Qa and stenosis surveillance were not associated with improved graft survival, although thrombosis was reduced in the stenosis group. The most important factors in this result may be that monthly Qa and quarterly stenosis measurements were not accurate or timely indicators of risk of thrombosis or progressive stenosis. This study does not support the concept that Qa or stenosis surveillance are superior to aggressive clinical monitoring.

BackgroundPTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice.Methods and FindingsPurified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.ConclusionsIncreased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1−/− mice to inflammation and injury-induced cell death.

Most recent randomized controlled trials (RCTs) have found that hemodialysis graft surveillance combined with preemptive correction of stenosis does not prolong graft survival. Nevertheless, such programs may be justified if they reduce other adverse outcomes or decrease the cost of care. This study tested this hypothesis by applying a secondary analysis to our original RCT. This study of 101 patients evaluated correction of stenosis based upon blood flow (Q) and stenosis surveillance. Patients were randomly assigned to control, flow, or stenosis groups, and were followed for up to 28 months. Q was measured monthly by ultrasound dilution; stenosis was measured quarterly by duplex ultrasound. Stenosis of 50% was corrected by percutaneous transluminal angioplasty (PTA) after referral for angiography. Referral criteria were: control group, clinical criteria; flow group, Q < 600 ml/min or clinical criteria; stenosis group, stenosis > 50% or clinical criteria. We compared access-related hospitalizations and cost of care, and use of central venous dialysis catheters (CVCs), among the three groups. Hospitalization rates were higher in the control and flow groups than in the stenosis group (0.50, 0.57, 0.18/patient-year, respectively [p < 0.01]), and hospitalization costs were lowest in the stenosis group (p = 0.026). The stenosis group had a trend toward lowest CVC rates (0.44, 0.32, 0.20/patient-year, respectively [p = 0.20]). The costs of care were higher in the control and flow groups than in the stenosis group (dollar 3727, dollar 4839, dollar 3306/patient-year, respectively [p = 0.015]). The costs of stenosis (dollar 142/patient-year) and Q (dollar 279/patient-year) measurements were minimal compared to the total cost of access-related care. In conclusion, stenosis surveillance by duplex ultrasound combined with preemptive correction yielded reduced hospitalization rates and costs, reduced total cost of access-related care, and a trend of reduced CVC rates. In contrast, flow surveillance did not yield a significant benefit. Stenosis surveillance provides important benefits that may justify application of such programs.

Background. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are under preclinical investigation as a cell-based therapy for heart failure post-myocardial infarction. In a previous study, tissue-engineered cardiac grafts were found to improve hosts’ cardiac electrical and mechanical functions. However, the durability of effect, immune response, and in vitro properties of the tissue graft remained uncharacterized. This present study is aimed at confirming the graft therapeutic efficacy in an immune-competent chronic heart failure (CHF) model and providing evaluation of the in vitro properties of the tissue graft. Methods. hiPSC-CMs and human dermal fibroblasts were cultured into a synthetic bioabsorbable scaffold. The engineered grafts underwent epicardial implantation in infarcted immune-competent male Sprague-Dawley rats. Plasma samples were collected throughout the study to quantify antibody titers. At the study endpoint, all cohorts underwent echocardiographic, hemodynamic, electrophysiologic, and histopathologic assessments. Results. The epicardially placed tissue graft therapy improved ( p < 0.05 ) in vivo and ex vivo cardiac function compared to the untreated CHF cohort. Total IgM and IgG increased for both the untreated and graft-treated CHF cohorts. An immune response to the grafts was detected after seven days in graft-treated CHF rats only. In vitro, engineered grafts exhibited responsiveness to beta-adrenergic receptor agonism/antagonism and SERCA inhibition and elicited complex molecular profiles. Conclusions. This hiPSC-CM-derived cardiac graft improved systolic and diastolic cardiac function in immune-competent CHF rats. The improvements were detectable at seven weeks post-graft implantation despite an antibody response beginning at week one and peaking at week three. This suggests that non-integrating cell-based therapy delivered by a bioengineered tissue graft for ischemic cardiomyopathy is a viable treatment option.

Objective The frequency and implications of an elevated cardiac troponin (4th or 5th generation TnT) in patients outside of the emergency department or presenting with non-cardiac conditions is unclear. Methods Consecutive patients aged 18 years or older admitted for a primary non-cardiac condition who had the 4th generation TnT drawn had the 5th generation TnT run on the residual blood sample. Primary and secondary outcomes were all-cause mortality (ACM) and major adverse cardiovascular events (MACE) respectively at 1 year. Results 918 patients were included (mean age 59.8 years, 55% male) in the cohort. 69% had elevated 5th generation TnT while 46% had elevated 4th generation TnT. 5th generation TnT was more sensitive and less specific than 4th generation TnT in predicting both ACM and MACE. The sensitivities for the 5th generation TnT assay were 85% for ACM and 90% for MACE rates, compared to 65% and 70% respectively for the 4th generation assay. 5th generation TnT positive patients that were missed by 4th generation TnT had a higher risk of ACM (27.5%) than patients with both assays negative (27.5% vs 11.1%, p<0.001), but lower than patients who had both assay positive (42.1%). MACE rates were not better stratified using the 5th generation TnT assay. Conclusions In patients admitted for a non-cardiac condition, 5th generation TnT is more sensitive although less specific in predicting MACE and ACM. 5th generation TnT identifies an intermediate risk group for ACM previously missed with the 4th generation assay.