Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection.

To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score >37%  = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection

A New Kilohertz Gravitational-Wave Feature from Rapidly Rotating Core-Collapse Supernovae

We present self-consistent three-dimensional core-collapse supernova simulations of a rotating $20M_\odot$ progenitor model with various initial angular velocities from $0.0$ to $4.0$ rad s$^{-1}$ using a smoothed particle hydrodynamics code, SPHYNX, and a grid-based hydrodynamics code, FLASH. We identify two strong gravitational-wave features, with peak frequencies of $\sim300$ Hz and $\sim1.3$ kHz in the first $100$ ms postbounce. We demonstrate that these two features are associated with the $m=1$ deformation from the proto-neutron star (PNS) modulation induced by the low-$T/|W|$ instability, regardless of the simulation code. The $300$ Hz feature is present in models with an initial angular velocity between $1.0$ and $4.0$ rad s$^{-1}$, while the $1.3$ kHz feature is present only in a narrower range, from $1.5$ to $3.5$ rad s$^{-1}$. We show that the $1.3$ kHz signal originates from the high-density inner core of the PNS, and the $m=1$ deformation triggers a strong asymmetric distribution of electron anti-neutrinos. In addition to the $300$ Hz and $1.3$ kHz features, we also observe one weaker but noticeable gravitational-wave feature from higher-order modes in the range between $1.5$ and $3.5$ rad s$^{-1}$. Its peak frequency is around $800$ Hz initially and gradually increases to $900-1000$ Hz. Therefore, in addition to the gravitational bounce signal, the detection of the $300$ Hz, $1.3$ kHz, the higher-order mode, and even the related asymmetric emission of neutrinos, could provide additional diagnostics to estimate the initial angular velocity of a collapsing core.Comment: 20 pages, 14 figures,. Accepted for publication in the Astrophysical Journa

Characterization of intra-graft B cells during renal allograft rejection

Intra-graft CD20+ B-cell clusters are found during acute rejection of renal allografts and correlate with graft recovery following rejection injury. Here using archived kidney tissue we conducted immunohistochemical studies to measure specific subsets of pathogenic B cells during graft rejection. Cluster-forming CD20+ B cells in the rejected graft are likely derived from the recipient and are composed of mature B cells. These cells are activated (CD79a+), and present MHC Class II antigen (HLADR+) to CD4+ T cells. Some of these clusters contained memory B cells (CD27+) and they did not correlate with intra-graft C4d deposition or with detection of donor-specific antibody. Further, several non-cluster forming CD20− B-lineage CD38+ plasmablasts and plasma cells were found to infiltrate the rejected grafts and these cells strongly correlated with circulating donor-specific antibody, and to a lesser extent with intra-graft C4d. Both CD20+ B cells and CD38+ cells correlated with poor response of the rejection to steroids. Reduced graft survival was associated with the presence of CD20 cells in the graft. In conclusion, a specific subset of early lineage B cells appears to be an antigen-presenting cell and which when present in the rejected graft may support a steroid-resistant T-cell-mediated cellular rejection. Late lineage interstitial plasmablasts and plasma cells may also support humoral rejection. These studies suggest that detailed analysis of interstitial cellular infiltrates may allow better use of B-cell lineage specific treatments to improve graft outcomes

α-Lactosylceramide Protects Against iNKT-Mediated Murine Airway Hyperreactivity and Liver Injury Through Competitive Inhibition of Cd1d Binding.

Invariant natural killer T (iNKT) cells, which are activated by T cell receptor (TCR)-dependent recognition of lipid-based antigens presented by the CD1d molecule, have been shown to participate in the pathogenesis of many diseases, including asthma and liver injury. Previous studies have shown the inhibition of iNKT cell activation using lipid antagonists can attenuate iNKT cell-induced disease pathogenesis. Hence, the development of iNKT cell-targeted glycolipids can facilitate the discovery of new therapeutics. In this study, we synthesized and evaluated α-lactosylceramide (α-LacCer), an α-galactosylceramide (α-GalCer) analog with lactose substitution for the galactose head and a shortened acyl chain in the ceramide tail, toward iNKT cell activation. We demonstrated that α-LacCer was a weak inducer for both mouse and human iNKT cell activation and cytokine production, and the iNKT induction by α-LacCer was CD1d-dependent. However, when co-administered with α-GalCer, α-LacCer inhibited α-GalCer-induced IL-4 and IFN-γ production from iNKT cells. Consequently, α-LacCer also ameliorated both α-GalCer and GSL-1-induced airway hyperreactivity and α-GalCer-induced neutrophilia when co-administered in vivo. Furthermore, we were able to inhibit the increases of ConA-induced AST, ALT and IFN-γ serum levels through α-LacCer pre-treatment, suggesting α-LacCer could protect against ConA-induced liver injury. Mechanistically, we discerned that α-LacCer suppressed α-GalCer-stimulated cytokine production through competing for CD1d binding. Since iNKT cells play a critical role in the development of AHR and liver injury, the inhibition of iNKT cell activation by α-LacCer present a possible new approach in treating iNKT cell-mediated diseases

A General Phase Matching Condition for Quantum Searching Algorithm

A general consideration on the phase rotations in quantum searching algorithm is taken in this work. As four phase rotations on the initial state, the marked states, and the states orthogonal to them are taken account, we deduce a phase matching condition for a successful search. The optimal options for these phase are obtained consequently.Comment: 3 pages, 3 figure

A novel trivalent non-Fc anti-CD3 Collabody preferentially induces Th1 cell apoptosis in vitro and long-lasting remission in recent-onset diabetic NOD mice

Specific anti-CD3 treatment is deemed to be a promising therapy for allograft rejection and type 1 diabetes (T1D). Fc receptor (FcR) reduced-binding antibodies, by avoiding adverse effects of Fc and FcR interaction, have good therapeutic potential. We generated a trivalent anti-mouse-CD3 Collabody, h145CSA, by using a triplex-forming collagen-like peptide (Gly-Pro-Pro)10 to drive the trimerization of the Fab fragments. Exposure to h145CSA, but not its bivalent counterparts 145-2C11 and h145chIgGAA (FcR reduced-binding format), upregulates FasL expression on Th1 cells and causes Th1 cell apoptosis. Administration of h145CSA invokes minimal mitogenic effects in mice. The ability of multiple dosing of h145CSA to induce splenic CD4+ T-cell depletion is comparable to bivalent antibodies but is characterized by more rapid CD4+ T-cell recovery kinetics. h145CSA is more potent than h145chIgGAA in inducing long-lasting remission in recent-onset diabetic NOD mice. Its therapeutic effect is accompanied by a significantly lower percentage of CD4+IFNγ+ T cells and a higher Treg/Th1 ratio in pancreatic and mesenteric lymph nodes. The results of our study demonstrate that trivalent non-Fc anti-CD3 Collabody has the potential to be used in the treatment of T1D

Outcome for self-expandable metal stents in patients with malignant gastroduodenal obstruction: A single center experience

SummaryBackgroundMalignant gastric outlet obstruction causes significant malnutrition and morbidity. The implantation of a metallic stent is an alternative palliative treatment to allow the intake of food in these patients.Patients and MethodsThirty-eight consecutive patients with malignant gastric outlet obstruction who had received an uncovered metallic stent placement in our department from April 2010 to April 2012 were enrolled for analysis. The mean follow-up time was 6.3 months. Food intake, measured by the Gastric Outlet Obstruction Scoring System, complications, duration of stent patency, and survival were evaluated.ResultsThe technical and clinical success rates of the procedure were 100% and 94.7%, respectively. The Gastric Outlet Obstruction Scoring System scores were significantly improved at 1 day, 7 days, and 30 days after the implantation compared with those prior to the procedure (p < 0.001). Aspiration pneumonia developed in two patients (5.2%) after the procedure. One of these patients developed respiratory failure and died 3 days later. Stent dysfunction developed in 11 of 38 patients (28.9%) during the follow-up period; one patient (2.6%) experienced migration of the stent 38 days later due to resolution of the stricture; 10 patients (26.3%) had stent restenosis. The median time of stent patency was 120 days. The presence of peritoneal carcinomatosis when the procedure was carried out was a significantly poor predictive factor of stent patency [hazard ratio (HR) 7.9, p = 0.039]. The median survival of the patients was 156 days. Poor performance status ≥3; HR 2.647, p = 0.012) and nongastric cancer origin (HR 3.466, p = 0.008) were associated with a significantly short survival time.ConclusionMetallic stent placement is an effective and relatively safe treatment for patients with malignant gastric outlet obstruction

Ventricular divergence correlates with epicardial wavebreaks and predicts ventricular arrhythmia in isolated rabbit hearts during therapeutic hypothermia

INTRODUCTION: High beat-to-beat morphological variation (divergence) on the ventricular electrogram during programmed ventricular stimulation (PVS) is associated with increased risk of ventricular fibrillation (VF), with unclear mechanisms. We hypothesized that ventricular divergence is associated with epicardial wavebreaks during PVS, and that it predicts VF occurrence. METHOD AND RESULTS: Langendorff-perfused rabbit hearts (n = 10) underwent 30-min therapeutic hypothermia (TH, 30°C), followed by a 20-min treatment with rotigaptide (300 nM), a gap junction modifier. VF inducibility was tested using burst ventricular pacing at the shortest pacing cycle length achieving 1:1 ventricular capture. Pseudo-ECG (p-ECG) and epicardial activation maps were simultaneously recorded for divergence and wavebreaks analysis, respectively. A total of 112 optical and p-ECG recordings (62 at TH, 50 at TH treated with rotigaptide) were analyzed. Adding rotigaptide reduced ventricular divergence, from 0.13±0.10 at TH to 0.09±0.07 (p = 0.018). Similarly, rotigaptide reduced the number of epicardial wavebreaks, from 0.59±0.73 at TH to 0.30±0.49 (p = 0.036). VF inducibility decreased, from 48±31% at TH to 22±32% after rotigaptide infusion (p = 0.032). Linear regression models showed that ventricular divergence correlated with epicardial wavebreaks during TH (p<0.001). CONCLUSION: Ventricular divergence correlated with, and might be predictive of epicardial wavebreaks during PVS at TH. Rotigaptide decreased both the ventricular divergence and epicardial wavebreaks, and reduced the probability of pacing-induced VF during TH