Diagnosis And Treatment Of Congenital Hemophilia With Inhibitors. A Latin American Perspective

The Committee of Latin America on the Therapeutics of Inhibitor Groups (CLOTTING) is composed of a number of hemophilia specialists from Latin America. The group aims to encourage the adoption of a good standard of care for Latin American patients with hemophilia. The occurrence of inhibitors in patients with hemophilia poses clinical challenges, and it is estimated that between 1 000 and 3 000 patients in Latin America are affected by hemophilia with inhibitors. There is an urgent need to establish a regional consensus and clinical guidelines for the diagnosis and treatment of these patients. We present an extensive review based on best current clinical practice and published literature, as seen from a Latin American perspective, taking into account the variable nature of hemophilia care available in the various countries in this Region.683227242Ehrenforth, S., Kreuz, W., Scharrer, I., Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs (1992) Lancet, 339, pp. 594-598Katz, J., Prevalence of factor IX inhibitors among patients with haemophilia B: Results of a large-scale North American study (1996) Haemophilia, 2, pp. 28-31Goudemand, J., Pharmaco-economic aspects of inhibitor treatment (1998) Eur J Haematol, 61, pp. 24-27World Hemophilia Federation Report on Global Survey 2006. World Federation of Hemophilia, 2007. 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Association of Hemophilia Centre Directors of Canada. Factor VIII/IX Subcommittee of Scientific and Standardization Committee of International Society on Thrombosis and Haemostasis (1998) Thromb Haemost, 79, pp. 872-875Verbruggen, B., van Heerde, W., Novakova, I., Lillicrap, D., Giles, A., A 4% solution of bovine serum albumin may be used in place of factor VIII:C deficient plasma in the control sample in the Nijmegen modification of the Bethesda factor VIII:C inhibitor assay (2002) Thromb Haemost, 88, pp. 362-364White II, G.C., Rosendaal, F., Aledort, L.M., Lusher, J.M., Rothschild, C., Ingerslev, J., Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis (2001) Thromb Haemost, 85, p. 560Kitchen, S., McCraw, A., (2000) Diagnosis of hemophilia and other bleeding disorders, , A laboratory manual. 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A multi-centre, randomized, double blind, cross-over trial (2006) Thromb Haemost, 95, pp. 600-605Santagostino, E., Mancuso, M.E., Rocino, A., Mancuso, G., Scaraggi, F., Mannucci, P.M., A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of haemarthroses in hemophiliacs with inhibitors (2006) J Thromb Haemost, 4, pp. 367-371Schneiderman, J., Nugent, D.J., Young, G., Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe hemophilia and inhibitors (2004) Haemophilia, 10, pp. 347-351Lusher, J.M., Shapiro, S.S., Palascak, J.E., Rao, A.V., Levine, P.H., Blatt, P.M., Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII: A multicenter therapeutic trial (1980) NEJM, 303, pp. 421-425Teitel, J., Berntorp, E., Collins, P., A systematic approach to controlling problem bleeds in patients with severe congenital hemophilia A and high-titre inhibitors (2007) Haemophilia, 13, pp. 256-263Lloyd Jones, M., Wight, J., Paisley, S., Knight, C., Control of bleeding in patients with hemophilia A with inhibitors: A systematic review (2003) Haemophilia, 9, pp. 464-520Ewenstein, B.M., Takemoto, C., Warrier, I., Nephrotic syndrome as a complication of immune tolerance in hemophilia B (1997) Blood, 89, pp. 1115-1116Warrier, I., Lenk, H., Saidi, P., Pollmann, H., Tengborn, L., Berntorp, E., Nephrotic syndrome in hemophilia B patients with inhibitors (1998) Haemophilia, 4, p. 248Warrier, I., Management of hemophilia B patients with inhibitors and anaphylaxis (1998) Haemophilia, 4, pp. 574-576Strawczynski, H., Stachewitsch, A., Morgenstern, G., Shaw, M.E., Delivery of care to hemophilic children: Home care versus hospitalization (1973) Pediatrics, 51, pp. 986-991Rabiner, S.F., Telfer, M.C., Fajardo, R., Home transfusions of hemophiliacs (1972) JAMA, 221, pp. 885-887Levine, P., The home therapy program at the New England area hemophilia center (1977) Scand J Haematol, 31, pp. 37-51Soucie, J.M., Symons, J.I., Evatt, B., Brettler, D., Huszti, H., Linden, J., Home-based factor infusion therapy and hospitalization for bleeding complications among males with hemophilia (2001) Haemophilia, 7, pp. 198-206Solovieva, S., Clinical severity of disease, functional disability and health-related quality of life. 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bleeding in various surgical procedures in hemophilic patients with factor VIII and factor IX inhibitors (2000) Semin Thromb Hemost, 26, pp. 425-432Tjønnfjord, G.E., Brinch, L., Gedde-Dahl III, T., Brosstad, F.R., Activated prothrombin complex concentrate (FEIBA) treatment during surgery in patients with inhibitors to FVIII/IX (2004) Haemophilia, 10, pp. 174-178Ingerslev, J., Sorensen, B., Role of recombinant activated factor VII as hemostatic support in orthopedic surgery (2006) TATM, 8, pp. 35-42Obergfell, A., Auvinen, M.K., Mathew, P., Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: A review of the literature (2008) Haemophilia, 14, pp. 233-241Ewenstein, B.M., Valentino, L.A., Journeycake, J.M., Consensus recommendations for use of central venous access devices in hemophilia (2004) Haemophilia, 10, pp. 629-648Morado, M., Jimenez-Yuste, V., Villar, A., Complications of central venous catheters in patients with hemophilia and inhibitors (2001) Haemophilia, 7, pp. 551-556Bollard, C.M., Teague, L.R., Berry, E.W., Ockelford, P.A., The use of central venous catheters (portacaths) in children with hemophilia (2000) Haemophilia, 6, pp. 66-70O'Connell, N., Mc Mahon, C., Smith, J., Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with hemophilia and high responding inhibitors (2002) Br J Haematol, 116, pp. 632-635Cooper, H.A., Jones, C.P., Campion, E., Roberts, H.R., Hedner, U., Rationale for the use of high dose rFVIIa in a high-titre inhibitor patient with hemophilia B during major orthopaedic procedures (2001) Haemophilia, 7, pp. 517-522Colowick, A.B., Bohn, R.L., Avorn, J., Ewenstein, B.M., Immune tolerance induction in hemophilia patients with inhibitors: Costly can be cheaper (2000) Blood, 96, pp. 1698-1702Brackmann, H.H., Gormsen, J., Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder (1977) Lancet, 2, p. 933Key, N.S., 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with hemophilia A (2004) Haemophilia, 10, p. 57DiMichele, D., Immune tolerance therapy dose as an outcome predictor (2003) Haemophilia, 9, pp. 382-386Mariani, G., Kroner, B., Immune tolerance in hemophilia with factor VIII inhibitors: Predictors of success (2001) Haematologica, 86, pp. 1186-1193DiMichele, D., Inhibitors: Resolving diagnostic and therapeutic dilemmas (2002) Haemophilia, 8, pp. 280-287Lenk, H., The German Registry of immune tolerance treatment in hemophilia-1999 update (2000) Haematologica, 85, pp. 45-47Haya, S., Lopez, M.F., Aznar, J.A., Batlle, J., Immune tolerance treatment in hemophilia patients with inhibitors: The Spanish Registry (2001) Haemophilia, 7, pp. 154-159DiMichele, D.M., Hoots, W.K., Pipe, S.W., Rivard, G.E., Santagostino, E., International workshop on immune tolerance induction: Consensus recomendations (2007) Haemophilia, 13, pp. 1-22Kreuz, W., Mentzer, D., Auerswald, G., Becker, S., Joseph-Steiner, J., Successful immune tolerance therapy of FVIII inhibitor in children after changing from high to intermediate purity FVIII concentrate (1996) Haemophilia, 2, p. 19Rocino, A., Papa, M.L., Salerno, E., Capasso, F., Miraglia, E., de Biasi, R., Immune tolerance induction in hemophilia A patients with high-responding inhibitors to factor VIII: Experience at a single institution (2001) Haemophilia, 7, pp. 33-38DiMichele, D., Rivard, G., Hay, C., Antunes, S., Inhibitors in hemophilia: Clinical aspects (2004) Haemophilia, 10, pp. 140-145Mauser-Bunschoten, E.P., Nieuwenhuis, H.K., Roosendaal, G., van den Berg, H.M., Low-dose immune tolerance induction in hemophilia A patients with inhibitors (1995) Blood, 86, pp. 983-988Almeida, J., Paula, J.C., Toscano, R., Immune tolerance such as salvage therapy in severe hemophilia A patient with ultra high-responders inhibitors (2002) Haemophilia, 8, p. 538Solano, M.H., Ramírez, C., Parra, L., Tratamiento de inhibidores del factor VIII en hemofilia. (1998) Acta Med Colomb, 23, p. 193Carneiro, J.D.A., Bassit, R.P., Villaça, P.R., Sandoval, E.P.N., Silva, C.S.S.S., D'amico, E.A., Low-dose immune tolerance induction in hemophilia A children with inhibitors (2002) Haemophilia, 8, pp. 538-539Wight, J., Paisley, S., Knight, C., Immune tolerance induction in patients with hemophilia A with inhibitors: A systematic review (2003) Haemophilia, 9, pp. 436-463Tengborg, L., Hansson, S., Fasth, A., Lübeck, P.O., Berg, A., Ljung, R., Anaphylactoid reactions and nephrotic syndrome - a considerable risk during factor IX treatment in patients with hemophilia B and inhibitors: A report on the outcome in two brothers (1998) Haemophilia, 4, pp. 854-859Schulman, S., Safety, efficacy and lessons from continuous infusion with rFVIIa (1998) Haemophilia, 4, pp. 564-567Schulman, S., Continuous infusion of recombinant factor VIIa in hemophilic patients with inhibitors: Safety, monitoring, and cost effectiveness (2000) Semin Thromb Hemost, 26, pp. 421-424Pruthi, R.K., Mathew, P., Valentino, L.A., Sumner, M.J., Seremetis, S., Hoots, W.K., Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in hemophilia patients with inhibitors undergoing major surgery. 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Blockade of hemichannels normalizes the differentiation fate of myoblasts and features of skeletal muscles from dysferlin-deficient mice

Indexación: Scopus.Dysferlinopathies are muscle dystrophies caused by mutations in the gene encoding dysferlin, a relevant protein for membrane repair and trafficking. These diseases are untreatable, possibly due to the poor knowledge of relevant molecular targets. Previously, we have shown that human myofibers from patient biopsies as well as myotubes derived from immortalized human myoblasts carrying a mutated form of dysferlin express connexin proteins, but their relevance in myoblasts fate and function remained unknown. In the present work, we found that numerous myoblasts bearing a mutated dysferlin when induced to acquire myogenic commitment express PPARγ, revealing adipogenic instead of myogenic commitment. These cell cultures presented many mononucleated cells with fat accumulation and within 48 h of differentiation formed fewer multinucleated cells. In contrast, dysferlin deficient myoblasts treated with boldine, a connexin hemichannels blocker, neither expressed PPARγ, nor accumulated fat and formed similar amount of multinucleated cells as wild type precursor cells. We recently demonstrated that myofibers of skeletal muscles from blAJ mice (an animal model of dysferlinopathies) express three connexins (Cx39, Cx43, and Cx45) that form functional hemichannels (HCs) in the sarcolemma. In symptomatic blAJ mice, we now show that eight-week treatment with a daily dose of boldine showed a progressive recovery of motor activity reaching normality. At the end of this treatment, skeletal muscles were comparable to those of wild type mice and presented normal CK activity in serum. Myofibers of boldine-treated blAJ mice also showed strong dysferlin-like immunoreactivity. These findings reveal that muscle dysfunction results from a pathophysiologic mechanism triggered by mutated dysferlin and downstream connexin hemichannels expressed de novo lead to a drastic reduction of myogenesis and favor muscle damage. Thus, boldine could represent a therapeutic opportunity to treat dysfernilopathies. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.https://www.mdpi.com/1422-0067/21/17/602

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

The t(7;11)(p15;p15.4) has been reported to fuse the NUP98 gene (11p15), a component of the nuclear pore complex, with the class-1 homeobox gene HOXA9 at 7p15. This translocation has been associated with myeloid leukemias, predominantly acute myeloid leukemia (AML) M2 subtype with trilineage myelodysplastic features, and with a poor prognosis. The derived fusion protein retains the FG repeat motif of NUP98 N-terminus and the homeodomain shared by the HOX genes, acting as an oncogenic transcription factor critical for leukemogenesis. We report here a new complex t(7;11)-variant, i.e., t(7;11;13;17)(p15;p15;p?;p1?2) in a patient with AML-M2 and poor prognosis. The NUP98-HOXA9 fusion transcript was detected by RT-PCR, suggesting its role in the malignant transformation as it has been postulated for other t(7;11)-associated leukemias. No other fusion transcripts involving the NUP98 or HOXA9 genes were present, although other mechanisms involving several genes on chromosomes 13 and 17 may also be involved. To our knowledge, this is the first t(7;11) variant involving NUP98 described in hematological malignancies

Colloquium: Mechanical formalisms for tissue dynamics

The understanding of morphogenesis in living organisms has been renewed by tremendous progressin experimental techniques that provide access to cell-scale, quantitative information both on theshapes of cells within tissues and on the genes being expressed. This information suggests that ourunderstanding of the respective contributions of gene expression and mechanics, and of their crucialentanglement, will soon leap forward. Biomechanics increasingly benefits from models, which assistthe design and interpretation of experiments, point out the main ingredients and assumptions, andultimately lead to predictions. The newly accessible local information thus calls for a reflectionon how to select suitable classes of mechanical models. We review both mechanical ingredientssuggested by the current knowledge of tissue behaviour, and modelling methods that can helpgenerate a rheological diagram or a constitutive equation. We distinguish cell scale ("intra-cell")and tissue scale ("inter-cell") contributions. We recall the mathematical framework developpedfor continuum materials and explain how to transform a constitutive equation into a set of partialdifferential equations amenable to numerical resolution. We show that when plastic behaviour isrelevant, the dissipation function formalism appears appropriate to generate constitutive equations;its variational nature facilitates numerical implementation, and we discuss adaptations needed in thecase of large deformations. The present article gathers theoretical methods that can readily enhancethe significance of the data to be extracted from recent or future high throughput biomechanicalexperiments.Comment: 33 pages, 20 figures. This version (26 Sept. 2015) contains a few corrections to the published version, all in Appendix D.2 devoted to large deformation

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements

Search for dark matter produced in association with a hadronically decaying vector boson in pp collisions at sqrt (s) = 13 TeV with the ATLAS detector

A search is presented for dark matter produced in association with a hadronically decaying W or Z boson using 3.2 fb−1 of pp collisions at View the MathML sources=13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Events with a hadronic jet compatible with a W or Z boson and with large missing transverse momentum are analysed. The data are consistent with the Standard Model predictions and are interpreted in terms of both an effective field theory and a simplified model containing dark matter

A search for resonances decaying into a Higgs boson and a new particle X in the XH → qqbb final state with the ATLAS detector

A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb−1 of proton–proton collision data at collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle X is assumed to decay to a pair of light quarks, and the fully hadronic final state is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the resonance

Search for TeV-scale gravity signatures in high-mass final states with leptons and jets with the ATLAS detector at sqrt [ s ] = 13TeV

A search for physics beyond the Standard Model, in final states with at least one high transverse momentum charged lepton (electron or muon) and two additional high transverse momentum leptons or jets, is performed using 3.2 fb−1 of proton–proton collision data recorded by the ATLAS detector at the Large Hadron Collider in 2015 at √s = 13 TeV. The upper end of the distribution of the scalar sum of the transverse momenta of leptons and jets is sensitive to the production of high-mass objects. No excess of events beyond Standard Model predictions is observed. Exclusion limits are set for models of microscopic black holes with two to six extra dimensions

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented