Showing papers on "Transplantation published in 2006"
TL;DR: A workshop was convened by the AACR to discuss the rapidly emerging cancer stem cell model for tumor development and progression, and participants were charged with evaluating data suggesting that cancers develop from a small subset of cells with self-renewal properties analogous to organ regeneration.
Abstract: A workshop was convened by the AACR to discuss the rapidly emerging cancer stem cell model for tumor development and progression. The meeting participants were charged with evaluating data suggesting that cancers develop from a small subset of cells with self-renewal properties analogous to organ
2,948 citations
TL;DR: The present classification scheme recognizes the rapid evolution of molecular genetics in cardiology, as well as the introduction of several recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy.
Abstract: Classifications of heart muscle diseases have proved to be exceedingly complex and in many respects contradictory. Indeed, the precise language used to describe these diseases is profoundly important. A new contemporary and rigorous classification of cardiomyopathies (with definitions) is proposed here. This reference document affords an important framework and measure of clarity to this heterogeneous group of diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular genetics in cardiology, as well as the introduction of several recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy.
2,911 citations
TL;DR: Hematopoietic stem-cell transplantation was first conceived more than 50 years ago, but problems associated with transplanting a nonsolid organ and modulating the immune response had to be solved before the procedure could be used clinically as mentioned in this paper.
Abstract: Hematopoietic stem-cell transplantation, which is used to treat both malignant and nonmalignant conditions, was first conceived more than 50 years ago, but problems associated with transplanting a nonsolid organ and modulating the immune response had to be solved before the procedure could be used clinically. This review summarizes background information about hematopoietic stem-cell transplantation and discusses the current role of the procedure.
2,180 citations
TL;DR: It is shown that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo and establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs.
Abstract: The existence of mammary stem cells (MaSCs) has been postulated from evidence that the mammary gland can be regenerated by transplantation of epithelial fragments in mice. Interest in MaSCs has been further stimulated by their potential role in breast tumorigenesis. However, the identity and purification of MaSCs has proved elusive owing to the lack of defined markers. We isolated discrete populations of mouse mammary cells on the basis of cell-surface markers and identified a subpopulation (Lin-CD29hiCD24+) that is highly enriched for MaSCs by transplantation. Here we show that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo. The transplanted cell contributed to both the luminal and myoepithelial lineages and generated functional lobuloalveolar units during pregnancy. The self-renewing capacity of these cells was demonstrated by serial transplantation of clonal outgrowths. In support of a potential role for MaSCs in breast cancer, the stem-cell-enriched subpopulation was expanded in premalignant mammary tissue from MMTV-wnt-1 mice and contained a higher number of MaSCs. Our data establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs.
1,919 citations
Journal Article•
TL;DR: In this article, the mammary gland can be functionally regenerated in mice by serial transplantation of epithelial fragments, providing evidence for the existence of self-renewing, multipotential mammary stem cells (MaSCs).
Abstract: 4839 The mammary gland can be functionally regenerated in mice by serial transplantation of epithelial fragments, providing evidence for the existence of self-renewing, multipotential mammary stem cells (MaSCs). Recently the concept has emerged that MaSCs play a central role in breast tumorigenesis. However, the identity and purification of MaSC has proved elusive due to the lack of defined markers. Using specific cell surface markers and flow cytometry, we have identified a distinct subpopulation that is enriched for MaSCs, demonstrated by transplantation into cleared mammary fat pads at limiting dilution. Remarkably, a single mammary epithelial cell from this population, carrying the lacZ transgene, was found to generate a complete mammary gland in vivo. These cells contributed to both the luminal and myoepithelial lineages in transplanted virgin mammary glands, and extensive lobuloalveolar units were generated during pregnancy. Serial transplantation of the clonal outgrowths also yielded complete mammary glands, confirming that the cells were capable of self-renewal. These data establish that single cells from the enriched population have multipotential and self-renewing capacity, a hallmark of stem cells. It will be of interest to determine whether the stem cell is a target of transformation mammary tumorigenesis models.
1,810 citations
TL;DR: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable.
Abstract: Background Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). Methods We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. Results Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. Conclusions Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911.)
1,784 citations
TL;DR: A quantitative donor risk index was developed using national data from 1998 to 2002 to assess the risk of donor liver graft failure using seven donor characteristics that independently predicted significantly increased risk of graft failure.
1,657 citations
TL;DR: Micro-CT images of bone-like constructs that result from transplantation of osteoblasts on gels that degrade over a time frame of several months leading to improved bone formation are presented.
Abstract: [Image: see text] Alginate hydrogels are proving to have a wide applicability as biomaterials. They have been used as scaffolds for tissue engineering, as delivery vehicles for drugs, and as model extracellular matrices for basic biological studies. These applications require tight control of a number of material properties including mechanical stiffness, swelling, degradation, cell attachment, and binding or release of bioactive molecules. Control over these properties can be achieved by chemical or physical modifications of the polysaccharide itself or the gels formed from alginate. The utility of these modified alginate gels as biomaterials has been demonstrated in a number of in vitro and in vivo studies.Micro-CT images of bone-like constructs that result from transplantation of osteoblasts on gels that degrade over a time frame of several months leading to improved bone formation.
1,579 citations
1,254 citations
TL;DR: It is shown that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts and may be a new therapeutic strategy for cardiac tissue regeneration.
Abstract: Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue-derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration.
1,187 citations
TL;DR: In contrast to nontargeted liposomes, anti-HER2 immunoliposomes achieved intracellular drug delivery via MAb-mediated endocytosis, and this, rather than increased uptake in tumor tissue, was correlated with superior antitumor activity.
Abstract: We describe evidence for a novel mechanism of monoclonal antibody (MAb)-directed nanoparticle (immunoliposome) targeting to solid tumors in vivo. Long-circulating immunoliposomes targeted to HER2 (ErbB2, Neu) were prepared by the conjugation of anti-HER2 MAb fragments (Fab' or single chain Fv) to liposome-grafted polyethylene glycol chains. MAb fragment conjugation did not affect the biodistribution or long-circulating properties of i.v.-administered liposomes. However, antibody-directed targeting also did not increase the tumor localization of immunoliposomes, as both targeted and nontargeted liposomes achieved similarly high levels (7-8% injected dose/g tumor tissue) of tumor tissue accumulation in HER2-overexpressing breast cancer xenografts (BT-474). Studies using colloidal gold-labeled liposomes showed the accumulation of anti-HER2 immunoliposomes within cancer cells, whereas matched nontargeted liposomes were located predominantly in extracellular stroma or within macrophages. A similar pattern of stromal accumulation without cancer cell internalization was observed for anti-HER2 immunoliposomes in non-HER2-overexpressing breast cancer xenografts (MCF-7). Flow cytometry of disaggregated tumors posttreatment with either liposomes or immunoliposomes showed up to 6-fold greater intracellular uptake in cancer cells due to targeting. Thus, in contrast to nontargeted liposomes, anti-HER2 immunoliposomes achieved intracellular drug delivery via MAb-mediated endocytosis, and this, rather than increased uptake in tumor tissue, was correlated with superior antitumor activity. Immunoliposomes capable of selective internalization in cancer cells in vivo may provide new opportunities for drug delivery.
TL;DR: MSC is a very promising treatment for severe steroid-resistant acute GVHD and five patients are still alive between 2 months and 3 years after the transplantation and their survival rate was significantly better than that of 16 patients with steroid- resistant biopsy-proven gastrointestinal GV HD, not treated with MSC during the same period.
Abstract: Background Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD). Methods We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors. Results Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma. Conclusion MSC is a very promising treatment for severe steroid-resistant acute GVHD.
TL;DR: Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction and is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.
Abstract: Background Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown. Methods After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months’ follow-up. Results The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of BMC. The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to BMC or from CPC to BMC. Conclusions Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months. (ClinicalTrials.gov number, NCT00289822.)
TL;DR: Chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model, and β-adrenergic activation of the cAMP–PKA signaling pathway is identified as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth.
Abstract: Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma
TL;DR: It is shown that donor cells can integrate into the adult or degenerating retina if they are taken from the developing retina at a time coincident with the peak of rod genesis, and the ontogenetic stage of donor cells for successful rod photoreceptor transplantation is defined.
Abstract: Photoreceptor loss causes irreversible blindness in many retinal diseases. Repair of such damage by cell transplantation is one of the most feasible types of central nervous system repair; photoreceptor degeneration initially leaves the inner retinal circuitry intact and new photoreceptors need only make single, short synaptic connections to contribute to the retinotopic map. So far, brain- and retina-derived stem cells transplanted into adult retina have shown little evidence of being able to integrate into the outer nuclear layer and differentiate into new photoreceptors(1-4). Furthermore, there has been no demonstration that transplanted cells form functional synaptic connections with other neurons in the recipient retina or restore visual function. This might be because the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation. We hypothesized that committed progenitor or precursor cells at later ontogenetic stages might have a higher probability of success upon transplantation. Here we show that donor cells can integrate into the adult or degenerating retina if they are taken from the developing retina at a time coincident with the peak of rod genesis(5). These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function. Furthermore, we use genetically tagged postmitotic rod precursors expressing the transcription factor Nrl (ref. 6) ( neural retina leucine zipper) to show that successfully integrated rod photoreceptors are derived only from immature post-mitotic rod precursors and not from proliferating progenitor or stem cells. These findings define the ontogenetic stage of donor cells for successful rod photoreceptor transplantation.
TL;DR: These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in surgical patients and it is strongly recommended not to wait until severe undernutrition has developed, but to start EN therapy early, as soon as a nutritional risk becomes apparent.
Johns Hopkins University1, Université libre de Bruxelles2, Columbia University3, Newcastle University4, University College Dublin5, University of North Carolina at Chapel Hill6, University of Toronto7, University of Pennsylvania8, University of Michigan9, Inova Fairfax Hospital10, Duke University11, Washington University in St. Louis12, Alfred Hospital13, University of Pittsburgh14, St. Vincent's Health System15
TL;DR: This update to the international guidelines is based primarily on a consensus of opinion rendered by experts in the field and should not be considered to be hard and fast rules.
Abstract: Since the writing of the 1998 guidelines for the selection of candidates for lung transplantation, there has been an increased understanding of the natural history of various lung diseases as well as new treatment strategies developed that may forestall the need for transplantation for certain disorders. This has resulted in several changes to the current strategy for selecting patients for this procedure. The primary goal of this document is to provide up-to-date guidelines to help physicians in the referral and selection process of candidates for lung transplantation. With limited prospective randomized studies to support the recommendations outlined in this document, this update to the international guidelines is based primarily on a consensus of opinion rendered by experts in the field. The bulleted guidelines should therefore not be considered to be hard and fast rules. Because of the potential for long waiting times to transplantation, physicians should err on the side of early referral of their patients to a lung transplant center. © 2006 International Society for Heart and Lung Transplantation.
TL;DR: Comparing the incidence of cancer in patients receiving immune suppression after kidney transplantation with incidence in the same population in 2 periods before receipt of immune suppression suggests a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.
Abstract: ContextImmune suppression after organ transplantation is associated with a markedly increased risk of nonmelanoma skin cancer and a few virus-associated cancers. Although it is generally accepted that other cancers do not occur at increased rates, there have been few long-term population-based cohort studies performed.ObjectiveTo compare the incidence of cancer in patients receiving immune suppression after kidney transplantation with incidence in the same population in 2 periods before receipt of immune suppression: during dialysis and during end-stage kidney disease before renal replacement therapy (RRT).Design, Setting, and ParticipantsA population-based cohort study of 28 855 patients with end-stage kidney disease who received RRT, with 273 407 person-years of follow-up. Incident cancers (1982-2003) were ascertained by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House.Main Outcome MeasureStandardized incidence ratios (SIRs) of cancer, using age-specific, sex-specific, calendar year–specific, and state/territory–specific population cancer incidence rates.ResultsThe overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased after transplantation (n = 1236; SIR, 3.27; 95% confidence interval [CI], 3.09-3.46). In contrast, cancer incidence was only slightly increased during dialysis (n = 870; SIR, 1.35; 95% CI, 1.27-1.45) and before RRT (n = 689; SIR, 1.16; 95% CI, 1.08-1.25). After transplantation, cancer occurred at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites. Most of these cancers were of known or suspected viral etiology.ConclusionsKidney transplantation is associated with a marked increase in cancer risk at a wide variety of sites. Because SIRs for most types of cancer were not increased before transplantation, immune suppression may be responsible for the increased risk. These data suggest a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.
TL;DR: The ISHLT has reponded to this urgent need to re-evaluate the listing criteria for patients awaiting heart transplantation to provide succinct and clear guidance to transplant centers.
Abstract: wo of the previous International Society for Heart and ung Transplantation (ISHLT) consensus conferences ave addressed listing criteria for patients awaiting eart transplantation. Guidelines from these two onferences were completed before the acceptance of -blocker and device therapies in the clinical treatment f late-stage heart failure. Guidelines addressing the mangement of heart failure are now available from the uropean Society of Cardiology (ESC) as well as the merican College of Cardiology (ACC), American Heart ssociation (AHA) and Heart Failure Society of America HFSA) in the USA; however, these statements are not omprehensive regarding the criteria for listing patients or heart transplantation. Thus, the ISHLT has reponded to this urgent need to re-evaluate the listing riteria to provide succinct and clear guidance to ransplant centers. These recommendations can be sed to update listing and management policies for otential heart transplant recipients.
TL;DR: It appears that the spatial and temporal expression of NTPDases by various cell types within the vasculature, the nervous tissues and other tissues impacts on several patho-physiological processes.
Abstract: Ectonucleotidases are ectoenzymes that hydrolyze extracellular nucleotides to the respective nucleosides. Within the past decade, ectonucleotidases belonging to several enzyme families have been discovered, cloned and characterized. In this article, we specifically address the cell surface-located members of the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase/CD39) family (NTPDase1,2,3, and 8). The molecular identification of individual NTPDase subtypes, genetic engineering, mutational analyses, and the generation of subtype-specific antibodies have resulted in considerable insights into enzyme structure and function. These advances also allow definition of physiological and patho-physiological implications of NTPDases in a considerable variety of tissues. Biological actions of NTPDases are a consequence (at least in part) of the regulated phosphohydrolytic activity on extracellular nucleotides and consequent effects on P2-receptor signaling. It further appears that the spatial and temporal expression of NTPDases by various cell types within the vasculature, the nervous tissues and other tissues impacts on several patho-physiological processes. Examples include acute effects on cellular metabolism, adhesion, activation and migration with other protracted impacts upon developmental responses, inclusive of cellular proliferation, differentiation and apoptosis, as seen with atherosclerosis, degenerative neurological diseases and immune rejection of transplanted organs and cells. Future clinical applications are expected to involve the development of new therapeutic strategies for transplantation and various inflammatory cardiovascular, gastrointestinal and neurological diseases.
TL;DR: How a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment are described.
Abstract: Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new findings might further improve the efficacy of adoptive cell transfer through the use of vaccines, haematopoietic-stem-cell transplantation, modified preconditioning regimens, and alternative methods for the generation and selection of the T cells to be transferred.
TL;DR: The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients and is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients.
Abstract: Background A double-sandwich enzyme-linked immunosorbent galactomannan assay has been approved for surveillance for invasive aspergillosis in immunocompromised patients. We undertook a meta-analysis to assess the accuracy of a galactomannan assay for diagnosing invasive aspergillosis. Methods Studies of the galactomannan assay that used the European Organization for Research and Treatment of Cancer or similar criteria as a reference standard and provided data to calculate sensitivity and specificity were included. Pooled sensitivity and specificity and summary measures of accuracy, Q* (the upper left-most point on the summary receiver-operating characteristic curve), mean D (a log odds ratio), and Youden index were calculated. Subgroup analyses were performed to explore heterogeneity. Results Twenty-seven studies from 1966 to 28 February 2005 were included. Overall, the galactomannan assay had a sensitivity of 0.71 (95% confidence interval [CI], 0.68-0.74) and specificity of 0.89 (95% CI, 0.88-0.90) for proven cases of invasive aspergillosis. The Youden index, mean D, and Q* were 0.54 (95% CI, 0.41-0.65), 2.74 (95% CI, 21.12-3.36), and 0.80 (95% CI, 0.74-0.86), respectively, indicating moderate accuracy. Subgroup analyses showed that the performance of the test differed by patient population and type of reference standard used. Significant heterogeneity was present. Conclusions The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients. The test is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients. Further studies with attention to the impact of antifungal therapy, rigorous assessment of false-positive test results, and assessment of the utility of the test under nonsurveillance conditions are needed.
TL;DR: In children, DCM is a diverse disorder with outcomes that depend largely on cause, age, and heart failure status at presentation, and race, sex, and age affect the incidence of disease.
Abstract: ContextDilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and cause of cardiac transplantation in children. However, the epidemiology and clinical course of DCM in children are not well established.ObjectiveTo provide a detailed description of the incidence, causes, outcomes, and related risk factors for DCM in children.Design and SettingLongitudinal study based on a population-based, prospective cohort of children diagnosed as having DCM since January 1, 1996, at 89 pediatric cardiac centers and a retrospectively collected cohort of patients seen primarily at large tertiary care centers in North America and who had diagnoses between January 1, 1990, and December 31, 1995, and were enrolled through February 2003.ParticipantsA total of 1426 children from the United States and Canada diagnosed as having DCM at younger than 18 years. Primary DCM was determined by strict echocardiographic and/or pathologic criteria. Patients with disease due to endocrine, immunologic, drug toxicity, and other causes were excluded.Main Outcome MeasuresAnnual incidence per 100 000 children; mortality; cardiac transplantation.ResultsThe annual incidence of DCM in children younger than 18 years was 0.57 cases per 100 000 per year overall. The annual incidence was higher in boys than in girls (0.66 vs 0.47 cases per 100 000; P<.001), in blacks than in whites (0.98 vs 0.46 cases per 100 000; P<.001), and in infants (<1 year) than in children (4.40 vs 0.34 cases per 100 000; P<.001). The majority of children (66%) had idiopathic disease. The most common known causes were myocarditis (46%) and neuromuscular disease (26%). The 1- and 5-year rates of death or transplantation were 31% and 46%, respectively. Independent risk factors at DCM diagnosis for subsequent death or transplantation were older age, congestive heart failure, lower left ventricular fractional shortening Z score, and cause of DCM (P<.001 for all).ConclusionsIn children, DCM is a diverse disorder with outcomes that depend largely on cause, age, and heart failure status at presentation. Race, sex, and age affect the incidence of disease. Most children do not have a known cause of DCM, which limits the potential for disease-specific therapies.
TL;DR: This work has shown that directly stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult central nervous system can be a effective treatment for Parkinson's disease and multiple sclerosis.
Abstract: Many common neurological disorders, such as Parkinson's disease, stroke and multiple sclerosis, are caused by a loss of neurons and glial cells. In recent years, neurons and glia have been generated successfully from stem cells in culture, fuelling efforts to develop stem-cell-based transplantation therapies for human patients. More recently, efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult central nervous system. The next step is to translate these exciting advances from the laboratory into clinically useful therapies.
TL;DR: DSAEK surgery allows rapid, excellent BSCVA visual recovery, and the rate of visual recovery is more rapid than usually found with penetrating keratoplasty.
Abstract: Purpose:To evaluate the speed of visual recovery in 16 consecutive patients with corneal endothelial dysfunction who received Descemet-stripping automated endothelial keratoplasty (DSAEK).Methods:This is a retrospective study of a novel method for small-incision endothelial transplantation (DSAEK).
TL;DR: PAH is common in advanced cases of IPF and significantly impacts survival and might be an important adjunct in monitoring disease progression, triaging for transplantation, and guiding therapy.
TL;DR: Investigating the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma found it can be used to improve the outcome of patients with high-risk medullOBlastoma.
Abstract: Summary Background Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. Methods After resection, patients were classified as having average-risk medulloblastoma (≤1·5 cm 2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm 2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23·4 Gy for average-risk disease and 36·0–39·6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Findings Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75–94) in patients in the average-risk group and 70% (54–84) in those in the high-risk group (p=0·04); 5-year event-free survival was 83% (73–93) and 70% (55–85), respectively (p=0·046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0·04): 84% (74–95) for classic histology, 77% (49–100) for desmoplastic tumours, and 57% (33–80) for large-cell anaplastic tumours. Interpretation Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.
TL;DR: This novel approach may provide a standardized, objective, and reproducible assessment of pancreas surgery enabling meaningful comparison among centers and over time, and demonstrates the applicability and utility of a new classification in grading complications following pancreatic surgery.
Abstract: Mortality associated with pancreaticoduodenectomy (PD) has decreased dramatically to less than 5% over the past 2 decades in high-volume centers,1–6 but persistent high morbidity rates have remained an important concern for patients, healthcare providers, and payers. While mortality is an objective and easily quantifiable outcome parameter, morbidity is only poorly defined, and this shortcoming has severely hampered conclusive comparisons among centers and within the same institution over time.7–9 Similarly, the identification of risk factors related to specific complications has been difficult.
Recognizing this deficiency, there has been several recent attempts to define specific complications related to PD such as pancreatic fistula, either by individual groups10–14 or through consensus statements from a few experts.15 Although important, these definitions have focused only on one specific complication (pancreatic fistula), and typically lack a severity grading system. For example, when a pancreatic fistula is defined as the persistent drainage of amylase-rich fluid during the postoperative course or as radiologic evidence of pancreatic anastomotic disruption, no distinction is made between the minimal criteria and more severe manifestation leading to reoperation or even death. An attempt was recently made by a group of experts in pancreas surgery to grade pancreatic fistula by severity,15 but the grading system is complex, includes multiple subjective criteria, and is not applicable to other types of complications. Therefore, there is persistent need for the availability of a reproducible, simple, and widely acceptable system to grade all complications following PD.
A previously reported grading system7–9 was recently revisited and validated in a large cohort of patients undergoing general surgery. An international survey confirmed the simplicity and reproducibility of the new grading system.16 This classification was recently adopted by the International Transplantation Society17 to prospectively monitor the outcome of living liver donors. A key feature facilitating the use of the grading system is that it mostly relies on the therapies used to correct negative events. This is crucial to minimize down grading of complications as even nursing notes can be used to secure appropriate grading in retrospective analyses. Another attractive aspect of the new classification is that it considers the patient perspective through a strong emphasis on long lasting disability. Such a grading system can be adapted to any complication as long as the minimal criteria to define each specific complication are well described and widely accepted.
We adapted this novel classification of complications by severity16 to a large cohort of patients, who underwent a PD at Johns Hopkins Hospital, a high-volume center with the availability of a comprehensive database. We used the well-established Johns Hopkins definitions for pancreatic fistula and delayed gastric emptying (DGE),18,19 and stratified them according to severity criteria. Of importance, the John Hopkins definition of pancreatic fistula is consistent with a recent consensus statements.15
The primary aims of the study were to evaluate the feasibility of grading each recorded complication in the database according to the novel classification system, to present specific complications by severity, and to identify risk factors. A secondary aim was to test the novel classification system in comparing the incidence and severity of one type of complication, pancreatic fistula, with a previous series of patients in the same institution. Finally, an attempt was made to evaluate the impact of complications on long-term survival.
TL;DR: The traditional way to study the immunology of pregnancy follows the classical transplantation model, which views the fetus as an allograft, but a more recent approach focuses on the unique, local uterine immune response to the implanting placenta.
Abstract: The traditional way to study the immunology of pregnancy follows the classical transplantation model, which views the fetus as an allograft. A more recent approach, which is the subject of this Review, focuses on the unique, local uterine immune response to the implanting placenta. This approach requires knowledge of placental structure and its variations in different species, as this greatly affects the type of immune response that is generated by the mother. At the implantation site, cells from the mother and the fetus intermingle during pregnancy. Unravelling what happens here is crucial to our understanding of why some human pregnancies are successful whereas others are not.
TL;DR: The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways.