Patient-specific modeling of dyssynchronous heart failure: A case study

The development and clinical use of patient-specific models of the heart is now a feasible goal. Models have the potential to aid in diagnosis and support decision-making in clinical cardiology. Several groups are now working on developing multi-scale models of the heart for understanding therapeutic mechanisms and better predicting clinical outcomes of interventions such as cardiac resynchronization therapy. Here we describe the methodology for generating a patient-specific model of the failing heart with a myocardial infarct and left ventricular bundle branch block. We discuss some of the remaining challenges in developing reliable patient-specific models of cardiac electromechanical activity, and identify some of the main areas for focusing future research efforts. Key challenges include: efficiently generating accurate patient-specific geometric meshes and mapping regional myofiber architecture to them; modeling electrical activation patterns based on cellular alterations in human heart failure, and estimating regional tissue conductivities based on clinically available electrocardiographic recordings; estimating unloaded ventricular reference geometry and material properties for biomechanical simulations; and parameterizing systemic models of circulatory dynamics from available hemodynamic measurements.     

Direct flow cytometric quantification of alkaline phosphatase activity in rat bone marrow stromal cells.

Cell preparations in cytochemistry are conventionally analyzed with transmitted light after fixation and reaction with agents such as azo-coupling dyes. With cell suspensions stained with fluorescent cytochemical dyes, cells can also be analyzed and sorted by flow cytometry. We have exploited the intense red fluorescence of Fast Red Violet LB generated in cytochemical reactions to perform flow cytometric analyses of alkaline phosphatase (AP) expression in rat bone marrow stromal cells. By modifying staining protocols of single-cell suspensions, we demonstrate that in comparison to staining with Fast Red TR, the method is specific, can distinguish among various levels of enzyme expression within the whole population, and permits enzyme kinetic studies of heterogeneous cell populations. The method was applied to study the effect of the glucocorticoid dexamethasone (Dx) on cell proliferation and AP expression. In low AP-expressing cells, Dx treatment at 10(-8) M increased the [3H]-thymidine labeling index from 3.85% to 5.24% (p less than 0.01). In contrast, high AP-expressing cells were unlabeled by [3H]-thymidine. The staining and analytical methods reported here facilitate the detection, isolation, and quantification of subpopulations of bone marrow stromal cells that express alkaline phosphatase activity. These experiments demonstrate the value of flow cytometry as an adjunct to conventional cytochemical methods.     

Recovery of kidney function after dialysis initiation in children and adults in the US: A retrospective study of United States Renal Data System data

BackgroundLittle is known about factors associated with recovery of kidney function—and return to dialysis independence—or temporal trends in recovery after starting outpatient dialysis in the United States. Understanding the characteristics of individuals who may have the potential to recover kidney function may promote better recognition of such events. The goal of this study was to determine factors associated with recovery of kidney function in children compared with adults starting dialysis in the US.Methods and findingsWe determined factors associated with recovery of kidney function—defined as survival and discontinuation of dialysis for ≥90-day period—in children versus adults who started maintenance dialysis between 1996 and 2015 according to the United States Renal Data System (USRDS) followed through 2016 in a retrospective cohort study. We also examined temporal trends in recovery rates over the last 2 decades in this cohort. Among 1,968,253 individuals included for study, the mean age was 62.6 ± 15.8 years, and 44% were female. Overall, 4% of adults (83,302/1,953,881) and 4% of children (547/14,372) starting dialysis in the outpatient setting recovered kidney function within 1 year. Among those who recovered, the median time to recovery was 73 days (interquartile range [IQR] 43–131) in adults and 100 days (IQR 56–189) in children. Accounting for the competing risk of death, children were less likely to recover kidney function compared with adults (sub-hazard ratio [sub-HR] 0.81; 95% CI 0.74–0.89, p-value <0.001; point estimates <1 indicating increased risk for a negative outcome). Non-Hispanic black (NHB) adults were less likely to recover compared with non-Hispanic white (NHW) adults, but these racial differences were not observed in children. Of note, a steady increase in the incidence of recovery of kidney function was noted initially in adults and children between 1996 and 2010, but this trend declined thereafter. The diagnoses associated with the highest recovery rates of recovery were acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) in both adults and children, where 25%–40% of patients recovered kidney function depending on the calendar year of dialysis initiation. Limitations to our study include the potential for residual confounding to be present given the observational nature of our data.ConclusionsIn this study, we observed that discontinuation of outpatient dialysis due to recovery occurred in 4% of patients with end-stage kidney disease (ESKD) and was more common among those with ATN or AIN as the cause of their kidney disease. While recovery rates rose initially, they declined starting in 2010. Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.

In a retrospective study, Elaine Ku and colleagues investigate factors associated with recovery of kidney function among adults and children receiving dialysis reported in the United States Renal Data System.     

How we know universals the perception of auditory and visual forms

Two neural mechanisms are described which exhibit recognition of forms. Both are independent of small perturbations at synapses of excitation, threshold, and synchrony, and are referred to partiular appropriate regions of the nervous system, thus suggesting experimental verification. The first mechanism averages an apparition over a group, and in the treatment of this mechanism it is suggested that scansion plays a significant part. The second mechanism reduces an apparition to a standard selected from among its many legitimate presentations. The former mechanism is exemplified by the recognition of chords regardless of pitch and shapes regardless of size. The latter is exemplified here only in the reflexive mechanism translating apparitions to the fovea. Both are extensions to contemporaneous functions of the knowing of universals heretofore treated by the authors only with respect to sequence in time. John Simon Guggenheim Fellow for 1947     

Fibroblasts inhibit mineralised bone nodule formation by rat bone marrow stromal cells in vitro

The ability of rat skin fibroblasts (RSF) and human periodontal ligament fibroblasts (HPL) to inhibit the formation of mineralised bone nodules in rat bone marrow stromal cell (BMSC) cultures was studied. Co-culture of HPL or RSF with BMSC resulted in a large reduction of bone nodule formation when compared with controls. Conditioned medium from HPL or RSF cultures inhibited bone nodule formation in a dose-dependent manner. HPL-conditioned medium depressed cell proliferation and alkaline phosphatase expression in BMSC cultures. These effects were not due to increased cytotoxicity or nutrient depletion. Inhibitory activity was recovered in a fraction of less than 1 kD following ultrafiltration and was insensitive to freeze-thawing. The inhibitory activity was blocked when HPL cultures were grown in the presence of 10(-5) M indomethacin. Dose-dependent inhibiton of bone nodule formation was also observed in cultures incubated with prostaglandins E2 (at 10(-6) M) or F2 alpha (at 10(-7) M). The results indicate that fibroblasts may inhibit osteoblast differentiation and function in part by release of soluble factors including prostaglandins.