Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation.

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val-)ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen.

Growing experience with mTOR inhibitors in pediatric solid organ transplantation.

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single-arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low-dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.

The CERTAIN Registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe.

BACKGROUND: The results of pediatric renal transplantation have improved markedly in the last decade. However, a number of relevant clinical problems remain, such as organ damage caused by chronic rejection, long-term toxicity of immunosuppressive therapy, difficulty in developing tolerance-inducing protocols, secondary cardiovascular comorbidity, post-transplantation lymphoproliferative disease, suboptimal longitudinal growth, quality of life, adherence to immunosuppressive medication, and structured transition programs to adult care. These unmet clinical needs require intense collaborative and interdisciplinary clinical research. We recently founded the Cooperative European Paediatric Renal TransplAnt INitiative (CERTAIN; www.certain-registry.eu) as a research network and platform built on a novel, web-based registry. RESULTS: The registry's dataset provides essential information on generic kidney transplantation-related topics and also captures pediatric-specific topics, such as growth, physical and psychosocial development, and adherence. Due to its flexibility the system can be used as follows: (1) as a registry capturing a minimal or an extended dataset; (2) as a center and/or country-specific transplantation database; or (3) as a patient-specific electronic transplantation chart. The data can be exported directly from the CERTAIN web application into statistical software packages for scientific analyses. The rights regarding data ownership, evaluation, and publications are regulated in the registry's rules of procedure. Data quality is ensured by automatic software validation and a manual data review process. To avoid redundant data entry, CERTAIN has established interfaces for data change with Eurotransplant, the Collaborative Transplant Study (CTS), and the registry of the European Society of Pediatric Nephrology (ESPN) and European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) (ESPN/ERA-EDTA registry). CERTAIN fulfils all regulatory and ethical requirements of the European Union and Germany, in particular, regarding patients' data privacy and security. CONCLUSION: Using modern information technology, the recently established multinational CERTAIN Registry fills a gap in Europe for collaborative 5 research and quality assurance in the field of pediatric renal transplantation.

Mycophenolate mofetil in pediatric renal transplantation.

Since mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), has been approved for maintenance immunosuppressive therapy also in children after renal transplantation it has become an important part of immunosuppressive protocols. By inhibiting inosine monophosphate dehydrogenase, the key enzyme in the de novo purine biosynthesis of proliferating T and B lymphocytes, MMF acts as a relatively specific inhibitor of human lymphocyte proliferation. MMF is more effective than azathioprine in combination with cyclosporin A (CsA) and corticosteroids and distinctly reduces the incidence of acute rejection episodes in the 1st year post-transplant in adults as well as in children. Beneficial effects on steroid-resistant rejection and chronic allograft dysfunction have been shown. In general, MMF is well tolerated. Major adverse events in pediatric renal transplant recipients include leukopenia, infections and gastrointestinal problems. Pharmacokinetic monitoring of MPA can help to optimise MMF therapy after renal transplantation, as associations between the risk of acute rejection episodes and MPA-AUC values and MPA predose levels have been demonstrated. The incidence of MMF-related side effects such as leukopenia and/or infections, however, is associated with pharmacokinetic parameters of free MPA. Reference data of relevant pharmacokinetic parameters are available. The possible steroid-sparing potential of MMF is an important issue in pediatric renal transplantation. Preliminary data demonstrate improved longitudinal growth, less cushingoid habitus and lower blood pressure after steroid-withdrawal in pediatric renal transplant recipients under MMF and CsA therapy.

Divergent evolution of (betaalpha)8-barrel enzymes.

The (betaalpha)8-barrel is the most versatile and most frequently encountered fold among enzymes. It is an interesting question how the contemporary (betaalpha)8-barrels are evolutionarily related and by which mechanisms they evolved from more simple precursors. Comprehensive comparisons of amino acid sequences and three-dimensional structures suggest that a large fraction of the known (betaalpha)8-barrels have divergently evolved from a common ancestor. The mutational interconversion of enzymatic activities of several (betaalpha)8-barrels further supports their common evolutionary origin. Moreover, the high structural similarity between the N- and C-terminal (betaalpha)4 units of two (betaalpha)8-barrel enzymes from histidine biosynthesis indicates that the contemporary proteins evolved by tandem duplication and fusion of the gene of an ancestral 'half-barrel' precursor. In support of this hypothesis, recombinantly produced 'half-barrels' were shown to be folded, dimeric proteins.

Stability, catalytic versatility and evolution of the (beta alpha)(8)-barrel fold.

The (beta alpha)(8)-barrel is a versatile single-domain protein fold that is adopted by a large number of enzymes. The (beta alpha)(8)-barrel fold has been used as a model to elucidate the structural basis of protein thermostability and in studies to interconvert catalytic activities or substrate specificities by rational design or directed evolution. Recently, the (beta alpha)(4)-half-barrel was identified as a possible structural subdomain.

Dissection of a (betaalpha)8-barrel enzyme into two folded halves.

The (betaalpha)8-barrel, which is the most frequently encountered protein fold, is generally considered to consist of a single structural domain. However, the X-ray structure of the imidazoleglycerol phosphate synthase (HisF) from Thermotoga maritima has identified it as a (betaalpha) 8-barrel made up of two superimposable subdomains (HisF-N and HisF-C). HisF-N consists of the four N-terminal (betaalpha) units and HisF-C of the four C-terminal (betaalpha) units. It has been postulated, therefore, that HisF evolved by tandem duplication and fusion from an ancestral half-barrel. To test this hypothesis, HisF-N and HisF-C were produced in Escherichia coli, purified and characterized. Separately, HisF-N and HisF-C are folded proteins, but are catalytically inactive. Upon co-expression in vivo or joint refolding in vitro, HisF-N and HisF-C assemble to the stoichiometric and catalytically fully active HisF-NC complex. These findings support the hypothesis that the (betaalpha)8-barrel of HisF evolved from an ancestral half-barrel and have implications for the folding mechanism of the members of this large protein family.

[Coping with illness by chronically ill adolescents and young adults--an empirical study]. / Krankheitsverarbeitung bei chronisch kranken Jugendlichen und jungen Erwachsenen--eine empirische Untersuchung.

From June 1990 to January 1991 86 chronically ill adolescents and young adults who had come to the vocational assessment unit of the rehabilitation center or for vocational guidance to the rehabilitation hospital, both in Neckargemünd/Germany, were examined with regard to their coping with their illnesses. The Freiburg questionnaire for coping with illness was applied, and the Trait-instruction was given because persons with inborn disabilities were part of the sample. Also, the type of illness or disability and motorial handicap as well as the non-verbal intelligence were included. The results of three different medical diagnosis groups don't show any differences in the coping with illness. Persons with motorial handicaps are able to cope with their disabilities as well as persons without motorial handicaps. Adolescents and young adults with inborn or early acquired illness/handicap show a greater loss of confidence in the medical doctors than persons who were taken ill at the age of 6 or later.