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Cell Transplantation (cell + transplantation)
Kinds of Cell Transplantation Selected AbstractsNeoHepatocytes From Alcoholics and Controls Express Hepatocyte Markers and Display Reduced Fibrogenic TGF-,/Smad3 Signaling: Advantage for Cell Transplantation?ALCOHOLISM, Issue 4 2010Sabrina Ehnert Background:, Liver transplantation is the only definitive treatment for end stage liver disease. Donor organ scarcity raises a growing interest in new therapeutic options. Recently, we have shown that injection of monocyte-derived NeoHepatocytes can increase survival in rats with extended liver resection. In order to apply this technology in humans with chronic liver diseases in an autologous setting, we generated NeoHepatocytes from patients with alcoholic liver disease and healthy controls and compared those to human hepatocytes. Methods:, We generated NeoHepatocytes from alcoholics with Child A and B cirrhosis and healthy controls. Hepatocytes marker expression and transforming growth factor (TGF)-, signaling was investigated by RT-PCR, Western blot, immunofluorescent staining, and adenoviral reporter assays. Glucose and urea was measured photometrically. Phase I and II enzyme activities were measured using fluorogenic substrates. Neutral lipids were visualized by Oil Red O staining. Results:, There was no significant difference in generation and yield of NeoHepatocytes from alcoholics and controls. Hepatocyte markers, e.g., cytokeratin18 and alcohol dehydrogenase 1, increased significantly throughout differentiation. Glucose and urea production did not differ between alcoholics and controls and was comparable to human hepatocytes. During differentiation, phase I and II enzyme activities increased, however remained significantly lower than in human hepatocytes. Fat accumulation was induced by treatment with insulin, TGF-, and ethanol only in differentiated cells and hepatocytes. TGF-, signaling, via Smad transcription factors, critically required for progression of chronic liver disease, was comparable among the investigated cell types, merely expression of Smad1 and -3 was reduced (,30 and ,60%) in monocytes, programmable cells of monocytic origin, and NeoHepatocytes. Subsequently, expression of TGF-, regulated pro-fibrogenic genes, e.g., connective tissue growth factor and fibronectin was reduced. Conclusions:, Generation of NeoHepatocytes from alcoholics, displaying several features of human hepatocytes, offers new perspectives for cell therapeutic approaches, as cells can be obtained repeatedly in a noninvasive manner. Furthermore, the autologous setting reduces the need for immunosuppressants, which may support recovery of patients which are declined for liver transplantation. [source] Principles of Peripheral Blood Mononuclear Cell Apheresis in a Preclinical Canine Model of Hematopoietic Cell TransplantationJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2008M. Lupu Background: Preclinical studies of peripheral blood mononuclear cell (PBMC) transplantation conducted in a well-established canine hematopoietic cell transplantation (HCT) model have been successfully translated to human patients over the past 5 decades. Objective: We retrospectively investigated the safety and feasibility of PBMC apheresis in the canine model of HCT by analyzing apheresis parameters, cell yields, and the impacts of donor-related and apheresis-related variables on collection yields and donor stability. Animals: One hundred and twenty dogs that underwent PBMC aphereses were evaluated. Methods: Aphereses were performed with a COBE Spectra blood separator and a central dual-lumen catheter, with or without recombinant canine granulocyte colony-stimulating factor (rcG-CSF) stem cell mobilization. Results: Aphereses from dogs not given rcG-CSF yielded an average volume of 280 ± 42 mL containing an average of 15,086 ± 9,834 leukocytes/mL. Aphereses from dogs given rcG-CSF yielded an average volume of 261 ± 55 mL containing an average of 39,711 ± 24,488 leukocytes/mL. Higher pre-apheresis white blood cell (WBC) counts correlated with higher apheresis WBC yields (R=0.50, P<.0001). The correlations of collection time, inlet volume, and collection flow rate on WBC yields were statistically significant but only weak to moderate in magnitude (R=0.34, P=.0001; R=0.38, P=.0006; R=0.26, P=.002, respectively) as were the correlations of collection time and inlet volume on collection volumes (R=0.30, P=.002; R=0.42, P<.0001, respectively). All dogs recovered promptly after PBMC aphereses and catheter removal, without complications. Conclusions and Clinical Importance: These data may be useful for translating PBMC apheresis technology to the field of veterinary oncology for the treatment of dogs with hematologic malignancies. [source] Experience with a Novel Efalizumab-Based Immunosuppressive Regimen to Facilitate Single Donor Islet Cell TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010N. A. Turgeon Islet transplantation is an experimental therapy for selected patients with type 1 diabetes (T1DM). It remains limited by immunosuppressive drug toxicity, progressive loss of insulin independence, allosensitization and the need for multiple islet donors. We describe our experience with an efalizumab-based immunosuppressive regimen as compared to the prevailing standard regimen, the Edmonton protocol. Twelve patients with T1DM received islet transplants: eight were treated with the Edmonton protocol; four were treated with daclizumab induction, a 6-month course of tacrolimus, and maintenance with efalizumab and mycophenolate mofetil. The primary endpoint was insulin independence after one islet infusion. Only two Edmonton protocol treated patients achieved the primary endpoint; six required islets from multiple donors, and all experienced leukopenia, mouth ulcers, anemia, diarrhea and hypertransaminasemia. Four became allosensitized. All patients treated with the efalizumab-based regimen achieved insulin independence with normal hemoglobin A1c after a single islet cell infusion and remained insulin independent while on efalizumab. These patients experienced significantly fewer side effects and none became allosensitized. Trial continuation was terminated by withdrawal of efalizumab from the market. These data suggest that this efalizumab-based regimen prevents islet rejection, is well tolerated, and allows for single donor islet transplantation. [source] Solid Organ Transplantation After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective, Multicenter Study of the EBMTAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010C. Koenecke To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984 and 2007 in Europe. Forty-five SOT in 40 patients were reported. Fifteen liver, 15 renal, 13 lung, 1 heart and 1 skin transplantations were performed in 28 centers. Overall survival (OS) of patients after SOT was 78% at 5 years (95% confidence interval [CI], 64% to 92%). OS at 5 years was 100% for renal, 71% (95% CI, 46% to 96%) for liver and 63% (95% CI, 23% to 100%) for lung transplant recipients. The 2-year-incidence of SOT failure was 20% (95% CI, 4% to 36%) in patients with graft-versus-host disease (GvHD) and 7% (95% CI, 0% to 21%) in patients without GvHD before SOT. The relapse incidence for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT. [source] Allograft-Specific Cytokine Profiles Associate with Clinical Outcome After Islet Cell TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009V. A. L. Huurman Islet cell transplantation can cure type 1 diabetes, but allograft rejection and recurrent autoimmunity may contribute to decreasing insulin independence over time. In this study we report the association of allograft-specific proliferative and cytokine profiles with clinical outcome. Peripheral blood mononuclear cells were obtained of 20 islet recipients. Cytokine values in mixed lymphocyte cultures (MLC) were determined using stimulator cells with graft-specific HLA class II. Qualitative and quantitative cytokine profiles were determined before and after islet transplantation, blinded from clinical outcome. Cytotoxic T Lymphocyte precursor (CTLp) assays were performed to determine HLA class I alloreactivity. Allograft-specific cytokine profiles were skewed toward a Th2 or regulatory (Treg) phenotype after transplantation in insulin-independent, but not in insulin-requiring recipients. IFN,/IL10 ratio and MLC proliferation decreased after transplantation in insulin-independent recipients (p = 0.006 and p = 0.01, respectively). Production of the Treg cytokine IL10 inversely correlated with proliferation in alloreactive MLC (p = 0.008) and CTLp (p = 0.005). Production of IL10 combined with low-MLC reactivity associated significantly with insulin independence. The significant correlation between allograft-specific cytokine profiles and clinical outcome may reflect the induction of immune regulation in successfully transplanted recipients. Islet donor-specific IL10 production correlates with low alloreactivity and superior islet function. [source] Chronic Kidney Disease Following Non-Myeloablative Hematopoietic Cell TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2006A. S. Weiss Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3,250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors. [source] Effectiveness of Prophylactic Anti-HBV Therapy in Allogeneic Hematopoietic Stem Cell Transplantation with HBsAg Positive DonorsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005Chee-kin Hui Use of hepatitis B surface antigen (HBsAg) positive donors for allogeneic hematopoietic stem cell transplantation (HSCT) causes serious hepatitis B virus (HBV)-related liver morbidity and mortality in the recipient. We compared the effectiveness of anti-HBV therapy in 29 recipients who underwent HSCT using HBsAg positive marrow (group I) against a historical control group of 25 patients who received HBsAg positive marrow without pre-HSCT prophylaxis (group II). Anti-HBV therapy consisted of lamivudine for HBsAg-positive donors and all recipients (n = 29) as well as HBV vaccination to all HBsAg-negative recipients (n = 10) before HSCT. After transplantation, HBV-related hepatitis was significantly higher in group II than group I recipients [12 of 25 recipients (48%) vs. 2 of 29 recipients (6.9%), p = 0.002] and in recipients whose donors had detectable serum HBV DNA by Digene Hybrid Capture II assay [8 of 14 recipients (57.1%) vs. 6 of 40 recipients (15.0%), p = 0.02]. Six recipients in group II and none in group I died of HBV-related hepatic failure (24.0% vs. 0%, p = 0.01). By multivariate Cox analysis, anti-HBV therapy effectively reduces post-HSCT HBV-related hepatitis (p = 0.01, adjusted hazards ratio 7.27, 95%CI 1.62,32.58). Our data support the use of prophylactic therapy in preventing HBV-related hepatitis after allogeneic HSCT from HBsAg-positive donor. [source] Can the life span of human marrow stromal cells be prolonged by bmi-1, E6, E7, and/or telomerase without affecting cardiomyogenic differentiation?THE JOURNAL OF GENE MEDICINE, Issue 8 2004Yukiji Takeda Abstract Background Cell transplantation has recently been challenged to improve cardiac function of severe heart failure. Human mesenchymal stem cells (hMSCs) are multipotent cells that can be isolated from adult marrow stroma, but because of their limited life span, it is difficult to study them further. To overcome this problem, we attempted to prolong the life span of hMSCs and investigate whether the hMSCs modified with cell-cycle-associated genes can differentiate into cardiomyocytes in vitro. Methods We attempted to prolong the life span of hMSCs by infecting retrovirus encoding bmi-1, human papillomavirus E6 and E7, and/or human telomerase reverse transcriptase genes. To determine whether the hMSCs with an extended life span could differentiate into cardiomyocytes, 5-azacytidine-treated hMSCs were co-cultured with fetal cardiomyocytes in vitro. Result The established hMSCs proliferated over 150 population doublings. On day 3 of co-cultivation, the hMSCs became elongated, like myotubes, began spontaneously beating, and acquired automaticity. Their rhythm clearly differed from that of the surrounding fetal mouse cardiomyocytes. The number of beating cardiomyocytes increased until 3 weeks. hMSCs clearly exhibited differentiated cardiomyocyte phenotypes in vitro as revealed by immunocytochemistry, RT-PCR, and action potential recording. Conclusions The life span of hMSCs was prolonged without interfering with cardiomyogenic differentiation. hMSCs with an extended life span can be used to produce a good experimental model of cardiac cell transplantation and may serve as a highly useful cell source for cardiomyocytic transplantation. Copyright © 2004 John Wiley & Sons, Ltd. [source] Long-Term Evaluation of Myoblast Seeded Patches Implanted on Infarcted Rat HeartsARTIFICIAL ORGANS, Issue 6 2010Marie-Noëlle Giraud Abstract Cell transplantation presents great potential for treatment of patients with severe heart failure. However, its clinical application was revealed to be more challenging than initially expected in experimental studies. Further investigations need to be undertaken to define the optimal treatment conditions. We previously reported on the epicardial implantation of a bio-engineered construct of skeletal myoblast-seeded polyurethane and its preventive effect on progression toward heart failure. In the present study, we present a long-term evaluation of this functional outcome. Left anterior descending coronary ligation was performed in female Lewis rats. Two weeks later, animals were treated with either epicardial implantation of biograft, acellular scaffold, sham operation, or direct intramyocardial skeletal myoblast injection. Functional assessments were performed with serial echocardiographies every 3 months and end point left ventricle pressure was assessed. Hearts were then harvested for histological examinations. Myocardial infarction induced a slow and progressive reduction in fractional shortening after 3 months. Progression toward heart failure was significantly prevented for up to 6 months after injection of myoblasts and for up to 9 months following biograft implantation. Nevertheless, this effect vanished after 12 months, with immunohistological examinations revealing an absence of the transplanted myoblasts within the scaffold. We demonstrated that tissue therapy is superior to cell therapy for stabilization of heart function. However, beneficial effects are transient. [source] Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardiumCATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS, Issue 3 2005Demosthenes G. Katritsis MD PhD Abstract The aim of the study was to investigate whether a combination of mesenchymal stem cells (MSCs) capable of differentiating into cardiac myocytes and endothelial progenitors (EPCs) that mainly promote neoangiogenesis might be able to facilitate tissue repair in myocardial scars. Previous studies have shown that intracoronary transplantation of autologous bone marrow stem cells results in improvement of contractility in infracted areas of human myocardium. Eleven patients with an anteroseptal myocardial infarction (MI) underwent transcoronary transplantation of bone marrow-derived MSCs and EPCs to the infarcted area through the left anterior descending artery. Eleven age- and sex-matched patients served as controls. Wall motion score index was significantly lower at follow-up in the transplantation (P = 0.04) but not in the control group. On stress echocardiography, there was improvement of myocardial contractility in one or more previously nonviable myocardial segments in 5 out of 11 patients (all with recent infarctions) and in none of the controls (P = 0.01). Restoration of uptake of Tc99m sestamibi in one or more previously nonviable myocardial scars was seen in 6 out of 11 patients subjected to transplantation and in none of the controls (P = 0.02). Cell transplantation was an independent predictor of improvement of nonviable tissue. Intracoronary transplantation of MSCs and EPCs is feasible, safe, and may contribute to regional regeneration of myocardial tissue early or late following MI. © 2005 Wiley-Liss, Inc. [source] Cell transplantation with a catheter-based approach: an efficient method for the treatment of heart failure with multiple lesionsCELL PROLIFERATION, Issue 6 2006M. Chen At present, popular methods of cell delivery may not be efficient in perfusing cells through the whole myocardium. We have developed a novel catheter-based method for global transplantation of cells. Heart failure was induced in rabbit by intravenous administration of doxorubicin. Autologous bone marrow mononuclear cells were transplanted into failing hearts via the root of the aorta. Bilateral sinus aortae and coronary arteries were visualized by angiography during the cell transplantation procedure; there was no intraprocedural death. Four weeks after cell transplantation, there was an improvement in the mean left ventricular ejection fraction from baseline 72.13% to 81.54% (P = 0.034). Transplanted cells were observed throughout the cardiac layers of left and right ventricles. In conclusion, cell transplantation through the root of the aorta is a useful approach to globally supply cells into the heart. [source] Transient recovery of endogenous immune function following haploidentical peripheral stem cell transplantation in a patient with severe combined immunodeficiency without evidence of engraftmentACTA PAEDIATRICA, Issue 2 2000J Levy No abstract is available for this article. [source] Thalidomide for the treatment of multiple myelomaCONGENITAL ANOMALIES, Issue 3 2004Yutaka Hattori ABSTRACT Although thalidomide was withdrawn in the 1960s after its teratogenic property was recognized, it was subsequently found that this drug possesses immunomodulatory and anti-inflammatory effects. Recent studies have also demonstrated that thalidomide has antineoplastic activity via an antiangiogenic mechanism. Observations in the late 1990s that the microenvironment in the bone marrow plays a role in tumor progression in multiple myeloma provided an impetus to use thalidomide for the treatment of this disease. It is known that thalidomide monotherapy is effective in one-third of refractory cases, and in combination with glucocorticoids and/or antineoplastic drugs, thalidomide provides a response rate of more than 50%. Thus, thalidomide therapy is considered a standard approach for the treatment of relapsed and refractory myeloma. The exact mechanism of the antimyeloma effect of thalidomide is not yet clearly understood. Anti-angiogenic effects, direct activity in tumor cells such as the induction of apoptosis or G1 arrest of the cell cycle, the inhibition of growth factor production, the regulation of interactions between tumor and stromal cells, and the modulation of tumor immunity have been considered as possible mechanisms. In addition to its teratogenicity, the adverse effects of thalidomide have been general symptoms such as somnolence and headache, peripheral neuropathy, constipation, skin rash, and other symptoms. Although these adverse effects are generally reversible and mild, grade 3 and 4 toxicities such as peripheral neuropathy, deep venous thrombosis, neutropenia, and toxic dermal necrosis have occasionally been reported. The application of thalidomide therapy in patients with multiple myeloma is being broadened to include not only cases of refractory myeloma, but also previously untreated cases, as well as for maintenance therapy after hematopoietic stem cell transplantation and for the treatment of other hematological diseases. The safe use of this drug will depend on the establishment of diagnostic and treatment guidelines. In addition, the establishment of a nation-wide regulation system is urgently needed in Japan. [source] Monitoring cytomegalovirus IE-1 and pp65-specific CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations ,CYTOMETRY, Issue 4 2008Jan W. Gratama Abstract We studied the recovery of CMV-specific CD4+ and CD8+ T-cell immunity in 52 recipients of allogeneic stem cell transplantation (SCT). The proportions of IFN-,-producing CD4+ and CD8+ T cells upon in vitro activation using peptide pools representing the CMV pp65 and IE-1 proteins were assessed at multiple time points post SCT, and correlated with the occurrence of CMV reactivation. In a retrospective analysis, recurrent CMV reactivations occurred in 9 patients and were associated with low pp65-specific CD4+ T-cell and low IE-1-specific CD8+ T-cell reactivities, whereas patients without detectable CMV reactivation (n = 30) or a single reactivation (n = 13) showed a better recovery of these immune responses. CD4+ T-cell responses to IE-1 were infrequent in most patients, whereas CD8+ T-cell responses to pp65 occurred frequently, but did not correlate with protection against (recurrent) reactivation. Prospectively, CMV-specific T-cell responses could be studied prior to 14 reactivation episodes in 8 patients. CD4+ T-cell responses to IE-1 and pp65 were positive in only 1 and 2 episodes, respectively. CD8+ T-cell responses against IE-1 were positive in 4, but against pp65 in 12 episodes, again showing that CD8+ T-cell reactivity against pp65 did not prevent CMV reactivation. Thus, monitoring of particular CMV-specific CD4+ and CD8+ T-cell responses after allogeneic SCT may identify patients at risk for recurrent CMV reactivations. © 2008 Clinical Cytometry Society [source] Reticulated platelet counts correlate with treatment response in patients with idiopathic thrombocytopenic purpura and help identify the complex causes of thrombocytopenia in patients after allogeneic hematopoietic stem cell transplantationCYTOMETRY, Issue 4 2007Anna-Katharina Thomas-Kaskel Abstract Background: In thrombocytopenic conditions of unknown origin, quantification of reticulated platelets (RP) in the peripheral blood by flow cytometry has been shown to differentiate increased platelet (Plt) turnover from insufficient Plt production. Methods: We used a whole blood flow cytometry method combining thiazole orange and anti-CD41a-staining to assess RP in 71 healthy subjects, six with thrombocytopenic myelodysplastic syndrome (MDS), nine with liver cirrhosis, 14 patients with idiopathic thrombocytopenic purpura (ITP), and 12 patients who had undergone hematopoietic stem cell transplantation (HSCT). Results: Patients with MDS had normal, patients with liver cirrhosis had slightly elevated RP counts compared to healthy subjects. ITP patients had elevated RP counts, and RP >15% were associated with treatment response (P = 0.015). In 7/10 patients after HSCT, an increase of RP preceded Plt recovery, whereas in patients with secondary thrombocytopenia after normal regeneration, the assessment of RP allowed the differentiation between conditions with high Plt turnover, such as GvHD and microangiopathy, indicated by high RP counts, and graft failure, indicated by low RP counts. Conclusions: Our data provide the rationale for prospective studies on the diagnostic and prognostic value of RP counts in larger patient populations with ITP and after HSCT. © 2007 Clinical Cytometry Society [source] Stretching the limits: Stem cells in regeneration scienceDEVELOPMENTAL DYNAMICS, Issue 12 2008David L. Stocum Abstract The focus of regenerative medicine is rebuilding damaged tissues by cell transplantation or implantation of bioartificial tissues. In either case, therapies focus on adult stem cells (ASCs) and embryonic stem cells (ESCs) as cell sources. Here we review four topics based on these two cell sources. The first compares the current performance of ASCs and ESCs as cell transplant therapies and the drawbacks of each. The second explores somatic cell nuclear transfer (SCNT) as a method to derive ESCs that will not be immunorejected. The third topic explores how SCNT and ESC research has led to the ability to derive pluripotent ESCs by the dedifferentiation of adult somatic cells. Lastly, we discuss how research on activation of intrinsic adult stem cells and on somatic cell dedifferentiation can evolve regenerative medicine from a platform consisting of cell transplantation to one that includes the chemical induction of regeneration from the body's own cells at the site of injury. Developmental Dynamics 237:3648,3671, 2008. © 2008 Wiley-Liss, Inc. [source] Prevalence of autoimmune diseases in islet transplant candidates with severe hypoglycaemia and glycaemic lability: previously undiagnosed coeliac and autoimmune thyroid disease is identified by screeningDIABETIC MEDICINE, Issue 2 2007M. Walter Abstract Aims, Autoimmune diseases such as Addison's or coeliac disease can contribute to hypoglycaemia or malabsorption and are more common in Type 1 diabetes (T1DM). This brief report describes the prevalence of known and newly detected autoimmune disease in clinical islet transplant candidates with longstanding T1DM and severe hypoglycaemia and/or glycaemic lability who are routinely screened for coexisting autoimmune disease. Methods, One hundred and twenty-four C-peptide negative T1DM subjects [77 (62%) female, mean age 44 ± 9 years, diabetes duration 28 ± 11 years, body mass index 24.9 ± 3.5 kg/m2] with indications for clinical islet transplantation at the University of Alberta were screened for autoimmune disease by history and measurement of anti-transglutaminase antibodies (positive > 10 U/ml), 09.00 h cortisol (followed by adrenocorticotrophic hormone-stimulation if < 495 nmol/l) and thyroid-stimulating hormone to determine the prevalence of coeliac disease, Addison's disease and autoimmune thyroid disease, respectively. Results, Forty per cent of subjects had one or more coexisting autoimmune disease. The prevalence of autoimmune disease was 35%, coeliac disease 8% and Addison's disease 1.6%. In 11 individuals (9%), one or more autoimmune disease were newly detected (seven coeliac disease and five thyroid disease). Seven of 10 cases of coeliac disease were newly detected. A gluten-free diet in individuals with newly diagnosed coeliac disease reduced gastrointestinal symptoms, but indications for clinical islet cell transplantation persisted. Conclusions, Coexisting autoimmune disease is common in candidates for clinical islet cell transplantation. Screening in this group identified a substantial number of previously unrecognized cases. Clinicians should consider the presence of autoimmune disease even in the absence of classical symptoms. [source] Animal models of diabetes mellitusDIABETIC MEDICINE, Issue 4 2005D. A. Rees Abstract Animal models have been used extensively in diabetes research. Early studies used pancreatectomised dogs to confirm the central role of the pancreas in glucose homeostasis, culminating in the discovery and purification of insulin. Today, animal experimentation is contentious and subject to legal and ethical restrictions that vary throughout the world. Most experiments are carried out on rodents, although some studies are still performed on larger animals. Several toxins, including streptozotocin and alloxan, induce hyperglycaemia in rats and mice. Selective inbreeding has produced several strains of animal that are considered reasonable models of Type 1 diabetes, Type 2 diabetes and related phenotypes such as obesity and insulin resistance. Apart from their use in studying the pathogenesis of the disease and its complications, all new treatments for diabetes, including islet cell transplantation and preventative strategies, are initially investigated in animals. In recent years, molecular biological techniques have produced a large number of new animal models for the study of diabetes, including knock-in, generalized knock-out and tissue-specific knockout mice. [source] Human islet cell transplantation , future prospectsDIABETIC MEDICINE, Issue 2 2001S. A. White Summary Background Islet transplantation has the potential to cure diabetes mellitus. Nevertheless despite successful reversal of diabetes in many small animal models, the clinical situation has been far more challenging. The aim of this review is to discuss why insulin-independence after islet allotransplantation has been so difficult to achieve. Methods A literature review was undertaken using Medline from 1975 to July 2000. Results reported to the International Islet Transplant Registry (ITR) up to December 1998 were also analysed. Results Up to December 1998, 405 islet allotransplants have been reported the ITR. Of those accurately documented between 1990 and 1998 (n = 267) only 12% have achieved insulin-independence (greater than 7 days). However with refined peri-transplant protocols insulin indepedence at 1 year can reach 20%. Conclusions There are many factors which can explain the failure of achieving insulin-independence after islet allotransplantation. These include the use of diabetogenic immunosuppressive agents to abrogate both islet allo-immunity and auto-immunity, the critical islet mass to achieve insulin-independence and the detrimental effects of transplanting islets in an ectopic site. However recent evidence most notably from the Edmonton group demonstrates that islet allotransplantation still has great potential to become an established treatment option for diabetic patients. [source] Interstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignanciesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 6 2010Benigno C. Valdez Abstract Despite successful molecularly targeted, highly specific, therapies for hematologic malignancies, the DNA interstrand crosslinking agents, which are among the oldest and least specific cytotoxic drugs, still have an important role. This is particularly true in stem cell transplantation, where virtually every patient receives conditioning therapy with a DNA-alkylating agent-based program. However, due to concern about serious additive toxicities with combinations of different alkylating drugs, the last several years have seen nucleoside analogs, whose cytotoxic action follows vastly different molecular pathways, introduced in combination with alkylating agents. The mechanistic differences paired with different metabolic pathways for the respective drugs have clinically translated into increased safety without appreciable loss of antileukemic activity. In this report, we review pre-clinical evidence for synergistic antileukemic activity when nucleoside analog(s) and DNA-alkylating agent(s) are combined in the most appropriate manner(s), without a measurable decrease in clinical efficacy compared with the more established alkylating agent combinations. Data from our own laboratory using combinations of fludarabine, clofarabine, and busulfan as prototype representatives for these respective classes of cytotoxic agents are combined with information from other investigators to explain how the observed molecular events will result in greatly enhanced synergistic cytotoxicity. We further present possible mechanistic pathways for such desirable cytotoxic synergism. Finally, we propose how this information-backed hypothesis can be incorporated in the design of the next generation conditioning therapy programs in stem cell transplantation to optimize antileukemic efficacy while still safeguarding patient safety. Environ. Mol. Mutagen., 2010. © 2010 Wiley-Liss, Inc. [source] Gene therapy in epilepsyEPILEPSIA, Issue 1 2009Véronique Riban Summary Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile. Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies. [source] Health psychology and distress after haematopoietic stem cell transplantationEUROPEAN JOURNAL OF CANCER CARE, Issue 1 2009V. DeMARINIS phd The purpose of this study of 23 adult haematopoietic stem cell transplantation (HSCT) recipients is to compare the presence of post-transplantation depression disorders by gender and to compare the outcomes among those with and without depressive disorders using a health psychology focus. This cross-sectional pilot study of mid-term survivors took place in hospital outpatient clinic. Main outcome measures are depression disorders, health status (Short Form-12) and health anxiety. Female survivors had a higher rate of depression disorders, but those with treated depressive disorders were similar to those without depression on health-related quality of life and health anxiety. Neither patient age nor time since HSCT was associated with depressive disorders. A health psychology approach may enhance management of HSCT survivorship. [source] Patients' health beliefs and coping prior to autologous peripheral stem cell transplantationEUROPEAN JOURNAL OF CANCER CARE, Issue 2 2007E. FRICK md The aim of this study was to determine the associations between health locus of control (LoC), causal attributions and coping in tumour patients prior to autologous peripheral blood stem cell transplantation. Patients completed the Questionnaire of Health Related Control Expectancies, the Questionnaire of Personal Illness Causes (QPIC), and the Freiburg Questionnaire of Coping with Illness. A total of 126 patients (45% women; 54% suffering from a multiple myeloma, 29% from non-Hodgkin lymphomas, and 17% from other malignancies) participated in the study. Cluster analysis yielded four LoC clusters: ,fatalistic external', ,powerful others', ,yeah-sayer' and ,double external'. Self-blaming QPIC items were positively correlated with depressive coping, and ,fate or destiny' attributions with religious coping (P < 0.001). The highest scores were found for ,active coping' in the LoC clusters ,powerful others' and ,yeah-sayer'. External LoC and an active coping style prevail before undergoing autologous peripheral blood stem cell transplantation, whereas the depressive coping is less frequent, associated with self-blaming causal attributions. Health beliefs include causal and control attributions, which can improve or impair the patient's adjustment. A mixture between internal and external attributions seems to be most adaptive. [source] Health-related quality of life, symptom distress and sense of coherence in adult survivors of allogeneic stem-cell transplantationEUROPEAN JOURNAL OF CANCER CARE, Issue 2 2001L. Edman This is the first Swedish study to evaluate the health-related quality of life and sense of coherence in adult survivors of allogeneic, haematopoietic stem cell transplantation (HSCT). Twenty-five recipients completed three questionnaires 2,4 years after the transplantation. The questionnaires used were the Sickness Impact Profile (SIP), the Symptom Frequency Intensity and Distress (SFID-BMT) scale and the Sense of Coherence (SOC) scale measuring subjective functional status, symptom distress and coping ability. Impairments in functional status were found, as compared with a population norm. The most common impairments were found in the areas of social interaction and sleep and rest. Eye problems, dry mouth, cough, sexual problems, tiredness, anxiety and changes of taste were symptoms reported by more than half of the patients. Despite impaired functioning and a high incidence of symptoms, the general health was described as quite good or excellent by 80% (n = 20) of the patients. The majority (20/22) had also been able to return to work or to attend school. No difference in the sense of coherence was seen, as compared with the population norm. Functional impairments were significantly correlated to a lower degree of sense of coherence. [source] Cardiac regeneration by progenitor cells , bedside before bench?EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2005J. Bauersachs Abstract Recent experimental and clinical trials give rise to the hope that progenitor cells could replace scar tissue after myocardial infarction with healthy functional myocardium. However, while a significant increase in left ventricular ejection fraction has been described after progenitor cell transplantation in several clinical trials, long-term results are lacking, and the mechanisms underlying the improvement of ejection fraction are unclear. Therefore, the efficacy of progenitor cell transplantation after myocardial infarction has not been established, and potential problems may have been underestimated. In-depth laboratory and animal studies are needed to determine the best cell type, optimal amount of cells, and time point for transplantation. Treatment of patients with progenitor cells outside well controlled prospective trials should be avoided. [source] First-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitroEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Thomas Lund Abstract Objectives:, The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in bisphosphonate-naïve, previously untreated patients with myeloma. Methods:, Twenty newly diagnosed patients received four cycles of bortezomib treatment, initially as monotherapy and then combined with a glucocorticoid from cycle two to four. Bone remodeling markers were monitored closely during treatment. Furthermore, the effects of bortezomib and a glucocorticoid on immature and mature osteoblasts were also studied in vitro. Results:, Treatment with bortezomib caused a significant increase in bone-specific alkaline phosphatase and pro-collagen type I N-terminal propeptide, a novel bone formation marker. The addition of a glucocorticoid resulted in a transient decrease in collagen deposition. In vitro bortezomib induced osteoblast proliferation and differentiation. Differentiation but not proliferation was inhibited by glucocorticoid treatment. Conclusions:, Bortezomib used as first-line treatment significantly increased collagen deposition in patients with multiple myeloma and osteolytic lesions, but the addition of a glucocorticoid to the treatment transiently inhibited the positive effect of bortezomib, suggesting that bortezomib may result in better healing of osteolytic lesions when used without glucocorticoids in patients that have obtained remission with a previous therapy. The potential bone-healing properties of single-agent bortezomib are currently being explored in a clinical study in patients who have undergone high-dose therapy and autologous stem cell transplantation. [source] Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Fortunato Morabito Abstract The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression-free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front-line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review. [source] Epigenetic therapy in myelodysplastic syndromesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2010Caterina Musolino Abstract The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies , with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life-threatening infections, bleeding, and progression to acute myeloid leukemia (AML) , that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so-called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting. [source] ThaDD plus high dose therapy and autologous stem cell transplantation does not appear superior to ThaDD plus maintenance in elderly patients with de novo multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2010Massimo Offidani Abstract Objectives:,With the aim to address the issue whether high-dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT-autologous stem cell transplantation (ASCT). Methods: Sixty-two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100,200 mg/m2 and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group. Results and conclusions:,Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT-ASCT (P = 0.0232). However, after a median follow-up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five-year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3,4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients. [source] Voriconazole as primary antifungal prophylaxis in patients with neutropenia after hematopoietic stem cell transplantation or chemotherapy for acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Antonio Torres No abstract is available for this article. [source] | ||||||||||||||||||||||||||||||||||