Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9–60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.
Gas6, une nouvelle proteine vitamino-K dependante, interagit avec les phospholipides membranaires grâce a sa region riche en residus de l'acide gamma-carboxyglutamique et se lie aux recepteurs tyrosine kinases de la famille Tyro 3 par le domaine globulaire de sa region carboxy-terminale. La liaison de Gas6 a l'un ou l'autre de ses recepteurs declenche une serie d'evenements intra-cellulaires qui vont traduire le signal envoye par Gas6. Depuis sa decouverte initiale dans les fibroblastes en arret de croissance, de multiples fonctions ont ete attribuees a Gas6, allant de l'inhibition de l'apoptose et de la croissance cellulaire a l'adhesion et a la migration des cellules. Afin de mettre en evidence le role de cette proteine dans la thrombose et l'hemostase, des souris presentant une inactivation du gene gas6 ont ete recemment generees. Les souris deficientes en Gas6 sont protegees contre les thromboses aussi bien arterielles que veineuses. Elles ne souffrent cependant pas d'hemorragies spontanees ou induites par des traumatismes mineurs. Le mecanisme anti-thrombotique de la deficience en Gas6 est du, du moins en partie, a un trouble de la fonction plaquettaire. Des travaux recents suggerent que Gas6 agit comme un « amplificateur » de la reponse des plaquettes a leurs agonistes. Il fonctionnerait de maniere autocrine en etant secrete a partir des granules alpha lors de l'activation plaquettaire initiale. Gas6 apparait comme etant redondant pour l'hemostase en conditions basales, comme le demontre l'absence d'hemorragies spontanees et le temps de saignement normal des souris deficientes en Gas6. Il est cependant a l'origine d'un important systeme d'« amplification » dans les situations pathologiques. Les decouvertes concernant cette nouvelle molecule impliquee dans la fonction plaquettaire pourraient avoir un interet pour la pratique medicale clinique. Tout abord, le trouble de la fonction des plaquettes deficientes en Gas6 ressemble a celui des patients souffrant d'un syndrome hemorragique mineur du a un « defaut primaire de la transduction du signal », dont les mecanismes sous-jacents sont encore inconnus. D'un interet clinique plus general, il y a la decouverte de l'inhibition de l'agregation de plaquettes humaines in vitro par des anticorps anti-Gas6 et la prevention de thrombo-embolies fatales chez la souris par ces memes anticorps sans effets secondaires hemorragiques. C'est ainsi que l'inhibition de Gas6 pourrait constituer un nouveau moyen d'empecher la survenue de thrombose sans entrainer de complications hemorragiques.
ABSTRACT: A subset of cytokine mediators belonging to the tumor necrosis factor (TNF) family cause apoptosis, acting through receptors and signaling pathways that have recently come to light. Further, at least one autoimmune disease results from a defined defect of apoptosis (mutations of the Fas ligand or its receptor). It is offered that many, and perhaps most autoimmune diseases may result from primary defects of apoptosis. Such defects may cause reflexive overproduction of TNF and other pro-apoptotic cytokines. The collateral damage produced by these mediators may be of pathogenetic importance in complex autoimmune disorders such as rheumatoid arthritis and Crohn disease, wherein TNF blockade is known to have ameliorative effects.
Transplantation of autologous peripheral blood progenitor cells (PBPC) is now a well established method to reconstitute haematopoiesis after high-dose chemoradiotherapy. Allogeneic PBPCs have rarely been used as the sole measure to induce haematopoietic recovery after myeloablative therapy because of uncertainties regarding the durability of engraftment and the risk of acute and chronic graft-vs-host disease (GVHD). In addition, this technique requires the exposure of normal donors to granulocyte colony stimulating factor (G-CSF) in order to mobilise a sufficient number of PBPCs which can then be collected by leukapheresis. We report here our initial experience with allogeneic transplantation of PBPCs in order to demonstrate the feasibility and safety of harvesting sufficient numbers of PBPCs in healty donors. In addition, the early results presented in this communication show that allogeneic PBPCs can successfully be used to restore haematopoiesis in HLA-identical siblings of the donor without causing devastating graft-vs-host disease.
The term thalassemia is used to define various hereditary anemias that are identified by a reduced production of one of the globin chains that form the hemoglobin molecule. Thalassemia syndromes are widely distributed throughout Mediterranean, Middle Eastern, and Asian countries, and occur with a significant incidence worldwide in populations that originated in these regions. The thalassemias probably represent the most common single gene disorder to cause a major public health problem in the world [1]. In the Mediterranean area alone there are more than 200,000 β-homozygous thalassemia patients, and according to the World Health Organization approximately 180 million people are heterozygous for one of several forms of genetic disorder of hemoglobin synthesis [2]. In β-thalassemia there is deficient or absent synthesis of the β-globin chains that constitute the adult hemoglobin molecule. Because β-thalassemia is a genetic disease in which the known expression of the genetic defect is located in the hematopoietic system, it is rationally curable by allogeneic bone marrow transplantation. The first successful transplant in β-thalassemia was in an untransfused 14- month-old child and was reported by Thomas in 1982 [3]. At about the same time a 14-year-old thalassemic patient who had received 150 red cell transfusions was transplanted in Pesaro but had recurrence of thalassemia after rejection of the graft. The first report from Pesaro on this topic was in 1984 [4], and since then several centers have reported experience with marrow transplantation for thalassemia (Table 1).
Circulating thrombomodulin (TM) and von Willebrand factor (vWF) were determined in smokers before and after smoking of two filter cigarettes and in control subjects. The basal levels of TM and vWF were significantly increased in smokers relative to controls (p < 0.001). However, levels of these two factors remained unchanged immediately after smoking of two filter cigarettes, while a statistically significant correlation was observed only between plasma TM and number of years of smoking (p < 0.05).
Bone marrow purging with cyclophosphamide derivatives in autologous bone marrow transplantation has demonstrated that the killing of leukemic cells and simultaneous preservation of normal progenitor cells depends on a number of parameters, in particular the haematocrit, nucleated cell concentration and nature of the cells. We have previously described a reliable experimental procedure for in vitro bone marrow treatment, based on individual adjustment of the drug dosage. The present study reveals an inhibitory action of plasma on the toxicity of mafosfamide to normal haematopoietic progenitor cells. In an initial series of 42 successive patients, determination of the CFU-GM lethal dose 95% (CFU-GM LD 95) showed this parameter to be inversely correlated to the nucleated cell concentration (NCC) (p < 0.001). Assuming the plasma content of the buffy coat cells (BC) to be higher in the less rich marrow samples, we then investigated the role of plasma in progenitor cell sensitivity to the drug. Results were as follows: (1) in the presence of 60% autologous or allogeneic plasma, CFU-GM LD 95 was increased by a factor of 2.18 +/- 0.35 or 1.98 +/- 0.23 respectively as compared to controls in a solution of 2% bovine serum albumin (p = 0.014), (2) this observation remained valid whatever the origin of the plasma and (3) the same was true whatever the nature of the cells, derived from normal donors or patients with haematological malignancies. These data suggest that plasma contains an inhibitor(s) of mafosfamide.(ABSTRACT TRUNCATED AT 250 WORDS)
Restoration of a haemocompatible surface after endothelial damage induced by treatments such as embolectomy, angioplasty, endarterectomy or irradiation or following vascular graft implantation is an important factor for the ultimate success of these interventions. The development of substances which enhance endothelial cell growth and accelerate their proliferation is therefore of great interest in such situations. In the present work naftazone was shown to accelerate human saphenous vein endothelial cell proliferation in vitro at concentrations which did not alter the hemostatic balance, resulting in a cell density at confluence 20% higher than in controls. This compound was able to partially substitute for serum requirements and further displayed additive effects in the presence of fibroblast growth factors. Thus naftazone, an original synthetic molecule distinct from growth factor peptides, is a promising candidate drug for the amelioration of vascular repair.
The aim of this study was to investigate whether the epitopes recognized by anti-beta(2)-glycoprotein I antibodies (anti-beta(2)-GPI Abs) were similar in the presence and absence of anticardiolipin antibodies (aCLA). For this purpose, the inhibition of binding to beta(2)-GPI was assayed with sera from 3 patients with antiphospholipid syndrome (APS). Two of the sera were positive for both beta(2)-GPI Abs and aCLA, the other was only beta(2)-GPI Ab-positive. The inhibitors used were a mixture of beta(2)-GPI and cardiolipin micelles, beta(2)-GPI-coated latex beads and fluid-phase beta(2)-GPI. Sera were diluted 200-fold to avoid the influence of endogenous beta(2)-GPI. The results show that in the absence of aCLA, anti-beta(2)-GPI reactivity was reduced by all the inhibitors, suggesting recognition of a native structure. In contrast, in the presence of aCLA, reactivity was inhibited only by conformational epitopes present on beta(2)-GPI reacting with cardiolipin micelles. These data indicate that there is heterogeneity among anti-beta(2)-GPI antibodies with respect to antigenic specificities.
Haemophagocytic syndrome is a heterogenous disease characterized by disordered macrophage activation associated with viral, bacterial or parasitic infection. The few reports of haemophagocytosis occurring in the presence of mycobacterial infection show a high mortality rate and we present two further cases notable for their favourable issue. Rapidity of diagnosis and immediate treatment could explain the avoidance of a fatal outcome.
In the present study, we found a high prevalence (46.8%) of serum IgG anticardiolipin antibodies (aCLA) in a group of 111 unselected HIV-seropositive individuals. The presence of aCLA was correlated with that of IgG antibodies to endothelial cells (AECA) but not with that of anti-beta(2)-glycoprotein I antibodies, which were found only in 7.4% of patients. The presence of IgG aCLA was not associated with detectable lupus anticoagulants or a history of thrombosis. Serum titres of aCLA were not correlated with absolute numbers of circulating CD4(+) cells and we found no relationship between the presence and titres of aCLA, hypergammaglobulinaemia and serum titres of natural IgG autoantibodies to a panel of self antigens. Our results suggest that increased levels of aCLA in HIV infection result from a biased expansion of B cell clones producing natural autoantibodies.
Prevalences of anticardiolipin (aCLA), anti-beta(2)-glycoprotein I (anti-beta(2)-GPI) and anti-prothrombin IgG antibodies were determined by ELISA in 2174 patients and 107 blood donors. Among patients, 137 had systemic lupus erythematosus (SLE), while 683 displayed at least one clinical or biological feature suggestive of antiphospholipid syndrome: 497 patients had thrombosis, 51 patients had experienced at least 3 miscarriages or a foetal death at more than 12 weeks of gestation, 67 had thrombocytopenia, 50 had lupus anticoagulants (LA), 13 had thrombosis and LA, 3 had thrombocytopenia and LA and 2 had a history of foetal lass and LA. Connective tissue or related disorders were present in 595 patients, 759 others were suffering from miscellaneous diseases and cases of HIV infection were excluded from the study. Prevalences of aCLA and anti-beta(2)-GPI antibodies were increased in patients with SLE and/or LA in comparaison to all other groups (p < 0.001). In these patients, anti-beta(2)-GPI antibodies were often associated with aCLA, 34 (77%) of 44 patients with anti-beta(2)-GPI antibodies also having aCLA (p < 0.001). In other patients the reverse was true, anti-p,GPI antibodies being infrequent and when present rarely associated with aCLA (p < 0.001). The prevalence of sera with anti-beta(2)-GPI antibodies but no aCLA was similar in all patient groups and in blood donors. These results suggest that at least two types of antiphospholipid containing sera exist, those containing only one kind of antibody (aCLA or anti-beta(2)-GPI antibodies, type 1) which are poorly specific and those associating aCLA and anti-beta(2)-GPI antibodies (type 2), highly specific for SLE and/or LA. The prevalence of anti-prothrombin antibodies was increased in patients with SLE and/or LA (p < 0.01) and in those with an unexplained prolongation of APTT (p < 0.01). In the latter case, since these antibodies were not associated with LA, aCLA or anti-beta(2)-GPI antibodies, this indicates that anti-prothrombin antibodies may interfere in the APTT test and should therefore be screened in patients presenting an unexplained prolongation of APTT.
