Sirolimus,tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation

We studied the feasibility and activity of adding sirolimus to tacrolimus and low-dose methotrexate as graft-versus-host disease (GVHD) prophylaxis in recipients of alternative donor transplants. Forty-one patients with hematologic malignancies were conditioned with cyclophosphamide and total body irradiation. Marrow stem cells were from an HLA-A, -B, and -DR compatible, unrelated donor (n = 26, 68%), from a 5 of 6 antigen-matched unrelated donor (n = 8, 20%), or from a 5 of 6 antigen-matched family member (n = 5, 12%). Therapeutic serum levels of sirolimus were attained in most patients. All evaluable patients engrafted. An absolute neutrophil count of 500/microL was achieved on day +18 (range, 11-32 days). Sustained platelet counts of more than 20 000/ microL were attained on day +29 (range, 14-98 days). Grades 0-I acute GVHD occurred in 75% of patients. Grades II, III, and IV acute GVHD occurred in 13%, 8%, and 5%, respectively (total grades II-IV GVHD, 26%). Median survival is 366 days (95% CI 185, not estimable) and actuarial survival at 1 year is 52%. Oral sirolimus is tolerable, adequate blood levels are achievable, and there is a low rate of acute GVHD compared with historical data in this high-risk population. This novel agent is worthy of further study in allogeneic transplantation.     

Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

A novel rapid single nucleotide polymorphism (SNP)-based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation

A major end point of nonmyeloablative hematopoietic stem cell transplantation is the attainment of either mixed chimerism or full donor hematopoiesis. Because the majority of human genetic disparity is generated by single nucleotide polymorphisms (SNPs), direct measurement of SNPs should provide a robust tool for the detection and quantitation of chimerism. Using pyrosequencing, a rapid quantitative sequencing technology, we developed a SNP-based assay for hematopoietic chimerism. Based on 14 SNPs with high allele frequencies, we were able to identify at least 1 informative SNP locus in 55 patients with HLA-identical donors. The median number of informative SNPs in related pairs was 5 and in unrelated pairs was 8 (P <.0001). Assessment of hematopoietic chimerism in posttransplantation DNA was shown to be quantitative, accurate, and highly reproducible. The presence of 5% donor cells was reliably detected in replicate assays. Compared with current measures of engraftment based on identification of short tandem repeats (STRs), variable number of tandem repeats (VNTRs), or microsatellite polymorphisms, this SNP-based method provides a more rapid and quantitative assessment of chimerism. A large panel of SNPs enhances the ability to identify an informative marker in almost all patient/donor pairs and also facilitates the simultaneous use of multiple markers to improve the statistical validity of chimerism measurements. The inclusion of SNPs that encode minor histocompatibility antigens or other genetic polymorphisms that may influence graft-versus-host disease or other transplantation outcomes can provide additional clinically relevant data. SNP-based assessment of chimerism is a promising technique that will assist in the analysis of outcomes following transplantation.     

Determinants of acquisition of MR imaging units in an era of prospective payment

A survey was undertaken to examine the impact of Medicare's Prospective Payment System (PPS) and other recent changes in the health care environment on providers' decisions regarding acquisition of high-cost technologic equipment. The survey group included 199 hospitals and freestanding imaging centers known to have acquired magnetic resonance (MR) imaging units, as well as a random sample of 400 hospitals whose acquisition decisions were unknown to the authors. Fifty-eight percent of the known adopters and 61% of the randomly selected hospitals responded to the survey. Nonadopters' decisions were dominated by economic considerations, including the high cost of MR imagers and concerns about Medicare's reimbursement policies. Competition and a desire to provide the highest quality of care are counterbalancing the retardant effects of PPS, however, and are stimulating widespread diffusion of MR imagers.     

Developmental expression of polypeptide PEP-19 in cerebellar cell suspensions transplanted into the cerebellum of pcd mutant mice

Summary Cerebellar cell suspensions were prepared from normal mouse embryos and implanted into the cerebellum of Purkinje cell degeneration (pcd) mutant mice, which are characterized by a virtually complete degeneration of Purkinje cells between postnatal day (P) 17 and P45. The expression of immunoreactivity for PEP-19, a developmentally-regulated brain-specific polypeptide, was analyzed in normal mouse cerebellum, as well as in pcd mutants with or without grafts. In the normal cerebellum, PEP-19 immunoreactivity was present in Purkinje cells. In unoperated mutants, 45 days of age or older, Purkinje cells were absent. In grafted pcd mice, numerous PEP-19 immunoreactive, neuroblast-like cells were seen in the graft at 5 days after transplantation. By 9 days, large PEP-19 immunoreactive neurons were found in the host molecular layer; by 17 days after transplantation, such neurons displayed an extensive dendritic tree and resembled differentiated Purkinje cells. The vast majority of PEP-19 immunoreactive cells was located in the molecular layer of the host at 9 days after transplantation and beyond; nonetheless, the same cells extended axonal processes toward the graft, indicating an affinity for co-grafted (possibly deep nuclei) neurons. These results point to the ability of donor Purkinje cells for survival, migration into the host brain and morphological and chemical differentiation following transplantation to the degenerated cerebellar cortex of the recipient mutants.On sabbatical leave from the Institute of Neurosciences, National Yang-Ming Medical College, Taipei, Taiwan 112, ROC     

Algorithm for the treatment of type 2 diabetes: a position statement of Brazilian Diabetes Society

The Brazilian Diabetes Society is starting an innovative project of quantitative assessment of medical arguments of and implementing a new way of elaborating SBD Position Statements. The final aim of this particular project is to propose a new Brazilian algorithm for the treatment of type 2 diabetes, based on the opinions of endocrinologists surveyed from a poll conducted on the Brazilian Diabetes Society website regarding the latest algorithm proposed by American Diabetes Association /European Association for the Study of Diabetes, published in January 2009.An additional source used, as a basis for the new algorithm, was to assess the acceptability of controversial arguments published in international literature, through a panel of renowned Brazilian specialists. Thirty controversial arguments in diabetes have been selected with their respective references, where each argument was assessed and scored according to its acceptability level and personal conviction of each member of the evaluation panel.This methodology was adapted using a similar approach to the one adopted in the recent position statement by the American College of Cardiology on coronary revascularization, of which not only cardiologists took part, but also specialists of other related areas.