Varicose vein treatment reduces edema not only in the treated legs but also in the entire body.

OBJECTIVES: We explored the connection between varicose vein and edema, by investigating extracellular water ratio (E/T) using bioelectrical impedance analysis. METHODS: In a prospective cohort study 120 patients underwent varicose vein surgery with extracellular fluid to total body water ratio (E/T) and E/T postop divided by E/Tpreop (E/T ratio) measured using a body composition analyzer. Edema was defined as E/T ≥0.390. Seventy-nine patients received unilateral treatment, while 41 underwent bilateral. p < .05 is statistically significant. RESULTS: Preoperatively, patients exhibited edema (E/T) in the treated leg (0.394 ± 0.009), untreated leg (0.392 ± 0.009), trunk (0.390 ± 0.007), and whole body (0.391 ± 0.007). Postoperatively, E/T decreased across body (p < .05). The lowest E/T ratio was observed in the treated leg (0.991 ± 0.012), followed by the untreated leg (0.994 ± 0.012), the trunk (0.995 ± 0.009), and the whole body (0.994 ± 0.009). E/T ratio of bilateral group were lower than unilateral group (p < .05). CONCLUSION: Varicose vein contributes to generalized edema, and treatment alleviates edema in the treated leg and the entire body.

Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.

Folding of Staphylococcal Nuclease Induced by Binding of Chemically Modified Substrate Analogues Sheds Light on Mechanisms of Coupled Folding/Binding Reactions.

Several proteins have been shown to undergo a shift in the mechanism of ligand binding-induced folding from conformational selection (CS; folding precedes binding) to induced fit (IF; binding precedes folding) with increasing ligand concentration. In previous studies of the coupled folding/binding reaction of staphylococcal nuclease (SNase) in the presence of a substrate analogue, adenosine-3',5'-diphosphate (prAp), we found that the two phosphate groups make important energetic contributions toward stabilizing its complex with the native protein as well as transient conformational states encountered at high ligand concentrations favoring IF. However, the structural contributions of each phosphate group during the reaction remain unclear. To address this question, we relied on fluorescence, nuclear magnetic resonance (NMR), absorption, and isothermal titration calorimetry to study the effects of deletion of the phosphate groups of prAp on the kinetics of ligand-induced folding, using a strategy analogous to mutational ϕ-value analysis to interpret the results. Kinetic measurements over a wide range of ligand concentrations, together with structural characterization of a transient protein-ligand encounter complex using 2D NMR, indicated that, at high ligand concentrations favoring IF, (i) the 5'-phosphate group interacts weakly with denatured SNase during early stages of the reaction, resulting in loose docking of the two domains of SNase, and (ii) the 3'-phosphate group engages in some specific contacts with the polypeptide in the transition state prior to formation of the native SNase-prAp complex.

Angina After Percutaneous Coronary Intervention: Patient and Procedural Predictors.

BACKGROUND: Twenty percent to 40% of patients are affected by angina after percutaneous coronary intervention (PCI), which is associated with anxiety, depression, impaired physical function, and reduced quality of life. Understanding patient and procedural factors associated with post-PCI angina may inform alternative approaches to treatment. METHODS: Two hundred thirty patients undergoing PCI completed the Seattle Angina Questionnaire (SAQ-7) and European quality of life-5 dimension-5 level (EQ-5D-5L) questionnaires at baseline and 3 months post-PCI. Patients received blinded intracoronary physiology assessments before and after stenting. A post hoc analysis was performed to compare clinical and procedural characteristics among patients with and without post-PCI angina (defined by follow-up SAQ-angina frequency score <100). RESULTS: Eighty-eight of 230 patients (38.3%) reported angina 3 months post-PCI and had a higher incidence of active smoking, atrial fibrillation, and history of previous myocardial infarction or PCI. Compared with patients with no angina at follow-up, they had lower baseline SAQ summary scores (69.48±24.12 versus 50.20±22.59, P<0.001) and EQ-5D-5L health index scores (0.84±0.15 versus 0.69±0.22, P<0.001). Pre-PCI fractional flow reserve (FFR) was lower among patients who had no post-PCI angina (0.56±0.15 versus 0.62±0.13, P=0.003). Percentage change in FFR after PCI had a moderate correlation with angina frequency score at follow-up (r=0.36, P<0.0001). Patients with post-PCI angina had less improvement in FFR (43.1±33.5% versus 67.0±50.7%, P<0.001). There were no between-group differences in post-PCI FFR, coronary flow reserve, or corrected index of microcirculatory resistance. Patients with post-PCI angina had lower SAQ-summary scores (64.01±22 versus 95.16±8.72, P≤0.001) and EQ-5D-5L index scores (0.69±0.26 versus 0.91±0.17, P≤0.001) at follow-up. CONCLUSIONS: Larger improvements in FFR following PCI were associated with less angina and better quality of life at follow-up. In patients with stable symptoms, intracoronary physiology assessment can inform expectations of angina relief and quality of life improvement after stenting and thereby help to determine the appropriateness of PCI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03259815.

PDLIM3 supports hedgehog signaling in medulloblastoma by facilitating cilia formation.

Elevated levels of PDLIM3 expression are frequently detected in sonic hedgehog (SHH) group of medulloblastoma (MB). However, the possible role of PDLIM3 in MB tumorigenesis is still unknown. Here, we found that PDLIM3 expression is necessary for hedgehog (Hh) pathway activation in MB cells. PDLIM3 is present in primary cilia of MB cells and fibroblasts, and such cilia localization is mediated by the PDZ domain of PDLIM3 protein. Deletion of PDLIM3 significantly compromised cilia formation and interfered the Hh signaling transduction in MB cells, suggesting that PDLIM3 promotes the Hh signaling through supporting the ciliogenesis. PDLIM3 protein physically interacts with cholesterol, a critical molecule for cilia formation and hedgehog signaling. The disruption of cilia formation and Hh signaling in PDLIM3 null MB cells or fibroblasts, was significantly rescued by treatment with exogenous cholesterol, demonstrating that PDLIM3 facilitates the ciliogenesis through cholesterol provision. Finally, deletion of PDLIM3 in MB cells significantly inhibited their proliferation and repressed tumor growth, suggesting that PDLIM3 is necessary for MB tumorigenesis. Our studies elucidate the critical functions of PDLIM3 in the ciliogenesis and Hh signaling transduction in SHH-MB cells, supporting to utilize PDLIM3 as a molecular marker for defining SHH group of MB in clinics.

Multiparametric Strategy to Predict Early Disease Decompensation in Asymptomatic Severe Aortic Regurgitation.

BACKGROUND: Use of the current echocardiography-based indications for aortic regurgitation (AR) surgery might result in late valve replacement at the stage of irreversible myocardial damage. Therefore, we aimed to identify simple models combining multiple echocardiography or magnetic resonance imaging (MRI)-derived indices and natriuretic peptides (BNP [brain natriuretic peptide] or NT-proBNP [N-terminnal pro-B type natriuretic peptide]) to predict early disease decompensation in asymptomatic severe AR. METHODS: This prospective and multicenter study included asymptomatic patients with severe AR, preserved left ventricular ejection fraction (>50%), and sinus rhythm. The echocardiography and MRI images were analyzed centrally in the CoreLab. The study end point was the onset of indication for aortic valve surgery as per current guidelines. RESULTS: The derivative cohort consisted of 127 asymptomatic patients (age 45±14 years, 84% males) with 41 (32%) end points during a median follow-up of 1375 (interquartile range, 1041-1783) days. In multivariable Cox regression analysis, age, BNP, 3-dimensional vena contracta area, MRI left ventricular end-diastolic volume index, regurgitant volume, and a fraction were identified as independent predictors of end point (all P<0.05). However, a combined model including one parameter of AR assessment (MRI regurgitant volume or regurgitant fraction or 3-dimensional vena contracta area), 1 parameter of left ventricular remodeling (MRI left ventricular end-diastolic volume index or echocardiography 2-dimensional global longitudinal strain or E wave), and BNP showed significantly higher predictive accuracy (area under the curve, 0.74-0.81) than any parameter alone (area under the curve, 0.61-0.72). These findings were confirmed in the validation cohort (n=100 patients, 38 end points). CONCLUSIONS: In asymptomatic severe AR, multimodality and multiparametric model combining 2 imaging indices with natriuretic peptides, showed high accuracy to identify early disease decompensation. Further prospective studies are warranted to explore the clinical benefit of implementing these models to guide patient management. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02910349.

Influence of fractional flow reserve on grafts patency: Systematic review and patient-level meta-analysis.

OBJECTIVE: To investigate the impact of invasive functional guidance for coronary artery bypass graft surgery (CABG) on graft failure. BACKGROUND: Data on the impact of fractional flow reserve (FFR) in guiding CABG are still limited. METHODS: Systematic review and individual patient data meta-analysis were performed. Primary objective was the risk of graft failure, stratified by FFR. Risk estimates are reported as odds ratios (ORs) derived from the aggregated data using random-effects models. Individual patient data were analyzed using mixed effect model to assess relationship between FFR and graft failure. This meta-analysis is registered in PROSPERO (CRD42020180444). RESULTS: Four prospective studies comprising 503 patients referred for CABG, with 1471 coronaries, assessed by FFR were included. Graft status was available for 1039 conduits at median of 12.0 [IQR 6.6; 12.0] months. Risk of graft failure was higher in vessels with preserved FFR (OR 5.74, 95% CI 1.71-19.29). Every 0.10 FFR units decrease in the coronaries was associated with 56% risk reduction of graft failure (OR 0.44, 95% CI 0.34 to 0.59). FFR cut-off to predict graft failure was 0.79. CONCLUSION: Surgical grafting of coronaries with functionally nonsignificant stenoses was associated with higher risk of graft failure.

Simplified Assessment of the Index of Microvascular Resistance.

BACKGROUND: To validate a simplified invasive method for the calculation of the index of microvascular resistance (IMR). METHODS: This is a prospective, single-center study of patients with chronic coronary syndromes presenting with nonobstructive coronary artery disease. IMR was obtained using both intravenous (IV) adenosine and intracoronary (IC) papaverine. Each IMR measurement was obtained in duplicate. The primary objective was the agreement between IMR acquired using adenosine and papaverine. Secondary objectives include reproducibility of IMR and time required for the IMR measurement. RESULTS: One hundred and sixteen IMR measurements were performed in 29 patients. The mean age was 68.8 ± 7.24 years, and 27.6% was diabetics. IMR values were similar between papaverine and adenosine (17.7 ± 7.26 and 20.1 ± 8.6, p=0.25; Passing-Bablok coefficient A 0.58, 95% CI -2.42 to 3.53; coefficient B 0.90, 95% CI -0.74 to 1.07). The reproducibility of IMR was excellent with both adenosine and papaverine (ICC 0.78, 95% CI 0.63 to 0.88 and ICC 0.93, 95% CI 0.87 to 0.97). The time needed for microvascular assessment was significantly shortened by the use of IC papaverine (3.23 (2.84, 3.78) mins vs. 5.48 (4.94, 7.09) mins, p < 0.0001). CONCLUSION: IMR can be reliably measured using IC papaverine with similar results compared to intravenous infusion of adenosine with increased reproducibility and reduced procedural time. This approach simplifies the invasive assessment of the coronary microcirculation in the catheterization laboratory.

Comparisons of Nonhyperemic Pressure Ratios: Predicting Functional Results of Coronary Revascularization Using Longitudinal Vessel Interrogation.

OBJECTIVES: The aim of this study was to investigate the accuracy of pre-percutaneous coronary intervention (PCI) predicted nonhyperemic pressure ratios (NHPRs) with actual post-PCI NHPRs and to assess the efficacy of PCI strategy using pre-PCI NHPR pullback. BACKGROUND: Predicting the functional results of PCI is feasible using pre-PCI longitudinal vessel interrogation with the instantaneous wave-free ratio (iFR), a pressure-based, adenosine-free NHPR. However, the reliability of novel NHPRs (resting full-cycle ratio [RFR] and diastolic pressure ratio [dPR]) for this purpose remains uncertain. METHODS: In this prospective, multicenter, randomized controlled trial, vessels were randomly assigned to receive pre-PCI iFR, RFR, or dPR pullback (50 vessels each). The pre-PCI predicted NHPRs were compared with actual NHPRs after contemporary PCI using intravascular imaging. The number and the total length of treated lesions were compared between NHPR pullback-guided and angiography-guided strategies. RESULTS: The predicted NHPRs were strongly correlated with actual NHPRs: iFR, r = 0.83 (95% confidence interval: 0.72 to 0.90; p < 0.001); RFR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001), and dPR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001). The number and the total length of treated lesions were lower with the NHPR pullback strategy than with the angiography-guided strategy, leading to physiological improvement. CONCLUSIONS: Predicting functional PCI results on the basis of pre-procedural RFR and dPR pullbacks yields similar results to iFR. Compared with an angiography-guided strategy, a pullback-guided PCI strategy with any of the 3 NHPRs reduced the number and the total length of treated lesions. (Study to Examine Correlation Between Predictive Value and Post PCI Value of iFR, RFR and dPR; UMIN000033534).

Mitral Valve Repair of Atrial Functional Mitral Regurgitation in Heart Failure with Preserved Ejection Fraction.

Our objective was to describe the long-term effects of endoscopic mitral valve (MV) repair on outcome in patients with heart failure with preserved ejection fraction (HFpEF) and atrial functional mitral regurgitation (AFMR). In patients with HFpEF, even mild AFMR has been associated with poor outcome. The study population consisted of consecutive patients with HFpEF (left ventricular ejection fraction (LVEF) ≥ 50%, H2FPEF score ≥ 5) and AFMR, who underwent isolated, minimally invasive endoscopic MV repair (MVRepair group) (n = 131) or remained on standard of care (StanCare group) (n = 139). Patients with coronary artery disease or organic mitral regurgitation (MR) were excluded. Patients were matched using inverse probability of treatment weighting. Endpoints were all-cause mortality and a composite of all-cause mortality and HFpEF readmissions. The median follow-up was 5.03 years (interquartile range (IQR) 2.6-7.9 years). In the MVRepair group, the perioperative, 30-day, 1-year, and 5-year mortality were 0, 1%, 1%, and 12%, respectively. Additionally, 13 (10%) patients were readmitted for worsening HFpEF, while 2 (1%) individuals underwent redo MV surgery for recurrent MR. MVRepair compared with StanCare showed 21-29% (Standard Error (SE) 6-8%) and 19-26% (SE 6-8%) absolute risk reduction of all-cause mortality and HFpEF readmissions, respectively (all p < 0.05). MVRepair emerged as the strongest independent predictor of all-cause mortality (Hazard Ratio (HR) 0.16, 95% (Confidence Interval (CI) 0.07-0.34, p < 0.001) and HFpEF readmissions (HR 0.21, 95% CI 0.09-0.51, p < 0.001). At 5-year follow-up, in the MVRepair group, a total of 88% were alive and 80% were alive without readmission for HFpEF. We can conclude that endoscopic MV repair is associated with low perioperative mortality as well as high long-term efficacy, and appears to improve clinical outcome in patients with AFMR and HFpEF.

Energetics and kinetics of substrate analog-coupled staphylococcal nuclease folding revealed by a statistical mechanical approach.

Protein conformational changes associated with ligand binding, especially those involving intrinsically disordered proteins, are mediated by tightly coupled intra- and intermolecular events. Such reactions are often discussed in terms of two limiting kinetic mechanisms, conformational selection (CS), where folding precedes binding, and induced fit (IF), where binding precedes folding. It has been shown that coupled folding/binding reactions can proceed along both CS and IF pathways with the flux ratio depending on conditions such as ligand concentration. However, the structural and energetic basis of such complex reactions remains poorly understood. Therefore, we used experimental, theoretical, and computational approaches to explore structural and energetic aspects of the coupled-folding/binding reaction of staphylococcal nuclease in the presence of the substrate analog adenosine-3',5'-diphosphate. Optically monitored equilibrium and kinetic data, combined with a statistical mechanical model, gave deeper insight into the relative importance of specific and Coulombic protein-ligand interactions in governing the reaction mechanism. We also investigated structural aspects of the reaction at the residue level using NMR and all-atom replica-permutation molecular dynamics simulations. Both approaches yielded clear evidence for accumulation of a transient protein-ligand encounter complex early in the reaction under IF-dominant conditions. Quantitative analysis of the equilibrium/kinetic folding revealed that the ligand-dependent CS-to-IF shift resulted from stabilization of the compact transition state primarily by weakly ligand-dependent Coulombic interactions with smaller contributions from specific binding energies. At a more macroscopic level, the CS-to-IF shift was represented as a displacement of the reaction "route" on the free energy surface, which was consistent with a flux analysis.

Association of Potentially Inappropriate Medications With All-Cause Mortality in the Elderly Acute Decompensated Heart Failure Patients: Importance of Nonsteroidal Anti-Inflammatory Drug Prescription.

BACKGROUND: Acute decompensated heart failure (ADHF) is the most common cause of readmissions in the hospital. ADHF patients are associated with polypharmacy. It is a common problem among elderly patients due to frequently occurring multiple morbidities and is associated with the use of potentially inappropriate medications (PIMs). The aim of this study was to examine the association between PIMs and all-cause mortality in elderly ADHF patients. METHODS: This retrospective study included ADHF patients who were admitted to the Showa University Fujigaoka Hospital between January 2015 and August 2016. We investigated the proportion of patients taking at least one PIM at admission and the characteristics of patients at admission. PIMs were defined based on the Screening Tool of Older People's potentially inappropriate Prescriptions (STOPP). Multiple Cox regression analysis was performed to examine the association between PIM use and all-cause mortality. RESULTS: A total of 193 elderly patients (median age 81 years, interquartile range (IQR) 65 - 99 years) were included in the study. All-cause death occurred in 30 patients. The median number of medications at admission was 7 (IQR 0 - 18). The number of medications (greater than or equal to six) at admission was associated with mortality. Multivariate Cox regression analysis revealed that systolic blood pressure (SBP) < 100 mm Hg at admission, chronic obstructive pulmonary disease (COPD), and use of non-steroidal anti-inflammatory drugs (NSAIDs) at admission were independent predictors for all-cause mortality. CONCLUSIONS: The medical staff should attempt to stop unnecessary medications that are prone to be inappropriate prescribing. In particular, prescription of NSAIDs should be carefully assessed and monitored.

Graft patency and progression of coronary artery disease after CABG assessed by angiography-derived fractional flow reserve.

BACKGROUND: Graft occlusion after coronary artery bypass graft surgery (CABG) has been associated with native coronary artery competitive flow. OBJECTIVES: The present study aims to characterize the functional progression of coronary artery disease (CAD) in native vessels after CABG, and to assess the relationship between preoperative FFR as derived from angiography and graft occlusion. METHODS: Multicenter study of consecutive patients undergoing CABG between 2013 and 2018, in whom a follow-up angiogram had been performed. Serial vessel-fractional flow reserve (vFFR) analyses were obtained in each major native coronary vessel before and after CABG, excluding post-anastomotic segments and graft conduits. RESULTS: In 73 patients, serial angiograms were suitable for vFFR analysis, including 118 grafted (86 arterial and 32 saphenous grafts) and 64 non-grafted vessels. The median time between CABG and follow-up angiography was 2.4 years [IQR 1.5, 3.3]. Functional CAD progression, by means of decline in vFFR, was observed in grafted but not in non-grafted vessels (delta vFFR in grafted vessels 0.10 [IQR 0.05, 0.18] vs. 0.01 [IQR -0.01, 0.03], in non-grafted vessels, p < 0.001). Preoperative vFFR predicted graft occlusion (AUC: 0.66, 95% CI 0.52 to 0.80, p = 0.031). CONCLUSIONS: In patients undergoing CABG, preoperative vFFR derived from conventional angiograms without use of pressure wire was able to predict graft occlusion. Graft occlusion was more frequent in vessels with high vFFR values. Grafted native coronary vessels exhibited accelerated functional CAD progression, whereas in non-grafted native coronaries the functional status remained unchanged.

Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease.

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.

Endoscopic submucosal dissection for early squamous cell carcinoma in the anal canal and Lugol chromoendoscopy for assessment of the lateral margin.

A 66-year-old man underwent follow-up colonoscopy after colon polypectomy. The retroflexed view of the anal canal with white-light imaging revealed a whitish, slightly elevated lesion on the dentate line and an ill-defined flat lesion. A biopsy of the whitish elevation revealed squamous cell carcinoma (SCC), and endoscopic submucosal dissection (ESD) was planned. The lateral margin of the SCC was identified by spraying with Lugol's iodine, and the tumor was resected en bloc with no complications. The pathological findings were SCC in situ with parakeratosis in the whitish elevation and high-grade intraepithelial neoplasia in the ill-defined flat lesion, which exhibited a wide iodine-unstained area by chromoendoscopy. Early SCC in the anal canal is a rare gastrointestinal cancer, and Lugol chromoendoscopy helped visualize the tumor margin for ESD.