Umbilical cord blood banking and the next generation of human tissue regulation: An agenda for research

The transformation of umbilical cord blood from being a waste product to being a valuable source of stem cells has led to the emergence of significant legal, ethical and social issues. This editorial proposes an agenda for research into the regulation of umbilical cord blood banking which focuses on issues of characterisation, consent, the interplay of public and private services, and the importance of applying property concepts. It concludes by stressing the need for reform to be based on well-informed public debate

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Anti-IL-2R alpha therapy in renal transplantation: The promise of steroid-free immunosuppresion.

Contains fulltext : 59271.pdf (publisher's version ) (Open Access)In the last two decades the results of renal transplantation have tremendously improved. However, recipients of a renal transplant frequently experience several side effects related to the use of the immunosuppressive drugs, such as corticosteroids. In this thesis we describe if the use of daclizumab, a monoclonal antibody against the interleukin-2 receptor would allow steroid-free immunosuppression. In this thesis, we demonstrate, that a two-dose regimen of daclizumab resulted in a blockade of the IL-2R -chain, which lasted for more than 10 weeks after transplantation. In this thesis, we describe the development and implementation of a novel method for monitoring the duration of IL-2R blockade after treatment with daclizumab. This method is more sensitive and easier to perform method compared with the standard method for monitoring IL-2R blockade after treatment with daclizumab, flow cytometry. In this thesis, we demonstrate in a prospective randomized multicenter study, that treatment with two doses of daclizumab combined with tacrolimus and mycophenolate mofetil, enabled the use of a steroid-free immunosuppressive regimen after renal transplantation. Compared with withdrawal of steroids at four months after transplantation, there was no difference in the incidence of biopsy-proven acute rejection. The steroid-free immunosuppressive regimen had a temporary beneficial effect on several cardiovascular risk factors (lower blood pressure, lower serum cholesterol, and less new-onset diabetes mellitus). No important benefit was found on prevention of accelerated bone loss after transplantation during the first year after transplantation. In fact, the steroid-free regimen as well as the regimen with limited steroid exposure prevented accelerated bone loss in the first year after transplantation. So, the beneficial effect of the steroid-free regimen on cardiovascular risk factors should be balanced against the increased costs associated with the steroid-free regimen.KUN, 23 maart 2004Promotor : Wetzels, J.F.M. Co-promotores : Hoitsma, A.J., Hilbrands, L.B.152 p

Influence of corticosteroids on QUS parameters of the calcaneus in the 1st year after renal transplantation: authors' reply to Dr. Adamczyk.

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Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone.

Item does not contain fulltextIn a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection

Two doses of daclizumab are sufficient for prolonged interleukin-2Ralpha chain blockade.

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Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil.

BACKGROUND: In an attempt to reduce calcineurin inhibitor toxicity, transplant patients treated with tacrolimus can be switched to maintenance treatment with sirolimus. METHODS: In a prospective, randomized, multicenter trial, 33 kidney transplant recipients on steroid-free maintenance treatment with tacrolimus and mycophenolate mofetil continued tacrolimus and mycophenolate mofetil (control group, n=18) or were converted from tacrolimus to sirolimus (study group, n=15) at 1 year after transplantation. RESULTS: The study was prematurely stopped as a result of a cluster of nine patients suffering from painful oral ulcerations in the study group. Oral ulcerations did not occur in the control group. The authors here report on the individual cases suffering from this side effect of the instituted immunosuppressive regimen. CONCLUSIONS: The authors review the literature with respect to the occurrence of oral ulcers associated with the use of sirolimus or mycophenolate mofetil and speculate on the causes of the high incidence of oral ulcers in their study group. Possible explanations are overimmunosuppression during the period of the conversion from tacrolimus to sirolimus without antiviral prophylaxis, the use of the oral emulsion instead of tablets, or the lack of corticosteroid co-administration

The influence of corticosteroids on quantitative ultrasound parameters of the calcaneus in the 1st year after renal transplantation.

Contains fulltext : 48403.pdf (publisher's version ) (Closed access

Decreased renal excretion of soluble interleukin-2 receptor alpha after treatment with daclizumab.

Item does not contain fulltextBACKGROUND: Daclizumab (+/-150 kD), a humanized monoclonal antibody (mAb) against the alpha-chain of the membrane-bound interleukin-2 (IL-2) receptor (IL-2R) also binds soluble interleukin-2R alpha (sIL-2R alpha; +/-45 kD), and thus may influence the glomerular filtration of sIL-2R alpha. METHODS: We have studied the influence of daclizumab on the renal excretion of sIL-2R alpha in 38 recipients of a renal transplant (32 treated with daclizumab and six controls). sIL-2R alpha was measured every 2 weeks after transplantation in serum and urine with Immulite IL-2R, a solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS: In the control population, the fractional excretion of sIL-2R alpha was relatively constant with a median value of 1.7%+/- 0.5%. In daclizumab-treated patients, sIL-2R alpha was not detectable in the urine immediately after the administration of daclizumab. sIL-2R alpha became detectable in the urine at a mean of 8 +/- 3 weeks after transplantation. In additional experiments, serum compounds were separated by size-exclusion chromatography and sIL-2R alpha was measured in the collected fractions. In the control patients, sIL-2R alpha was only present in the low-molecular-weight fractions of serum. In contrast, in daclizumab-treated patients evaluated several weeks after transplantation, sIL-2R alpha was merely detected in the high-molecular-weight fractions of serum. During follow-up there was a relative shift of sIL-2R alpha from the high- to the low-molecular-weight fractions and this coincided with normalization of sIL-2R alpha excretion. CONCLUSION: Daclizumab inhibits the renal excretion of sIL-2R alpha by the formation of a complex with sIL-2R alpha in serum, which is too large for glomerular filtration. Measurement of urinary sIL-2R alpha may provide information on the concentration of anti-IL-2R alpha mAb in serum