Showing papers on "Transplantation published in 2004"

The Regulation of Labor

Abstract: Author(s): Botero, Juan; Djankov, Simeon; La Porta, Rafael; Lopez-de-Silanes, Florencio; Shleifer, Andrei | Abstract: We investigate the regulation of labor markets through employment, collective relations, and social security laws in 85 countries. We find that the political power of the left is associated with more stringent labor regulations and more generous social security systems, and that socialist, French and Scandinavian legal origin countries have sharply higher levels of labor regulation than do common law countries. However, the effects of legal origins are larger, and explain more of the variation in regulations, than those of politics. Heavier regulation of labor is associated with lower labor force participation and higher unemployment, especially of the young. These results are most naturally consistent with legal theories, according to which countries have pervasive regulaory styles inherited from the transplantation of legal systems.

Iron oxide MR contrast agents for molecular and cellular imaging.

Abstract: Molecular and cellular MR imaging is a rapidly growing field that aims to visualize targeted macromolecules or cells in living organisms. In order to provide a different signal intensity of the target, gadolinium-based MR contrast agents can be employed although they suffer from an inherent high threshold of detectability. Superparamagnetic iron oxide (SPIO) particles can be detected at micromolar concentrations of iron, and offer sufficient sensitivity for T2(*)-weighted imaging. Over the past two decades, biocompatible particles have been linked to specific ligands for molecular imaging. However, due to their relatively large size and clearance by the reticuloendothelial system (RES), widespread biomedical molecular applications have yet to be implemented and few studies have been reproduced between different laboratories. SPIO-based cellular imaging, on the other hand, has now become an established technique to label and detect the cells of interest. Imaging of macrophage activity was the initial and still is the most significant application, in particular for tumor staging of the liver and lymph nodes, with several products either approved or in clinical trials. The ability to now also label non-phagocytic cells in culture using derivatized particles, followed by transplantation or transfusion in living organisms, has led to an active research interest to monitor the cellular biodistribution in vivo including cell migration and trafficking. While most of these studies to date have been mere of the ‘proof-of-principle’ type, further exploitation of this technique will be aimed at obtaining a deeper insight into the dynamics of in vivo cell biology, including lymphocyte trafficking, and at monitoring therapies that are based on the use of stem cells and progenitors. Copyright © 2004 John Wiley & Sons, Ltd.

Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium.

Abstract: Background Ocular trauma or disease may lead to severe corneal opacification and, consequently, severe loss of vision as a result of complete loss of corneal epithelial stem cells. Transplantation of autologous corneal stem-cell sources is an alternative to allograft transplantation and does not require immunosuppression, but it is not possible in many cases in which bilateral disease produces total corneal stem-cell deficiency in both eyes. We studied the use of autologous oral mucosal epithelial cells as a source of cells for the reconstruction of the corneal surface. Methods We harvested 3-by-3-mm specimens of oral mucosal tissue from four patients with bilateral total corneal stem-cell deficiencies. Tissue-engineered epithelial-cell sheets were fabricated ex vivo by culturing harvested cells for two weeks on temperature-responsive cell-culture surfaces with 3T3 feeder cells that had been treated with mitomycin C. After conjunctival fibrovascular tissue had been surgically removed from the ocular surfa...

Immunosuppressive Drugs for Kidney Transplantation

Abstract: Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction.

Abstract: Sixty-nine patients who underwent primary percutaneous coronary intervention within 12 hours after onset of acute myocardial infarction were randomized to receive intracoronary injection of autologous bone marrow mesenchymal stem cell or standard saline. Several imagining techniques demonstrated that bone marrow mesenchymal stem cells significantly improved left ventricular function.

Transplants of Umbilical-Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia

Abstract: results Recipients of cord blood were younger than recipients of bone marrow (median, 24.5 vs. 32 years of age; P<0.001), weighed less (median, 58 vs. 68 kg; P<0.001), and had more advanced disease at the time of transplantation (52 percent vs. 33 percent, P<0.001). All marrow transplants were HLA matched, whereas 94 percent of cord-blood grafts were HLA mismatched (P<0.001). The median number of nucleated cells that were infused was 0.23¬10 8 per kilogram of the recipient’s body weight for cord blood and 2.9¬10 8 per kilogram for bone marrow (P<0.001). Multivariate analysis showed lower risks of grade II, III, or IV acute graft-versus-host disease (GVHD) after cord-blood transplantation (relative risk, 0.57; 95 percent confidence interval, 0.37 to 0.87; P=0.01), but neutrophil recovery was significantly delayed (relative risk, 0.49; 95 percent confidence interval, 0.41 to 0.58; P<0.001). The incidence of chronic GVHD, transplantation-related mortality, relapse rate, and leukemia-free survival were not significantly different in the two groups. conclusions Cord blood from an unrelated donor is an alternative source of hematopoietic stem cells for adults with acute leukemia who lack an HLA-matched bone marrow donor.

A New Human Somatic Stem Cell from Placental Cord Blood with Intrinsic Pluripotent Differentiation Potential

Abstract: Here a new, intrinsically pluripotent, CD45-negative population from human cord blood, termed unrestricted somatic stem cells (USSCs) is described. This rare population grows adherently and can be expanded to 1015 cells without losing pluripotency. In vitro USSCs showed homogeneous differentiation into osteoblasts, chondroblasts, adipocytes, and hematopoietic and neural cells including astrocytes and neurons that express neurofilament, sodium channel protein, and various neurotransmitter phenotypes. Stereotactic implantation of USSCs into intact adult rat brain revealed that human Tau-positive cells persisted for up to 3 mo and showed migratory activity and a typical neuron-like morphology. In vivo differentiation of USSCs along mesodermal and endodermal pathways was demonstrated in animal models. Bony reconstitution was observed after transplantation of USSC-loaded calcium phosphate cylinders in nude rat femurs. Chondrogenesis occurred after transplanting cell-loaded gelfoam sponges into nude mice. Transplantation of USSCs in a noninjury model, the preimmune fetal sheep, resulted in up to 5% human hematopoietic engraftment. More than 20% albumin-producing human parenchymal hepatic cells with absence of cell fusion and substantial numbers of human cardiomyocytes in both atria and ventricles of the sheep heart were detected many months after USSC transplantation. No tumor formation was observed in any of these animals.

Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells

Abstract: We have observed karyotypic changes involving the gain of chromosome 17q in three independent human embryonic stem (hES) cell lines on five independent occasions. A gain of chromosome 12 was seen occasionally. This implies that increased dosage of chromosome 17q and 12 gene(s) provides a selective advantage for the propagation of undifferentiated hES cells. These observations are instructive for the future application of hES cells in transplantation therapies in which the use of aneuploid cells could be detrimental.

Stem cell therapy for human neurodegenerative disorders-how to make it work.

Abstract: Recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. These findings raise hope for the development of stem cell therapies in human neurodegenerative disorders. Before clinical trials are initiated, we need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.

Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Leukemia

Abstract: BACKGROUND Data regarding the outcome of cord-blood transplantation in adults are scant, despite the fact that these grafts are increasingly used in adults. METHODS We compared the outcomes of the transplantation of hematopoietic stem cells from unrelated donors in adults with leukemia who had received cord blood that was mismatched for one HLA antigen (34 patients) or two antigens (116 patients), bone marrow that had one HLA mismatch (83 patients), and HLA-matched bone marrow (367 patients). We used Cox proportional-hazards models to analyze the data. RESULTS Cord-blood recipients were younger and more likely to have advanced leukemia than were bone marrow recipients, and they received lower doses of nucleated cells. Hematopoietic recovery was slower with transplantation of mismatched bone marrow and cord blood than with matched marrow transplantations. Acute graft-versus-host disease (GVHD) was more likely to occur after mismatched marrow transplantation, and chronic GVHD was more likely to occur after cord-blood transplantation. The rates of treatment-related mortality, treatment failure, and overall mortality were lowest among patients who received matched marrow transplants. Patients who received mismatched bone marrow transplants and those who received mismatched cord-blood transplants had similar rates of treatment-related mortality (P=0.96), treatment failure (P=0.69), and overall mortality (P=0.62). There were no differences in the rate of recurrence of leukemia among the groups. There were no differences in outcome after cord-blood transplantation between patients with one HLA mismatch and those with two HLA mismatches. CONCLUSIONS HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor.

Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells

Abstract: Spermatogonial stem cells (SSCs) self-renew and produce large numbers of committed progenitors that are destined to differentiate into spermatozoa throughout life. However, the growth factors essential for self-renewal of SSCs remain unclear. In this study, a serum-free culture system and a transplantation assay for SSCs were used to identify exogenous soluble factors that promote proliferation of SSCs. Mouse pup testis cells were enriched for SSCs by selection with an anti-Thy-1 antibody and cultured on STO (SIM mouse embryo-derived thioguanine and ouabain resistant) feeders in a serum-free defined medium. In the presence of glial cell line-derived neurotrophic factor (GDNF), SSCs from DBA/2J strain mice formed densely packed clumps of cells and continuously proliferated. However, other strains of mice required the addition of soluble GDNF-family receptor α-1 and basic fibroblast growth factor to support replication. The functional transplantation assay proved that the clump-forming cells are indeed SSCs. Thus, GDNF-induced cell signaling plays a central role in SSC self-renewal. The number of SSCs in culture doubled every 5.6 days, and the clump-forming cells strongly expressed Oct-4. Under these conditions, SSCs proliferated over 6 months, reconstituted long-term spermatogenesis after transplantation into recipient testes, and restored fertility to infertile recipients. The identification of exogenous factors that allow continuous proliferation of SSCs in vitro establishes the foundation to study the basic biology of SSCs and makes possible germ-line modification by sophisticated technologies. Moreover, the ability to recover, culture indefinitely, and transplant SSCs will make the germ-line of individual males available for periods extending beyond a normal lifetime.

Essential role of Plzf in maintenance of spermatogonial stem cells

Abstract: Little is known of the molecular mechanisms whereby spermatogonia, mitotic germ cells of the testis, self-renew and differentiate into sperm. Here we show that Zfp145, encoding the transcriptional repressor Plzf, has a crucial role in spermatogenesis. Zfp145 expression was restricted to gonocytes and undifferentiated spermatogonia and was absent in tubules of W/W(v) mutants that lack these cells. Mice lacking Zfp145 underwent a progressive loss of spermatogonia with age, associated with increases in apoptosis and subsequent loss of tubule structure but without overt differentiation defects or loss of the supporting Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice before testis degeneration showed alterations in the expression profile of genes associated with spermatogenesis. These results identify Plzf as a spermatogonia-specific transcription factor in the testis that is required to regulate self-renewal and maintenance of the stem cell pool.

Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers

Abstract: background Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability of palifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. methods This double-blind study compared the effect of palifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 µg per kilogram of body weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation.

Plzf is required in adult male germ cells for stem cell self-renewal.

Abstract: Adult germline stem cells are capable of self-renewal, tissue regeneration and production of large numbers of differentiated progeny. We show here that the classical mouse mutant luxoid affects adult germline stem cell self-renewal. Young homozygous luxoid mutant mice produce limited numbers of normal spermatozoa and then progressively lose their germ line after birth. Transplantation studies showed that germ cells from mutant mice did not colonize recipient testes, suggesting that the defect is intrinsic to the stem cells. We determined that the luxoid mutant contains a nonsense mutation in the gene encoding Plzf, a transcriptional repressor that regulates the epigenetic state of undifferentiated cells, and showed that Plzf is coexpressed with Oct4 in undifferentiated spermatogonia. This is the first gene shown to be required in germ cells for stem cell self-renewal in mammals.

Long-Term Survival of Children with End-Stage Renal Disease

Abstract: BACKGROUND Although renal-replacement therapy for children with end-stage renal disease has been used for several decades, data on patients' long-term survival are sparse. METHODS We examined the long-term survival of all children and adolescents who were under 20 years of age when renal-replacement therapy commenced (study period, April 1963 through March 2002), using data from the Australia and New Zealand Dialysis and Transplant Registry. Survival was analyzed with the use of Kaplan-Meier methods and age-standardized mortality rates. Risk factors for death were analyzed with the use of Cox regression analysis with time-dependent covariates. RESULTS A total of 1634 children and adolescents were followed for a median of 9.7 years. The long-term survival rate among children requiring renal-replacement therapy was 79 percent at 10 years and 66 percent at 20 years. Mortality rates were 30 times as high as for children without end-stage renal disease. Risk factors for death were a young age at the time renal-replacement therapy was initiated (especially for children under 1 year of age, among whom the risk was four times as high as for children 15 to 19 years of age) and treatment with dialysis (which was associated with a risk more than four times as high as for renal transplantation). Overall, a trend toward improved survival was observed over the four decades of the study. CONCLUSIONS Despite improvement in long-term survival, mortality rates among children requiring renal-replacement therapy remain substantially higher than those among children without end-stage renal disease. Increasing the proportion of children treated with renal transplantation rather than with dialysis can improve survival further.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation.

Abstract: The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

Study of Telomere Length Reveals Rapid Aging of Human Marrow Stromal Cells following In Vitro Expansion

Abstract: Human marrow stromal cells (MSCs) can be isolated from bone marrow and differentiate into multiple tissues in vitro and in vivo. These properties make them promising tools in cell and gene therapy. The lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion prior to clinical use. This may severely reduce MSC proliferative capacity to the point that the residual proliferative potential is insufficient to maintain long-term tissue regeneration upon reinfusion. In this study we determined the effect of in vitro expansion on the replicative capacity of MSCs by correlating their rate of telomere loss during in vitro expansion with their behavior in vivo. We report that even protocols that involve minimal expansion induce a rapid aging of MSCs, with losses equivalent to about half their total replicative lifespan.

CD40/CD154 interactions at the interface of tolerance and immunity

Abstract: Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.