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Carla E.M. Hollak Stephan vom Dahl Johannes M.F.G. Aerts Nadia Belmatoug Bruno Bembi Yossi Cohen Tanya Collin-Histed Patrick Deegan Laura van Dussen Pilar Giraldo Eugen Mengel Helen Michelakakis Jeremy Manuel Martin Hrebicek Rosella Parini Jörg Reinke Maja di Rocco Miguel Pocovi Maria Clara Sa Miranda Anna Tylki-Szymanska Timothy M. Cox 《Blood cells, molecules & diseases》2010,44(1):41-47
Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously — usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase — and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed. 相似文献
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De Keersmaecker B Heirman C Corthals J Empsen C van Grunsven LA Allard SD Pen J Lacor P Thielemans K Aerts JL 《Journal of leukocyte biology》2011,89(6):989-999
One of the consequences of HIV infection is a progressive loss of T cell functions, resulting in decreased cytokine secretion and proliferation and an increased sensitivity to apoptosis. Therefore, successful therapeutic vaccination approaches should aim at restoring the functionality of existing HIV-specific T cells, as well as to efficiently induce potent, HIV-specific T cells from na?ve T cells. In this study, we wanted to determine the stimulatory capacity of DCs coelectroporated with mRNA encoding for different costimulatory molecules of the TNFSF, together with HIV antigen-encoding mRNA. We show that DCs electroporated with 4-1BBL can enhance the proliferation, functionality, cytokine production, and survival of HIV-specific CD8(+) T cells. Furthermore, we are the first to show that a combination of 4-1BBL and CD40L overexpression on DCs dramatically enhances CD4(+) and CD8(+) T cell responses. Finally, we demonstrate that signaling through 4-1BB, but not through CD40, can alleviate the suppressive effect of Tregs on CD8(+) T cell proliferation. Thus, the combination of 4-1BBL and CD40L enhances HIV-specific CD8(+) T cell responses in a synergistic way, resulting in enhanced proliferation of CD4(+) and CD8(+) T cell subsets, an increased cytokine secretion, and a reduced sensitivity to Treg-mediated immune suppression. 相似文献
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Serlie MJ Meijer AJ Groener JE Duran M Endert E Fliers E Aerts JM Sauerwein HP 《The Journal of clinical endocrinology and metabolism》2007,92(4):1524-1529
CONTEXT: Increased plasma free fatty acid (FFA) concentrations may be in part responsible for the increased levels of ceramide in skeletal muscle of obese subjects. OBJECTIVE: We studied the effect of lowering and increasing plasma FFA levels on muscle ceramide and glucosylceramide concentrations in lean and obese subjects. DESIGN: Plasma FFAs were either increased or decreased for 6 h by infusing a lipid emulsion or using Acipimox, respectively. Muscle biopsies were performed before and after the intervention for measurements of ceramide and glucosylceramide. STUDY SUBJECTS: Eight lean [body mass index 21.9 (range, 19.6-24.6) kg/m2] and six overweight/obese [body mass index 34.4 (27.8-42.5) kg/m2] subjects without type 2 diabetes mellitus participated in the study. MAIN OUTCOME MEASURE: Differences in muscle ceramide and glucosylceramide upon manipulation of plasma FFAs were measured. RESULTS: There were no differences in muscle ceramide and glucosylceramide between lean and obese subjects, respectively. Increasing or decreasing plasma FFAs for 6 h had no effect on ceramide [high FFAs: 24 (19-25) vs. 24 (22-27) pmol/mg muscle, P=0.46; and 22 (20-28) vs. 24 (18-26) pmol/mg muscle, P=0.89 in lean and obese, respectively; low FFAs: 26 (24-35) vs. 23 (18-27) pmol/mg muscle, P=0.17 and 24 (15-44) vs. 24 (19-42) pmol/mg muscle, P=0.6 in lean and obese, respectively] and glucosylceramide [high FFAs: 2.0 (1.7-4.3) vs. 3.4 (2.1-4.6) pmol/mg muscle, P=0.17; and 3.0 (1.3-6.7) vs. 2.6 (1.2-3.9) pmol/mg muscle, P=0.89 in lean and obese, respectively; low FFAs: 2.2 (1.0-4.4) vs. 1.7 (1.4-3.0) pmol/mg muscle, P=0.92; and 6.6 (1.0-25.0) vs. 4.3 (1.3-7.6) pmol/mg muscle, P=0.7 in lean and obese, respectively] concentrations in skeletal muscle. CONCLUSION: Short-term manipulation of plasma FFAs has no effect on ceramide and glucosylceramide concentrations in skeletal muscle from lean and obese subjects. 相似文献
108.
Gender-related differences in the metabolic response to fasting 总被引:2,自引:0,他引:2
Soeters MR Sauerwein HP Groener JE Aerts JM Ackermans MT Glatz JF Fliers E Serlie MJ 《The Journal of clinical endocrinology and metabolism》2007,92(9):3646-3652
CONTEXT: Free fatty acids (FFA) may induce insulin resistance via synthesis of intramyocellular ceramide. During fasting, women have lower plasma glucose levels than men despite higher plasma FFA, suggesting protection from FFA-induced insulin resistance. OBJECTIVE: We studied whether the relative protection from FFA-induced insulin resistance during fasting in women is associated with lower muscle ceramide concentrations compared with men. MAIN OUTCOME MEASURES AND DESIGN: After a 38-h fast, measurements of glucose and lipid fluxes and muscle ceramide and fatty acid translocase/CD36 were performed before and after a hyperinsulinemic euglycemic clamp. RESULTS: Plasma glucose levels were significantly lower in women than men with a trend for a lower endogenous glucose production in women, whereas FFA and lipolysis were significantly higher. Insulin-mediated peripheral glucose uptake was not different between sexes. There was no gender difference in muscle ceramide in the basal state, and ceramide did not correlate with peripheral glucose uptake. Muscle fatty acid translocase/CD36 was not different between sexes in the basal state and during the clamp. CONCLUSION: After 38 h of fasting, plasma FFA were higher and plasma glucose was lower in women compared with men. The higher plasma FFA did not result in differences in peripheral insulin sensitivity, possibly because of similar muscle ceramide and fatty acid translocase/CD36 levels in men and women. We suggest that during fasting, women are relatively protected from FFA-induced insulin resistance by preventing myocellular accumulation of ceramide. 相似文献
109.
Albiges L Cottu PH Cojean-Zelek I Raymond F Zerkak D Aerts J Ziza JM 《La Revue de médecine interne / fondée ... par la Société nationale francaise de médecine interne》2007,28(3):176-178
INTRODUCTION: We report two cases of patients with prostate cancer who underwent haematological complications from the disease. CLINICAL CASES: Diffuse intravascular coagulopathy (with thrombopenia) was observed in two patients (55 and 59 years-old) diagnosed with prostate cancer. In one patient who had normal prostate at clinical examination, thrombopenia with incomplete diffuse intravascular coagulopathy and biological inflammatory led to diagnosis. It was initially controlled by hormonal therapy and secondary by chemotherapy. In the other patient diffuse intravascular coagulopathy followed introduction of hormonal therapy and lead to the patient's death. DISCUSSION: Patients with metastatic hormone-refractory prostate carcinoma may have life-threatening coagulation complications due to their disease. Diffuse intravascular coagulopathy is the most frequent coagulation complication. Other coagulopathies associated with prostate cancer are thrombocytopenic thrombotic purpura, thrombosis, Trousseau's syndrome and acquired factor VIII inhibitor development. Usually these haematological manifestations complicate the course of the disease and appear to have a bad prognosis. But thrombopenia or haematologic features may lead to the diagnosis of medullary metastatic prostatic cancer, even if the prostate appears normal at the initial clinical examination. 相似文献
110.
Adiponectin and, especially, its oligomeric complex composition have been suggested to be critical in determining insulin sensitivity. Pro-inflammatory cytokines play an important role in the development of insulin resistance in obesity and associated diseases. Therefore, we investigated the effect of long-term exposure of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, and interferon (IFN)-gamma on total insulin-sensitizing adiponectin secretion and adiponectin complex formation from human adipocytes. In parallel, adipocyte delipidation and leptin production levels were monitored. The present study demonstrates that TNF-alpha, IL-1beta, and IFN-gamma dose and time dependently suppressed total adiponectin secretion within 7 days (60, 70, and 35% reduction respectively). IL-6 was also able to reduce (50%) adiponectin production, although only in combination with exogenous soluble IL-6 receptors (sIL-6R). However, the oligomeric distribution (high, middle, and low molecular weight (HMW) complexes) of secreted adiponectin was not altered by any of these cytokines. All studied pro-inflammatory cytokines resulted in delipidation and reduction of lipid-laden adipocyte numbers. Despite this reduction of lipid-laden adipocytes, TNF-alpha, IL-6/sIL-6R, and IL-1beta stimulated leptin release. Our data indicate that (i) long-term pro-inflammatory cytokine exposure downregulates total adiponectin secretion from delipidizing adipocytes and (ii) pro-inflammatory cytokines are not important regulators of adipocyte-derived adiponectin oligomerization. Hence, their individual contribution to low expression of HMW adiponectin found in insulin-resistant conditions seems unlikely. Furthermore, delipidizing adipocytes and preadipocytes are active leptin producers when stimulated by TNF-alpha, IL-6/sIL-6R, and IL-1beta. 相似文献