373-Leu results from the inability of thrombin to cleave the mutant at position 372-373, and propose that this is due to steric hindrance by the side chain of leucine 373, preventing correct formation of the enzyme substrate complex.

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

    Science.gov (United States)

    Josephson, Cassandra D; Abshire, Thomas

    2004-07-01

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

  14. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A

    NARCIS (Netherlands)

    Collins, P. W.; Blanchette, V. S.; Fischer, K.; Bjorkman, S.; Oh, M.; Fritsch, S.; Schroth, P.; Spotts, G.; Astermark, J.; Ewenstein, B.

    Background: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1).

  15. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A

    DEFF Research Database (Denmark)

    Hvas, Anne-Mette; Sørensen, Hanne Thykjær; Norengaard, Lisbeth

    2007-01-01

    examined whether the clot stability in hemophiliacs could be improved by treatment with tranexamic acid (TXA) in combination with recombinant factor VIII (rFVIII). PATIENTS/METHODS: Baseline blood samples were obtained from eight males with severe hemophilia A. Thereafter, a bolus injection of r...

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

    Science.gov (United States)

    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...

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

    Science.gov (United States)

    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

  18. Potential role of a new PEGylated recombinant factor VIII for hemophilia A

    Directory of Open Access Journals (Sweden)

    Wynn TT

    2016-06-01

    Full Text Available Tung Thanh Wynn,1 Burak Gumuscu,2,3 1Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Florida, Gainesville, FL, 2Pediatric Hematology-Oncology, Bon Secours Health System, St. Mary’s Hospital, Richmond, VA, 3Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Virginia, Charlottesville, VA, USA Abstract: Hemophilia A, a deficiency in the activity of coagulation factor (F VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing ­activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half

  19. Purification and characterization of factor VIII 1,689-Cys: a nonfunctional cofactor occurring in a patient with severe hemophilia A.

    Science.gov (United States)

    O'Brien, D P; Tuddenham, E G

    1989-06-01

    We have purified the factor VIII from a CRM+ Hemophilia A plasma (90 U/dL VIII:Ag but 0 U/dL VIII:C) and analyzed the protein before and after thrombin activation by Western blotting with monoclonal antibodies (MoAbs). Normal or patient citrated plasma was ultracentrifuged, cryo-ethanol-precipitated and chromatographed on Sepharose 6B. The void volume fractions were reduced and subjected to ion exchange chromatography yielding material of specific activity approximately 1,000 U/mg protein (VIII:C or VIII:Ag). Factor VIII purified in this way from normal plasma is fully activatable by thrombin with proteolytic fragmentation as previously described by F. Rotblat et al (Biochemistry 24: 4294, 1985). Factor VIII 1,689-Cys has the normal distribution of factor VIII light and heavy chains prior to thrombin activation. After exposure to thrombin the heavy chain polypeptides were fully proteolysed but the light chain was totally resistant to cleavage. This is consistent with the demonstration in the patient's leucocyte DNA of a C to T transition in codon 1,689 converting Arg to Cys at the light chain thrombin cleavage site as previously described by J. Gitschier et al (Blood 72:1022, 1988). Uncleaved light chain of Factor VIII 1,689-Cys is not released from von Willebrand factor (vWF) by thrombin, but this is not the sole cause of the functional defect since the protein purified free of vWF has no coagulant activity. We conclude that the functional defect in factor VIII 1,689-Cys is a consequence of failure to release the acidic peptide from the light chain upon thrombin activation.

  20. Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy.

    Directory of Open Access Journals (Sweden)

    Brandon K Sack

    Full Text Available The major complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors against factor VIII (FVIII. The current method for eradicating inhibitors, termed immune tolerance induction (ITI, is costly and protracted. Clinical protocols that prevent rather than treat inhibitors are not yet established. Liver-directed gene therapy hopes to achieve long-term correction of the disease while also inducing immune tolerance. We sought to investigate the use of adeno-associated viral (serotype 8 gene transfer to induce tolerance to human B domain deleted FVIII in hemophilia A mice. We administered an AAV8 vector with either human B domain deleted FVIII or a codon-optimized transgene, both under a liver-specific promoter to two strains of hemophilia A mice. Protein therapy or gene therapy was given either alone or in conjunction with anti-CD20 antibody-mediated B cell depletion. Gene therapy with a low-expressing vector resulted in sustained near-therapeutic expression. However, supplementary protein therapy revealed that gene transfer had sensitized mice to hFVIII in a high-responder strain but not in mice of a low-responding strain. This heightened response was ameliorated when gene therapy was delivered with anti-murine CD20 treatment. Transient B cell depletion prevented inhibitor formation in protein therapy, but failed to achieve a sustained hypo-responsiveness. Importantly, use of a codon-optimized hFVIII transgene resulted in sustained therapeutic expression and tolerance without a need for B cell depletion. Therefore, anti-CD20 may be beneficial in preventing vector-induced immune priming to FVIII, but higher levels of liver-restricted expression are preferred for tolerance.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2016-01-01

    Activity of factor VIII (FVIII) increased above 150% of reference range predisposes to venous thromboembolism (VTE). The aim of this study was to identify predictors of increased FVIII activity in patients following VTE. 241 (38% men) patients presented due to objectively documented VTE episode at least 3 months ago were included in this study. FVIII activity was measured using a clotting assay on the analyzer BCS XP. Among 241 patients with VTE, activity of FVIII above 150% (FVIII ≥ 150%) was observed in 96 (40%). These patients were older (p = 0.035) and their concentrations of fibrinogen and C-reactive protein (CRP) were higher by 12% and 88% (p 200%) and this group was also older (p = 0.015), more patients in that group had obesity (p = 0.015), idiopathic VTE (p = 0.043), less of them had positive family history (p = 0.010) and they were characterized by fibrinogen and CRP increased by 28% (p 200% (p = 0.016). The activity of FVIII in patients after VTE episode is influenced by age, concentration of fibrinogen, bilirubin, hemoglobin, glucose, CRP and homocysteine. Our results suggest the role of environmental factors, mainly inflammatory response in maintaining elevated FVIII activity following VTE.

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

    Science.gov (United States)

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

    2004-02-01

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

  4. Transgenic rabbits as a model organism for production of human clotting factor VIII

    International Nuclear Information System (INIS)

    Vasicek, D.; Chrenek, P.; Makarevich, A.; Bauer, M.; Jurcik, R.; Suvegova, K.; Rafay, J.; Bulla, J.; Hetenyi, L.; Erickson, J.; Paleyanda, R.K.

    2005-01-01

    Human clotting factor VIII (hFVIII) is a very complex and large protein whose expression is difficult, as hFVIII requires extensive post-translational modification to be biologically active. This paper reports the generation of transgenic rabbits as a model species for testing the expression of hFVIII in the mammary gland. For micro-injection, a fusion gene construct was used, consisting of 2.5 kb murine whey acidic protein (mWAP) promoter, 7.2 kb cDNA of hFVIII, and 4.6 kb of 3' flanking sequences of the mWAP gene. from 130 micro-injected zygotes transferred into recipients, 30 offspring were delivered. The pups were screened for the transgene by PCR, using DNA isolated from the ear, and results were confirmed by Southern blot analysis. The transgene was identified in one female founder animal, and it was transmitted to the offspring in a Mendelian fashion, thus demonstrating stable integration of the gene construct into the germline of the transgenic rabbits. (author)

  5. An immunoradiometric assay for procoagulant factor VIII antigen: results in haemophilia, von Willebrand's disease and fetal plasma and serum

    International Nuclear Information System (INIS)

    Peake, I.R.; Bloom, A.L.; Giddings, J.C.; Ludlam, C.A.

    1979-01-01

    An immunoradiometric assay (IRMA) has been developed based on the inhibitor which arose in a polytransfused severe haemophiliac. The two-site IRMA measured antigens closely associated with the procoagulant parts of the factor VIII complex, which are termed FVIIIC antigens or FVIIICAG. FVIIICAG was present in normal plasma and also, at a slightly lower concentration, in normal serum. In 37 patients with haemophilia A, 36 had FVIIICAG levels of less than 10% of the normal plasma pool. In patients with von Willebrand's disease the levels of FVIIIC and FVIIICAG were in good agreement, both before and after treatment with cryoprecipitate or DDAVP. FVIIICAG was relatively stable in plasma at 37 0 C and could also be detected in cord and fetal serum. The assay is of potential value for detecting reduced levels of factor VIII, for carrier detection and for the prenatal diagnosis of haemophilia. (author)

  6. Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Juul, Rasmus Vestergaard; Groth, Andreas Velsing

    2018-01-01

    activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and r...

  7. Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

    Energy Technology Data Exchange (ETDEWEB)

    Young, M.; Antonarakis, S.E. [Univ. of Geneva (Switzerland); Inaba, Hiroshi [Tokyo Medical College (Japan)] [and others

    1997-03-01

    Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A{sub 8}TA{sub 2} sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient`s plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) {open_quotes}ribosomal frameshifting{close_quotes} resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A{sub 10} instead of A{sub 8}TA{sub 2}, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. 36 refs., 6 figs.

  8. Estudo citofotométrico da expressão do marcador tumoral Fator VIII e fatores prognósticos no adenocarcinoma gástrico Cytophotometric study of the expression of the tumoral marker Factor VIII and prognostic factors in gastrci adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Mary Tossa Nakamura

    2007-12-01

    ção III ou IV apresentaram índice de marcagem maiores do que aqueles com Bormann I ou II, porém sem correlação com a profundidade de invasão tumoral, grau de diferenciação, envolvimento nodal e padrão histológico. CONCLUSÕES: O presente estudo identificou e marcou 95,24% das amostras para o Fator VIII. Em relação aos fatores prognósticos não houve correlação significativa exceto entre o Fator VIII e a classificação de Bormann no qual o tipo III ou IV foi maior que o tipo I ou II.INTRODUCTION: Regarding gastric cancer, the incidence, diagnosis and therapeutic options showed improvement in the last decades, but prognosis remains gloomy, specially due the fact that most patients, already diagnosed present advanced tumors, metastatic and not liable to be surgically resected. Molecular biology is an area in science, which can give the answer to many questions and current scientific facts show that the this should be through detection of tumoral markers. The great advances in informatics refined cell image analysis by image cytophotometry makes it possible to study cell proliferation and angiogenesis in various tumor processes using immunohistochemistry and several markers. At present, studies are conducted to demonstrate the prognostic value of their expressions, however, in gastric adenocarcinoma the results have been divergent and studies are scarce. AIM: To identify and quantify the expression of cell proliferation markers using Ki-67 and of angiogenesis with Factor VIII in gastric adenocarcinoma using cytophotometry, and compare their expressions with factors such as Bormanns´ classification, tumor invasion depth, degree of differentiation, nodal involvement, histologic pattern and age. METHODS: Twenty-one patients with gastric adenocarcinoma identified between 1998 and 2006 were studied. Ki-67 and Factor VIII expressions were performed using immunohistochemistry with clone MIB-1 primary antibodies, monoclonal for Ki-67 and policlonal for Factor VIII

  9. Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A.

    Science.gov (United States)

    Cannavò, Antonino; Valsecchi, Carla; Garagiola, Isabella; Palla, Roberta; Mannucci, Pier Mannuccio; Rosendaal, Frits R; Peyvandi, Flora

    2017-03-09

    The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors. © 2017 by The American Society of Hematology.

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

    Energy Technology Data Exchange (ETDEWEB)

    Fong, I.; Lai, P.S.; Ouah, T.C. [National Univ. of Singapore (Malaysia)] [and others

    1994-09-01

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

  11. Genotype and phenotype report on patients with combined deficiency of factor V and factor VIII in Iran.

    Science.gov (United States)

    Karimi, Mehran; Cairo, Andrea; Safarpour, Mohammad M; Haghpanah, Sezaneh; Ekramzadeh, Maryam; Afrasiabi, Abdolreza; Shahriari, Mahdi; Menegatti, Marzia

    2014-06-01

    Combined factor V (FV) and factor VIII (FVIII) deficiency is a rare autosomal recessive bleeding disorder characterized by mild-to-moderate bleeding. Epistaxis, postsurgical bleeding and menorrhagia are the most common symptoms. The aim of this study is to report the phenotype-genotype characterization carried out in patients affected with combined FV and FVIII deficiency from Iran. A cross-sectional study was conducted in Shiraz Hemophilia Center, southern Iran. Twelve cases, seven men and five women coming from eight families were included in our study after taking consent form. Coagulation activity for all patients was measured. All exons and intron-exon junctions of lectin mannose binding protein 1 (LMAN1) gene and multiple coagulation factor deficiency 2 genes were amplified by PCR, and subsequently sequenced by the Sanger method. Patients[Combining Acute Accent] age ranged from 6 to 59 years mean ± SD: 23.8 ± 15.4 years and median: 22 years. No patient presented with severe bleeding symptom. Only one patient had severe FV and FVIII deficiency (both factor levels stop codon. Larger studies are needed to calculate the correlation between factor levels, genetic and bleeding symptoms.

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

    Science.gov (United States)

    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 hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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).

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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 blood groups showed a significant increase in FVIII activity (P = 0.001) and VWF levels (P 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.

  17. Pathogen inactivation in fresh frozen plasma using riboflavin and ultraviolet light: Effects on plasma proteins and coagulation factor VIII

    Directory of Open Access Journals (Sweden)

    Stanojković Zoran

    2011-01-01

    Full Text Available Background/Aim. Riboflavin (vitamin B2 activated by ultraviolet (UV light, produces active oxygen which damages cell membrane and prevents replication of the carrier of diseases (viruses, bacteria, protozoa in all blood products. The aim of this study was to establish the influence of the process of photo inactivation in pathogens using riboflavin and UV rays on the concentration of coagulation factor VIII:C (FVIII:C and proteins in plasma that were treated before freezing. Methods. The examination included 20 units of plasma, separated from whole blood donated by voluntary blood donors around 6 hours from the moment of collection. The units were pooled and separated in to two groups: one consisted of 10 control units and the other of 10 experimental units. Experimental units of the plasma were treated by riboflavin (35 mL and UV rays (6.24 J/mL, 265-370 nm on Mirasol aparature (Caridian BCT Biotechnologies, USA in approximate duration of 6 minutes. Furthermore, 35 mL of saline solution was added to the control plasma. One sample for examining was taken from the control plasma (KG and two residual were taken from experimental plasma after the addition of riboflavin either before (EG1 or post illumination (EG2. Results. Comparing the mean values of FVIII:C (% we noticed statistically significantly higher level in the EG1 group than in the EG2 group (65.00 ± 4.52 vs 63.20 ± 4.73; t = 4.323, p = 0.002, while between the KG and experimental groups (EG1 and EG2 there was no statistically significant difference in the concentration of FVIII:C. There was a statistically significant decrease of albumin concentration (g/L in the EG2 group comparing to the KG (33.35 ± 0.94 vs 31.94 ± 0.84; t = 3.534, p = 0.002, but there was no mentioned difference in albumin concentration between the KG and the EG1, so as between the EG1 and the EG2. Conclusion. Plasma inactivated by riboflavin and UV rays (Mirasol PRT sistem, Caridian BCT, USA keeps all the

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

    Science.gov (United States)

    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.

  19. Storage of factor VIII variants with impaired von Willebrand factor binding in Weibel-Palade bodies in endothelial cells.

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    Maartje van den Biggelaar

    Full Text Available BACKGROUND: Point mutations resulting in reduced factor VIII (FVIII binding to von Willebrand factor (VWF are an important cause of mild/moderate hemophilia A. Treatment includes desmopressin infusion, which concomitantly increases VWF and FVIII plasma levels, apparently from storage pools containing both proteins. The source of these VWF/FVIII co-storage pools and the mechanism of granule biogenesis are not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: We studied intracellular trafficking of FVIII variants implicated in mild/moderate hemophilia A together with VWF in HEK293 cells and primary endothelial cells. The role of VWF binding was addressed using FVIII variants displaying reduced VWF interaction. Binding studies using purified FVIII proteins revealed moderate (Arg2150His, Del2201, Pro2300Ser to severe (Tyr1680Phe, Ser2119Tyr VWF binding defects. Expression studies in HEK293 cells and primary endothelial cells revealed that all FVIII variants were present within VWF-containing organelles. Quantitative studies showed that the relative amount of FVIII storage was independent of various mutations. Substantial amounts of FVIII variants are co-stored in VWF-containing storage organelles, presumably by virtue of their ability to interact with VWF at low pH. CONCLUSIONS: Our data suggest that the potential of FVIII co-storage with VWF is not affected in mild/moderate hemophilia A caused by reduced FVIII/VWF interaction in the circulation. These data support the hypothesis that Weibel-Palade bodies comprise the desmopressin-releasable FVIII storage pool in vivo.

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

    Science.gov (United States)

    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

  1. Borderline Personality Disorder: Therapeutic Factors.

    Science.gov (United States)

    Stone, Michael H

    2016-01-01

    Proponents of the now half-dozen major psychotherapeutic approaches tend to claim the superiority of their different approaches-known widely by their acronyms: CBT for Cognitive Behavioral Therapy, DBT for Dialectic Behavioral Therapy, MBT for Mentalization-Based Therapy, TFP for Transference- Focused Psychotherapy, and so on. The data thus far support the utility of each method, but do not show clear-cut superiority of any one method. A large percentage of BPD patients eventually improve or even recover, but these favorable results appear to derive from a multiplicity of factors. These include the personality traits of both patient and therapist, the unpredictable life events over time, the socioeconomic and cultural background of the patient, and the placebo effect of simply being in treatment. These latter factors constitute the contextual model, which operates alongside the medical model, each playing a role in eventual outcome. The contextual model will be discussed extensively in a separate article.

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

    Science.gov (United States)

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

    2017-05-01

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

  3. Recurrent myocardial infarctions in a young football player secondary to thrombophilia, associated with elevated factor VIII activity

    Directory of Open Access Journals (Sweden)

    Vacek TP

    2014-10-01

    Full Text Available Thomas P Vacek, Shipeng Yu, Shahnaz Rehman, Blair P Grubb, Daniel Kosinski, Cherian Verghese, Ehab A Eltahawy, Shafiq Qaiser Department of Medicine, University of Toledo Medical Center, Toledo, OH, USAAbstract: Myocardial infarction (MI due to coronary atherosclerosis in young adults is uncommon; rare causes such as cocaine abuse, arterial dissection, and thromboembolism should be considered. A 21-year-old football player, and otherwise healthy African American man, developed chest pain during exercise while bench-pressing 400 lbs. Acute MI was diagnosed based on physical examination, electrocardiography findings, and elevated cardiac enzymes. Coronary arteriography showed a thrombus occluding the proximal left anterior descending artery (LAD. Aggressive antiplatelet therapy with aspirin, clopidogrel, and eptifibatide was pursued, in addition to standard post-MI care. This led to the successful resolution of symptoms and dissolution of the thrombus, demonstrated by repeat coronary arteriography. Five months later, he presented with similar symptoms during exercise after lifting heavy weights, and was found to have another acute MI. Coronary arteriography again showed a thrombus occluding the LAD. No evidence of coronary artery dissection or vasospasm was found. Only mild atherosclerotic plaque burden was observed on both occasions by intravascular ultrasound. A bare metal stent was placed at the site as it was thought this site had acted as a nidus for small plaque rupture and thrombus formation. Elevated serum factor VIII activity at 205% (reference range 60%–140% was found, a rare cause of hypercoagulability. Further workup revealed a patent foramen ovale during a Valsalva maneuver by transesophageal echocardiography. Both events occurred during weight lifting, which can transiently increase right heart pressure in a similar way to the Valsalva maneuver. In light of all the findings, we concluded that an exercise-related increase in factor

  4. Production of factor VIII by human liver sinusoidal endothelial cells transplanted in immunodeficient uPA mice.

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    Marina E Fomin

    Full Text Available Liver sinusoidal endothelial cells (LSECs form a semi-permeable barrier between parenchymal hepatocytes and the blood. LSECs participate in liver metabolism, clearance of pathological agents, immunological responses, architectural maintenance of the liver and synthesis of growth factors and cytokines. LSECs also play an important role in coagulation through the synthesis of Factor VIII (FVIII. Herein, we phenotypically define human LSECs isolated from fetal liver using flow cytometry and immunofluorescence microscopy. Isolated LSECs were cultured and shown to express endothelial markers and markers specific for the LSEC lineage. LSECs were also shown to engraft the liver when human fetal liver cells were transplanted into immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA transgene (uPA-NOG mice. Engrafted cells expressed human Factor VIII at levels approaching those found in human plasma. We also demonstrate engraftment of adult LSECs, as well as hepatocytes, transplanted into uPA-NOG mice. We propose that overexpression of uPA provides beneficial conditions for LSEC engraftment due to elevated expression of the angiogenic cytokine, vascular endothelial growth factor. This work provides a detailed characterization of human midgestation LSECs, thereby providing the means for their purification and culture based on their expression of CD14 and CD32 as well as a lack of CD45 expression. The uPA-NOG mouse is shown to be a permissive host for human LSECs and adult hepatocytes, but not fetal hepatoblasts. Thus, these mice provide a useful model system to study these cell types in vivo. Demonstration of human FVIII production by transplanted LSECs encourages further pursuit of LSEC transplantation as a cellular therapy for the treatment of hemophilia A.

  5. 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.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  7. Joint bleeds increase the inhibitor response to human factor VIII in a rat model of severe haemophilia A

    DEFF Research Database (Denmark)

    Löfgren, Karin Maria; Søndergaard, H.; Skov, Søren

    2016-01-01

    Introduction The most serious complication in haemophilia A (HA) replacement therapy with coagulation factor VIII (FVIII) is neutralizing antibodies, i.e. inhibitors. It has been hypothesized that danger signals generated during a bleed might have an adjuvant effect on the immune response to FVIII...... in on-demand treatment, increasing the inhibitor risk. Aim To compare the antibody response to treatment with recombinant human FVIII (rhFVIII) in relation to induced knee joint bleeds and treatment without concurrent bleeds in a HA rat model. Method HA rats were divided into two groups: one group (n...... = 10) receiving three needle induced knee joint bleeds 14 days apart and a control group (n = 9) receiving three sham procedures. Three hours after each injury/sham 50 IU kg−1 rhFVIII was administrated intravenously. Subsequently, both groups continued rhFVIII treatment for another 9 weeks. Binding...

  8. 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

    NARCIS (Netherlands)

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

    2016-01-01

    Introduction: 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

  9. Milk fat globule-epidermal growth factor-factor VIII-derived peptide MSP68 is a cytoskeletal immunomodulator of neutrophils that inhibits Rac1.

    Science.gov (United States)

    Hendricks, Louie; Aziz, Monowar; Yang, Weng-Lang; Nicastro, Jeffrey; Coppa, Gene F; Symons, Marc; Wang, Ping

    2017-02-01

    Prolonged neutrophil infiltration leads to exaggerated inflammation and tissue damage during sepsis. Neutrophil migration requires rearrangement of their cytoskeleton. Milk fat globule-epidermal growth factor-factor VIII-derived short peptide 68 (MSP68) has recently been shown to be beneficial in sepsis-induced tissue injury and mortality. We hypothesize that MSP68 inhibits neutrophil migration by modulating small GTPase Rac1-dependent cytoskeletal rearrangements. Bone marrow-derived neutrophils (BMDNs) or whole lung digest isolated neutrophils were isolated from 8 to 10 wk old C57BL/6 mice by Percoll density gradient centrifugation. The purity of BMDN was verified by flow cytometry with CD11b/Gr-1 staining. Neutrophils were stimulated with N-formylmethionine-leucine-phenylalanine (f-MLP) (10 nM) in the presence or absence of MSP68 at 10 nM or cecal ligation and puncture (CLP) was used to induce sepsis, and MSP68 was administered at 1 mg/kg intravenously. Cytoskeletal organization was assessed by phalloidin staining, followed by analysis using fluorescence microscopy. Activity of the Rac1 GTPase in f-MLP or CLP-activated BMDN in the presence or absence of MSP68 was assessed by GTPase enzyme-linked immunosorbent assay. Mitogen-activated protein (MAP) kinase activity was determined by western blot densitometry. BMDN treatment with f-MLP increased cytoskeletal remodeling as revealed by the localization of filamentous actin to the periphery of the neutrophil. By contrast, cells pretreated with MSP68 had considerably reduced filamentous actin polymerization. Cytoskeletal spreading is associated with the activation of the small GTPase Rac1. We found BMDN-treated with f-MLP or that were exposed to sepsis by CLP had increased Rac1 signaling, whereas the cells pretreated with MSP68 had significantly reduced Rac1 activation (P Rac1-MAP kinase-mediated neutrophil motility. Thus, MSP68 is a novel therapeutic candidate for regulating inflammation and tissue damage caused

  10. Elevated Factor VIII and von Willebrand Factor Levels Predict Unfavorable Outcome in Stroke Patients Treated with Intravenous Thrombolysis

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    Noémi Klára Tóth

    2018-01-01

    Full Text Available IntroductionPlasma factor VIII (FVIII and von Willebrand factor (VWF levels have been associated with the rate and severity of arterial thrombus formation and have been linked to outcomes following thrombolytic therapy in acute myocardial infarction patients. Here, we aimed to investigate FVIII and VWF levels during the course of thrombolysis in acute ischemic stroke (AIS patients and to find out whether they predict long-term outcomes.Materials and methodsStudy population included 131 consecutive AIS patients (median age: 69 years, 60.3% men who underwent i.v. thrombolysis with recombinant tissue plasminogen activator (rt-PA. Blood samples were taken on admission, 1 and 24 h after rt-PA administration to measure FVIII activity and VWF antigen levels. Neurological deficit of patients was determined according to the National Institutes of Health Stroke Scale (NIHSS. ASPECT scores were assessed using computer tomography images taken before and 24 h after thrombolysis. Intracranial hemorrhage was classified according to the European Cooperative Acute Stroke Study (ECASS II criteria. Long-term functional outcome was determined at 90 days after the event by the modified Rankin scale (mRS.ResultsVWF levels on admission were significantly elevated in case of more severe AIS [median and IQR values: NIHSS <6:189.6% (151.9–233.2%; NIHSS 6–16: 199.6% (176.4–250.8%; NIHSS >16: 247.8% (199.9–353.8%, p = 0.013]; similar, but non-significant trend was observed for FVIII levels. FVIII and VWF levels correlated well on admission (r = 0.748, p < 0.001 but no significant correlation was found immediately after thrombolysis (r = 0.093, p = 0.299, most probably due to plasmin-mediated FVIII degradation. VWF levels at all investigated occasions and FVIII activity before and 24 h after thrombolysis were associated with worse 24 h post-lysis ASPECT scores. In a binary backward logistic regression analysis including age, gender

  11. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors.

    Science.gov (United States)

    Heimberger, Amy B; Crotty, Laura E; Archer, Gary E; Hess, Kenneth R; Wikstrand, Carol J; Friedman, Allan H; Friedman, Henry S; Bigner, Darell D; Sampson, John H

    2003-09-15

    The epidermal growth factor receptor (EGFR) is often amplified and structurally rearranged in malignant gliomas and other tumors such as breast and lung, with the most common mutation being EGFRvIII. In the study described here, we tested in mouse models a vaccine consisting of a peptide encompassing the tumor-specific mutated segment of EGFRvIII (PEP-3) conjugated to keyhole limpet hemocyanin [KLH (PEP-3-KLH)]. C57BL/6J or C3H mice were vaccinated with PEP-3-KLH and subsequently challenged either s.c. or intracerebrally with a syngeneic melanoma cell line stably transfected with a murine homologue of EGFRvIII. Control mice were vaccinated with KLH. To test its effect on established tumors, C3H mice were also challenged intracerebrally and subsequently vaccinated with PEP-3-KLH. S.c. tumors developed in all of the C57BL/6J mice vaccinated with KLH in Freund's adjuvant, and there were no long-term survivors. Palpable tumors never developed in 70% of the PEP-3-KLH-vaccinated mice. In the C57BL/6J mice receiving the PEP-3-KLH vaccine, the tumors that did develop were significantly smaller than those in the control group (P PEP-3-KLH vaccination did not result in significant cytotoxic responses in standard cytotoxicity assays; however, antibody titers against PEP-3 were enhanced. The passive transfer of sera from the immunized mice to nonimmunized mice protected 31% of the mice from tumor development (P PEP-3-KLH-vaccinated mice. Peptide vaccination was also sufficiently potent to have marked efficacy against intracerebral tumors, resulting in a >173% increase in median survival time, with 80% of the C3H mice achieving long-term survival (P = 0.014). In addition, C3H mice with established intracerebral tumor that received a single treatment of PEP-3-KLH showed a 26% increase in median survival time, with 40% long-term survival (P = 0.007). Vaccination with an EGFRvIII-specific peptide is efficacious against both s.c. and established intracerebral tumors. The

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

    Science.gov (United States)

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

    2016-10-01

    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 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 (pDengue guidelines in order to standardize the admission criteria and time across hospitals.

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

    Directory of Open Access Journals (Sweden)

    Jason Echavez Abello

    2016-10-01

    Full Text Available 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

  14. Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of two unrelated patients with cross-reacting material-positive hemophilia A.

    Science.gov (United States)

    Arai, M; Higuchi, M; Antonarakis, S E; Kazazian, H H; Phillips, J A; Janco, R L; Hoyer, L W

    1990-01-15

    The molecular defect responsible for moderate and severe hemophilia A has been identified for two unrelated patients with the CRM-positive form of this disorder (factor VIII activity of 0.02 and 0.05 U/mL with factor VIII antigen of 0.87 and 2.20 U/mL). In both cases, the immunopurified dysfunctional factor VIII protein is abnormal, in that the 80 Kd light chain is not cleaved by thrombin at arginine-1689. The basis for this failure was identified by polymerase chain reaction amplification of exon 14 of the variant factor VIII genes and direct sequencing of the amplified products. In both cases, a single base substitution (C to T) was identified that produces an arginine to cysteine substitution at amino acid residue 1689. These data identify the molecular defects of the two identical factor VIII variant proteins. The dysfunctional factor VIII has been designated "Factor VIII-East Hartford," the residence of the patient in whom the defect was first identified.

  15. Limit of detection and threshold for positivity of the Centers for Disease Control and Prevention assay for factor VIII inhibitors.

    Science.gov (United States)

    Miller, C H; Boylan, B; Shapiro, A D; Lentz, S R; Wicklund, B M

    2017-10-01

    Essentials Immunologic methods detect factor VIII (FVIII) antibodies in some inhibitor-negative specimens. Specimens were tested by modified Nijmegen-Bethesda assay (NBA) and fluorescence immunoassay. The NBA with preanalytical heat inactivation detects FVIII inhibitors down to 0.2 NBU. IgG 4 frequency validates the established threshold for positivity of ≥ 0.5 NBU for this NBA. Background The Bethesda assay for measurement of factor VIII inhibitors called for quantification of positive inhibitors by using dilutions producing 25-75% residual activity (RA), corresponding to 0.4-2.0 Bethesda units, with the use of 'more sensitive methods' for samples with RA closer to 100% being recommended. The Nijmegen modification (Nijmegen-Bethesda assay [NBA]) changed the reagents used but not these calculations. Some specimens negative by the NBA have been shown to have FVIII antibodies detectable with sensitive immunologic methods. Objective To examine the performance at very low inhibitor titers of the Centers for Disease Control and Prevention (CDC)-modified NBA (CDC-NBA), which includes preanalytic heat inactivation to liberate bound anti-FVIII antibodies. Methods Specimens with known inhibitors were tested with the CDC-NBA. IgG 4 anti-FVIII antibodies were measured by fluorescence immunoassay (FLI). Results Diluted inhibitors showed linearity below 0.4 Nijmegen-Bethesda units (NBU). With four statistical methods, the limit of detection of the CDC-NBA was determined to be 0.2 NBU. IgG 4 anti-FVIII antibodies, which correlate most strongly with functional inhibitors, were present at rates above the background rate of healthy controls in specimens with titers ≥ 0.2 NBU and showed an increase in frequency from 14.3% at 0.4 NBU to 67% at the established threshold for positivity of 0.5 NBU. Conclusions The CDC-NBA can detect inhibitors down to 0.2 NBU. The FLI, which is more sensitive, demonstrates anti-FVIII IgG 4 in some patients with negative (NBA, supporting the need for

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

    Science.gov (United States)

    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.

  17. Desmopressin acetate as a haemostatic elevator in individuals with combined deficiency of factors V and VIII: a clinical trial.

    Science.gov (United States)

    Mansouritorghabeh, H; Shirdel, A

    2016-02-01

    ESSENTIALS: Combined factor V (FV) and factor VIII (FVIII) deficiency (CF5F8D) is an autosomal recessive coagulation disorder. Desmopressin acetate (DDAVP) was intravenously infused in 20 adult patients with CF5F8D. DDAVP can enhance FVIII levels but has no effect on FV levels in patients with CF5F8D. DDAVP can be substituted for FVIII concentrates in patients with CF5F8D. Combined factor V (FV) and FVIII deficiency (CF5F8D) is a rare inherited autosomal recessive double-gene disorder most frequently seen in the Middle East. Although affected individuals have deficiency of two coagulation factors (range 5-30%), their bleeding tendencies are similar to patients who have deficiency of a single coagulation factor at the same level. The mainstay of their treatment is infusion of FVIII concentrate and fresh frozen plasma. Here, the effect of intravenous infusion of desmopressin acetate (DDAVP) on elevation of coagulation FV and FVIII was investigated through a clinical trial in May 2015. In a registered controlled trial, DDAVP (dosage 0.3 μg kg(-1) ) was intravenously infused into 20 adult patients with CF5F8D over 20 min. After an hour, blood samples were collected and plasma levels of FV and FVIII were measured. This study revealed that DDAVP can enhance FVIII levels but has no effect on FV plasma concentration in patients with CF5F8D. Based on these findings, FVIII concentrates may be substituted for DDAVP in patients with CF5F8D. © 2015 International Society on Thrombosis and Haemostasis.

  18. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A.

    Science.gov (United States)

    Collins, P W; Blanchette, V S; Fischer, K; Björkman, S; Oh, M; Fritsch, S; Schroth, P; Spotts, G; Astermark, J; Ewenstein, B

    2009-03-01

    The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level break-through bleeding in patients with severe hemophilia A on prophylaxis. This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1). The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance. These data have important implications for the management of patients with severe hemophilia.

  19. An Acquired Factor VIII Inhibitor in a Patient with HIV and HCV: A Case Presentation and Literature Review

    Directory of Open Access Journals (Sweden)

    S. B. Zeichner

    2013-01-01

    Full Text Available Introduction. Despite its low incidence, acquired factor VIII inhibitor is the most common autoantibody affecting the clotting cascade. The exact mechanism of acquisition remains unclear, but postpartum patients, those with autoimmune conditions or malignancies, and those with exposure to particular drugs appear most susceptible. There have been several case reports describing acquired FVIII inhibitors in patients receiving interferon alpha for HCV treatment and in patients being treated for HIV. To our knowledge, this is the first case of a patient with HCV and HIV who was not actively receiving treatment for either condition. Case Presentation. A 57-year-old Caucasian male with a history of HIV and HCV was admitted to our hospital for a several day history of progressively worsening right thigh bruising and generalized weakness. CTA of the abdominal arteries revealed large bilateral retroperitoneal hematomas. Laboratory studies revealed the presence of a high titer FVIII inhibitor. Conclusion. Our case of a very rare condition highlights the importance of recognizing and understanding the diagnosis of acquired FVIII inhibitor. Laboratory research and clinical data on the role of newer agents are needed in order to better characterize disease pathogenesis, disease associations, genetic markers, and optimal disease management.

  20. Factor VIII (F8) inversions in severe hemophilia A: Male germ cell origin and diagnosis with RT-PCR

    Energy Technology Data Exchange (ETDEWEB)

    Antonarakis, S.E. [Geneva Medical School (Switzerland)]|[Johns Hopkins School of Medicine, Baltimore, MD (United States); Rossiter, J.P. [Johns Hopkins School of Medicine, Baltimore, MD (United States); Young, M. [Geneva Medical School (Switzerland)] [and others

    1994-09-01

    The Factor VIII (F8) gene, which is defective in hemophilia A, is located in the most telomeric megabase of Xq. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of the cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that therefore the event originates predominantly in male germ cells. In all 21 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis using markers within or very closely linked to F8, determined that it occurred in the male germline. In addition, all but one of 56 mothers of sporadic cases due to inversions were carriers. The data indicate that the F8 gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells. The mean age of maternal grandfathers at the birth of their carrier daughters was 29.9 years (13 cases), i.e. not different from the mean paternal age in the general population, supporting the hypothesis that the inversions occur in meiosis. The inversions can be diagnosed by Southern blot analysis. For more rapid diagnosis we have used RT-PCR of RNA ectopically expressed in blood. Oligonucleotides were used to PCR amplify, after the initial RT reaction of RNA samples using random hexamers, either the normal transcript (F8 exons 21 to 24;312 bp product) or the novel abnormal transcript that is generated after the inversion. Both type 1 and 2 inversions can be recognized in affecteds and carriers by the presence of the diagnostic PcR product of 248 bp. Correct diagnoses were made in samples from 6 patients and 2 carriers with type 1 inversions, 2 patients and 2 carriers with type 2 inversions and 5 normal controls.

  1. Severe hemophilia A in a female by cryptic translocation: Order and orientation of factor VIII within Xq28

    Energy Technology Data Exchange (ETDEWEB)

    Migeon, B.R.; McGinniss, M.J.; Antonarakis, S.E.; Axelman, J.; Stasiowski, B.A.; Youssoufian, H.; Kearns, W.G.; Chung, A.; Pearson, P.L.; Kazazian, H.H. Jr. (Johns Hopkins Univ., Baltimore, MD (United States)); Muneer, R.S. (Univ. of Oklahoma, Norman (United States))

    1993-04-01

    The authors report studies of a female with severe hemophilia A resulting from a complex de novo translocation of chromosomes X and 17 (46,X,t(X; 17)). Somatic cell hybrids containing the normal X, the der(X), or the der(17) were analyzed for coagulation factor VIII (F8C) sequences using Southern blots and polymerase chain reaction. The normal X, always late replicating, contains a normal F8C gene, whereas the der(X) has no F8C sequences. The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1--15. Also, it lacks the DXYS64-X locus, situated between the F8C locus and the Xq telomere. These results indicate that a cryptic breakpoint within Xq28 deleted the 5[prime] end of F8C, but left the more proximal G6PD locus intact on the der(17)chromosome. As the deleted segment includes the 5[prime] half of F8C as well as the subtelomeric DXYS64 locus, F8C must be oriented on the chromosome with its 5[prime] region closest to the telomere. Therefore, the order of these loci is Xcen-G6PD-3[prime]F8C-5[prime]F8C-DXYS64-Xqtel. The analysis of somatic cell hybrids has elucidated the true nature of the F8C mutation in the pro-band, revealing a more complex rearrangement (three chromosomes involved) than that expected from cytogenetic analysis, chromosome painting, and Southern blots. A 900-kb segment within Xq28 has been translocated to another autosome. Hemophilia A in this heterozygous female is due to the decapitation of the F8C gene on the der(17) and inactivation of the intact allele on the normal X. 27 refs., 5 figs., 1 tab.

  2. Optimisation of the Factor VIII yield in mammalian cell cultures by reducing the membrane bound fraction

    DEFF Research Database (Denmark)

    Kolind, Mille Petersen; Nørby, Peder Lisby; Berchtold, Martin Werner

    2011-01-01

    and forms the tenase complex together with clotting Factor IX. In vitro, during serum free production of recombinant FVIII (rFVIII), production cells also expose PS, and since vWF is not present to hinder interaction of secreted rFVIII with PS, rFVIII is partly associated with the cell membrane...... of active membrane bound rFVIII to the culture medium. Moreover, the attachment of rFVIII to cell membranes of un-transfected HEK293 cells was studied in the presence of compounds that competes for interactions between rFVIII and PS. Competitive assays between iodinated rFVIII (¹²5I-rFVIII) and annexin V...... or ortho-phospho-L-serine (OPLS) demonstrated that annexin V and OPLS were able to reduce the membrane bound fraction of rFVIII by 70% and 30%, respectively. Finally, adding OPLS to CHO cells stably expressing FVIII increased the yield by 50%. Using this new knowledge, the recovery of rFVIII could...

  3. Influences of ABO blood group, age and gender on plasma coagulation factor VIII, fibrinogen, von Willebrand factor and ADAMTS13 levels in a Chinese population.

    Science.gov (United States)

    Wang, Zongkui; Dou, Miaomiao; Du, Xi; Ma, Li; Sun, Pan; Cao, Haijun; Ye, Shengliang; Jiang, Peng; Liu, Fengjuan; Lin, Fangzhao; Zhang, Rong; Li, Changqing

    2017-01-01

    ABO blood group is a hereditary factor of plasma levels of coagulation factor VIII (FVIII) and von Willebrand factor (VWF). Age and gender have been shown to influence FVIII, VWF, fibrinogen (Fbg), and ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 motif, 13). We investigated the effects of ABO type, age, and gender on plasma levels of FVIII, Fbg, VWF, and ADAMTS13 in a Chinese population. A total of 290 healthy volunteers were eligible for this study. ABO blood group was determined by indirect technique. FVIII:C and Fbg were measured by clotting assays. VWF antigen (VWF:Ag), collagen-binding activity (VWF:CBA), and ADAMTS13 antigen were assessed by ELISA, whereas VWF ristocetin cofactor activity (VWF:Rcof) was performed by agglutination of platelets with ristocetin. Mean FVIII:C and VWF levels (VWF:Ag, VWF:CBA, and VWF:Rcof) were significantly higher in non-O than in O type subjects ( p  blood group, age, and gender showed different effects on plasma levels of FVIII:C, Fbg, VWF:Ag, VWF:CBA, VWF:Rcof, and ADAMTS13 antigen. These new data on a Chinese population are quite helpful to compare with other ethnic groups.

  4. Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment.

    Directory of Open Access Journals (Sweden)

    Gouri Shankar Pandey

    Full Text Available The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6 of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants. Using a computational binding predictor, we were able to expand our analysis to (a include all wild type peptides spanning each polymorphic position; and (b consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population. Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes

  5. Fluid-phase immunoradiometric assay for the detection of qualitative abnormalities of factor VIII/von Willebrand factor in variants of von Willebrand's disease

    International Nuclear Information System (INIS)

    Girma, J.P.; Ardaillou, N.; Meyer, D.; Lavergne, J.M.; Larrieu, M.J.

    1979-01-01

    Antigenic reactivity of F.VIII/WF in variants of von Willebrand's disease (vWd) was studied with both fluid-phase and solid-phase immunoradiometric assays. Two different (rabbit and goat) 125 I-labeled specific antibodies against purified F.VIII/WF were used in both their divalent (lgG) and their monovalent (Fab fragment) forms. Dose-response curves obtained by reacting a constant amount of antibody with serial dilutions of plasmas from normal or homozygous vWd demonstrated the specificity of the test. The accuracy was significantly higher with 125 I-Fab fragments of goat anti-F.VIII/WF antiserum than intact goat lgG or rabbit lgG or Fab fragments. The significant decrease of the slope of the dose-response curves obtained with plasma from variants of vWd has been interpreted as due to the presence of abnormal F.VIII/WF molecules with decreased antigenic reactivity. A similar anomaly was found in cryosupernatant prepared from normal plasma, paralleling similarities demonstrated between variants of vWd and cryosupernatant. Results of experiments performed by reacting constant plasma dilutions from control or variants of vWd and varying concentrations of anti-F.VIII/WF Fab fragments (rabbit or goat) confirmed the decreased antigenic reactivity of variant F.VIII/WF

  6. 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.

    Science.gov (United States)

    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.

  7. 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.

    Science.gov (United States)

    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.

  8. Patient preference and ease of use for different coagulation factor VIII reconstitution device scenarios: a cross-sectional survey in five European countries

    Directory of Open Access Journals (Sweden)

    Cimino E

    2014-12-01

    Full Text Available Ernesto Cimino,1 Silvia Linari,2 Mara Malerba,3 Susan Halimeh,4 Francesca Biondo,5 Martina Westfeld5 1Dipartimento Medicina Clinica e Sperimentale, Universita’ degli Studi di Napoli Federico II, Naples, Italy; 2Agenzia per l’ Emofilia, AOU Careggi di Firenze, Florence, Italy; 3Fondazione Cà Granda Ospedale Maggiore Policlinico, Centro Emofilia e Trombosi “A Bianchi Bonomi”, Milan, Italy; 4CRC Coagulation Research Centre GmbH, Duisburg, Germany; 5Pfizer Italia, Rome, Italy Introduction: Hemophilia A treatment involves replacing the deficient coagulation factor VIII. This process may involve multiple steps that might create a barrier to adherence. A new dual-chamber syringe (DCS; FuseNGo® was recently introduced with the aim of simplifying reconstitution. Aim: This study aimed to identify factors associated with adult patients’ preferences for different coagulation factor VIII reconstitution systems and to test ease of use and patient preference for the DCS. Methods: A cross-sectional survey of adults with hemophilia A in five European countries was conducted; a subset of subjects also participated in a practical testing session of the DCS. Results: Among the 299 survey participants, the device scenario requiring the least equipment and reconstitution steps (the DCS received a median preference rating of 71 out of 100 (0 being “the least desirable” and 100 “the most desirable” rating. This was significantly higher than the other scenarios (the next highest achieved a median of 50 points; P<0.001. Participants would be more likely to use this device prophylactically (P<0.001. Among the 98 participants who tested the DCS, 57% preferred this device over their current device, 26% preferred their current device, and 17% had no preference. The DCS was rated as easier to use than current treatment devices (median score 9/10 versus 7/10 for current treatment, P=0.001. Conclusion: The survey indicates that the prefilled DCS, Fuse

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

    Science.gov (United States)

    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

  10. Murine leukemia virus-derived retroviral vector has differential integration patterns in human cell lines used to produce recombinant factor VIII

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    Marcela Cristina Correa de Freitas

    2014-06-01

    Full Text Available OBJECTIVE: Nowadays recombinant factor VIII is produced in murine cells including in Chinese hamster ovary (CHO and baby hamster kidney cells (BHK. Previous studies, using the murine leukemia virus-derived retroviral vector pMFG-FVIII-P140K, modified two recombinant human cell lines, HepG2 and Hek293 to produce recombinant factor VIII. In order to characterize these cells, the present study aimed to analyze the integration pattern of retroviral vector pMFG-FVIII-P140K.METHODS: This study used ligation-mediated polymerase chain reaction to locate the site of viral vector integration by sequencing polymerase chain reaction products. The sequences were compared to genomic databases to characterize respective clones.RESULTS: The retroviral vector presented different and non-random profiles of integration between cells lines. A preference of integration for chromosomes 19, 17 and 11 was observed for HepG2FVIIIdB/P140K and chromosome 9 for Hek293FVIIIdB/P140K. In genomic regions such as CpG islands and transcription factor binding sites, there was no difference in the integration profiles for both cell lines. Integration in intronic regions of encoding protein genes (RefSeq genes was also observed in both cell lines. Twenty percent of integrations occurred at fragile sites in the genome of the HepG2 cell line and 17% in Hek293.CONCLUSION: The results suggest that the cell type can affect the profile of chromosomal integration of the retroviral vector used; these differences may interfere in the level of expression of recombinant proteins.

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

    Science.gov (United States)

    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 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 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.

  12. Descripción de un inmunoensayo enzimático que reconoce anticuerpos anti-factor VIII/von Willebrand obtenidos a partir de hibridomas múridos Description of an enzime immunoassay that recognizes anti-factor VIII/von Willebrand antibodies obtained from murine hybridomas

    Directory of Open Access Journals (Sweden)

    Renée González Sampedro

    1999-04-01

    Full Text Available Se describe un inmunoensayo enzimático (ELISA que detecta anticuerpos anti-Factor-VIII/von Willebrand (FVIII/vW, con una relación de enlace > 5, que permite reconocer dichos anticuerpos tempranamente en los cultivos de hibridomas múridos. Para la adsorción de las placas del inmunoensayo se utilizaron preparados semipurificados de FVIII/vW obtenidos en Cuba. Se inmunizaron ratones Balb/c con la finalidad de generar los anticuerpos monoclonales detectados por este ELISA. Se obtuvo un clon con crecimiento estable y varios subclones positivos por el ELISA con actividad biológica específica de anticuerpos inhibidores de FVIIIAn enzime immunoassay (ELISA that detects anti-Factor VIII/von Willebrand (FVIII/vw antibodies with a binding relationship > 5 that allows the early recognition of such antibodies in the cultures of murine hybridomas is described. Semipurified preparations of FVIII/vw obtained in Cuba were used for the adsorption of the immunoassay plates. Balb/c mice were immunized in order to generate the monoclonal antibodies detected by this ELISA. A clone with stable growth and several positive subclones were obtained by ELISA with specific biological activity of FVIII-inhibiting antibodies

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

    Science.gov (United States)

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

    2016-05-01

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

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

    Science.gov (United States)

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

    2017-07-01

    Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  15. The effect of factor VIII deficiencies and replacement and bypass therapies on thrombus formation under venous flow conditions in microfluidic and computational models.

    Directory of Open Access Journals (Sweden)

    Abimbola A Onasoga-Jarvis

    Full Text Available Clinical evidence suggests that individuals with factor VIII (FVIII deficiency (hemophilia A are protected against venous thrombosis, but treatment with recombinant proteins can increase their risk for thrombosis. In this study we examined the dynamics of thrombus formation in individuals with hemophilia A and their response to replacement and bypass therapies under venous flow conditions. Fibrin and platelet accumulation were measured in microfluidic flow assays on a TF-rich surface at a shear rate of 100 s⁻¹. Thrombin generation was calculated with a computational spatial-temporal model of thrombus formation. Mild FVIII deficiencies (5-30% normal levels could support fibrin fiber formation, while severe (1 nM, but too low to support fibrin formation (<10 nM. In the absence of platelets, fibrin formation was not supported even at normal FVIII levels, suggesting platelet adhesion is necessary for fibrin formation. Individuals treated by replacement therapy, recombinant FVIII, showed normalized fibrin formation. Individuals treated with bypass therapy, recombinant FVIIa, had a reduced lag time in fibrin formation, as well as elevated fibrin accumulation compared to healthy controls. Treatment of rFVIIa, but not rFVIII, resulted in significant changes in fibrin dynamics that could lead to a prothrombotic state.

  16. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®).

    LENUS (Irish Health Repository)

    Bacon, C L

    2011-05-01

    Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin-free recombinant full-length FVIII product (ADVATE(®)). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell-produced to a baby hamster kidney cell-produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.

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

    Science.gov (United States)

    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 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.

  18. Enhanced glycosylation of factor VIII:C in capillary endothelial cells following β-adrenoreceptor stimulation is not due to increased sugar transport

    International Nuclear Information System (INIS)

    Tavarez-Pagan, J.J.; Oliveira, C.M.; Banerjee, D.K.

    1990-01-01

    Factor VIII:C (Antihemophilia Factor A) in capillary endothelial cells from bovine adrenal medulla found to contain M r 200,000 and M r 46,000 dalton protein species when analyzed by SDS-PAGE under reduced condition. But the secretory FVIII:C under non-reduced condition gave rise to a protein of M r 270,000 dalton indicating that the heavy and light chains are held together by S-S bridge. Upon stimulation of these cells with β-agonist, isoproterenol (10 -7 M), a 2-fold increase in the ratio of [ 3 H]-mannose to [ 35 S]-methionine incorporation in immunoprecipitated FVIII:C was observed. In order to understand the molecular mechanism of this increase, a detail study of sugar transport was carried out. The transport of 2-deoxy-D-[ 3 H]-glucose in these cells was time and temperature dependent. Furthermore, inhibition of 2-deoxy-D-[ 3 H]-glucose uptake by cytochalasin B strongly supported for a carrier mediated process. However, when the transport studies were conducted in the presence of isoproterenol at 10 -5 M or 10 -7 M or 8 Br-cAMP (2 mM) no increase was observed. The kinetic studies indicated that the K m and V max for 2 deoxy-D-[ 3 H]-glucose were 0.24 mM and 0.88 nmol/mg protein/minute, respectively under normal conditions but these values were changed to 0.37 mM and 0.69 nmol/mg protein/minute when stimulated with isoproterenol (10 -7 M)

  19. [Therapeutic education of total laryngectomy patients: Influence of social factors].

    Science.gov (United States)

    Woisard, V; Galtier, A; Baumann, L; Delpierre, C; Puech, M; Balaguer, M

    Current health policies promote patient education, parti­cu­lar­ly in oncology. Therapeutic education program must be tailo­red to the characteristics, needs and expectations of the population. In the ENT Department of Head and Neck Surgery, Larrey Hospital in Toulouse, a therapeutic education program for patient with total laryngectomy has been experienced since 2011. But its propagation remains difficult. The aim of this study is to determine if social factors are nfluencing the parti­cipation of the laryngectomized population in the program. The brochure explaining this program and a registration form coupled with a survey questionnaire were distributed to the regio­nal population of patient with total laryngectomy. After two months of investigation we collected 42 responses. It is clear from their analysis that social factors underlie partici­pa­tion, particularly educational level, available financial resources level and the socio-professional group.

  20. Dependence of therapeutic gain factor on stage of oral cancer

    International Nuclear Information System (INIS)

    Velmurugan, J.; Solomon, J.G.R.; Koteshwer Rao, K.; Supe, S.S.; Prasad, G.N.S.

    1998-01-01

    To achieve therapeutic gain, unconventional dose per fraction has been employed in radiotherapy, in addition to the conventional dose per fraction of 2 Gy. Dose fractionation factor (DFF) and therapeutic gain factor (TGF) have been utilised to test the efficiency of such unconventional fractionation schedules. In this study, isoeffective dose for 100% tumour regression and mucosal and skin reactions were estimated. CRE, TDF and ERD values for tumour and normal tissue reactions were evaluated. DEF and TGF values have been determined on the basis of dose, CRE, TDF and ERD, in order to understand the influence of these bioeffect models and stage of cancer on TGF associated with differing fractionation schedules. There was a noticeable difference in TGF values determined on the basis of four criteria, which is in agreement with radiobiological phenomenon, that tissues with different α/β values differ in their responsiveness. (author)

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

    Science.gov (United States)

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

    2015-01-01

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

  2. Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

    Science.gov (United States)

    Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

    2015-01-01

    Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

  3. 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.

    Science.gov (United States)

    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 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.

  4. Safety of PEGylated recombinant human full-length coagulation factor VIII (BAX 855) in the overall context of PEG and PEG conjugates.

    Science.gov (United States)

    Stidl, R; Fuchs, S; Bossard, M; Siekmann, J; Turecek, P L; Putz, M

    2016-01-01

    BAX 855 is a PEGylated human full-length recombinant factor VIII (rFVIII) based on licensed rFVIII (ADVATE). The applied PEGylation technology has been optimized to retain functionality of the FVIII molecule, improve its pharmacokinetic properties and allow less frequent injections while maintaining efficacy. The aim of this study was to confirm that the excellent safety profile of ADVATE remains unchanged after PEGylation. Non-clinical safety studies with BAX 855 and its respective unbound polyethylene glycol (PEG) were conducted in several species. The distribution of a single dose of radiolabelled BAX 855 was further investigated in rats. Publically available safety data on PEG alone and PEGylated biomolecules were summarized and reviewed for specific safety findings attributable to PEG or PEGylated biopharmaceuticals. Safety pharmacology studies in rabbits and macaques and repeated dose toxicity studies in rats and macaques identified no safety issues. Results of a distribution study in rats administered radiolabelled BAX 855 showed that radioactivity was completely excreted; urine was the major elimination route. A 28-day study in rats dosed with the unbound PEG constituent (PEG2ru20KCOOH) of BAX 855 showed no adverse or non-adverse effects. Safety data for PEG and PEG-protein conjugates indicate no safety concerns associated with PEG at clinically relevant dose levels. Although vacuolation of certain cell types has been reported in mammals, no such vacuolation was observed with BAX 855 or with the unbound PEG constituent. Non-clinical safety evaluation of PEG and BAX 855 identified no safety signals; the compound is now in clinical development for the treatment of patients with haemophilia A. © 2015 Baxalta Innovations GmbH. Haemophilia Published by John Wiley & Sons Ltd.

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

    Science.gov (United States)

    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.

  6. The B-domain of factor VIII reduces cell membrane attachement to host cells in serum free conditions

    DEFF Research Database (Denmark)

    Kolind, Mille Petersen; Nørby, Peder Lisby; Flintegaard, Thomas Veje

    2010-01-01

    engineered extensively throughout the years to increase the low production yields that initially were obtained from mammalian cell cultures. The scope of this work was to investigate the interaction of rFVIII with the cell membrane surface of the producing cells in serum free medium. We wondered whether...... binding of rFVIII to the cell membrane could be a factor diminishing the production yield. We studied the contribution of the rFVIII B-domain to membrane attachment by transfecting several constructs containing increasing lengths of the B-domain into cells under serum free conditions. We found that 90......% of rFVIII is attached to the cell membrane of the producing cell when the rFVIII variant contains a short B-domain (21 aa). By increasing the length of the B-domain the membrane attached fraction can be reduced to 50% of the total expressed rFVIII. Further, our studies show that the N...

  7. Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

    Directory of Open Access Journals (Sweden)

    Alanna McEneny-King

    2017-10-01

    Full Text Available The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

  8. The vestibulocochlear nerve (VIII).

    Science.gov (United States)

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

    2013-10-01

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

  9. Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

    International Nuclear Information System (INIS)

    Messerschmidt, G.L.; Hoover, R.; Young, R.C.

    1980-01-01

    Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

  10. Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.

    Science.gov (United States)

    Sinha Roy, Rituparna; Soni, Shivani; Harfouche, Rania; Vasudevan, Pooja R; Holmes, Oliver; de Jonge, Hugo; Rowe, Arthur; Paraskar, Abhimanyu; Hentschel, Dirk M; Chirgadze, Dimitri; Blundell, Tom L; Gherardi, Ermanno; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-08-03

    Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.

  11. Obtenção e caracterização de anticorpo monoclonal murino anti-fator VIII da coagulação sangüínea Attainment and characterization of murine monoclonal anti-factor VIII antibodies

    Directory of Open Access Journals (Sweden)

    Rosana Rossi-Ferreira

    2006-06-01

    Full Text Available Entre os avanços da engenharia celular e biotecnologia nas últimas décadas, destaca-se a produção de anticorpos monoclonais murinos (AcMm utilizados no aprimoramento diagnóstico nas rotinas laboratoriais. A produção de fator VIII de alta pureza sempre foi o desejo e a preocupação das indústrias de hemoderivados para tratamento de pacientes portadores de hemofilia A, porém este produto inexiste no Brasil, sendo necessária sua obtenção no mercado internacional a custos elevados. O trabalho tem por objetivo a produção de AcMm anti-fator VIII humano (FVIII H através da expansão dos clones e caracterização imunoquímica do anticorpo. Camundongos Balb/c foram imunizados com FVIII H purificado como também proveniente de crioprecipitado e as células esplênicas dos animais foram fusionadas com células mielomatosas murinas segundo o método descrito por Kohler e Milstein para produção de híbridos em cultura. Foram testados 1.983 híbridos dos quais 105 foram submetidos à clonagem. Destes, 39 obtiveram monoclonalidade e 7 destes clones foram caracterizados através de técnicas de immunoblotting. Foram submetidas à purificação por cromatografia três imunoglobulinas de diferentes classes pertencentes aos clones LAMB1-10A1A4, LAMB1-17A1A1 e LAMB1-24A2A1. A imunoglobulina purificada pertencente ao clone LAMB1-10A1A4 foi adsorvida em coluna de imunoafinidade para purificação de concentrado de FVIII proveniente de crioprecipitado plasmático.Among the advances in cellular engineering and biotechnology over the last decades, the production of murine monoclonal antibodies (AcMm, used to improve laboratory diagnoses, stands out. The production of very pure factor VIII has always been a concern of suppliers of blood products to treat patients with hemophilia A and this product is still not produced in Brazil. Hence, it can only be attained on the international market at a high cost. The aim of this work was to produce AcMm anti-factor

  12. Review Blood coagulation factor VIII

    Indian Academy of Sciences (India)

    Unknown

    the development of inhibitors in patients with hemophilia A. 2. Lifespan. 2.1 FVIII gene .... intron 22 inversion is principally an error of DNA repli- cation during ..... Pittman D D, Wang J H and Kaufman R J 1992 Identification and functional ...

  13. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type-dependent sex ratio of mutation frequencies

    Energy Technology Data Exchange (ETDEWEB)

    Becker, J.; Schmidt, W.; Olek, K. [Univ. of Bonn (Germany)] [and others

    1996-04-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients-all exclusively from sporadic families-were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7%). Fifty-five patients (37.4%) showed a F8A-gene inversion, 47 (32.0%) a point mutation, 14 (9.5%) a small deletion, 8 (5.4%) a large deletion, and 2 (1.4%) a small insertion. Further, four (2.7%) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6%). Sixteen (10.9%) of the P identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9%) of 76 patients` mothers, comprising 3 of 16 de novo mutations in the patients` mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patient`s mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold- higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its proportion of the different mutation types. 68 refs., 1 fig., 5 tabs.

  14. 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.

    Science.gov (United States)

    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.

  15. Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

    International Nuclear Information System (INIS)

    Messerschmidt, G.L.; Hoover, R.; Young, R.C.

    1981-01-01

    Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. Care must be exercised in associating previous therapy and a subsequent malignancy. Naturally occurring second cancers must be separated from those which are iatrogenic. Associations in the literature have been made involving malignancies as a sequelae of prior gynecologic therapy. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. Irradiation therapy, however, has not yet been shown to be related to leukemia in cervical cancer patients. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

  16. Physiochemical and biochemical factors influencing the pharmacokinetics of antibody therapeutics.

    Science.gov (United States)

    Bumbaca, Daniela; Boswell, C Andrew; Fielder, Paul J; Khawli, Leslie A

    2012-09-01

    Monoclonal antibodies are increasingly being developed to treat multiple disease areas, including those related to oncology, immunology, neurology, and ophthalmology. There are multiple factors, such as charge, size, neonatal Fc receptor (FcRn) binding affinity, target affinity and biology, immunoglobulin G (IgG) subclass, degree and type of glycosylation, injection route, and injection site, that could affect the pharmacokinetics (PK) of these large macromolecular therapeutics, which in turn could have ramifications on their efficacy and safety. This minireview examines how characteristics of the antibodies could be altered to change their PK profiles. For example, it was observed that a net charge modification of at least a 1-unit shift in isoelectric point altered antibody clearance. Antibodies with enhanced affinity for FcRn at pH 6.0 display longer serum half-lives and slower clearances than wild type. Antibody fragments have different clearance rates and tissue distribution profiles than full length antibodies. Fc glycosylation is perceived to have a minimal effect on PK while that of terminal high mannose remains unclear. More investigation is warranted to determine if injection route and/or site impacts PK. Nonetheless, a better understanding of the effects of all these variations may allow for the better design of antibody therapeutics.

  17. Snakebite Prognostic Factors: Leading Factors of Weak Therapeutic Response Following Snakebite Envenomation

    Directory of Open Access Journals (Sweden)

    Bita Dadpour

    2012-12-01

    Full Text Available Background: The goal of antivenom administration for snake-bitten patients is to achieve therapeutic response (initial control, which means reversal of the venom-induced effects through neutralizing the venom. The aim of this study was to identify snakebite prognostic factors of weak therapeutic response prior to antivenom administration. Methods: This was a retrospective study of patients with viperidae snakebite envenomation who were admitted to Mashhad Toxicology Centre during 2007-2011. Demographic features, clinical manifestations and snakebite severity score (SSS were collected prior to antivenom administration. Total number of antivenom vials administered to achieve therapeutic response and duration of hospitalization were also recorded. Potential factors in snakebite prognosis were analyzed by comparing in two groups of achieving therapeutic response with less than 5 vials and over 5 to calculate odds ratio.  Results: Total of 108 patients (male/female: 85/23 with mean (SD age of 34.5 (17.0 were studied. The most common manifestations included fang marks (100%, pain (100%, ecchymosis (89%, swelling (83%, blister formation (48% and thrombocytopenia (25%. In univariate analysis, thrombocytopenia (P=0.01, spontaneous bleeding (P=0.02, coagulopathic disturbances (P=0.007, swelling (P=0.003, progressive swelling (P=0.005, ecchymosis (P=0.05 and respiratory distress (P= 0.05 were significantly correlated to weak therapeutic response. Swelling and spontaneous bleeding were the strongest snakebite prognostic factors, as respectively they put the patients at 12.4 and 10.4 fold risks for difficult achievement of therapeutic response. Conclusions: In snakebite, some clinical manifestations in the first hours of admission and prior to antivenom administration are associated with weak therapeutic response. Identifying these prognostic factors, can assist health care providers to better estimate the patient’s needs and predict the final

  18. Therapeutic outcomes, assessments, risk factors and mitigation efforts of immunogenicity of therapeutic protein products.

    Science.gov (United States)

    Yin, Liusong; Chen, Xiaoying; Vicini, Paolo; Rup, Bonita; Hickling, Timothy P

    2015-06-01

    Therapeutic protein products (TPPs) are of considerable value in the treatment of a variety of diseases, including cancer, hemophilia, and autoimmune diseases. The success of TPP mainly results from prolonged half-life, increased target specificity and decreased intrinsic toxicity compared with small molecule drugs. However, unwanted immune responses against TPP, such as generation of anti-drug antibody, can impact both drug efficacy and patient safety, which has led to requirements for increased monitoring in regulatory studies and clinical practice, termination of drug development, or even withdrawal of marketed products. We present an overview of current knowledge on immunogenicity of TPP and its impact on efficacy and safety. We also discuss methods for measurement and prediction of immunogenicity and review both product-related and patient-related risk factors that affect its development, and efforts that may be taken to mitigate it. Lastly, we discuss gaps in knowledge and technology and what is needed to fill these. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    International Nuclear Information System (INIS)

    Thonel, Aurelie de; Mezger, Valerie; Garrido, Carmen

    2011-01-01

    Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents

  20. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    Energy Technology Data Exchange (ETDEWEB)

    Thonel, Aurelie de [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); Mezger, Valerie, E-mail: valerie.mezger@univ-paris-diderot.fr [CNRS, UMR7216 Epigenetics and Cell Fate, Paris (France); University Paris Diderot, 75013 Paris (France); Garrido, Carmen, E-mail: valerie.mezger@univ-paris-diderot.fr [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); CHU, Dijon BP1542, Dijon (France)

    2011-03-07

    Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents.

  1. Functional Role of Milk Fat Globule-Epidermal Growth Factor VIII in Macrophage-Mediated Inflammatory Responses and Inflammatory/Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Young-Su Yi

    2016-01-01

    Full Text Available Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8 is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing. Recently, emerging studies have reported that MFG-E8 plays a role in inflammatory responses and inflammatory/autoimmune diseases. This review describes the characteristics of MFG-E8-mediated signaling pathways, summarizes recent findings supporting the roles of MFG-E8 in inflammatory responses and inflammatory/autoimmune diseases, and discusses MFG-E8 targeting as a potential therapeutic strategy for the development of anti-inflammatory/autoimmune disease drugs.

  2. Structural Instability in Ice VIII under Pressure

    International Nuclear Information System (INIS)

    Besson, J.; Klotz, S.; Hamel, G.; Marshall, W.; Nelmes, R.; Loveday, J.

    1997-01-01

    Below 125K, tetragonal ice VIII remains in a metastable form at ambient pressure. This form has long been considered to be identical to ice VIII, although unexplained discrepancies exist between their vibrational spectra. Neutron diffraction studies reveal an isostructural phase transformation below 2GPa related to a weakening of the bonds between the two D 2 O sublattices of ice VIII. In this new phase, ice VIII ' , the tetragonal distortion is 20% larger than in ice VIII, which accounts for the differences between the vibrational frequencies of the two phases. copyright 1997 The American Physical Society

  3. Trp[superscript 2313]-His[superscript 2315] of Factor VIII C2 Domain Is Involved in Membrane Binding Structure of a Complex Between the C[subscript 2] Domain and an Inhibitor of Membrane Binding

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhuo; Lin, Lin; Yuan, Cai; Nicolaes, Gerry A.F.; Chen, Liqing; Meehan, Edward J.; Furie, Bruce; Furie, Barbara; Huang, Mingdong (Harvard-Med); (UAH); (Maastricht); (Chinese Aca. Sci.)

    2010-11-03

    Factor VIII (FVIII) plays a critical role in blood coagulation by forming the tenase complex with factor IXa and calcium ions on a membrane surface containing negatively charged phospholipids. The tenase complex activates factor X during blood coagulation. The carboxyl-terminal C2 domain of FVIII is the main membrane-binding and von Willebrand factor-binding region of the protein. Mutations of FVIII cause hemophilia A, whereas elevation of FVIII activity is a risk factor for thromboembolic diseases. The C2 domain-membrane interaction has been proposed as a target of intervention for regulation of blood coagulation. A number of molecules that interrupt FVIII or factor V (FV) binding to cell membranes have been identified through high throughput screening or structure-based design. We report crystal structures of the FVIII C2 domain under three new crystallization conditions, and a high resolution (1.15 {angstrom}) crystal structure of the FVIII C2 domain bound to a small molecular inhibitor. The latter structure shows that the inhibitor binds to the surface of an exposed {beta}-strand of the C2 domain, Trp{sup 2313}-His{sup 2315}. This result indicates that the Trp{sup 2313}-His{sup 2315} segment is an important constituent of the membrane-binding motif and provides a model to understand the molecular mechanism of the C2 domain membrane interaction.

  4. Transcription Factors in Heart: Promising Therapeutic Targets in Cardiac Hypertrophy

    OpenAIRE

    Kohli, Shrey; Ahuja, Suchit; Rani, Vibha

    2011-01-01

    Regulation of gene expression is central to cell growth, differentiation and diseases. Context specific and signal dependent regulation of gene expression is achieved to a large part by transcription factors. Cardiac transcription factors regulate heart development and are also involved in stress regulation of the adult heart, which may lead to cardiac hypertrophy. Hypertrophy of cardiac myocytes is an outcome of the imbalance between prohypertrophic factors and anti-hypertrophic factors. Thi...

  5. Factors that influence therapeutic outcomes in symptomatic gastroesophageal reflux disease.

    LENUS (Irish Health Repository)

    Quigley, Eamonn M M

    2012-02-03

    The term "symptomatic gastroesophageal reflux disease" (GERD) refers to those patients who present with the typical GERD symptoms of heartburn and regurgitation, yet do not have endoscopic evidence of esophagitis. The primary goals of managing symptomatic GERD are to control symptoms and improve quality of life. A clinical assessment of the GERD patient can identify important clinical features, such as atypical and extraesophageal symptoms for which acid-suppressive agents tend to be less effective. Performing an endoscopy can further identify the patient as having nonerosive reflux disease, erosive esophagitis, or Barrett\\'s esophagus-diagnoses which can help determine treatment but may not prove predictive of therapeutic response. Determining acid exposure through pH testing can predict therapeutic response, with those revealing an abnormal acid exposure time being more responsive to acid-suppressive therapy. However, the performance of an endoscopy and pH testing on each patient is clearly not practical. Whereas the natural history of symptomatic GERD is still largely undefined, acid-suppressive therapy appears to be the best approach available for both the short-term and long-term management of this disease.

  6. Factors associated with therapeutic inertia in hypertension: validation of a predictive model.

    Science.gov (United States)

    Redón, Josep; Coca, Antonio; Lázaro, Pablo; Aguilar, Ma Dolores; Cabañas, Mercedes; Gil, Natividad; Sánchez-Zamorano, Miguel Angel; Aranda, Pedro

    2010-08-01

    To study factors associated with therapeutic inertia in treating hypertension and to develop a predictive model to estimate the probability of therapeutic inertia in a given medical consultation, based on variables related to the consultation, patient, physician, clinical characteristics, and level of care. National, multicentre, observational, cross-sectional study in primary care and specialist (hospital) physicians who each completed a questionnaire on therapeutic inertia, provided professional data and collected clinical data on four patients. Therapeutic inertia was defined as a consultation in which treatment change was indicated (i.e., SBP >or= 140 or DBP >or= 90 mmHg in all patients; SBP >or= 130 or DBP >or= 80 in patients with diabetes or stroke), but did not occur. A predictive model was constructed and validated according to the factors associated with therapeutic inertia. Data were collected on 2595 patients and 13,792 visits. Therapeutic inertia occurred in 7546 (75%) of the 10,041 consultations in which treatment change was indicated. Factors associated with therapeutic inertia were primary care setting, male sex, older age, SPB and/or DBP values close to normal, treatment with more than one antihypertensive drug, treatment with an ARB II, and more than six visits/year. Physician characteristics did not weigh heavily in the association. The predictive model was valid internally and externally, with acceptable calibration, discrimination and reproducibility, and explained one-third of the variability in therapeutic inertia. Although therapeutic inertia is frequent in the management of hypertension, the factors explaining it are not completely clear. Whereas some aspects of the consultations were associated with therapeutic inertia, physician characteristics were not a decisive factor.

  7. Factors associated with therapeutic strategies in patients with splanchnic vein thrombosis: Results of an international registry

    NARCIS (Netherlands)

    Riva, N.; Ageno, W.; Schulman, S.; Bang, S.M.; Sartori, M.T.; Grandone, E.; Beyer, J.; Barillari, G.; Di Minno, D.; Duce, R.; Malato, A.; Santoro, R.; Poli, D.; Verhamme, P.; Martinelli, I.; Kamphuisen, P.; Alatri, A.; Becattini, C.; Bucherini, E.; Piana, A.; De Stefano, V.; Dentali, F.

    2012-01-01

    Background Treatment of splanchnic vein thrombosis (SVT) is challenging due to the heterogeneous clinical presentation and the increased bleeding risk. We aimed to describe current treatment strategies and factors associated with therapeutic decisions. Materials and Methods Between May 2008 and

  8. Status and trend analysis of prophylactic usage of recombinant factor VIII in Chinese pediatric patients with hemophilia A: ReCare - a retrospective, phase IV, non-interventional study.

    Science.gov (United States)

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

    2017-09-01

    No study has reported the status and chronological trend of prophylactic recombinant factor VIII (rFVIII) use in Chinese pediatric patients with hemophilia A (HA). We aimed to analyze the status and trend of rFVIII-containing prophylaxis in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained REgular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers across China. The trend of prophylaxis was evaluated by determining the mean duration of prophylaxis, mean injection frequency (per week), mean dose of each injection (IU/kg), mean total dose injected/week (IU) and proportion of rFVIII consumption relative to factor VIII (FVIII) consumption over the study period. We analyzed 183 male pediatric patients with HA (mean age, 7.1 ± 4.23 years), who received intermittent prophylaxis between 1 November 2007 and 31 May 2013. The mean duration of prophylaxis with rFVIII increased from 16.72 weeks in 2008 to 32.77 in 2012. Per injection dose of rFVIII increased significantly from 2008 to 2013 (25.89 to 28.31 IU/kg, p < .001). An increase was also reported in the mean total FVIII consumed (699.97 ± 173.25 IU in 2008 and 891.30 ± 730.341 in 2013) and mean proportion of rFVIII used (33.33 ± 57.73% in 2008 to 85.50 ± 29.077% in 2013). Our data revealed an overall improvement in treatment dosage and duration with an increase in the number of patients receiving prophylaxis. The total proportion of rFVIII also increased gradually indicating the development of economy and safety awareness. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02263066).

  9. [Therapeutic use of hematopoietic growth factors. II. GM-CSF and G-CSF].

    Science.gov (United States)

    Royer, B; Arock, M

    1998-01-01

    The second part of this review on haematopoietic growth factors is focused on the therapeutic use of GM-CSF and G-CSF. Such therapeutic applications have raised very great hopes for clinical haematology. However, it should not be forgotten that these haematopoietic growth factors, which are very costly, are powerful two-edged weapons capable of triggering a cascade of reactions, and have a field of activity that often goes beyond the single highly specific property which it is hoped they possess. The risks and costs of their use are currently being evaluated. Waited developments concerning these molecules focus on three axes: a best use of factors already commercialized, especially concerning adaptation of posologies and new indications, the development of hybrid molecules from already known haematopoietic growth factors, possessing the advantages of respective factors, but not their disadvantages, the discovery of new haematopoietic growth factors with potential therapeutic application.

  10. Fibroblast growth factors as tissue repair and regeneration therapeutics

    Directory of Open Access Journals (Sweden)

    Quentin M. Nunes

    2016-01-01

    Full Text Available Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine or systemically (endocrine. The fibroblast growth factor (FGF family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West.

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

    Science.gov (United States)

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

    2017-07-01

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

  12. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Directory of Open Access Journals (Sweden)

    Zhong SHI

    2015-02-01

    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Science.gov (United States)

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

    2015-11-01

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

  15. Blood coagulation factor VIII: An overview

    Indian Academy of Sciences (India)

    Unknown

    Solvent, detergent and heat treatment. Hemofil-M. Baxter. Pooled human venous plasma. Immunoaffinity chromatography using murine monoclonal anti- body. Solvent and detergent. Monarc-M. American. Red Cross. Pooled human venous plasma. Immunoaffinity chromatography using murine monoclonal antibody.

  16. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    Science.gov (United States)

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  17. Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334 ameliorates murine colitis

    Directory of Open Access Journals (Sweden)

    Gupta R

    2014-01-01

    Full Text Available Ram Gupta,1 Anita R Chaudhary,2 Binita N Shah,1 Avinash V Jadhav,3 Shitalkumar P Zambad,1 Ramesh Chandra Gupta,4 Shailesh Deshpande,4 Vijay Chauthaiwale,4 Chaitanya Dutt4 1Department of Pharmacology, 2Cellular and Molecular Biology, 3Preclinical Safety Evaluation, 4Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India Background and aim: Mucosal healing in inflammatory bowel disease (IBD can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods: The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results: TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion: Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor

  18. Adverse drug events associated with vitamin K antagonists: factors of therapeutic imbalance

    Directory of Open Access Journals (Sweden)

    El-Helou N

    2013-03-01

    Full Text Available Nancy El-Helou, Amal Al-Hajje, Rola Ajrouche, Sanaa Awada, Samar Rachidi, Salam Zein, Pascale SalamehClinical and Epidemiological Research Laboratory, Faculty of Pharmacy, Lebanese University, Beirut, LebanonBackground: Adverse drug events (ADE occur frequently during treatment with vitamin K antagonists (AVK and contribute to increase hemorrhagic risks.Methods: A retrospective study was conducted over a period of 2 years. Patients treated with AVK and admitted to the emergency room of a tertiary care hospital in Beirut were included. The aim of the study was to identify ADE characterized by a high international normalized ratio (INR and to determine the predictive factors responsible for these events. Statistical analysis was performed with the SPSS statistical package.Results: We included 148 patients. Sixty-seven patients (47.3% with an INR above the therapeutic range were identified as cases. The control group consisted of 81 patients (54.7% with an INR within the therapeutic range. Hemorrhagic complications were observed in 53.7% of cases versus 6.2% of controls (P < 0.0001. No significant difference was noticed between cases and controls regarding the indication and the dose of AVK. Patients aged over 75 years were more likely to present an INR above the therapeutic range (58.2%, P = 0.049. Recent infection was present in 40.3% of cases versus 6.2% of controls (P < 0.0001 and hypoalbuminemia in 37.3% of cases versus 6.1% of controls (P < 0.0001. Treatment with antibiotics, amiodarone, and anti-inflammatory drugs were also factors of imbalance (P < 0.0001.Conclusion: Many factors may be associated with ADE related to AVK. Monitoring of INR and its stabilization in the therapeutic range are important for preventing these events.Keywords: adverse drug events, vitamin K antagonists, bleeding risks, therapeutic imbalance

  19. [Transgenic cell cultures that synthesize neurotrophic factors and the possibility of therapeutic use of its cells].

    Science.gov (United States)

    Pavlova, G V; Kanaĭkina, N N; Panteleev, D Iu; Okhotin, V E; Revishchin, A V

    2012-01-01

    Under the leadership of Corresponding Member of the Russian Academy of Sciences L.I. Korochkin, the Laboratory of Neurogenetics and Developmental Genetics (Institute of Gene Biology, Russian Academy of Sciences) for many years has been conducting studies of nervous system development, neural cell differentiation, and application of gene and cell technology to cure neurodegenerative diseases. The results of the study initiated by L.I. Korochkin and continued by his scientific successors support the direction of allocation of transgenic neurotrofic factors and heat-shock proteins as neuroprotectors for cell therapy. Potential for usage of promoter of HSP70 heat-shock gene of Drosophila to create transgenic constructs for therapy has been shown. Further improvement of technology of nonvirus transfer for therapeutic genes, as well as production of multicomponent genetic constructs coding several therapeutic factors with synergy effect, would stimulate creation of efficient cell medicals to cure neurodegenerative diseases.

  20. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    International Nuclear Information System (INIS)

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-01-01

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response

  1. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  2. Therapeutic interventions and success in risk factor control for secondary prevention of stroke.

    Science.gov (United States)

    Alvarez-Sabin, Jose; Quintana, Manuel; Hernandez-Presa, Miguel Angel; Alvarez, Carlos; Chaves, Jose; Ribo, Marc

    2009-01-01

    We sought to evaluate the success rates in achieving preventive therapeutic goals in patients who experienced an ischemic stroke (IS) and compare them with those achieved in patients with coronary artery disease (CAD). This was an observational multicenter case-control study (3 patients with IS and one control subject with CAD) performed in 1444 primary health centers in Spain. Preventive therapeutic objectives according to American Heart Association guidelines were predefined. Demographic data, vascular risk factors, and success/failure in achievement of objectives were recorded and compared between patients with IS and CAD. A total of 5458 patients were included, 4098 (75.1%) had IS and 1360 (24.9%) had CAD. Although more than 90% of patients with hypertension, diabetes, or dyslipidemia were under specific drug regimens, only about 25% achieved the recommended therapeutic objective for each risk factor. Success rate was especially low among patients with IS compared with CAD: hypertension (23.8% v 27.2%; P = .028); dyslipidemia (13.6% v 20.3%; P risk factors under control, compared with 5.6% of those with CAD (P = .006). For all patients, multivariate logistic regression model showed that independent predictors of full risk factor control were: presence of CAD as compared with IS (odds ratio [OR] 2.11; 95% confidence interval [CI] 1.35-3.29; P = .001), older age (OR 1.02; 95% CI 1.00-1.04; P = .028), and having less than 3 risk factors (OR 16.98; 95% CI 9.02-31.97; P risk factor control.

  3. Rheumatoid factor interference in immunogenicity assays for human monoclonal antibody therapeutics.

    Science.gov (United States)

    Tatarewicz, Suzanna; Miller, Jill M; Swanson, Steven J; Moxness, Michael S

    2010-05-31

    Rheumatoid factors (RFs) are endogenous human antibodies that bind to human gamma globulins. RFs demonstrate preferential binding to aggregated gamma globulins and are involved in the clearing mechanism of immune complexes. Immunoassays designed to measure human anti-human antibodies (HAHA) after administration of monoclonal antibody therapeutics are thus vulnerable to interference from RFs. When using a sensitive electrochemiluminescent (ECL) bridging immunoassay, samples from subjects with rheumatoid arthritis demonstrated much higher baseline reactivity than healthy subjects. Interference was found to be dependent on the aggregation state of the therapeutic antibody that had been conjugated with the detection reagent (ruthenium). Size exclusion high performance liquid chromatography (SE-HPLC) demonstrated that of the total integrated peaks, as little as 0.55% high molecular weight aggregates (>600kDa) were sufficient to cause increased reactivity. Stability studies of the ruthenium and biotin conjugated therapeutic antibody indicated that storage time, temperature and buffer formulation were critical in maintaining the integrity of the reagents. Through careful SE-HPLC monitoring we were able to choose appropriate storage and buffer conditions which led to a reduction in the false reactivity rate in therapeutic-naïve serum from a rheumatoid arthritis population.

  4. Factors associated with therapeutic success in HIV-positive individuals in southern Brazil.

    Science.gov (United States)

    Silveira, M P T; Maurer, P; Guttier, M C; Moreira, L B

    2015-04-01

    Therapeutic success is characterized by undetectable viral load, immune reconstitution confirmed by CD4+ T-cell count and no clinical manifestations of disease. High treatment adherence is a major determinant of therapeutic success that needs prevention of viral replication, allowing immune reconstitution. Adherence to treatment minimum wage (IQR 1·0-2·3). Therapeutic success was achieved by 90% (122 patients), and it was associated with previously undetectable viral load (PR = 1·30; 95% CI = 1·13-1·49) and treatment adherence prior to study entry (PR = 1·34; 95% CI = 1·07-1·69), independently of sex, age and previous immune status. When undetectable viral load, CD4+ cell count ≥200 cells/mm(3) and treatment adherence above 95% are included in the definition of therapeutic success, the rate was elevated (90%) and the factors associated were previous history of adherence to HAART and previous undetectable viral load. © 2014 John Wiley & Sons Ltd.

  5. Retrospective analysis of 104 histologically proven adult brainstem gliomas: clinical symptoms, therapeutic approaches and prognostic factors

    International Nuclear Information System (INIS)

    Reithmeier, Thomas; Kuzeawu, Aanyo; Hentschel, Bettina; Loeffler, Markus; Trippel, Michael; Nikkhah, Guido

    2014-01-01

    Adult brainstem gliomas are rare primary brain tumors (<2% of gliomas). The goal of this study was to analyze clinical, prognostic and therapeutic factors in a large series of histologically proven brainstem gliomas. Between 1997 and 2007, 104 patients with a histologically proven brainstem glioma were retrospectively analyzed. Data about clinical course of disease, neuropathological findings and therapeutic approaches were analyzed. The median age at diagnosis was 41 years (range 18-89 years), median KPS before any operative procedure was 80 (range 20-100) and median survival for the whole cohort was 18.8 months. Histopathological examinations revealed 16 grade I, 31 grade II, 42 grade III and 14 grade IV gliomas. Grading was not possible in 1 patient. Therapeutic concepts differed according to the histopathology of the disease. Median overall survival for grade II tumors was 26.4 months, for grade III tumors 12.9 months and for grade IV tumors 9.8 months. On multivariate analysis the relative risk to die increased with a KPS ≤ 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age ≥ 40 by the factor 1.7. External beam radiation reduced the risk to die by factor 0.4. Adult brainstem gliomas present with a wide variety of neurological symptoms and postoperative radiation remains the cornerstone of therapy with no proven benefit of adding chemotherapy. Low KPS, age ≥ 40 and higher tumor grade have a negative impact on overall survival

  6. Pharmacokinetic properties of 2nd-generation fibroblast growth factor-1 mutants for therapeutic application.

    Directory of Open Access Journals (Sweden)

    Xue Xia

    Full Text Available Fibroblast growth factor-1 (FGF-1 is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for therapeutic use. We report a pharmacokinetic (PK study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.

  7. Factors Associated with Therapeutic Efficacy of Intravesical OnabotulinumtoxinA Injection for Overactive Bladder Syndrome.

    Directory of Open Access Journals (Sweden)

    Sheng-Mou Hsiao

    Full Text Available To analyze the predictors of therapeutic efficacy after intravesical botulinum toxin A injection for overactive bladder syndrome (OAB refractory to antimuscarinic therapy.All consecutively OAB patients, who visited the urologic outpatient clinics of a medical center and refractory to antimuscarinic treatment, were prospectively enrolled. All enrolled patients received intravesical injection of 100 U onabotulinumtoxinA (Botox. The Global Response Assessment (GRA score ≥ 2 at 3 months after Botox injection was defined as a successful treatment, otherwise failed.Overall, 89 patients received intravesical injection. Eighty patients, including 42 men and 38 women, had received follow-up at 3 months. The overall success rate was 63.8%. The global response assessment, urgency severity score, urgency, urgency urinary incontinence and frequency episodes, and functional bladder capacity improved after treatment. However, post-void residual volume (PVR increased, and voiding efficiency (VE decreased after treatment. Female gender (odds ratio = 3.75 was the only independent factor associated with the success. Female gender (coefficient = 0.74, low baseline overactive bladder symptoms score (coefficient = -0.12 and the presence of OAB-wet (coefficient = 0.79 were independent factors associated with therapeutic efficacy (i.e., GRA score. VE (odds ratio = 0.062 was the only predictor for a large PVR at 3 months. The optimum cutoff value of VE was <87% with the area under the ROC curve being 0.64 (sensitivity = 63.8%, specificity = 57.1%.The therapeutic effects of Botox can persist till 6 months after treatment. Female gender, low overactive bladder symptoms score and OAB-wet are associated better therapeutic efficacy, and low baseline VE is associated with large PVR. These findings can serve as an initial guide or assist in consultation regarding the treatment of OAB patients with Botox injection.ClinicalTrials.gov NCT01657409.

  8. Ozone dosing alters the biological potential and therapeutic outcomes of plasma rich in growth factors.

    Science.gov (United States)

    Anitua, E; Zalduendo, M M; Troya, M; Orive, G

    2015-04-01

    Until now, ozone has been used in a rather empirical way. This in-vitro study investigates, for the first time, whether different ozone treatments of plasma rich in growth factors (PRGF) alter the biological properties and outcomes of this autologous platelet-rich plasma. Human plasma rich in growth factors was treated with ozone using one of the following protocols: a continuous-flow method; or a syringe method in which constant volumes of ozone and PRGF were mixed. In both cases, ozone was added before, during and after the addition of calcium chloride. Three ozone concentrations, of the therapeutic range 20, 40 and 80 μg/mL, were tested. Fibrin clot properties, growth factor content and the proliferative effect on primary osteoblasts and gingival fibroblasts were evaluated. Ozone treatment of PRGF using the continuous flow protocol impaired formation of the fibrin scaffold, drastically reduced the levels of growth factors and significantly decreased the proliferative potential of PRGF on primary osteoblasts and gingival fibroblasts. In contrast, treatment of PRGF with ozone using the syringe method, before, during and after the coagulation process, did not alter the biological outcomes of the autologous therapy. These findings suggest that ozone dose and the way that ozone combines with PRGF may alter the biological potential and therapeutic outcomes of PRGF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. 77 FR 64401 - Order of Succession for HUD Region VIII

    Science.gov (United States)

    2012-10-19

    ... Region VIII AGENCY: Office of Field Policy and Management, HUD. ACTION: Notice of Order of Succession... Field Offices (Region VIII). This Order of Succession supersedes all previous Orders of Succession for HUD Region VIII. DATES: Effective Date: October 9, 2012. FOR FURTHER INFORMATION CONTACT: Lawrence D...

  10. [Ehler-Danlos syndrome type VIII].

    Science.gov (United States)

    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.

  11. Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

    International Nuclear Information System (INIS)

    Sadri, Navid; Zhang, Paul J.

    2013-01-01

    Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression

  12. Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer's disease.

    Science.gov (United States)

    Faustino, Célia; Rijo, Patrícia; Reis, Catarina Pinto

    2017-06-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-β peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Factors influencing adherence with therapeutic sunlight exposure in older people in intermediate care facilities.

    Science.gov (United States)

    Durvasula, Seeta; Sambrook, Philip N; Cameron, Ian D

    2012-01-01

    The purpose of this study was to investigate the factors influencing low adherence with therapeutic sunlight exposure in a randomized controlled trial conducted with older people living in intermediate care facilities. The study involved participants in the FREEDOM (Falls Risk Epidemiology: Effect of vitamin D on skeletal Outcomes and other Measures) study, a randomized controlled trial of therapeutic sun exposure to reduce falls in older people in intermediate care facilities. Semi-structured interviews were conducted with thirty participants in the FREEDOM trial, and with ten sunlight officers who were employed to facilitate the sun exposure. Two focus groups involving 10 participants in the FREEDOM trial were also held at the end of the intervention period. Common themes were derived from the interview and focus group transcripts. The study showed that the perceived health benefits did not influence adherence with the sun exposure. Factors such as socializing with others and being outdoors were more important in encouraging attendance. The main barriers to adherence included the perceived inflexibility and regimentation of daily attendance, clash with other activities, unsuitable timing and heat discomfort. This study showed that providing greater flexibility and autonomy to older people in how and when they receive sun exposure is likely to improve adherence. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

    Science.gov (United States)

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-06-03

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

  15. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target

    International Nuclear Information System (INIS)

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo JA; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-01-01

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression. The online version of this article (doi:10.1186/s12885-015-1450-3) contains supplementary material, which is available to authorized users

  16. Main clinical, therapeutic and technical factors related to patient's maximum skin dose in interventional cardiology procedures

    Science.gov (United States)

    Journy, N; Sinno-Tellier, S; Maccia, C; Le Tertre, A; Pirard, P; Pagès, P; Eilstein, D; Donadieu, J; Bar, O

    2012-01-01

    Objective The study aimed to characterise the factors related to the X-ray dose delivered to the patient's skin during interventional cardiology procedures. Methods We studied 177 coronary angiographies (CAs) and/or percutaneous transluminal coronary angioplasties (PTCAs) carried out in a French clinic on the same radiography table. The clinical and therapeutic characteristics, and the technical parameters of the procedures, were collected. The dose area product (DAP) and the maximum skin dose (MSD) were measured by an ionisation chamber (Diamentor; Philips, Amsterdam, The Netherlands) and radiosensitive film (Gafchromic; International Specialty Products Advanced Materials Group, Wayne, NJ). Multivariate analyses were used to assess the effects of the factors of interest on dose. Results The mean MSD and DAP were respectively 389 mGy and 65 Gy cm−2 for CAs, and 916 mGy and 69 Gy cm−2 for PTCAs. For 8% of the procedures, the MSD exceeded 2 Gy. Although a linear relationship between the MSD and the DAP was observed for CAs (r=0.93), a simple extrapolation of such a model to PTCAs would lead to an inadequate assessment of the risk, especially for the highest dose values. For PTCAs, the body mass index, the therapeutic complexity, the fluoroscopy time and the number of cine frames were independent explanatory factors of the MSD, whoever the practitioner was. Moreover, the effect of technical factors such as collimation, cinematography settings and X-ray tube orientations on the DAP was shown. Conclusion Optimising the technical options for interventional procedures and training staff on radiation protection might notably reduce the dose and ultimately avoid patient skin lesions. PMID:22457404

  17. Emergence of Yalom's therapeutic factors in a peer-led, asynchronous, online support group for family caregivers.

    Science.gov (United States)

    Diefenbeck, Cynthia A; Klemm, Paula R; Hayes, Evelyn R

    2014-01-01

    Support groups fill a critical void in the health care system, harnessing the power of shared experiences to provide support to group members. Likewise, family caregivers fill a void in the health care system, providing billions in unpaid care to the chronically ill. Caregiver support groups offer an opportunity for alleviating the psychological burden of caregiving. The power of any group, including a support group, to foster psychological well-being lies in its ability to cultivate Yalom's therapeutic factors. Gaps in the literature remain regarding the ability of non-prototypical groups to promote therapeutic mechanisms of change. The purpose of this study was to determine if and when Yalom's therapeutic group factors emerged in a peer-led support group delivered in an asynchronous, online format. Qualitative content analysis utilizing deductive category application was employed. Participants' responses were coded and frequency counts were conducted. Results revealed that 9 of 11 therapeutic factors emerged over the course of the group, with Group Cohesiveness, Catharsis, Imparting of Information, and Universality occurring most often. Several factors, including Interpersonal Learning, Corrective Recapitulation of the Primary Family Group, Imitative Behavior, and Development of Socializing Techniques were absent or virtually absent, likely due to the peer-led format of the group. Progression of therapeutic factors over the course of the group is presented. Findings demonstrate the presence of a variety of Yalom's therapeutic factors in an asynchronous, peer-led online support group.

  18. Lithium ionophore VIII as an extraordinarily effective receptor for the strontium cation: Experimental and theoretical study

    Czech Academy of Sciences Publication Activity Database

    Makrlík, E.; Novák, Vít; Vaňura, P.; Bouř, Petr

    2014-01-01

    Roč. 1061, Mar 5 (2014), s. 110-113 ISSN 0022-2860 Institutional support: RVO:61388963 Keywords : strontium cation * lithium ionophore VIII * complexation * extraction and stability constants * DFT calculations * structures Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 1.602, year: 2014

  19. Complexation of the cesium cation with lithium ionophore VIII: extraction and DFT study

    Czech Academy of Sciences Publication Activity Database

    Makrlík, E.; Novák, Vít; Vaňura, P.; Bouř, Petr

    2013-01-01

    Roč. 298, č. 3 (2013), s. 2065-2068 ISSN 0236-5731 Institutional support: RVO:61388963 Keywords : cesium cation * lithium ionophore VIII * complexation * extraction and stability constants * water-nitrobenzene system * DFT calculations * structures Subject RIV: CB - Analytical Chemistry , Separation Impact factor: 1.415, year: 2013

  20. Arcanobacterium pyogenes: Virulence factors, importance in mastitis etiology and therapeutic (impossibilities

    Directory of Open Access Journals (Sweden)

    Milanov Dubravka

    2011-01-01

    Full Text Available Arcanobacterium pyogenes is an opportunistic pathogen, a causative agent of suppurative infections of organs and tissues in economically important livestock species. Most frequently this bacteria is isolated from inflamed lung lesions in pigs and cattle, in samples of uterine mucus of cows with endometritis and milk from cows with clinical mastitis. A. pyogenes possesses a number of virulence factors: cholesterol-dependent cytolysin (pyolysin, two neuraminidases, several proteases, extracellular matrix-binding proteins, DNases, fimbriae. The virulence factors are well studied in laboratory conditions, but the role of these factors in the pathogenesis of A. pyogenes infections remains to be elucidated. Lately, the ability of A. pyogenes to form biofilm in vivo has also been implicated as a virulence factor and a possible cause of therapeutic failure. Despite the fact that A. pyogenes milk isolates in cows with mastitis in vitro are very sensitive to β-lactam drugs and tetracycline, experience has shown that therapy is usually ineffective, prognosis is poor and the affected quarter is lost for milk production.

  1. Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    So Yeon Kim

    2015-11-01

    Full Text Available Hypoxia-inducible factor (HIF prolyl hydroxylases (PHDs are members of the 2-oxoglutarate dependent non-heme iron dioxygenases. Due to their physiological roles in regulation of HIF-1α stability, many efforts have been focused on searching for selective PHD inhibitors to control HIF-1α levels for therapeutic applications. In this review, we first describe the structure of PHD2 as a molecular basis for structure-based drug design (SBDD and various experimental methods developed for measuring PHD activity. We further discuss the current status of the development of PHD inhibitors enabled by combining SBDD approaches with high-throughput screening. Finally, we highlight the clinical implications of small molecule PHD inhibitors.

  2. Adherencia terapéutica y factores psicosociales en pacientes hipertensos Therapeutic adherence and psychosocial factors in hypertensive patients

    Directory of Open Access Journals (Sweden)

    Yadmila Rosa Matos La

    2007-03-01

    Full Text Available La terapéutica de las enfermedades cardiovasculares requiere de la modificación de ciertos hábitos y comportamientos, de ahí la importancia del cumplimiento de las prescripciones médicas. Con la finalidad de describir los factores psicosociales asociados a la adherencia terapéutica se realizó un estudio descriptivo, de corte transversal, en una muestra de 263 pacientes hipertensos distribuidos en 13 consultorios del Médico de Familia del Policlínico Docente “Edor de los Reyes Martínez”, en el Consejo Popular Sur, del área urbana del municipio Jiguaní, provincia Granma. La información se obtuvo a través de la aplicación de un cuestionario elaborado para este fin. Los resultados más relevantes fueron: las creencias que tiene el paciente acerca del tratamiento como beneficio para su salud, los conocimientos adecuados sobre las características de la enfermedad, los afrontamientos al tratamiento con autoeficacia y la percepción de suficientes redes de apoyo social, que son los que más se asocian a la adherencia terapéutica.The therapeutics of the cardiovascular diseases requires the modification of certain habits and behaviors, that's why the fulfillment of the medical prescriptions is so important. With the objective of describing the psychosical factors associated with therapeutical adherence, a descriptive, cross-sectional study was undertaken in a sample of 263 hypertensive patients distributed in 13 family physicians' offices of “Edor de los Reyes Martínez” Teaching Polyclinic in the Southern People's Council of the urban area of Jiguaní municipality, Granma province. The information was obtained by applying a questionnaire made to this end. The most relevant results were: the patient's belief that the treatment benefits his health, the adequate knowledge of the characteristics of the disease, the facing of the treatment with self-efficiency, and the perception of enough social support networks. These outcomes are

  3. Contributing factors for therapeutic diet adherence in patients receiving haemodialysis treatment: an integrative review.

    Science.gov (United States)

    Oquendo, Lissete González; Asencio, José Miguel Morales; de Las Nieves, Candela Bonill

    2017-12-01

    The objective of this integrative review is to identify the factors that contribute to diet adherence in people suffering from kidney disease who are receiving haemodialysis treatment. Adherence to the therapeutic regimen determines therapeutic success, quality of life and survival in patients on haemodialysis. Lack of diet adherence ranges from 25%-86% in patients receiving haemodialysis treatment and affects patient morbidity and mortality. An integrative literature review was conducted based on the criteria of Whittemore & Knafl. A literature review was performed by two members of the team using twelve databases including PubMed, CUIDEN, CINAHL, The Cochrane Library and ScienceDirect. The main issues identified after analysing the results were as follows: the intrinsic barriers (age, dialysis time, motivation, perceived benefit, distorted perception of adherence) and facilitators (self-efficacy, perception of disease, perception of control), extrinsic barriers (family dysfunction, lack of social support, cultural patterns of consumption of food) and facilitators (social support, relationship with healthcare providers), and interventions to encourage diet adherence, such as the use of motivational interviewing in educational interventions, and the training and education of relevant professionals in communication skills. Diet nonadherence remains a serious health problem and suffers from a lack of solid criteria to identify this condition. The onset of depression signs and the level of social support available to the patient should be assessed, because these are important factors that determine adherence to treatment. Professionals should be trained in health education and communication techniques to contribute to the patient's self-management and motivation for diet adherence. Controlled and randomised clinical studies involving predialysis stages should be performed to investigate the impact of the assessment and control of barriers to diet adherence. © 2017

  4. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer

    International Nuclear Information System (INIS)

    Yoshida, Kazumichi; Tsujimoto, Hironori; Matsumura, Kouji; Kinoshita, Manabu; Takahata, Risa; Matsumoto, Yusuke; Hiraki, Shuichi; Ono, Satoshi; Seki, Shuhji; Yamamoto, Junji; Hase, Kazuo

    2015-01-01

    CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence-activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid-forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47 hi gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47 lo , and CD44 hi CD47 hi cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer

  5. Relationship of Personal- Social and Therapeutic Factors with Medication Compliance in TB Patients in Ahwaz

    Directory of Open Access Journals (Sweden)

    S Jahani

    2012-01-01

    Full Text Available Introduction: Despite the implementation of DOTS strategy, TB remains one of the ten leading causes of death in developing countries. Compliance with treatment is affected by social, cultural, and economic factors, and patients’ knowledge and attitude as well. The aim of this study was to determine the relationship between compliance with treatment and personal, social and therapeutic factors in TB patients in Ahwaz. Methods: This cross-sectional descriptive study was conducted on 167 TB patients. Subjects were selected based on target. The data were collected using a questionnaire, and by observation, sputum analysis, and Kvzart Ponce urine test. The validity of the questionnaire was tested by the method of content validity, and its internal consistency and reliability was tested by Cronbach's alpha coefficient. Data analyzed by SpSS. Results: Among all subjects, 52.7% of patients showed complete compliance and 35.2% and 12% of them showed partial and poor compliance, respectively. There was a significant relationship between treatment compliance and gender(p=0.009, quality of monthly income(p=0.007, and addiction(p=0.001. The quality of treatment compliance was not significantly related to age, marital status, educational level, ethnicity, and medical complications. Conclusion: The findings showed that Incomplete treatment of TB is much worse than not treating it, because the lack of precision in the administration and consumption of anti-tuberculosis drugs, leads to the emergence of resistant TB. Paying attention to the factors decreasing treatment compliance and trying to eliminate them may lead to better treatment and lower incidence and prevalence of tuberculosis in the community.

  6. Effects of certain therapeutic factors on facial development in isolated cleft palate.

    Science.gov (United States)

    Smahel, Z

    1989-01-01

    Roentgencephalometry was used during the investigation of the effects of some therapeutic factors on the growth and development of the jaws in 64 adult males with an isolated cleft palate repaired by pushback. The anterior growth of the maxilla was not related to the age at the time of surgery or to orthodontic therapy with removable appliances. A small number of individuals operated during adolescence had also a shorter depth of the maxilla similarly as patients operated upon during early childhood. Anterior crossbite developed mostly in patients with reduced proclination of the upper alveolar process, while, on the contrary, a retrusion of the maxilla played no essential part. This observation proves useful for the prediction of the development of this malocclusion. The angle of sagittal jaw relations does not represent necessarily a valid criterion of the development of the jaws. In the presence of an overbite retrusion of the maxilla is associated with a retroposition of the mandible and thus the angle of sagittal jaw relations remains unchanged. Thus overbite represents an effective mechanism acting on the position of the mandible. A differentiated approach for the determination of the age of choice at the time of palate surgery according to the type and extent of the cleft is proposed.

  7. Hypoxia-Inducible Factor-1 as a Therapeutic Target in Endometrial Cancer Management

    Directory of Open Access Journals (Sweden)

    Laura M. S. Seeber

    2010-01-01

    Full Text Available In the Western world, endometrial cancer (EC is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1 (HIF-1 plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF-1 protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials.

  8. Contextual factors and clinical reasoning: differences in diagnostic and therapeutic reasoning in board certified versus resident physicians.

    Science.gov (United States)

    McBee, Elexis; Ratcliffe, Temple; Picho, Katherine; Schuwirth, Lambert; Artino, Anthony R; Yepes-Rios, Ana Monica; Masel, Jennifer; van der Vleuten, Cees; Durning, Steven J

    2017-11-15

    The impact of context on the complex process of clinical reasoning is not well understood. Using situated cognition as the theoretical framework and videos to provide the same contextual "stimulus" to all participants, we examined the relationship between specific contextual factors on diagnostic and therapeutic reasoning accuracy in board certified internists versus resident physicians. Each participant viewed three videotaped clinical encounters portraying common diagnoses in internal medicine. We explicitly modified the context to assess its impact on performance (patient and physician contextual factors). Patient contextual factors, including English as a second language and emotional volatility, were portrayed in the videos. Physician participant contextual factors were self-rated sleepiness and burnout.. The accuracy of diagnostic and therapeutic reasoning was compared with covariates using Fisher Exact, Mann-Whitney U tests and Spearman Rho's correlations as appropriate. Fifteen board certified internists and 10 resident physicians participated from 2013 to 2014. Accuracy of diagnostic and therapeutic reasoning did not differ between groups despite residents reporting significantly higher rates of sleepiness (mean rank 20.45 vs 8.03, U = 0.5, p reasoning performance. Further, the processes of diagnostic and therapeutic reasoning, although related, may not be interchangeable. This raises important questions about the impact that contextual factors have on clinical reasoning and provides insight into how clinical reasoning processes in more authentic settings may be explained by situated cognition theory.

  9. In vitro assessment of TAT — Ciliary Neurotrophic Factor therapeutic potential for peripheral nerve regeneration

    International Nuclear Information System (INIS)

    Barbon, Silvia; Stocco, Elena; Negro, Alessandro; Dalzoppo, Daniele; Borgio, Luca; Rajendran, Senthilkumar; Grandi, Francesca; Porzionato, Andrea; Macchi, Veronica; De Caro, Raffaele

    2016-01-01

    In regenerative neurobiology, Ciliary Neurotrophic Factor (CNTF) is raising high interest as a multifunctional neurocytokine, playing a key role in the regeneration of injured peripheral nerves. Despite its promising trophic and regulatory activity, its clinical application is limited by the onset of severe side effects, due to the lack of efficient intracellular trafficking after administration. In this study, recombinant CNTF linked to the transactivator transduction domain (TAT) was investigated in vitro and found to be an optimized fusion protein which preserves neurotrophic activity, besides enhancing cellular uptake for therapeutic advantage. Moreover, a compelling protein delivery method was defined, in the future perspective of improving nerve regeneration strategies. Following determination of TAT-CNTF molecular weight and concentration, its specific effect on neural SH-SY5Y and PC12 cultures was assessed. Cell proliferation assay demonstrated that the fusion protein triggers PC12 cell growth within 6 h of stimulation. At the same time, the activation of signal transduction pathway and enhancement of cellular trafficking were found to be accomplished in both neural cell lines after specific treatment with TAT-CNTF. Finally, the recombinant growth factor was successfully loaded on oxidized polyvinyl alcohol (PVA) scaffolds, and more efficiently released when polymer oxidation rate increased. Taken together, our results highlight that the TAT domain addiction to the protein sequence preserves CNTF specific neurotrophic activity in vitro, besides improving cellular uptake. Moreover, oxidized PVA could represent an ideal biomaterial for the development of nerve conduits loaded with the fusion protein to be delivered to the site of nerve injury. - Highlights: • TAT-CNTF is an optimized fusion protein that preserves neurotrophic activity. • In neural cell lines, TAT-CNTF triggers the activation of signal transduction. • Fast cellular uptake of TAT-CNTF was

  10. In vitro assessment of TAT — Ciliary Neurotrophic Factor therapeutic potential for peripheral nerve regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Barbon, Silvia, E-mail: silvia.barbon@yahoo.it [Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via Marzolo 5, 35131 Padua (Italy); Foundation for Biology and Regenerative Medicine, Tissue Engineering and Signaling (TES) ONLUS, Via De Sanctis 10, Caselle di Selvazzano Dentro, 35030 Padua (Italy); Stocco, Elena, E-mail: elena.stocco@gmail.com [Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via Marzolo 5, 35131 Padua (Italy); Foundation for Biology and Regenerative Medicine, Tissue Engineering and Signaling (TES) ONLUS, Via De Sanctis 10, Caselle di Selvazzano Dentro, 35030 Padua (Italy); Negro, Alessandro, E-mail: alessandro.negro@unipd.it [Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35121 Padua (Italy); Dalzoppo, Daniele, E-mail: daniele.dalzoppo@unipd.it [Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via Marzolo 5, 35131 Padua (Italy); Borgio, Luca, E-mail: borgio.luca@gmail.com [Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via Marzolo 5, 35131 Padua (Italy); Rajendran, Senthilkumar, E-mail: senthilstem@gmail.com [Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via Marzolo 5, 35131 Padua (Italy); Grandi, Francesca, E-mail: francesca.grandi7825@gmail.com [Department of Women' s and Children' s Health, Pediatric Surgery, University of Padua, Via Giustiniani 3, 35121 Padua (Italy); Porzionato, Andrea, E-mail: andrea.porzionato@unipd.it [Section of Human Anatomy, Department of Molecular Medicine, University of Padua, Via Gabelli 65, 35121 Padua (Italy); Macchi, Veronica, E-mail: veronica.macchi@unipd.it [Section of Human Anatomy, Department of Molecular Medicine, University of Padua, Via Gabelli 65, 35121 Padua (Italy); De Caro, Raffaele, E-mail: raffaele.decaro@unipd.it [Section of Human Anatomy, Department of Molecular Medicine, University of Padua, Via Gabelli 65, 35121 Padua (Italy); and others

    2016-10-15

    In regenerative neurobiology, Ciliary Neurotrophic Factor (CNTF) is raising high interest as a multifunctional neurocytokine, playing a key role in the regeneration of injured peripheral nerves. Despite its promising trophic and regulatory activity, its clinical application is limited by the onset of severe side effects, due to the lack of efficient intracellular trafficking after administration. In this study, recombinant CNTF linked to the transactivator transduction domain (TAT) was investigated in vitro and found to be an optimized fusion protein which preserves neurotrophic activity, besides enhancing cellular uptake for therapeutic advantage. Moreover, a compelling protein delivery method was defined, in the future perspective of improving nerve regeneration strategies. Following determination of TAT-CNTF molecular weight and concentration, its specific effect on neural SH-SY5Y and PC12 cultures was assessed. Cell proliferation assay demonstrated that the fusion protein triggers PC12 cell growth within 6 h of stimulation. At the same time, the activation of signal transduction pathway and enhancement of cellular trafficking were found to be accomplished in both neural cell lines after specific treatment with TAT-CNTF. Finally, the recombinant growth factor was successfully loaded on oxidized polyvinyl alcohol (PVA) scaffolds, and more efficiently released when polymer oxidation rate increased. Taken together, our results highlight that the TAT domain addiction to the protein sequence preserves CNTF specific neurotrophic activity in vitro, besides improving cellular uptake. Moreover, oxidized PVA could represent an ideal biomaterial for the development of nerve conduits loaded with the fusion protein to be delivered to the site of nerve injury. - Highlights: • TAT-CNTF is an optimized fusion protein that preserves neurotrophic activity. • In neural cell lines, TAT-CNTF triggers the activation of signal transduction. • Fast cellular uptake of TAT-CNTF was

  11. The labour ward analgesic service at King Edward VIII Hospital ...

    African Journals Online (AJOL)

    The labour ward analgesic service at King Edward VIII. Hospital, Durban. D. A. ROCKE, C. C. ROUT, H. D. RUSSELL, S. SINGH. Abstract The provision of analgesic services to the labour ward at King Edward VIII Hospital was studied during a I-week period. Of249 patients, 113 (45%) received no analgesia whatsoever.

  12. Therapeutic Factors and Members' Perception of Co-Leaders' Attitudes in a Psychoeducational Group for Greek Children with Social Anxiety

    Science.gov (United States)

    Brouzos, Andreas; Vassilopoulos, Stephanos P.; Baourda, Vasiliki C.

    2015-01-01

    The purpose of this study was to investigate therapeutic factors and perception of co-leaders' attitudes in elementary children. The Critical Incident Questionnaire was collected from participants during 8 sessions of 3 psychoeducational groups for social anxiety, whereas the Barrett-Lennard Relationship Inventory was administered twice. It was…

  13. Understanding Factors Associated with Early Therapeutic Alliance in PTSD Treatment: Adherence, Childhood Sexual Abuse History, and Social Support

    Science.gov (United States)

    Keller, Stephanie M.; Zoellner, Lori A.; Feeny, Norah C.

    2010-01-01

    Objective: Therapeutic alliance has been associated with better treatment engagement, better adherence, and less dropout across various treatments and disorders. In treatment of posttraumatic stress disorder (PTSD), it may be particularly important to establish a strong early alliance to facilitate treatment adherence. However, factors such as…

  14. Impact of therapeutic factors on local control in T2-T3 anal carcinoma treated by radiation or radiochemotherapy

    International Nuclear Information System (INIS)

    Allal, Abdelkarim S.; Mermillod, Bernadette; Kurtz, John M.; Marti, Marc-Claude

    1996-01-01

    Purpose: To investigate the influence of therapeutic parameters on local control in T2-T3 anal carcinoma treated by chemo-radiotherapy or radiation therapy alone. Materials and Methods: From 1976 to 1993, 137 patients with anal carcinoma staged T2 (85) or T3 (52) completed curative sphincter-conservating treatment, 54 with radiotherapy alone and 83 with concomitant chemo-radiotherapy. Radiation therapy was delivered in two sequences with a median gap of 46 days. The two main techniques used for the first sequence were a direct perineal cobalt field ± a sacral arc field with a median dose of 30 Gy/10 fractions/19 days (27.7%) and two antero-posterior opposed pelvic fields (≥ 6 MV photons) with a median dose of 40 Gy/20 fractions/31 days (62%). Iridium-192 implant boost was used in 116 patients (median dose 20 Gy, Paris system) and external radiation boost in 21 patients (median dose 20 Gy/10 fractions/13 days). Generally the chemoradiotherapy patients received starting on day 1 an IV bolus of Mitomycin-C (0.4 mg/kg, maximum 20 mg) and a 5-day continuous infusion of 5-fluorourcil 600-800 mg/m 2 /day. For surviving patients median follow-up was 65 months. Univariate and multivariate analyses were carried out to determine therapeutic parameters affecting local control after adjustment for clinical factors. Results: The 5-year actuarial local control was 77%. Factors associated with a decrease of local control in univariate analysis included: age less than 66 years (67% vs 85%), male gender (65% vs 81%), tumor extension more than (1(3)) circumference of the anal canal (68% vs 90%), lymph node involvement (64% vs 81%), use of external irradiation for the boost (62% vs 79%), and overall treatment time more than 74 days (69% vs 85%). In a multivariate analysis none of the therapeutic parameters remained significant when adjusted for the four significant clinical factors. The only therapeutic factor which might have had an impact was overall treatment time (p = .09

  15. Multiple factor analysis of the therapeutic effect of 131I in treating 783 cases of Graves disease

    International Nuclear Information System (INIS)

    Cai Min; Li Xianfeng; Li Sijin; Chen Haibin

    2008-01-01

    Objective: To study the factors influencing therapeutic effect of 131 I in treating 783 cases of Graves disease. Methods: The values of various indexes were quantized on influencing factors such as age, sex, course of disease, mass of thyroid gland, the absorbed dose of 131 I per gram of thryoid gland, the given dose of 131 I, thyroid 24 h 131 I uptaking percentage, thyroid hormone and thyroid autoantibodys. The assessment of the therapeutic effect was made according to complete remission (including hypothyroidism) and partial remission after 131 I therapy. CMH χ 2 , Wilcoxon signed-rank test and Logistic regression were used to analyze the variable parameters before the treatment. Results: The therapeutic effect of 131 I is significant in the follow-up period (CMH χ 2 =69.21, P 131 I therapy for 12 months. The therapeutic effect was related to such factors as age thyroid mass, the absorbed dose of 131 I per gram of thryoid gland, thyroid 24 h 131 I uptaking percentage, etc (all the values of P 131 I uptaking percentage is higher, thyroid mass is bigger, thyroid gland is with noduses, the given dose of 131 I should be increased. Conversely decreased. (authors)

  16. One-electron spectrum of Xe VIII

    International Nuclear Information System (INIS)

    Roberts, J.R.; Knystautas, E.J.; Sugar, J.

    1979-01-01

    The spectrum of Xe VIII has been observed in a theta-pinch discharge. New line identifications were made that determine the energies of the 6s, 7s, 6p, and 5f terms relative to the 5s 2 S ground state and confirm the previously known 5p and 5d terms. An independent system of levels derived from the observed 4f-ng (n = 5,6) transitions was found. Its position relative to the ground state is obtained from a predicted value for the 5g effective quantum number n*. From the ns series (n=5--7) a value for the ionization enegy of 105.91 +- 0.05 eV was derived

  17. VIII International Meeting on Lorentzian Geometry

    CERN Document Server

    Flores, José; Palomo, Francisco; GeLoMa 2016; Lorentzian geometry and related topics

    2017-01-01

    This volume contains a collection of research papers and useful surveys by experts in the field which provide a representative picture of the current status of this fascinating area. Based on contributions from the VIII International Meeting on Lorentzian Geometry, held at the University of Málaga, Spain, this volume covers topics such as distinguished (maximal, trapped, null, spacelike, constant mean curvature, umbilical...) submanifolds, causal completion of spacetimes, stationary regions and horizons in spacetimes, solitons in semi-Riemannian manifolds, relation between Lorentzian and Finslerian geometries and the oscillator spacetime. In the last decades Lorentzian geometry has experienced a significant impulse, which has transformed it from just a mathematical tool for general relativity to a consolidated branch of differential geometry, interesting in and of itself. Nowadays, this field provides a framework where many different mathematical techniques arise with applications to multiple parts of mathem...

  18. VIII Brazilian Meeting on Simulational Physics (BMSP)

    International Nuclear Information System (INIS)

    Branco, N. S.; Figueiredo, W.; Plascak, J. A.; Santos, M.

    2016-01-01

    This special issue includes invited and selected articles of the VIII Brazilian Meeting on Simulational Physics (BMSP), held in Florianópolis, Santa Catarina, Brazil, from 3rd to 8th August, 2015. This is the eighth such meeting, and the second one to have contributed papers published in Journal of Physics: Conference Series (the other was the VII BMSP). The previous meetings in the BMSP series took place in the mountains of Minas Gerais, in the region of the Brazilian Pantanal, and in the shores of Paraíba. Now, for the first time, the Meeting was held in Florianópolis, with its pleasing shores, the capital of Santa Catarina state. The VIII BMSP brought together about 50 researchers from all over the world for a vibrant and productive conference. As in the previous meetings, the talks and posters highlighted recent advances in applications, algorithms, and implementation of computer simulation methods for the study of condensed matter, materials, and out of equilibrium, quantum and biologically motivated systems. We are sure that this meeting series will continue to be an important occasion for people working in simulational physics to exchange ideas and discuss the state of the art of this always expanding field. We are very glad to put together this special issue, and are most appreciative of the efforts of the editors of the Journal of Physics: Conference Series for making this publication possible. We are grateful for the outstanding work of the Florianopolis team, for the financial support of the Brazilian agencies CAPES and CNPq, and of the Federal Universities UFPB and UFSC. At last, but not least, we would like to acknowledge all of the authors for their written submissions. (paper)

  19. Myostatin and insulin-like growth factor I: potential therapeutic biomarkers for pompe disease.

    Directory of Open Access Journals (Sweden)

    Yin-Hsiu Chien

    Full Text Available OBJECTIVE: Myostatin and insulin-like growth factor 1 (IGF-1 are serum markers for muscle growth and regeneration. However, their value in the clinical monitoring of Pompe disease - a muscle glycogen storage disease - is not known. In order to evaluate their possible utility for disease monitoring, we assessed the levels of these serum markers in Pompe disease patients receiving enzyme replacement therapy (ERT. DESIGN: A case-control study that included 10 patients with Pompe disease and 10 gender- and age-matched non-Pompe disease control subjects was performed in a referral medical center. Average follow-up duration after ERT for Pompe disease patients was 11.7 months (range: 6-23 months. Measurements of serum myostatin, IGF-1, and creatine kinase levels were obtained, and examinations of muscle pathology were undertaken before and after ERT in the patient group. RESULTS: Compared with control subjects, Pompe disease patients prior to undergoing ERT had significantly lower serum IGF-1 levels (98.6 ng/ml vs. 307.9 ng/ml, p = 0.010 and lower myostatin levels that bordered on significance (1.38 ng/ml vs. 3.32 ng/ml, p = 0.075. After ERT, respective myostatin and IGF-1 levels in Pompe disease patients increased significantly by 129% (from 1.38 ng/ml to 3.16 ng/ml, p = 0.047 and 74% (from 98.6 ng/ml to 171.1 ng/ml, p = 0.013; these values fall within age-matched normal ranges. In contrast, myostatin and IGF-1 serum markers did not increase in age-matched controls. Follistatin, a control marker unrelated to muscle, increased in both Pompe disease patients and control subjects. At the same time, the percentage of muscle fibers containing intracytoplasmic vacuoles decreased from 80.0±26.4% to 31.6±45.3%. CONCLUSION: The increase in myostatin and IGF-1 levels in Pompe disease patients may reflect muscle regeneration after ERT. The role of these molecules as potential therapeutic biomarkers in Pompe disease and other neuromuscular

  20. Therapeutic efficacy of fibroblast growth factor 10 in a rabbit model of dry eye.

    Science.gov (United States)

    Zheng, Wenjing; Ma, Mingming; Du, Ergang; Zhang, Zhengwei; Jiang, Kelimu; Gu, Qing; Ke, Bilian

    2015-11-01

    The aim of the present study was to investigate the therapeutic efficacy of fibroblast growth factor 10 (FGF10) in the promotion of healing, survival and expression of mucin in corneal epithelial cells in a rabbit dry eye model. A total of 12 healthy female New Zealand white rabbits were divided randomly into three groups. The lacrimal glands were injected with saline either alone (normal control group) or with concanavalin A (Con A), with either topical phosphate‑buffered saline (PBS; PBS control group) or 25 µg/ml FGF10 (FGF10 treatment group). Lacrimal gland inflammation, tear function, corneal epithelial cell integrity, cell apoptosis and mucin expression were subsequently assessed. Lacrimal gland tissue biopsies were performed in conjunction with histology and electron microscopy observations. Tear meniscus height (TMH) and tear meniscus area (TMA) were measured using Fourier domain‑optical coherence tomography. Tear membrane break‑up time (TBUT) was also assessed and corneal fluorescein staining was performed. The percentages of apoptotic corneal and conjunctival (Cj) epithelial cells (ECs) were counted using a terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling method. The mRNA expression levels of Muc1 were determined using reverse transcription‑quantitative polymerase chain reaction analyses. The TMH and TMA values of the PBS and treatment groups were found to be significantly reduced, compared with those of the normal control group 3 days after Con A injection. However, the TMH and TMA of the FGF10 treatment group were higher, compared with those of the PBS group 3 and 7 days after treatment, respectively. Furthermore, the FGF10 treatment group exhibited prolonged TBUT, reduced corneal fluorescein staining and repaired epithelial cell ultrastructure7 days after treatment. The percentages of apoptotic corneal‑ and Cj‑ECs in the FGF10 treatment group were significantly reduced, compared with those in the PBS group. FGF10

  1. Acquired hemophilia A: a review of recent data and new therapeutic options.

    Science.gov (United States)

    Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

    2017-10-01

    Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

  2. Cellular and molecular mechanisms of chronic rhinosinusitis and potential therapeutic strategies: review on cytokines, nuclear factor kappa B and transforming growth factor beta.

    Science.gov (United States)

    Phan, N T; Cabot, P J; Wallwork, B D; Cervin, A U; Panizza, B J

    2015-07-01

    Chronic rhinosinusitis is characterised by persistent inflammation of the sinonasal mucosa. Multiple pathophysiological mechanisms are likely to exist. Previous research has focused predominantly on T-helper type cytokines to highlight the inflammatory mechanisms. However, proteins such as nuclear factor kappa B and transforming growth factor beta are increasingly recognised to have important roles in sinonasal inflammation and tissue remodelling. This review article explores the roles of T-helper type cytokines, nuclear factor kappa B and transforming growth factor beta in the pathophysiological mechanisms of chronic rhinosinusitis. An understanding of these mechanisms will allow for better identification and classification of chronic rhinosinusitis endotypes, and, ultimately, improved therapeutic strategies.

  3. Significance of forecasting factors for correction of therapeutic tactics in children with lymphogranulomatosis

    International Nuclear Information System (INIS)

    Kobikov, S.Kh.

    1989-01-01

    Ways of reducing the frequency of lymphogranulomatosis recurrences in 347 children after radio and chemotherapy are considered. Children are irradiated using the Rocus gamma therapeutic device and accelerators applying 15-25 MeV energy electron beam. Integral focal doses make up 40-45 Gy

  4. Therapeutic groin dissection for melanoma : Risk factors for short term morbidity

    NARCIS (Netherlands)

    Poos, H. P. A. M.; Kruijff, S.; Bastiaannet, E.; van Ginkel, R. J.; Hoekstra, H. J.

    Aims: Ilio-inguinal lymph node dissection for stage III melanoma is often complicated by wound healing disturbances. A retrospective study was performed to investigate the wound healing disturbances after therapeutic ili-inguinal lymphj node dissection. Patients and methods: Between 1989 and 2007,

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

    Science.gov (United States)

    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

  6. Experimental Methodology used by Cell Cultures Laboratory from INRMFB to assess the therapeutic effect of natural factors

    Directory of Open Access Journals (Sweden)

    Munteanu Constantin

    2010-11-01

    Full Text Available The experimental study design on cell cultures allows the direct biological evaluation at the cellular level, of the therapeutic effect that natural factors can play over the organism.Techniques for obtaining cell cultures requires a complex and laborious task that starts from live tissue sampling, continuous with isolation of cells and their preparation for sowing a culture plate. This preparation involves mechanical and enzymatic action from the researcher on biological material. Derived cell cultures are monitored morphologically by high-performance inverted biological microscope, with video camera for image acquisition. In the final stage, the cells are scraped, and through biochemical and molecular techniques, the therapeutic efficiency hypothesis of the investigated natural factor is verified experimentally. The cell cultures can be crioconservated in special containers with liquid nitrogen.

  7. Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.

    LENUS (Irish Health Repository)

    Cathcart, Mary-Clare

    2011-03-01

    Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease.

  8. Growth/differentiation factor-5: a candidate therapeutic agent for periodontal regeneration? A review of pre-clinical data.

    Science.gov (United States)

    Moore, Yolanda R; Dickinson, Douglas P; Wikesjö, Ulf M E

    2010-03-01

    Therapeutic concepts involving the application of matrix, growth and differentiation factors have been advocated in support of periodontal wound healing/regeneration. Growth/differentiation factor-5 (GDF-5), a member of the bone morphogenetic protein family, represents one such factor. The purpose of this review is to provide a background of the therapeutic effects of GDF-5 expressed in various musculoskeletal settings using small and large animal platforms. A comprehensive literature search was conducted to identify all reports in the English language evaluating GDF-5 using the PubMed and Google search engines, and a manual search of the reference lists from the electronically retrieved reports. Two reviewers independently screened the titles and abstracts from a total of 69 reports, 22 of which were identified as pre-clinical (in vivo) evaluations of GDF-5. The full-length article of the 22 pre-clinical reports was then reviewed. Various applications including cranial and craniofacial bone formation, spine fusion, long bone fracture healing, cartilage, and tendon/ligament repair using a variety of small and large animal platforms evaluating GDF-5 as a therapeutic agent were identified. A majority of studies, using biomechanical, radiographic, and histological analysis, demonstrated significant dose-dependent effects of GDF-5. These include increased/enhanced local bone formation, fracture healing/repair, and cartilage and tendon/ligament formation. GDF-5 frequently was shown to accelerate wound maturation. Several studies demonstrated GDF-5 to be a realistic alternative to autograft bone. Studies using pre-clinical models and human histology suggest GDF-5 may also increase/enhance periodontal wound healing/regeneration. GDF-5 appears a promising therapeutic agent for periodontal wound healing/regeneration as GDF-5 supports/accelerates bone and tendon/ligament formation in several musculoskeletal settings including periodontal tissues.

  9. Understanding factors associated with early therapeutic alliance in PTSD treatment: adherence, childhood sexual abuse history, and social support.

    Science.gov (United States)

    Keller, Stephanie M; Zoellner, Lori A; Feeny, Norah C

    2010-12-01

    Therapeutic alliance has been associated with better treatment engagement, better adherence, and less dropout across various treatments and disorders. In treatment of posttraumatic stress disorder (PTSD), it may be particularly important to establish a strong early alliance to facilitate treatment adherence. However, factors such as childhood sexual abuse (CSA) history and poor social support may impede the development of early alliance in those receiving PTSD treatment. We sought to examine treatment adherence, CSA history, and social support as factors associated with early alliance in individuals with chronic PTSD who were receiving either prolonged exposure therapy (PE) or sertraline. At pretreatment, participants (76.6% female; 64.9% Caucasian; mean age = 37.1 years, SD = 11.3) completed measures of trauma history, general support (Inventory of Socially Supportive Behaviors), and trauma-related social support (Social Reactions Questionnaire). Over the course of 10 weeks of PE or sertraline, they completed early therapeutic alliance (Working Alliance Inventory) and treatment adherence measures. Early alliance was associated with PE adherence (r = .32, p history was not predictive of a lower early alliance. Given the associations with adherence, clinicians may find it useful to routinely assess alliance early in treatment. Positive trauma support, not CSA history, may be particularly important in the development of a strong early therapeutic alliance. (c) 2010 APA, all rights reserved.

  10. Factors influencing patient compliance with therapeutic regimens in chronic heart failure: A critical incident technique analysis.

    Science.gov (United States)

    Strömberg, A; Broström, A; Dahlström, U; Fridlund, B

    1999-01-01

    The aim of this study was to identify factors influencing compliance with prescribed treatment in patients with chronic heart failure. A qualitative design with a critical incident technique was used. Incidents were collected through interviews with 25 patients with heart failure strategically selected from a primary health care clinic, a medical ward, and a specialist clinic. Two hundred sixty critical incidents were identified in the interviews and 2 main areas emerged in the analysis: inward factors and outward factors. The inward factors described how compliance was influenced by the personality of the patient, the disease, and the treatment. The outward factors described how compliance was influenced by social activities, social relationships, and health care professionals. By identifying the inward and outward factors influencing patients with chronic heart failure, health care professionals can assess whether intervention is needed to increase compliance.

  11. Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma—A Review

    Science.gov (United States)

    Siriwardena, Samadarani B. S. M.; Tsunematsu, Takaaki; Qi, Guangying; Ishimaru, Naozumi; Kudo, Yasusei

    2018-01-01

    It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. PMID:29758011

  12. Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential

    Directory of Open Access Journals (Sweden)

    Tom J. Burdon

    2011-01-01

    Full Text Available During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.

  13. [Post-therapeutic evolution and prognostic factors of intestinal lymphomas, Retrospective analysis of 42 cases].

    Science.gov (United States)

    Sánchez-Fayos, M P; Hernández Guío, C; Rivas, M C; Outeiriño, J; González-Campos, C; Lobo, F

    1993-12-01

    To evaluate in retrospect the response to therapy and long-term evolution of a series of primitive intestinal lymphomas. The series was comprised of 42 patients diagnosed in our hospital during 1960-1962. The mean age was 34.5 years (range, 3-73), the M/F ratio was 21/21, and the histopathology distributes as follows: high grade (HG), 24 cases, low grade (LG), 12 cases, and mixed (LG/HG), 6 cases. B/T immunophenotype: 40/2. Staging: IE1,29 cases, IIE2-IV, 11 cases. The treatment applied in the series was classified in various types: ample surgical resection (aSR), 21 cases; partial surgical resection (pSR), 9 cases; abdominal radiation therapy (RT), 7 cases; monochemotherapy (MCT), 7 cases, and polychemotherapy (PCT), 28 cases. The correlation of clinicobiological variables with immediate response to treatment was evaluated by means of the chi square test, and the acturial post-therapeutic survival curves in accordance to the life tables, differences being calculated by the log rank test. Small intestine was the commonest site of involvement, 31 cases; ileocecal region, 7 cases; colon, 2 cases, and colon plus small intestine, 2 cases. Regardless of therapy type, complete remission (CR) was attained in 20 patients (47.5%), partial remission in 5; 11 cases were unresponsive (26.5%) and early death occurred in 6 instances (14.2%). The acturial post-therapeutic survival offered an 8-year expectancy of 47%. The correlation between immediate complete response and 16 clinico-biologic variables showed favourable significance for tumoral proliferation index (i.e., Pc10-positive cells studies. 2) Female sex, type of therapy, multifocal involvement, the need of emergency surgery and high LDH levels have significant value in univariate analyses.

  14. How was it for you? What factors influence job satisfaction for band 5 and 6 therapeutic radiographers

    International Nuclear Information System (INIS)

    Hutton, Daniel; Eddy, Angie

    2013-01-01

    Effective recruitment, retention and development of the existing workforce will become increasingly important as cancer incidence increases, patient numbers increase, and challenging targets are set to deliver world class radiotherapy in the UK. This study aimed to explore the experiences of therapy radiographers working at band five and six with specific reference to job satisfaction. The key objectives were: 1.To explore and understand the experiences of Therapeutic Radiographers from graduation to their first senior/supervisory position. 2.To identify the factors that influence perceptions of job satisfaction. 3.To suggest supportive strategies which could lead to increased job satisfaction? Method: A qualitative case study approach using focus groups was adopted to explore the professional experience of therapeutic radiographers in two large departments. Thematic analysis was used to identify categories and themes, which informed the development of a framework that identified factors that influence job satisfaction. Results and discussion: The participants identified diverse but interlinking facets that influence job satisfaction. The core theme was continuous professional development and subthemes were; organisation issues, transition into role, workload and teamwork. Job satisfaction appears to be multifaceted and is dependent on the individual, context of work and the working environment. Conclusion: Significant factors which impact on job satisfaction for band 5–6 therapy radiographers have been identified. It would appear that these could be positively influenced by managers and organisations. Further insight into the professional experiences of therapeutic radiographers is needed with specific reference to preceptorship/mentoring, staff appraisals and career aspirations/expectations. This insight would be valuable to inform future retention and development strategies

  15. Factors affecting length of stay in forensic hospital setting: need for therapeutic security and course of admission.

    LENUS (Irish Health Repository)

    Davoren, Mary

    2015-01-01

    Patients admitted to a secure forensic hospital are at risk of a long hospital stay. Forensic hospital beds are a scarce and expensive resource and ability to identify the factors predicting length of stay at time of admission would be beneficial. The DUNDRUM-1 triage security scale and DUNDRUM-2 triage urgency scale are designed to assess need for therapeutic security and urgency of that need while the HCR-20 predicts risk of violence. We hypothesized that items on the DUNDRUM-1 and DUNDRUM-2 scales, rated at the time of pre-admission assessment, would predict length of stay in a medium secure forensic hospital setting.

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

    Science.gov (United States)

    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 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 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 hemophilia A. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and

  17. Factors influencing GPs’ choice between drugs in a therapeutic drug group. A qualitative study

    DEFF Research Database (Denmark)

    Buusman, Allan; Andersen, Morten; Merrild, Camilla Hoffmann

    2007-01-01

    (GPs) were selected with reference to variation in organizational structure, age, and gender. Main outcome measures. GPs' description of drug choice in relation to specific patient encounters involving a prescription. Results. All informants appeared to consider drug price important...... as it was a recurring theme during all interviews. External factors outside the GP's control such as governmental regulation on prescribing and the pharmaceutical industry influenced most GPs. Internal factors related to the actual consultation included characteristics of the GP and the patient, drug characteristics......, and repeat prescriptions. These factors interact in a non-linear and unpredictable way similar to complex adaptive systems. Conclusion. GPs balance both internal and external factors when choosing between analogues. Drug choice is a regulated process in the realm of complex prescribing behaviour with drug...

  18. Pre-therapeutic factors for predicting survival after radioembolization: a single-center experience in 389 patients

    International Nuclear Information System (INIS)

    Paprottka, K.J.; Schoeppe, F.; Ingrisch, M.; Ruebenthaler, J.; Sommer, N.N.; Paprottka, P.M.; Toni, E. de; Ilhan, H.; Zacherl, M.; Todica, A.

    2017-01-01

    To determine pre-therapeutic predictive factors for overall survival (OS) after yttrium (Y)-90 radioembolization (RE). We retrospectively analyzed the pre-therapeutic characteristics (sex, age, tumor entity, hepatic tumor burden, extrahepatic disease [EHD] and liver function [with focus on bilirubin and cholinesterase level]) of 389 consecutive patients with various refractory liver-dominant tumors (hepatocellular carcinoma [HCC], cholangiocarcinoma [CCC], neuroendocrine tumor [NET], colorectal cancer [CRC] and metastatic breast cancer [MBC]), who received Y-90 radioembolization for predicting survival. Predictive factors were selected by univariate Cox regression analysis and subsequently tested by multivariate analysis for predicting patient survival. The median OS was 356 days (95% CI 285-427 days). Stable disease was observed in 132 patients, an objective response in 71 (one of which was complete remission) and progressive disease in 122. The best survival rate was observed in patients with NET, and the worst in patients with MBC. In the univariate analyses, extrahepatic disease (P < 0.001), large tumor burden (P = 0.001), high bilirubin levels (>1.9 mg/dL, P < 0.001) and low cholinesterase levels (CHE <4.62 U/I, P < 0.001) at baseline were significantly associated with poor survival. Tumor entity, tumor burden, extrahepatic disease and CHE were confirmed in the multivariate analysis as independent predictors of survival. Sex, applied RE dose and age had no significant influence on OS. Pre-therapeutic baseline bilirubin and CHE levels, extrahepatic disease and hepatic tumor burden are associated with patient survival after RE. Such parameters may be used to improve patient selection for RE of primary or metastatic liver tumors. (orig.)

  19. Pre-therapeutic factors for predicting survival after radioembolization: a single-center experience in 389 patients

    Energy Technology Data Exchange (ETDEWEB)

    Paprottka, K.J.; Schoeppe, F.; Ingrisch, M.; Ruebenthaler, J.; Sommer, N.N.; Paprottka, P.M. [LMU - University of Munich, Department of Clinical Radiology, Munich (Germany); Toni, E. de [LMU - University of Munich, Department of Hepatology, Munich (Germany); Ilhan, H.; Zacherl, M.; Todica, A. [LMU - University of Munich, Department of Nuclear Medicine, Munich (Germany)

    2017-07-15

    To determine pre-therapeutic predictive factors for overall survival (OS) after yttrium (Y)-90 radioembolization (RE). We retrospectively analyzed the pre-therapeutic characteristics (sex, age, tumor entity, hepatic tumor burden, extrahepatic disease [EHD] and liver function [with focus on bilirubin and cholinesterase level]) of 389 consecutive patients with various refractory liver-dominant tumors (hepatocellular carcinoma [HCC], cholangiocarcinoma [CCC], neuroendocrine tumor [NET], colorectal cancer [CRC] and metastatic breast cancer [MBC]), who received Y-90 radioembolization for predicting survival. Predictive factors were selected by univariate Cox regression analysis and subsequently tested by multivariate analysis for predicting patient survival. The median OS was 356 days (95% CI 285-427 days). Stable disease was observed in 132 patients, an objective response in 71 (one of which was complete remission) and progressive disease in 122. The best survival rate was observed in patients with NET, and the worst in patients with MBC. In the univariate analyses, extrahepatic disease (P < 0.001), large tumor burden (P = 0.001), high bilirubin levels (>1.9 mg/dL, P < 0.001) and low cholinesterase levels (CHE <4.62 U/I, P < 0.001) at baseline were significantly associated with poor survival. Tumor entity, tumor burden, extrahepatic disease and CHE were confirmed in the multivariate analysis as independent predictors of survival. Sex, applied RE dose and age had no significant influence on OS. Pre-therapeutic baseline bilirubin and CHE levels, extrahepatic disease and hepatic tumor burden are associated with patient survival after RE. Such parameters may be used to improve patient selection for RE of primary or metastatic liver tumors. (orig.)

  20. Mycobacterium biofilms: factors involved in development, dispersal, and therapeutic strategies against biofilm-relevant pathogens.

    Science.gov (United States)

    Xiang, Xiaohong; Deng, Wanyan; Liu, Minqiang; Xie, Jianping

    2014-01-01

    Many bacteria can develop biofilm (BF), a multicellular structure largely combining bacteria and their extracellular polymeric substances (EPS). The formation of biofilm results in an alternative existence in which microbes ensure their survival in adverse environments. Biofilm-relevant infections are more persistent, resistant to most antibiotics, and more recalcitrant to host immunity. Mycobacterium tuberculosis, the causative agent of tuberculosis, can develop biofilm, though whether M. tuberculosis can form biofilm within tuberculosis patients has yet to be determined. Here, we summarize the factors involved in the development and dispersal of mycobacterial biofilms, as well as underlying regulatory factors and inhibitors against biofilm to deepen our understanding of their development and to elucidate potential novel modes of action for future antibiotics. Key factors in biofilm formation identified as drug targets represent a novel and promising avenue for developing better antibiotics.

  1. VIII International Congress of Engineering Physics

    International Nuclear Information System (INIS)

    2017-01-01

    The Physicist Engineering is a multidisciplinary profession in which an undergraduate student integrates and applies their knowledge of Physics, Mathematics, and Computing to adapt and innovate all kind of technologies, as well as to development and apply theoretical knowledge to different fields of science and engineering. A Physicist Engineer, supported by a solid preparation in science and engineering is available to study, analyze, identify, and solve problems in different fields of science and technology for industries, hospitals, research laboratories, institutes and governmental organizations focused on metrology, optics, energy, materials, instrumentation of sophisticated equipment. The Physicist Engineering bachelor degree is a national and international reference to encouraging all those students to apply knowledge through active participation in the operation, planning, and management of projects. The technological and scientific impact of a Physicist Engineering undergraduate and graduate students, as well as the tutorial of the research professor that are interested in Physics and Physics Engineering, may be found in a biennial event like the International Conference on Physicist Engineering, through the diffusion of both experimental and theoretical research and teaching. In order to promote and encourage strength academic goals among universities and research institutions, the International Conference on Physics Engineering Committee, integrated by a faculty meeting of the Universidad Autónoma Metropolitana, Campus Azcapotzalco, has decided to grant the VIII International Congress of Physics Engineering to the Universidad Autónoma de Yucatán, which is going to take place on Mérida, November 7 th to 11 th , 2016. This conference considers different topics as: Renewables Energies Engineering Materials Technology Nanotechnology Medical Physics Education in Physics Engineering Nuclear Engineering High Precision Instrumentation Atmosphere Physics

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

    Science.gov (United States)

    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.

  3. Vascular risk factors and Alzheimer’s disease. Therapeutic approaches in mouse models

    NARCIS (Netherlands)

    Wiesmann, M.

    2017-01-01

    The first aim of this thesis was to elucidate the impact of major vascular risk factors like hypertension, apoE4 and stroke during the very early phase of Alzheimer’s disease (AD) using several mice models. Hypertension has proven to be associated with cerebrovascular impairment already at young age

  4. Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

    NARCIS (Netherlands)

    Barker, J.M.; Taylor, J.R.; de Vries, T.J.; Peters, J.

    2015-01-01

    Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural

  5. Non-Therapeutic Risk Factors for Onset of Tardive Dyskinesia in Schizophrenia : A Meta-Analysis

    NARCIS (Netherlands)

    Tenback, Diederik E.; van Harten, Peter N.; van Os, Jim

    2009-01-01

    A meta-analysis of prospective studies with schizophrenia patients was conducted to examine whether the evidence exists for risk factors for the emergence of Tardive Dyskinesia (TD) in schizophrenia. A computer assisted Medline/PubMed and Embase search was' conducted in January 2008 for the years

  6. Alzheimer Disease and Its Growing Epidemic: Risk Factors, Biomarkers, and the Urgent Need for Therapeutics.

    Science.gov (United States)

    Hickman, Richard A; Faustin, Arline; Wisniewski, Thomas

    2016-11-01

    Alzheimer disease (AD) represents one of the greatest medical challenges of this century; the condition is becoming increasingly prevalent worldwide and no effective treatments have been developed for this terminal disease. Because the disease manifests at a late stage after a long period of clinically silent neurodegeneration, knowledge of the modifiable risk factors and the implementation of biomarkers is crucial in the primary prevention of the disease and presymptomatic detection of AD, respectively. This article discusses the growing epidemic of AD and antecedent risk factors in the disease process. Disease biomarkers are discussed, and the implications that this may have for the treatment of this currently incurable disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. New Insights into Biology, Prognostic Factors, and Current Therapeutic Strategies in Chronic Lymphocytic Leukemia

    OpenAIRE

    Smolewski, Piotr; Witkowska, Magdalena; Korycka-Wołowiec, Anna

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of mature B lymphocytes. CLL cells show an antiapoptotic profile, suggesting the important role of apoptosis inhibition in the disease development. However, there is some population of proliferating CLL cells, which may also play a role in progression of the disease. There are several newer, biological prognostic factors in CLL. Currently, cytogenetic abnormalities with different prognostic values...

  8. Janez Rugelj's alternative therapeutic community after the five-factor model of personality

    Directory of Open Access Journals (Sweden)

    Judita Bagon

    2000-12-01

    Full Text Available The Alternative Therapeutic Community (ATC of Dr. J. Rugelj is a specific social community consisting of people in distress (always consisting of about 120 people, who have all been handicapped in their lives in one way or another. The group is also specific because of their way towards recovery, i.e., intensively reactivating the mecanisms of healthy life to surmount their psychical and social deficiency. The results of measuring the structure of personality according to BFQ – the "Big Five" model of personality – show that the ATC as a whole achieves lower scores than the normal population on all dimensions and subdimensions. The difference is statistically significant regarding the dimension of Emotional stability as well as the subdimension Emotional control. The ATC is not a uniform group, so the results differ according to the diagnosis. The members with the diagnosis of 'a neurotic' or 'a psychotic' achieve below-average results, while the accompanying members achieve similar results as the control group (selected from the non-members of the ATC. The results of the members diagnosed as 'an alcoholic' are somewhat surprising – they do not differ considerably on any dimension or subdimension from the results achieved by the control group – not even on the Emotional stability scale. As regards the total period of staying in the program, the results of subdimensions remain mostly unchanged. However, during the time spent in the program the results on the subdimensions change: the group which has been in the program for 1 to 2 years generally scores higher than the group of beginners (the difference is statistically significant only for the dimension Emotional control, but the results of the group participating in the program for longer time (more than three years are lower again, until they stabilize in the central position (T=50. The results on theHonesty scale (which may also show positive or negative self-image show no

  9. Modeling silicon diode energy response factors for use in therapeutic photon beams.

    Science.gov (United States)

    Eklund, Karin; Ahnesjö, Anders

    2009-10-21

    Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high-energy component are treated according to Spencer-Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 x 5 cm(2), 10 x 10 cm(2) and 20 x 20 cm(2) fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams.

  10. Precipitating factors and therapeutic outcome in epilepsy with generalized tonic-clonic seizures.

    Science.gov (United States)

    Bauer, J; Saher, M S; Burr, W; Elger, C E

    2000-10-01

    The aim of the study was to evaluate the influence of precipitating factors and therapy on the outcome of epilepsy with generalized tonic-clonic seizures. Retrospective analysis of data from 34 patients (mean age at seizure onset 19 years; mean duration of follow-up 9.2 years) suffering from epilepsy of either cryptogenic or remote symptomatic (n = 19), or idiopathic (n = 15) etiology. The total number of seizures in all patients was 146. Without treatment 97 seizures manifested during 90.5 years without treatment (1.07 seizures/year), during treatment with carbamazepine or valproate 49 seizures occurred within 224 years (0.2 seizures/year). The frequency of seizures was significantly lower during treatment. Precipitating factors were found in relation to 31% of seizures in patients with remote symptomatic or cryptogenic epilepsy, and for 51% of seizures in patients with idiopathic epilepsy. There was a low frequency of seizures in patients with generalized tonic-clonic seizures. Precipitating factors are common. Antiepileptic drug treatment is effective.

  11. Modeling silicon diode energy response factors for use in therapeutic photon beams

    International Nuclear Information System (INIS)

    Eklund, Karin; Ahnesjoe, Anders

    2009-01-01

    Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high-energy component are treated according to Spencer-Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 x 5 cm 2 , 10 x 10 cm 2 and 20 x 20 cm 2 fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams.

  12. The expanding universe of neurotrophic factors: therapeutic potential in aging and age-associated disorders.

    Science.gov (United States)

    Lanni, C; Stanga, S; Racchi, M; Govoni, S

    2010-01-01

    Multiple molecular, cellular, structural and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively by employing multiple mechanisms in order to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands. Otherwise, they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. An important role in this balancement is played by neurotrophic factors, which are central to many aspects of nervous system function since they regulate the development, maintenance and survival of neurons and neuron-supporting cells such as glia and oligodendrocytes. A vast amount of evidence indicates that alterations in levels of neurotrophic factors or their receptors can lead to neuronal death and contribute to aging as well as to the pathogenesis of diseases of abnormal trophic support (such as neurodegenerative diseases and depression) and diseases of abnormal excitability (such as epilepsy and central pain sensitization). Cellular and molecular mechanisms by which neurotrophic factors may influence cell survival and excitability are also critically examined to provide novel concepts and targets for the treatment of physiological changes bearing detrimental functional alterations and of different diseases affecting the central nervous system during aging.

  13. Ultrasound Elasticity Imaging Predicts Therapeutic Outcomes of Patients With Crohn's Disease Treated With Anti-Tumour Necrosis Factor Antibodies.

    Science.gov (United States)

    Orlando, Stefania; Fraquelli, Mirella; Coletta, Marina; Branchi, Federica; Magarotto, Andrea; Conti, Clara Benedetta; Mazza, Stefano; Conte, Dario; Basilisco, Guido; Caprioli, Flavio

    2018-01-05

    Ultrasound elasticity imaging is a non-invasive technique developed to evaluate fibrosis. Measuring tissue strain by ultrasound elasticity imaging can reliably detect severe ileal fibrosis in patients with Crohn's disease [CD]. We have hypothesised that a more severe range of fibrosis might influence the therapeutic response to anti-tumour necrosis factor [TNF] treatment. The aim of this study was to assess the ability of ultrasound elasticity imaging to predict the therapeutic outcome for CD patients. Consecutive patients with ileal/ileocolonic CD, starting anti-TNF treatment, were enrolled for the study. These patients underwent bowel ultrasound and ultrasound elasticity imaging at baseline and at 14 and 52 weeks after anti-TNF treatment. Bowel wall stiffness was quantified by calculating the strain ratio between the mesenteric tissue and the bowel wall. Strain ratio ≥ 2 was used to identify severe ileal fibrosis. Transmural healing at 14 and 52 weeks was defined as bowel wall thickness ≤ 3 mm. Thirty patients with CD were enrolled. Five patients underwent surgery for bowel obstruction. The frequency of surgeries was significantly greater in patients with a strain ratio ≥ 2 at baseline [p = 0.003]. A significant reduction of the bowel thickness was observed after 14 and 52 weeks of anti-TNF treatment [p < 0.005]. A significant inverse correlation was observed between the strain ratio values at baseline and the thickness variations following anti-TNF therapy [p = 0.007]; 27% of patients achieved transmural healing at 14 weeks. The baseline strain ratio was significantly lower in patients with transmural healing [p < 0.05]. This study shows that ultrasound elasticity imaging predicts therapeutic outcomes for CD patients treated with anti-TNF. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

  14. Prognostic Factors Influencing the Patency of Hemodialysis Vascular Access: Literature Review and Novel Therapeutic Modality by Far Infrared Therapy

    Directory of Open Access Journals (Sweden)

    Chih-Ching Lin

    2009-03-01

    Full Text Available In Taiwan, more than 85% of patients with end-stage renal disease undergo maintenance hemodialysis (HD. The native arteriovenous fistula (AVF accounts for a prevalence of more than 80% of the vascular access in our patients. Some mechanical factors may affect the patency of hemodialysis vascular access, such as surgical skill, puncture technique and shear stress on the vascular endothelium. Several medical factors have also been identified to be associated with vascular access prognosis in HD patients, including stasis, hypercoagulability, endothelial cell injury, medications, red cell mass and genotype polymorphisms of transforming growth factor-β1 and methylene tetrahydrofolate reductase. According to our previous study, AVF failure was associated with a longer dinucleotide (GTn repeat (n ≥ 30 in the promoter of the heme oxygenase-1 (HO-1 gene. Our recent study also demonstrated that far-infrared therapy, a noninvasive and convenient therapeutic modality, can improve access flow, inflammatory status and survival of the AVF in HD patients through both its thermal and non-thermal (endothelial-improving, anti-inflammatory, antiproliferative, antioxidative effects by upregulating NF-E2-related factor-2-dependent HO-1 expression, leading to the inhibition of expression of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1.

  15. Therapeutic results and prognostic factors after irradiation of loco-regional prostate cancer

    International Nuclear Information System (INIS)

    Debrigode, C.; Dubois, J.; Hay, H.M.; Astre, C.; Savu, N.M.

    1994-01-01

    The present study concerns 140 patients with loco-regional prostatic cancer, treated with external beam irradiation at the CRLC Val-d'Aurelle in Montpellier, France, between 1982 and 1988, with a minimum of 54 months follow-up. The local control after radiotherapy is 78.6%, all stages and histological grades combined. The median overall survival is 114 months and the median disease-free survival 59 months. The most frequent modality of treatment failure is metastatic disease, isolated (32.8%) or combined to local relapse (10%). The rate of urinary intolerance symptoms during treatment was 87.1 and 80.6% for the digestive ones. The late urinary complications and sequellae rate was 21.4% for the cystitis-type and 12.9% for post-radiotherapy urethral structures; the latter has imposed in 2/3 of cases one or more trans-urethral resections that never showed pathological signs of recurrence. Digestive complications and sequellae occurred in 31.3% of the patients; in the latter group there were two internal digestive fistulae which needed surgical treatment and three postradiotherapeutic stenosis of the anal canal. The prognostic factors revealed by statistical analysis are clinical stage, pathological grade for overall and disease-free survival, age for overall survival and trans-urethral resection for disease-free survival, the latter being equally a risk factor for cystitis-type complications and urethral structures. (authors). 26 refs., 8 figs., 7 tabs

  16. Therapeutic effects of neurotrophic factors in experimental spinal cord injury models

    Directory of Open Access Journals (Sweden)

    Enomoto M

    2016-03-01

    Full Text Available Mitsuhiro Enomoto1,21Department of Orthopaedic and Spinal Surgery, Graduate School, 2Hyperbaric Medical Center, Tokyo Medical and Dental University, Tokyo, JapanAbstract: Neurotrophic factors (NFs play important roles in regenerative medicine approaches to mitigate primary and secondary damage after spinal cord injury (SCI because their receptors are still present in the injured spinal cord even though the expression of the NFs themselves is decreased. Several reports have shown that NF administration increases regenerative signaling after SCI, particularly by stimulating axonal growth. However, few NFs cross the blood–brain barrier, and most of them show low stability and limited diffusion within the central nervous system. To overcome this problem, transplantation strategies using genetically modified NF-secreting Schwann cells, neural and glial progenitor cells, and mesenchymal stem cells have been applied to animal models of SCI. In particular, multifunctional NFs that bind to TrkB, TrkC, and p75NTR receptors have been discovered in the last decade and utilized in preclinical cell therapies for spinal cord repair. To achieve functional recovery after SCI, it is important to consider the different effects of each NF on axonal regeneration, and strategies should be established to specifically harness the multifunctional properties of NFs. This review provides an overview of multifunctional NFs combined with cell therapy in experimental SCI models and a proposal to implement their use as a clinically viable therapy.Keywords: spinal cord injury, neurotrophic factor, multineurotrophin, regeneration, cell transplantation

  17. The Therapeutic Potential of Insulin-Like Growth Factor-1 in Central Nervous System Disorders

    Science.gov (United States)

    Costales, Jesse; Kolevzon, Alexander

    2016-01-01

    Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for insulin-like growth factor-1 (IGF-1) in normal CNS development. Work in model systems has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of efficacy in disorders of the CNS, including autism spectrum disorder (ASD). In this review, we explore the molecular pathways and downstream effects of IGF-1 and summarize the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. This aim of this review is to provide evidence for the potential of IGF-1 as a treatment for neurodevelopmental disorders and ASD. PMID:26780584

  18. Hypoxia Inducible Factor Signaling and Experimental Persistent Pulmonary Hypertension of the Newborn: A Therapeutic Opportunity

    Directory of Open Access Journals (Sweden)

    Stephen eWedgwood

    2015-03-01

    Full Text Available BACKGROUND: Mitochondrial reactive oxygen species levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN. These events can trigger hypoxia inducible factor (HIF signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood.AIM: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms. RESULTS: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1Hz and 15% elongation for 24h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB.CONCLUSION: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.

  19. Cross-Cultural Approach of Postpartum Depression: Manifestation, Practices Applied, Risk Factors and Therapeutic Interventions.

    Science.gov (United States)

    Evagorou, Olympia; Arvaniti, Aikaterini; Samakouri, Maria

    2016-03-01

    It is a well known fact that postpartum depression (PPD) is a global phenomenon that women may experience, regardless of cultural identity and beliefs. This literature review presents the cultural beliefs and postnatal practices around the world, in each continent and people's origins, looking through the extent to which they contribute positively or negatively to the onset of the disease. 106 articles were used in this research, through a systematic electronic search of Pubmed (Medline) and Scopus. Comparison is also made between the prevalence, the risk factors and the different ways of appearance of the disease around the world and among immigrants. Finally, the initiatives and interventions made so far by the governments and institutions with a view to prevent and address this global problem are presented. The results showed (a) that different cultures share the same risk factors towards the disease (b) significant differences in the prevalence of the disease among both Western and non Western cultures and between the cultures themselves (c) more tendencies for somatization of depressive symptoms in non-Western cultures, (d) different postnatal practices between cultures, which are not always effective (e) the more non-West a culture is, the less interventions concern on mental health; the same phenomenon is observed on populations burdened by immigration. The beliefs held by culture should be taken seriously in detecting of PPD, as well as the assessment of the needs of women who have recently given birth.

  20. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α in Major Depressive Disorder: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Ke Ma

    2016-05-01

    Full Text Available Major depressive disorder (MDD is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α, play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

  1. Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients.

    Science.gov (United States)

    Yeh, Chun-Nan; Chang, Yu-Chan; Su, Yeu; Shin-Shian Hsu, Dennis; Cheng, Chi-Tung; Wu, Ren-Chin; Chung, Yi-Hsiu; Chiang, Kun-Chun; Yeh, Ta-Sen; Lu, Meng-Lun; Liu, Chun-Yu; Mu-Hsin Chang, Peter; Chen, Ming-Han; Huang, Chi-Ying F; Hsiao, Michael; Chen, Ming-Huang

    2017-12-26

    Intrahepatic cholangiocarcinoma (CCA) is an aggressive cancer that lacks an effective targeted therapy. Here, we assessed the therapeutic efficacy of regorafenib in CCA, as well as elucidated its underlying mechanism. We first demonstrated that regorafenib not only inhibited growth but also induced apoptosis in human CCA cells. Subsequently, we used in silico approaches to identify MALT1 (Mucosa-associated lymphoid tissue protein 1), which plays an important role in activating NF-κB, as a potential target of regorafenib. Overexpression of Elk-1, but not Ets-1, in HuCCT1 cells markedly reduced their sensitivity to regorafenib, which might be attributed to a significant increase in MALT1 levels. Our results further demonstrated that this drug drastically inhibited MALT1 expression by suppressing the Raf/Erk/Elk-1 pathway. The efficacy of regorafenib in decreasing in vivo CCA growth was confirmed in animal models. Regorafenib efficacy was observed in two MALT1-positive CCA patients who failed to respond to several other lines of therapy. Finally, MALT1 was also identified as an independent poor prognostic factor for patients with intrahepatic CCA. In conclusion, our study identified MALT1 to be a downstream mediator of the Raf/Erk/Elk-1 pathway and suggested that MALT1 may be a new therapeutic target for successful treatment of CCA by regorafenib.

  2. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review

    Science.gov (United States)

    Ma, Ke; Zhang, Hongxiu; Baloch, Zulqarnain

    2016-01-01

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies. PMID:27187381

  3. Clinical holistic medicine: factors influencing the therapeutic decision-making. From academic knowledge to emotional intelligence and spiritual "crazy" wisdom.

    Science.gov (United States)

    Ventegodt, Søren; Kandel, Isack; Merrick, Joav

    2007-12-10

    Scientific holistic medicine is built on holistic medical theory, on therapeutic and ethical principles. The rationale is that the therapist can take the patient into a state of salutogenesis, or existential healing, using his skills and knowledge. But how ever much we want to make therapy a science it remains partly an art, and the more developed the therapist becomes, the more of his/her decisions will be based on intuition, feeling and even inspiration that is more based on love and human concern and other spiritual motivations than on mental reason and rationality in a simple sense of the word. The provocative and paradoxal medieval western concept of the "truth telling clown", or the eastern concepts of "crazy wisdom" and "holy madness" seems highly relevant here. The problem is how we can ethically justify this kind of highly "irrational" therapeutic behavior in the rational setting of a medical institution. We argue here that holistic therapy has a very high success rate and is doing no harm to the patient, and encourage therapists, psychiatrists, psychologist and other academically trained "helpers" to constantly measure their own success-rate. This paper discusses many of the important factors that influence clinical holistic decision-making. Sexuality could, as many psychoanalysts from Freud to Reich and Searles have believed, be the most healing power that exists and also the most difficult for the mind to comprehend, and thus the most "crazy-wise" tool of therapy.

  4. Choice of therapeutic tactics after failure of the first tumor necrosis factor-α inhibitor

    Directory of Open Access Journals (Sweden)

    N. V. Chichasova

    2017-01-01

    Full Text Available The paper discusses whether the effect of different biological agents (BAs can be achieved in patients with active rheumatoid arthritis (RA when they inadequately respond to therapy with tumor necrosis factor-α (TNF-α inhibitors. It gives data on the efficacy of BAs with another mechanism of action (abatacept, tocilizumab, and rituximab and on the comparable efficacy of golimumab (GLM in this group of patients. It is shown that the effect of GLM therapy does not depend on the reasons for discontinuation of a previously used TNF-α inhibitors (inefficacy, adverse events, etc.. It is conclusion that GLM is effective after failure of one or two TNF-α inhibitors.

  5. Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

    Science.gov (United States)

    Harper, Shavonn C; Brack, Andrew; MacDonnell, Scott; Franti, Michael; Olwin, Bradley B; Bailey, Beth A; Rudnicki, Michael A; Houser, Steven R

    2016-04-01

    This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good. © 2016 American Heart Association, Inc.

  6. Comercio Internacional mediterráneo en el siglo VIII a.C.

    Directory of Open Access Journals (Sweden)

    Paloma Cabrera Bonet

    2018-01-01

    Full Text Available The VIII century B.C. saw, for the first time after the breakdown of the system in the Late Bronze Age, the revival of a true intemational trade at a growing scale, especíally protagonized by Phoenicians and Greeks. In this article we analyze sorne aspects of this phenomenon, from the Aegean to the Far West, which made possíble, through a vaste network of trading routes, a large multinational ínteractíon. We understand the international trade as a key factor in the proccess of economic, social and political changes of the Mediterranean areas submerged in this complex "world-system".

  7. Socioeconomic and clinical factors are key to uncovering disparity in accrual onto therapeutic trials for breast cancer.

    Science.gov (United States)

    Behrendt, Carolyn E; Hurria, Arti; Tumyan, Lusine; Niland, Joyce C; Mortimer, Joanne E

    2014-11-01

    To monitor and address disparity in accrual, patient participation in cancer clinical trials is routinely summarized by race/ethnicity. To investigate whether confounding obscures racial/ethnic disparity in participation, all women with breast cancer treated by medical oncologists at City of Hope Comprehensive Cancer Center from 2004 through 2009 were classified by birthplace and self-reported race/ethnicity, and followed for accrual onto therapeutic trials through 2010. Undetectable on univariate analysis, significantly reduced participation by subjects of African, Asian, Eastern European, Latin American, and Middle Eastern ancestries was revealed after accounting for age, socioeconomic factors, tumor and oncologist characteristics, and intrapractice clustering of patients. Copyright © 2014 by the National Comprehensive Cancer Network.

  8. Risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation.

    Science.gov (United States)

    Atchison, Christie M; Amankwah, Ernest; Wilhelm, Jean; Arlikar, Shilpa; Branchford, Brian R; Stock, Arabela; Streiff, Michael; Takemoto, Clifford; Ayala, Irmel; Everett, Allen; Stapleton, Gary; Jacobs, Marshall L; Jacobs, Jeffrey P; Goldenberg, Neil A

    2018-02-01

    Paediatric hospital-associated venous thromboembolism is a leading quality and safety concern at children's hospitals. The aim of this study was to determine risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation. We conducted a retrospective, case-control study of children admitted to the cardiovascular intensive care unit at Johns Hopkins All Children's Hospital (St. Petersburg, Florida, United States of America) from 2006 to 2013. Hospital-associated venous thromboembolism cases were identified based on ICD-9 discharge codes and validated using radiological record review. We randomly selected two contemporaneous cardiovascular intensive care unit controls without hospital-associated venous thromboembolism for each hospital-associated venous thromboembolism case, and limited the study population to patients who had undergone cardiothoracic surgery or therapeutic cardiac catheterisation. Odds ratios and 95% confidence intervals for associations between putative risk factors and hospital-associated venous thromboembolism were determined using univariate and multivariate logistic regression. Among 2718 admissions to the cardiovascular intensive care unit during the study period, 65 met the criteria for hospital-associated venous thromboembolism (occurrence rate, 2%). Restriction to cases and controls having undergone the procedures of interest yielded a final study population of 57 hospital-associated venous thromboembolism cases and 76 controls. In a multiple logistic regression model, major infection (odds ratio=5.77, 95% confidence interval=1.06-31.4), age ⩽1 year (odds ratio=6.75, 95% confidence interval=1.13-160), and central venous catheterisation (odds ratio=7.36, 95% confidence interval=1.13-47.8) were found to be statistically significant independent risk factors for hospital-associated venous thromboembolism in these children. Patients with all three

  9. Epithelial ovarian tumours: 70 cases study: prognostic value factors analysis: therapeutic results

    International Nuclear Information System (INIS)

    Viola Alles, A.; Barrios Herrera, E.; Sabini Gaye, G.; Muse Sevrini, I.

    1992-01-01

    70 cases of TEO, as well age average it plows analyzed it was 54 years. It staging in E I 23 cases(33%), in E II 17 (24%) in E III 20 (29%) and 10 (14%) in E IV. Predominate over the serous varieties with 29 casos(42%) and mucinosa with 24 (34%), the remaining was 8 endometroids,7 anaplasics and only one tumour to clear cells and of Brenner. The treatment it was surgical predominant complete or not of radiotherapy or Melfalan in those E I-II; and with systemic treatment (CMF or Hexa-CAF) for those E III-IV. The The survive to 5 years was of 77% in E I,55% in E II, 38% in E III, and 0% in E IV. It was not found that the age or other types of histologicos except for the forms anaplasics were prognostic significance factors. In the advanced forms (E III-IV), different predicts of agreement is marked with the volume residual tumoral post surgery, survival of 55% to 5 years with smaller volumes to 2cm of diameter and 0% with higher volume. It conludes in the importance of forming subgroups in which value interrelate predict that orient the processing [es

  10. Protective, restorative, and therapeutic properties of recombinant colony-stimulating factors

    International Nuclear Information System (INIS)

    Talmadge, J.E.; Tribble, H.; Pennington, R.; Bowersox, O.; Schneider, M.A.; Castelli, P.; Black, P.L.; Abe, F.

    1989-01-01

    Pretreatment of mice with recombinant murine (rM) colony-stimulating factor-granulocyte-macrophage (CSF-gm) or recombinant human (rH) CSF-g provides partial protection from the lethal effects of ionizing radiation or the alkylating agent cyclophosphamide (CTX). In addition, these agents can significantly prolong survival if administered following lethal doses of irradiation or CTX. To induce protective activity, cytokines were injected 20 hours before lethal irradiation or CTX administration. To accelerate recovery from lethal irradiation, the cytokines must be administered shortly following irradiation, and the induction of maximal levels of activity is dependent on chronic administration. In contrast, because of their longer half-lives, accelerated recovery from alkylating agents requires a delay of at least 24 to 48 hours to allow complete clearance of CTX before administration of a CSF. Studies quantitating peripheral blood leukocytes and bone marrow cellularity as well as colony-forming units per culture (CFU-C) frequency and CFU-C per femur revealed a significant correlation between these parameters and the ability to survive lethal irradiation

  11. Igor Zabel 14. VIII 1958 - 23. VII 2005

    Index Scriptorium Estoniae

    2005-01-01

    Igor Zabel oli Ida-Euroopa tuntumaid kunstiteoreetikuid ja kuraatoreid. Töötas 1986. aastast Ljubljana moodsa kunsti muuseumi kuraatorina. 9. VIII avatakse seal viimane I. Zabeli kureeritud näitus "Territories, Identities, Nets-Slovene Art 1995-2005"

  12. Extended analyses of Se VII and Se VIII

    International Nuclear Information System (INIS)

    Vankleef, Th.A.M.; Joshi, Y.N.

    1984-01-01

    Joshi et al. (1984) have conducted an analysis of the 3d8 4s-3d8 4p transitions in As VII. The present investigation is concerned with an analysis of similar transitions in Se VIII. The selenium spectrum was photographed in the 400-1200-A wavelength region on a variety of normal-incidence spectrographs. Attention is given to least-squares-fit (LSF) and Hartree-Fock (HF) parameter values for the 3d9 4d configuration of Se VII, LSF and HF parameter values for the 3d8 4s and 3d8 4p configurations of Se VIII, the energy and composition of the levels of the 3d9 4d configuration of Se VII, classified lines in Se VII, energy levels and composition of the 3d8 4s configuration and the revised and newly determined levels of the 3d8 4p configuration of Se VIII, and newly classified lines of Se VIII. 15 references

  13. Prognostic factors and therapeutic options of radiotherapy in pediatric brain stem gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yu-Ming; Shiau, Cheng-Ying; Wong, Tai-Tong; Wang, Ling-Wei; Wu, Le-Jung; Chi, Kwan-Hwa; Chen, Kuang Y.; Yen, Sang-Hue [Veterans General Hospital-Taipei, Taipei, Taiwan (China)

    1998-08-01

    A retrospective analysis was made to clarify the relationship between prognosis, radiation dose and survival of brain stem gliomas. From 1983 to 1995, 22 children with brain stem tumors were treated by radiotherapy in the Veterans General Hospital-Taipei. Twelve patients had pathology proof and the remainder were diagnosed by computerized tomography and/or magnetic resonance imaging. Seven patients had postoperative radiotherapy. Fifteen patients had radiotherapy as primary management, five of whom had adjuvant chemotherapy. All patients received 4000-7060 cGy, either in conventional daily or hyperfractionated twice daily radiotherapy. Survival from date of diagnosis was calculated by the Kaplan-Meier method. Univariate analyses and multivariate analyses were calculated by the log rank test and the Cox proportional hazard model, respectively. Most patients showed improvement following treatment. The overall 2-year survival rate was 55.5% with a median survival of 27.1 months. Two-year survival for patients with primary management of operation and radiotherapy (n=7), radiotherapy alone (n=10) and radiotherapy with adjuvant chemotherapy (n=5) were 66.7, 50 and 53.3%, respectively. In univariate analysis, the study revealed that the growth pattern of tumors and the simultaneous presence of cranial neuropathy and long tract sign were significant prognostic factors (P=0.017 and 0.036). A trend of better outcome with radiation dose >6600 cGy and the hyperfractionation scheme was also noted in our study (P=0.0573 and 0.0615). However, only the hyperfractionation scheme showed significance in multivariate analyses (P=0.0355). Survival was not significantly affected by age, gender or method of diagnosis. Radiotherapy appears to be an effective treatment modality of brain stem tumors. Patients with both cranial neuropathy and long tract signs had a poorer outcome. Hyperfractionated radiotherapy may give better local control and lead to better survival. (author)

  14. Prognostic factors and therapeutic options of radiotherapy in pediatric brain stem gliomas

    International Nuclear Information System (INIS)

    Liu, Yu-Ming; Shiau, Cheng-Ying; Wong, Tai-Tong; Wang, Ling-Wei; Wu, Le-Jung; Chi, Kwan-Hwa; Chen, Kuang Y.; Yen, Sang-Hue

    1998-01-01

    A retrospective analysis was made to clarify the relationship between prognosis, radiation dose and survival of brain stem gliomas. From 1983 to 1995, 22 children with brain stem tumors were treated by radiotherapy in the Veterans General Hospital-Taipei. Twelve patients had pathology proof and the remainder were diagnosed by computerized tomography and/or magnetic resonance imaging. Seven patients had postoperative radiotherapy. Fifteen patients had radiotherapy as primary management, five of whom had adjuvant chemotherapy. All patients received 4000-7060 cGy, either in conventional daily or hyperfractionated twice daily radiotherapy. Survival from date of diagnosis was calculated by the Kaplan-Meier method. Univariate analyses and multivariate analyses were calculated by the log rank test and the Cox proportional hazard model, respectively. Most patients showed improvement following treatment. The overall 2-year survival rate was 55.5% with a median survival of 27.1 months. Two-year survival for patients with primary management of operation and radiotherapy (n=7), radiotherapy alone (n=10) and radiotherapy with adjuvant chemotherapy (n=5) were 66.7, 50 and 53.3%, respectively. In univariate analysis, the study revealed that the growth pattern of tumors and the simultaneous presence of cranial neuropathy and long tract sign were significant prognostic factors (P=0.017 and 0.036). A trend of better outcome with radiation dose >6600 cGy and the hyperfractionation scheme was also noted in our study (P=0.0573 and 0.0615). However, only the hyperfractionation scheme showed significance in multivariate analyses (P=0.0355). Survival was not significantly affected by age, gender or method of diagnosis. Radiotherapy appears to be an effective treatment modality of brain stem tumors. Patients with both cranial neuropathy and long tract signs had a poorer outcome. Hyperfractionated radiotherapy may give better local control and lead to better survival. (author)

  15. [Food addiction: Definition, measurement and limits of the concept, associated factors, therapeutic and clinical implications].

    Science.gov (United States)

    Cathelain, Sarah; Brunault, Paul; Ballon, Nicolas; Réveillère, Christian; Courtois, Robert

    2016-12-01

    Addictions, which are characterized by the inability to control a behavior despite existence of physical or psychological consequences, have biological, psychological and social determinants. Although the possibility of developing an addiction to some psychoactive substances (e.g. alcohol, tobacco, cannabis) and to gambling (i.e., gambling disorder) is now well demonstrated, the possibility to develop a non-drug addiction (i.e., behavioral addiction) to certain behaviors which provide pleasure (e.g. eating, having sex, buying things) is still in debate. The concept of food addiction, which refers to people who exhibit substance dependence criteria in relation to some high-fat and high-sugar foods, was recently proposed by applying substance dependence DSM criteria to eating behavior. To assess food addiction, the Yale Food Addiction Scale is now the only self-administered questionnaire (diagnosis and estimate of the number of symptoms of food addiction). Prevalence for food addiction is higher in overweight and obese patients, and in patients with certain psychopathological characteristics (i.e., depression, Attention Deficit Hyperactivity Disorder, high impulsivity), in patients who are single and in patients with neurobiological alterations in the reward system. However, it is still unclear whether food addiction is necessary associated with subsequent increase in body weight and/or obesity. An increasing number of studies demonstrated that drug addiction and food addiction shares some similar clinical, neurobiological and psychopathological and sociocultural risk factors. To test the pertinence to include food addiction as an addiction, it would be interesting to conduct future studies in patients who may experience harms related to their food addiction, including not only patients with obesity, but also patients with metabolic syndrome, type 2 diabetes, hypertension, dyslipidemia, atherosclerosis, stroke, or coronary heart disease. Food addiction is a clinical

  16. Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

    LENUS (Irish Health Repository)

    Cathcart, Mary-Clare

    2011-03-09

    Abstract Background Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease. Methods TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation\\/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.

  17. Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup.

    Science.gov (United States)

    Baldia, Philipp H; Maurer, Angela; Heide, Timon; Rose, Michael; Stoehr, Robert; Hartmann, Arndt; Williams, Sarah V; Knowles, Margaret A; Knuechel, Ruth; Gaisa, Nadine T

    2016-11-01

    Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies.

  18. Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases.

    Science.gov (United States)

    Sardiello, Marco

    2016-05-01

    The lysosome is the main catabolic hub of the cell. Owing to its role in fundamental processes such as autophagy, plasma membrane repair, mTOR signaling, and maintenance of cellular homeostasis, the lysosome has a profound influence on cellular metabolism and human health. Indeed, inefficient or impaired lysosomal function has been implicated in the pathogenesis of a number of degenerative diseases affecting various organs and tissues, most notably the brain, liver, and muscle. The discovery of the coordinated lysosomal expression and regulation (CLEAR) genetic program and its master controller, transcription factor EB (TFEB), has provided an unprecedented tool to study and manipulate lysosomal function. Most lysosome-based processes-including macromolecule degradation, autophagy, lysosomal exocytosis, and proteostasis-are under the transcriptional control of TFEB. Interestingly, impaired TFEB signaling has been suggested to be a contributing factor in the pathogenesis of several degenerative storage diseases. Preclinical studies based on TFEB exogenous expression to reinstate TFEB activity or promote CLEAR network-based lysosomal enhancement have highlighted TFEB as a candidate therapeutic target for the treatment of various degenerative storage diseases. © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

  19. New study on the XeVIII spectrum

    International Nuclear Information System (INIS)

    Gallardo, M.; Raineri, M.; Giuliani, M.; Lagorio, C.; Padilla, S.; Sarmiento, R.; Reyna Almandos, J.G.

    2005-01-01

    Capillary light sources were used to observe the spectrum of seven-times-ionized xenon, XeVIII, in the 300-6000 A wavelength range. Twenty-eight energy levels belonging to the 5s-9s, 5d-9d, 5g-9g, 7i-10i, 9l, 5p-9p, 4f-9f, 6h-9h and 8k-10k configurations were adjusted and 38 new spectral lines were classified. The XeVIII ionization energy was determined with improved accuracy using the polarization model. The analysis was supported by Hartree-Fock calculations. The weighted oscillator strengths for all the observed spectral lines were also calculated considering the fitted values for the energy parameters

  20. Evidence for the formation of sodium hassate(VIII)

    International Nuclear Information System (INIS)

    Zweidorf, A. von; Angert, R.; Bruechle, W.; Buerger, S.; Eberhardt, K.; Eichler, R.; Hummrich, H.; Jaeger, E.; Kling, H.O.; Kratz, J.V.; Kuczewski, B.; Langrock, G.; Mendel, M.; Rieth, U.; Schaedel, M.; Schausten, B.; Schimpf, E.; Thoerle, P.; Trautmann, N.; Tsukada, K.; Wiehl, N.; Wirth, G.

    2004-01-01

    Hassium, element 108, was produced in the fusion reaction between 26 Mg and 248 Cm. The hassium recoils were oxidized in-situ to a highly volatile oxide, presumably HsO 4 , and were transported in a mixture of He and O 2 to a deposition and detection system. The latter consisted of 16 silicon PIN-photodiodes facing a layer of NaOH, which served, in the presence of a certain partial pressure of water in the transport gas, as reactive surface for the deposition of the volatile tetroxides. Six correlated α-decay chains of Hs were detected in the first 5 detectors centred around detection position 3. In analogy to OsO 4 , which forms Na 2 [OsO 4 (OH) 2 ], an osmate(VIII), with aqueous NaOH, HsO 4 presumably was deposited as Na 2 [HsO 4 (OH) 2 ], a hassate(VIII). (orig.)

  1. Henry VIII, McLeod syndrome and Jacquetta's curse.

    Science.gov (United States)

    Stride, P; Lopes Floro, K

    2013-01-01

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

  2. New study on the XeVIII spectrum

    Energy Technology Data Exchange (ETDEWEB)

    Gallardo, M. [Centro de Investigaciones Opticas (CIOp) Casilla de Correo 124, 1900 La Plata (Argentina)]. E-mail: gallardom@ciop.unlp.edu.ar; Raineri, M. [Centro de Investigaciones Opticas (CIOp) Casilla de Correo 124, 1900 La Plata (Argentina)]. E-mail: monicar@ciop.unlp.edu.ar; Giuliani, M. [Dto. de Fisica, Fac. de C. Exactas y Naturales, Universidad Nacional de Mar del Plata Funes 3350 (7600) Mar del Plata (Argentina); Lagorio, C. [Dto. de Fisica, Fac. de C. Exactas y Naturales, Universidad Nacional de Mar del Plata Funes 3350 (7600) Mar del Plata (Argentina); Padilla, S. [Dto. de Fisica, Fac. de C. Exactas y Naturales, Universidad Nacional de Mar del Plata Funes 3350 (7600) Mar del Plata (Argentina); Sarmiento, R. [Dto. De Fisica, Universidad del Atlantico, A.A 1890 Barranquilla (Colombia); Reyna Almandos, J.G. [Centro de Investigaciones Opticas (CIOp) Casilla de Correo 124, 1900 La Plata (Argentina)]. E-mail: jreyna@ciop.unlp.edu.ar

    2005-10-15

    Capillary light sources were used to observe the spectrum of seven-times-ionized xenon, XeVIII, in the 300-6000 A wavelength range. Twenty-eight energy levels belonging to the 5s-9s, 5d-9d, 5g-9g, 7i-10i, 9l, 5p-9p, 4f-9f, 6h-9h and 8k-10k configurations were adjusted and 38 new spectral lines were classified. The XeVIII ionization energy was determined with improved accuracy using the polarization model. The analysis was supported by Hartree-Fock calculations. The weighted oscillator strengths for all the observed spectral lines were also calculated considering the fitted values for the energy parameters.

  3. The spectrum and term system of S VIII

    International Nuclear Information System (INIS)

    Bengtsson, P.; Jupen, C.; Engstroem, L.; Redfors, A.; Westerlind, M.

    1993-01-01

    The spectrum of seven times ionized sulfur, S VIII, has been observed in the wavelength range 50-1200 A. Both beam-foil and laser-produced plasma light sources have been used. 71 new lines representing the transitions 2p 5 -2p 4 3d, 2p 4 3s-3p, 3p-3d, 3d-4f, 4f-5g and 5g-6h have been identified and 100 energy levels, of which 46 are new, are now accurately established. The spectral analysis is supported by isoelectronic comparisons along the F I-sequence and by parametric least-squares fits of Slater integrals to the observed levels. The ionization potential in S VIII is determined to 2 651 899 ± 60 cm -1 and estimated ionization energies are derived for the isoelectronic elements between F I and Ar X. (orig.)

  4. Therapeutic potential of brain-derived neurotrophic factor (BDNF and a small molecular mimics of BDNF for traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Mary Wurzelmann

    2017-01-01

    Full Text Available Traumatic brain injury (TBI is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF, a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

  5. Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury.

    Science.gov (United States)

    Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

    2017-01-01

    Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

  6. Connective tissue growth factor acts as a therapeutic agent and predictor for peritoneal carcinomatosis of colorectal cancer.

    Science.gov (United States)

    Lin, Been-Ren; Chang, Cheng-Chi; Chen, Robert Jeen-Chen; Jeng, Yung-Ming; Liang, Jin-Tung; Lee, Po-Huang; Chang, King-Jen; Kuo, Min-Liang

    2011-05-15

    Here, we aimed to investigate the role of connective tissue growth factor (CTGF) in peritoneal carcinomatosis (PC) associated with colorectal cancer (CRC) and to characterize the underlying mechanism of CTGF mediating adhesion. A cohort of 136 CRC patient specimens was analyzed in this study. CRC cell lines were used for in vitro adhesion assay and in vivo peritoneal dissemination experiment. Recombinant CTGF protein treatment, transfection of CTGF expression plasmids, and knockdown of CTGF expression in CRC cells were utilized to evaluate the integrin α5, which served as a target of CTGF in inhibiting peritoneal seeding. The analysis of CRC tissues revealed an inverse correlation between CTGF expression and prevalence of PC. Lower CTGF level in CRC patients was associated with higher peritoneal recurrence rate after surgery. Inducing CTGF expression in cancer cells resulted in decreased incidence of PC and increased rate of mice survival. The mice received intraperitoneal injection of recombinant CTGF protein simultaneously with cancer cells or following tumor formation; in both cases, peritoneal tumor dissemination was found to be effectively inhibited in the mouse model. Functional assay revealed that CTGF significantly decreased the CRC cell adhesion ability, and integrin α5 was confirmed by reverse transcriptase PCR and functional blocking assay as a downstream effector in the CTGF-mediated inhibition of CRC cell adhesion. CTGF acts as a molecular predictor of PC and could be a potential therapeutic target for the chemoprevention and treatment of PC in CRC patients. ©2011 AACR.

  7. Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

    Science.gov (United States)

    Xu, Xiao-juan; Liu, Liang; Yao, Shu-kun

    2016-01-01

    Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.

  8. Treatment outcome and factors affecting time to recovery in children with severe acute malnutrition treated at outpatient therapeutic care program

    Directory of Open Access Journals (Sweden)

    Melkamu Merid Mengesha

    2016-07-01

    Full Text Available Background: The outpatient therapeutic care program (OTP of children with severe acute malnutrition (SAM has been decentralized to health post level in Ethiopia since 2008–2009. However, there is a lack of evidence regarding treatment outcomes and factors related to the duration of stay on treatment after its decentralization to health post level. Objective: This study was aimed to assess treatment outcome and factors affecting time to recovery in children with SAM treated at OTP. Design: Health facility–based retrospective cohort study was conducted using data from 348 patient cards. The outcome variable was time to recovery. Descriptive analysis was done using percentages for categorical data and mean/median for continuous variables. A robust method of analyzing time to event data, the Cox proportional-hazard regression, was used. All statistical tests in this study are declared significant at p<0.05. Result: 89.1% of children with kwashiorkor and 69.4% of children with marasmus were recovered. Of the total children studied, 22% were readmitted cases. The median time of recovery was 35 days for children with kwashiorkor and 49 days for children with marasmus. Children older than 3 years were 33% less likely to achieve nutritional recovery [adjusted hazard ratio, AHR=0.67, 95% confidence interval, CI (0.46, 0.97]. Similarly, marasmic children stayed longer on treatment [AHR=0.42, 95% CI (0.32, 0.56]. However, children who gained Mid-Upper Arm Circumference (MUAC ≥ 0.24 mm/day were 59% more likely to recover faster [AHR=1.59, 95% CI (1.23, 2.06]. Conclusions: Close monitoring of weight and MUAC gain to assess nutritional improvement with due emphasis given to children with lower admission weight, children of age 3 years and above and marasmic children will have a positive effect on treatment duration and outcome.

  9. Therapeutic effect of radiofrequency ablation on children with supraventricular tachycardia and the risk factors for postoperative recurrence.

    Science.gov (United States)

    Li, Chunli; Jia, Libo; Wang, Zhenzhou; Niu, Ling; An, Xinjiang

    2018-05-01

    The present study investigated the therapeutic effect of radiofrequency ablation on children with supraventricular tachycardia (SVT), and explored the risk factors for postoperative recurrence. A total of 312 patients with pediatric SVT were selected in the Affiliated Children's Hospital of Xuzhou Medical University from April, 2011 to March, 2017. All the patients were subjected to radiofrequency ablation, and clinical data were retrospectively analyzed. Tilt table test was performed before and after treatment, and heart rate, systolic and diastolic blood pressure before and after treatment were compared. Plasma levels of D-dimer (D-D), platelet α-granule membrane protein (GMP-140) and thrombin-antithrombin III complex (TAT) were detected by enzyme-linked immunosorbent assay before treatment, immediately after radiofrequency oblation, and at 1, 3 and 7 days after treatment. Treatment outcomes were compared between the atrioventricular reentrant tachycardia (AVRT) and atrioventricular nodal reentrant tachycardia (AVNRT) groups. Risk factors for postoperative recurrence were analyzed. Supine position heart rate after treatment was not significantly different from that before treatment (P>0.05), while the upright position heart rate was significantly increased after treatment (P0.05). No significant difference in radiofrequency ablation rate, recurrence rate and incidence of complications were found between the AVRT and AVNRT groups (P>0.05). After radiofrequency, the levels of D-D, GMP-140 and TAT ablation showed an upward trend, but decreased at day 7 to reach preoperative levels. Logistic regression analysis revealed that residual slow pathway (OR=6.718, P=0.005) and inaccurate targeting (OR=2.815, P=0.007) were independent risk factors for postoperative recurrence (Pradiofrequency ablation can damage the cardiac vagal nerve, resulting in an increase in the heart rate after ablation during the course of the tilt table test and changed hemagglutination state

  10. Ehlers-Danlos Syndrome Type VIII: A Rare Cause of Leg Ulcers in Young Patients

    Directory of Open Access Journals (Sweden)

    Sophie Ronceray

    2013-01-01

    Full Text Available Ehlers-Danlos syndrome type VIII (EDS-VIII is a very rare autosomal dominant disease characterized by early-onset periodontitis associated with features of Ehlers-Danlos syndrome. We report a 32-year-old man whose chronic leg ulcer led to the diagnosis of EDS-VIII. He had severe periodontitis with complete loss of permanent teeth and skin fragility with thin skin, atrophic scars, and brownish atrophic pretibial plaques. Leg ulcer is not a prominent feature of EDS-VIII. We suggest adding EDS-VIII to the list of rare diseases accounting for chronic leg ulcers, if this case report prompts others to report leg ulcers associated with EDS-VIII.

  11. [Choledocholithiasis in Edgardo Rebagliati Martins Hospital. Lima-Peru. 2010-2011. Incidence, risk factors, diagnostic and therapeutic aspects].

    Science.gov (United States)

    Llatas Pérez, Juan; Hurtado Roca, Yamilee; Frisancho Velarde, Oscar

    2011-01-01

    to determine the incidence, frequency of risk factors, diagnostic aspects (clinics, biochemical, and images) and therapeutic aspects of the choledocholithiasis. Descriptive and prospective analysis of 51 patients who signed informed consent for study of choledocholithiasis by ERCP (endoscopic retrograde cholangiopancreatography). Of the 51 patients, 36 (70.6%) confirmed choledocholithiasis by ERCP. Its incidence was 10.4%. The mean age was 63.75 years, BMI 25.59 kg/m2 and 55.6% were women. Abdominal pain was present in 94.4% of patients. Total bilirubin in the group with choledocholithiasis was 5.8 mg / dl at baseline and 4.2 mg / dl in hospitalization. 11.1% debuted with pancreatitis and 30.6% with cholangitis. In 68.7% of patients with cholangitis was confirmed choledocholithiasis by ERCP. The specificity of ultrasound was 0.80 (95% CI 0.6- 1). The specificity of the nuclear magnetic resonance was 0.25 (95% CI 0.17-0.67). Of the 51 patients with ERCP, 4 (7.80%) do pancreatitis, 1(1.96%) cholangitis and 2 (3.92%) bleeding Choledocholithiasis occurs in older people, female and overweight with an incidence of 10.4%. Abdominal pain is the most common symptom. A total bilirubin more tan 4mg/dl occurs in patients with choledocholithiasis. The complications of choledocholithiasis (pancreatitis and cholangitis) were more frequent than reported in the literature. Both the specificity of cholangitis for choledocholithiasis, the specificity of ultrasound and the specificity of the nuclear magnetic resonance were lower than reported in the literature. ERCP complications were slightly higher than that reported in the literature.

  12. Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

    Directory of Open Access Journals (Sweden)

    Melanie Vincent

    2010-09-01

    Full Text Available Niemann-Pick type C (NPC disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048 will slow the progression of NPC liver disease.Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown.Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

  13. 40 CFR Appendix Viii to Part 600 - Fuel Economy Label Formats

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 29 2010-07-01 2010-07-01 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...

  14. Citation trend and suggestions for improvement of impact factor of Journal of Korean Therapeutic Radiology and Oncology

    International Nuclear Information System (INIS)

    Kim, Seong Hwan; Hwang, Seong Su; Ahn, Myeong Im; Jeong, So Na

    2006-01-01

    To analyze the recent citation trend and to find a way to improve impact factor (IF) of the Journal of Korean Therapeutic Radiology and Oncology (JKSTRO) by analysis of Korean Medical Citation index (KoMCI) citation data of JKSTRO and comparison with that of mean citation data of all journals enlisted on KoMCI (KoMCI journals) during 2000-2005. All citation data of entire journals enlisted on KoMCI and JKSTRO from 2000 to 2005 were obtained from KoMCI. The trend of total and annual number of published articles and reference citations, total citations and self-citations per paper, IF and impact factor excluding self-citations (ZIF) were described and compared on both KoMCI journals an JKSTRO. Annual number of published articles was decreased for 6 years on both KoMCI journals and JKSTRO (32% and 38% reduction rate). The number of Korean journal references per article is 1.6 papers of JKSTRO comparing to 2.0 papers on KoMCI journals. The percentage of Korean references/total references increased from 5.0% in 2000 to 7.7% in 2005 on JKSTRO and from 8.5% in 2000 to 10.1% on KoMCI journals. The number of total citations received/paper on JKSTRO (average 1.333) is smaller than that of KoMCI journals (average 1.694), there was an increased rate of 67% in 2005 comparing to 2000. The percentage of self-citations/total citations (average 72%) on JKSTRO is slightly higher than that of KoMCI journals (average 61%)/ IF of JKSTRO was gradually improved and 0.144, 0.125, 0.088, 0.107, 0.187 and 0.203 in 2000-2005 respectively. However, ZIF of JKSTRO is steadily decreased from 0.038 in 2000 to 0.013 in 2005 except 0.044 in 2004. IF of JKSTRO was slightly improved but had some innate problem of smaller number of citations received . To make JKSTRO as a highly cited journal, the awareness of academic status of JKSTRO and active participation of every member of JKSTRO including encouraging self-citations of papers published recent 2 years and submission of English written papers, and

  15. Thermoelectrical properties of the compounds ScM{sup VIII}Sb and YM{sup VIII}Sb (M{sup VIII} = Ni, Pd, Pt)

    Energy Technology Data Exchange (ETDEWEB)

    Oestreich, J; Probst, U; Richardt, F; Bucher, E [University of Konstanz, PO Box X916, D-78457 Konstanz (Germany)

    2003-02-05

    The research into new materials with good thermoelectric properties has revealed new compounds consisting of metallic elements (Bando Y, Suemitsu T, Takagi K, Tokushima H, Echizen Y, Katoh K, Umeo K, Maeda Y and Takabatake T 2000 J. Alloys Compounds 313 1-6, Ghelani N, Loo S, Chung D, Sportouch S, Nardi S, Kanatzidis M, Hogan T and Nolas G 2000 Mater. Res. Soc. 626 Z8.6.1). The half-Heusler compound ZrNiSn, in particular, shows promising thermoelectric properties and has been studied by many scientists during recent years (Uher C, Hu S, Yang J, Meisner G P and Morelli D T 1997 Proc. ICT'97: 16th Int. Conf. on Thermoelectrics pp 485-8, Romaka L P, Stadnyk Yu V, Goryn A M, Gorelenko Yu K and Skolozdra R V 1997 Proc. ICT'97: 16th Int. Conf. on Thermoelectrics pp 516-19, Hohl H, Ramirez A P, Goldmann C, Ernst G, Woelfing B and Bucher E 1998 J. Phys.: Condens. Matter 11 1697-709, Oestreich J, Kaefer W, Richardt F, Probst U and Bucher E 1999 Proc. 5th European Workshop on Thermoelectrics pp 192-5). In an effort to find new thermoelectric materials, the half-Heusler compounds of the groups ScM{sup VIII}Sb and YM{sup VIII}Sb (M{sup VIII} = Ni, Pd, Pt) were synthesized by arc melting and the thermoelectric properties were examined by standard characterization methods. Doping experiments showed that it is possible to change the electrical properties of the compounds while retaining the half-Heusler structure. Within the two groups, YPtSb showed the best thermoelectrical properties. At a temperature of 400 K the electrical conductivity of YPtSb is 748{omega}{sup -1} cm{sup -1} and the Seebeck coefficient is 116.3{mu}V K{sup -1}. The thermal conductivity at 400 K extrapolated using the Wiedemann-Franz law is 2.87 W K{sup -1} m{sup -1}. This leads to a dimensionless figure of merit of 0.14.

  16. Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21.

    Science.gov (United States)

    Iglesias, Pedro; Selgas, Rafael; Romero, Sara; Díez, Juan J

    2012-09-01

    Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as

  17. El factor de crecimiento transformante beta como blanco terapéutico Transforming growth factor-beta as a therapeutic target

    Directory of Open Access Journals (Sweden)

    Francisco Javier Gálvez-Gastélum

    2004-08-01

    Full Text Available El factor de crecimiento transformante beta (TGF-beta es una familia de proteínas que incluye al TGF-beta, activinas y a la proteína morfogénica de hueso (BMP, por sus siglas en inglés, citocinas que son secretadas y se relacionan estructuralmente en diferentes especies de metazoarios. Los miembros de la familia del TGF-beta regulan diferentes funciones celulares como proliferación, apoptosis, diferenciación, migración, y tienen un papel clave en el desarrollo del organismo. El TGF-beta está implicado en varias patologías humanas, incluyendo desórdenes autoinmunes y vasculares, así como enfermedades fibróticas y cáncer. La activación del receptor del TGF-beta propicia su fosforilación en residuos de serina/treonina y dispara la fosforilación de proteínas efectoras intracelulares (smad, que una vez activas se translocan al núcleo para inducir la transcripción de genes blanco, y así regular procesos y funciones celulares. Se están desarrollando novedosas estrategias terapéuticas encaminadas a corregir las alteraciones presentes en patologías que involucran al TGF-beta como actor principal.Transforming growth factor-beta (TGF-beta family members include TGF-beta, activins, and bone morphogenetic proteins (BMP. These proteins are structurally related cytokines secreted in diverse Metazoans. TGF-beta family members regulate cellular functions such as proliferation, apoptosis, differentiation, and migration, and play an important role in organism development. Deregulated TGF-beta family signaling participates in various human pathologies including auto-immune diseases, vascular disorders, fibrotic disease, and cancer. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity, triggers phosphorylation of the intracellular effectors of TGF-beta signaling, the Smads proteins. Once these proteins are activated they translocate into the nucleus, where they induce transcription of target

  18. A model measuring therapeutic inertia and the associated factors among diabetes patients: A nationwide population-based study in Taiwan.

    Science.gov (United States)

    Huang, Li-Ying; Shau, Wen-Yi; Yeh, Hseng-Long; Chen, Tsung-Tai; Hsieh, Jun Yi; Su, Syi; Lai, Mei-Shu

    2015-01-01

    This article presents an analysis conducted on the patterns related to therapeutic inertia with the aim of uncovering how variables at the patient level and the healthcare provider level influence the intensification of therapy when it is clinically indicated. A cohort study was conducted on 899,135 HbA1c results from 168,876 adult diabetes patients with poorly controlled HbA1c levels. HbA1c results were used to identify variations in the prescription of hypoglycemic drugs. Logistic regression and hierarchical linear models (HLMs) were used to determine how differences among healthcare providers and patient characteristics influence therapeutic inertia. We estimated that 38.5% of the patients in this study were subject to therapeutic inertia. The odds ratio of cardiologists choosing to intensify therapy was 0.708 times that of endocrinologists. Furthermore, patients in medical centers were shown to be 1.077 times more likely to be prescribed intensified treatment than patients in primary clinics. The HLMs presented results similar to those of the logistic model. Overall, we determined that 88.92% of the variation in the application of intensified treatment was at the within-physician level. Reducing therapeutic inertia will likely require educational initiatives aimed at ensuring adherence to clinical practice guidelines in the care of diabetes patients. © 2014, The American College of Clinical Pharmacology.

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

    Science.gov (United States)

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

    2016-01-01

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

  20. 40 CFR Appendix Viii to Part 266 - Organic Compounds for Which Residues Must Be Analyzed

    Science.gov (United States)

    2010-07-01

    ... AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF SPECIFIC HAZARDOUS WASTES AND SPECIFIC TYPES OF HAZARDOUS WASTE MANAGEMENT FACILITIES Pt. 266, App. VIII Appendix VIII to Part 266... 40 Protection of Environment 26 2010-07-01 2010-07-01 false Organic Compounds for Which Residues...

  1. 40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false LDR Effective Dates of Injected Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION... to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

  2. Type VIII collagen is elevated in diseases associated with angiogenesis and vascular remodeling

    DEFF Research Database (Denmark)

    Hansen, N. U. B.; Willumsen, N.; Bülow Sand, Jannie Marie

    2016-01-01

    Objectives Type VIII collagen is involved in angiogenesis and remodeling of arteries. We hypothesized that type VIII collagen was upregulated in diseases associated with vascular remodeling, e.g. pulmonary fibrosis and cancer. In this paper we present the development and validation of a competitive...

  3. Effectiveness of Mind Mapping in English Teaching among VIII Standard Students

    Science.gov (United States)

    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…

  4. 4p-5s transitions in YVII, VIII, ZrVIII, IX, NbIX, X and MoX, XI

    International Nuclear Information System (INIS)

    Rahimullah, K.; Chaghtai, M.S.Z.; Khatoon, S.

    1976-01-01

    The spectra of Y VII, VIII, Zr VIII, IX, Nb X and Mo X, XI are studied for the first time and the 1971 analysis of Nb IX is improved. By analyses of the transitions 4s 2 4psup(k)-4s 2 4psup(k-1)5s all the levels of the configurations 4p 3 , 4p 2 5s, 4p 2 and 4p5s are established in the spectra concerned. (Auth.)

  5. Identification of the APC/C co-factor FZR1 as a novel therapeutic target for multiple myeloma.

    Science.gov (United States)

    Crawford, Lisa J; Anderson, Gordon; Johnston, Cliona K; Irvine, Alexandra E

    2016-10-25

    Multiple Myeloma (MM) is a haematological neoplasm characterised by the clonal proliferation of malignant plasma cells in the bone marrow. The success of proteasome inhibitors in the treatment of MM has highlighted the importance of the ubiquitin proteasome system (UPS) in the pathogenesis of this disease. In this study, we analysed gene expression of UPS components to identify novel therapeutic targets within this pathway in MM. Here we demonstrate how this approach identified previously validated and novel therapeutic targets. In addition we show that FZR1 (Fzr), a cofactor of the multi-subunit E3 ligase complex anaphase-promoting complex/cyclosome (APC/C), represents a novel therapeutic target in myeloma. The APC/C associates independently with two cofactors, Fzr and Cdc20, to control cell cycle progression. We found high levels of FZR1 in MM primary cells and cell lines and demonstrate that expression is further increased on adhesion to bone marrow stromal cells (BMSCs). Specific knockdown of either FZR1 or CDC20 reduced viability and induced growth arrest of MM cell lines, and resulted in accumulation of APC/CFzr substrate Topoisomerase IIα (TOPIIα) or APC/CCdc20 substrate Cyclin B. Similar effects were observed following treatment with proTAME, an inhibitor of both APC/CFzr and APC/CCdc20. Combinations of proTAME with topoisomerase inhibitors, etoposide and doxorubicin, significantly increased cell death in MM cell lines and primary cells, particularly if TOPIIα levels were first increased through pre-treatment with proTAME. Similarly, combinations of proTAME with the microtubule inhibitor vincristine resulted in enhanced cell death. This study demonstrates the potential of targeting the APC/C and its cofactors as a therapeutic approach in MM.

  6. Evidence supporting the use of recombinant activated factor VII in congenital bleeding disorders

    DEFF Research Database (Denmark)

    Johansson, Pär I; Ostrowski, Sisse R

    2010-01-01

    Recombinant activated factor VII (rFVIIa, NovoSeven) was introduced in 1996 for the treatment of hemophilic patients with antibodies against coagulation factor VIII or IX.......Recombinant activated factor VII (rFVIIa, NovoSeven) was introduced in 1996 for the treatment of hemophilic patients with antibodies against coagulation factor VIII or IX....

  7. Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

    Science.gov (United States)

    Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

    2015-05-30

    Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

  8. Key factors which concur to the correct therapeutic evaluation of herbal products in free radical-induced diseases.

    Directory of Open Access Journals (Sweden)

    Cesare eMancuso

    2015-04-01

    Full Text Available For many years now the world's scientific literature has been perfused with articles on the therapeutic potential of natural products, the vast majority of which have herbal origins, as in the case of free radical-induced diseases. What is often overlooked is the effort of researchers who take into consideration the preclinical and clinical evaluation of these herbal products, in order to demonstrate the therapeutic efficacy and safety. The first critical issue to be addressed in the early stages of the preclinical studies is related to pharmacokinetics, which is sometimes not very favorable, of some of these products, which limits the bioavailability after oral intake. In this regard, it is worthy underlining how it is often unethical to propose the therapeutic efficacy of a compound on the basis of preclinical results obtained with far higher concentrations to those which, hopefully, could be achieved in organs and tissues of subjects taking these products by mouth. The most widely used approach to overcome the problem related to the low bioavailability involves the complexation of the active ingredients of herbal products with non-toxic carriers that facilitate the absorption and distribution. Even the induction or inhibition of drug metabolizing enzymes by herbal products, and the consequent variations of plasma concentrations of co-administered drugs, are phenomena to be carefully evaluated as they can give rise to side-effects. This risk is even greater when considering that people lack the perception of the risk arising from an over use of herbal products that, by their very nature, are considered risk-free.

  9. Efeitos de humor no poema VIII de Catulo

    Directory of Open Access Journals (Sweden)

    Paulo Sérgio Vasconcellos

    1997-12-01

    Full Text Available Neste artigo apresenta-se uma contribuição ao estudo dos efeitos de humor no poema VIII de Catulo; de fato, além do metro dessa composição e de outros elementos criadores de distanciamento irônico que os estudiosos têm apontado, um outro aspecto de sua forma, ainda pouco percebido, guia a leitura para essa interpretação: o jogo, a maneira de anagrama imperfeito (o “hipograma”, ou, mais precisamente, “criptograma”, de Saussure, com os sons do nome da amada, aparentemente calado. E mais uma das maneiras com que o poeta elabora a jocosa diferença entre o que se diz e o que, sentido e reprimido, deixa-se, porém, transparecer.

  10. Energies and lifetimes of excited states in copperlike Kr VIII

    International Nuclear Information System (INIS)

    Livingston, A.E.; Curtis, L.J.; Schectman, R.M.; Berry, H.G.

    1980-01-01

    The spectrum of Kr VIII has been observed between 180 and 2000 A by using foil excitation of 2.5--3.5-MeV krypton ions. Twenty new transitions have been classified and eleven new excited-state energies have been determined within the n=4 --7 shells. The ionization potential is derived to be 1 015 800 +- 200 cm -1 . The excited-state energies and fine structures are compared with recent relativistic Hartree-Fock calculations. The 4p-state lifetime has been measured by performing a simultaneous analysis of decay data for the 4p level and for its dominant cascade-repopulating levels. The 4p lifetime is found to be 30% shorter than previously measured values and is in excellent agreement with the result of a recent multiconfiguration Hartree-Fock calculation. The source of the discrepancy between this result and earlier measurements is discussed

  11. Valor preditivo da expressão dos anticorpos Antifator VIII no carcinoma epidermóide do esôfago Predictive value of antifactor VIII antibody expression in squamous cell carcinoma of the esophagus

    Directory of Open Access Journals (Sweden)

    Sebastião Gonzaga Barbosa-Neto

    2007-12-01

    to progress knowledge on protein expression alterations for such neoplasia. AIM: To quantify protein expression implicated in the angiogenesis process and correlate to clinical-pathological features. METHODS: Using immunohistochemistry procedure, cytophotometric imaging by SAMBA, 29 sampled-tissue embedded in paraffin blocks of squamous cell carcinoma of the esophagus were analyzed. Clinical criteria, such as age and gender, as well as histophatological criteria, such as differentiated grade features, size and tumor location, were considered. Parameters evaluated were labeling index and optical density. The marker used in the present study was antifactor VIII. RESULTS: Verification on the expression of the marker in labeling index parameter was greater than optical density. Factor VIII presented homogeneous reading out. Labeling index was 80,17 + 10,40 (P=0,073 and optical density 51,25 + 11,02 (P=0,245. CONCLUSION: Protein expression reading analysis involved in angiogenesis process allows to define subgroups according to differentiated grade carcinoma, tumoral staging, size and tumor localization, although it does not allow association with gender and patient age. Optical density for factor VIII does not have statistical significant expression in any subgroup evaluated.

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

    Science.gov (United States)

    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.

  13. Prognostic significance of pretherapeutic and therapeutic factors in patients with advanced cancer of the uterine cervix treated with radical radiotherapy alone

    Energy Technology Data Exchange (ETDEWEB)

    Karolewski, K.; Korzeniowski, S.; Urbanski, K.; Kojs, Z. [Centre of Oncology, Maia Sklodowska-Curie Memorial Inst., Krakow (Poland); Sokolowski, A. [Dept. of Statistics, Cracow Univ. of Economics (Poland)

    1999-11-01

    The prognostic importance of various pretherapeutic and therapeutic factors was analysed in a group of 413 cervical cancer patients with stage IIB (183 pts) and IIIB (230 pts) treated with radical radiotherapy, which consisted of external irradiation and intracavitary brachytherapy. Univariate analysis of pretherapeutic factors revealed the prognostic significance of patient age, history of abortion, stage, haemoglobin and hematocrit levels. Five-year overall survival rate in stage IIB patients was 51% in stage IIIB 40% and the respective rates for local control at each stage were 61%, and 46%. Univariate analysis of therapeutic factors showed that survival and local control rates increased with the dose, but a significant difference was found only in the case of a paracentral (point A) dose. In a multivariate analysis only patient age, abortions, and clinical stage appeared to have a significant and independent impact on survival. Linear regression analysis results indicated that prolongation of treatment time between 33 and 108 days caused a loss of local control of 0.36% per day. (orig.)

  14. Time Transfer Experiment by TCE on the ETS-VIII Satellite

    National Research Council Canada - National Science Library

    Nakagawa, Fumimaru; Takahashi, Yasuhiro; Amagai, Jun; Tabuchi, Ryo; Hama, Shin'ichi; Hosokawa, Mizuhiko

    2007-01-01

    .... At NICT, we developed Time Comparison Equipment (TCE) both onboard ETS-VIII and in the Earth station for precise time transfer between the atomic clocks on the satellite and a ground reference clock...

  15. Class VIII Medical Materiel Controls in the U.S. European Command

    National Research Council Canada - National Science Library

    1991-01-01

    .... Class VIII medical materiel inventories are maintained as part of the U.S. war reserve stocks to ensure military readiness and to provide needed health care during wartime or contingencies. The U.S...

  16. Mechanistic aspects of Os(VIII) catalysed oxidation of loop diuretic ...

    Indian Academy of Sciences (India)

    furosemide by Ag(III) periodate complex in aqueous alkaline medium. SHWETA J .... Os(VIII) catalysed DPA oxidation, the order in [OH. −. ] ... Victoria-3170, Australia) connected to a rapid ..... follows. The furosemide, periodate and hydroxide ion.

  17. Spectra of the W VIII isoelectronic sequence: III. Re IX

    International Nuclear Information System (INIS)

    Ryabtsev, A N; Kononov, E Ya; Kildiyarova, R R; Tchang-Brillet, W-Ü L; Wyart, J-F; Champion, N; Blaess, C

    2015-01-01

    Rhenium spectra excited in vacuum spark sources of different setups and electric circuits were recorded on two high resolution vacuum spectrographs: a 10 m normal incidence spectrograph with a 3600 l mm −1 grating in the Meudon Observatory and a 3 m grazing incidence spectrograph with a 3600 l mm −1 grating in the Institute of Spectroscopy in Troitsk. A total of 112 lines in the region 146–244 Å were identified as transitions from the interacting excited even configurations 4f 12 5s 2 5p 6 5d + 4f 13 5s 2 5p 5 (5d + 6s) + 4f 14 5s 2 5p 4 (5d + 6s) to the low-lying odd configurations 4f 13 5s 2 5p 6 and 4f 14 5s 2 5p 5 . A change of the ground configuration from 4f 13 5s 2 5p 6 to 4f 14 5s 2 5p 5 in a comparison with the previous spectra of the isoelectronic sequence Hf VI–W VIII was observed. Fine structure splittings and relative positions of the odd terms were established, and 83 levels of the excited even configurations were found. (paper)

  18. Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence

    Energy Technology Data Exchange (ETDEWEB)

    Campana, Davide; Nori, Francesca; Cacciari, Giulia; Tomassetti, Paola [University of Bologna, Department of Medical and Surgical Sciences, Bologna (Italy); Capurso, Gabriele; Panzuto, Francesco; Delle Fave, Gianfranco [University of Rome, Digestive and Liver Disease Unit, Rome (Italy); Partelli, Stefano [Sacro Cuore Don Calabria Hospital, Department of Surgery, Negrar (Italy); University of Verona, Department of Surgery, Verona (Italy); Universita Politecnica delle Marche, Pancreas Surgical Unit, Ancona (Italy); Tamburrino, Domenico; Falconi, Massimo [University of Verona, Department of Surgery, Verona (Italy); Universita Politecnica delle Marche, Pancreas Surgical Unit, Ancona (Italy)

    2013-08-15

    Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment modality for patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs). The aim of this study was to determine the time to progression of patients treated with PRRT and to identify the prognostic factors related to treatment response. Patients with sporadic GEP NETs prospectively treated with PRRT were retrospectively analysed. The primary end point was progression-free survival (PFS). A total of 69 patients (37 men and 32 women; 45 with pancreatic and 24 with gastrointestinal lesion; 22 NET G1 and 41 NET G2) were treated with {sup 90}Y or {sup 177}Lu. The objective response rate was 27.5 % (partial response, PR), while 50.7 % had stable disease and 23.2 % had progressive disease. Significant differences in PFS were observed in relationship to the stage of the disease (44 months for stage III, 23 months for stage IV), the evidence of a PR 6 months after the end of the PRRT (39 months in patients with a PR, 22 months in patients without a PR) and previous transarterial chemoembolization (TACE, yes 13 months vs no 31 months). Stage IV, NET G2 and previous TACE were found to be significant factors for tumour progression at multivariate analysis. Low tumour burden and a low proliferation index represent independent prognostic factors for long PFS, while previous chemoembolization techniques represent independent prognostic factors for early tumour progression and shorter PFS. Our data suggest that chemoembolization techniques to reduce the hepatic tumour burden should be avoided. (orig.)

  19. INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A

    NARCIS (Netherlands)

    van Velzen, A.S.

    2016-01-01

    Hemophilia A is an inherited X-linked bleeding disorder that occurs in male offspring of carrier females. In these individuals a mutation in the F8 gene, located on the X-chromosome, causes a deficiency of the factor VIII protein, clotting factor VIII. The worldwide prevalence of hemophilia is 1 in

  20. Knowledge of HIV-AIDS a dominant factor of antiretroviral therapeutic adherence in women with HIV-AIDS

    Directory of Open Access Journals (Sweden)

    Surilena

    2015-08-01

    Full Text Available Background Antiretroviral therapy adherence (ART adherence is a factor significantly extending life expectancy of people living with HIV/AIDS. The objective of this study was determine several factors on ART adherence in women infected with HIV/AIDS. Methods A cross-sectional study involving 99 women with HIV/AIDS who were infected through their sexual partner or spouse was conducted in Dharmais Hospital between March and August 2014. The instruments used were demographic and self-esteem questionnaires, Hamilton rating scale for depression, Hamilton rating scale for anxiety, knowledge, perception of ART benefits and limitations, family support, peer support as well as assessment of ART adherence. The knowledge questionnaire has been validated with Cronbach’s alpha = 0.823. Data were analyzed using Chi-Square test and multivariate logistic regression. Results A total of 99 women with HIV/AIDS participated in the study, with an age range of 30- 60 years and mean age of 36 ± 3.72 years. A total of 57.58% of participants showed poor ART adherence. Multivariate logistic regression analysis showed that knowledge, ART side effects, depression, peer support and ARV availability significantly affected ART adherence (p<0.05. The most dominant factor affecting ART adherence was knowledge, with OR = 64.02 (95% CI 4.99-670.12. Conclusion With good knowledge about HIV/AIDS infection, ART benefits, and possible ARV side effects, women living with HIV/AIDS are expected to carry out ART adherence according to the recommended rules.

  1. Macromolecular therapeutics.

    Science.gov (United States)

    Yang, Jiyuan; Kopeček, Jindřich

    2014-09-28

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Evaluation of outpatient therapeutic programme (OTP) for treatment of severe acute malnutrition in Yemen: a focus on treatment default and its risk factors.

    Science.gov (United States)

    Al Amad, Mohammed; Al-Eryani, Lina; Al Serouri, Abdulwahed; Khader, Yousef S

    2017-12-01

    This study aimed to measure the treatment default rate among children with severe acute malnutrition (SAM) who were admitted to the outpatient therapeutic programme (OTP) in Yemen and determine its risk factors. A prospective study was conducted among children with SAM who were newly admitted to the 11 OTPs in primary health centres of Sana'a city. A pretested semistructured questionnaire was used for data collection at admission and at after 2 months of admission to the OTP. Univariate and multivariate analysis using binary logistic regression were used to analyse the risk factors of treatment default. This study included 339 SAM children. Of those, 186 (55%) children discharged as defaulters, 141 (42%) were cured, and 12 (3%) were transferred to other treatment sites. Many factors related to poor accessibility, poor satisfaction with staff and system, and treatment and acceptability of OTP services factors were significantly associated with treatment default. Having difficulty to attend OTP every week (OR 8.4), unavailability of medication during follow-up visits (OR 5.0), not liking to eat Plumpy'Nut (OR 5.8), and not gaining weight since the start of treatment (OR 9.3) were the strongest predictors of treatment default. This study showed a high default rate among SAM children in Sana'a city. Factors related to poor accessibility, poor satisfaction with staff and system, and factors related to treatment and acceptability of OTP services were significantly associated with high default rate. Expansion of OTP services and training OTPs staff on SAM treatment protocols are highly recommended. © 2017 John Wiley & Sons, Ltd.

  3. Upregulation of Trefoil Factor 3 (TFF3) After Rectal Cancer Chemoradiotherapy Is an Adverse Prognostic Factor and a Potential Therapeutic Target

    Energy Technology Data Exchange (ETDEWEB)

    Casado, Enrique, E-mail: enrique.casado@salud.madrid.org [Unidad de Oncologia, Hospital Infanta Sofia, Madrid (Spain); Moreno Garcia, Victor [Servicio de Oncologia Medica, Hospital Universitario La Paz, Madrid (Spain); Laboratorio de Oncologia Traslacional, Hospital Universitario La Paz, Madrid (Spain); Sanchez, Jose Javier [Departamento de Bioestadistica, Universidad Autonoma de Madrid, Madrid (Spain); Gomez del Pulgar, Maria Teresa [Unidad de Oncologia Traslacional, Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Cientificas, Madrid (Spain); Feliu, Jaime [Servicio de Oncologia Medica, Hospital Universitario La Paz, Madrid (Spain); Laboratorio de Oncologia Traslacional, Hospital Universitario La Paz, Madrid (Spain); Maurel, Joan [Departamento de Oncologia, Hospital Clinic, Barcelona (Spain); Castelo, Beatriz [Servicio de Oncologia Medica, Hospital Universitario La Paz, Madrid (Spain); Moreno Rubio, Juan; Lopez, Rocio A.B. [Laboratorio de Oncologia Traslacional, Hospital Universitario La Paz, Madrid (Spain); Garcia-Cabezas, Miguel Angel; Burgos, Emilio [Departamento de Anatomia Patologica, Hospital Universitario La Paz, Madrid (Spain); and others

    2012-12-01

    Purpose: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. Methods: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. Results: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. Conclusion: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.

  4. Critical analysis of the potential for the therapeutic targeting of the Sp1 transcription factor in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Jutooru I

    2014-06-01

    . This review summarizes the role of Sp1 in pancreatic cancer and delineates the mechanisms of action of various drugs that downregulate expression of Sp1 and other Sp transcription factors.Keywords: Sp transcription factors, microRNAs, ZBTB repressors, ROS

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

    Science.gov (United States)

    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 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 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.

  6. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    Science.gov (United States)

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  7. Novel therapeutic approach for pulmonary emphysema using gelatin microspheres releasing basic fibroblast growth factor in a canine model.

    Science.gov (United States)

    Chang, Sung Soo; Yokomise, Hiroyasu; Matsuura, Natsumi; Gotoh, Masashi; Tabata, Yasuhiko

    2014-08-01

    The prognosis of patients with emphysema is poor as there is no truly effective treatment. Our previous study showed that the alveolar space was smaller and the microvessel density was higher in a canine emphysema model after the intrapulmonary arterial administration of gelatin microspheres slowly releasing basic fibroblast growth factor (bFGF-GMS). In the present study, we evaluated the functional effect of injecting bFGF-GMS via the pulmonary artery in this canine pulmonary emphysema model. Using the porcine pancreatic elastase (PPE)-induced total emphysema model, we approximated the value of lung compliance with a Power Lab System, and performed blood gas analysis in a control group, a total emphysema group, and a bFGF group in which bFGF-GMS were injected toward the whole pulmonary artery via the femoral vein. Each group comprised five dogs. Lung compliance was higher in the total emphysema group than in the control group (p = 0.031), and the bFGF group showed no significant improvement of lung compliance vs. the total emphysema group (p = 0.112). PaO2 (partial pressure of oxygen in arterial blood) was improved by administering bFGF-GMS in the total emphysema model (p = 0.027). In the canine total emphysema model, blood gas parameters were improved by the whole pulmonary arterial administration of bFGF-GMS. This method has the potential to be an effective novel therapy for pulmonary emphysema.

  8. Therapeutic Nanodevices

    Science.gov (United States)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  9. On existence and properties of plutonium(VIII) derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Kiselev, Yu.M.; Dolzhenko, V.D.; Ermilov, A.Yu. [Moscow State Univ. (Russian Federation). Chemistry Dept.; Nikonov, M.V.; Myasoedov, B.F. [Russian Academy of Science, Moscow (Russian Federation). Inst. of Geochemistry and Analytical Chemistry; Tananaev, I.G. [Russian Academy of Science, Moscow (Russian Federation). Inst. of Physical Chemistry and Electrochemistry

    2014-04-01

    The existence of Pu(VIII) was shown in alkaline solutions and in nonpolar solvents (CCl{sub 4} and CHCl{sub 3}) on the ground of such experimental facts like extraction of plutonium species, obtained by means of ozonization of Pu(VI) alkaline solutions into CCl{sub 4} and CHCl{sub 3}; volatility of Pu compounds out of aqueous alkaline solutions, and the mentioned solvents. The product of interaction between PuO{sub 3}.0.8H{sub 2}O and XeF{sub 2} in CCl{sub 4} and CHCl{sub 3} was of the same chemical form for both cases and identical with the form of the product of volatility of Pu out of these organic solutions. The electronic absorbance spectra of these products in CCl{sub 4} and CHCl{sub 3} were fairly similar to the ones for OsO{sub 4} and RuO{sub 4}. The band of absorption in these spectra with the maximum at 332 nm corresponds to the charge transfer of metal-ligand type [π(O)→Pu], as the value of molar extinction coefficient e was found to be higher than 2 x 10{sup 3} L/mole cm. A satisfactory agreement between the energies for the transitions of PuO{sub 4} molecule designed by X{sub α}-SW method and experimental data was observed. A similar accordance was observed for the designed vibration frequency (DFT-method) with the one found as result of analysis of the vibration structure of the experimental spectra. (orig.)

  10. Pengembangan Perangkat Pembelajaran Matematika Berbasis Problem Based Learning (PBL untuk Meningkatkan Kemampuan Pemecahan Masalah Peserta Didik Kelas VIII

    Directory of Open Access Journals (Sweden)

    Rizza Yustianingsih

    2017-09-01

    Full Text Available Abstrak. Berdasarkan hasil penelitian pendahuluan pada kelas VIII SMP di lapangan, masih ditemukan kemampuan pemecahan masalah matematis siswa dalam masalah nyata yang belum optimal dan aktivitas siswa tidak mendukung proses belajar mereka. Salah satu faktornya adalah tidak cocoknya perangkat pembelajaran yang dapat memudahkan pembelajar untuk memperbaiki pemecahan kemampuan matematika dan kemampuan belajar siswa. Dari situ, untuk mendasari melakukan pengembangan perangkat pembelajaran matematika, ada rencana rencana pembelajaran (RPP dan lembar kerja siswa (LKPD berbasis Problem Based Learning (PBL, yang dapat memberikan pengalaman belajar untuk belajar pemecahan masalah dan dapat memberikan efek potensial yang baik pada aktivitas siswa selama proses belajar. Data dikumpulkan melalui observasi, kuesioner, wawancara, dan uji kemampuan pemecahan masalah. Subyek penelitian ini adalah siswa kelas VIII SMP N 3 Sawahlunto. Pengembangan penelitian ini yang digunakan adalah mode Plomp yang terdiri dari tahap awal penelitian, tahap prototipe, dan tahap penilaian. Berdasarkan hasil analisis data, terlihat bahwa alat pembelajaran berdasarkan PBL telah memenuhi kriteria yang valid dalam hal isi dan konstruksi. Peralatan pelajaran telah dianggap praktis dalam hal pelaksanaan dan efisiensi penggunaan waktu oleh guru dan siswa. Alat pelajaran juga efektif dalam hal proses penguasaan presentasi siswa belajar setelah menggunakan pembelajaran berbasis perangkat berbasis pembelajaran lebih besar dari atau sama dengan 75% sedangkan dalam hal hasil rata-rata siswa telah aktif dalam belajar. Kata kunci: Perangkat Pelajaran Matematika, Pemecahan Masalah, PBL.   Abstract. Based on the results of preliminary studies at grade VIII SMP in the field, it is still  found a mathematical problem solving ability of students in real problem who have not optimally and students activities do not support their learning process. One of the  factor is unsuitable of learning tools

  11. Myosin VIII regulates protonemal patterning and developmental timing in the moss Physcomitrella patens.

    Science.gov (United States)

    Wu, Shu-Zon; Ritchie, Julie A; Pan, Ai-Hong; Quatrano, Ralph S; Bezanilla, Magdalena

    2011-09-01

    Plants have two classes of myosins. While recent work has focused on class XI myosins showing that myosin XI is responsible for organelle motility and cytoplasmic streaming, much less is known about the role of myosin VIII in plant growth and development. We have used a combination of RNAi and insertional knockouts to probe myosin VIII function in the moss Physcomitrella patens. We isolated Δmyo8ABCDE plants demonstrating that myosin VIII is not required for plant viability. However, myosin VIII mutants are smaller than wild-type plants in part due to a defect in cell size. Additionally, Δmyo8ABCDE plants produce more side branches and form gametophores much earlier than wild-type plants. In the absence of nutrient media, Δmyo8ABCDE plants exhibit significant protonemal patterning defects, including highly curved protonemal filaments, morphologically defective side branches, as well as an increase in the number of branches. Exogenous auxin partially rescues protonemal defects in Δmyo8ABCDE plants grown in the absence of nutrients. This result, together with defects in protonemal branching, smaller caulonemal cells, and accelerated development in the Δmyo8ABCDE plants, suggests that myosin VIII is involved in hormone homeostasis in P. patens.

  12. Practical experience and lessons learned through implementation of Appendix VIII performance demonstration requirements

    International Nuclear Information System (INIS)

    Ashwin, P.J.; Becker, F.L.; Latiolais, C.L.; Spanner, J.C.

    1996-01-01

    To provide the US nuclear industry with a uniform implementation of the Performance Demonstration requirements within the 1989 edition of ASME Section XI, Appendix VIII, representatives from all US nuclear utilities formed the Performance Demonstration Initiative (PDI). The PDI recognized the potential benefits that Appendix VIII offered the nuclear industry and initiated a proactive approach to implement the requirements. In doing so it was expected that performance demonstration of ultrasonic examination procedures would allow for improvement in the efficiency and credibility of inservice inspection to be realized. Explicit within the performance demonstration requirements of Appendix VIII is the need for a Performance Demonstration Administrator, a difficult requirement to fulfill. Not only must the administrator exhibit the attributes of understanding the demonstration requirements, but also have solid technical knowledge, integrity and be able to interface with the industry at all levels, from operations to regulatory. For the nuclear industry, the EPRI NDE Center is an obvious choice to fulfill this position. This paper provides a brief background of the PDI, a nuclear industry-wide initiative to implement the performance demonstration requirements of Appendix VIII. Even though the consensus approach adopted by the PDI is discussed, the paper's primary objective is to provide examples of the lessons learned by the Center through the specific requirements of Appendix VIII

  13. Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor.

    Directory of Open Access Journals (Sweden)

    Suguru Fukushima

    Full Text Available Malignant peripheral nerve sheath tumor (MPNST is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1 plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear.The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α-specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α.The nuclear expression of HIF-1α was positive in 75.6% of MPNST samples (62/82 cases. Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048 and multivariate (P ≤ 0.0001 analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis.Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.

  14. Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

    Science.gov (United States)

    Bianchi, Enrica; Taurone, Samanta; Bardella, Lia; Signore, Alberto; Pompili, Elena; Sessa, Vincenzo; Chiappetta, Caterina; Fumagalli, Lorenzo; Di Gioia, Cira; Pastore, Francesco S; Scarpa, Susanna; Artico, Marco

    2015-10-01

    Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD). © 2015 Authors; published by Portland Press Limited.

  15. Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis-Dependent as Well as Macrophage-Associated Human Diseases

    Directory of Open Access Journals (Sweden)

    Zhiwei Hu

    2018-01-01

    Full Text Available Accumulating evidence suggests that tissue factor (TF is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD, endometriosis and rheumatoid arthritis (RA. Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola. It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1 and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases.

  16. Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation.

    Science.gov (United States)

    Wen, Ti; Li, Yangguang; Wu, Meng; Sun, Xiaolin; Bao, Xiucong; Lin, Yuquan; Hao, Jianlei; Han, Lin; Cao, Guangchao; Wang, Ziwen; Liu, Yuxiu; Wu, Zhenzhou; Hong, Zhangyong; Wang, Puyue; Zhao, Liqing; Li, Zhanguo; Wang, Qingmin; Yin, Zhinan

    2012-09-01

    To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms. We determined the effect of NK-007 on lipopolysaccharide (LPS)-triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry. NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay. For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis. Copyright © 2012 by the American College of Rheumatology.

  17. Clinical Holistic Medicine: Factors Influencing The Therapeutic Decision-Making. From Academic Knowledge to Emotional Intelligence and Spiritual “Crazy” Wisdom

    Directory of Open Access Journals (Sweden)

    Søren Ventegodt

    2007-01-01

    Full Text Available Scientific holistic medicine is built on holistic medical theory, on therapeutic and ethical principles. The rationale is that the therapist can take the patient into a state of salutogenesis, or existential healing, using his skills and knowledge. But how ever much we want to make therapy a science it remains partly an art, and the more developed the therapist becomes, the more of his/her decisions will be based on intuition, feeling and even inspiration that is more based on love and human concern and other spiritual motivations than on mental reason and rationality in a simple sense of the word. The provocative and paradoxal medieval western concept of the “truth telling clown”, or the eastern concepts of “crazy wisdom” and “holy madness” seems highly relevant here. The problem is how we can ethically justify this kind of highly “irrational” therapeutic behavior in the rational setting of a medical institution. We argue here that holistic therapy has a very high success rate and is doing no harm to the patient, and encourage therapists, psychiatrists, psychologist and other academically trained “helpers” to constantly measure their own success-rate. This paper discusses many of the important factors that influence clinical holistic decision-making. Sexuality could, as many psychoanalysts from Freud to Reich and Searles have believed, be the most healing power that exists and also the most difficult for the mind to comprehend, and thus the most “crazy-wise” tool of therapy.

  18. Roles of HTLV-1 basic Zip Factor (HBZ in Viral Chronicity and Leukemic Transformation. Potential New Therapeutic Approaches to Prevent and Treat HTLV-1-Related Diseases

    Directory of Open Access Journals (Sweden)

    Jean-Michel Mesnard

    2015-12-01

    Full Text Available More than thirty years have passed since human T-cell leukemia virus type 1 (HTLV-1 was described as the first retrovirus to be the causative agent of a human cancer, adult T-cell leukemia (ATL, but the precise mechanism behind HTLV-1 pathogenesis still remains elusive. For more than two decades, the transforming ability of HTLV-1 has been exclusively associated to the viral transactivator Tax. Thirteen year ago, we first reported that the minus strand of HTLV-1 encoded for a basic Zip factor factor (HBZ, and since then several teams have underscored the importance of this antisense viral protein for the maintenance of a chronic infection and the proliferation of infected cells. More recently, we as well as others have demonstrated that HBZ has the potential to transform cells both in vitro and in vivo. In this review, we focus on the latest progress in our understanding of HBZ functions in chronicity and cellular transformation. We will discuss the involvement of this paradigm shift of HTLV-1 research on new therapeutic approaches to treat HTLV-1-related human diseases.

  19. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Su [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jeon, Seong-Uk; Lee, Chan-Ju; Kim, Young-Eun; Bok, Seoyeon; Hong, Beom-Ju; Park, Dong-Young [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Ahn, G-One, E-mail: goneahn@postech.ac.kr [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Kim, Hak Jae, E-mail: khjae@snu.ac.kr [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-07-01

    Purpose: To establish and characterize radiation-induced esophagitis (RIE) in vivo and in vitro. Methods and Materials: Fractionated thoracic irradiation at 0, 8, 12, or 15 Gy was given daily for 5 days to Balb/c or C57Bl/6 mice. Changes in body weight gain and daily food intake were assessed. At the end of the study, we removed the esophagus and examined histology by hematoxylin and eosin staining, immune cell infiltration and apoptosis by fluorescence-activated cell sorting, and gene expression changes by quantitative real-time polymerase chain reaction. Het-1A human esophageal epithelial cells were irradiated at 6 Gy, treated with recombinant human growth factors, and examined for gene expression changes, apoptosis, proliferation, and signal transduction pathways. Results: We observed that irradiation at 12 Gy or 15 Gy per fraction produced significant reduction in body weight and decreased food intake in Balb/c mice but not as much in C57Bl/6 mice. Further analyses of Balb/c mice irradiated at 12 Gy/fraction revealed attenuated epithelium, inflamed mucosa, and increased numbers of infiltrating CD4+ helper T cells and apoptotic cells. Moreover, we found that expression of tissue inhibitor for metalloproteinase-1, plasminogen activator inhibitor-1, granulocyte macrophage-colony stimulating factor, vascular endothelial growth factor, and stromal-derived factor-1 were increased, whereas epidermal growth factor (EGF) was decreased. Irradiated Het-1A cells similarly showed a significant decrease in expression of EGF and connective tissue growth factor (CTGF). Treatment of EGF but not CTGF partially protected Het-1A cells from radiation-induced apoptosis and revealed phosphorylation of EGFR, AKT, and ERK signaling pathways. Conclusions: We established a mouse model of RIE in Balb/c mice with 12 Gy × 5 fractions, which showed reduced body weight gain, food intake, and histopathologic features similar to those of human esophagitis. Decreased EGF expression

  20. Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Gu Qing

    2009-06-01

    Full Text Available Abstract Background New strategies for the treatment of Parkinson's disease (PD are shifted from dopamine (DA replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE cells as substitution for degenerated dopaminergic (DAergic neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA. Methods We evaluated the protective effects of conditioned medium (CM from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF and brain derived neurotrophic factor (BDNF released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR. Results We report here: (1 CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2 cultured RPE cells express L-dopa decarboxylase (DDC and synthesize DA; (3 RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4 GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues. Conclusion These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.

  1. Spectrophotometric determination of hydrogen peroxide with osmium(VIII) and m-carboxyphenylfluorone.

    Science.gov (United States)

    Hoshino, Mitsuru; Kamino, Shinichiro; Doi, Mitsunobu; Takada, Shingo; Mitani, Shota; Yanagihara, Rika; Asano, Mamiko; Yamaguchi, Takako; Fujita, Yoshikazu

    2014-01-03

    Spectrophotometric determination of hydrogen peroxide was accomplished with osmium(VIII) and m-carboxyphenylfluorone (MCPF) in the presence of cetyltrimethylammonium chloride (CTAC). In the determination of hydrogen peroxide based on the fading of the color of osmium(VIII)-MCPF complex, Beer's law was obeyed in the range 20-406 ng mL(-1), with an effective molar absorption coefficient (at 580 nm) of 5.21×10(4) L mol(-1) cm(-1) and a relative standard deviation of 0.33% (n=6). Further, we performed the characterization of MCPF and obtained the crystal structure. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Lacerations to Zones VIII and IX: It Is Not Just a Tendon Injury

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    Charla R. Fischer

    2011-01-01

    Full Text Available Extensor tendon injuries are widely believed to be straightforward problems that are relatively simple to manage. However, these injuries can be complex and demand a thorough understanding of anatomy to achieve the best functional outcomes. When lacerations occur in the forearm as in Zones VIII and IX injury, the repair of the extensor tendon and muscle, and posterior interosseous nerve (PIN is often challenging. A review of the literature shows little guidance and attention for these injuries. We present four patients with injuries to Zones VIII and IX as well as a review of surgical technique, postoperative rehabilitation, and pearls that may be of benefit to those managing these injuries.

  3. An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS

    Directory of Open Access Journals (Sweden)

    Enrique Meléndez Hevia

    2008-10-01

    Full Text Available Salvador Harguindey1, Gorka Orive2,6, Ramón Cacabelos3, Enrique Meléndez Hevia4, Ramón Díaz de Otazu5, et al1Institute of Clinical Biology and Metabolism, Vitoria, Spain; 2Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of The Basque Country, Vitoria, Spain; 3Department of Clinical Neuroscience, EuroEspes Biomedical Research Center, Bergondo, La Coruña, Spain; 4Institute for Cellular Metabolism, Tenerife, Spain; 5Department of Pathology, Hospital Txagorritxu, Vitoria, Spain; 6Biotechnology Institute (BTI, Vitoria, SpainAbstract: A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs and cancer based upon the disruption of the intracellular dynamics of the hydrogen ion (H+ and its physiopathology, is advanced. From an etiopathological perspective, the activity and/or deficiency of different growth factors (GFs in these pathologies are studied, and their relationships to intracellular acid-base homeostasis reviewed. Growth and trophic factor withdrawal in HNDDs indicate the need to further investigate the potential utilization of certain GFs in the treatment of Alzheimer disease and other neurodegenerative diseases.  Platelet abnormalities and the therapeutic potential of platelet-derived growth factors in these pathologies, either through platelet transfusions or other clinical methods, are considered. Finally, the etiopathogenic mechanisms of apoptosis and antiapoptosis in HNDDs and cancer are viewed as opposite biochemical and biological disorders of cellular acid-base balance and their secondary effects on intracellular signaling pathways and aberrant cell metabolism are considered in the light of the both the seminal and most recent data available. The “trophic factor withdrawal syndrome” is described for the first time in English-speaking medical literature, as well as a Darwinian-like interpretation of cellular behavior related to specific and nonspecific

  4. Therapeutic ultrasound

    International Nuclear Information System (INIS)

    Crum, Lawrence A

    2004-01-01

    The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. These applications broadly include: tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally non-invasive, imageguided therapy. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the introduction of acoustic hemostasis, especially in organs which are difficult to treat using conventional medical and surgical techniques. (amum lecture)

  5. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism.

    Science.gov (United States)

    Wendt, Daniel J; Dvorak-Ewell, Melita; Bullens, Sherry; Lorget, Florence; Bell, Sean M; Peng, Jeff; Castillo, Sianna; Aoyagi-Scharber, Mika; O'Neill, Charles A; Krejci, Pavel; Wilcox, William R; Rimoin, David L; Bunting, Stuart

    2015-04-01

    Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  6. [Therapeutic effect of insulin-like growth factor-1 injection into the inner ears through scala tympani fenestration on gentamicin-induced hearing loss in guinea pigs].

    Science.gov (United States)

    Li, Yong-he; Chen, Hao; Guo, Meng-he

    2008-02-01

    To study the therapeutic effect of insulin-like growth factor-1 (IGF-1) injection into the inner ears through a scala tympani fenestration on sensorineural deafness in a guinea pig model of gentamicin-induced hearing loss. Twenty guinea pigs with gentamicin-induced hearing loss were randomized equally into IGF-1 group and control group. In both groups, scala tympani fenestration was performed for injection of IGF-1 (10 microl) or artificial perilymphatic fluid (10 microl). Auditory brainstem responses (ABR) test was performed before and 7 and 14 days after surgery, respectively, and the cochlea was removed by decollation of 3 guinea pigs from each group after ABR test for observing the changes in the hair cells using scanning electron microscope. Significant reduction in the ABR response threshold (RT) occurred in IGF-1 group 7 and 14 days after the surgery, and on day 14, ABR RT showed significant difference between IGF-1 group and the control group. Scanning electron microscopy revealed severer damages of the hair cells in the control group, and in the IGF-1 group, finger-like microvilli was detected on the surface of the damaged hair cells. IGF-1 injection in the inner ear through the scala tympani fenestration may ameliorate the damages of the auditory function and relieve sustained toxicity of gentamicin in guinea pigs possibly by protection and partial repair of the damaged cochlea hair cells as well as protection of the afferent nerves.

  7. T-lymphokine-activated killer cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in glioma

    Science.gov (United States)

    Duan, Qiuhong; Yuan, Ping; Xue, Peipei; Lu, Hui; Yan, Meng; Guo, Dongsheng; Xu, Sanpeng; Zhang, Xiaohui; Lin, Xuan; Wang, Yong; Dogan, Soner; Zhang, Jianmin; Zhu, Feng; Ke, Changshu; Liu, Lin

    2018-01-01

    TOPK is overexpressed in various types of cancer and associated with poor outcomes in different types of cancer. In this study, we first found that the expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was significantly higher in Grade III or Grade IV than that in Grade II in glioma (P = 0.007 and P < 0.001, respectively). Expression of TOPK was positively correlated with Ki67 (P < 0.001). Knockdown of TOPK significantly inhibited cell growth, colony formation and increased sensitivities to temozolomide (TMZ) in U-87 MG or U-251 cells, while TOPK overexpression promoted cell growth and colony formation in Hs 683 or A-172 cells. Glioma patients expressing high levels of TOPK have poor survival compared with those expressing low levels of TOPK in high-grade or low-grade gliomas (hazard ratio = 0.2995; 95% CI, 0.1262 to 0.7108; P = 0.0063 and hazard ratio = 0.1509; 95% CI, 0.05928 to 0.3842; P < 0.0001, respectively). The level of TOPK was low in TMZ-sensitive patients compared with TMZ-resistant patients (P = 0.0056). In TMZ-resistant population, patients expressing high TOPK have two months’ shorter survival time than those expressing low TOPK. Our findings demonstrated that TOPK might represent as a promising prognostic and predictive factor and potential therapeutic target for glioma. PMID:29487691

  8. Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

    Directory of Open Access Journals (Sweden)

    Tayra Judith

    2010-04-01

    Full Text Available Abstract Background Mesenchymal stem cells (MSCs are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL staining. Results Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. Conclusions Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

  9. Living in a physical world VIII. Gravity and life in water

    Indian Academy of Sciences (India)

    2006-07-31

    Jul 31, 2006 ... Home; Journals; Journal of Biosciences; Volume 31; Issue 3. Living in a physical world VIII. Gravity and life in water. Steven Vogel. Series Volume 31 Issue 3 September 2006 pp 309-322. Fulltext. Click here to view fulltext PDF. Permanent link: https://www.ias.ac.in/article/fulltext/jbsc/031/03/0309-0322 ...

  10. Visualizing the Life and Legacy of Henry VIII: Guiding Students with Eight Types of Graphic Organizers

    Science.gov (United States)

    Gallavan, Nancy P.; Kottler, Ellen

    2010-01-01

    Delving into the life and legacy of Henry VIII is both complex and captivating. People seem compelled to learn more abut his critical contributions and controversial conduct that range from the significant to the scandalous. Reflecting on the history of the world would be incomplete without investigating the events and escapades associated with…

  11. Quark matter coupled to domain walls in Bianchi types II, VIII and IX ...

    Indian Academy of Sciences (India)

    In this study of Bianchi types II, VIII and IX Universes, quark matter coupled to domain walls in the ... The self-bound state appears to be at ρ ... The observations suggest that the Hubble expansion of the Universe ... Taking motivation from.

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

    Science.gov (United States)

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

    2018-04-03

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

  13. Synthesization of the Ar VIII 3s-3p beam-foil decay curve

    International Nuclear Information System (INIS)

    Lindgaard, A.; Veje, E.

    1981-01-01

    The beam-foil decay curve for the 3s-3p transition in Ar VIII has been simulated from experimentally determined relative initial level populations and transition probabilities calculated in the numerical Coulomb approximation. Good agreement is observed between simulated and measured decay curves. A discussion of the simulation is given. (Auth.)

  14. Quark matter coupled to domain walls in Bianchi types II, VIII and IX ...

    Indian Academy of Sciences (India)

    In this study of Bianchi types II, VIII and IX Universes, quark matter coupled to domain walls in the context of general relativity are explored. To obtain deterministic solution of the Einstein's field equations, various techniques are adopted. The features of the obtained solution are discussed.

  15. Chaos in long-term behavior of some Bianchi-type VIII models

    Energy Technology Data Exchange (ETDEWEB)

    Halpern, P

    1987-01-01

    The long-term behavior of Bianchi-type VIII models with three different types of stress-energy tensors are examined and compared. The vacuum model, a matter-filled model, and a model with an electromagnetic field are considered. In each case the existence of chaotic behavior and transitions to chaotic behavior are discussed.

  16. Absorption signatures of warm-hot gas at low redshift : Ne VIII

    NARCIS (Netherlands)

    Tepper-García, T

    2013-01-01

    At z {lt} 1 a large fraction of the baryons is thought to reside in diffuse gas that has been shock-heated to high temperatures (10$^{5}$-10$^{6}$ K). Absorption by the 770.41, 780.32 å doublet of Ne VIII in quasar spectra represents a unique tool to study this elusive warm-hot phase. We have

  17. Fatores terapêuticos em grupo de diabéticos Factores terapéuticos en grupo de diabéticos Therapeutic factors in a group of people with diabetes

    Directory of Open Access Journals (Sweden)

    Nunila Ferreira de Oliveira

    2009-09-01

    Full Text Available O objetivo da presente pesquisa foi analisar os fatores terapêuticos presentes nos relatos dos participantes de um grupo de diabéticos. Pesquisa exploratória, de avaliação, cujos dados foram obtidos por meio de entrevista semiestruturada, cuja análise permitiu a identificação dos seguintes fatores terapêuticos: oferecimento de informações (100%; coesão (100%; universalidade (86%; aprendizagem interpessoal (57%; desenvolvimento de técnicas de socialização (57%; altruísmo (28,5%; comportamento imitativo (28,5% e instilação de esperança (28,5%. Intervenções grupais, realizadas na promoção do autocuidado às pessoas portadoras de diabetes, podem promover interação benéfica entre os membros, permitindo troca de experiências, compreensão de uma dimensão maior do problema e outras vivências positivas evidenciadas pela presença dos fatores terapêuticos.El objetivo de la presente investigación fue analizar los factores terapéuticos presentes en los relatos de los participantes de un grupo de diabéticos. Investigación exploratoria, de evaluación, cuyos datos fueron obtenidos por medio de entrevista semiestructurada; el análisis permitió la identificación de los siguientes factores terapéuticos: ofrecimiento de informaciones (100%; cohesión (100%; universalidad (86%; aprendizaje interpersonal (57%; desarrollo de técnicas de socialización (57%; altruismo (28,5%; comportamiento imitativo (28,5% e introducción de esperanza (28,5%. Las intervenciones grupales realizadas en la promoción del auto cuidado a las personas portadoras de diabetes pueden promover una interacción benéfica entre los miembros, permitiendo el intercambio de experiencias, la comprensión de una dimensión mayor del problema y de otras vivencias positivas evidenciadas por la presencia de los factores terapéuticos.The objective of the present research was to analyze the therapeutic factors identified in the accounts of the participants of a

  18. RELATIONSHIP OF INTEREST, LEARNING MOTIVATION AND ATTITUDE WITH RESULTS LEARNING CLASS VIII SMP STATE 13 MAKASSAR

    Directory of Open Access Journals (Sweden)

    Putri Athirah Azis

    2016-12-01

    Full Text Available The study aims at examining (1 the correlation of learning interest towards learning result of grade students, (2 the correlation of learning motivation towards learning result of grade students, (3 the correlation of students attitude towards learning result, (4 the correlationof interest, learning motivation, and attitude collaboratively towards learning result. The study is an ex post facto. The population of the study was grade VIII at SMPN 13 Makassar. Samples were 105 students taken by employing random sampling technique. Data were collected through questionnaire and documentation. Data were analyzed using regression test. The result of study reveal that (1 there is significant correlation (p<0,01 of interest towards learning result of grade VIII students at SMPN 13 Makassar. Co-efficient correlation (r is 0,718 and its effectiveness contribution (R2 is 51,5%, (2 there is significant correlation (p<0,01 of motivation towards learning result of grade VIII students at SMPN 13 Makassar. Co-efficient correlation (r is 0,775 and its effectiveness contribution (R2 is 60,1%, (3 there is significant correlation (p<0,01 of attitude towards learning result of grade VIII students at SMPN 13 Makassar. Co-efficient correlation (r is 0,737 and its effectiveness contribution (R2 is 54,4%, (4 there is significant correlation (p<0,01 of interest, motivation and attitude collaboratively towards learning result of grade VIII students at SMPN 13 Makassar. Co-efficient correlation (r is 0,861 and its effectiveness contribution (R2 is 74,1%,

  19. VIII Olimpíada Brasileira de Astronomia e Astronáutica

    Science.gov (United States)

    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.

  20. Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism

    Directory of Open Access Journals (Sweden)

    Sivakumar Loganathan

    2011-01-01

    Full Text Available Purpose: To examine the role of both protein kinase C (PKC-β and vascular endothelial growth factor receptor (VEGFR-2 in malignant pleural mesothelioma (MPM using respective inhibitors, enzastaurin and KRN633. Materials and Methods: MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-β, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors. Results: PKC-β1, PKC-β2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-β, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity. Conclusions: PKC-β1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.

  1. Prognostic factors for carcinoma of unknown primary localized to the neck only (CUP Syndrome) and the role of F-18-FDG PET for diagnosis and therapeutic management

    International Nuclear Information System (INIS)

    Baum, R.P.; Schmuecking, M.; Niesen, A.; Bank, P.; Lopatta, E.C.; Wendt, T.G.; Koscielny, S.; Beleites, E.

    2002-01-01

    Aim: Treatment of patients with carcinoma of unknown primary localized to the neck only is still controversial. To determine both patient related prognostic factors and the influence of treatment parameters the records of 99 patients were analyzed retrospectively, to evaluate the role of F-18-FDG PET for diagnostics and therapy management 33 patients were analyzed prospectively. Material and Methods: Retrospectively: Out of 99 patients with carcinoma of unknown primary, 51 received surgery as a sole treatment. 48 were treated with a combination of surgery and radiation therapy. 8/99 patients received a F-18-FDG PET. Statistical analyses: Kaplan-Meier, log-rank-test, chi-square-test. Prospectively: All PET studies were carried out after conventional diagnostic procedures failed to detect the primary tumor. PET findings were correlated with histology and/or clinical course of the patients. Results: Retrospectively: Disease specific survival (DSS) was significant longer for patients with N1/N2 vs. N3 (p=0.03), for upper nodal involvement vs. lower and/or supraclavicular nodal involvement (p=0.031) and for absence of extracapsular spread (p=0.041). No influence of DSS was noted for grading (p=0.469), treatment volume (p=0.82) and applied dose (>50Gy vs. <50Gy). In 2/8 patients, PET detected the primary tumor, in 1/8 bone metastases. Prospectively: Detection of the primary tumor by PET was successful in 21%, mostly in patients with lower and/or supraclavicular nodal involvement. In these patients the primary tumor was located extracervically in 72%, e.g. lung or gastric cancer. Distant metastases were detected in 33%. Conclusion: The presence of ECS, the extend and localization of nodal involvement are prognostic factors in patients suffering from CUP localized to the neck only. Patients with upper nodal involvement should be treated with curative intention. The irradiation fields should cover the whole neck including the potential region of the primary tumor with doses

  2. Onychomycosis of Toenails and Post-hoc Analyses with Efinaconazole 10% Solution Once-daily Treatment: Impact of Disease Severity and Other Concomitant Associated Factors on Selection of Therapy and Therapeutic Outcomes.

    Science.gov (United States)

    Del Rosso, James Q

    2016-02-01

    Topical treatment for toenail onychomycosis has been fraught with a long-standing reputation of poor efficaey, primarily due to physical properties of the nail unit that impede drug penetration. Newer topical agents have been formulated as Solution, which appear to provide better therapeutic response in properly selected patients. It is important to recognize the impact the effects that mitigating and concomitant factors can have on efficaey. These factors include disease severity, gender, presence of tinea pedis, and diabetes. This article reviews results achieved in Phase 3 pivotal studies with topical efinaconazole 10% Solution applied once daily for 48 weeks with a focus on how the aforementioned factors influenced therapeutic outcomes. It is important for clinicians treating patients for onychomycosis to evaluate severity, treat concomitant tinea pedis, address control of diabetes if present by encouraging involvement of the patient's primary care physician, and consider longer treatment courses when clinically relevant.

  3. TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

    Science.gov (United States)

    Lai, De-Wei; Lin, Keng-Hung; Sheu, Wayne Huey-Herng; Lee, Maw-Rong; Chen, Chung-Yu; Lee, Wen-Jane; Hung, Yi-Wen; Shen, Chin-Chang; Chung, Tsung-Ju; Liu, Shing-Hwa; Sheu, Meei-Ling

    2017-09-01

    Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N ε -(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum N ε -(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N ε -(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the N ε -(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. © 2017

  4. Intra-arterial embolization with pingyangmycin-lipiodol emulsion for the treatment of hepatic cavernous hemangioma: an analysis of factors affecting therapeutic results

    International Nuclear Information System (INIS)

    Zeng Qingle; Chen Yong; Zhao Jianbo; Zhang Kewei; Li Yanhao

    2009-01-01

    Objective: To analyze the factors that might affect the therapeutic results of pingyangmycin-lipiodol emulsion intra-arterial sclerosing embolization (PLE-IASE) in treating symptomatic cavernous hemangioma of liver (SCHL). Methods: PLE-IASE was performed in 89 patients with SCHL (32 males and 57 females). Before treatment the mean diameter of the hemangioma was (8.3±3.8) cm. Of 89 patients, 53 experienced anxiety, 35 suffered from right upper abdominal pain and the remaining one developed Kasabach-Merrit syndrome. Before PLE-IASE, the arteriographic classification was conducted based on hepatic arteriographic findings. Then pingyangmycin-lipiodol emulsion (PLE) was injected through the feeding artery. The dosage of pingyangmycin (PYM) was (9.8 ± 4.4) mg and the dosage of lipiodol (LP) was (5.9 ± 2.9) ml. The lipiodol deposition status was judged by the follow-up spot film taken immediately after PLE-IASE. The observations of the occurrence of complications, the relief of symptoms and the minification of SCHL were followed for 6-72 months after PLE-IASE. The linear regression analysis statistics was conducted by taking the minification as dependent variable and taking the arteriographic classification, lipiodol deposition status, the dosage of PYM, the dosage of lipiodol and the preoperative SCHL diameter as independent variable. Results: Of all 89 cases of SCHL, hypervascular type was seen in 51, hypovascular type in 26 and arteriovenous shunt (AVS) type in 12. Good lipiodol deposition status was found in 64 patients and poor deposition in 25 patients after PLE-IASE. After PLE-IASE, the symptom of anxiety in 53 patients was relieved and the right upper abdominal pain was reduced in 33 cases although intermittent pain still remained in 2 patients. The blood platelet count of the patient with Kasabach-Merrit syndrome returned to normal after the treatment. The symptomatic relieve rate was 98.7%. No serious complications occurred in the follow-up period. The linear

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

    Science.gov (United States)

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

    2017-01-03

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

  6. The Experiences of Patients´ Close Relatives with Risk Factors of Gastric Cancer and Health-Therapeutic Personnel from the Determinants of Nutritional Behaviors: A Theory-based Qualitative Content Analysis

    Directory of Open Access Journals (Sweden)

    MH Baghiani Moghadam

    2016-03-01

    Full Text Available Introduction: Cancers are one of the most common causes of death at age groups above 50 years old that Life style modification has an important role in prevention of them. Diets are the most important factor at the risk of gastric cancer. The aim of present study was explanation of the Experiences of Patients´ Close Relatives with Risk Factors of Gastric Cancer and Health-Therapeutic Personnel from the Determinants of Nutritional Behaviors based on protection motivation theory. Methods: The present qualitative study was done with content analysis method application at Babol health-therapeutic centers covered by Babol University of Medical Sciences for eight months in 2013. semi-structure d face to face interview were used to collect the data with 9 participants from Patients´ Close Relatives with Risk Factors of Gastric Cancer and 19 participants from Health-Therapeutic Personnel. Data analysis and collection were simultaneously done by using the method of theory-based (directed or conductive content analysis. Results:From data analysis 487initial codes and after integration,186 main codes were extracted .This codes were pasted at 2 pre-determined categories and 7 pre-determined sub-categories related to protection motivation theory(perceived sensitivity, perceived severity, reward, fear, perceived response-efficacy, self-efficacy and perceived cost-benefit. The most main perceived problem, was the low level of awareness, attitude and practice at people about nutritional risk factors related to gastric cancer and a result the low level of disease fear. Conclusion: The findings of present study are the indicator of effective determinants on nutritional behaviors that can help to health-therapeutic policy –makers to provide and approve the most appropriate solutions and strategies with aim of changing these determinants in order to reduce nutritional risk factors related to gastric cancer.

  7. Compact invariant sets of the Bianchi VIII and Bianchi IX Hamiltonian systems

    International Nuclear Information System (INIS)

    Starkov, Konstantin E.

    2011-01-01

    In this Letter we prove that all compact invariant sets of the Bianchi VIII Hamiltonian system are contained in the set described by several simple linear equalities and inequalities. Moreover, we describe invariant domains in which the phase flow of this system has no recurrence property and show that there are no periodic orbits and neither homoclinic, nor heteroclinic orbits contained in the zero level set of its Hamiltonian. Similar results are obtained for the Bianchi IX Hamiltonian system. -- Highlights: → Zero level set of Hamiltonian of Bianchi VIII/IX systems contains no periodic orbits. → Similar conditions for homoclinic/heteroclinic orbits are given. → General nonexistence conditions of compact invariant sets are got.

  8. Compact invariant sets of the Bianchi VIII and Bianchi IX Hamiltonian systems

    Energy Technology Data Exchange (ETDEWEB)

    Starkov, Konstantin E., E-mail: konst@citedi.mx [CITEDI-IPN, Av. del Parque 1310, Mesa de Otay, Tijuana, BC (Mexico)

    2011-08-22

    In this Letter we prove that all compact invariant sets of the Bianchi VIII Hamiltonian system are contained in the set described by several simple linear equalities and inequalities. Moreover, we describe invariant domains in which the phase flow of this system has no recurrence property and show that there are no periodic orbits and neither homoclinic, nor heteroclinic orbits contained in the zero level set of its Hamiltonian. Similar results are obtained for the Bianchi IX Hamiltonian system. -- Highlights: → Zero level set of Hamiltonian of Bianchi VIII/IX systems contains no periodic orbits. → Similar conditions for homoclinic/heteroclinic orbits are given. → General nonexistence conditions of compact invariant sets are got.

  9. PENGARUH KEMANDIRIAN BELAJAR DAN PENGGUNAAN UANG SAKU TERHADAP PRESTASI BELAJAR KOMPETENSI DASAR EKONOMI KELAS VII DAN VIII

    OpenAIRE

    Apri Dwi Astuti

    2012-01-01

    Kemandirian belajar membantu siswa untuk bertanggung jawab dan menumbuhkan kesadaran belajar. Penggunaan uang saku menumbuhkan jiwa mandiri, jujur dan komitmen. Adapun hasil observasi awal menunjukkan masih ada siswa kels VII dan VIII SMP Semesta untuk kompetensi dasar ekonomi dibawah KKM. Tujuan penelitian ini untuk mengetahui pengaruh kemandirian belajar dn penggunaan uang saku terhadap prestasi belajar kompetensi dasar ekonomi kelas VII dan VIII SMP Semesta. Populasi penelitian ini adalah ...

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

    Science.gov (United States)

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

    2018-06-18

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

  11. Historical intensity VIII earthquakes along the Rhone valley (Valais, Switzerland): primary and secondary effects

    Energy Technology Data Exchange (ETDEWEB)

    Fritsche, S.; Faeh, D.; Schwarz-Zanetti, G.

    2012-06-15

    In recent years the upper Rhone Valley has been one of the most intensively investigated regions by the Swiss Seismological Service. The high seismicity in the region encourages research in the seismological field and one main focus has been historical seismology. This report presents the state of the art of our historical investigations by giving an overview of the effects of four damaging earthquakes with intensity larger than VII, for which a fairly large number of documents could be found and analyzed. The overview includes the events of 1584 (Aigle, epicentral intensity VIII), 1755 (Brig, epicentral intensity VIII), 1855 (Visp, epicentral intensity VIII), and 1946 (Sierre, epicentral intensity VIII for the main shock and intensity VII for the largest aftershock). The paper focuses mainly on primary and secondary effects in the epicentral region, providing the key data and a general characterization of the event. Generally, primary effects such as the reaction of the population and impact on buildings took more focus in the past. Thus building damage is more frequently described in historic documents. However, we also found a number of sources describing secondary effects such as landslides, snow avalanches, and liquefaction. Since the sources may be useful, we include citations of these documents. The 1584 Aigle event, for example, produced exceptional movements in the Lake of Geneva, which can be explained by an expanded sub aquatic slide with resultant tsunami and seiche. The strongest of the aftershocks of the 1584 event triggered a destructive landslide covering the villages Corbeyrier and Yvorne, Vaud. All macroseismic data on the discussed events are accessible through the web page of the Swiss Seismological Service (http://www.seismo.ethz.ch). (authors)

  12. VIII All-Russian symposium on molecular liquid chromatography and capillary electrophoresis. Program. Summary of reports

    International Nuclear Information System (INIS)

    2001-01-01

    Program and summary of reports of the VIII All-Russian symposium on molecular liquid chromatography and capillary electrophoresis are performed. The meeting took place 15-19 October, 2001 in Moscow. Many problems of liquid and ion exchange chromatography, capillary electrophoresis, thin-layer chromatography have been discussed extensively. Reports covering properties of sorbents and devices for chromatography are incorporated in the collection [ru

  13. VIII. Safety and method of work in ionizing radiation applications

    International Nuclear Information System (INIS)

    1984-01-01

    Ionizing radiation may damage the organism in two ways: the damage may be chronic or acute. The characteristics of the two types of damage are described. The Czechoslovak State Standard allows the level of 50 mSv as the maximum permissible dose for whole-body exposure for personnel working with radiation. In case of sources incorporated in the body of the workers the maximum permissible dose should not exceed the value of 2.8 μSv/h during decay. Precautions are given for operation with X-ray instruments. In the X-ray room good ventilation must be provided in view of the presence of ozone and oxides. Diagnostic and therapeutical instruments are placed in a separate room from control instruments. The walls are reinforced with barite concrete. Tables are given showing excitation voltage in kV of primary radiation at which the shortest wavelengths and corresponding voltage would be o.enerated scattered at different angles and with minimum wavelength. Also given are thicknesses of the lead layer in mm for different distances from the source and for different voltages in kV at 10 mA. Corrections are given for other current intensities. Radiation protection of personnel working with sealed sources may be achieved by shielding, shortening the time required for handling and the distance at which the source is operated. For operating unsealed radioactive sources various types of shieldings are used depending on the type of radiation. Workplaces are classified into three categories and hygiene regulations are summed up for work with unsealed sources. (E.S.)

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

    Energy Technology Data Exchange (ETDEWEB)

    Boyko, Konstantin M., E-mail: kmb@inbi.ras.ru [Bach Institute of Biochemistry, Federal Research Centre of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt. 33, Bld. 2, 119071, Moscow (Russian Federation); National Research Center “Kurchatov Institute”, Kurchatov Complex of NBICS-technologies, Akad. Kurchatova sqr., 1, Moscow, 123182 (Russian Federation); Gorbacheva, Marina A.; Korzhenevskiy, Dmitry A. [National Research Center “Kurchatov Institute”, Kurchatov Complex of NBICS-technologies, Akad. Kurchatova sqr., 1, Moscow, 123182 (Russian Federation); Alekseeva, Maria G.; Mavletova, Dilara A.; Zakharevich, Natalia V.; Elizarov, Sergey M.; Rudakova, Natalia N.; Danilenko, Valery N. [Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina str. 3, Moscow, 119333 (Russian Federation); Popov, Vladimir O. [Bach Institute of Biochemistry, Federal Research Centre of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt. 33, Bld. 2, 119071, Moscow (Russian Federation); National Research Center “Kurchatov Institute”, Kurchatov Complex of NBICS-technologies, Akad. Kurchatova sqr., 1, Moscow, 123182 (Russian Federation)

    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 with 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.

  15. PERSEPSI SISWA KELAS VIII TENTANG KESEHATAN REPRODUKSI REMAJA DAN PENYAKIT MENULAR SEKSUAL

    Directory of Open Access Journals (Sweden)

    Omega Rianda Rustian

    2015-06-01

    This study is based on interviews conducted in one of the BK school teacher. This study aimed to determine the perception class VIII student perceptions on adolescent reproductive health and sexually transmitted diseases in SMP Islam Sultan Agung 1 Semarang. The method used in this research is descriptive quantitative survey methods. Population in this research is class VIII SMP Islam Sultan Agung 1 Semarang totaling 151 students with a sampling technique used is accidental to obtain a sample of 60. Data collection tools in the form of a psychological scale with data analysis techniques using descriptive analysis percentage. The average result of students' perceptions on adolescent reproductive health in the high category (74% and perceptions of students about sexually transmitted diseases in the very high category (76%. That class VIII SMP Islam Sultan Agung 1 Semarang already have an idea of the meaning of adolescent reproductive health is a state of good health both physically healthy, functioning, as well as reproductive performance in adolescent and the  meaning of sexually transmitted diseases are caused by viruses, parasites, or function as a result of sexual intercourse.

  16. Stroke and Therapeutic Hypothermia

    Directory of Open Access Journals (Sweden)

    Ozlem Ozkan Kuscu

    2016-09-01

    Full Text Available Stroke is significant cause of morbidity and mortality caused by disruption of blood flow. Neural injury occurs with two stage; while primary neural injury occurs with disruption of blood flow, after days and hours with metabolic processes secondary injury develops in tissues which is non injured in the first stage. Therefore it is important to prevent and treat the secondary injury as much as preventing and treating the primary neural injury. In this article developing pathophysiological changes after stroke, mechanisms of therapeutic hypothermia, application methods, the factors that determine the effectiveness, side effects and complications were reviewed. [Archives Medical Review Journal 2016; 25(3.000: 351-368

  17. The therapeutic relationship after psychiatric admission.

    LENUS (Irish Health Repository)

    Roche, Eric

    2014-03-01

    The therapeutic relationship is one of the most central and important factors in the treatment of mental health disorders. A better therapeutic relationship is associated with service engagement, medication adherence, and satisfaction with services. This study aimed to compare the demographic and clinical factors associated with the therapeutic relationship in voluntarily and involuntarily admitted psychiatric service users. We found that individuals who had been admitted involuntarily, who had a diagnosis of a psychotic disorder, and who reported higher levels of perceived pressures on admission were more likely to have a poorer therapeutic relationship with their consultant psychiatrist. Greater levels of insight and treatment satisfaction, together with higher levels of procedural justice experienced on admission, were associated with a better therapeutic relationship. We found that the level of perceived coercion on admission was not related to the therapeutic relationship. Targeted interventions to improve the therapeutic relationship, particularly for involuntarily admitted service users, are discussed.

  18. Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years

    DEFF Research Database (Denmark)

    Björkman, Sven; Folkesson, Anna; Jönsson, Siv

    2009-01-01

    in the sparse clinical data. Model-predicted doses (based on age and body weight) to maintain a recommended 0.01 U/mL trough level of FVIII with administration on alternate days started at around 60 U/kg in the small children, decreasing to 10 U/kg or less in middle age. However, "true" dose requirements......, as estimated from individual PK parameter data, showed a much greater variation. CONCLUSION: Appropriate dosing of FVIII for prophylactic treatment cannot be calculated only from body weight and/or age. However, plausible starting doses for most patients would be 1,000 U every other day. FVIII levels should...... can be calculated according to patient characteristics, and (3) to present dosing recommendations for initiating prophylactic treatment. METHODS: A population PK model was developed using data from four PK studies on patients aged 7-74 years. The model was tested on sparse FVIII data from 42...

  19. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

    Science.gov (United States)

    Mahlangu, Johnny; Powell, Jerry S.; Ragni, Margaret V.; Chowdary, Pratima; Josephson, Neil C.; Pabinger, Ingrid; Hanabusa, Hideji; Gupta, Naresh; Kulkarni, Roshni; Fogarty, Patrick; Perry, David; Shapiro, Amy; Pasi, K. John; Apte, Shashikant; Nestorov, Ivan; Jiang, Haiyan; Li, Shuanglian; Neelakantan, Srividya; Cristiano, Lynda M.; Goyal, Jaya; Sommer, Jurg M.; Dumont, Jennifer A.; Dodd, Nigel; Nugent, Karen; Vigliani, Gloria; Luk, Alvin; Brennan, Aoife

    2014-01-01

    This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128. PMID:24227821

  20. Characterization of Chinese Hamster Ovary Cells Producing Coagulation Factor VIII Using Multi-omics Tools

    DEFF Research Database (Denmark)

    Kaas, Christian Schrøder

    The first public draft of a genome from Chinese hamster ovary (CHO) cells was published in 2011, an entire decade after the first draft of the human genome. This publication of a relevant CHO reference genome, in combination with the fact that the cost for DNA sequencing has dropped more than 10...... using omics tools. A wide range of methods were applied including whole-genome sequencing, targeted genome sequencing, mRNA sequencing, miRNA sequencing and mass spectrometry based shotgun proteomics on a number of clones in order to get a more holistic picture of the inner workings of these CHO...... transfectants. From the whole-genome sequencing of two CHO genomes (CHO DXB11 and the FVIII producing transfectant: F435) it was observed that roughly 20% of the genes in the genome were haploid and roughly 10% had a copy number of three or higher indicating extensive rearrangements compared to the Chinese...

  1. Identification of the factors that govern the ability of therapeutic antibodies to provide postchallenge protection against botulinum toxin: a model for assessing postchallenge efficacy of medical countermeasures against agents of bioterrorism and biological warfare.

    Science.gov (United States)

    Al-Saleem, Fetweh H; Nasser, Zidoon; Olson, Rebecca M; Cao, Linsen; Simpson, Lance L

    2011-08-01

    Therapeutic antibodies are one of the major classes of medical countermeasures that can provide protection against potential bioweapons such as botulinum toxin. Although a broad array of antibodies are being evaluated for their ability to neutralize the toxin, there is little information that defines the circumstances under which these antibodies can be used. In the present study, an effort was made to quantify the temporal factors that govern therapeutic antibody use in a postchallenge scenario. Experiments were done involving inhalation administration of toxin to mice, intravenous administration to mice, and direct application to murine phrenic nerve-hemidiaphragm preparations. As part of this study, several pharmacokinetic characteristics of botulinum toxin and neutralizing antibodies were measured. The core observation that emerged from the work was that the window of opportunity within which postchallenge administration of antibodies exerted a beneficial effect increased as the challenge dose of toxin decreased. The critical factor in establishing the window of opportunity was the amount of time needed for fractional redistribution of a neuroparalytic quantum of toxin from the extraneuronal space to the intraneuronal space. This redistribution event was a dose-dependent phenomenon. It is likely that the approach used to identify the factors that govern postchallenge efficacy of antibodies against botulinum toxin can be used to assess the factors that govern postchallenge efficacy of medical countermeasures against any agent of bioterrorism or biological warfare.

  2. The Carina Project. VIII. The α-element abundances

    Science.gov (United States)

    Fabrizio, M.; Nonino, M.; Bono, G.; Primas, F.; Thévenin, F.; Stetson, P. B.; Cassisi, S.; Buonanno, R.; Coppola, G.; da Silva, R. O.; Dall'Ora, M.; Ferraro, I.; Genovali, K.; Gilmozzi, R.; Iannicola, G.; Marconi, M.; Monelli, M.; Romaniello, M.; Walker, A. R.

    2015-08-01

    We have performed a new abundance analysis of Carina red giant (RG) stars from spectroscopic data collected with UVES (high spectral resolution) and FLAMES/GIRAFFE (high and medium resolution) at ESO/VLT. The former sample includes 44 RGs, while the latter consists of 65 (high-resolution) and ~800 (medium-resolution) RGs, covering a significant fraction of the galaxy's RG branch, and red clump stars. To improve the abundance analysis at the faint magnitude limit, the FLAMES/GIRAFFE data were divided into ten surface gravity and effective temperature bins. The spectra of the stars belonging to the same gravity and temperature bin were stacked. This approach allowed us to increase the signal-to-noise ratio in the faint magnitude limit (V≥ 20.5 mag) by at least a factor of five. We took advantage of the new photometry index cU,B,I introduced recently as an age and probably a metallicity indicator to split stars along the red giant branch. These two stellar populations display distinct [Fe/H] and [Mg/H] distributions: their mean iron abundances are -2.15 ± 0.06 dex (σ = 0.28), and -1.75 ± 0.03 dex (σ = 0.21), respectively. The two iron distributions differ at the 75% level. This supports preliminary results. Moreover, we found that the old and intermediate-age stellar populations have mean [Mg/H] abundances of -1.91 ± 0.05 dex (σ = 0.22) and -1.35 ± 0.03 dex (σ = 0.22); these differ at the 83% level. Carina's α-element abundances agree, within 1σ, with similar abundances for field halo stars and for cluster (Galactic and Magellanic) stars. The same outcome applies to nearby dwarf spheroidals and ultra-faint dwarf galaxies in the iron range covered by Carina stars. Finally, we found evidence of a clear correlation between Na and O abundances, thus suggesting that Carina's chemical enrichment history is quite different from that in the globular clusters. Based on spectra retrieved from the ESO/ST-ECF Science Archive Facility and collected either with UVES at

  3. AKTIVITAS FISIK, ASUPAN ENERGI DAN STATUS GIZI WANITA PEMETIK TEH DI PTPN VIII BANDUNG, JAWA BARAT

    Directory of Open Access Journals (Sweden)

    Venny Agustiani Mahardikawati

    2012-03-01

    Full Text Available 800x600 Normal 0 false false false IN X-NONE X-NONE MicrosoftInternetExplorer4 Quality of human resources is very important to improve productivity. The worker productivity is correlated with nutritional status and health status. The objective of the research is to analyze physical activity, energy intake, nutritional status, of women workers at Tea Plantation PTPN VIII Bandung, West Java. The cross sectional design was used in this study to elaborate physical activity, nutritional status, and productivity of tea picker’s women. The criteria of study sample were tea picker’s women at cluster area of Malabar tea plantation of PTPN VIII Bandung, having infant and they were willing to be interviewed. The total number of 92 women sample was chosen randomly. Primary data consisted of physical activity recall (2x24 hours, food consumption recall (2x24 hours, anthropometry data (weight and height, and productivity (passage of tea sprout. Secondary data were included data of PT Perkebunan Nusantara VIII Bandung, West Java. The result showed that more than a half of samples having active or moderate physical activity level (PAL. The physical activity level of samples during work day (average PAL=1.87 was higher than holiday (average PAL=1.69 (p2362 kcal and 2134 kcal. The average energy adequacy level during workday and day off according to Schofield and Oxford equation were not significantly different, respectively 97,2% and 103,3%. The majority of samples had normal nutritional status, and 30.4% of the sample was overweight. The energy adequacy level according to Schofield and Oxford equation are related to nutritional status of women workers. Keywords: physical activity, energy expenditure, nutritional status, plantation women

  4. Prospects and Challenges of Implementing the Hydrographic Region VIII Basin Plan

    Directory of Open Access Journals (Sweden)

    Nathalia Silva Duarte

    2011-12-01

    Full Text Available The current “National Water Law” states that water resources plans must be elaborated by basins, states, and for the country. This essay discusses the water management process considering federal and state legislations and their interrelations, for the purpose of elucidating the gaps found in them , aiming at their applicability to the system of water resources management within the CBH- Macaé and Ostras scope. It also discusses the construction and evolution process of the above-mentioned committee, and developments in the implementation of the Basin Plan of Hydrographic Region VIII.

  5. Leonor Plantagenet y la consolidación castellana en el reinado de Alfonso VIII

    Directory of Open Access Journals (Sweden)

    Cerda, José Manuel

    2012-12-01

    Full Text Available The kingdom of Castile experienced a process of political and territorial consolidation between the death of Sancho III in 1158 and the Curia of Carrión de los Condes in 1188, leaving behind the troublesome minority of Alfonso VIII and the subordination to the kingdom of Leon, and thus becoming a dominant power within the peninsula, and one that achieved considerable success in the Reconquest. The following article is part of a biographical approach to Eleanor Plantagenet, queen consort of Alfonso VIII, and by means of a specifi c focus offers an analysis of the role played by the English queen in this process of political consolidation of Castile. As we approach the eighth centenary of her death, the life and work of this little-studied woman emerges as a testimony to the important diplomatic and cultural tasks assumed by queens in twelfth-century Europe.

    Desde la muerte de Sancho III en 1158 a la Curia de Carrión de los Condes en 1188, el reino castellano experimentó una consolidación política y territorial que dejó atrás la problemática minoría de Alfonso VIII y la subordinación al reino de León, que lo constituyó en un poder dominante dentro de la península y que logró un avance importante en la empresa reconquistadora. El presente trabajo es parte de un acercamiento biográfico a Leonor Plantagenet, consorte de Alfonso VIII, y que por medio de un enfoque particular ofrece un análisis de la incidencia que tuvo la reina inglesa en este proceso de afianzamiento político de Castilla. En las vísperas del octavo centenario de su muerte, la vida y obra de esta mujer hasta ahora poco estudiada, surge como un testimonio importante a la labor diplomática y cultural que asumían las reinas en la Europa del siglo XII.

  6. IMPLIKASI YURIDIS PUTUSAN MK NOMOR 46/PUU- VIII/ 2010 TERHADAP AKTA KELAHIRAN ANAK LUAR KAWIN

    Directory of Open Access Journals (Sweden)

    Djumikasih Djumikasih

    2014-08-01

    Full Text Available Abstract This paper aims to identify and analyze what the juridical implications of the publication of the decision of the Constitutional Court No. 46/PUU-VIII / 2010 on Child Outside Marriage Deed which has been published by the Department of Population and Civil Registration prior to the establishment of the Constitutional Court's decision . The method used in this study is a normative juridical approach legislation. From the discussion, it can be concluded that the Constitutional Court 46/PUU-VIII/2010 Number of Tests on Article 43 paragraph ( 1 Marriage Act ( Act No. 1 of 1974 when viewed from the angle of legal certainty it will lead to legal certainty . But the decision will not have any juridical implications of the child's birth certificate that has been published outside of marriage and illegitimate child who was born before the date of February 17, 2012, as if enacted would be contrary to the principle of legality is interpreted Article 47 of the Law on the Constitutional Court and Article 28 ( i of the 1945 Constitution . Likewise, if the terms of the fairness and usefulness , especially for justice seekers / applicant , the timing of this decision is not fair and not useful , because although the Court granted the petition but the Constitutional Court can not be applied to her .   Key words: yuridical implication, birth certificate, children who are born outside of marriage   Abstrak   Tulisan ini bertujuan untuk mengetahui dan menganalisis apa implikasi yuridis dari terbitnya putusan MK Nomor 46/PUU-VIII/ 2010 terhadap Akta Anak Luar Kawin yang sudah diterbitkan oleh Dinas Kependudukan dan Catatan Sipil sebelum lahirnya putusan MK tersebut. Metode yang digunakan dalam penelitian ini adalah yuridis normative dengan pendekatan perundang-undangan. Dari pembahasan dapat disimpulkan bahwa Putusan MK Nomer 46/PUU-VIII/2010 tentang Pengujian terhadap Pasal 43 ayat (1 UU Perkawinan (UU NO 1 Tahun 1974 jika dilihat dari sudut kepastian

  7. Grotrian diagrams for highly ionized cobalt Co VIII through Co XXVII

    Energy Technology Data Exchange (ETDEWEB)

    Shirai, Toshizo [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Sugar, J.; Wiese, W.L.

    1997-07-01

    Grotrian diagrams are presented to provide graphical overviews for 1,247 spectral lines of highly ionized cobalt, Co VIII through Co XXVII. In the usual diagram display such as that by Bashkin and Stoner (North-Holland, Amsterdam, 1975), the density of transitions is often too high to allow each transition to be drawn separately. Here in our modified diagrams, the transitions are also represented by lines connecting the upper and lower energy levels, but the lower energy levels are extended and repeated for successive configurations as needed. As a sequence, dense packing is avoided and all lines in a multiplet can be accommodated. (author)

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

    Energy Technology Data Exchange (ETDEWEB)

    None

    1996-12-01

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

  9. Isidore of Seville and comici ueteres. Ad Isid., Orig. VIII 7.7

    Directory of Open Access Journals (Sweden)

    Krzysztof Rzepkowski

    2012-12-01

    Full Text Available In chapter 7 of book VIII of Etymologies dedicated to Roman poets (De poetis, Isidore draws a dividing line between the so-called ueteres and noui comici. Among ueteres he counts Plautus, Accius, Terentius, although Accius, according to our knowledge, composed only tragedies and can hardly be considered a comic playwright. In this paper I try to prove that all the palaeographic, phonetic, historical, and literary arguments speak in favour of emending in the discussed passage the peculiar «Accius» to the expected «Caecilius» (i.e. Caecilius Statius.

  10. Molecular characterization of a novel family VIII esterase from burkholderia multivorans UWC10

    CSIR Research Space (South Africa)

    Rashamuse, KJ

    2007-02-01

    Full Text Available et al., 1992). Here we report the cloning, purification, and 3D model of a novel family VIII esterase from Burkholderia multivorans UWC10. To our knowledge no report of esterolytic activity from B. multivorans is currently available. METHODOLOGY... stream_source_info Rashamuse1_2007_d.pdf.txt stream_content_type text/plain stream_size 9884 Content-Encoding UTF-8 stream_name Rashamuse1_2007_d.pdf.txt Content-Type text/plain; charset=UTF-8 Molecular Characterization...

  11. Estudo da articulação temporomandibular em camundongos deficientes de fator VIII

    OpenAIRE

    Patricia do Socorro Queiroz Feio

    2010-01-01

    Resumo: A hemofilia é uma doença hemorrágica hereditária ligada ao cromossomo X, decorrente da ausência ou da baixa quantidade no plasma dos fatores de coagulação Fator VIII (hemofilia A) ou do Fator IX (hemofilia B). Clinicamente, a hemofilia se caracteriza por episódios recorrentes de sangramentos profundos, que podem ocorrer espontaneamente ou em decorrência de traumatismos. O sistema músculo-esquelético é freqüentemente afetado pelos eventos hemorrágicos nos pacientes portadores de hemofi...

  12. Alternative pathways of thromboplastin-dependent activation of human factor X in plasma

    International Nuclear Information System (INIS)

    Marlar, R.A.; Griffin, J.H.

    1981-01-01

    To determine the interrelationships of the major coagulation pathways, the activation of 3H-labeled factor X in normal and various deficient human plasmas was evaluated when clotting was triggered by dilute rabbit or human thromboplastin. Various dilutions of thromboplastin and calcium were added to plasma samples containing 3H-factor X, and the time course of factor X activation was determined. At a 1/250 dilution of rabbit brain thromboplastin, the rate of factor X activation in plasmas deficient in factor VIII or factor IX was 10% of the activation rate of normal plasma or of factor XI deficient plasma. Reconstitution of the deficient plasmas with factors VIII or IX, respectively, reconstituted normal factor X activation. Similar results were obtained when various dilutions of human thromboplastin replaced the rabbit thromboplastin. From these plasma experiments, it is inferred that the dilute thromboplastin-dependent activation of factor X requires factors VII, IX, and VIII. An alternative extrinsic pathway that involves factors IX and VIII may be the physiologic extrinsic pathway and hence help to explain the consistent clinical observations of bleeding diatheses in patients deficient in factors IX or VIII

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

    Science.gov (United States)

    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 competences.

  14. Role of VI/II ratio on the growth of ZnO nanostructures using chemical bath deposition

    Energy Technology Data Exchange (ETDEWEB)

    Urgessa, Z.N., E-mail: zelalem.urgessa@nmmu.ac.za [Department of Physics, P.O. Box 77000, Nelson Mandela Metropolitan University, Port Elizabeth 6031 (South Africa); Oluwafemi, O.S. [Department of Chemistry and Chemical Technology, Walter Sisulu University, Mthatha Campus, Private Bag XI, 5117 (South Africa); Botha, J.R. [Department of Physics, P.O. Box 77000, Nelson Mandela Metropolitan University, Port Elizabeth 6031 (South Africa)

    2012-05-15

    In this paper the growth process and morphological evolution of ZnO nanostructures were investigated in a series of experiments using chemical bath deposition. The experimental results indicate that the morphological evolution depends on the reaction conditions, particularly on OH{sup -} to Zn{sup 2+} ratio (which directly affects the pH). For low VI/II ratios, quasi-spherical nanoparticles of an average diameter 30 nm are obtained, whereas for larger VI/II ratios, nanorods with an average diameter less than 100 nm are produced, which indicates that by systematically controlling the VI/II ratio, it is possible to produce different shapes and sizes of ZnO nanostructures. A possible mechanism for the nanostructural change of the as-synthesized ZnO from particle to rod was elucidated based on the relative densities of H{sup +} and OH{sup -} in the solution.

  15. Role of VI/II ratio on the growth of ZnO nanostructures using chemical bath deposition

    International Nuclear Information System (INIS)

    Urgessa, Z.N.; Oluwafemi, O.S.; Botha, J.R.

    2012-01-01

    In this paper the growth process and morphological evolution of ZnO nanostructures were investigated in a series of experiments using chemical bath deposition. The experimental results indicate that the morphological evolution depends on the reaction conditions, particularly on OH − to Zn 2+ ratio (which directly affects the pH). For low VI/II ratios, quasi-spherical nanoparticles of an average diameter 30 nm are obtained, whereas for larger VI/II ratios, nanorods with an average diameter less than 100 nm are produced, which indicates that by systematically controlling the VI/II ratio, it is possible to produce different shapes and sizes of ZnO nanostructures. A possible mechanism for the nanostructural change of the as-synthesized ZnO from particle to rod was elucidated based on the relative densities of H + and OH − in the solution.

  16. KEANEKARAGAMAN HYMENOPTERA PARASITOID PADA PERKEBUNAN KELAPA SAWIT PTPN VIII CINDALI, BOGOR

    Directory of Open Access Journals (Sweden)

    Ichsan Luqmana Indra Putra

    2016-09-01

    Full Text Available Diversity of parasitic Hymenoptera in PTPN VIII oil palm plantation Cindali, Bogor. One group of important natural enemies in oil palm plantation is parasitic Hymenoptera. The purpose of this research is to know the diversity and fluctuation of parasitic Hymenoptera PTPN VIII Cindali oil palm plantation. This research was conducted in 6 blocks of oil palm in September 2014 – June 2015. There were 5 plots in every observation blocks 39.2 x 39.2 m in size, and used direct and indirect method. Direct method done by 5 plants in every plots was taken randomized to observed and taken the herbivore insects to reared until the parasitic Hymenoptera came out. Observation of cover crops conducted by 3 subplots determined diagonally in every plots 9.8 x 9.8 m in size and herbivore insects was observed and collected. Indirect methods used sweep net and yellow pan trap. The result of this research, 26 parasitic Hymenoptera families was found, with the Braconidae was the most morphospecies found and the most individual amount was Scelionidae. The abundance of parasitoid in every month fluctuated.

  17. Improving attitudes toward mathematics learning with problem posing in class VIII

    Science.gov (United States)

    Vionita, Alfha; Purboningsih, Dyah

    2017-08-01

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

  18. PENERAPAN MODEL PEMBELAJARAN BAKULIKAN UNTUK MENINGKATKAN KEMAMPUAN BERSIKAP ILMIAH PADA KONSEP PEMANTULAN CAHAYA KELAS VIII

    Directory of Open Access Journals (Sweden)

    N. A. Shofiah

    2012-01-01

    Full Text Available Penelitian tindakan kelas yang bertujuan untuk meningkatkan kemampuan bersikap ilmiah, telah dilakukan di kelas VIII semester IIpada sub pokok bahasan pemantulan cahaya. Untuk meningkatkan kemampuan bersikap ilmiah diterapkan model pembelajaranbakulikan. Penelitian tindakan kelas ini terdiri dari tiga sikus, dengan masing-masing siklus terdiri dari empat tahapan yaituperencanaan, pelaksanaan, observasi dan refleksi. Data sikap ilmiah siswa diambil dari lembar angket dan lembar observasi. Datahasil belajar kognitif diambil dari evaluasi yang ada di LKS tiap akhir siklus dan data hasil belajar psikomotorik diambil dari lembarobservasi tiap akhir siklus. Hasil penelitian menyatakan bahwa sikap ilmiah siswa mengalami peningkatan walaupun tidaksignifikan. Hasil belajar kognitif dan keterampilan psikomotorik siswa mengalami peningkatan tiap siklus dan mencapai ketuntasanpada siklus III. A classroom action research aimed to improve scientific attitude skill had been done in second semester of grade VIII MTs on thesubtopic light reflection. The 'bakulikan' learning model was chosen for improving the scientific attitude skills of the students. Thisaction research consisted of three cycles, and each cycle has four stages, namely, planning, conducting, observation andreflection. The data obtained through questionnaire and observation sheets. The cognitive achievement drawn from the evaluationon each worksheet at the end of each cycle, and the psychometrics recorded from observation sheet. The study concludes that thescientific attitude skill improved significantly. The achievement on cognitive and psychometrics increase gradually on each cycleand get mastery at the end of the last cycle.Keywords: bakulikan; classroom action research; scientific attitude

  19. 46 CFR 54.01-2 - Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code.

    Science.gov (United States)

    2010-10-01

    ... Boiler and Pressure Vessel Code. 54.01-2 Section 54.01-2 Shipping COAST GUARD, DEPARTMENT OF HOMELAND... division 1 of section VIII of the ASME Boiler and Pressure Vessel Code. (a) Pressure vessels shall be designed, constructed, and inspected in accordance with section VIII of the ASME Boiler and Pressure Vessel...

  20. Robustness of solvent/detergent treatment of plasma derivatives: a data collection from Plasma Protein Therapeutics Association member companies.

    Science.gov (United States)

    Dichtelmüller, Herbert O; Biesert, Lothar; Fabbrizzi, Fabrizio; Gajardo, Rodrigo; Gröner, Albrecht; von Hoegen, Ilka; Jorquera, Juan I; Kempf, Christoph; Kreil, Thomas R; Pifat, Dominique; Osheroff, Wendy; Poelsler, Gerhard

    2009-09-01

    Solvent/detergent (S/D) treatment is an established virus inactivation technology that has been applied in the manufacture of medicinal products derived from human plasma for more than 20 years. Data on the inactivation of enveloped viruses by S/D treatment collected from seven Plasma Protein Therapeutics Association member companies demonstrate the robustness, reliability, and efficacy of this virus inactivation method. The results from 308 studies reflecting production conditions as well as technical variables significantly beyond the product release specification were evaluated for virus inactivation, comprising different combinations of solvent and detergent (tri(n-butyl) phosphate [TNBP]/Tween 80, TNBP/Triton X-100, TNBP/Na-cholate) and different products (Factor [F]VIII, F IX, and intravenous and intramuscular immunoglobulins). Neither product class, process temperature, protein concentration, nor pH value has a significant impact on virus inactivation. A variable that did appear to be critical was the concentration of solvent and detergent. The data presented here demonstrate the robustness of virus inactivation by S/D treatment for a broad spectrum of enveloped test viruses and process variables. Our data substantiate the fact that no transmission of viruses such as human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or of other enveloped viruses was reported for licensed plasma derivatives since the introduction of S/D treatment.

  1. Efficacy of therapeutic nuclear medicine

    International Nuclear Information System (INIS)

    Hoefnagel, C.A.

    1998-01-01

    The following topics are discussed: (i) 131 I therapy of thyrotoxicosis; (ii) 131 I therapy of differentiated thyroid carcinoma; (iii) 32 P therapy of myeloproliferative disease; (iv) 131 MIBG therapy of neural crest tumors; (v) radiolabelled peptides in neuroendocrine tumors; (vi) radioimmunotherapy; (vii) palliative bone therapy of painful skeletal metastases; (viii) radiosynoviorthesis; (ix) alternative approaches; (x) side effects and long-term effects

  2. Psychological Considerations in the Assessment and Treatment of Pain in Neurorehabilitation and Psychological Factors Predictive of Therapeutic Response: Evidence and Recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

    Science.gov (United States)

    Castelnuovo, Gianluca; Giusti, Emanuele M; Manzoni, Gian Mauro; Saviola, Donatella; Gatti, Arianna; Gabrielli, Samantha; Lacerenza, Marco; Pietrabissa, Giada; Cattivelli, Roberto; Spatola, Chiara A M; Corti, Stefania; Novelli, Margherita; Villa, Valentina; Cottini, Andrea; Lai, Carlo; Pagnini, Francesco; Castelli, Lorys; Tavola, Mario; Torta, Riccardo; Arreghini, Marco; Zanini, Loredana; Brunani, Amelia; Capodaglio, Paolo; D'Aniello, Guido E; Scarpina, Federica; Brioschi, Andrea; Priano, Lorenzo; Mauro, Alessandro; Riva, Giuseppe; Repetto, Claudia; Regalia, Camillo; Molinari, Enrico; Notaro, Paolo; Paolucci, Stefano; Sandrini, Giorgio; Simpson, Susan G; Wiederhold, Brenda; Tamburin, Stefano

    2016-01-01

    In order to provide effective care to patients suffering from chronic pain secondary to neurological diseases, health professionals must appraise the role of the psychosocial factors in the genesis and maintenance of this condition whilst considering how emotions and cognitions influence the course of treatment. Furthermore, it is important not only to recognize the psychological reactions to pain that are common to the various conditions, but also to evaluate how these syndromes differ with regards to the psychological factors that may be involved. As an extensive evaluation of these factors is still lacking, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) aimed to collate the evidence available across these topics. To determine the psychological factors which are associated with or predictive of pain secondary to neurological conditions and to assess the influence of these aspects on the outcome of neurorehabilitation. Two reviews were performed. In the first, a PUBMED search of the studies assessing the association between psychological factors and pain or the predictive value of these aspects with respect to chronic pain was conducted. The included papers were then rated with regards to their methodological quality and recommendations were made accordingly. In the second study, the same methodology was used to collect the available evidence on the predictive role of psychological factors on the therapeutic response to pain treatments in the setting of neurorehabilitation. The first literature search identified 1170 results and the final database included 189 articles. Factors such as depression, anxiety, pain catastrophizing, coping strategies, and cognitive functions were found to be associated with pain across the various conditions. However, there are differences between chronic musculoskeletal pain, migraine, neuropathy, and conditions associated with complex disability with regards to the psychological aspects that are involved. The

  3. Ergonomic factors that cause the presence of pain muscle in students of dentistry

    OpenAIRE

    Díaz Caballero, Antonio José; Gomez Palencia, Isabel Patricia; Díaz Cárdenas, Shyrley

    2010-01-01

    Objective: To identify the ergonomic factors and the presence of muscular pain in dental students of VIII, IX, X semesters presently practicing at the clinics of the College of Dentistry of university of Cartagena, Colombia, South America. Materials and methods: This is a descriptive study carried out in dental students of the VIII, IX, and X semesters which were undergoing clinical practice at the College of Dentistry of University of Cartagena. A convenience sample of 83 students who m...

  4. Computationally derived points of fragility of a human cascade are consistent with current therapeutic strategies.

    Directory of Open Access Journals (Sweden)

    Deyan Luan

    2007-07-01

    Full Text Available The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein-protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of

  5. Effects of anti-aggregant, anti-inflammatory and anti-coagulant drug consumption on the preparation and therapeutic potential of plasma rich in growth factors (PRGF).

    Science.gov (United States)

    Anitua, Eduardo; Troya, María; Zalduendo, Mar; Orive, Gorka

    2015-02-01

    The prevalence and incidence of trauma-related injuries, coronary heart disease and other chronic diseases increase dramatically with age. This population sector is therefore a regular consumer of different types of drugs that may affect platelet aggregation and the coagulation cascade. We have evaluated whether the consumption of acetylsalicylic acid, acenocoumarol, glucosamine sulfate and chondroitin sulfate, and therefore their presence in blood, could interfere with the preparation and biological outcomes of plasma rich in growth factors (PRGF). Clotting time, clot retraction and platelet activation of PRGF was evaluated. PRGF growth factor content and the release of different biomolecules by tendon fibroblasts were also quantified, as well as cell proliferation and cell migration. The preparation and biological potential of PRGF is not affected by the intake of the evaluated drugs, and solely its angiogenic potential and its capacity to induce HA and fibronectin synthesis, is reduced in patients taking anti-coagulants.

  6. Keefektifan Experiential Learning Berbantuan Origami Terhadap Kemampuan Keruangan Siswa Kelas VIII

    Directory of Open Access Journals (Sweden)

    Isnaeni Umi Machromah

    2014-11-01

    Full Text Available AbstrakPenelitian eksperimen ini bertujuan untuk mengetahui keefektifan pembelajaran Experiential Learning berbantuan origami terhadap kemampuan keruangan siswa dengan kualifikasi keefektifan yang telah ditentukan. Populasi yaitu siswa kelas VIII SMP Negeri 3 Colomadu tahun pelajaran 2012/2013. Sampel diambil secara simple random sampling. Hasil penelitian ini yaitu: (1 Uji proporsi ketuntasan belajar menunjukkan siswa kelompok eksperimen telah mencapai ketuntasan belajar; (2 Uji perbedaan dua rata-rata menghasilkan simpulan bahwa rata-rata hasil post-test kemam-puan keruangan siswa kelompok eksperimen lebih dari kelompok kontrol; (3 Analisis re-gresi menunjukkan bahwa motivasi belajar siswa memberikan pengaruh positif sebesar 49,3% terhadap kemampuan keruangan siswa; (4 Uji gain ternormalisasi menunjukkan terdapat peningkatan kemampuan keruangan siswa secara signifikan pada kategaori sedang untuk kelompok eksperimen dan kategori rendah untuk kelompok kontrol. Simpulan yang diperoleh yaitu Experiential Learning berbantuan origami efektif terhadap kemampuan keruangan siswa kelas VIII. AbstractThis experiment research aims to determine the effectiveness of Experiential Learning with Origami to the students’s spatial abilities by the criteria of effectiveness. The population of this research is students of grade VIII of SMP Negeri 3 Colomadu 2012/2013 academic year. Independent variables used in this research are learning by Experiential Learning with origami and student’s motivation. While the dependent variable is the student’s spatial abilities. This research is using documentation, spatial abilities’s test, dan motivation’s scale for collecting data method. Result of this research are: (1 proportion test show that the experiment group has reached mastering of learning clasically and personally; (2 result of spatial ablities’s post test in experiment group better than control group; (3 result of regretion shows that student

  7. 75 FR 36426 - Legislative Changes to Nursing Student Loan Program Authorized Under Title VIII of the Public...

    Science.gov (United States)

    2010-06-25

    ... Changes to Nursing Student Loan Program Authorized Under Title VIII of the Public Health Service Act....) 111-148. Section 5202 of the ACA changes the Nursing Student Loan (NSL) program by: (1) Increasing the... degree in nursing. Below are details on how the ACA changes Sections 836(a), 836(b)(1), and 836(b)(3) of...

  8. Angiogenesis with intramyocardial administration of basic fibroblast growth factor in canine ischemic myocardium

    International Nuclear Information System (INIS)

    Sun Lijun; Liu Ying; Zhao Haitao; Huan Yi; Ge Yali; Gao Fabao

    2004-01-01

    Objective: To evaluate the effect of intramyocardial administration of basic fibroblast growth factor on angiogenesis of infarcted myocardium in dogs. Methods: Twenty-four mongrel dogs were randomized into control group and therapeutic group. Acute myocardial infarction was made by ligation of the left anterior descending coronary artery distal to its first diagonal branch. As soon as coronary artery was occluded, 50 mg of basic fibroblast growth factor in 15 ml of saline was injected into the infarcted and border zone in therapeutic group, whereas 15 ml saline alone was used in the same way in control dogs. Every 3 dogs in each group was studied on the 1 st day, the 3 rd day, the 10 th day, and the 17 th day, respectively. Electron microscope was used to observe the growth of capillaries. Angiogenesis was evaluated by immunohistochemical studies with VIII factor. With sensitivity encoded technique, cine MR and MR perfusion imaging were performed on each dog within 3 hours after surgery and before euthanasia to evaluate cardiac function and the characteristics of myocardial perfusion. Results: In therapeutic group, LVEF improved markedly since the 10 th day (on the 10 th day: control group 24.09 ± 3.32, therapeutic group 45.71 ± 6.27; on the 17 th day: control group 31.46 ± 4.60, therapeutic group 53.46 ± 5.24). Hypoenhancement on first pass and hyperenhancement on delayed phase appeared in infarcted myocardium. There were significant differences for the time of upslope, peak time of signal intensity, upslope curves ratio, and contrast enhancement ratio between infarcted and normal myocardium. The size of infarcted myocardium was markedly decreased on the 17 th day [control group (9.04 ± 1.59)%, therapeutic group (4.07 ± 1.20)%]. The capillaries grew actively in therapeutic group and microvessel density was higher in therapeutic group than in control group except the first day (control group and therapeutic group respectively on the 3 rd day: 92.3 ± 11

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

    Science.gov (United States)

    Herman, M.; Trkov, A.; Capote, R.; Nobre, G. P. A.; Brown, D. A.; Arcilla, R.; Danon, Y.; Plompen, A.; Mughabghab, S. F.; Jing, Q.; Zhigang, G.; Tingjin, L.; Hanlin, L.; Xichao, R.; Leal, L.; Carlson, B. V.; Kawano, T.; Sin, M.; Simakov, S. P.; Guber, K.

    2018-02-01

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

  10. MENINGKATKAN TANGGUNG JAWAB SOSIAL SISWA KELAS VIII MELALUI LAYANAN BIMBINGAN KELOMPOK

    Directory of Open Access Journals (Sweden)

    Ummi Farikhatun Nisa

    2012-12-01

    Full Text Available The purpose of this research was to determine the efforts and success in improving students' social responsibility through group counseling services. Type of research used action research. Subjects were 12 students who had low social responsibility and being. Data collection technique used were psychological scales and observation. Data analysis techniques used are non-parametric statistics with the Wilcoxon test. Based on the calculations for the Wilcoxon test, a small amount of levels or Z value was 78.0. While Ztabel for n = 12 with an error level of 5% value is 14. So Z 78.0> 14.0 Ztabel or imply hypothesis accepted. These results demonstrate social responsibility of students prior to obtaining counseling services group at 51.93% (low. After following the guidance services at 81.51% (high. Conclusions from this research is a social responsibility to the students of class VIII SMP Putra Bangsa Bantarkawung increase after getting tutoring services group.

  11. X-ray spectral line coincidences between fluorine VIII (and IX) and transition metal lines

    International Nuclear Information System (INIS)

    Charatis, G.; Rockett, P.D.; Burkhalter, P.G.

    1983-01-01

    X-ray spectroscopy was performed in the 12 to 15 A region, recording L-shell lines from selected laser-irradiated transition metals. Line coincidences and near coincidences were identified between Fe, Cr, Mn, and Ni L-spectra, and F VIII and F IX K-shell lines. Wavelengths were determined to accuracies of 1 to 3 mA and will be utilized in selecting potential pumping candidates in future x-ray lasing schemes. High-resolution x-ray spectra were collected under controlled illumination and target conditions using 1.05 μm and 0.527 μm laser excitation with the KMS CHROMA laser

  12. Symposium by NATO Defense Research Group Panel VIII on Computer-Based Instruction in Military Environments

    CERN Document Server

    Weddle, Peter

    1987-01-01

    This collection of papers is the result of a symposium sponsored by NATO's Defense Research Group Panel VIII in the Spring of 1985. The symposium came into being when it became obvious to the NATO countries that research, development and utilization of advanced technologies for training was the best means of increasing both training effectiveness and efficiency. This symposium was the second in a series of three devoted to training. The series was structured to cover all aspects of training. The first series addressed the value of training, the second one dealt with the application of training technologies and the third and last of the series focused on academic issues concerned with the effect of prior learning on subsequent learning. The fact that a major American publisher has determined that computer based instruction is the technology of greatest interest to the NATO community is not surprising. Advances in microprocessor technology have revolutionized both how and where we train. During this symposium t...

  13. PENERAPAN PENDEKATAN CINEMATHERAPY UNTUK MENINGKATKAN PERILAKU PROSOSIAL PADA SISWA KELAS VIII DI BOSOWA INTERNATIONAL SCHOOL MAKASSAR

    Directory of Open Access Journals (Sweden)

    Haeruddin Niva

    2016-06-01

    Full Text Available The objectives of the research are: (i to know the prosocial behavioral level of the students in Bosowa International School Makassar before and after giving cinematography approach, and (ii to know whether or not the approach is able to enhance the prosocial behavior of the students in Bosowa International School Makassar. The research is a quantitative research using experimental method. The research design used is quasi experimental design with non-equivalent control group design. The data collection technique applied is scale and FGD (Focus Group Discussion. The findings shows that (i the prosocial behavioral level of the students was low in pretest while after giving treatment there were significant increase to the prosocial behavior in the experimental group, and (ii the cinematography approach was able to increase the prosocial behavior of the Grade VIII students in Bosowa Internatinal School Makassar. 

  14. The transitions 4p-5s in Y VI, Zr VII, Nb VIII and Mo IX

    International Nuclear Information System (INIS)

    Chaghtai, M.S.Z.; Rahimullah, K.; Khatoon, S.

    1976-01-01

    With the help of the spectra recorded in the Physics Department of Lund University, Y VI, Zr VII, Nb VIII and Mo IX are freshly analysed. The five 4s 2 4p 4 ground levels and the ten 4s 2 4p 3 5s levels of previous analyses are confirmed in the first three spectra, except for revising in Y VI the 4p 4 1 S 0 and 4p 3 5s( 4 Ssub(3/2)) 2 levels and interchanging 5s( 2 Dsub(3/2)) 1 with 5s( 2 Dsub(3/2)) 2 . All level values are improved due to the new measurements. A new analysis of Mo IX establishing all the 4p 4 and 4p 3 5s levels is being reported. (Auth.)

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

    Science.gov (United States)

    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.

  16. Monitoring low molecular weight heparins at therapeutic levels: dose-responses of, and correlations and differences between aPTT, anti-factor Xa and thrombin generation assays.

    Directory of Open Access Journals (Sweden)

    Owain Thomas

    Full Text Available Low molecular weight heparins (LMWH's are used to prevent and treat thrombosis. Tests for monitoring LMWH's include anti-factor Xa (anti-FXa, activated partial thromboplastin time (aPTT and thrombin generation. Anti-FXa is the current gold standard despite LMWH's varying affinities for FXa and thrombin.To examine the effects of two different LMWH's on the results of 4 different aPTT-tests, anti-FXa activity and thrombin generation and to assess the tests' concordance.Enoxaparin and tinzaparin were added ex-vivo in concentrations of 0.0, 0.5, 1.0 and 1.5 anti-FXa international units (IU/mL, to blood from 10 volunteers. aPTT was measured using two whole blood methods (Free oscillation rheometry (FOR and Hemochron Jr (HCJ and an optical plasma method using two different reagents (ActinFSL and PTT-Automat. Anti-FXa activity was quantified using a chromogenic assay. Thrombin generation (Endogenous Thrombin Potential, ETP was measured on a Ceveron Alpha instrument using the TGA RB and more tissue-factor rich TGA RC reagents.Methods' mean aPTT at 1.0 IU/mL LMWH varied between 54s (SD 11 and 69s (SD 14 for enoxaparin and between 101s (SD 21 and 140s (SD 28 for tinzaparin. ActinFSL gave significantly shorter aPTT results. aPTT and anti-FXa generally correlated well. ETP as measured with the TGA RC reagent but not the TGA RB reagent showed an inverse exponential relationship to the concentration of LMWH. The HCJ-aPTT results had the weakest correlation to anti-FXa and thrombin generation (Rs0.62-0.87, whereas the other aPTT methods had similar correlation coefficients (Rs0.80-0.92.aPTT displays a linear dose-response to LMWH. There is variation between aPTT assays. Tinzaparin increases aPTT and decreases thrombin generation more than enoxaparin at any given level of anti-FXa activity, casting doubt on anti-FXa's present gold standard status. Thrombin generation with tissue factor-rich activator is a promising method for monitoring LMWH's.

  17. New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis.

    Science.gov (United States)

    Verma, Dinesh Kumar; Gupta, Sonam; Biswas, Joyshree; Joshi, Neeraj; Singh, Abhishek; Gupta, Parul; Tiwari, Shubhangini; Sivarama Raju, K; Chaturvedi, Swati; Wahajuddin, M; Singh, Sarika

    2018-03-16

    Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Therapeutic Efficacy of Ginger, Cisplatin and Radiation on Chemically-Induced Cancer in Male Albino Rats

    International Nuclear Information System (INIS)

    El-Beih, N.M.; Galal, S.M.; Fahmy, N.M.; Abd El-Azime, M.G.

    2015-01-01

    This study aimed to investigate the in vivo effect of dietary supplementation with ginger to evaluate its therapeutic effect against lung and kidney cancer and in combination with cisplatin as chemotherapy and radiotherapy in male albino rats. 54 male albino rats were divided into nine groups of 6 animals each, all animals were allowed to food and water ad libitum . Group I was treated with 0.5 ml saline, orlly for 12 consecutive weeks serve as con - trol group Group II injected with N-nitrosodimethylamine (NDMA) and carbon tetrachloride (CCl 4 ); all groups were injected with NDMA + CCl 4 for 6 weeks. Group III were given ginger for 6 consecutive weeks (200 mg/kg, b.wt./day). Group IV animals received cisplatin, group V irradiated with 2 Gy, group VI treated with ginger then irradiated, group VII treated with ginger then injected with cisplatin, group VIII injected with cisplatin then irradiated and group IX treated with ginger and cisplatin then irradiated. Antioxidant status in both kidney and lung tissues were estimated by determining the activity of antioxidant enzyme superoxide dismutase (SOD); as well as the level of reduced glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO). In parallel to histopathological investigations of lung and kidney tissues. In addition, Tumor Necrosis Factor Alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid. Remarkable disturbances were observed in the levels of all tested parameters in NDMA + CCl 4 group. On the other hand, rats injected with the cancer agents then treated with cisplatin+radiation showed moderate improvements in the studied parameters while, treatment with ginger + cisplatin + radiation ameliorated the levels of the disturbed bio

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

    Science.gov (United States)

    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.

  20. Keratinocyte Growth Factor Gene Electroporation into Skeletal Muscle as a Novel Gene Therapeutic Approach for Elastase-Induced Pulmonary Emphysema in Mice

    International Nuclear Information System (INIS)

    Tobinaga, Shuichi; Matsumoto, Keitaro; Nagayasu, Takeshi; Furukawa, Katsuro; Abo, Takafumi; Yamasaki, Naoya; Tsuchiya, Tomoshi; Miyazaki, Takuro; Koji, Takehiko

    2015-01-01

    Pulmonary emphysema is a progressive disease with airspace destruction and an effective therapy is needed. Keratinocyte growth factor (KGF) promotes pulmonary epithelial proliferation and has the potential to induce lung regeneration. The aim of this study was to determine the possibility of using KGF gene therapy for treatment of a mouse emphysema model induced by porcine pancreatic elastase (PPE). Eight-week-old BALB/c male mice treated with intra-tracheal PPE administration were transfected with 80 μg of a recombinant human KGF (rhKGF)-expressing FLAG-CMV14 plasmid (pKGF-FLAG gene), or with the pFLAG gene expressing plasmid as a control, into the quadriceps muscle by electroporation. In the lung, the expression of proliferating cell nuclear antigen (PCNA) was augmented, and surfactant protein A (SP-A) and KGF receptor (KGFR) were co-expressed in PCNA-positive cells. Moreover, endogenous KGF and KGFR gene expression increased significantly by pKGF-FLAG gene transfection. Arterial blood gas analysis revealed that the PaO 2 level was not significantly reduced on day 14 after PPE instillation with pKGF-FLAG gene transfection compared to that of normal mice. These results indicated that KGF gene therapy with electroporation stimulated lung epithelial proliferation and protected depression of pulmonary function in a mouse emphysema model, suggesting a possible method of treating pulmonary emphysema

  1. High-altitude hypoxia as a therapeutic factor in the management of X-ray and cytostatic lymphocytopenias in cancer patients

    International Nuclear Information System (INIS)

    Kulish, u.P.; Galkina, K.A.; Karabekova, Z.K.; Kudryavtsev, V.I.; Gudi, T.P.

    1984-01-01

    An attempt is made to clarify possibilities of high-altitude conditions use in clinics to restore hematological indices deteriorating as a result of antitumoral radiation or cytostatic therapy. Using conventional methods the content of hemoglobin, the number of erythrocytes and leukocytes, leukocytic formula in the blood of patients have been determined. Using the method of hemocultures the ability of the blood serum to affect leukocyte migration of practically healthy people (donors) has been studied and by the method of amperometric titration the content of SH-groups in the blood is determined. In patients examined under high-altitude conditions the content of hemoglobin and the number of erythrocytes in blood increased, the level of total SH-groups of blood also grew. Blood serum of patients with the expressed lymphocytopenia instead of suppressing effect on leukocyte migration, observed under low-altitude conditions (Frunze), under high-altitude conditions attained the ability to increase leukocyte migration. The conclusion is made that high-altitude hypoxia is a positive factor in the treatment of radiation and cytostatic lymphopenias in cancer patients

  2. Insights into the therapeutic potential of hypoxia-inducible factor-1α small interfering RNA in malignant melanoma delivered via folate-decorated cationic liposomes

    Directory of Open Access Journals (Sweden)

    Chen Z

    2016-03-01

    Full Text Available Zhongjian Chen,1,* Tianpeng Zhang,2,* Baojian Wu,2 Xingwang Zhang2 1Department of Pharmaceutics, Shanghai Dermatology Hospital, 2Division of Pharmaceutics, College of Pharmacy, Jinan University, Gangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Malignant melanoma (MM represents the most dangerous form of skin cancer, and its incidence is expected to rise in the coming time. However, therapy for MM is limited by low topical drug concentration and multidrug resistance. This article aimed to develop folate-decorated cationic liposomes (fc-LPs for hypoxia-inducible factor-1α (HIF-1α small interfering (siRNA delivery, and to evaluate the potential of such siRNA/liposome complexes in MM therapy. HIF-1α siRNA-loaded fc-LPs (siRNA-fc-LPs were prepared by a film hydration method followed by siRNA incubation. Folate decoration of liposomes was achieved by incorporation of folate/oleic acid-diacylated oligochitosans. The resulting siRNA-fc-LPs were 95.3 nm in size with a ζ potential of 2.41 mV. The liposomal vectors exhibited excellent loading capacity and protective effect toward siRNA. The in vitro cell transfection efficiency was almost parallel to the commercially available Lipofectamine™ 2000. Moreover, the anti-melanoma activity of HIF-1α siRNA was significantly enhanced through fc-LPs. Western blot analysis and apoptosis test demonstrated that siRNA-fc-LPs substantially reduced the production of HIF-1α-associated protein and induced the apoptosis of hypoxia-tolerant melanoma cells. Our designed liposomal vectors might be applicable as siRNA delivery vehicle to systemically or topically treat MM. Keywords: malignant melanoma, HIF-1α siRNA, chitosan, cationic liposomes, gene therapy

  3. Is exercise a therapeutic tool for improvement of cardiovascular risk factors in adolescents with type 1 diabetes mellitus? A randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Salem Mona A

    2010-07-01

    Full Text Available Abstract Background Type 1 diabetes mellitus (T1DM is associated with a high risk for early atherosclerotic complications especially risk of coronary heart disease. Objective To evaluate the impact of six months exercise prgram on glycemic control, plasma lipids values, blood pressure, severity and frequency of hypoglycemia, anthropometric measurements and insulin dose in a sample of adolescents with T1DM. Research design and methods A total of 196 type 1 diabetic patients participated in the study. They were classified into three groups: Group (A did not join the exercise program(n = 48, group (B attended the exercise sessions once/week (n = 75, group (C attended the exercise sessions three times/week (n = 73. Studied parameters were evaluated before and six months after exercise programe. Results Exercise improved glycemic control by reducing HbA1c values in exercise groups (P = 0.03, P = 0.01 respectively and no change in those who were not physically active (P = 0.2. Higher levels of HbA1c were associated with higher levels of cholesterol, LDL-c, and triglycerides (P = 0.000 each. In both groups, B and C, frequent exercise improved dyslipidemia and reduced insulin requirements significantly (P = 0.00 both, as well as a reduction in BMI (P = 0.05, P = 0.00 respectively and waist circumference(P = 0.02, P = 0.00 respectively. The frequency of hypoglycemic attacks were not statistically different between the control group and both intervention groups (4.7 ± 3.56 and 4.82 ± 4.23, P = 0.888 respectively. Reduction of blood pressure was statistically insignificant apart from the diastolic blood presure in group C (P = 0.04. Conclusion Exercise is an indispensable component in the medical treatment of patients with T1DM as it improves glycemic control and decreases cardiovascular risk factors among them.

  4. Cardiovascular Risk Factors After Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S): a New Effective Therapeutic Approach?

    Science.gov (United States)

    Torres, Antonio; Rubio, Miguel A; Ramos-Leví, Ana M; Sánchez-Pernaute, Andrés

    2017-11-07

    weight loss and improvement of blood pressure, lipid profile, and insulin resistance seem to be better with SADI-S than with Roux-en-Y gastric bypass (RYGB), and this difference may be probably still relevant in the long-term evaluation. Mid-term follow-up of patients who underwent SADI-S has proven that this procedure seems, at least, as effective as other malabsorptive techniques such as BPD/DS and significantly reduces the four main cardiovascular risk factors to a higher extent than RYGB. One of the main advantages inherent to this intervention modality is that it truly simplifies any of the prior derivative procedures and that it may be specifically adapted and individualized to each patient, according to his BMI and associated metabolic comorbidities.

  5. Quantitative Tyrosine Phosphoproteomics of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-treated Lung Adenocarcinoma Cells Reveals Potential Novel Biomarkers of Therapeutic Response.

    Science.gov (United States)

    Zhang, Xu; Maity, Tapan; Kashyap, Manoj K; Bansal, Mukesh; Venugopalan, Abhilash; Singh, Sahib; Awasthi, Shivangi; Marimuthu, Arivusudar; Charles Jacob, Harrys Kishore; Belkina, Natalya; Pitts, Stephanie; Cultraro, Constance M; Gao, Shaojian; Kirkali, Guldal; Biswas, Romi; Chaerkady, Raghothama; Califano, Andrea; Pandey, Akhilesh; Guha, Udayan

    2017-05-01

    Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence 747 LREA 750 , are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations. However, 30-40% of patients with EGFR mutations exhibit primary resistance to these TKIs, underscoring the unmet need of identifying additional biomarkers of treatment response. Here, we sought to characterize the dynamics of tyrosine phosphorylation upon EGFR TKI treatment of mutant EGFR-driven human lung adenocarcinoma cell lines with varying sensitivity to EGFR TKIs, erlotinib and afatinib. We employed stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative mass spectrometry to identify and quantify tyrosine phosphorylated peptides. The proportion of tyrosine phosphorylated sites that had reduced phosphorylation upon erlotinib or afatinib treatment correlated with the degree of TKI-sensitivity. Afatinib, an irreversible EGFR TKI, more effectively inhibited tyrosine phosphorylation of a majority of the substrates. The phosphosites with phosphorylation SILAC ratios that correlated with the TKI-sensitivity of the cell lines include sites on kinases, such as EGFR-Y1197 and MAPK7-Y221, and adaptor proteins, such as SHC1-Y349/350, ERRFI1-Y394, GAB1-Y689, STAT5A-Y694, DLG3-Y705, and DAPP1-Y139, suggesting these are potential biomarkers of TKI sensitivity. DAPP1, is a novel target of mutant EGFR signaling and Y-139 is the major site of DAPP1 tyrosine phosphorylation. We also uncovered several off-target effects of these TKIs, such as MST1R-Y1238

  6. Fatores terapêuticos em grupo de suporte na perspectiva da coordenação e dos membros do grupo Factores terapéuticos en un grupo de soporte en la perspectiva de la coordinación y de los miembros del grupo Therapeutic factors in group support from the perspective of the coordinators and group members

    Directory of Open Access Journals (Sweden)

    Leidiene Ferreira Santos

    2012-01-01

    importante que puede ser usada para evaluar si los miembros se están beneficiando participando en el grupo.OBJECTIVES: To identify the therapeutic factors present in the sessions of a Parent and Family Support Group for those with hospitalized children, from the perspective of the participants and the group coordinators. METHODS: A descriptive, exploratory study. The data were obtained by means of a checklist of the families and through identification of therapeutic factors by the coordinators of the group. RESULTS: The families indicated the presence of the following therapeutic factors in the group: cohesion, sharing of information, universality, existential factors, developing social skills, instillation of hope, altruism, interpersonal learning and imitative behavior; the coordinators identified cohesion, sharing of information, universality and existential factors. CONCLUSION: Identification of therapeutic factors is an important therapeutic tool for evaluating whether members are benefitting from their participation in the group.

  7. Psychological considerations in the assessment and treatment of pain in neurorehabilitation and psychological factors predictive of therapeutic response: evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

    Directory of Open Access Journals (Sweden)

    Gianluca eCastelnuovo

    2016-04-01

    Full Text Available BackgroundIn order to provide effective care to patients suffering from chronic pain secondary to neurological diseases, health professionals must appraise the role of the psychosocial factors in the genesis and maintenance of this condition whilst considering how emotions and cognitions influence the course of treatment. Furthermore, it is important not only to recognize the psychological reactions to pain that are common to the various conditions, but also to evaluate how these syndromes differ with regards to the psychological factors that may be involved. As an extensive evaluation of these factors is still lacking, the Italian Consensus Conference on Pain in Neurorehabilitation aimed to collate the evidence available across these topics. ObjectivesTo determine the psychological factors which are associated with or predictive of pain secondary to neurological conditions and to assess the influence of these aspects on the outcome of neurorehabilitation. MethodsTwo reviews were performed. In the first, a PUBMED search of the studies assessing the association between psychological factors and pain or the predictive value of these aspects with respect to chronic pain was conducted. The included papers were then rated with regards to their methodological quality and recommendations were made accordingly. In the second study, the same methodology was used to collect the available evidence on the predictive role of psychological factors on the therapeutic response to pain treatments in the setting of neurorehabilitation.ResultsThe first literature search identified 1170 results and the final database included 189 articles. Factors such as depression, anxiety, pain catastrophizing, coping strategies and cognitive functions were found to be associated with pain across the various conditions. However, there are differences between chronic musculoskeletal pain, migraine, neuropathy and conditions associated with complex disability with regards to the

  8. Intrinsic clotting factors in dependency of age, sex, body mass index, and oral contraceptives: definition and risk of elevated clotting factor levels.

    Science.gov (United States)

    Luxembourg, Beate; Schmitt, Joern; Humpich, Marek; Glowatzki, Matthias; Seifried, Erhard; Lindhoff-Last, Edelgard

    2009-10-01

    Elevated clotting factors have been demonstrated to be a risk factor for venous thromboembolism (VTE). The aim of our study was to investigate the impact of age, sex, body mass index, and oral contraceptives on the clotting factor activities of factors VIII, IX, XI, and XII and their impact on the cutoff definition and risk of VTE associated with elevated clotting factors. Factor VIII, IX, XI, and XII activities were measured in 499 blood donors and 286 patients with VTE. Age and body mass index predicted significantly and independently the clotting factor activities of factors VIII, IX, and XI, whereas use of oral contraceptives predicted factor IX, XI, and XII levels. Percentiles of clotting factor activities, which are often used for the cutoff definition of elevated clotting factors, varied due to the effect of age, body mass index, and oral contraceptives. The adjusted odds ratios for VTE were 10.3 [95% confidence interval (CI) 5.1-20.7], 6.1 (95% CI 3.1-12.0), and 3.3 (95% CI 1.9-5.8) for elevated factors VIII, IX, and XI, respectively. Furthermore, our study demonstrates for the first time that elevated factor XII is associated with an increased risk of VTE (adjusted odds ratio 2.9, 95% CI 1.6-5.3).

  9. Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor.

    Science.gov (United States)

    Yamaura, Takumi; Ezaki, Junji; Okabe, Naoyuki; Takagi, Hironori; Ozaki, Yuki; Inoue, Takuya; Watanabe, Yuzuru; Fukuhara, Mitsuro; Muto, Satoshi; Matsumura, Yuki; Hasegawa, Takeo; Hoshino, Mika; Osugi, Jun; Shio, Yutaka; Waguri, Satoshi; Tamura, Hirosumi; Imai, Jun-Ichi; Ito, Emi; Yanagisawa, Yuka; Honma, Reiko; Watanabe, Shinya; Suzuki, Hiroyuki

    2018-02-01

    Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor ( EGFR ) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B ( FAM83B ) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR . Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR . Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR .

  10. PREVALENCE, RISK FACTORS, PROPHYLACTIC BEHAVIOR, THERAPEUTIC BEHAVIOR AND STATE OF KNOWLEDGE REGARDING URINARY TRACT INFECTIONS AMONG CHOSEN POPULATION OF NURSING/MIDWIFERY STUDENTS AND QUALIFIED NURSES/MIDWIFES FROM MEDICAL UNIVERSITY OF ¸ÓDè

    Directory of Open Access Journals (Sweden)

    Aleksandra Grzelewska

    2010-03-01

    Full Text Available evalence, risk factors, therapeutic behavior, knowledge level, prophylactic and treatment methods regarding uncomplicated urinary tract infections (UTI. Materials and methods: Anonymous, closed, previously validated questionnaire, consisting of 12 questions on UTI in women was used in 267 adult nursing/midwifery students and nurses/midwifes from many different clinics/wards of the Medical University of Lodz. Results: 83% of respondents reported UTI at least once in a lifetime, 80% of them periodically, with cystitis being a main diagnosis. 40% of respondents reported periodical presence of UTI signs and symptoms without physician diagnosis confirmation. Main UTI causes were body cooling and cold water baths. 40% of respondents had symptoms suggesting UTI in the past but no diagnosis by physician. The risk of UTI symptoms disregarding or self-treatment prevalence decreased with time of professional practice, and in respondents with UTI symptoms connected with sexual activity, antibiotics treatment or sufficient level of knowledge of UTI. 64% UTI positive respondents had mothers with history of UTI. Conclusions: Cystitis is an important problem in Lodz Medical University students and nurses, however their knowledge level regarding risk factors, prophylactic and management of UTI are insufficient what may lead to underdiagnosis and undertreatment.

  11. Pengembangan Perangkat Pembelajaran Matematika Berbasis Concept Attainment Model (CAM untuk Peserta Didik Kelas VIII SMP

    Directory of Open Access Journals (Sweden)

    Eka Jihadah Syaspasbandah

    2018-01-01

    Full Text Available Penelitian ini merupakan penelitian pengembangan yang bertujuan untuk menghasilkan perangkat pembelajaran matematika berbasis Concept Attainment Model (CAM yang valid, praktis, dan efektif terhadap hasil belajar dan aktivitas peserta didik SMP kelas VIII. Perangkat pembelajaran yang dikembangkan mengikuti prosedur pengembangan Model Plomp yang terdiri dari 3 tahap, yaitu tahap analisis pendahuluan, tahap pengembangan atau pembuatan prototipe, dan tahap penilaian. Uji validitas perangkat pembelajaran dilakukan oleh lima orang ahli dari bidang matematika, teknologi pendidikan, dan bahasa Indonesia. Pengujian kepraktisan perangkat pembelajaran diukur dari tiga hal yaitu: keterlaksanaan perangkat pembelajaran, respon peserta didik, dan respon guru. Untuk menilai efektifitas perangkat pembelajaran, dilakukan dengan mengumpulkan data melalui pengamatan terhadap aktivitas belajar matematika peserta didik selama kegiatan pembelajaran dan nilai tes hasil belajar matematika peserta didik. Hasil pegujian tersebut mengidentifikasi bahwa perangkat pembelajaran matematika berbasis CAM yang dikembangkan dinyatakan valid menurut para ahli, praktis berdasarkan guru dan peserta didik sebagai pengguna, dan efektif terlihat dari aktivitas peserta didik selama proses pembelajaran yang mengalami peningkatan. Kata kunci: penelitian pengembangan, Concept Attainment Model, hasil belajar, aktivitas belajar, Model Plomp   ABSTRACT This research is development research aims to produces mathematics learning equipment based on valid, practical, and effective CAM for learning outcome and students activity of VIII grade junior high school. The developed learning equipment uses the procedure of Plomp Model that consists of 3 stages, they are preliminary research, development or prototyping phase, and assessment phase. Validity test of learning equipment is done by 5 experts from mathematics, eduaction technology, and indonesian language. Practical learning equipment test is

  12. PENGARUH KEMANDIRIAN BELAJAR DAN PENGGUNAAN UANG SAKU TERHADAP PRESTASI BELAJAR KOMPETENSI DASAR EKONOMI KELAS VII DAN VIII

    Directory of Open Access Journals (Sweden)

    Apri Dwi Astuti

    2012-10-01

    Full Text Available Kemandirian belajar membantu siswa untuk bertanggung jawab dan menumbuhkan kesadaran belajar. Penggunaan uang saku menumbuhkan jiwa mandiri, jujur dan komitmen. Adapun hasil observasi awal menunjukkan masih ada siswa kels VII dan VIII SMP Semesta untuk kompetensi dasar ekonomi dibawah KKM. Tujuan penelitian ini untuk mengetahui pengaruh kemandirian belajar dn penggunaan uang saku terhadap prestasi belajar kompetensi dasar ekonomi kelas VII dan VIII SMP Semesta. Populasi penelitian ini adalah semua siswa kelas VII dan VIII SMP Semesta Boarding School Semarang. Variabel penelitian ini adalah kemandirian belajar dan penggunaan uang saku sebagai variabel bebas, sedangkan untuk� variabel terikat adalah prestasi belajar kompetensi dasar ekonomi. Data diambil dengan metode wawancara, kuesioner dan dokumentasi guru. Analisis data menggunakan analisis regresi linear berganda.Berdasarkan penelitian secara simultan menunjukkan adanya pengaruh antara kemandirian belajar dan penggunaan uang saku terhadap prestasi belajar kompetensi dasar ekonomi sebesar 51,3%. Secara parsial, pengaruh kemandirian belajar terhadap prestasi belajar kompetensi dasar ekonomi sebesar 66,2% dan pengaruh penggunaan uang saku terhadap prestasi belajar kompetensi dasar ekonomi sebesar 62,5%.Berdasarkan hasil penelitian diatas disimpulkan bahwa kemandirian belajar dan penggunaan uang saku berpengaruh positif baik secara simultan maupun parsial terhadap prestasi belajar kompetensi dasar ekonomi kelas VII dan VIII SMP Semesta Boarding school semarang tahun pelajaran 2011/2012. Saran yang berkaitan dengan penelitian ini yaitu : 1 Sekolah disarankan untuk memberikan batasan siswa pulang ke rumah agar dapat membantu siswa beradaptasi dengan cepat dan mudah tinggal di asrama. 2 Orang tua disarankan untuk memberikan uang saku yang disesuaikan dengan kebutuhan siswa. 3 Siswa disarankan untuk meningkatkan kemandirian dalam aspek belajar terutama bagi mata pelajaran yang masih kurang dari

  13. Penerapan Model Learning Cycle 5E untuk Meningkatkan Keterampilan Berpikir Kritis Siswa Pada Materi Fluida Statis Kelas VIII

    Directory of Open Access Journals (Sweden)

    Irhamna Irhamna

    2017-08-01

    Full Text Available Penerapan model learning cycle 5E telah dilakukan pada siswa kelas VIII dengan materi fluida statis. Penelitian ini bertujuan untuk mendapatkan gambaran mengenai peningkatan keterampilan berpikir kritis siswa setelah diterapkan model learning cycle 5E pada materi fluida statis. Bentuk desain penelitian yang digunakan adalah pre-experimental dengan one group pre-test post-test design. Populasi pada penelitian ini adalah seluruh siswa kelas VIII di SMP Torsina Singkawang. Teknik pengambilan sampel menggunakan sampling purposive yang berjumlah 23 orang. Hasil penelitian menunjukkan bahwa model learning cyle 5E dapat meningkatkan keterampilan berpikir kritis siswa yaitu pada indikator pemecahan masalah dengan skor N-gain sebesar 0,43 dengan kategori sedang, indikator membuat keputusan dengan skor N-gain sebesar 0,42 dengan kategori sedang, indikator penyelidikan percobaan dengan skor N-gain sebesar 0,33 dengan kategori sedang dan indikator menyimpulkan dengan skor N-gain sebesar 0,37 dengan kategori sedang.

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

    Science.gov (United States)

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

    2012-08-07

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

  15. Influence Model Assisted Learning Cycle Mind Map to Achievement Physics Laboratory Judging from the performance Grade VIII SMPN 1 Rejoso Pasuruan

    OpenAIRE

    Ary Analisa Rahma

    2014-01-01

    Pengaruh Model Siklus Belajar Berbantuan Mind Map terhadap Prestasi Belajar Fisika Ditinjau dari Kinerja Laboratorium Siswa Kelas VIII SMPN 1 Rejoso Kabupaten Pasuruan Abstract: This study aimed to examine the effect of the learning cycle models aided the mind map on the learning achievement in terms of the performance of laboratory physics class VIII student on light material in SMP Negeri 1 Rejoso Pasuruan. This study is a quasi-experimental research. The research design used is a 2 x 2...

  16. Penggunaan Media Presentase Microsoft Power Point Untuk Meningkatkan Hasil Belajar IPS Terpadu Pada Siswa Kelas VIII a SMP Negeri 2 Tanantovea

    OpenAIRE

    Hitler, Ahmad

    2014-01-01

    Permasalahan yang diangkat dalam penelitian adalah apakah dengan penggunaan media Presentase Microsoft Power Point pada mata pembelajaran IPS Terpadu dapat meningkatkan hasil belajar siswa kelas VIII A di SMP Negeri 2 Tanantovea. Penelitian ini bertujuan untuk meningkatkan hasil belajar siswa pada pokok bahasan Kolonialisme dan Imperialisme Barat di kelas VIII A SMP Negeri 2 Tanantovea. Penelitian ini dilakukan dalam 2 siklus, setiap siklus terdiri dari perencanaan, pelaksanaan tindakan, obs...

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

    Science.gov (United States)

    Sukariasih, Luh

    2017-05-01

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

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

    Science.gov (United States)

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

    2008-01-01

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

  19. Neurotology findings in patients with diagnosis of vascular loop of cranial nerves VIII in magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Grocoske, Francisco Luiz Busato

    Full Text Available Introduction: The vascular compression by redundant vessels under the VIII cranial nerves has been studied since the 80's, and many authors proposed correlations between the compression and the otoneurological findings (vertigo, tinnitus, hypoacusis, audiometry and electrophysiological findings. Objective: Analyze and correlate the different signs and otoneurological symptoms, the audiological findings and its incidence over individuals with Vascular Loop (VL diagnosis of VIII cranial nerves by magnetic resonance imaging (MRI. Method: Retrospective study through the analysis of medical records of 47 patients attended in the otoneurology clinic of Clinical Hospital of UFPR. All the patients have MRI exams with compatible pictures of VL of the VIII cranial nerves. Results: The tinnitus was the most frequent symptom, in 83% of the patients, followed by hypoacusis (60% and vertigo (36%. The audiometry presented alterations in 89%, the brainstem evoked auditory potential in 33% and the vecto-electronystagmography in 17% of the patients. Was not found statistically significant relation between the buzz or hypoacusis, and the presence of VL in MRI. Only 36% of patients had complaints of vertigo, the main symptom described in theory of vascular compression of the VIII pair of nerve. As in the audiometry and in brainstem evoked auditory potential was not found a statistically significant relation between the exam and the presence of the VL in the RMI. Conclusion: The results show independence between the findings of the RMI, clinical picture and audiological results (p>0,05 suggesting that there are no exclusive and direct relation between the diagnosis of vascular loop in the MRI and the clinical picture matching.

  20. Psychodrama Participants' Perception of Therapeutic Factors.

    Science.gov (United States)

    Kellermann, Peter Felix

    1987-01-01

    Administered questionnaire to 40 psychodrama participants and 42 controls with no psychotherapy experience to assess which specific events they would find helpful in psychotherapy. Psychodrama participants perceived emotional abreaction and cognitive insight most helpful while controls considered nonspecific healing aids most helpful. Suggests…

  1. PENGEMBANGAN KARAKTER KEDISIPLINAN DAN KEMAMPUAN PEMECAHAN MASALAH MELALUI MODEL LAPS-HEURISTIK MATERI LINGKARAN KELAS-VIII

    Directory of Open Access Journals (Sweden)

    Sri Wahyuni

    2015-08-01

    Full Text Available Tujuan penelitian ini adalah untuk mengetahui (1 apakah pembelajaran dengan model pembelajaran LAPS-Heuristik pada materi lingkaran kelas-VIII dapat mengembangkan karakter kedisiplinan peserta didik, (2 apakah pembelajaran dengan model pembelajaran LAPS-Heuristik pada materi lingkaran kelas-VIII dapat meningkatkan kemampuan pemecahan masalah peserta didik, (3 apakah kemampuan pemecahan masalah matematika peserta didik yang diajar dengan model pembelajaran LAPS-Heuristik pada materi lingkaran kelas-VIII dapat mencapai kriteria ketuntasan minimal yang ditentukan. Desain penelitian ini adalah kualitatif deskriptif, artinya menggambarkan atau mendeskripsikan kejadian-kejadian yang menjadi pusat perhatian secara kualitatif dan berdasar data kualitatif. Penentuan sumber data dalam penelitian ini menggunakan teknik purposive sampling, yaitu dipilih dengan pertimbangan dan tujuan tertentu. Data diperoleh dengan observasi, wawancara, dan tes yang kemudian dianalisis menggunakan analisis kualitatif dan analisis gain untuk mengukur peningkatan. Analisis kualitatif menunjukkan karakter kedisiplinan dan kemampuan pemecahan masalah peserta didik meningkat, serta kemampuan pemecahan masalah peserta didik mencapai KKM melalui model pembelajaran LAPS-Heuristik.

  2. Grotrian diagrams of highly ionized iron Fe(VIII)-Fe(XXVI)

    International Nuclear Information System (INIS)

    Mori, Kazuo; Otsuka, Masamoto; Kato, Takako.

    1977-08-01

    Energy levels and Grotrian diagrams of Fe(VIII) to Fe(XXVI) are presented. This report summarized the data published recently up to 1976, and the wavelength tables compiled were converted to the Grotrian diagrams. The diagrams showing transition from one energy level to another are called Grotrian diagrams. Typical examples of the diagrams are found in the book by Bashkin et al. In the present diagrams, all lines are drawn in parallel, and connected to the extended lines from lower levels. As the results, locally dense packing of lines and figures is avoided. The ordinate of the diagrams indicates level energy, and the J values are shown on the left side of the levels. The wavelength values in angstrom unit are written in parallel with the vertical transition lines. This vertical lines show the resonance transition having absorption oscillator strength f larger than 0.1. The present diagrams are the combination of the tables of wavelength and energy level. Accordingly, the desired wavelength and level energy are easily found. The figures of wavelength are lined up in various groups, so that the characteristics of the transition can be discriminated at a glance. Wavelength and level energy have been mostly derived from experimental spectra in laboratory or solar plasma, except a few by Fawcett's prediction. (Kato, T.)

  3. Synthesis of methyl acetate from dimethyl ether using group VIII metal salts of phosphotungstic acid

    Energy Technology Data Exchange (ETDEWEB)

    Sardesai, A.; Lee, S.; Tartamella, T.

    2002-04-01

    Dimethyl ether (DME) can be produced much more efficiently in a single-stage, liquid-phase process from natural gas-based syngas as compared to the conventional process via dehydration of methanol. This process, based on dual catalysts slurried in inert oil, alleviates the chemical equilibrium limitation governing the methanol synthesis reaction and concurrently improves per-pass syngas conversion and reactor productivity. The potential, therefore, for production of methyl acetate via dimethyl ether carbonylation is of industrial importance. In the present study, conversion of dimethyl ether and carbon monoxide to methyl acetate is investigated over a variety of group VIII metal-substituted phosphotungstic acid salts. Experimental results of this catalytic reaction using rhodium, iridium, ruthenium, and palladium catalysts are evaluated and compared in terms of selectivity toward methyl acetate. The effects of active metal, support types, multiple metal loading, and feed conditions on carbonylation activity of DME are examined. Iridium metal substituted phosphotungstic acid supported on Davisil type 643 (pore size 150 A, surface area 279 m{sup 2}/g, mesh size 230-425) silica gel shows the highest activity for DME carbonylation. (author)

  4. The spectrum of seven times ionized tungsten (W VIII) relevant to tokamak divertor plasmas

    International Nuclear Information System (INIS)

    Ryabtsev, A N; Kononov, E Ya; Kildiyarova, R R; Tchang-Brillet, W-Ü L; Wyart, J-F

    2013-01-01

    Tungsten spectra excited in the vacuum sparks of different setups and electric circuits were recorded on two high-resolution vacuum spectrographs. For the region 190–500 Å, a 10 m normal incidence spectrograph with a 3600 lines/mm grating was used in the Meudon Observatory. In the region below 350 Å, a set of spectra was produced using a 3 m grazing incidence spectrograph with a 3600 lines/mm grating in the Institute of Spectroscopy in Troitsk. A total of 187 lines in the region 160–271 Å were identified as transitions to the low-lying odd configurations 4f 13 5s 2 5p 6 and 4f 14 5s 2 5p 5 from the interacting excited even 4f 12 5s 2 5p 6 5d + 4f 13 5s 2 5p 5 (5d + 6s) + 4f 14 5s 2 5p 4 (5d + 6s) + 4f 14 5s5p 6 configurations. It was found that 4f 13 5s 2 5p 6 2 F 7/2 is the ground level of W VIII. The fine structure splitting and relative positions of the odd terms were established, and 98 levels of the excited even configurations were found. (paper)

  5. PENGGUNAAN MIND MAP DIIRINGI MUSIK KLASIK DALAM PEMBELAJARAN MATEMATIKA UNTUK SISWA KELAS VIII SMPN 1 SAWAHLUNTO

    Directory of Open Access Journals (Sweden)

    Rezky Ramadhona

    2016-06-01

    Full Text Available Penelitian ini bertujuan untuk mengetahui apakah motivasi dan hasil belajar belajar matematika siswa kelas VIII SMPN 1 Sawahlunto setelah menggunakan mind map dan musik klasik lebih baik dari sebelum menggunakan mind map dan musik klasik. Jenis penelitian ini adalah penelitian eksperimen dengan menggunakan dua model rancangan yaitu One Group Pretest Posttest Design untuk melihat dampak perlakuan terhadap motivasi belajar dan Randomized Control Group Only Design untuk melihat dampak perlakuan terhadap hasil belajar. Pengumpulan data dalam penelitian ini menggunakan angket dan tes akhir berupa soal essai. Data yang diperoleh dianalisis dengan menggunakan Uji-t. Hasil penelitian menunjukkan bahwa motivasi belajar matematika siswa cenderung meningkat. Jadi disimpulkan bahwa motivasi belajar matematika siswa setelah menggunakan mind map dan musik klasik lebih baik dari pada sebelum menggunakan mind map dan musik klasik. Dari hasil uji hipotesis untuk data hasil belajar pada selang kepercayaan α = 0,05 diperoleh P-value = 0,022. Jadi dapat disimpulkan bahwa hasil belajar matematika siswa yang menggunakan mind map dan musik klasik lebih baik dari hasil belajar matematika siswa yang tidak menggunakan mind map dan musik klasik. Kata Kunci: Mind Map, Musik Klasik DOI: http://dx.doi.org/10.22342/jpm.10.2.3636.87-92

  6. The 4p5rd10 and 4d86p configurations of Te VIII

    International Nuclear Information System (INIS)

    Churilov, S.S.; Rossijskaya Akademiya Nauk, Troitsk; Joshi, Y.N.; Kildiyarova, R.R.

    1998-01-01

    The spectrum of tellurium was photographed in the 100-500 A region on a variety of grazing incidence spectrographs using a triggered spark source. The analysis of the lines in the 117-216 A region has lead to establishing 42 out of 45 levels of the 4d 8 6p configuration of Te VIII. Four levels of the 4d 8 4f configuration were confirmed and their level values revised, and an additional 4d 8 4f level was established. The 4p 5 4d 10 levels reported earlier were found to be erroneous and new values have been found for them. Eighty seven (87) new lines have been classified in the (4d 9 + 4d 8 5s)-(4d 8 4f + 4p 5 4d 10 + 4d 8 6p) transition array. Hartree-Fock with relativistic corrections (HFR) and parametric least-squares-fitted (lSF) calculations were carried out to interpret the present analysis adequately. (orig.)

  7. Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: a review.

    Science.gov (United States)

    Ozkan, Emine Elif

    2011-09-15

    Cancer database analysis indicates that prostate cancer is one of the most seen cancers in men meanwhile composing the leading cause of morbidity and mortality among developed countries. Current available therapies are surgery, radiotherapy and androgene ablation for prostate carcinoma. The response rate is as high nearly 90% however, most of these recur or become refractory and androgene independent (AI). Therefore recent studies intensified on molecular factors playing role on development of prostate carcinoma and novel treatment strategies targetting these factors and their receptors. Insulin-like growth factor-I (IGF-I) and its primary receptor insulin-like growth factor receptor-I (IGF-IR) are among these factors. Biologic functions and role in malign progression are primarily achieved via IGF-IR which is a type 2 tyrosine kinase receptor. IGF-IR plays an important role in mitogenesis, angiogenesis, transformation, apoptosis and cell motility. It also generates intensive proliferative signals leading to carcinogenesis in prostate tissue. So IGF-IR and its associated signalling system have provoked considerable interest over recent years as a novel therapeutic target in cancer. In this paper it is aimed to sum up the lately published literature searching the relation of IGF-IR and prostate cancer in terms of incidence, pathologic features, and prognosis. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417

  8. 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.

    Science.gov (United States)

    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.

  9. Therapeutical aspect of trichomoniasis

    Directory of Open Access Journals (Sweden)

    Vukićević Jelica

    2003-01-01

    phases proceeding in succession, in so far TV had not been eliminated by previous one. The number of cured patients, according to therapeutical phases, was shown in Table 4. Three patients (1.39 %, 2 males and 1 female were not cured in spite of all three completed phases of therapeutical protocol. In all three cases, TV was eliminated by MND application in dose of 3 g/daily, during two days. The failure of minute MND treatment was analyzed in relation to clinical forms of the infection (manifested or asymptomatic, as well as in relation to types of infection (single- or associated infection. The incidence of refractory trichomoniasis treated by a single metronidazole dose of 2 g was significantly higher in the group of patients with polyinfection (c2=18.270 p<0.01. There was no significant difference of resistance to a single MND dose between the groups with manifested and asymptomatic trichomoniasis (c2=0.321; p<0.01. The prevalence of TV in vaginal and urethral smears indicates the significant incidence of trichomoniasis in STD. TV was more frequently isolated in patients with clinically manifested infection. TV susceptibility to MND was tested in vitro in aerobic and anaerobic conditions. The resistance of strains under in vitro conditions did not correlate with refractory feature of trichomoniasis to MND application [7 17, 18]. The success of trichomoniasis treatment depends upon multiple factors, including: a TV susceptibility to drug, b intravaginal redox potential, c drug concentration in situ, d associated microorganisms that may modify the amount of the drug available in situ [7, 18, 21]. The results of our investigation argue for the latter item, verifying that TV resistance to MND is higher in patients with polyinfection in relation to those with monoinfection (significant difference, c2=18.270; p<0.01. Repeated administration of low metronidazole doses may prolong the therapy of trichomonas infections, while application of high doses (over 3 g/day may result

  10. Therapeutic HIV Peptide Vaccine

    DEFF Research Database (Denmark)

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

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

    Science.gov (United States)

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

    2002-12-01

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

  12. Rancang Bangun Perangkat Eksperimen Hukum Archimedes untuk MTs LB/A Yaketunis Kelas VIII

    Directory of Open Access Journals (Sweden)

    Rofiqoh Utami

    2014-06-01

    Full Text Available Blind students find difficulties whenever they are involved in the experiment of Archimedes principle as it requests an active visual role. Thus, it is very important to design a special tool for blind students so their practice of Archimedes principle become easier. This paper discusses a research finding which is an innovation of adaptive tools for blind students, such as beaker glass with Braille number, dynamometer with modification and Braille number (Braille Spring Balance and recording lesson about Archimedes principle. This research done for students MTs LB / A Yaketunis Class VIII which aims at analyzing the quality of each tool by media experts, lesson experts, and physics teacher of MTs LB/A.This research is R & D with procedural models adapted from the development of the 4-D models, namely Define, Design, Develop, and Disseminate. According to media expert assessment, beaker glass with Braille number and Braille spring balance has a very good quality with percentage of their respective 100% of the ideal score, while the assessment by lesson experts for each tool have a good quality with percentage 80% and 73.33% of the ideal score, and physics teacher of MTs LB / A assessment for each tool have a very good quality with percentage 100%. According to the media and lesson experts, the recording lesson about Archimedes principle have a good quality with percentage 80% of the ideal score, according to physics teacher MTs LB / A, the recording tool has excellent quality either with percentage 91.82% of the ideal score. This research recommends the blinds students to utilize these innovative-adaptive tools which will enable them appropriately practice Archimedes principle as non-blind students.

  13. Marketing therapeutic recreation services.

    Science.gov (United States)

    Thorn, B E

    1984-01-01

    The use of marketing strategies can enhance the delivery of therapeutic recreation services. This article discusses how agencies can adapt marketing techniques and use them to identify potential markets, improve image, evaluate external pressures, and maximize internal strengths. Four variables that can be controlled and manipulated in a proposed marketing plan are product, price, place and promotion.

  14. Therapeutic Recombinant Monoclonal Antibodies

    Science.gov (United States)

    Bakhtiar, Ray

    2012-01-01

    During the last two decades, the rapid growth of biotechnology-derived techniques has led to a myriad of therapeutic recombinant monoclonal antibodies with significant clinical benefits. Recombinant monoclonal antibodies can be obtained from a number of natural sources such as animal cell cultures using recombinant DNA engineering. In contrast to…

  15. Therapeutic applications of radiopharmaceuticals

    International Nuclear Information System (INIS)

    Baker, W.J.; Datz, F.L.; Beightol, R.W.

    1987-01-01

    Whether a radiopharmaceutical has diagnostic or therapeutic application depends on both the isotope and pharmaceutical used. For diagnostic applications, the isotope should undergo only γ-decay, since usually only γ-radiation is detected by nuclear medicine cameras. The half-life should be just long enough to allow the procedure to be performed. In contrast, the isotope needed for therapeutic purposes should have particulate radiation, such as a β-particle (electron), since these are locally absorbed an increase the local radiation dose. γ-Radiation, which penetrates the tissues, produces less radiation dose than do Β-particles. Several references dealing with radioactive decay, particulate interactions, and diagnostic and therapeutic applications of radiopharmaceuticals are available. Radiopharmaceuticals can legally be used only by physicians who are qualified by specific training in the safe handling of radionuclides. The experience and training of these physicians must be approved by the Nuclear Regulatory Commission or Agreement State Agency authorized to license the use of radiopharmaceuticals. A list of all byproduct material and procedures is available in the Code of Federal Regulations. Of the many radiopharmaceuticals available for diagnostic and therapeutic use, only those commonly used are discussed in this chapter

  16. Therapeutic working alliance: From a psychoanalitical to a pantheoretical conception

    Directory of Open Access Journals (Sweden)

    Peter Praper

    2004-05-01

    Full Text Available Although the concept of therapeutic working alliance was rooted in psychoanalysis, today it is more prominent in psychoanalytic psychotherapies than psychoanalysis. It is rather surprising that we cannot find the concept in the Laplanche and Pontalis Dictionary. During the last two decades a growing body of empirical research material on therapeutic working alliance was published, confirming the idea of the alliance as a separate dimension of therapeutic relationship with few recognisable components. The dimension of the therapeutic working alliance was examined in several approaches and proved as one of the most important therapeutic factors, regardless of the approach, and it has finally been accepted as a pantheoretical concept.

  17. MENINGKATKAN AKTIVITAS BELAJAR SISWA DENGAN MENGGUNAKAN METODE GROUP INVESTIGATION (GI PADA POKOK BAHASAN PASAR DI KELAS VIII SMP 5 KUDUS

    Directory of Open Access Journals (Sweden)

    Mutthofiyah Mutthofiyah

    2016-03-01

    Full Text Available Penelitian ini bertujuan untukmeningkatkan aktivitas belajar siswa dengan menggunakan metode group investigation (GI pada pokok bahasan pasar pada penelitian ini menggunakan penelitian tindakan kelas (PTK. Dalam penelitian ini dirancang menggunakan siklus, masing-masing siklus dengan tahapan perencanaan, pelaksanaan tindakan, observasi dan refleksi. Teknik pengumpulan data pada penelitian ini adalah dokumentasi, observasi dan tes.Hasil penelitian menunjukkan melalui meningkatkan metode group investigation (GI aktivitas siswa SMP 5 Kudus ada peningkatan yang sigifikan, dari siklus I kelas VIII F 15,8 (41,62% meningkat di siklus II menjadi 24,8 (72,9%, sedangkan di kelas VIII G siklus I 18,5 (47,04% meningkat menjadi 26,2 (74,7%; melalui penerapan metode group investigation hasil belajar siswa SMP 5 kudus meningkat sangat signifkan, ketuntasan belajar secara klasikal dari kelas VIII F pra siklus sebesar 17,64% terjadi peningkatan 47% ke siklus I dan meningkat menjadi 82,35% di siklus II. Sedangkan di kelas VII G pra siklus sebesar 22,85% meningkat 54,28% di siklus I dan meningkat menjadi 94,28% di siklus II. Saran yang peneliti berikan adalah sebagai berikut:1Kepada para guru diharapkan dapat menerapkan pembelajaran kooperatif khususnya pembelajaran kooperatif tipe Group Investigation (GI dalam proses pembelajaran ekonomi dan mata pelajaran lainya dan mengembangkannya; 2 Kepada para peneliti selanjutnya diharapkan dapat melakukan penelitian tentang penerapan model pembelajaran yang dapat membangkitkan keaktifan siswa untuk belajar ekonomi. This study aims to improve students' learning activities using group investigation (GI on the subject of markets in class VIII SMP 5 Kudus. In this study is designed to use cycles, with each cycle stages of planning, action, observation and reflection. Data collection techniques in this study is documentation, observation and tests. Results showed through improved methods of group investigation (GI junior 5 high

  18. Exogenous Restoration of TUSC2 Expression Induces Responsiveness to Erlotinib in Wildtype Epidermal Growth Factor Receptor (EGFR Lung Cancer Cells through Context Specific Pathways Resulting in Enhanced Therapeutic Efficacy.

    Directory of Open Access Journals (Sweden)

    Bingbing Dai

    Full Text Available Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC cell lines resistant to the epidermal growth factor receptor (EGFR tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.

  19. Anticancer effects of the engineered stem cells transduced with therapeutic genes via a selective tumor tropism caused by vascular endothelial growth factor toward HeLa cervical cancer cells.

    Science.gov (United States)

    Kim, Hye-Sun; Yi, Bo-Rim; Hwang, Kyung-A; Kim, Seung U; Choi, Kyung-Chul

    2013-10-01

    The aim of the present study was to investigate the therapeutic efficacy of genetically engineered stem cells (GESTECs) expressing bacterial cytosine deaminase (CD) and/or human interferon-beta (IFN-β) gene against HeLa cervical cancer and the migration factors of the GESTECs toward the cancer cells. Anticancer effect of GESTECs was examined in a co-culture with HeLa cells using MTT assay to measure cell viability. A transwell migration assay was performed so as to assess the migration capability of the stem cells to cervical cancer cells. Next, several chemoattractant ligands and their receptors related to a selective migration of the stem cells toward HeLa cells were determined by real-time PCR. The cell viability of HeLa cells was decreased in response to 5-fluorocytosine (5-FC), a prodrug, indicating that 5-fluorouracil (5-FU), a toxic metabolite, was converted from 5-FC by CD gene and it caused the cell death in a co-culture system. When IFN-β was additionally expressed with CD gene by these GESTECs, the anticancer activity was significantly increased. In the migration assay, the GESTECs selectively migrated to HeLa cervical cancer cells. As results of real-time PCR, chemoattractant ligands such as MCP-1, SCF, and VEGF were expressed in HeLa cells, and several receptors such as uPAR, VEGFR2, and c-kit were produced by the GESTECs. These GESTECs transduced with CD gene and IFN-β may provide a potential of a novel gene therapy for anticervical cancer treatments via their selective tumor tropism derived from VEGF and VEGFR2 expressions between HeLa cells and the GESTECs.

  20. The Effect of Growth Temperature and V/III Flux Ratio of MOCVD Antimony Based Semiconductors on Growth Rate and Surface Morphology

    Directory of Open Access Journals (Sweden)

    Ramelan Ari Handono

    2017-01-01

    Full Text Available Epitaxial Alx Ga1-x Sb layers on GaSb and GaAs substrates have been grown by atmospheric pressure metalorganic chemical vapor deposition using TMAl, TMGa and TMSb. Nomarski microscope and a profiler were employed to examine the surface morphology and growth rate of the samples. We report the effect of growth temperature and V/III flux ratio on growth rate and surface morphology. Growth temperatures in the range of 520°C and 680°C and V/III ratios from 1 to 5 have been investigated. A growth rate activation energy of 0.73 eV was found. At low growth temperatures between 520 and 540°C, the surface morphology is poor due to antimonide precipitates associated with incomplete decomposition of the TMSb. For layers grown on GaAs at 580°C and 600°C with a V/III ratio of 3 a high quality surface morphology is typical, with a mirror-like surface and good composition control. It was found that a suitable growth temperature and V/III flux ratio was beneficial for producing good AlGaSb layers. Undoped AlGaSb grown at 580°C with a V/III flux ratio of 3 at the rate of 3.5 μm/hour shows p-type conductivity with smooth surface morphology

  1. EFFECT OF INFORMATION SERVICES USING THE MEDIA FILM TO SELF-CONFIDENCE STUDENT OF CLASS VIII SMP NEGERI 8 METRO

    Directory of Open Access Journals (Sweden)

    MUDAIM MUDAIM

    2015-06-01

    Full Text Available Abstract: Pessimism and attitudes that consider themselves weak and does not have the ability when facing a problem will make individual impediment in the task of development. Problems confidence that underlies the research are: a Students are less confident in the ability it has, b Students feel pessimistic when faced with an issue, c Student perception subjectively, d Students still do not do the work independently, and e negative minded students with a state-owned. The problems of this study are whether there is an influence of information services using the medium of film to the confidence of eighth-grade students of SMP Negeri 8 Metro. The purpose of this study was to determine whether there is an influence of information services using the medium of film to the self-confidence of students in class VIII SMP Negeri 8 Metro. Subject participant is graders VIII-E total 30 students. Data were collected by questionnaire self-confidence and analyzed the data used is the t-test. The results of this study, shown by the difference in change scores of confidence from the pre-test and post-test of 17.1. Testing the hypothesis obtained calculation results thitung6,036> table = 1.699. The conclusion is that the information services implemented using the film medium can be a positive influence on self-esteem, especially students of class VIII. The advice given is to use the medium of film should be done intensively and more creative by BK teachers in giving information service. Keywords: Confidence, Service Information Using Media Film.

  2. Seleucid, Demotic and Mediterranean mathematics versus Chapters VIII and IX of the Nine Chapters: accidental or significant similarities?

    DEFF Research Database (Denmark)

    Høyrup, Jens

    Similarities of geometrical diagrams and arithmetical structures of problems have often been taken as evidence of transmission of mathematical knowledge or techniques between China and “the West”. Confronting on one hand some problems from Chapter VIII of the Nine Chapters with comparable problems...... known from Ancient Greek sources, on the other a Seleucid collection of problems about rectangles with a subset of the triangle problems from Chapter IX, it is concluded, (1) that transmission of some arithmetical riddles without method – not “from Greece” but from a transnational community of traders...

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

    Science.gov (United States)

    Androutsos, Georges

    2005-09-01

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

  4. Evaluation of the integrity of reactor vessels designed to ASME Code, Sections I and/or VIII

    International Nuclear Information System (INIS)

    Hoge, K.G.

    1976-01-01

    A documented review of nuclear reactor pressure vessels designed to ASME Code, Sections I and/or VIII is made. The review is primarily concerned with the design specifications and quality assurance programs utilized for the reactor vessel construction and the status of power plant material surveillance programs, pressure-temperature operating limits, and inservice inspection programs. The following ten reactor vessels for light-water power reactors are covered in the report: Indian Point Unit No. 1, Dresden Unit No. 1, Yankee Rowe, Humboldt Bay Unit No. 3, Big Rock Point, San Onofre Unit No. 1, Connecticut Yankee, Oyster Creek, Nine Mile Point Unit No. 1, and La Crosse

  5. EK(b)P Keskkomitee VIII pleenumi stenogramm / tõlk. Mart Arold, tõlk. Jaan Isotamm

    Index Scriptorium Estoniae

    1999-01-01

    EK(b)P Keskkomitee VIII pleenum, 21.-23. märts 1950. Sõnavõtud: N. Karotamm, P. Ponomarenko, I. Käbin, V. Kuusik, A. Jaanus, V. Hiznjakov, E. Ristimägi, I. Suija, H. Ajo, A. Meri, G. Abels, M. Assin, G. Latõshov, Rumjantsev, Müürisepp. Kommenteerinud Viktor Niitsoo. Algus: Akadeemia (1998) nr. 12, lk. 2655-2683 ; Järg nr.2;3;4;5;6;7;8;9;10 lk.415-446;639-670;863-894;1087-1118;1310-1342;1534-1566;1759-1790;2017-2048;2220-2256

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

    Science.gov (United States)

    Fink, Bruce

    2015-02-01

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

  7. PYTHIOSIS: A THERAPEUTIC APPROACH

    Directory of Open Access Journals (Sweden)

    C. M. C. Falcão

    2015-10-01

    Full Text Available Pythiosis, a disease caused by the oomycete Pythium insidiosum, often presents inefficient response to chemotherapy. It is a consensus that, in spite the several therapeutic protocols, a combination of surgery, chemotherapy and immunotherapy should be used. Surgical excision requires the removal of the entire affected area, with a wide margin of safety. The use of antifungal drugs has resulted in variable results, both in vitro and in vivo, and presents low therapeutic efficiency due to differences in the agent characteristics, which differ from true fungi. Immunotherapy is a non-invasive alternative for the treatment of pythiosis, which aims at modifying the immune response of the host, thereby producing an effective response to the agent. Photodynamic therapy has emerged as a promising technique, with good activity against P. insidiosum in vitro and in vivo. However, more studies are necessary to increase the efficiency of the current treatment protocols and consequently improve the cure rates. This paper aims to conduct a review covering the conventional and recent therapeutic methods against P. insidiosum infections

  8. PENGARUH PENGUASAAN KONSEP TEOREMA PYTHAGORAS TERHADAP KEMAMPUAN MENYELESAIKAN SOAL-SOAL BANGUN RUANG SISI DATAR PADA SISWA KELAS VIII MTS NEGERI BALANG-BALANG

    Directory of Open Access Journals (Sweden)

    Syahrida Zaerani

    2017-12-01

    Abstract: This study aims to determine the impact of the mastery of Pythagoras Theorem concepts on the ability of MTs Negeri Balang-Balang grade VIII students to solve polyhedron problems. This study is a quantitative research with ex post facto design. Statistical population consists of all grade VIII students in MTs Negeri Balang-Balang which was 204 students. The number of sampling used is 102 respondents taken by simple random sampling technique. The research instrument was a test related to Pythagorean an polyhedron problems. Descriptive and inferential statistics were performed as the statistical analysis. The descriptive analysis result shows that the mastery of Pythagoras Theorem concepts is within the category of ‘high’ and the ability of solving polyhedron problems is as well. The inferential statistical analysis using simple linear regression shows that there is an impact of the mastery of Pythagoras Theorem concepts on polyhedron problem solving ability of Grade VIII students of MTs Negeri Balang-Balang.

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

    Science.gov (United States)

    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.

  10. THERAPEUTIC DECISION-MAKING OF PHYSICIANS

    NARCIS (Netherlands)

    DENIG, P; HAAIJER-RUSKAMP, FM

    1992-01-01

    In this review the therapeutic decision-making process of physicians is described. This process is divided into two steps: the generation of a limited set of possible options (the 'evoked set') and the selection from this evoked set of a treatment for a specific patient. Factors that are important

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shuai; Nakano, Kazuhiko; Zhang, Shu-liang; Yu, Hui-min, E-mail: yuhm@tsinghua.edu.cn [Tsinghua University, Key Laboratory of Industrial Biocatalysis of the Ministry of Education, Department of Chemical Engineering (China)

    2015-10-15

    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 FeCl{sub 2} and AgNO{sub 3} solution before reduction.

  12. Una frontera casi invisible: los territorios al norte del Sistema Central en la Alta Edad Media (siglos VIII-XI

    Directory of Open Access Journals (Sweden)

    Iñaki MARTÍN VISO

    2009-12-01

    Full Text Available RESUMEN: Los territorios al norte del Sistema Central no estuvieron sujetos a un dominio por parte de una autoridad centralizada entre los siglos VIII a XI. Los instrumentos del poder central, en especial la tributación y la organización episcopal, se descompusieron tras el siglo VIII y asumieron un papel determinante las estructuras de poder local, las cuales deben ser el principal objeto de estudio. A partir de su análisis, se descubre un espacio fronterizo abierto, con un dominio político informal, que es invisible para los poderes centrales. Palabras clave: Poderes Locales. Sitios de Altura. Necrópolis. Frontera. Tributación. Mozárabes.ABSTRACT: The territories at the North of the Iberian Central System were not ruled by any central authority between eighth and eleventh centuries. The main tools of the central power, especially the tribute and the episcopal organization, were broken down after the 8th century and the structures of local power, which must be studied particularly, got a very influential role. The analysis discover an opened frontier area, with an informal political control, that is invisible from the perspective of the central power

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

    Science.gov (United States)

    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.

  14. Il ruolo di El Escorial, V.III.6 e dei suoi discendenti nella tradizione manoscritta del Lucullus

    Directory of Open Access Journals (Sweden)

    Corinna Senore

    2017-05-01

    Full Text Available L’articolo riguarda un gruppo di sette codici che tramanda il testo del Lucullus di Cicerone e che appartiene al ramo della tradizione discendente dal manoscritto Wien, Österreichische Nationalbibliothek 189. I sette manoscritti costituiscono uno stadio della tradizione caratterizzato dalla presenza di tre lacune testuali. Sulla base di alcuni elementi paleografici e della presenza di una glossa riportata a margine del testo di uno di essi, El Escorial, V.III.6 (Scor4, e inglobata all’interno del testo degli altri sei, è possibile individuare in Scor4 il capostipite di questo gruppo della tradizione. Lo studio si occupa inoltre di fare chiarezza sui rapporti che intercorrono tra i sei discendenti di Scor4. The article focuses on a group of seven codices which carry the text of Cicero’s Lucullus. This group belongs to the branch of the tradition descending from the manuscript Wien, Österreichische Nationalbibliothek 189. The seven manuscripts represent a step of the tradition marked by the presence of some textual lacunas. I start from some paleographic elements and from the presence of a gloss on text’s margin of one of them, El Escorial, V.III.6 (Scor4. The gloss has been then incorporated in the text of the other six manuscripts and I assume that Scor4 is the founder of this group of tradition. Furthermore, this article aims to clarify the relations between the six descendants of Scor4.

  15. Pisanello’s hat. The costume and weapons depicted in Pisanello’s medal for John VIII Palaeologus. A discussion of the saber and related weapons

    Directory of Open Access Journals (Sweden)

    Alexander, David

    2004-12-01

    Full Text Available A group of six drawings by the Veronese artist Antonio Pisano depicted the Bizantine Emperor John VIII Paleologus wearing costumes and weapons according to islamic types. This paper studies these objects in relation to other contemporary islamic weapons.

    Un grupo de seis dibujos del artista veronés Antonio Pisano representa al emperador bizantino Juan VIII Paleólogo vestido y armado según modelos islámicos. Este trabajo estudia dichos objetos en relación a otras armas islámicas contemporáneas.

  16. Angiogenesis and Its Therapeutic Opportunities

    Directory of Open Access Journals (Sweden)

    So Young Yoo

    2013-01-01

    Full Text Available Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies. Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

  17. Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A

    DEFF Research Database (Denmark)

    Löfgren, Karin Maria; Sondergaard, H.; Skov, Søren

    2016-01-01

    Background: Neutralizing antibodies towardFVIII replacement therapy (inhibitors) are the most seri-ous treatment-related complication in hemophilia A(HA). A rat model of severe HA (F8/) has recentlybeen developed, but an immunological characterization isneeded to determine the value of using...

  18. Association of Single Nucleotide Polymorphisms in the ST3GAL4 Gene with VWF Antigen and Factor VIII Activity.

    Directory of Open Access Journals (Sweden)

    Jaewoo Song

    Full Text Available VWF is extensively glycosylated with biantennary core fucosylated glycans. Most N-linked and O-linked glycans on VWF are sialylated. FVIII is also glycosylated, with a glycan structure similar to that of VWF. ST3GAL sialyltransferases catalyze the transfer of sialic acids in the α2,3 linkage to termini of N- and O-glycans. This sialic acid modification is critical for VWF synthesis and activity. We analyzed genetic and phenotypic data from the Atherosclerosis Risk in Communities (ARIC study for the association of single nucleotide polymorphisms (SNPs in the ST3GAL4 gene with plasma VWF levels and FVIII activity in 12,117 subjects. We also analyzed ST3GAL4 SNPs found in 2,535 subjects of 26 ethnicities from the 1000 Genomes (1000G project for ethnic diversity, SNP imputation, and ST3GAL4 haplotypes. We identified 14 and 1,714 ST3GAL4 variants in the ARIC GWAS and 1000G databases respectively, with 46% being ethnically diverse in their allele frequencies. Among the 14 ST3GAL4 SNPs found in ARIC GWAS, the intronic rs2186717, rs7928391, and rs11220465 were associated with VWF levels and with FVIII activity after adjustment for age, BMI, hypertension, diabetes, ever-smoking status, and ABO. This study illustrates the power of next-generation sequencing in the discovery of new genetic variants and a significant ethnic diversity in the ST3GAL4 gene. We discuss potential mechanisms through which these intronic SNPs regulate ST3GAL4 biosynthesis and the activity that affects VWF and FVIII.

  19. Association of Single Nucleotide Polymorphisms in the ST3GAL4 Gene with VWF Antigen and Factor VIII Activity.

    Science.gov (United States)

    Song, Jaewoo; Xue, Cheng; Preisser, John S; Cramer, Drake W; Houck, Katie L; Liu, Guo; Folsom, Aaron R; Couper, David; Yu, Fuli; Dong, Jing-Fei

    2016-01-01

    VWF is extensively glycosylated with biantennary core fucosylated glycans. Most N-linked and O-linked glycans on VWF are sialylated. FVIII is also glycosylated, with a glycan structure similar to that of VWF. ST3GAL sialyltransferases catalyze the transfer of sialic acids in the α2,3 linkage to termini of N- and O-glycans. This sialic acid modification is critical for VWF synthesis and activity. We analyzed genetic and phenotypic data from the Atherosclerosis Risk in Communities (ARIC) study for the association of single nucleotide polymorphisms (SNPs) in the ST3GAL4 gene with plasma VWF levels and FVIII activity in 12,117 subjects. We also analyzed ST3GAL4 SNPs found in 2,535 subjects of 26 ethnicities from the 1000 Genomes (1000G) project for ethnic diversity, SNP imputation, and ST3GAL4 haplotypes. We identified 14 and 1,714 ST3GAL4 variants in the ARIC GWAS and 1000G databases respectively, with 46% being ethnically diverse in their allele frequencies. Among the 14 ST3GAL4 SNPs found in ARIC GWAS, the intronic rs2186717, rs7928391, and rs11220465 were associated with VWF levels and with FVIII activity after adjustment for age, BMI, hypertension, diabetes, ever-smoking status, and ABO. This study illustrates the power of next-generation sequencing in the discovery of new genetic variants and a significant ethnic diversity in the ST3GAL4 gene. We discuss potential mechanisms through which these intronic SNPs regulate ST3GAL4 biosynthesis and the activity that affects VWF and FVIII.

  20. Advanced imaging techniques show progressive arthropathy following experimentally induced knee bleeding in a factor VIII-/- rat model

    DEFF Research Database (Denmark)

    Sorensen, K. R.; Roepstorff, K.; Petersen, M.

    2015-01-01

    Background: Joint pathology is most commonly assessed by radiogra-phy, but ultrasonography (US) is increasingly recognized for its acces-sibility, safety and ability to show soft tissue changes, the earliestindicators of haemophilic arthropathy (HA). US, however, lacks theability to visualize...

  1. Determinants of immunogenic response to protein therapeutics.

    Science.gov (United States)

    Singh, Satish K; Cousens, Leslie P; Alvarez, David; Mahajan, Pramod B

    2012-09-01

    Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation. Copyright © 2012. Published by Elsevier Ltd.. All rights reserved.

  2. Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility?

    Science.gov (United States)

    Easley, Charles A; Simerly, Calvin R; Schatten, Gerald

    2013-07-01

    Recent advances in assisted reproduction treatment have enabled some couples with severe infertility issues to conceive, but the methods are not successful in all cases. Notwithstanding the significant financial burden of assisted reproduction treatment, the emotional scars from an inability to conceive a child enacts a greater toll on affected couples. While methods have circumvented some root causes for male and female infertility, often the underlying causes cannot be treated, thus true cures for restoring a patient's fertility are limited. Furthermore, the procedures are only available if the affected patients are able to produce gametes. Patients rendered sterile by medical interventions, exposure to toxicants or genetic causes are unable to utilize assisted reproduction to conceive a child - and often resort to donors, where permitted. Stem cells represent a future potential avenue for allowing these sterile patients to produce offspring. Advances in stem cell biology indicate that stem cell replacement therapies or in-vitro differentiation may be on the horizon to treat and could cure male and female infertility, although significant challenges need to be met before this technology can reach clinical practice. This article discusses these advances and describes the impact that these advances may have on treating infertility. Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  3. Pharmacogenetics approach to therapeutics.

    Science.gov (United States)

    Koo, Seok Hwee; Lee, Edmund Jon Deoon

    2006-01-01

    1. Pharmacogenetics refers to the study of genetically controlled variations in drug response. Functional variants caused by single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolising enzymes, transporters, ion channels and drug receptors have been known to be associated with interindividual and interethnic variation in drug response. Genetic variations in these genes play a role in influencing the efficacy and toxicity of medications. 2. Rapid, precise and cost-effective high-throughput technological platforms are essential for performing large-scale mutational analysis of genetic markers involved in the aetiology of variable responses to drug therapy. 3. The application of a pharmacogenetics approach to therapeutics in general clinical practice is still far from being achieved today owing to various constraints, such as limited accessibility of technology, inadequate knowledge, ambiguity of the role of variants and ethical concerns. 4. Drug actions are determined by the interplay of several genes encoding different proteins involved in various biochemical pathways. With rapidly emerging SNP discovery technological platforms and widespread knowledge on the role of SNPs in disease susceptibility and variability in drug response, the pharmacogenetics approach to therapeutics is anticipated to take off in the not-too-distant future. This will present profound clinical, economic and social implications for health care.

  4. Therapeutic nuclear medicine

    International Nuclear Information System (INIS)

    Baum, Richard P.

    2014-01-01

    Discusses all aspects of radionuclide therapy, including basic principles, newly available treatments, regulatory requirements, and future trends. Provides the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Explains the role of the therapeutic nuclear physician in effectively coordinating a diverse multidisciplinary team. Written by leading experts. The recent revolution in molecular biology offers exciting new opportunities for targeted radionuclide therapy. The selective irradiation of tumor cells through molecular biological mechanisms is now permitting the radiopharmaceutical control of tumors that are unresectable and unresponsive to either chemotherapy or conventional radiotherapy. In this up-to-date, comprehensive book, world-renowned experts discuss the basic principles of radionuclide therapy, explore in detail the available treatments, explain the regulatory requirements, and examine likely future developments. The full range of clinical applications is considered, including thyroid cancer, hematological malignancies, brain tumors, liver cancer, bone and joint disease, and neuroendocrine tumors. The combination of theoretical background and practical information will provide the reader with all the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Careful attention is also paid to the important role of the therapeutic nuclear physician in delivering the effective coordination of a diverse multidisciplinary team that is essential to the safe provision of treatment.

  5. Mechanisms of Plasma Therapeutics

    Science.gov (United States)

    Graves, David

    2015-09-01

    In this talk, I address research directed towards biomedical applications of atmospheric pressure plasma such as sterilization, surgery, wound healing and anti-cancer therapy. The field has seen remarkable growth in the last 3-5 years, but the mechanisms responsible for the biomedical effects have remained mysterious. It is known that plasmas readily create reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS (or RONS), in addition to a suite of other radical and non-radical reactive species, are essential actors in an important sub-field of aerobic biology termed ``redox'' (or oxidation-reduction) biology. It is postulated that cold atmospheric plasma (CAP) can trigger a therapeutic shielding response in tissue in part by creating a time- and space-localized, burst-like form of oxy-nitrosative stress on near-surface exposed cells through the flux of plasma-generated RONS. RONS-exposed surface layers of cells communicate to the deeper levels of tissue via a form of the ``bystander effect,'' similar to responses to other forms of cell stress. In this proposed model of CAP therapeutics, the plasma stimulates a cellular survival mechanism through which aerobic organisms shield themselves from infection and other challenges.

  6. Therapeutic nuclear medicine

    Energy Technology Data Exchange (ETDEWEB)

    Baum, Richard P. (ed.) [ENETS Center of Excellence, Bad Berka (Germany). THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging

    2014-07-01

    Discusses all aspects of radionuclide therapy, including basic principles, newly available treatments, regulatory requirements, and future trends. Provides the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Explains the role of the therapeutic nuclear physician in effectively coordinating a diverse multidisciplinary team. Written by leading experts. The recent revolution in molecular biology offers exciting new opportunities for targeted radionuclide therapy. The selective irradiation of tumor cells through molecular biological mechanisms is now permitting the radiopharmaceutical control of tumors that are unresectable and unresponsive to either chemotherapy or conventional radiotherapy. In this up-to-date, comprehensive book, world-renowned experts discuss the basic principles of radionuclide therapy, explore in detail the available treatments, explain the regulatory requirements, and examine likely future developments. The full range of clinical applications is considered, including thyroid cancer, hematological malignancies, brain tumors, liver cancer, bone and joint disease, and neuroendocrine tumors. The combination of theoretical background and practical information will provide the reader with all the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Careful attention is also paid to the important role of the therapeutic nuclear physician in delivering the effective coordination of a diverse multidisciplinary team that is essential to the safe provision of treatment.

  7. Perspectives for Preventive and Therapeutic HPV Vaccines

    Science.gov (United States)

    Lin, Ken; Doolan, Kimberley; Hung, Chien-Fu; Wu, T-C

    2010-01-01

    Cervical cancer is the second most common cause of female cancer death worldwide. Persistent infection with `high risk' HPV genotypes is the major etiological factor in cervical cancer and thus effective vaccination against HPV provides an opportunity to reduce the morbidity and mortality associated with HPV. The FDA has approved two preventive vaccines to limit the spread of HPV. However, these are unlikely to impact upon HPV prevalence and cervical cancer rates for many years. Furthermore, preventive vaccines do not exert therapeutic effects on pre-existing HPV infections and HPV-associated lesions. In order to further impact upon the burden of HPV infections worldwide, therapeutic vaccines are being developed. These vaccines aim to generate a cell-mediated immune response to infected cells. This review discusses current preventive and therapeutic HPV vaccines and their future directions. PMID:20123582

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

    Science.gov (United States)

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

    2012-11-03

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

  9. Analisis Deskriptif Soal Geometri dalam Buku Matematika Bilingual untuk Sekolah Menengah Pertama Kelas VIII Berdasarkan Kriteria International Assessment TIMSS 2007

    Directory of Open Access Journals (Sweden)

    Etik Rahayu

    2012-06-01

    Full Text Available Tujuan penelitian ini adalah untuk mendeskripsikan  domain kognitif dan aspek kognitif (required behavior soal matematika dalam Buku Matematika Bilingual untuk Sekolah Menengah Pertama (SMP Kelas VIII berdasarkan kriteria International Assessment TIMSS 2007 dan proporsinya. Metode penelitian yang digunakan adalah deskriptif kualitatif, dengan subjek penelitian adalah soal geometri dalam Buku Matematika Bilingual SMP. yang berjudul “Mathematics for Junior High School Grade VIII 1st Semester” dan “Mathematics for Junior High School Grade VIII 2nd Semester” karangan karangan M. Cholik Adinawan dan Sugijono. Pengumpulan data menggunakan metode observasi dan wawancara tentang penggunaan buku matematika bilingual yang paling banyak digunakan di kota semarang. Pedoman analisis soal berdasarkan kriteria International Assessment TIMSS 2007, dengan validasi hasil oleh ahli. Hasil penelitian menunjukkan bahwa soal yang dianalisis memuat satu hingga tujuh aspek kognitif. Sebagian besar soal memuat 4 aspek kognitif yaitu 44.04 %, diikuti soal dengan 3 aspek kognitif  yaitu 36, 42%,  soal dengan 2 aspek kognitif yaitu 14, 90%, kemudian 1,99% untuk soal dengan 1 atau 5 aspek kognitif, dan 0,33% untuk soal dengan 6 atau 7 aspek kognitif. Proporsi tinggi pada recall (28.26% dan compute (26.57%, diikuti dengan SRP (10.85%, implement (10.65%, retrieve (8.36%, recognize (6.17%, analyze (1.99%, measure (1.59%, generalize (1.09%, SNRP (1.00%, classify (0.80%, represent (0.80%, justify (0.80%, select (0.60%, model (0.30%, synthesis (0.20%. Secara keseluruhan berdasarkan International Assessment TIMSS 2007 soal yang termasuk domain knowing memiliki persentase paling tinggi (52.28%, domain knowing-applying (24.83%, domain knowing- reasoning (12.91%, dan hanya sedikit yang termasuk domain knowing-apllying-reasoning (3.97%. Serta terdapat 4 soal (1.32% yang mempunyai ketidaksesuaian penggunaan mathematics terms serta 1 soal (0

  10. Antibody Engineering and Therapeutics

    Science.gov (United States)

    Almagro, Juan Carlos; Gilliland, Gary L; Breden, Felix; Scott, Jamie K; Sok, Devin; Pauthner, Matthias; Reichert, Janice M; Helguera, Gustavo; Andrabi, Raiees; Mabry, Robert; Bléry, Mathieu; Voss, James E; Laurén, Juha; Abuqayyas, Lubna; Barghorn, Stefan; Ben-Jacob, Eshel; Crowe, James E; Huston, James S; Johnston, Stephen Albert; Krauland, Eric; Lund-Johansen, Fridtjof; Marasco, Wayne A; Parren, Paul WHI; Xu, Kai Y

    2014-01-01

    The 24th Antibody Engineering & Therapeutics meeting brought together a broad range of participants who were updated on the latest advances in antibody research and development. Organized by IBC Life Sciences, the gathering is the annual meeting of The Antibody Society, which serves as the scientific sponsor. Preconference workshops on 3D modeling and delineation of clonal lineages were featured, and the conference included sessions on a wide variety of topics relevant to researchers, including systems biology; antibody deep sequencing and repertoires; the effects of antibody gene variation and usage on antibody response; directed evolution; knowledge-based design; antibodies in a complex environment; polyreactive antibodies and polyspecificity; the interface between antibody therapy and cellular immunity in cancer; antibodies in cardiometabolic medicine; antibody pharmacokinetics, distribution and off-target toxicity; optimizing antibody formats for immunotherapy; polyclonals, oligoclonals and bispecifics; antibody discovery platforms; and antibody-drug conjugates. PMID:24589717

  11. Therapeutic and diagnostic nanomaterials

    CERN Document Server

    Devasena T

    2017-01-01

    This brief highlights nanoparticles used in the diagnosis and treatment of prominent diseases and toxic conditions. Ecofriendly methods which are ideal for the synthesis of medicinally valued nanoparticles are explained and the characteristic features of these particles projected. The role of these particles in the therapeutic field, and the induced biological changes in some diseases are discussed. The main focus is on inflammation, oxidative stress and cellular membrane integrity alterations. The effect of nanoparticles on these changes produced by various agents are highlighted using in vitro and in vivo models. The mechanism of nanoparticles in ameliorating the biological changes is supported by relevant images and data. Finally, the brief demonstrates recent developments on the use of nanoparticles in diagnosis or sensing of some biological materials and biologically hazardous environmental materials.

  12. [Therapeutic education didactic techniques].

    Science.gov (United States)

    Valverde, Maite; Vidal, Mercè; Jansa, Margarida

    2012-10-01

    This article includes an introduction to the role of Therapeutic Education for Diabetes treatment according to the recommendations of the American Diabetes Association (ADA), the Diabetes Education Study Group (DESG) of the "European Association for Study of Diabetes (EASD) and the clinical Practice Guidelines (CPG) of the Spanish Ministry of Health. We analyze theoretical models and the differences between teaching vs. learning as well as current trends (including Internet), that can facilitate meaningful learning of people with diabetes and their families and relatives. We analyze the differences, similarities, advantages and disadvantages of individual and group education. Finally, we describe different educational techniques (metaplan, case method, brainstorming, role playing, games, seminars, autobiography, forums, chats,..) applicable to individual, group or virtual education and its application depending on the learning objective.

  13. 20 CFR 404.535 - How much will we withhold from your title VIII and title XVI benefits to recover a title II...

    Science.gov (United States)

    2010-04-01

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

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

    Science.gov (United States)

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

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

    Science.gov (United States)

    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.