Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. ...Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of
, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold
interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.
Membrane fusion is the cell’s delivery process, enabling its many compartments to receive cargo and machinery for cell growth and intercellular communication. The overall activation energy of the ...process must be large enough to prevent frequent and nonspecific spontaneous fusion events, yet must be low enough to allow it to be overcome upon demand by specific fusion proteins such as soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs). Remarkably, to the best of our knowledge, the activation energy for spontaneous bilayer fusion has never been measured. Multiple models have been developed and refined to estimate the overall activation energy and its component parts, and they span a very broad range from 20 kBT to 150 kBT, depending on the assumptions. In this study, using a bulk lipid-mixing assay at various temperatures, we report that the activation energy of complete membrane fusion is at the lowest range of these theoretical values. Typical lipid vesicles were found to slowly and spontaneously fully fuse with activation energies of ∼30 kBT. Our data demonstrate that the merging of membranes is not nearly as energy consuming as anticipated by many models and is ideally positioned to minimize spontaneous fusion while enabling rapid, SNARE-dependent fusion upon demand.
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•Advanced wound dressings market is worth $11.4 billion annually.•Increased cases of diabetes and diabetic ulcers drive the wound dressing industry.•Novel hydrogel materials are ...suitable for many types of wounds.•High production costs of hydrogels limits their further commercialization.•Innovative wound dressings need to be developed but costs must be kept low.
Wound treatment has increased in importance in the wound care sector due to the pervasiveness of chronic wounds in the high-risk population including, but not limited to, geriatric population, immunocompromised and obese patients. Furthermore, the number of people diagnosed with diabetes is rapidly growing. According to the World Health Organization (WHO), the global diabetic occurrence has increased from 4.7% in 1980 to 8.5% in 2014. As diabetes becomes a common medical condition, it has also become one of the major causes of chronic wounds which require specialised care to address patients’ unique needs. Wound dressings play a vital role in the wound healing process as they protect the wound site from the external environment. They are also capable of interacting with the wound bed in order to facilitate and accelerate the healing process. Advanced dressings such as hydrogels are designed to maintain a moist environment at the site of application and due to high water content are ideal candidates for wound management. Hydrogels can be used for both exudating or dry necrotic wounds. Additionally, hydrogels also demonstrate other unique features such as softness, malleability and biocompatibility. Nowadays, advanced wound care products make up around $7.1 billion of the global market and their production is growing at an annual rate of 8.3% with the market projected to be worth $12.5 billion by 2022.
The presented review focuses on novel hydrogel wound dressings, their main characteristics and their wound management applications. It also describes recent methodologies used for their production and the future potential developments.
Introduction
Radiofrequency (RF) lesion metrics are influenced by underlying parameters like RF power, duration, and contact force (CF), and utilization of lesion metric indices (ablation index AI) ...is a proposed strategy to predict lesion quality. The aim of this study was to analyze the influence of underlying parameters on lesion metrics of high‐power short‐duration (HPSD) and standard RF applications using an in silico and ex vivo model.
Methods and Results
An in silico simulation study was designed to simulate HPSD and standard ablations, in which ablation parameters could systematically be varied. For each simulated ablation process (n = 5732), the corresponding AI value was calculated. HPSD and standard RF settings were then applied in a porcine ex vivo model (
n = 120 lesions). The resulting lesion metrics were compared and analyzed regarding underlying parameters. RF applications of 50 W/13 seconds, 60 W/10 seconds, 70 W/7 seconds, and 80 W/6 seconds resulted in lesion volumes not significantly different from standard RF applications (30 W/30 seconds,
P > 0.05). HPSD lesion diameters were significantly larger and lesion depths were significantly smaller (
P < 0.01) when compared with standard settings. Prolonging RF duration from 5 to 10 seconds resulted in a +27.5% increase, whereas a prolongation of RF duration from 35 to 40 seconds resulted in a +4.8% increase of AI value only. An increase of CF from 1 to 10 g resulted in a +73.0%, an increase of CF from 20 to 30 g resulted in a +10.1% increase of AI value.
Conclusion
HPSD RF applications resulted in similar lesion volumes but significantly different lesion geometries when compared with standard setting RF applications.
Atrial tachycardias (ATs) are often seen in the context of atrial fibrillation (AF) ablation.
To evaluate the role of the Marshall bundle (MB) network in left atrial (LA) ATs using high-density ...3-dimensional mapping.
A total of 199 ATs were mapped in 140 patients (112 male, mean age: 61.8 years); 133 (66.8%) were macroreentrant and 66 (33.2%) were scar-related reentry circuits. MB-dependent ATs were suggested by activation mapping analysis and confirmed with entrainment along the circuit.
The MB network participated in 60 (30.2%) reentrant ATs: 31 perimitral ATs (PMATs) and 29 localized reentry circuits. Of 60 MB-related ATs, 49 (81.6%) terminated with radiofrequency (RF) ablation: 44 (73.3%) at the MB-LA junction and 5 (8.3%) at the MB-coronary sinus (CS) junction, while 9 (15%) terminated after 2.5-5 cc of ethanol infusion inside the vein of Marshall (VOM). Of the 31 PMATs, 17 (54.8%) terminated at the MB-LA junction, 5 (16.1%) at the MB-CS junction, and 7 (22.6%) with ethanol infusion. Of the 29 localized reentry circuits using the MB, 27 (93.1%) terminated at the MB-LA junction, none at the MB-CS junction, and 2 (6.9%) after ethanol infusion. Recurrences were mostly observed after RF ablation (18 of 37 patients, 49%) compared to ethanol infusion (1 of 9 patients, 11%) (P = .06).
MB reentrant ATs accounted for up to 30.2% of the left ATs after AF ablation. Ablation of the MB-LA or CS-MB connections or ethanol infusion inside the VOM is required to treat these arrhythmias.
Introduction
The QDOT‐MicroTM catheter is a novel irrigated contact force (CF) sensing catheter which benefits from thermocouples for temperature monitoring, allowing temperature‐flow‐controlled ...(TFC) ablation. We compared lesion metrics at fixed ablation index (AI) value during TFC‐ablation and conventional power‐controlled (PC)‐ablation.
Methods
A total of 480 RF‐applications were performed on ex‐vivo swine myocardium with predefined AI targets (400/550) or until steam‐pop occurred, using the QDOT‐MicroTM (TFC‐ablation) and Thermocool SmartTouch SFTM (PC‐ablation).
Results
Both TFC‐ablation and PC‐ablation produced similar lesions in volume (218 ± 116 vs. 212 ± 107 mm3, p = .65); however, lesions using TFC‐ablation were larger in surface area (41.3 ± 8.8 vs. 34.8 ± 8.0 mm2, p < .001) and shallower in depth (4.0 ± 1.0 vs. 4.2 ± 1.1 mm, p = .044). Average power tended to be lower in TFC‐alation (34.2 ± 8.6 vs. 36.9 ± 9.2, p = .005) compared to PC‐ablation due to automatic regulation of temperature and irrigation‐flow. Although steam‐pops were less frequent in TFC‐ablation (24% vs. 15%, p = .021), they were particularly observed in low‐CF (10 g) and high‐power ablation (50 W) in both PC‐ablation (n = 24/240, 10.0%) and TFC‐ablation (n = 23/240, 9.6%). Multivariate analysis revealed that high‐power, low‐CF, long application time, perpendicular catheter orientation, and PC‐ablation were risk factors for steam‐pops. Furthermore, activation of automatic regulation of temperature and irrigation‐flow was independently associated with high‐CF and long application time while ablation power had no significant relationship.
Conclusions
With a fixed target AI, TFC‐ablation reduced the risk of steam‐pops, producing similar lesions in volume, but with different metrics in this ex‐vivo study. However, lower CF and higher power in fixed‐AI ablation may increase the risk of steam‐pops.
When the ablation index was fixed during radiofrequency ablation, temperature‐flow‐controlled ablation provided lesions with larger surface, shallower depth and similar volume with lower incidence of steam‐pops compared to conventional power‐controlled ablation.
Introduction
We present the first worldwide use of pulsed‐field ablation (PFA) for ventricular tachycardia (VT) ablation via a retrograde approach.
Methods
The patient had previously failed ...conventional ablation of an intramural circuit underneath the aortic valve. The same VT circuit was inducible during the procedure. The Farawave PFA catheter and Faradrive sheath were used to deliver PFA applications.
Results
Post ablation mapping demonstrated scar homogenization. There was no evidence of coronary spasm during PFA applications and no other complications occurred. VT was non‐inducible post ablation and the patient has remained free of arrhythmia at follow‐up.
Conclusion
PFA for VT via a retrograde approach is feasible and effective.
Mutations in the transmembrane protein nephrin (encoded by NPHS1) underlie nearly half of all cases of congenital nephrotic syndrome (CNS), which is caused by aberrations in the blood filtering ...function of glomerular podocytes. Nephrin directly contributes to the structure of the filtration barrier, and it also serves as a signaling scaffold in podocytes, undergoing tyrosine phosphorylation on its cytoplasmic tail to recruit intracellular effector proteins. Nephrin phosphorylation is lost in several human and experimental models of glomerular disease, and genetic studies have confirmed its importance in maintenance of the filtration barrier. To date, however, the effect of CNS-associated NPHS1 variants on nephrin phosphorylation remains to be determined, which hampers genotype-phenotype correlations. Here, we have characterized a novel nephrin sequence variant, A419T, which is expressed along with C623F in a patient presenting with CNS. Nephrin localization is altered in kidney biopsies, and we further demonstrate reduced surface expression and ER retention of A419T and C623F in cultured cells. Moreover, we show that both mutations impair nephrin tyrosine phosphorylation, and they exert dominant negative effects on wildtype nephrin signaling. Our findings thus reveal that missense mutations in the nephrin extracellular region can impact nephrin signaling, and they uncover a potential pathomechanism to explain the spectrum of clinical severity seen with mild NPHS1 mutations.
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