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• The effect of sex on chemotherapy-associated heart failure has not been clearly established. • In this retrospective cohort study, female sex was not associated with heart failure after anthracycline treatment in multivariable analyses, including in a Cox proportional hazards model and in a competing risk model accounting for all-cause death. • Age, coronary artery disease and hematopoietic stem cell transplant were associated with an increased risk of incident heart failure within 5 years after anthracycline treatment in a multivariable Cox proportional hazards model. • Age and body mass index were associated with an increased risk of incident heart failure within 5 years after anthracycline treatment in a multivariable competing risk model. Female sex is frequently cited as a risk factor for anthracycline cardiotoxicity based on pediatric data, but the role of sex in the development of cardiotoxicity has not been clearly established in adults. To assess the effect of female sex on the development of incident heart failure (HF) in adult patients treated with anthracyclines. This was a retrospective cohort study of 1525 adult patients with no prior history of HF or cardiomyopathy who were treated with anthracyclines between 1992 and 2019. The primary outcome was new HF within 5 years of the first dose of anthracyclines. The effect of sex was assessed using Cox proportional hazards and competing risk models. Over a median (IQR) follow-up of 1.02 (0.30–3.01) years, 4.78% of patients developed HF (44 men and 29 women). Female sex was not associated with the primary outcome in a multivariable Cox proportional hazards model (HR 0.87; 95% CI 0.53–1.43; P = 0.58). Similar results were observed in a multivariable model accounting for the competing risk of death (HR 0.94; 95% CI 0.39–2.25; P = 0.88). Age, coronary artery disease and hematopoietic stem cell transplant were associated with the primary outcome in a multivariable Cox proportional hazards model. Age and body mass index were associated with the primary outcome in a multivariable competing risk model. In this large, single-center, retrospective cohort study, female sex was not associated with incident HF in adult patients treated with anthracyclines. Female sex is frequently cited as a risk factor for anthracycline cardiotoxicity based on pediatric data, but the role of sex in the development of cardiotoxicity has not been clearly established in adults. In this retrospective cohort study, we assessed the effect of female sex on the development of incident heart failure in adult patients treated with anthracyclines. Using Cox proportional hazards and competing risk regression models, we found that there was no association between female sex and heart failure after treatment with anthracyclines. [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with significant morbidity and mortality in older adults. Whether frailty predicts adverse outcomes after percutaneous left atrial appendage closure (LAAC) remains uncertain.Objective: The purpose of this study was to examine the association between frailty and clinical outcomes after percutaneous LAAC.Methods: We identified patients 65 years and older in Medicare fee-for-service claims who underwent LAAC between October 1, 2016, and December 31, 2019. Patients were identified as frail on the basis of the Hospital Frailty Risk Score (HFRS), a validated frailty measure centered on health resource utilization, with the cohort stratified into low (<5), intermediate (5-15), and high (>15) risk groups.Results: Of the 21,787 patients who underwent LAAC, 10,740 (49.3%) were considered frail (HFRS >5), including 3441 (15.8%) in the high-risk group. The mortality rate (up to 1095 days) were 16.1% in the low-risk group, 26.7% in the intermediate-risk group, and 41.1% in the high-risk group (P < .001). After adjusting for age, sex, and comorbidities, HFRS >15 (compared with HFRS <5) was associated with a higher risk of long hospital stay (odds ratio [OR] 8.29; 95% confidence interval [CI] 5.94-11.57), 30-day readmission (OR 1.80, 95% CI 1.58-2.05), 30-day mortality (OR 5.68, 95% CI 3.40-9.40), and 1-year mortality (OR 2.83, 95% CI 2.39-3.35). In restricted cubic spline models, the adjusted OR for all outcomes monotonically increased with increasing HFRS.Conclusion: Frailty is common in patients undergoing LAAC and is associated with increased risks of long hospital stay, readmissions, and short-term mortality. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the applicability of pivotal transcatheter aortic valve replacement (TAVR) trials to the real-world population of Medicare patients undergoing TAVR. It is unclear whether randomized controlled trial results of novel cardiovascular devices apply to patients encountered in clinical practice. Characteristics of patients enrolled in the U.S. CoreValve pivotal trials were compared with those of the population of Medicare beneficiaries who underwent TAVR in U.S. clinical practice between November 2, 2011, and December 31, 2017. Inverse probability weighting was used to reweight the trial cohort on the basis of Medicare patient characteristics, and a "real-world" treatment effect was estimated. A total of 2,026 patients underwent TAVR in the U.S. CoreValve pivotal trials, and 135,112 patients underwent TAVR in the Medicare cohort. Trial patients were mostly similar to real-world patients at baseline, though trial patients were more likely to have hypertension (50% vs 39%) and coagulopathy (25% vs 17%), whereas real-world patients were more likely to have congestive heart failure (75% vs 68%) and frailty. The estimated real-world treatment effect of TAVR was an 11.4% absolute reduction in death or stroke (95% CI: 7.50%-14.92%) and an 8.7% absolute reduction in death (95% CI: 5.20%-12.32%) at 1 year with TAVR compared with conventional therapy (surgical aortic valve replacement for intermediate- and high-risk patients and medical therapy for extreme-risk patients). The trial and real-world populations were mostly similar, with some notable differences. Nevertheless, the extrapolated real-world treatment effect was at least as high as the observed trial treatment effect, suggesting that the absolute benefit of TAVR in clinical trials is similar to the benefit of TAVR in the U.S. real-world setting. [Display omitted] [ABSTRACT FROM AUTHOR]

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The aim of this study was to evaluate the performance of administrative claims in ascertaining trial clinical events committee–adjudicated outcomes in the U.S. CoreValve studies. Real-world data offer tremendous opportunity to improve outcome ascertainment in clinical trials. However, little is known about the validity of outcomes ascertained using real-world data to capture trial endpoints. Patients enrolled in 3 pivotal trials and 2 pre-market continued-access studies evaluating transcatheter aortic valve replacement were linked to Medicare fee-for-service inpatient claims. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa agreement statistic of claims to detect clinical endpoints and procedural complications in trial patients were calculated. Claims accurately identified trial-adjudicated deaths (sensitivity, specificity, PPV, and NPV all >99.6%; kappa 1.00). Claims had good performance in identifying trial-adjudicated permanent pacemaker implantation (sensitivity 92.2%, specificity 99.1%, PPV 96.1%, NPV 98.2%, kappa 0.93) and aortic valve reintervention (sensitivity 84.4%, specificity 99.6%, PPV 69.1%, NPV 99.8%, kappa 0.76). Claims had more modest performance in ascertaining trial-adjudicated myocardial infarction (sensitivity 63.6%, specificity 97.2%, PPV 29.9%, NPV 99.3%, kappa 0.39) and acute kidney injury (sensitivity 70.2%, specificity 85.4%, PPV 38.2%, NPV 95.7%, kappa 0.41) and the poorest performance for identifying trial-adjudicated bleeding events (sensitivity 86.4%, specificity 36.8%, PPV 35.0%, NPV 86.3%, kappa 0.16). Compared with trial-adjudicated outcomes, claims data performed well in ascertaining death and outcomes with procedural billing codes and more modestly in identifying other outcomes. Claims may be cautiously and selectively used to augment data collection in future cardiovascular device trials. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials are the "gold standard" for comparing the safety and efficacy of therapies but may be limited due to high costs, lack of feasibility, and difficulty enrolling "real-world" patient populations. The Extending Trial-Based Evaluations of Medical Therapies Using Novel Sources of Data (EXTEND) Study seeks to evaluate whether data collected within procedural registries and claims databases can reproduce trial results by substituting surrogate non-trial-based variables for exposures and outcomes.Methods and Results: Patient-level data from 2 clinical trial programs-the Dual Antiplatelet Therapy Study and the United States CoreValve Studies-will be linked to a combination of national registry, administrative claims, and health system data. The concordance between baseline and outcomes data collected within nontrial data sets and trial information, including adjudicated end point events, will be assessed. We will compare the study results obtained using these alternative data sources to those derived using trial-ascertained variables and end points using trial-adjudicated end points and covariates.Conclusions: Linkage of trials to registries and claims data represents an opportunity to use alternative data sources in place of and as adjuncts to randomized clinical trial data but requires further validation. The results of this research will help determine how these data sources can be used to improve our present and future understanding of new medical treatments. [ABSTRACT FROM AUTHOR]

Abstract Objectives This study sought to evaluate the trends in isolated surgical aortic valve replacement (SAVR) procedures across hospitals with different transcatheter aortic valve replacement (TAVR) volumes among Medicare beneficiaries. Background The volume of TAVR has increased in the United States since its approval, now exceeding that of isolated SAVR. Methods Hospitalizations of adults (≥18 years of age) with International Classification of Diseases-9th Revision-Clinical Modification procedure codes for SAVR (35.21 or 35.22) or TAVR (35.05 or 35.06) who were included in the Medicare Provider Analysis and Review database between January 1, 2011, and December 31, 2014, were included. Trends in isolated SAVR patient characteristics, procedural volumes, and outcomes by quartile (Q) of hospital-level TAVR use were assessed over the study period. Results A total of 37,705 isolated SAVR procedures were analyzed for the study. The annual volume of isolated SAVR procedures decreased in hospitals performing the largest number of TAVR procedures (Q3: 1,557 in 2011 to 1,391 in 2014; and Q4: 2,607 in 2011 to 1,791 in 2014). Thirty-day and 1-year mortality after SAVR also declined over the study period in hospitals with the largest TAVR volume (annual change rate in mortality for Q3: −16.4%; p < 0.001; Q4: −20.8%; p < 0.001). Conclusions The advent of TAVR was associated with a reduction in isolated SAVR volumes, a decrease in comorbidities among patients undergoing SAVR, and corresponding reductions in observed short- and long-term SAVR mortality among hospitals performing the greatest number of TAVRs. Graphical abstract [ABSTRACT FROM AUTHOR]

Summary The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and α cell mass. Conversely, liver-limited overexpression of foxn3 increases α cell mass. Supporting these genetic findings in model organisms, non-diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose. [ABSTRACT FROM AUTHOR]

The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression. [ABSTRACT FROM AUTHOR]

Background: Off-label magnetic resonance imaging (MRI) for patients with cardiac implantable electrical devices has been limited owing to concerns about safety and unclear diagnostic and prognostic utility.Objective: The purpose of this study was to define major and minor adverse events with off-label MRI scans.Methods: We prospectively evaluated patients with non-MRI-conditional cardiac implantable electrical devices referred for MRI scans under a strict clinical protocol. The primary safety outcome was incidence of major adverse events (loss of pacing, inappropriate shock or antitachycardia pacing, need for system revision, or death) or minor adverse events (inappropriate pacing, arrhythmias, power-on-reset events, heating at the generator site, or changes in device parameters at baseline or at 6 months).Results: A total of 189 MRI scans were performed in 123 patients (63.1% [78] men; median age 70 ± 18.5 years; 56.9% [70] patients with implantable cardioverter-defibrillators; 33.3% [41] pacemaker-dependent patients) predominantly for brain or spinal conditions. A minority of scans (22.7% [43]) were performed for urgent or emergent indications. Major adverse events were rare: 1 patient with loss of pacing, no deaths, or system revisions (overall rate 0.5%; 95% confidence interval 0.01-2.91). Minor adverse events were similarly rare (overall rate 1.6%; 95% confidence interval 0.3-4.6). Nearly all studies (98.4% [186]) were interpretable, while 75.1% [142] were determined to change management according to the prespecified criteria. No clinically significant changes were observed in device parameters acutely after MRI or at 6 months as compared with baseline across all patient and device categories.Conclusion: Off-label MRI scans performed under a strict protocol demonstrated excellent short- and medium-term safety while providing interpretable imaging that frequently influenced clinical care. [ABSTRACT FROM AUTHOR]

Abstract: The flocculation properties of a natural silt–clay mud taken from the San Jacinto estuary near Houston, TX were investigated over a range of suspended sediment concentrations, salinities, and turbulent shear rates. The study was conducted in a laboratory using a paddle mixer to create a turbulent shear field for driving the flocculation process; floc settling velocity and size attributes were measured in a settling column with a camera system and image analysis. In general, maximum floc sizes were observed at turbulent shear rates less than 30s−1. For turbulent shear rates less than 50s−1, flocs originating in saline water at 10 and 15ppt were larger and more loosely packed than those created in freshwater at identical turbulent shear rates and suspended sediment concentrations. At turbulent shear rates of 50s−1, floc properties of size, submerged specific gravity and fractal dimension were approximately equal for all conditions. Two ranges of behavior were observed in regards to the fractal dimension of flocs at a constant turbulent shear rate. In the first region, for floc sizes less than , a variable fractal dimension was needed to describe the submerged specific gravity as a function of floc size. It is suggested that this variability in fractal dimension may physically be the result of ploysized primary particles. In the second region, for floc sizes greater than , a constant fractal dimension was found to suffice in describing the submerged specific gravity. The constant fractal dimension for this second region was n f =2.3 for freshwater flocs and n f =1.95 for saltwater flocs. Based on the observation of the two-region behavior, a new variable fractal dimension model is presented using a simple exponential decay which asymptotically approaches a constant fractal dimension at a specified floc size. The model itself is based on the uniform-size primary particle formulation of the relationship between floc size and fractal dimension, but the equation was able to model the average shift from variable to constant fractal dimension, which was thought to primarily be due to polysized primary particles. [Copyright &y& Elsevier]

In short, manipulation of cytokine pathways shows promise as a mean to tilt the balance of immunity toward tolerance. Effective and regulatory T cells vary in their response to a variety of cytokines. In particular, the ability of certain cytokines, for example, IL-2, to provide vital survival signals to regulatory cells and to trigger death of effector T cells or impede IL-15 driven expansion of memory cells has spurred several trials. The ability of IFNγ, IL-4, TNFα, and lymphotoxin to exert selective effects upon crucial lymphocyte subset populations in vivo may also enable translation into potent therapies. [Copyright &y& Elsevier]

Abstract: Transplantation exposes vascularized grafts to several potential injuries, including ischemia-reperfusion injury and rejection. These processes are associated with, at least in part, extracellular nucleotide-triggered (type 2 purinergic receptor) inflammatory responses that if left unchecked might compromise the long-term function and survival of the graft. Modulation of type 2 purinergic receptor–mediated signaling occurs by ectoenzymes that hydrolyze nucleotides to adenosine, which in turn activate type-1 purinergic receptors, and play a critical role in limiting inflammation and thrombosis. CD39 is the prototype nucleoside triphosphate diphosphohydrolase and is highly expressed on the endothelium. Different levels of CD39 expression by the vasculature influence the fate of the transplanted organ in ischemia-reperfusion injury and transplant rejection models. Additional roles for extracellular nucleotides/adenosine have also been defined within the immune system. Moreover, CD39 is a phenotypic marker of regulatory T cells, and through the generation of adenosine, contributes to the suppressive capabilities of these cells in vitro and in vivo. Our experimental models suggest that purinergic mechanisms may provide an integration point for the vascular and immunological responses in transplantation. CD39, the dominant ectonucleotidase, receptors for nucleotide mediators and adenosine are expressed in a regulated manner on both vascular and immune cells. We predict that administration of soluble CD39 and adenosine agonists or the targeted expression of CD39 through genetically modified organs or cells may have future therapeutic application in transplant-associated and other vascular diseases. [Copyright &y& Elsevier]

The therapeutic use of stem cells is a popular topic that is often in the news. Stem cells are of particular relevance to the transplant community, as stem cell-based therapies will probably be derived from allogeneic sources. Stem cells may be obtained from somatic (adult) cell or embryonic cell origin. The ability to establish stem cell lines in vitro means that we can standardize therapeutic grafting applications, which is a prerequisite for the widespread application of stem cell therapy. This attribute also means that we can produce large batches of allogeneic terminally differentiated cells, which can be administered to patients. Three important barriers to the deployment of this therapy currently exist; in addition to the many ethical issues facing the widespread use of stem cell therapy, it is also important to develop methods to derive pure terminally differentiated cells for transplantation and to induce immune tolerance to these allogeneic cells, as daily anti-rejection therapy cannot be justified for many potential applications. [Copyright &y& Elsevier]

Despite an increase in the prevalence of advanced heart failure in women, women are less likely to be treated with durable LVAD therapy and may have increased risk of early post LVAD complications. Previous studies have shown that women have increased risk of post LVAD early right heart failure (ERHF) and need for RVAD support. However, it is unclear if women have a higher risk of developing late right heart failure (LRHF). We sought to investigate whether women are more likely to develop ERHF and LRHF post LVAD implantation and further assess whether sex modifies the relationship between ERHF and long term outcomes. We included 12,923 patients from the INTERMACS registry who received primary continuous-flow (CF)-LVAD between 2012-2017. ERHF was defined as death due to RHF by one month, need for RVAD by one month, or need for inotropes for more than 2 weeks. Cox regression was used to model the relationship of sex and both ERHF and LRHF, adjusting for the competing risk of death and receiving a heart transplantation using Fine-Gray methods. The interaction of sex and the relationship of ERHF and LRHF as well as sex and the relationship of ERHF and mortality were evaluated. Of those included, 22% were women and 78% were men. Women were younger (55 vs 58 y, p<0.001), more frequently had non-ischemic cardiomyopathy (60% vs 48%, P<0.001), and had more severe tricuspid regurgitation (p <0.001) prior to LVAD implantation. Women had more ERHF than men (24% vs 20%, p<0.001), driven mostly by early RVAD or prolonged inotrope use. After adjusting for covariates*, women were more likely to have ERHF (HR 1.15, p 0.037), but did not have an increased risk of developing LRHF (HR 0.85, p 0.1). ERHF was a significant predictor of LRHF (HR 2.14, p <0.0001) and sex did not affect this relationship (p for interaction 0.7; see Figure). Furthermore, sex did not affect the relationship between ERHF and mortality (HR 1.7, p<0.001; p for interaction 0.65). Among those in the INTERMACS registry receiving primary CF-LVAD, females had a higher risk of ERHF but not LRHF. Further studies are needed to investigate reasons for the observed discrepancies. [ABSTRACT FROM AUTHOR]

Tim-1, a phosphatidylserine receptor expressed on B cells, induces interleukin 10 (IL-10) production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion develop tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrates that besides IL-10, Tim-1+ B cells also differentially express a number of co-inhibitory checkpoint receptors including TIGIT. Mice with B cell-specific TIGIT deletion develop spontaneous paralysis with CNS inflammation, but with limited inflammation in other organs. Our findings suggest that Tim-1+ B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 signaling-dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of aryl hydrocarbon receptor (AhR) in regulating the B cell function is discussed, as we find that AhR is among the preferentially expressed transcription factors in Tim-1+ B cells and regulates their TIGIT and IL-10 expression. • Tim-1+ B cells are required for maintaining immune tolerance • Tim-1+ B cells differentially express TIGIT and other co-inhibitory molecules • B cell expression of TIGIT and many other regulators requires Tim-1 signaling • B cell TIGIT expression is preferentially required for maintaining CNS tolerance Xiao et al. find that Tim-1 expression and signaling in B cells is required for maintaining self-tolerance. Tim-1+ B cells execute their regulatory function by expressing a set of negative immune regulators, of which checkpoint receptor TIGIT is preferentially required for the B cell-mediated tolerance in the central nervous system. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate changes in volume, risk profile, and outcomes among elderly individuals undergoing isolated aortic valve replacement (AVR) after TAVR approval in the United States. Retrospective cohort study of patients ≥65 years old with at least one procedural code for isolated SAVR or TAVR among the Medicare beneficiaries between January 1, 2009 and December 31, 2014. A total of 137,563 hospitalizations for isolated AVR between 2009 and 2014 were included (SAVR: 102,968 [74.9%]; TAVR: 34,595 [25.1%]). Overall AVR volumes increased by 21.8% per year after TAVR introduction, compared with 2.3% prior (p ≪ 0.001). Changes in SAVR volumes were similar both before and after TAVR introduction, (2.3% per year growth before vs. 2.1% after, p = 0.24). Although patient risk profiles increased among the AVR population (predicted 30-day mortality 4.0% in 2009 vs. 5.4% in 2014; p for trend =0.048), observed 30-day mortality (4.0% in 2009 vs. 3.9% in 2014; p for trend =0.96) and 1-year mortality (10.8% in 2009 to 12.2% in 2014; p for trend =0.069) rates remained stable. Among elderly U.S. patients enrolled in the Medicare, the introduction and the dissemination in the early phase of TAVR was associated with an expansion of AVR to high risk patients, without an observed reduction in the use of SAVR. This expansion was associated with similar mortality among all AVR patients, despite an increase in patient risk. • SAVR and TAVR volumes both increased in the early phase of expansion of TAVR. • TAVR use led primarily to the expansion of AVR to an elderly and higher risk population. • This expansion was associated with similar mortality among all AVR patients. [ABSTRACT FROM AUTHOR]

Editorial. Discusses two studies on the effectiveness of rapamycin in blocking tumor progression in transplanted kidneys, published in the journal 'Kidney International.' Inhibition of both primary and metastatic tumor growth by antiangiogenic mechanisms; Effects of rapamycin on tumor cell growth, apoptosis and the expression of vascular endothelial growth factor and transforming growth factor-beta.

Transplantation of organs between genetically different individuals of the same species causes a T cell–mediated immune response that, if left unchecked, results in rejection and graft destruction. The potency of the alloimmune response is determined by the antigenic disparity that usually exists between donors and recipients and by intragraft expression of proinflammatory cytokines in the early period after transplantation. Studies in animal models have identified many molecules that, when targeted, inhibit T-cell activation. In addition, some of these studies have shown that certain immunologic interventions induce transplantation tolerance, a state in which the allograft is specifically accepted without the need for chronic immunosuppression. Tolerance is an important aspect of liver transplantation, because livers have a unique microenvironment that promotes tolerance rather than immunity. In contrast to the progress achieved in inducing tolerance in animal models, patients who receive transplanted organs still require nonspecific immunosuppressant drugs. The development of calcineurin inhibitors has reduced the acute rejection rate and improved short-term, but not long-term, graft survival. However, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of overimmunosuppression such as opportunistic infections and cancers. The status of pharmacologic immunosuppression in the clinic is therefore not ideal. We review recently developed therapeutic strategies to promote tolerance to transplanted livers and other organs and diagnostic tools that might be used to identify patients most likely to accept or reject allografts. [Copyright &y& Elsevier]

Abstract: The emphasis of this paper is on the fractal-analysis of irregular objects like particle clusters that fill the two-dimensional Euclidean space R 2. A common fractal descriptor of such objects is D L (1< D L <2), which defines the fractal dimension of the object outline and is determined by the divider method. In this case, an object may possibly exhibit only two statistically self-similar scales, namely ‘structural’ and ‘textural’. The structural fractal dimension describes the form structure (or the degree of convolution) of the object perimeter and the textural describes the crenellations (or edge effects) found on the object perimeter. Recent studies have shown that the D L does not uniquely define the morphology of complex objects like clusters as it does not include the morphologic attributes, associated with the objects enclosed projected area. A key contribution of this work is the recognition that the ‘total areal’ fractal dimension of the object, D AT (1< D AT <2) offers a unique description of cluster morphology as it accounts for the collective contributions from the crenellations found on the object perimeter and its form structure, as well as contributions from the object core structure or equivalently object projected area. The D AT , which is theoretically interrelated to D L , satisfies the key self-similarity principle of fractals and is employed here to differentiate among four cluster morphologic groups observed in field and laboratory studies, namely, in-line clusters with elongation ratio, ER <5 and ER >5, pseudo-triangle, and -rhomboid. The analysis for this study is performed by applying the box-counting method for analyzing cluster planview images from four groups of cluster morphologies derived from synthetic, laboratory, and field data sets. The D AT is determined via Richardson plots by estimating the slope of the best-fit line over the entire range of box sizes. Doing so, provides a single aggregate dimension that includes the embedded effects from the objects projected area and perimeter. The results show that the average and its standard deviation can effectively discriminate the four cluster morphologic groups. The provides a clear demarcation between the nonlinear morphologies and the in-line morphology with ER >5. The analysis also shows that the in-line clusters with ER <5 change between pseudo-linear and pseudo-nonlinear morphologies. Moreover, it is found that most morphologies in the field are statistically well represented by the corresponding laboratory and synthetic morphologies. Finally, the analysis of the laboratory cluster data reveals the utility of for portraying the correspondence between cluster morphology and physical processes responsible for cluster formation and morphologic evolution, such as flow and sediment supply. Future research should build on the knowledge gained on this topic and further examine the links between the fractal dimension of different cluster morphologies and the physical processes that produce the characteristic scale captured by . [Copyright &y& Elsevier]

Background: To tilt the immunologic balance toward tolerance and away from rejection, non-human primate recipients of cardiac allografts were treated with interleukin (IL)-2/Fc, mutant (m) antagonist type mIL-15/Fc, and sirolimus. Methods: Heterotopic heart transplants were performed on 8 fully mismatched cynomolgus macaques. An untreated control recipient rejected its graft by post-operative Day 6. The remaining 7 animals received oral or intramuscular immunosuppression with sirolimus. A recipient treated with sirolimus alone rejected at the end of 28 days of immunosuppression. The remaining 6 monkeys also received IL-2/Fc and mIL-15/Fc intramuscularly until 28 days after transplant. One animal received a second 28-day course of fusion protein starting at Day 50. In these 6 animals, sirolimus was continued for 28 days (n = 4) or until protein levels were low (n = 2). Results: In the 4 monkeys treated with a 28-day course of sirolimus and fusion proteins, mean graft survival was 51.5 days (range, 28–76 days). The animal receiving a second course of fusion protein rejected its graft on Day 177, despite detectable levels of the fusion proteins and sirolimus. The central memory, effector memory, and naïve CD4+ and CD8+ T-cell populations in the peripheral blood did not change significantly during fusion protein administration. A 2.5-fold expansion in CD4+CD25+ lymphocytes occurred in recipients treated with fusion proteins and sirolimus that was not observed in the recipient treated with sirolimus alone. Conclusions: Although IL-2/Fc, mIL-15/Fc, and sirolimus administered in this manner permitted modest prolongation of graft survival and expansion of CD4+CD25+ T cells, tolerance was not achieved. [ABSTRACT FROM AUTHOR]

Abstract: We have previously demonstrated that biomarkers of inflammation and immune activity detected within intraoperative renal transplant allograft biopsies are linked to adverse short-term post-transplantation clinical outcomes. Now we provide a post hoc analysis of our earlier data in the light of longer clinical follow-up. A total of 75 consecutively performed renal allografts were analyzed for gene expression of proinflammatory molecules, inflammation-induced adhesion molecules, and antiapoptotic genes expressed 15 minutes after vascular reperfusion to determine whether this analysis can aid in predicting long-term quality of renal function, proteinuria, graft loss, and death-censored graft. We have built predictive models for proteinuria (area under the curve = 0.859, p = 0.0001) and graft loss (area under the curve = 0.724, p = 0.027) 2 years post-transplantation using clinical variables in combination with intragraft gene expression data of tumor necrosis factor–α, interleukin-6, CD40, CD3, and tumor necrosis factor–α, Bcl-2, and interferon-γ, respectively. This post hoc analysis demonstrates that hypothesis-driven, targeted polymerase chain reaction profiling of gene expression in the donor kidney at the time of engraftment can predict 2-year post-transplantation clinical outcomes. [Copyright &y& Elsevier]

The immunosuppressant rapamycin has been shown to inhibit G1/S transition of the cell cycle. This inhibition is thought to be mediated by maintenance of the thresh. old levels of cyclin-dependent kinase (CDK) inhibitor p27Kip1 (p27) and inhibition of p70 s6 kinase (p70s6k). However, recent evidence suggests that cells still remain sensitive to rapamycin in the absence of functional p27 or p70s6k. Here, we show that rapamycin represses cyclin D3 levels in activated human T lymphocytes with no inhibitory effects on cyclin D2. Furthermore, rapamycin elicits similar cyclin D3 modulatory effects in B lymphocytes. The overall effect of rapamycin on cyclin D3 leads to impaired formation of active complexes with Cdk4 or Cdk6 and subsequent inhibition of cyclin D3/ CDK kinase activity. Decrease in cyclin D3 protein levels is due to translational repression and not due to attenuated transcription of the cyclin D3 gene. Importantly, stable overexpression of cyclin D3 (2-2.5 fold) in Jurkat T cell transfectants renders them resistant to lower doses (1-10 ng/ml) of rapamycin. These results point to a critical role of eyclin D3 in rapamycin-mediated immunosuppressive effects in T cells and cell cycle regulation in lymphocytes in general. [ABSTRACT FROM AUTHOR]

Activated intrarenal transcription of CTL-effectors and TGF-β1 in children with focal segmental glomerulosclerosis.. Background: The pathogenesis of childhood nephrotic syndrome (NS), whether the lesion is minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), remains elusive. Based on the presence of elevated cytokine levels in peripheral blood, a T cell-induced injury could be postulated. Methods: To test the hypothesis that infiltrating T cells actively contribute to the glomerular injury in children with NS, we studied the intrarenal transcription of various T cell-related chemokines, cytokines and cytotoxic T-lymphocyte (CTL) effector molecules in the renal biopsy tissue of 52 nephrotic children with a variety of histologic lesions. Intrarenal gene expression was studied using reverse transcription (RT)-assisted–polymerase chain reaction (PCR). Results: Interleukin-2 (IL-2) and IL-4 transcripts were not observed in any of the specimens. IL-2 receptor alpha mRNA was detected in 24 of 40 proteinuric patients, but also in 6 of 10 patients in remission and showed no significant differences with regard to steroid response. Intrarenal gene expression of CTL mediators and transforming growth factor-β1 (TGF-β1) was noted particularly in patients with progressive disease leading to chronic renal failure. TGF-β1 gene expression was noted in 23 of 29 steroid resistant (SR) children with NS not caused by lupus nephritis and in 18 of 20 FSGS patients. In contrast TGF-β1 gene expression was detected in only 3 of 14 steroid-sensitive patients (P < 0.001). Two of these patients later developed FSGS. In patients with steroid-resistant NS, intrarenal TGF-β1 gene expression showed a positive predictive value of 90% and a negative predictive value of 88% to identify FSGS (P < 0.0001). Conclusion: These results support the notion that immunologically mediated events contribute to the progressive renal damage seen in... [ABSTRACT FROM AUTHOR]