Regional ion channel gene expression heterogeneity and ventricular fibrillation dynamics in human hearts.

RATIONALE: Structural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role. OBJECTIVES: To define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics. METHODS AND RESULTS: High throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavalpha2delta2, Cavbeta2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na(+)/K(+) ATPase ss1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships. CONCLUSIONS: Ion channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships

Predicting High-Grade Glioma Response to Chemoradiation via MRI-Calibrated

https://openworks.mdanderson.org/sumexp21/1085/thumbnail.jp

Mental health stigma at primary health care centres in Lebanon: qualitative study

Background: Mental health-related stigma is a global public health concern and a major barrier to seeking care. In this study, we explored the role of stigma as a barrier to scaling up mental health services in primary health care (PHC) centres in Lebanon. We focused on the experiences of Healthcare Providers (HCPs) providing services to patients with mental health conditions (MHCs), the views of policy makers, and the perceptions of stigma or discrimination among individuals with MHCs. This study was conducted as part of INDIGO-PRIMARY, a larger multinational stigma reduction programme. Methods: Semi-structured qualitative interviews (n = 45) were carried out with policy makers (n = 3), PHC management (n = 4), PHC staff (n = 24), and service users (SUs) (n = 14) between August 2018 and September 2019. These interviews explored mental health knowledge, attitudes and behaviour of staff, challenges of providing treatment, and patient outcomes. All interviews were coded using NVivo and a thematic coding framework. Results: The results of this study are presented under three themes: (1) stigma at PHC level, (2) stigma outside PHC centres, and (3) structural stigma. SUs did not testify to discrimination from HCPs but did describe stigmatising behaviour from their families. Interestingly, at the PHC level, stigma reporting differed among staff according to a power gradient. Nurses and social workers did not explicitly report incidents of stigma but described patients with MHCs as uncooperative, underscoring their internalized negative views on mental health. General practitioners and directors were more outspoken than nurses regarding the challenges faced with mental health patients. Mental health professionals revealed that HCPs still hold implicitly negative views towards patients with MHCs however their attitude has improved recently. Our analysis highlights five layers of stigma affecting SUs. Conclusion: This qualitative study reveals that stigma was still a key concern that affects patients with MHC. SUs reported experiencing overt stigmatising behaviour in the community but less explicit discrimination in a PHC setting. Our findings emphasise the importance of (1) combatting structural stigma through legal reform, (2) addressing interpersonal stigma, (3) committing PHC management to deliver high quality mental health integrated services, and (4) reducing intrapersonal stigma by building public empathy. Keywords: Mental health Stigma; Primary health care (PHC); Qualitative researc

Layered, Tunable Graphene Oxide-Nylon Heterostructures for Wearable Electrocardiogram Sensors

Nanoscale engineered materials combined with wearable wireless technologies can deliver a new level of health monitoring. A reduced graphene oxide-nylon composite material is developed and tested, demonstrating its usefulness as a material for sensors in wearable, long-term electrocardiogram (ECG) monitoring via a comparison to one of the widely used ECG sensors. The structural analysis by scanning electron (SEM) and atomic force microscopy (AFM) shows a limited number of defects on a macroscopic scale. Fourier Transform Infrared (FTIR) and Raman spectroscopy confirm the presence of rGOx, and the ratio of D- and G-features as a function of thickness correlates with the resistivity analysis. The negligible effect of the defects and the tunability of electrical and optical properties, together with live ECG data, demonstrate its signal transduction capability.Comment: 7 main text and 4 supporting figures, under revie

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p &#60; 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p &#60; 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Process sequence of soil aggregate formation disentangled through multi-isotope labelling

Microaggregates (250 µm) that resisted 60 J mL−1 ultrasonic dispersion. Afterwards, we assessed the C, N, Fe, and Si stable isotope composition in each size fraction. After four weeks we found a rapid build-up of stable macroaggregates comprising almost 50 % of soil mass in the treatment with plants and respective soil rooting, but only 5 % when plants were absent. The formation of these stable macroaggregates proceeded with time. Soil organic carbon (SOC) contents were elevated by 15 % in the large macroaggregates induced by plant growth. However, the recovery of EPS-derived 13C was below 20 % after 4 weeks, indicating rapid turnover in treatments both with and without plants. The remaining EPS-derived C was mainly found in macroaggregates when plants were present and in the occluded small microaggregates (<20 µm) when plants were absent. The excess of bacterial 15N closely followed the pattern of EPS-derived 13C (R2 = 0.72). In contrast to the organic gluing agents, the goethite-57Fe and montmorillonite-29Si were relatively equally distributed across all size fractions. Overall, microaggregates were formed within weeks. Roots enforced this process by stabilizing microaggregates within stable macroaggregates. As time proceeded the labelled organic components decomposed, while the labelled secondary oxides and clay minerals increasingly contributed to aggregate stabilization and turnover at the scale of months and beyond. Consequently, the well-known hierarchical organization of aggregation follows a clear chronological sequence of stabilization and turnover processes

Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs

Background-Atrial fibrillation impairs atrial contractility, inducing atrial stunning that promotes thromboembolic stroke. Action potential (AP)-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial tachycardia remodeling (ATR). Here, we addressed the role of AP duration (APD) changes in ATR-induced hypocontractility. Methods and Results-ATR (7-day tachypacing) decreased APD (perforated patch recording) by approximate to 50%, atrial contractility (echocardiography, cardiomyocyte video edge detection), and [Ca2+](i) transients. ATR AP waveforms suppressed [Ca2+](i) transients and cell shortening of control cardiomyocytes; whereas control AP waveforms improved [Ca2+](i) transients and cell shortening in ATR cells. However, ATR cardiomyocytes clamped with the same control AP waveform had approximate to 60% smaller [Ca2+](i) transients and cell shortening than control cells. We therefore sought additional mechanisms of contractile impairment. Whole-cell voltage clamp revealed reduced I-CaL; I-CaL inhibition superimposed on ATR APs further suppressed [Ca2+](i) transients in control cells. Confocal microscopy indicated ATR-impaired propagation of the Ca2+ release signal to the cell center in association with loss of t-tubular structures. Myofilament function studies in skinned permeabilized cardiomyocytes showed altered Ca2+ sensitivity and force redevelopment in ATR, possibly due to hypophosphorylation of myosin-binding protein C and myosin light-chain protein 2a (immunoblot). Hypophosphorylation was related to multiple phosphorylation system abnormalities where protein kinase A regulatory subunits were downregulated, whereas autophosphorylation and expression of Ca2+-calmodulin-dependent protein kinase II delta and protein phosphatase 1 activity were enhanced. Recovery of [Ca2+](i) transients and cell shortening occurred in parallel after ATR cessation. Conclusions-Shortening of APD contributes to hypocontractility induced by 1-week ATR but accounts for it only partially. Additional contractility-suppressing mechanisms include I-CaL current reduction, impaired subcellular Ca2+ signal transmission, and altered myofilament function associated with abnormal myosin and myosin-associated protein phosphorylation. The complex mechanistic basis of the atrial hypocontractility associated with AF argues for upstream therapeutic targeting rather than interventions directed toward specific downstream pathophysiological derangements. (Circ Arrhythm Electrophysiol. 2010;3:530-541.

Cerebral Blood Volume Changes During Radiotherapy May Predict Pseudoprogression versus Disease Progression for Patients with High Grade Glioma

https://openworks.mdanderson.org/sumexp21/1040/thumbnail.jp

Automated Contouring and Planning in Radiation Therapy: What Is \u27Clinically Acceptable\u27?

Developers and users of artificial-intelligence-based tools for automatic contouring and treatment planning in radiotherapy are expected to assess clinical acceptability of these tools. However, what is \u27clinical acceptability\u27? Quantitative and qualitative approaches have been used to assess this ill-defined concept, all of which have advantages and disadvantages or limitations. The approach chosen may depend on the goal of the study as well as on available resources. In this paper, we discuss various aspects of \u27clinical acceptability\u27 and how they can move us toward a standard for defining clinical acceptability of new autocontouring and planning tools