Dynamic Epicardial Contribution to Cardiac Interstitial c-Kit and Sca1 Cellular Fractions.

Background: The cardiac interstitial cellular fraction is composed of multiple cell types. Some of these cells are known to express some well-known stem cell markers such as c-Kit and Sca1, but they are no longer accepted to be true cardiac stem cells. Although their existence in the cardiac interstitium has not been disputed, their dynamic throughout development, specific embryonic origin, and potential heterogeneity remain unknown. In this study, we hypothesized that both c-KitPOS and Sca1POS cardiac interstitial cell (CIC) subpopulations are related to the Wilms' tumor 1 (Wt1) epicardial lineage. Methods: In this study, we have used genetic cell lineage tracing methods, immunohistochemistry, and FACS techniques to characterize cardiac c-KitPOS and Sca1POS cells. Results: Our data show that approximately 50% of cardiac c-KitPOS cells are derived from the Wt1-lineage at E15.5. This subpopulation decreased along with embryonic development, disappearing from P7 onwards. We found that a large proportion of cardiac c-KitPOS cells express specific markers strongly suggesting they are blood-borne cells. On the contrary, the percentage of Sca1POS cells within the Wt1-lineage increases postnatally. In accordance with these findings, 90% of adult epicardial-derived endothelial cells and 60% of mEFSK4POS cardiac fibroblasts expressed Sca1. Conclusion: Our study revealed a minor contribution of the Wt1-epicardial lineage to c-KitPOS CIC from embryonic stages to adulthood. Remarkably, a major part of the adult epicardial-derived cell fraction is enriched in Sca1, suggesting that this subpopulation of CICs is heterogeneous from their embryonic origin. The study of this heterogeneity can be instrumental to the development of diagnostic and prognostic tests for the evaluation of cardiac homeostasis and cardiac interstitium response to pathologic stimuli.

Gait Speed and Grip Strength Are Associated With Dropping Out of the Liver Transplant Waiting List.

INTRODUCTION: Frailty measures can predict perioperative surgical risk in liver transplant patients. The 5-meter walk test (5MWT) and hand grip strength (HGS) are easy and reproducible frailty measures. We hypothesized that they could capture frailty in liver transplant listed patients and would be associated with dropping out of the waiting list. METHODS: We conducted a retrospective analysis of patients undergoing outpatient liver transplant listing at the University of Pittsburgh Medical Center from 2013 to 2016. We compared demographics, baseline laboratory markers, 5MWT, and HGS between patients who were dropped from the waiting list for medical reasons and those who remained or were successfully transplanted. Bivariate statistical analysis was performed using Fisher exact or χ2 tests. RESULTS: We reviewed 197 patients listed for liver transplant. Average age was 57.1 years (range 20-74), and patients were predominantly white (90.4%). Patients' most common etiology of liver disease was hepatitis C (32.5%), 14 (7.1%) had a previous liver transplant, and average Model for End-Stage Liver Disease score upon listing was 16.0. Of the cohort, 38 (19.3%) were ultimately dropped from the waitlist due to non-hepatocellular carcinoma-related reasons. Patients dropped from the waiting list had weaker HGS (46.14 lb vs 59.6 lb; P < .005) and slower 5MWT speed (5MWT: 0.92 m/s vs 1.03 m/s; P < .005). CONCLUSION: The 5MWT and HGS can easily measure frailty in patients being evaluated for liver transplant. These tests are associated with waiting list dropout, indicating that they can be valuable tools in the evaluation of these patients.

Retrospective evaluation of donor pain and pain management after laprascopic nephrectomy.

PURPOSE: The purpose of this study was to evaluate donor pain and pain management beginning immediately postoperatively until hospital discharge. METHODS: All kidney donors were included from 2008 and 2009. Demographic data, operative data, pain scores in the postanesthesia care unit, and visual analog pain scale (VAS) scores were collected for each patient. Standardization for comparison was made by converting doses to intravenous morphine equivalents (ME). RESULTS: Eighty-five patients were identified as donors, all of which underwent laparoscopic nephrectomy. Daily analgesic requirement was significantly reduced from postoperative day 1 to postoperative day 2 (42.2 mg ME versus 19.7 mg ME, P < .0001). The use of patient-controlled analgesia (PCA) did not demonstrate improved pain management with similar VAS scores for users and nonusers on the day of operation (5.4 vs 5.6, P = .87), postoperative day 1 (4.9 vs 5.4, P = .5), and postoperative day 2 (4.7 vs 4.5, P = .65), respectively. Even though similar VAS scores were found for PCA users and nonusers, PCA users had significantly higher opioid use on the day of operation (P = .007) and postoperative day 1 (P = .004). CONCLUSIONS: The average VAS score on the day of operation was 5.5, with patients experiencing a significant reduction in VAS score on postoperative day 1. PCA delivery did not provide any additional benefit in pain relief in this cohort.

CXCR1 deficiency does not alter liver regeneration after partial hepatectomy in mice.

Previous studies have shown that CXC chemokines containing Glu-Leu-Arg (ELR) in their amino-terminus stimulate hepatocyte proliferation and liver regeneration after partial hepatectomy. These ELR+CXC chemokines bind to two receptors, CXCR1 and CXCR2. Previous work has shown that CXCR2 is involved in the proliferative effects of CXC chemokines. However, the function of CXCR1 during the regenerative response has not been studied. The aim of the current study was to investigate the role of CXCR1 in liver regeneration after partial hepatectomy. C57BL/6 (wild type) or CXCR1-/- mice were subjected to 70% partial hepatectomy or sham surgery and sacrificed on day 2 and 4 after operation. There were no significant differences in liver-to-body weight ratio or hepatocyte proliferation. The data suggest that CXCR1 does not mediate the proliferative effects of ELR+ CXC chemokines during liver regeneration after partial hepatectomy.

Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss.

The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single-antigen beads. Fifty-two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow-up was 27.0 +/- 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA >20% (current) and/or >50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6-fold increased allograft loss risk, p = 0.017) to be significant. Four-year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/C4d) (65%) or antibody-mediated rejection (35%) (p < 0.001). Patients with >50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.

Proteasome inhibition reduces donor-specific antibody levels.

BACKGROUND: Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, rituximab, polyclonal antibodies) do not target the primary antibody producing B cells, that is, the plasma cell. We report the preliminary results from the first clinical experience with plasma cell targeted therapy with bortezomib. Bortezomib is approved by the US Food and Drug Administration for the treatment of plasma cell tumors (multiple myeloma). METHODS: Kidney transplant patients with mixed acute cellular rejection (ACR) and AMR episodes (by Banff '97 criteria, update 2005) were treated with bortezomib (1.3 mg/m(2) per dose x 4) at standard labeled doses. Patients were monitored by serial donor specific anti-HLA antibody (DSA) determinations [Luminex/Labscreen beads] and quantified by conversion to fluorescence intensity to molecules of equivalent soluble fluorescence (MESF). RESULTS: Five patients were treated with bortezomib. Each patient also had coexisting ACR. In each case, bortezomib treatment led to prompt ACR and AMR rejection reversal. DSA levels decreased significantly in all patients (except 1 patient who had short follow-up). Observed toxicities from bortezomib included a transient grade III thrombocytopenia (1 patient) and mild-to-moderate nausea, vomiting, and/or diarrhea (3/5 patients). Opportunistic infections were not observed. CONCLUSIONS: Bortezomib therapy provides effective reduction in DSA levels with long-term suppression. These preliminary results indicate that proteasome inhibition provides an effective means for reducing HLA antibody levels in transplant recipients.

[Importance of HDL cholesterol determination in the evaluation of coronary risk in clinical practice]. / Importancia de la determinación del colesterol HDL en la valoración del riesgo coronario en la práctica clínica.

OBJECTIVE: To validate to what extent the isolated determination of total Cholesterol (TC) is effective when seeking to predict coronary risk. DESIGN: An observational crossover study of the analytic determinations of the clinics which systematically request TC and HDL-Cholesterol (HDL)--case-finding method. SETTING: Health Centre. PARTICIPANTS: 631 analytic determinations, with samples from people who attended a Health Centre between May and November 1992, were studied. MEASUREMENTS AND MAIN RESULTS: As proof of certainty the Atherogenic Index (AI) was used for the relative risks (RR) of suffering a coronary event in line with the Framingham study. The confidence limits (CL) were calculated to 95% in order to quantify random error and permit comparison. On varying the cut-off points of TC the indicators changed, being more sensitive (S) and less specific (E) with the lower figures: 180 mg/dl, RR > 1, S = 97.5% (CL: 100-94.7) and E = 30.5% (36.8-24.2); RR > 2, S = 100%, E = 22.1% (26.9-17.3) and RR > 3, S = 100%, E = 20.8% (25.3-16.3). As values of TC increase, S diminishes and E increases: 250 mg/dl, RR > 1, S = 48.3% (57.2-39.4), E = 87.2% (91.8-82.6); RR > 2, S = 58.6% (76.5-40.7), E = 77.2% (82-72.4) and RR > 3, S = 63.6% (92-35.2), E = 75.3% (80.1-70.5). CONCLUSIONS: HDL must be determined if TC is -200 mg/dl. If everyone with RR > 2 is to be detected, HDL-cholesterol from TC > or = 180 mg/dl must be measured.