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El-Sayed Ahmad, A., Bayram, A., Salamate, S., Sirat, S., Amer, M., & Bakhtiary, F. (2022). Percutaneous versus surgical femoral access in minimally invasive cardiac operations. Eur J Cardiothorac Surg, 61(6), 1348–1354.
Abstract: OBJECTIVES: Both surgical and percutaneous femoral accesses for the establishment of extracorporeal circulation are used in minimally invasive cardiac surgeries. The goal of this study was to compare the outcomes with the MANTA vascular closure device after percutaneous arterial decannulation via the surgical approach. METHODS: Between November 2018 and January 2021, a total of 490 consecutive patients underwent minimally invasive cardiac operations at our institution. Cannulation and decannulation of femoral vessels were under direct vision surgically or percutaneously. The MANTA system was used to close the femoral artery in all patients with percutaneous cannulation. Demographic, clinical and procedural data were collected retrospectively. RESULTS: Surgical cut-down and suture closure of the femoral artery was performed in 222 patients (45.3%); percutaneous access and closure with the MANTA system was used in 268 patients (54.7%). The surgical group presented a significantly higher incidence of any access site complication compared to the percutaneous group [18 patients (8.1%) vs 6 patients (2.2%); P = 0.003]. Lymph fistula and wound healing disorders occurred more frequently in the surgical group (3.2% vs 0% [P = 0.004] and 3.6% vs 0% [P = 0.002], respectively). Median procedural duration and stays in the intensive care unit were significantly lower in the percutaneous group {127 [interquartile range (IQR) 97-158] min vs 150 (IQR 117-185) min (P < 0.001) and 1 (IQR 1-2) day vs 2 (IQR 1-3) days (P = 0.008), respectively}. CONCLUSIONS: Percutaneous access and closure with the MANTA system are feasible, safe and associated with lower incidences of all-cause access site complications and shorter stays in the intensive care unit compared to surgical access and closure in minimally invasive cardiac surgeries.
Keywords: *Cardiac Catheterization/adverse effects/instrumentation/methods; *Femoral Artery/surgery; Humans; Minimally Invasive Surgical Procedures; Retrospective Studies; Treatment Outcome; *Vascular Closure Devices; Cardiopulmonary bypass; Minimally invasive surgery; Vascular closure devise
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Ridker, P. M. (2016). From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ Res, 118(1), 145–156.
Abstract: Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.
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David Eddington. (2008). Presidential Address: Linguistics and the Scientific Method. Southwest Journal of Linguistics, 27(2).
Abstract: T. In the present paper, I contrast empirical and non-empirical approaches to linguistics by examining the extent to which they practice the
scientific method. I provide examples of linguistic analyses that follow and
depart from the scientific method and argue that valid explanations about
actual language processing rely on adherence to scientific methodology.
However, this is not a requirement for philosophical arguments about abstract
language structure. Charges of pseudoscience arise when empirical significance is attached to analyses that fail to follow the scientific method. Progress
in linguistics is only made to the extent that researchers adopt the method
that is standard in scientific endeavors.
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Fallon, J. L., Halling, D. B., Hamilton, S. L., & Quiocho, F. A. (2005). Structure of calmodulin bound to the hydrophobic IQ domain of the cardiac Ca(v)1.2 calcium channel. Structure, 13(12), 1881–1886.
Abstract: Ca2+-dependent inactivation (CDI) and facilitation (CDF) of the Ca(v)1.2 Ca2+ channel require calmodulin binding to a putative IQ motif in the carboxy-terminal tail of the pore-forming subunit. We present the 1.45 A crystal structure of Ca2+-calmodulin bound to a 21 residue peptide corresponding to the IQ domain of Ca(v)1.2. This structure shows that parallel binding of calmodulin to the IQ domain is governed by hydrophobic interactions. Mutations of residues I1672 and Q1673 in the peptide to alanines, which abolish CDI but not CDF in the channel, do not greatly alter the structure. Both lobes of Ca2+-saturated CaM bind to the IQ peptide but isoleucine 1672, thought to form an intramolecular interaction that drives CDI, is buried. These findings suggest that this structure could represent the conformation that calmodulin assumes in CDF.
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Klee, E. W., & Zimmermann, M. T. (2019). Molecular modeling of LDLR aids interpretation of genomic variants. Journal of Molecular Medicine, 97(4), 533–540.
Abstract: Genetic variants in low-density lipoprotein receptor (LDLR) are known to cause familial hypercholesterolemia (FH), occurring in up to 1 in 200 people (Youngblom E. et al. 1993 and Nordestgaard BG et al. 34:3478–3490a, 2013) and leading to significant risk for heart disease. Clinical genomics testing using high-throughput sequencing is identifying novel genomic variants of uncertain significance (VUS) in individuals suspected of having FH, but for whom the causal link to the disease remains to be established (Nordestgaard BG et al. 34:3478–3490a, 2013). Unfortunately, experimental data about the atomic structure of the LDL binding domains of LDLR at extracellular pH does not exist. This leads to an inability to apply protein structure-based methods for assessing novel variants identified through genetic testing. Thus, the ambiguities in interpretation of LDLR variants are a barrier to achieving the expected clinical value for personalized genomics assays for management of FH. In this study, we integrated data from the literature and related cellular receptors to develop high-resolution models of full-length LDLR at extracellular conditions and use them to predict which VUS alter LDL binding. We believe that the functional effects of LDLR variants can be resolved using a combination of structural bioinformatics and functional assays, leading to a better correlation with clinical presentation. We have completed modeling of LDLR in two major physiologic conditions, generating detailed hypotheses for how each of the 1007 reported protein variants may affect function. • Hundreds of variants are observed in the LDLR, but most lack interpretation. • Molecular modeling is aided by biochemical knowledge. • We generated context-specific 3D protein models of LDLR. • Our models allowed mechanistic interpretation of many variants. • We interpreted both rare and common genomic variants in their physiologic context. • Effects of genomic variants are often context-specific.
Keywords: gene:LDLR
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