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An 83-year-old woman was admitted to our center because of heart failure. Transthoracic echocardiography revealed severe mitral annular calcification resulting in a double mitral valve lesion. After discussion by the heart team, transcatheter mitral valve replacement with Tendyne (Abbott Structural, Santa Clara, CA, USA) was performed. Despite having a predicted neo-left ventricular outflow tract (LVOT) above the cut-off value, the patient developed clinically significant LVOT obstruction (LVOTO) refractory to medical treatment. This situation is often treated before the intervention, and dealing with LVOTO afterward can be challenging. After taking the patient's anatomy into consideration, we decided to perform alcohol septal ablation. Applying a combined strategy of medical treatment and intervention led to success. In this case report, we discuss this event and the strategies available for preventing and managing the condition.

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We carried out a comparison of the neuromuscular and clinical effects produced by electrostimulation therapies, as an adjuvant to the use of occlusal splints (removable muscle relaxation apparatus) in patients with temporomandibular disorders In this simple randomized clinical trial, 91 patients were randomly divided into three groups. Group A (GA) received transcutaneous electrostimulation therapy and an occlusal splint, Group B (GB) received percutaneous electrostimulation therapy and an occlusal splint, and Group C (GC) received an occlusal splint. The neuromuscular activity, as well as the signs and symptoms of each patient, were evaluated every week throughout the treatment (T0 = baseline; T1 = 7 days; T2 = 14 days; T3 = 21 days; T4 = 28 days; and T5 = 35 days). Pain was measured with a visual analog scale, and neuromuscular electrical activity was determined by the root mean square of the masseter muscles through the use of a UNAM-CINVESTAV 1.2 electromyograph. Comparisons were made using ANOVA for repeated measures (p-value = 0.05). The comparison between the groups determined that muscle fatigue (p-value = 0.001), joint pain (p-value = 0.009), and muscle pain (p-value = 0.003) decreased to a greater extent, and in the short term for the group treated with transcutaneous electrostimulation therapy as an adjuvant to the use of the occlusal splint. The comparison between the groups determined that muscle fatigue (p-value = 0.001), joint pain (p-value = 0.009), and muscle pain (p-value = 0.003) decreased to a greater extent and in a shorter term in the GA (calculation therapy, transcutaneous electrostimulation) and GB (occlusal splint). Transcutaneous electrostimulation is a feasible and faster alternative that was accepted by most of the patients for treating temporomandibular disorders.

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BACKGROUND: Residual transprosthetic gradient (TG) after transcatheter aortic valve replacement (TAVR) with balloon-expandable valves (BEV) may be due to suboptimal valve expansion. AIMS: To compare hemodynamics after TAVR with small BEV according to postdilation strategy. METHODS: This observational, retrospective cohort study included 184 consecutive patients from a single center treated with 23 mm Sapien 3 Ultra (Edwards Lifesciences) BEV implantation in the aortic position and enrolled between January 2020 and April 2023. Patients treated with routine postdilation (RP, n = 73) were compared to patients treated according to local standard practice (SP, n = 111). Primary endpoint was 30-day mean TG. Secondary endpoints were incidence of 30-day prosthesis-patient mismatch (PPM), technical success and device success. RESULTS: Thirty-day mean TG was lower in RP versus SP (12.3 ± 4.6 mmHg vs. 14.1 ± 5.7 mmHg, p = 0.031), and incidence of PPM was less common with RP versus SP (47.3% vs. 71.0%, p = 0.006). Technical success (98.6% vs. 99.1%, p = 0.637) and device success (93.1% vs. 90.1%, p = 0.330) did not differ between groups. Differences in 30-day mean TG were driven by patients at normal flow (12.1 ± 4.0 mmHg vs. 15.0 ± 5.5 mmHg, p = 0.014), while no differences were evident among patients at low flow (12.5 ± 5.5 mmHg vs. 11.7 ± 5.5 mmHg, p = 0.644). RP decreased height and increased width of BEV, and a linear regression established that final BEV width could predict 30-day mean TG (r = -0.6654, p < 0.0001). CONCLUSIONS: RP after TAVR with small BEV was associated with more favorable forward-flow hemodynamics than SP.

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Background: Percutaneous closure of aortic-to-right ventricle (ARV) fistula has emerged as an alternative to surgical management in selected cases. The use of three-dimensional (3D) printing in interventional planning for structural heart disease provides a concrete understanding, and it is useful in diagnostic assessment and to guide treatment approaches and to simulate procedures. Case summary: We report a case of a 70-year-old male presenting in cardiogenic shock due to severe aortic stenosis and reduced left ventricular ejection fraction. The patient had several comorbidities and was deemed not eligible for cardiac surgery. After transcatheter aortic valve replacement (TAVR), an ARV fistula was discovered on the TTE. Due to complex anatomical considerations, a 3D printed model of the patient's anatomy was employed to supplement the decision-making process and technical planning of percutaneous ARV closure. Successful closure of the fistula with the use of the Amplatzer atrial septal occluder was subsequently performed. Discussion: Three-dimensional printing improves the understanding of complex structures of cardiac diseases, allowing for enhanced planning and simulation of the procedure. This case, demonstrating the effective percutaneous closure of a TAVR-related ARV fistula facilitated by the use of 3D printed anatomical models in the pre-procedural phase, highlights the technology's potential in advancing patient-specific treatment approaches.

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Endothelial cells (ECs) line the wall of blood vessels and regulate arterial contractility to tune regional organ blood flow and systemic pressure. Chloride (Cl-) is the most abundant anion in ECs and the Cl- sensitive With-No-Lysine (WNK) kinase is expressed in this cell type. Whether intracellular Cl- signaling and WNK kinase regulate EC function to alter arterial contractility is unclear. Here, we tested the hypothesis that intracellular Cl- signaling in ECs regulates arterial contractility and examined the signaling mechanisms involved, including the participation of WNK kinase. Our data obtained using two-photon microscopy and cell-specific inducible knockout mice indicated that acetylcholine, a prototypical vasodilator, stimulated a rapid reduction in intracellular Cl- concentration ([Cl-]i) due to the activation of TMEM16A, a Cl- channel, in ECs of resistance-size arteries. TMEM16A channel-mediated Cl- signaling activated WNK kinase, which phosphorylated its substrate proteins SPAK and OSR1 in ECs. OSR1 potentiated transient receptor potential vanilloid 4 (TRPV4) currents in a kinase-dependent manner and required a conserved binding motif located in the channel C terminus. Intracellular Ca2+ signaling was measured in four dimensions in ECs using a high-speed lightsheet microscope. WNK kinase-dependent activation of TRPV4 channels increased local intracellular Ca2+ signaling in ECs and produced vasodilation. In summary, we show that TMEM16A channel activation reduces [Cl-]i, which activates WNK kinase in ECs. WNK kinase phosphorylates OSR1 which then stimulates TRPV4 channels to produce vasodilation. Thus, TMEM16A channels regulate intracellular Cl- signaling and WNK kinase activity in ECs to control arterial contractility.

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Many cells adhere to extracellular matrix for efficient cell migration. This adhesion is mediated by focal adhesions, a protein complex linking the extracellular matrix to the intracellular cytoskeleton. Focal adhesions have been studied extensively in mesenchymal cells, but recent research in physiological contexts and amoeboid cells suggest focal adhesion regulation differs from the mesenchymal focal adhesion paradigm. We used Dictyostelium discoideum to uncover new mechanisms of focal adhesion regulation, as Dictyostelium are amoeboid cells that form focal adhesion-like structures for migration. We show that PaxillinB, the Dictyostelium homologue of Paxillin, localizes to dynamic focal adhesion-like structures during Dictyostelium migration. Unexpectedly, reduced PaxillinB recruitment to these structures increases Dictyostelium cell migration. Quantitative analysis of focal adhesion size and dynamics show that lack of PaxillinB recruitment to focal adhesions does not alter focal adhesion size, but rather increases focal adhesion turnover. These findings are in direct contrast to Paxillin function at focal adhesions during mesenchymal migration, challenging the established focal adhesion model.

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BACKGROUND: Sodium increases during acute kidney injury (AKI) recovery. Both hypernatremia and positive fluid balances are associated with increased mortality. We aimed to evaluate the association between daily fluid balance and daily plasma sodium during the recovery from AKI among critical patients. METHODS: Adult patients with AKI were enrolled in four ICUs and followed up for four days or until ICU discharge or hemodialysis initiation. Day zero was the peak day of creatinine. The primary outcome was daily plasma sodium; the main exposure was daily fluid balance. RESULTS: 93 patients were included. The median age was 66 years; 68% were male. Plasma sodium increased in 79 patients (85%), and 52% presented hypernatremia. We found no effect of daily fluid balance on plasma sodium (ß -0.26, IC95%: -0.63-0.13; p = 0.19). A higher total sodium variation was observed in patients with lower initial plasma sodium (ß -0.40, IC95%: -0.53 to -0.27; p < 0.01), higher initial urea (ß 0.07, IC95%: 0.04-0.01; p < 0.01), and higher net sodium balance (ß 0.002, IC95%: 0.0001-0.01; p = 0.05). CONCLUSIONS: The increase in plasma sodium is common during AKI recovery and can only partially be attributed to the water and electrolyte balances. The incidence of hypernatremia in this population of patients is higher than in the general critically ill patient population.

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Acute hemodynamic compromise after transcatheter aortic valve replacement (TAVR) because of dynamic left ventricle (LV) obstruction (LVO), also known as suicide LV, is an infrequent but severe complication of TAVR that is poorly defined in previous studies. Understanding this complication is essential for its prompt diagnosis and optimal treatment. We conducted a systematic literature review using PubMed, Embase, Web of Science, and Medline databases for studies describing acute hemodynamic compromise after TAVR because of dynamic LVO or suicide LV. Each study was reviewed by 2 authors individually for eligibility, and a third author resolved disagreements. From a total of 506 studies, 25 publications were considered for the final analysis. The majority of patients with this condition were women demonstrating a hypertrophic septum, a small ventricle, and hyperdynamic contractility on pre-TAVR echocardiographic assessment. An intraventricular gradient before TAVR was found in half of the cases. Acute hemodynamic compromise after TAVR because of dynamic LVO manifested mainly as significant hypotension and occurred most often immediately after valve deployment. The LV outflow tract was the most common site of obstruction. Advanced therapies were required in nearly 65% of the cases. In conclusion, acute hemodynamic compromise after TAVR because of dynamic LVO occurred almost invariably in women. Echocardiography before TAVR may offer essential information to anticipate this complication. LV outflow tract obstruction appears to carry the highest risk of developing this phenomenon. Advanced therapies should be promptly considered as a bailout strategy in patients with hemodynamic collapse refractory to medical therapy.

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La lesión del manguito rotador es una causa importante de dolor y disfunción del hombro. El tratamiento de las roturas masivas e irreparables del manguito rotador sigue siendo un gran reto para los ortopedistas por su complejidad y severidad. Una de las alternativas prometedoras para su manejo es el uso del balón subacromial. Presentamos el caso de una mujer de 67 años con diagnóstico de rotura masiva e irreparable del manguito rotador en el hombro derecho (grado III de Patte, grado IV Goutallier y grado II de Hamada) sin artrosis glenohumeral, tenosinovitis del bíceps y subescapular íntegro. La escala de constant preoperatorio fue de 40 puntos. Se realizó una reparación parcial artroscópica del tendón supraespinoso e infraespinoso asociado a una tenodesis suprapectoral del bíceps y la colocación del balón subacromial. La paciente realizó rehabilitación con mejoría de los arcos de movilidad, disminución del dolor e incremento de la fuerza del hombro derecho. La escala de constant postoperatorio fue de 80 puntos a la semana doce. El balón subacromial es una buena alternativa de tratamiento para las lesiones irreparables del manguito rotador con resultados óptimos a corto plazo en cuanto a dolor y función.

The rotator cuff injury is a significant cause of shoulder pain and dysfunction. Treating massive and irreparable rotator cuff tears remains a major challenge for orthopedists due to their complexity and severity. One promising alternative for managing these cases is the use of subacromial balloons. In this study, we present the case of a 67-year-old woman diagnosed with a massive and irreparable rotator cuff tear in her right shoulder (Grade III Patte, Grade IV Goutallier, and Grade II Hamada), without glenohumeral arthritis, intact biceps tenosynovitis, and subscapularis. The preoperative Constant score was 40 points. The patient underwent partial arthroscopic repair of the supraspinatus and infraspinatus tendons, along with a suprapectoral biceps tenodesis and subacromial balloon placement. Postoperative rehabilitation led to improved range of motion, reduced pain, and increased strength in the right shoulder. The postoperative Constant score reached 80 points at the twelve-week mark. The subacromial balloon proves to be a promising treatment alternative for irreparable rotator cuff injuries, providing optimal short-term results in terms of pain relief and functionality.

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Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function. A linoleic acid (LA)-enriched diet increases PIEZO2 activity, mechano-excitability, and improves gait in male AS mice. Finally, LA supplementation increases PIEZO2 function in stem cell-derived neurons from individuals with AS. We propose a mechanism whereby loss of UBE3A expression reduces PIEZO2 function and identified a fatty acid that enhances channel activity and ameliorates AS-associated mechano-sensory deficits.

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TRPV4 channel activation in endothelial cells leads to vasodilation, while impairment of TRPV4 activity is implicated in vascular dysfunction. Strategies that increase TRPV4 activity could enhance vasodilation and ameliorate vascular disorders. Here, we show that supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid known to have beneficial cardiovascular effects, increases TRPV4 activity in human endothelial cells of various vascular beds. Mice carrying the C. elegans FAT-1 enzyme, which converts ω-6 to ω-3 polyunsaturated fatty acids, display higher EPA content and increased TRPV4-mediated vasodilation in mesenteric arteries. Likewise, mice fed an EPA-enriched diet exhibit enhanced and prolonged TRPV4-dependent vasodilation in an endothelial cell-specific manner. We also show that EPA supplementation reduces TRPV4 desensitization, which contributes to the prolonged vasodilation. Neutralization of positive charges in the TRPV4 N terminus impairs the effect of EPA on channel desensitization. These findings highlight the beneficial effects of manipulating fatty acid content to enhance TRPV4-mediated vasodilation.

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Cell-substrate adhesion is a critical aspect of many forms of cell migration. Cell adhesion to an extracellular matrix (ECM) generates traction forces necessary for efficient migration. One of the most well-studied structures cells use to adhere to the ECM is focal adhesions, which are composed of a multilayered protein complex physically linking the ECM to the intracellular actin cytoskeleton. Much of our understanding of focal adhesions, however, is primarily derived from in vitro studies in Metazoan systems. Though these studies provide a valuable foundation to the cell-substrate adhesion field, the evolution of cell-substrate adhesion machinery across evolutionary space and the role of focal adhesions in vivo are largely understudied within the field. Furthering investigation in these areas is necessary to bolster our understanding of the role cell-substrate adhesion machinery across Eukaryotes plays during cell migration in physiological contexts such as cancer and pathogenesis. In this review, we review studies of cell-substrate adhesion machinery in organisms evolutionary distant from Metazoa and cover the current understanding and ongoing work on how focal adhesions function in single and collective cell migration in an in vivo environment, with an emphasis on work that directly visualizes cell-substrate adhesions. Finally, we discuss nuances that ought to be considered moving forward and the importance of future investigation in these emerging fields for application in other fields pertinent to adhesion-based processes.

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Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin's globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

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Intestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca2+. Here we identify TRPV6, a Ca2+-permeable channel, as responsible for alcohol-induced elevation of intracellular Ca2+, intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca2+ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6-/- mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury.

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One of the major obstacles in treating brain cancers, particularly glioblastoma multiforme, is the occurrence of secondary tumor lesions that arise in areas of the brain and are inoperable while obtaining resistance to current therapeutic agents. Thus, gaining a better understanding of the cellular factors that regulate glioblastoma multiforme cellular movement is imperative. In our study, we demonstrate that the 5'-3' exoribonuclease XRN2 is important to the invasive nature of glioblastoma. A loss of XRN2 decreases cellular speed, displacement, and movement through a matrix of established glioblastoma multiforme cell lines. Additionally, a loss of XRN2 abolishes tumor formation in orthotopic mouse xenograft implanted with G55 glioblastoma multiforme cells. One reason for these observations is that loss of XRN2 disrupts the expression profile of several cellular factors that are important for tumor invasion in glioblastoma multiforme cells. Importantly, XRN2 mRNA and protein levels are elevated in glioblastoma multiforme patient samples. Elevation in XRN2 mRNA also correlates with poor overall patient survival. These data demonstrate that XRN2 is an important cellular factor regulating one of the major obstacles in treating glioblastomas and is a potential molecular target that can greatly enhance patient survival.

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