A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation.

To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.

Single application of low-dose mycophenolate mofetil-OX7-immunoliposomes ameliorates experimental mesangial proliferative glomerulonephritis.

IgA nephropathy, one of the most frequent forms of glomerulonephritis, characterized by mesangial hypercellularity and glomerular extracellular matrix (ECM) expansion, often leads to end-stage renal disease over a prolonged period. We investigated whether antiproliferative treatment in a single low dose specifically targeted to the glomerular mesangium by immunoliposomes (ILs) results in an amelioration of mesangial proliferative glomerulonephritis in rats (anti-Thy1.1 nephritis). Mycophenolate mofetil (MMF) containing ILs was generated that targets the Thy1.1 antigen (OX-7) in rat mesangial cells. Treatment benefit of a single intravenous dose of these ILs given 2 days after disease induction was investigated by stereology, immunohistochemistry, and functional analyses (creatinine, albuminuria) until day +9 and was compared among untreated and free MMF-treated rats using six male Wistar rats per group. MMF-loaded OX7-IL prevented creatinine increase and albuminuria. Stereological analyses of MMF OX7-IL-treated animals yielded 30% reduction of mesangial cells on day +9 and a 40% reduction of glomerular ECM volume on day +5, compared with all of the other nephritic animals. Furthermore, at days +5 and +9 we observed decreased ECM content and decreased glomerular volume (day +5) in the MMF-OX7-IL-treated group compared with the nephritic group treated with free MMF. In conclusion, MMF-OX7-IL-based directed drug delivery represents a novel approach for treating mesangial cell-mediated forms of glomerulonephritis.

Meta-analyses qualify metzincins and related genes as acute rejection markers in renal transplant patients.

Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T-cell-mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n = 20), borderline changes (BL, n = 4), AR (n = 10) and AR + IF/TA (n = 7). MARGS enriched in all data sets were further examined on mRNA and/or protein level in additional patients. METS and MARGS differentiated AR from BL, AR + IF/TA and N in a principal component analysis. Their expression changes correlated to Banff t- and i-scores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, -9, TIMP1, -2, thrombospondin2 (THBS2) and fibrillin1. RT-PCR using microdissected glomeruli/tubuli confirmed MMP7, -9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, -9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7/-9 represent potential molecular AR markers.

Renal allografts with IF/TA display distinct expression profiles of metzincins and related genes.

Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.

Effects of increased dietary phosphorus on magnesium balance in very low birthweight babies.

The effects of three dietary phosphorus concentrations on magnesium balance in very low birth weight (VLBW) infants were measured. The infants consumed one of three special formulas for 20 consecutive days. Magnesium balance was calculated by measuring food intake, urinary magnesium and fecal magnesium. The highest dietary phosphorus concentration resulted in a higher (P < 0.05) fecal loss of magnesium. Net absorption and net retention of magnesium were lower (P < 0.10) in the high phosphorus group. A modest (33 per cent) increase in dietary phosphorus resulted in a decrease in magnesium absorption in VLBW infants.

Organ donation in Switzerland: a survey on marginal or extended criteria donors (ECD) from 1998 to 2009.

BACKGROUND: The widening gap between the numbers of patients on the waiting list for organ transplantation and the insufficient numbers of organ donors results in the use of "critical" donors, so-called marginal donors or extended criteria donors. Data concerning the evaluation of extended criteria donors (ECD) in Switzerland are sparse. METHODS: All organ donors in Switzerland between 1.1.1998 and 30.6.2009 have been evaluated for special criteria. ECD were defined on the basis of at least one of seven criteria: six DOPKI criteria (ECD-DOPKI) and/or age ≥60 yr (ECD-Age). Once included in the study, special features, short time follow-up (first 7 days after transplantation) and the cold ischaemia time of all the transplanted organs were evaluated. RESULTS: During the period 1.1.1998 to 30.6.2009, a total of 408 organ donors were classified as ECD, reflecting 39% of all organ donors in this time period. Despite the fact that all organ donors in this study fulfilled at least one inclusion criterion, the number of recipients with satisfactory primary organ function was always higher than the respective number with a negative primary outcome within the first seven days after transplantation. A longer cold ischaemia time was associated with organs showing insufficient primary organ function compared to organs with satisfactory primary function. A relevant causal relationship cannot be investigated on the basis of our limited data. In addition, a longer observation period would be necessary to draw a more precise conclusion. CONCLUSIONS: ECD as defined by DOPKI and/or age represent a high proportion of all organ donors in Switzerland but show a remarkably good outcome.

[Pareto optimal communication of the medical qualities of practicing ophthalmologists: a new option for patient information?]. / Paretooptimale Kommunikation der medizinischen Stärken niedergelassener Augenärzte: Eine neue Möglichkeit der Patienteninformation?

BACKGROUND: This investigation analyzed the possibility to provide information about the medical qualities of ophthalmologists to make it easier for patients to find the right physician in a Pareto optimal way, i.e. to supply information so that nobody is harmed and at least one derives benefits. METHODS: Extensive interviews with key deciders in the system for ophthalmological care were carried out and analyzed. RESULTS: Pareto optimization is possible. However, implementation is not yet feasible mainly because of legal and economic restrictions and because of difficulties of the measuring system. In order to come to a result, a major medical, economic and legal effort would be required which is unlikely to come into place in the short-term. CONCLUSION: At least in the near future there will be no new Pareto optimal information systems available for patients in order to find the appropriate ophthalmologist. In the mid-term the situation could change if the open questions can be resolved.