Rapamycin has no effect on fibrosis-associated gene expression or extracellular matrix accumulation when administered to animals with established or early allograft vasculopathy

AbstractBackgroundMost patients with functioning heart transplants have established and progressive chronic allograft vasculopathy, a fibroproliferative process for which there is no effective treatment. Coronary artery disease is characterized by histologic evidence of extracellular matrix accumulation (fibrosis). This study compares the effect of rapamycin administered to rats with established allograft vasculopathy on histologic indices of disease progression, extracellular matrix accumulation (fibrosis), and the expression of genes known to regulate extracellular matrix turnover in this model.MethodsLewis recipients of Fisher 344 rat thoracic to abdominal aorta transplants were administered rapamycin starting at 8, 12, and 16 weeks posttransplant or no treatment. Six grafts in each group were harvested at 24 weeks. Vascular remodeling and collagen accumulation (Sirius red) were measured by computerized histomorphometry of aortic sections. mRNA was extracted from frozen tissue, and the expression of fibrosis-associated genes was studied by means of semiquantitative reverse transcriptase-polymerase chain reaction.ResultsRapamycin had no effect on the progression of early or established allograft vasculopathy with regard to intimal thickening, remodeling, extracellular matrix accumulation, or profibrotic gene expression, regardless of the time commenced.ConclusionThe attenuation of the fibroproliferative response in rodents by rapamycin is not seen if the onset of rapamycin therapy is delayed

Lattice Monte Carlo calculations for unitary fermions in a finite box

We perform lattice Monte Carlo simulations for up to 66 unitary fermions in a finite box using a highly improved lattice action for nonrelativistic spin 1/2 fermions. We obtain a value of $0.366^{+0.016}_{-0.011}$ for the Bertsch parameter, defined as the energy of the unitary Fermi gas measured in units of the free gas energy in the thermodynamic limit. In addition, for up to four unitary fermions, we compute the spectrum of the lattice theory by exact diagonalization of the transfer matrix projected onto irreducible representations of the octahedral group for small to moderate size lattices, providing an independent check of our few-body simulation results. We compare our exact numerical and simulation results for the spectrum to benchmark studies of other research groups, as well as perform an extended analysis of our lattice action improvement scheme, including an analysis of the errors associated with higher partial waves and finite temporal discretization.Comment: Significant revisions from previous version. Included data at a larger volume and performed an infinite volume extrapolation of the Bertsch parameter. Published versio

Anastomosis of dual renal transplant veins.

As there is usually considerable overlap in the renal venous drainage, it is often possible to ligate supernumerary transplant renal veins in order to simplify the implantation procedure. Nonetheless, decisions about whether to implant multiple veins can be difficult and are usually made subjectively. Here, we describe the use of intraoperative Doppler ultrasound as an adjunct to decision-making when there are two renal veins and a novel technique for the sequential anastomosis of dual veins. The kidney was reperfused after anastomosis of the main renal vein with the second vein clamped. On-table Doppler ultrasound demonstrated reversed flow in diastole indicating that the second renal vein also needed to be anastomosed. By clamping the external iliac vein inferior to the first venous anastomosis it was possible to complete the lower polar renal vein anastomosis to the external iliac vein without interrupting the perfusion of the kidney

Correlations, fluctuations and stability of a finite-size network of coupled oscillators

The incoherent state of the Kuramoto model of coupled oscillators exhibits marginal modes in mean field theory. We demonstrate that corrections due to finite size effects render these modes stable in the subcritical case, i.e. when the population is not synchronous. This demonstration is facilitated by the construction of a non-equilibrium statistical field theoretic formulation of a generic model of coupled oscillators. This theory is consistent with previous results. In the all-to-all case, the fluctuations in this theory are due completely to finite size corrections, which can be calculated in an expansion in 1/N, where N is the number of oscillators. The N -> infinity limit of this theory is what is traditionally called mean field theory for the Kuramoto model.Comment: 25 pages (2 column), 12 figures, modifications for resubmissio

Identifying Biomarkers from Transcriptomic Signatures in Renal Allograft Biopsies Using Deceased and Living Donors.

The survival of transplant kidneys using deceased donors (DD) is inferior to living donors (LD). In this study, we conducted a whole-transcriptome expression analysis of 24 human kidney biopsies paired at 30 minutes and 3 months post-transplantation using DD and LD. The transcriptome profile was found significantly different between two time points regardless of donor types. There were 446 differentially expressed genes (DEGs) between DD and LD at 30 minutes and 146 DEGs at 3 months, with 25 genes common to both time points. These DEGs reflected donor injury and acute immune responses associated with inflammation and cell death as early as at 30 minutes, which could be a precious window of potential intervention. DEGs at 3 months mainly represented the changes of adaptive immunity, immunosuppressive treatment, remodeling or fibrosis via different networks and signaling pathways. The expression levels of 20 highly DEGs involved in kidney diseases and 10 genes dysregulated at 30 minutes were found correlated with renal function and histology at 12 months, suggesting they could be potential biomarkers. These genes were further validated by quantitative polymerase chain reaction (qPCR) in 24 samples analysed by microarray, as well as in a validation cohort of 33 time point unpaired allograft biopsies. This analysis revealed that SERPINA3, SLPI and CBF were up-regulated at 30 minutes in DD compared to LD, while FTCD and TASPN7 were up-regulated at both time points. At 3 months, SERPINA3 was up-regulated in LD, but down-regulated in DD, with increased VCAN and TIMP1, and decreased FOS, in both donors. Taken together, divergent transcriptomic signatures between DD and LD, and changed by the time post-transplantation, might contribute to different allograft survival of two type kidney donors. Some DEGs including FTCD and TASPN7 could be novel biomarkers not only for timely diagnosis, but also for early precise genetic intervention at donor preservation, implantation and post-transplantation, in particular to effectively improve the quality and survival of DD

Comparative Analysis of Risk Factors in Declined Kidneys from Donation after Brain Death and Circulatory Death.

Background and objectives: Kidneys from donation after circulatory death (DCD) are more likely to be declined for transplantation compared with kidneys from donation after brain death (DBD). The aim of this study was to evaluate characteristics in the biopsies of human DCD and DBD kidneys that were declined for transplantation in order to rescue more DCD kidneys. Materials and Methods: Sixty kidney donors (DCD = 36, DBD = 24) were recruited into the study and assessed using donor demographics. Kidney biopsies taken post cold storage were also evaluated for histological damage, inflammation (myeloperoxidase, MPO), von Willebrand factor (vWF) expression, complement 4d (C4d) deposition and complement 3 (C3) activation using H&E and immunohistochemistry staining, and Western blotting. Results: More DBD donors (16/24) had a history of hypertension compared with DCDs (8/36, p = 0.001). The mean warm ischemic time in the DCD kidneys was 12.9 ± 3.9 min. The mean cold ischemic time was not significantly different between the two groups of kidney donors (DBD 33.3 ± 16.7 vs. DCD 28.6 ± 14.1 h, p > 0.05). The score of histological damage and MPO, as well as the reactivity of vWF, C4d and C3, varied between kidneys, but there was no significant difference between the two donor types (p > 0.05). However, vWF reactivity might be an early indicator for loss of tissue integrity, while C4d deposition and activated C3 might be better predictors for histological damage. Conclusions: Similar characteristics of DCD were shown in comparison with DBD kidneys. Importantly, the additional warm ischemic time in DCD appeared to have no further detectable adverse effects on tissue injury, inflammation and complement activation. vWF, C4d and C3 might be potential biomarkers facilitating the evaluation of donor kidneys