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2,335,100 |
Role of blocking ADAM10 hydrolysis site on N-cadherin by single-chain antibody in ventricular remodeling.
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The present study aimed to investigate the roles of the hydrolytic process of N-cadherin by A disintegrin and metalloproteases 10 (ADAM10) in sustaining myocardial structure and integrity, and discuss the mechanisms of ventricular remodeling in dilated cardiomyopathy (DCM). Single chain variable fragment antibody (ScFv) with the ability to specifically block the ADAM10 hydrolysis site of N-cadherin was designed and constructed. Western blot analysis and flow cytometry were used to detect the expression of N-cadherin and its C-terminal fragment 1 (CTF1) on cardiomyocytes, and cells were also subjected to a cell adhesion assay. Furthermore, in a rat model of dilated cardiomyopathy (DCM), the effects of intracardiac injection of the recombinant adenovirus on cardiac structure and contractile function were observed by hematoxylin and eosin staining and color Doppler echocardiography. The recombinant ScFv-expressing adenoviral plasmid with the ability to block the ADAM10 hydrolysis site on N-cadherin was successfully constructed and efficiently transfected into H9C2 cells. After transfection, N-cadherin protein expression was significantly increased, CTF1 protein was significantly decreased and the adhesion capability of myocardial cells was significantly improved. In the <i>in vivo</i> experiment, N-cadherin expression was significantly increased in the treatment group compared with that in the model group, and the structure and function of the heart were significantly improved. In conclusion, blocking of the ADAM10 hydrolysis site on N-cadherin by ScFv increased N-cadherin expression and improved ventricular remodeling. The present study provided experimental evidence for a novel approach for the treatment and prevention of DCM.
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2,335,101 |
Amylin and diabetic cardiomyopathy - amylin-induced sarcolemmal Ca<sup>2+</sup> leak is independent of diabetic remodeling of myocardium.
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Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial amylin accumulation is associated with myocyte Ca<sup>2+</sup> dysregulation in diabetic rats expressing human amylin. Whether deposition of amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used amylin knockout (AKO) mice intravenously infused with either human amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent amylin to test the hypothesis that aggregated amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human amylin, but not rodent amylin, showed amylin deposits in the myocardium. Cardiac amylin level was larger in males compared to females. Sarcolemmal Ca<sup>2+</sup> leak and Ca<sup>2+</sup> transients were increased in myocytes isolated from males infused with human amylin while no significant changes occurred in either females injected with human amylin or in rat amylin-infused mice. In isolated cardiac myocytes, the amylin receptor antagonist AC-187 did not effectively block the interaction of amylin with the sarcolemma. In conclusion, circulating aggregated amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca<sup>2+</sup> cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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2,335,102 |
Effect of interscalene block on intraocular pressure and ocular perfusion pressure.
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Interscalene block (ISB) is commonly associated with Horner's syndrome due to spread of local anesthetic to the cervical sympathetic chain. Postganglionic neurons that originate from superior cervical ganglia form the sympathetic innervation of eye. Decrease in sympathetic tone may change intraocular pressure (IOP) and ocular perfusion pressure (OPP). The aim of the study was to investigate whether ISB affects IOP and/or OPP.</AbstractText>Thirty patients scheduled for ambulatory shoulder surgery under regional anesthesia with a single-shot ISB (15 mL 0.5% bupivacaine and 15 mL 2% lidocaine) were recruited. The IOP and OPP in both eyes, mean arterial pressure (MAP), heart rate (HR) and end-tidal CO2</sub> (ETCO2</sub>) were measured before ISB and 5, 10, 20, 30 and 60 min after ISB in the beach-chair position.</AbstractText>The baseline IOP and OPP were similar in the blocked and unblocked sides (IOP 17.60 ± 1.69 and 17.40 ± 1.96 respectively p = 0.432; OPP 49.80 ± 8.20 and 50 ± 8.07 respectively p = 0.432). The IOP in the blocked side significantly decreased between 10th to 60th min following ISB, compared to the baseline values (p < 0.001). The OPP in the blocked side significantly increased from 10th to 60th min (p < 0.001) whereas, there were no significant changes in IOP and OPP throughout the measurement period in the unblocked side.</AbstractText>ISB decreased IOP in the blocked side. ISB could be considered as a safe regional technique of choice in elderly patients at high risk for developing glaucoma.</AbstractText>
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2,335,103 |
The Society of Thoracic Surgeons General Thoracic Surgery Database: 2017 Update on Research.
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The outcomes research efforts based on The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database include two established research programs with dedicated task forces and with data analyses conducted at the STS data analytic center: (1) The STS-sponsored research by the Access and Publications program, and (2) grant and institutionally funded research by the Longitudinal Follow-Up and Linked Registries Task Force. Also, the STS recently introduced the research program enabling investigative teams to apply for access to deidentified patient-level General Thoracic Surgery Database data sets and conduct related analyses at their own institution. Last year's General Thoracic Surgery Database-based research publications and the new Participant User File research program are reviewed.
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2,335,104 |
Cardiac magnetic resonance imaging-indeterminate/negative cardiac sarcoidosis revealed by <sup>18</sup>F-fluorodeoxyglucose-positron emission tomography: two case reports and a review of the literature.
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Sarcoidosis is an inflammatory disorder of immune dysregulation characterized by non-caseating granulomas that can affect any organ. Cardiac sarcoidosis is an under-recognized entity that has a heterogeneous presentation and may occur independently or with any severity of systemic disease. Diagnosing cardiac sarcoidosis remains problematic with endomyocardial biopsies associated with a high risk of complications. Several diagnostic algorithms are currently available that rely on histopathology or clinical and radiological measures. The dominant mode of diagnostic imaging to date for cardiac sarcoidosis has been cardiac magnetic resonance imaging with gadolinium enhancement.</AbstractText>We report the cases of two adult patients: case 1, a 50-year-old white man who presented with severe congestive cardiac failure; and case 2, a 37-year-old white woman who presented with complete heart block. Both patients had a background of untreated pulmonary sarcoidosis. Cardiac magnetic resonance imaging did not show evidence of sarcoidosis in either patient and both proceeded to 18</sup>F-fluorodeoxyglucose-positron emission tomography scans that were highly suggestive of cardiac sarcoidosis. Both patients were systemically immunosuppressed with orally administered prednisone and methotrexate and had subsequent improvement by clinical and nuclear medicine imaging measures.</AbstractText>Current consensus guidelines recommend all patients with sarcoidosis undergo screening for occult cardiac disease, with thorough history and examination, electrocardiogram, and transthoracic echocardiogram. If any abnormalities are detected, advanced cardiac imaging should follow. While cardiac magnetic resonance imaging identifies the majority of cardiac sarcoidosis, early disease may not be detected. These cases demonstrate 18</sup>F-fluorodeoxyglucose-positron emission tomography is warranted following an indeterminate or normal cardiac magnetic resonance imaging if clinical suspicion remains high. Unidentified and untreated cardiac sarcoidosis risks significant morbidity and mortality, but early detection can facilitate disease-modifying immunosuppression and cardiac-specific interventions.</AbstractText>
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2,335,105 |
Trigger vs. Substrate: Multi-Dimensional Modulation of QT-Prolongation Associated Arrhythmic Dynamics by a hERG Channel Activator.
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<b>Background:</b> Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore APD to control ranges, reversing the enhanced vulnerability to Ca<sup>2+</sup>-dependent afterdepolarisations (arrhythmia triggers) and increased transmural dispersion of repolarisation (arrhythmia substrate) associated with APD prolongation. However, such pharmacological modulation has been demonstrated to have limited effectiveness. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate. <b>Methods:</b> We implemented a multi-scale (cell and tissue) <i>in silico</i> approach using a model of the human ventricular action potential, integrated with a model of stochastic 3D spatiotemporal Ca<sup>2+</sup> dynamics, and parameter modification to mimic prolonged QT conditions. We used these models to examine the efficacy of the hERG activator MC-II-157c in restoring APD to control ranges, examined its effects on arrhythmia triggers and substrates, and the interaction of these arrhythmia triggers and substrates. <b>Results:</b> QT prolongation conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to prolonged QT conditions shortened the APD, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells. In tissue, QT prolongation resulted in an increased transmural dispersion of repolarisation, which manifested as an increased vulnerable window for uni-directional conduction block. In some cases, MC-II-157c further increased the vulnerable window through its effects on <i>I</i><sub>Na</sub>. The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia. <b>Conclusion:</b> The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval.
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2,335,106 |
Association of Natural Killer Cell Ligand Polymorphism HLA-C Asn80Lys With the Development of Anti-SSA/Ro-Associated Congenital Heart Block.
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Fetal exposure to maternal anti-SSA/Ro antibodies is necessary but not sufficient for the development of autoimmune congenital heart block (CHB), suggesting that other factors, such as fetal genetic predisposition, are important. Given the previously described association between major histocompatibility complex alleles and CHB risk, we undertook the present study to test the hypothesis that a variant form of HLA-C Asn80Lys, which binds with high affinity to an inhibitory killer cell immunoglobulin-like receptor (KIR) and thus renders natural killer (NK) cells incapable of restricting inflammation, contributes to the development of CHB.</AbstractText>Members of 192 pedigrees in the US and Europe (194 cases of CHB, 91 unaffected siblings, 152 fathers, 167 mothers) and 1,073 out-of-study controls were genotyped on the Immunochip single-nucleotide polymorphism microarray. Imputation was used to identify associations at HLA-C Asn80Lys (Asn, C1; Lys, C2) and KIR. Tests for association were performed using logistic regression. McNemar's test and the pedigree disequilibrium test (PDT) were used for matched analyses between affected and unaffected children.</AbstractText>Compared with out-of-study controls of the same sex, the C2 allele was less frequent in the mothers (odds ratio [OR] 0.63, P = 0.0014) and more frequent in the fathers (OR 1.40, P = 0.0123), yielding a significant sex-by-C2 interaction (P = 0.0002). The C2 allele was more frequent in affected siblings than in unaffected siblings (OR 3.67, P = 0.0025), which was consistent with the PDT results (P = 0.016); these results were observed in both sexes and across the US and European cohorts. There was no difference in the frequency of the inhibitory KIR genotype (KIR AA) between affected and unaffected children (P = 0.55).</AbstractText>These data establish C2 as a novel genetic risk factor associated with CHB. This observation supports a model in which fetuses with C2 ligand expression and maternal anti-SSA/Ro positivity may have impaired NK cell surveillance, resulting in unchecked cardiac inflammation and scarring.</AbstractText>© 2017, American College of Rheumatology.</CopyrightInformation>
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2,335,107 |
The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle.
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Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention.
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2,335,108 |
Anxiety and pain related to mandibular block injections: comparison of self-reported measures and physiological response.
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The aim of this study was to determine whether patients with a pain score ≥7 (high pain group) after a mandibular block injection had a higher physiologic response compared with patients with scores <7 (low pain group).</AbstractText>Before oral surgery, patients (n = 66) filled out questionnaires to measure anxiety and expected pain. The questionnaires also assessed patients' experiences with dental injections and dental anxiety, as well as their emotional state and intensity of anxiety. Before, during, and after the injection, physiologic responses were measured by using Nexus-10. Patients were then asked about the pain and anxiety they had experienced.</AbstractText>The mean score for pain experienced was 3.45 (standard deviation 2.17) on an 11-point rating scale. Eight patients (12.1%) experienced high injection pain. There was a significant increase in mean sweat secretion and a significant decrease in mean respiration between the relaxing phase and the injection phase. There was a significant positive relationship between experienced anxiety and mean heart rate during the injection phase. No significant difference in physiologic response was found between patients who experienced high pain and those who experienced low pain.</AbstractText>Reported pain was not associated with the physiologic response of patients receiving mandibular block injections.</AbstractText>Copyright © 2017 Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,335,109 |
Phagocytosis Assays for Borrelia burgdorferi.
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Phagocytosis of Borrelia burgdorferi, the causative agent of Lyme disease, is a poorly understood process, despite its importance during the host immune response to infection. Thus, macrophages infiltrate the infected tissues, including the base of the heart and phagocytose the spirochete, therefore contributing to their elimination from infected tissues and leading to inflammation. An impaired bacterial clearance will result in bacterial persistence that may interfere with normal physiology of the heart, such as electrical signals from the heart, resulting in an impaired coordination of the beating of the heart or "heart block." This chapter presents a protocol for establishing primary mouse macrophage cultures, a method for lentivirus silencing of primary cells, and a method for the in vitro study of macrophage phagocytosis of fluorescently labeled Borrelia burgdorferi.
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2,335,110 |
Regulation of Ca<sup>2+</sup> signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes.
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Ischemic heart disease is an arrhythmogenic condition, accompanied by hypoxia, acidosis, and impaired Ca2+</sup> signaling. Here we report on effects of acute hypoxia and acidification in rat neonatal cardiomyocytes cultures.</AbstractText>Two populations of neonatal cardiomyocyte were identified based on inactivation kinetics of L-type ICa</sub>: rapidly-inactivating ICa</sub> (τ~20ms) myocytes (prevalent in 3-4-day cultures), and slow-inactivating ICa</sub> (τ≥40ms) myocytes (dominant in 7-day cultures). Acute hypoxia (pO2</sub><5mmHg for 50-100s) suppressed ICa</sub> reversibly in both cell-types to different extent and with different kinetics. This disparity disappeared when Ba2+</sup> was the channel charge carrier, or when the intracellular Ca2+</sup> buffering capacity was increased by dialysis of high concentrations of EGTA and BAPTA, suggesting critical role for calcium-dependent inactivation. Suppressive effect of acute acidosis on ICa</sub> (~40%, pH6.7), on the other hand, was not cell-type dependent. Isoproterenol enhanced ICa</sub> in both cell-types, but protected only against suppressive effects of acidosis and not hypoxia. Hypoxia and acidosis suppressed global Ca2+</sup> transients by ~20%, but suppression was larger, ~35%, at the RyR2 microdomains, using GCaMP6-FKBP targeted probe. Hypoxia and acidosis also suppressed mitochondrial Ca2+</sup> uptake by 40% and 10%, respectively, using mitochondrial targeted Ca2+</sup> biosensor (mito-GCaMP6).</AbstractText>Our studies suggest that acute hypoxia suppresses ICa</sub> in rapidly inactivating cell population by a mechanism involving Ca2+</sup>-dependent inactivation, while compromised mitochondrial Ca2+</sup> uptake seems also to contribute to ICa</sub> suppression in slowly inactivating cell population. Proximity of cellular Ca2+</sup> pools to sarcolemmal Ca2+</sup> channels may contribute to the variability of inactivation kinetics of ICa</sub> in the two cell populations, while acidosis suppression of ICa</sub> appears mediated by proton-induced block of the calcium channel.</AbstractText>Copyright © 2017 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,335,111 |
Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche formation by solid cancers.
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Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied <i>in vivo</i>. On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche.
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2,335,112 |
Impedance-guided Radiofrequency Ablation: Using Impedance to Improve Ablation Outcomes.
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Despite the achievement of acute conduction block during catheter ablation, the recovery of conduction at previously ablated sites remains a primary factor implicated in arrhythmia recurrence after initial ablation. Real-time markers of adequate ablation lesion creation are needed to ensure durable ablation success. However, the assessment of acute lesion formation is challenging, and requires interpretation of surrogate markers of lesion creation that are frequently unreliable. Careful monitoring of impedance changes during radiofrequency catheter ablation has emerged as a highly specific marker of local tissue destruction. Ablation strategies guided by close impedance monitoring during ablation applications have been demonstrated to achieve high levels of success for ablation of atrial fibrillation. Impedance decrease during ablation may therefore be used as an additional endpoint beyond acute conduction block, in order to improve the durability of ablation lesions. In this manuscript, available methods of real-time lesion assessment are reviewed, and the rationale and technique for impedance-guided ablation are described.
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2,335,113 |
The association between distance to public amenities and cardiovascular risk factors among lower income Singaporeans.
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Existing evidence on the association between built environment and cardiovascular disease (CVD) risk factors focused on the general population, which may not generalize to higher risk subgroups such as those with lower socio-economic status (SES). We examined the associations between distance to 5 public amenities from residential housing (public polyclinic, subsidized private clinic, healthier eatery, public park and train station) and 12 CVD risk factors (physical inactivity, medical histories and unhealthy dietary habits) among a study sample of low income Singaporeans aged ≥ 40 years (N = 1972). Using data from the Singapore Heart Foundation Health Mapping Exercise 2013-2015, we performed a series of logistic mixed effect regressions, accounting for clustering of respondents in residential blocks and multiple comparisons. Each regression analysis used the minimum distance (in km) between residential housing and each public amenity as an independent continuous variable and a single risk factor as the dependent variable, controlling for demographic characteristics. Increased distance (geographical inaccessibility) to a train station was significantly associated with lower odds of participation in sports whereas greater distance to a subsidized private clinic was associated with lower odds of having high cholesterol diagnosed. Increasing distance to park was positively associated with higher odds of less vegetable and fruits consumption, deep fried food and fast food consumption in the preceding week/month, high BMI at screening and history of diabetes, albeit not achieving statistical significance. Our findings highlighted potential effects of health-promoting amenities on CVD risk factors in urban low-income setting, suggesting gaps for further investigations.
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2,335,114 |
Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.
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Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood.</AbstractText>To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam</i> (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication.</AbstractText>Tfam</i> inactivation by Nkx2.5Cre</sup> caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam</i> inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam</i> inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam</i> inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam</i> inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam</i> inactivation.</AbstractText>Mitochondrial dysfunction caused by Tfam</i> inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.</AbstractText>© 2017 American Heart Association, Inc.</CopyrightInformation>
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2,335,115 |
Evaluation of intraoperative analgesia provided by incisional lidocaine and bupivacaine in cats undergoing ovariohysterectomy.
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Objectives The objective of this study was to assess the intraoperative analgesic effect of preoperative infiltration of the incision site with lidocaine or a mixture of lidocaine with bupivacaine in cats undergoing ovariohysterectomy (OHE). Methods This was a prospective, randomised clinical study. Healthy female intact cats (n = 75) undergoing OHE under medetomidine-ketamine-buprenorphine anaesthesia were assigned randomly into three treatment groups (n = 25 per group) to receive one of two local anaesthesia protocols or placebo preoperatively in the midline incision: lidocaine 1.5 mg/kg (group GL) or mixture of lidocaine 1 mg/kg and bupivacaine 1 mg/kg (group GLB) or sodium chloride 0.9% (control group). Blood pressure, heart and respiratory rate, temperature, muscle tonus and pupillary reflex were registered during surgery. During recovery, the cats were observed for side effects. Postoperative analgesia was provided with meloxicam (0.2 mg/kg). Most cats were rechecked 2 weeks postoperatively to remove skin sutures. Results There was no significant difference between groups regarding breed, age, body weight, surgical time and postoperative complication rate. The majority of the cats (60%) included in the control group received a supplemental bolus of propofol during surgery, when compared with 43% and 44% of the cats included in the GL and GLB groups, respectively. Heart rate was significantly higher ( P <0.05) in the control group at the time of excision of the second ovary and the uterine body. Mean arterial pressure (MAP) was stable in both treatment groups; in contrast, it tended to increase in the control group. Heart rate and MAP were similar between treatment groups. Conclusions and relevance Preoperative incisional block with only lidocaine or combined with bupivacaine seems to produce a similar intraoperative analgesia in cats undergoing OHE. Despite the similar intraoperative analgesic effect between treatment groups, the combination of lidocaine and bupivacaine reduced the required doses, and had a faster onset of action and prolonged effect.
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2,335,116 |
Eleclazine exhibits enhanced selectivity for long QT syndrome type 3-associated late Na<sup>+</sup> current.
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Eleclazine (GS-6615) is a sodium channel blocker designed to improve the selectivity for cardiac late Na+</sup> current (INa</sub>) over peak INa</sub>.</AbstractText>The goals of this study were to investigate the inhibition of late INa</sub> by eleclazine using a sample of long QT syndrome type 3 (LQT3) and overlap LQT3/Brugada syndrome mutant channels; to compare the apparent binding rates for eleclazine with those for other class 1 antiarrhythmic agents; and to investigate the binding site.</AbstractText>Wild-type human cardiac voltage-gated sodium channel (hNaV</sub>1.5) and 21 previously reported variants were studied using patch clamp recordings from a heterologous expression system.</AbstractText>Eleclazine inhibited anemone toxin II-enhanced late INa</sub> from wild-type hNaV</sub>1.5 with a drug concentration that causes 50% block of 0.62 ± 0.12 μM (84-fold selectivity over peak INa</sub>). The drug concentration that causes 50% block of eleclazine to inhibit the enhanced late INa</sub> from LQT3 mutant channels ranged from 0.33 to 1.7 μM. At predicted therapeutic concentrations, eleclazine and ranolazine inhibited peak INa</sub> to a similar degree as assessed with 4 overlap LQT3/Brugada syndrome mutations. Eleclazine was found to interact with hNaV</sub>1.5 significantly faster than ranolazine and 6 other class 1 antiarrhythmic agents. Engineered mutations (F1760A/Y1767A) located within the local anesthetic binding site decreased the inhibition of late INa</sub> and peak INa</sub> by eleclazine.</AbstractText>At predicted therapeutic concentrations, eleclazine elicits potent inhibition of late INa</sub> across a cohort of NaV</sub>1.5 mutant channels. These properties are consistent with a class 1b antiarrhythmic agent that associates with unusually rapid binding/unbinding rates.</AbstractText>Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,335,117 |
Membrane Trafficking Modulation during Entamoeba Encystation.
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Entamoeba histolytica is an intestinal parasite that infects 50-100 million people and causes up to 55,000 deaths annually. The transmissive form of E. histolytica is the cyst, with a single infected individual passing up to 45 million cysts per day, making cyst production an attractive target for infection control. Lectins and chitin are secreted to form the cyst wall, although little is known about the underlying membrane trafficking processes supporting encystation. As E. histolytica does not readily form cysts in vitro, we assessed membrane trafficking gene expression during encystation in the closely related model Entamoeba invadens. Genes involved in secretion are up-regulated during cyst formation, as are some trans-Golgi network-to-endosome trafficking genes. Furthermore, endocytic and general trafficking genes are up-regulated in the mature cyst, potentially preserved as mRNA in preparation for excystation. Two divergent dynamin-related proteins found in Entamoeba are predominantly expressed during cyst formation. Phylogenetic analyses indicate that they are paralogous to, but quite distinct from, classical dynamins found in human, suggesting that they may be potential drug targets to block encystation. The membrane-trafficking machinery is clearly regulated during encystation, providing an additional facet to understanding this crucial parasitic process.
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2,335,118 |
High-potency block of Kir4.1 channels by pentamidine: Molecular basis.
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Inward rectifier potassium (Kir) channels are expressed in almost all mammalian tissues and contribute to a wide range of physiological processes. Kir4.1 channel expression is found in the brain, inner ear, eye, and kidney. Loss-of-function mutations in the pore-forming Kir4.1 subunit cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (SeSAME/EST syndrome). Despite its importance in physiological and pathological conditions, pharmacological research of Kir4.1 is limited. Here, we characterized the effect of pentamidine on Kir4.1 channels using electrophysiology, mutagenesis and computational methods. Pentamidine potently inhibited Kir4.1 channels when applied to the cytoplasmic side under inside-out patch clamp configuration (IC<sub>50</sub> = 97nM). The block was voltage dependent. Molecular modeling predicted the binding of pentamidine to the transmembrane pore region of Kir4.1 at aminoacids T127, T128 and E158. Mutation of each of these residues reduced the potency of pentamidine to block Kir4.1 channels. A pentamidine analog (PA-6) inhibited Kir4.1 with similar potency (IC<sub>50</sub> = 132nM). Overall, this study shows that pentamidine blocks Kir4.1 channels interacting with threonine and glutamate residues in the transmembrane pore region. These results can be useful to design novel compounds with major potency and specificity over Kir4.1 channels.
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2,335,119 |
Early Exclusion of Major Adverse Cardiac Events in Emergency Department Chest Pain Patients: A Prospective Observational Study.
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The current evaluation of patients with chest pain presenting to an emergency department (ED) with suspected acute coronary syndrome (ACS) is a lengthy process involving serial measurements of troponin.</AbstractText>We aimed to validate the diagnostic accuracy of a Thrombolysis in Myocardial Infarction (TIMI) score with single high-sensitive cardiac troponin T (hs-cTnT) for early rule out of 30-day major adverse cardiac events (MACE), and to compare the TIMI score with combinations of heart-type fatty acid binding protein (H-FABP) and a modified HEART (history, electrocardiogram, age, risk factors, troponin) score.</AbstractText>We recruited 602 consecutive adult patients with chest pain and suspected ACS in the ED. Each patient had TIMI and HEART scores, and a point-of-care H-FABP test.</AbstractText>MACE occurred in 42 (7.0%) patients within 30 days. A low risk for 30-day MACE was identified by a modified TIMI score of 0 in 65 (11%) patients, and by a HEART score ≤ 2 in 96 (16%) patients. No MACE occurred in these groups, giving both scores a sensitivity of 100% (95% confidence interval [CI] 91.6-100%), and specificity of 11.6% (95% CI 9.2-14.5%) and 17.1% (95% CI 14.2-20.5%), respectively. Use of combined TIMI and HEART scores improved the specificity further to 22.0% (95% CI 18.7-25.6%) without lowering sensitivity. Early H-FABP measurement > 7 μg/L had a sensitivity of 41.5% (95% CI 27.8-56.6%) and a specificity of 91.1% (95% CI 88.4-93.2%) for predicting 30-day MACE.</AbstractText>A modified TIMI score of 0 or a HEART score of ≤ 2, incorporating a single hs-cTnT level, will identify patients with low risk of 30-day MACE for early discharge within 2 h of ED arrival.</AbstractText>Copyright © 2017 Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,335,120 |
Favorable biodistribution, specific targeting and conditional endosomal escape of RNA nanoparticles in cancer therapy.
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The past decades have witnessed the successful transition of several nanotechnology platforms into the clinical trials. However, specific delivery of therapeutics to tumors is hindered by several barriers including cancer recognition and tissue penetration, particle heterogeneity and aggregation, and unfavorable pharmacokinetic profiles such as fast clearance and organ accumulation. With the advent of RNA nanotechnology, a series of RNA nanoparticles have been successfully constructed to overcome many of the aforementioned challenges for in vivo cancer targeting with favorable biodistribution profiles. Compared to other nanodelivery platforms, the physiochemical properties of RNA nanoparticles can be tuned with relative ease for investigating the in vivo behavior of nanoparticles upon systemic injection. The size, shape, and surface chemistry, especially hydrophobic modifications, exert significant impacts on the in vivo fate of RNA nanoparticles. Rationally designed RNA nanoparticles with defined stoichiometry and high homogeneity have been demonstrated to specifically target tumor cells while avoiding accumulation in healthy vital organs after systemic injection. RNA nanoparticles were proven to deliver therapeutics such as siRNA and anti-miRNA to block tumor growth in several animal models. Although the release of anti-miRNA from the RNA nanoparticles has achieved high efficiency of tumor regression in multiple animal models, the efficiency of endosomal escape for siRNA delivery needs further improvement. This review focuses on the advances and perspectives of this promising RNA nanotechnology platform for cancer targeting and therapy.
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2,335,121 |
Selective Scalp Nerve Block: A Useful Technique With Tissue Expansion in Postburn Pediatric Alopecia.
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Scalp defects can be reconstructed either with skin graft, local flaps, free flaps, or tissue expansion. Tissue expanders have been proved to be fruitful in the pediatric population. Scalp expansion has proved to be useful in the reconstruction of posttraumatic and postburn alopecic defects. Selective nerve block can be added for attenuation of sympathetic stimulation and decrease surgical stress in cranial surgeries. In this study, a comparison was done between using selective nerve block and without selective nerve block in both stages of tissue expansion procedure.</AbstractText>This study included 32 different children who underwent tissue expansions in the management of postburn alopecia. Pediatric patients presented with postburn alopecia of the scalp with mature scar were included in this work.</AbstractText>Postoperative analgesics were less in children who had received scalp block, whereas it was shorter in patients who did not receive any scalp block. Meperidine consumption was much more less in patients who received selective scalp nerve block. Pain score was markedly decreased in children who had received selective scalp nerve block in the immediate postoperative period. Children who received scalp block showed marked attenuation in the surgical stress responses with minimal changes in heart rate and mean arterial blood pressure after skin incision.</AbstractText>Scalp nerve block is considered an excellent choice for postoperative pain control with less need for opioid analgesia.</AbstractText>
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2,335,122 |
Multimodality Intracoronary Imaging With Near-Infrared Spectroscopy and Intravascular Ultrasound in Asymptomatic Individuals With High Calcium Scores.
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This study sought to determine the frequency of large lipid-rich plaques (LRP) in the coronary arteries of individuals with high coronary artery calcium scores (CACS) and to determine whether the CACS correlates with coronary lipid burden.</AbstractText>Combined near-infrared spectroscopy and intravascular ultrasound was performed in 57 vessels in 20 asymptomatic individuals (90% on statins) with no prior history of coronary artery disease who had a screening CACS ≥300 Agatston units. Among 268 10-mm coronary segments, near-infrared spectroscopy images were analyzed for LRP, defined as a bright yellow block on the near-infrared spectroscopy block chemogram. Lipid burden was assessed as the lipid core burden index (LCBI), and large LRP were defined as a maximum LCBI in 4 mm ≥400. Vessel plaque volume was measured by quantitative intravascular ultrasound. Vessel-level CACS significantly correlated with plaque volume by intravascular ultrasound (r</i>=0.69; P</i><0.0001) but not with LCBI by near-infrared spectroscopy (r</i>=0.24; P</i>=0.07). Despite a high CACS, no LRP was detected in 8 (40.0%) subjects. Large LRP having a maximum LCBI in 4 mm ≥400 were infrequent, found in only 5 (25.0%) of 20 subjects and in only 5 (1.9%) of 268 10-mm coronary segments analyzed.</AbstractText>Among individuals with a CACS ≥300 Agatston units mostly on statins, CACS correlated with total plaque volume but not LCBI. This observation may have implications on coronary risk among individuals with a high CACS considering that it is coronary LRP, rather than calcification, that underlies the majority of acute coronary events.</AbstractText>© 2017 American Heart Association, Inc.</CopyrightInformation>
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2,335,123 |
Comparison of Hemodynamic Changes in Unilateral Spinal Anesthesia Versus Epidural Anesthesia Below the T10 Sensory Level in Unilateral Surgeries: a Double-Blind Randomized Clinical Trial.
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Unilateral spinal anesthesia is used to limit the spread of block. The aim of the present study was to compare hemodynamic changes and complications in unilateral spinal anesthesia and epidural anesthesia below the T10 sensory level in unilateral surgeries.</AbstractText>In this double-blind randomized clinical trial in total 120 patients were randomly divided into a unilateral spinal anesthesia group (Group S) and an epidural anesthesia group (Group E). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rates were measured before and immediately after the administration of spinal or epidural anesthesia and then at 5-, 10-, 15-, 20-, 25-, and 30-min intervals. The rates of prescribed ephedrine and intraoperative respiratory arrest were recorded, in addition to postoperative nausea and vomiting, puncture headaches, and back pain during the first 24 h after the surgery.</AbstractText>SBP, DBP, and MAP values initially showed a statistically significant downward trend in both groups (p = 0.001). The prevalence of hypotension in Group S was lower than in Group E, and the observed difference was statistically significant (p < 0.0001). The mean heart rate change in Group E was greater than in Group S, although the difference was not statistically significant (p = 0.68). The incidence of prescribed ephedrine in response to a critical hemodynamic situation was 5.1% (n = 3) and 75% (n = 42) in Group S and Group E, respectively (p = 0.0001). The incidence of headaches, back pain, and nausea/vomiting was 15.3%, 15.3%, and 10.2% in Group S and 1.8%, 30.4%, and 5.4% in Group E (p = 0.017, 0.07, and 0.49, respectively).</AbstractText>Hemodynamic stability, reduced administration of ephedrine, a simple, low-cost technique, and adequate sensory and motor block are major advantages of unilateral spinal anesthesia.</AbstractText>
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2,335,124 |
Differential Effects of HCN Channel Block on On and Off Pathways in the Retina as a Potential Cause for Medication-Induced Phosphene Perception.
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Phosphene perception is a characteristic side effect of heart rate-reducing medication that acts on hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. It is hypothesized that these phosphenes are caused by blocking HCN channels in photoreceptors and neurons of the retina, yet the underlying changes in visual signal processing in the retina caused by the HCN channel block are still unknown.</AbstractText>We examined the effects of pharmacologic HCN channel block on the encoding of visual signals in retinal ganglion cells by recording ganglion cell spiking activity from isolated mouse retinas mounted on multielectrode arrays. Spontaneous activity and responses to various visual stimuli were measured before, during, and after administration of 3 μM ivabradine.</AbstractText>Retinal ganglion cells generally showed slower response kinetics and reduced sensitivity to high temporal frequencies under ivabradine. Moreover, ivabradine differentially affected the sensitivity of On and Off ganglion cells. On cells showed reduced response gain, whereas Off cells experienced an increase in response threshold. In line with these differential effects, Off cells, in contrast to On cells, also showed reduced baseline activity during visual stimulation and reduced spontaneous activity. Furthermore, Off cells, but not On cells, showed increased burst-like spiking activity in the presence of ivabradine.</AbstractText>Our data suggest that pharmacologic HCN channel block in the retina leads to a shift in the relative activity of the On and Off pathways of the retina. We hypothesize that this imbalance may underlie the medication-induced perception of phosphenes.</AbstractText>
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2,335,125 |
Diagnosis of Ilioinguinal Nerve Injury Based on Electromyography and Ultrasonography: A Case Report.
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Being located in the hypogastric area, the ilioinguinal nerve, together with iliohypogastric nerve, can be damaged during lower abdominal surgeries. Conventionally, the diagnosis of ilioinguinal neuropathy relies on clinical assessments, and standardized diagnostic methods have not been established as of yet. We hereby report the case of young man who presented ilioinguinal neuralgia with symptoms of burning pain in the right groin and scrotum shortly after receiving inguinal herniorrhaphy. To raise the diagnostic certainty, we used a real-time ultrasonography (US) to guide a monopolar electromyography needle to the ilioinguinal nerve, and then performed a motor conduction study. A subsequent US-guided ilioinguinal nerve block resulted in complete resolution of the patient's neuralgic symptoms.
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2,335,126 |
The Role of Contextual Socioeconomic Circumstances and Neighborhood Poverty Segregation on Mortality in 4 European Cities.
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Several studies have recognized the health disadvantage of residents in socioeconomically deprived neighborhoods, independent of the influence of individual socioeconomic conditions. The effect of neighborhood socioeconomic deprivation on general mortality has appeared heterogeneous among the cities analyzed: the underlying mechanisms have been less empirically explored, and explanations for this heterogeneous health effect remain unclear. The present study aimed to: (1) analyze the distribution of socioeconomically disadvantaged persons in neighborhoods of 4 European cities-Turin, Barcelona, Stockholm and Helsinki-trying to measure segregation of residents according to their socioeconomic conditions. Two measuring approaches were used, respectively, through dissimilarity index and clustering estimated from Bayesian models. (2) Analyze the distribution of mortality in the above mentioned cities, trying to disentangle the independent effects of both neighborhood socioeconomic deprivation and neighborhood segregation of residents according to their socioeconomic conditions, using multilevel models. A significantly higher risk of death was observed among residents in more deprived neighborhoods in all 4 cities considered, slightly heterogeneous across them. Poverty segregation appeared to be slightly associated with increasing mortality in Turin and, among females and only according to dissimilarity, in Barcelona. Few studies have explored the health effects of social clustering, and results could inform urban policy design with regard to social mix.
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2,335,127 |
Educational value of pocket-sized ultrasound devices to improve understanding of ultrasound examination principles and sonographic anatomy for medical student.
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Medical students must understand the principles of ultrasonography (US), because US examinations are an important component of patient care in clinical practice. Pocket-sized ultrasound devices have the benefits of accessibility and ease of use. The primary objective of the present study was to evaluate the educational value of these devices in terms of improving medical student interest and understanding of US and sonographic anatomy.</AbstractText>We added a US training program comprised of a self-study learning module and a hands-on training session to a two-week block curriculum of medical imaging for first year medical students (n = 40). Multiple pocket-sized US devices were used on a small-group basis during a single afternoon. Students were asked to complete a questionnaire before and after the US training session; these two questionnaires contained 6 and 10 questions, respectively, which were rated by students using a five-point Likert scale. In addition, understanding of sonographic anatomy was tested before and after the training program.</AbstractText>Forty students completed the two questionnaires and the anatomy-related tests. Students found the program educationally valuable (4.37 ± 0.54 of 5) and reported that US practice was useful for improving their understanding of the principles of US examinations (4.23 ± 0.66 of 5) and sonographic anatomy (4.40 ± 0.55 of 5). Overall confidence at performing US examinations and understanding of sonographic anatomy were significantly increased after US training (increased overall confidence score, 1.87 ± 0.91 and improvement in sonographic anatomy score, 6.55 ± 1.55, p values < 0.001).</AbstractText>US training using pocket-sized ultrasound devices was found to be educationally valuable for medical students in terms of improving understanding of US principles and familiarizing students with sonographic anatomy.</AbstractText>
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2,335,128 |
Environmental and lifestyle factors influencing risk of congenital heart block during pregnancy in anti-Ro/SSA-positive women.
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Congenital heart block (CHB) occurs in 1%-2% of anti-Ro/SSA antibody-positive pregnancies. A population-based recurrence rate of 12% indicates that factors other than maternal autoantibodies influence CHB development. Here we report the first investigation to identify environmental and lifestyle factors influencing the risk of CHB.</AbstractText>A questionnaire focused on environmental and lifestyle factors was distributed to anti-Ro/SSA antibody-positive women who had given birth to at least one child with CHB, and additional data were retrieved from national health registers. Statistical analysis was performed comparing pregnancies resulting in a child with CHB (n=81) and pregnancies resulting in unaffected siblings (n=108).</AbstractText>Analysis of maternal body mass index and weight gain during pregnancy as well as medication intake and sun exposure did not reveal significant differences between CHB-affected and non-CHB pregnancies. By contrast, we found that reports of infections and stressful events were significantly more frequent in CHB-affected pregnancies than in non-CHB affected pregnancies (OR 17.9, 95% CI 4.1 to 162.8, p<0.001 and OR 5.5, 95% CI 1.1 to 55.1, p<0.05, respectively). Notably, outdoor activity a few hours per day emerged as a protective factor (OR 0.52, 95% CI 0.27 to 0.99, p<0.05). The previously reported factor seasonal timing of pregnancy was confirmed (OR 2.2, 95% CI 1.1 to 4.2, p<0.05), and multivariate analysis revealed that this association was partly explained by infection and outdoor activity.</AbstractText>In this retrospective study, infections, stressful events and time spent with outdoor activities emerged as potential environmental and lifestyle factors influencing the risk of CHB, warranting confirmation in prospective studies.</AbstractText>
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2,335,129 |
Human <i>In Silico</i> Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.
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Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of <i>in silico</i> drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. <i>In silico</i> drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC<sub>50</sub>/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca<sup>2+</sup>-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes <i>in silico</i> vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca<sup>2+</sup>/late Na<sup>+</sup> currents and Na<sup>+</sup>/Ca<sup>2+</sup>-exchanger, reduced Na<sup>+</sup>/K<sup>+</sup>-pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na<sup>+</sup> and Ca<sup>2+</sup> currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities <i>in silico</i> predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: <i>in silico</i> AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca<sup>2+</sup>-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human <i>in silico</i> drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.
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2,335,130 |
Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol.
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Mitochondria play a crucial role in the cell fate; in particular, reducing the accumulation of calcium in the mitochondrial matrix offers cardioprotection. This affect is achieved by a mild depolarization of the mitochondrial membrane potential, which prevents the assembly and opening of the mitochondrial permeability transition pore. For this reason, mitochondria are an attractive target for pharmacological interventions that prevent ischaemia/reperfusion injury. Isosteviol is a diterpenoid created from the acid hydrolysis of <i>Stevia</i><i>rebaudiana</i> Bertoni (fam. Asteraceae) glycosides that has shown protective effects against ischaemia/reperfusion injury, which are likely mediated through the activation of mitochondrial adenosine tri-phosphate (ATP)-sensitive potassium (mitoKATP) channels. Some triphenylphosphonium (triPP)-conjugated derivatives of isosteviol have been developed, and to evaluate the possible pharmacological benefits that result from these synthetic modifications, in this study, the mitochondriotropic properties of isosteviol and several triPP-conjugates were investigated in rat cardiac mitochondria and in the rat heart cell line H9c2. This study's main findings highlight the ability of isosteviol to depolarize the mitochondrial membrane potential and reduce calcium uptake by the mitochondria, which are typical functions of mitochondrial potassium channel openings. Moreover, triPP-conjugated derivatives showed a similar behavior to isosteviol but at lower concentrations, indicative of their improved uptake into the mitochondrial matrix. Finally, the cardioprotective property of a selected triPP-conjugated derivative was demonstrated in an in vivo model of acute myocardial infarct.
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2,335,131 |
Effects of Whole Body Vibration on Glycemic Indices and Peripheral Blood Flow in Type II Diabetic Patients.
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Whole body vibration (WBV) training is a regime of training on a vibration platform that provides oscillatory movement to the body. Vibration training may be a potentially useful therapeutic strategy to control diabetes and its complications. This study aimed to evaluate the effect of WBV on glycemic indices and peripheral blood flow in type II diabetic patients.</AbstractText>A parallel group clinical trial was conducted with 1:1 allocation ratio at Khon Kaen University between February and May 2010. The study included diabetic patients receiving diet or oral medication control over the previous year and excluded patients with serious medical and musculoskeletal disorders. Forty type II diabetic patients [14 males, 26 females, 63.2 (7.7) y, mean (SD)] were randomised into two groups (WBV and control) by computer software using a block of four design. The WBV group was given two sets of six one-minute vibration squats, three times per week for twelve weeks. The control group maintained their normal physical activity levels. The primary outcome was the patients glycemic indices.</AbstractText>We found no significant difference in glycosylated haemoglobin (HbA1c), fasting blood sugar, insulin level and insulin sensitivity between WBV and control groups. Compared to the control group, WBV training resulted in a substantial reduction in resting diastolic blood pressure -7.1 mmHg (95% CI: -10.9, -3.3, P</i> = 0.001) and peak systolic velocity -7.3 cm.sec-1</sup> (95% CI: -14.7, -0.03, P</i> = 0.049), but made little difference to resting heart rate, systolic blood pressure, end diastolic velocity, and popliteal artery diameter.</AbstractText>Whole body vibration improved resting diastolic blood pressure and peak systolic velocity, however, any beneficial effect of WBV on glycemic indices remains unclear.</AbstractText>
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2,335,132 |
Toxicity evaluation of methoxy poly(ethylene oxide)-<i>block</i>-poly(ε-caprolactone) polymeric micelles following multiple oral and intraperitoneal administration to rats.
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Methoxy poly(ethylene oxide)-<i>block</i>-poly(ɛ-caprolactone) (PEO-<i>b</i>-PCL) copolymers are amphiphilic and biodegradable copolymers designed to deliver a variety of drugs and diagnostic agents. The aim of this study was to synthesize PEO-<i>b</i>-PCL block copolymers and assess the toxic effects of drug-free PEO-<i>b</i>-PCL micelles after multiple-dose administrations via oral or intraperitoneal (ip) administration in rats. Assembly of block copolymers was achieved by co-solvent evaporation method. To investigate the toxicity profile of PEO-<i>b</i>-PCL micelles, sixty animals were divided into two major groups: The first group received PEO-<i>b</i>-PCL micelles (100 mg/kg) by oral gavage daily for seven days, while the other group received the same dose of micelles by ip injections daily for seven days. Twenty-four hours following the last dose, half of the animals from each group were sacrificed and blood and organs (lung, liver, kidneys, heart and spleen) were collected. Remaining animals were observed for further 14 days and was sacrificed at the end of the third week, and blood and organs were collected. None of the polymeric micelles administered caused any significant effects on relative organ weight, animal body weight, leucocytes count, % lymphocytes, liver and kidney toxicity markers and organs histology. Although the dose of copolymers used in this study is much higher than those used for drug delivery, it did not cause any significant toxic effects in rats. Histological examination of all the organs confirmed the nontoxic nature of the micelles.
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2,335,133 |
Effects of HRV-Guided vs. Predetermined Block Training on Performance, HRV and Serum Hormones.
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The aim of this study was to compare heart rate variability -guided (HRVG) and predetermined (PD) block periodization of high intensity aerobic training (HIT). Endurance performance, neuromuscular performance, heart rate variability (HRV) and serum hormone concentrations were measured before, in the middle and after the 8-week training period in 24 endurance trained males. Both groups improved significantly maximal treadmill velocity (V<sub>max</sub>) (p<0.001) and 3000 m running performance (HRVG; p<0.001 and PD; p=0.001). The relative changes in V<sub>max</sub> and countermovement jump were significantly greater in HRVG (p<0.05). Nocturnal heart rate decreased in both groups (p<0.01), but HRV (RMSSD, LF and TP) increased significantly only in HRVG (p<0.05). The significant increase in serum testosterone concentration was observed from mid to post in HRVG (p<0.05). Significant correlations were found between individual V<sub>max</sub> changes and absolute serum testosterone levels. Individual baseline level of HF correlated significantly with V<sub>max</sub> changes in PD. Block periodization of HIT seems to be an effective way to improve endurance and running performance in already endurance trained males. Based on training induced increases in endurance and neuromuscular performance combined with significant changes in HRV and serum testosterone levels observed in HRVG, individually HRV -guided block training may be more optimal compared to predetermined training.
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2,335,134 |
The effect of muscle length on transcranial magnetic stimulation-induced relaxation rate in the plantar flexors.
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Transcranial magnetic stimulation (TMS) of the motor cortex during a maximal voluntary contraction (MVC) permits functionally relevant measurements of muscle group relaxation rate (i.e., when muscles are actively contracting under voluntary control). This study's purpose was twofold: (1) to explore the impact of muscle length on TMS-induced plantar flexor relaxation rate; and (2) to incorporate ultrasonography to measure relaxation-induced lengthening of medial gastrocnemius (MG) fascicles and displacement of the muscle-tendon junction (MTJ). Eleven males (24.8 ± 7.0 years) performed 21 brief isometric plantar flexor MVCs. Trials were block-randomized every three MVCs among 20° dorsiflexion (DF), a neutral ankle position, and 30° plantar flexion (PF). During each MVC, TMS was delivered and ultrasound video recordings captured MG fascicles or MTJ length changes. Peak relaxation rate was calculated as the steepest slope of the TMS-induced drop in plantar flexor torque or the rate of length change for MG fascicles and MTJ Torque relaxation rate was slower for PF (-804 ± 162 Nm·s<sup>-1</sup>) than neutral and DF (-1896 ± 298 and -2008 ± 692 Nm·s<sup>-1</sup>, respectively). Similarly, MG fascicle relaxation rate was slower for PF (-2.80 ± 1.10 cm·s<sup>-1</sup>) than neutral and DF (-5.35 ± 1.10 and -4.81 ± 1.87 cm·s<sup>-1</sup>, respectively). MTJ displacement rate showed a similar trend (<i>P</i> = 0.06), with 3.89 ± 1.93 cm·s<sup>-1</sup> for PF compared to rates of 6.87 ± 1.55 and 6.36 ± 2.97 cm·s<sup>-1</sup> for neutral and DF, respectively. These findings indicate muscle length affects the torque relaxation rate recorded after TMS during an MVC Comparable results were obtained from muscle fascicles, indicating ultrasound imaging is suitable for measuring evoked contractile properties during voluntary contraction.
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2,335,135 |
Metabolically Derived Lysine Acylations and Neighboring Modifications Tune the Binding of the BET Bromodomains to Histone H4.
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Recent proteomic studies discovered histone lysines are modified by acylations beyond acetylation. These acylations derive from acyl-CoA metabolites, potentially linking metabolism to transcription. Bromodomains bind lysine acylation on histones and other nuclear proteins to influence transcription. However, the extent bromodomains bind non-acetyl acylations is largely unknown. Also unclear are the effects of neighboring post-translational modifications, especially within heavily modified histone tails. Using peptide arrays, binding assays, sucrose gradients, and computational methods, we quantified 10 distinct acylations for binding to the bromodomain and extraterminal domain (BET) family. Four of these acylations (hydroxyisobutyrylation, malonylation, glutarylation, and homocitrullination) had never been tested for bromodomain binding. We found N-terminal BET bromodomains bound acetylated and propionylated peptides, consistent with previous studies. Interestingly, all other acylations inhibited binding of the BET bromodomains to peptides and nucleosomes. To understand how context tunes bromodomain binding, effects of neighboring methylation, phosphorylation, and acylation within histone H4 tails were determined. Serine 1 phosphorylation inhibited binding of the BRD4 N-terminal bromodomain to polyacetylated H4 tails by >5-fold, whereas methylation had no effect. Furthermore, binding of BRDT and BRD4 N-terminal bromodomains to H4K5acetyl was enhanced 1.4-9.5-fold by any neighboring acylation of lysine 8, indicating a secondary H4K8acyl binding site that is more permissive of non-acetyl acylations than previously appreciated. In contrast, C-terminal BET bromodomains exhibited 9.9-13.5-fold weaker binding for polyacylated than for monoacylated H4 tails, indicating the C-terminal bromodomains do not cooperatively bind multiple acylations. These results suggest acyl-CoA levels tune or block recruitment of the BET bromodomains to histones, linking metabolism to bromodomain-mediated transcription.
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2,335,136 |
The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs.
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Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t<sub>1/2</sub> of ∼1 h. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The C<sub>max</sub> in the brain ranged between 0.03 and 0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.
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2,335,137 |
Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K<sup>+</sup> current by different G-protein coupled receptors.
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Elevated angiotensin II (Ang II) and sympathetic activity contributes to a high risk of ventricular arrhythmias in heart disease. The rapidly activating delayed rectifier K+</sup> current (IKr</sub> ) carried by the hERG channels plays a critical role in cardiac repolarization, and decreased IKr</sub> is involved in increased cardiac arrhythmogenicity. Stimulation of α1A</sub> -adrenoreceptors or angiotensin II AT1</sub> receptors is known to inhibit IKr</sub> via PKC. Here, we have identified the PKC isoenzymes mediating the inhibition of IKr</sub> by activation of these two different GPCRs.</AbstractText>The whole-cell patch-clamp technique was used to record IKr</sub> in guinea pig cardiomyocytes and HEK293 cells co-transfected with hERG and α1A</sub> -adrenoreceptor or AT1</sub> receptor genes.</AbstractText>A broad spectrum PKC inhibitor Gö6983 (not inhibiting PKCε), a selective cPKC inhibitor Gö6976 and a PKCα-specific inhibitor peptide, blocked the inhibition of IKr</sub> by the α1A</sub> -adrenoreceptor agonist A61603. However, these inhibitors did not affect the reduction of IKr</sub> by activation of AT1</sub> receptors, whereas the PKCε-selective inhibitor peptide did block the effect. The effects of angiotensin II and the PKCε activator peptide were inhibited in mutant hERG channels in which 17 of the 18 PKC phosphorylation sites were deleted, whereas a deletion of the N-terminus of the hERG channels selectively prevented the inhibition elicited by A61603 and the cPKC activator peptide.</AbstractText>Our results indicated that inhibition of IKr</sub> by activation of α1A</sub> -adrenoreceptors or AT1</sub> receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms.</AbstractText>© 2017 The British Pharmacological Society.</CopyrightInformation>
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2,335,138 |
[Cave: interscalene catheters].
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Interscalene regional anesthesia is an established and highly effective procedure; however, it represents an increased level of risk due to the close proximity of anatomical structures, such as the cervical spinal cord and many vessels. Furthermore, due to inadvertent placement of a catheter close to the cervical spinal cord or into a vessel, as opposed to a single shot injection technique, it remains a latent danger until it is removed. This article describes seven  cases of misplaced catheters. The etiology and symptoms are discussed as well as recommendations regarding the prevention of catastrophic complications. As a result, internal practice guidelines are recommended for anesthesia departments in order to enhance the safety and quality of regional anesthesia.
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2,335,139 |
Chemotherapy for Hepatocellular Carcinoma: Current Evidence and Future Perspectives.
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Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor. The importance of this drug lies not only in the modest gain of patients' survival, but in having opened a roadmap towards the development of new molecules and targets. Unfortunately, after the introduction of sorafenib, during the last years, a wide number of clinical trials on antiangiogenic therapies failed in achieving significant results. However, many of these trials are still ongoing and promise to improve overall survival and progression-free survival. A recent clinical trial has proven regorafenib effective in patients showing tumor progression under sorafenib, thus opening new interesting therapeutic perspectives. Many other expectations have been borne from the discovery of the immune checkpoint blockade, already known in other solid malignancies. Furthermore, a potential role in hepatocellular carcinoma therapy may derive from the use of branched-chain amino acids and of nutritional support. This review analyses the biomolecular pathways of hepatocellular carcinoma and the ongoing studies, the actual evidence and the future perspectives concerning drug therapy in this open field.
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2,335,140 |
Vascular Aging: Implications for Cardiovascular Disease and Therapy.
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The incidence and prevalence of cardiovascular disease is highest among the elderly, in part, due to deleterious effects of advancing age on the heart and blood vessels. Aging, a known cardiovascular risk factor, is progressively associated with structural and functional changes to the vasculature including hemodynamic disturbance due to increased oxidative stress, premature cellular senescence and impairments in synthesis and/or secretion of endothelium-derived vasoactive molecules. These molecular and physiological changes lead to vessel wall stiffening and thickening, as well as other vascular complications that culminate to loss of vascular tone regulation and endothelial function. Intriguingly, the vessel wall, a biochemically active structure composed of collagen, connective tissue, smooth muscle and endothelial cells, is adversely affected by processes involved in premature or normal aging. Notably, the inner most layer of the vessel wall, the endothelium, becomes senescent and dysfunctional with advancing age. As a result, its ability to release vasoactive molecules such as acetylcholine (ACh), prostacyclin (PGI2), endothelium-derived hyperpolarizing factor (EDHF), and nitric oxide (NO) is reduced and the cellular response to these molecules is also impaired. By contrast, the vascular endothelium increases its generation and release of reactive oxygen (ROS) and nitrogen (RNS) species, vasoconstrictors such as endothelin (ET) and angiotensin (AT), and endogenous inhibitors of NO synthases (NOSs) to block NO. This skews the balance of the endothelium in favor of the release of highly tissue reactive and harmful molecules that promote DNA damage, telomere erosion, senescence, as well as stiffened and hardened vessel wall that is prone to the development of hypertension, diabetes, atherosclerosis and other cardiovascular risk factors. This Review discusses the impact of advancing age on cardiovascular health, and highlights the cellular and molecular mechanisms that underlie age-associated vascular changes. In addition, the role of pharmacological interventions in preventing or delaying age-related cardiovascular disease is discussed.
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2,335,141 |
Implantation of the Micra leadless pacemaker in a patient with a low body mass index of 16.
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A 71-year-old female patient has a history of complete heart block and recurrent pacemaker site infection requiring multiple pacemaker explanations. A leadless pacemaker using passive fixation was inserted into the right ventricular apex via transvenous approach without complications. This case illustrates the feasibility of implanting a leadless pacemaker system in a small-sized adult with a low body mass index of 16 (weight: 33.7 kg, height: 145 cm) which may have potential application in elderly Asian subjects.
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2,335,142 |
Comparative Efficacy of Minimal Concentration of Racemic Bupivacaine (0.0625%) with Fentanyl and Ropivacaine (0.1%) with Fentanyl for Epidural Labor Analgesia.
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This study aims to compare the minimum effective concentration of local anesthetic (LA) bupivacaine and ropivacaine with highly lipid soluble opioids fentanyl for providing optimal labor epidural analgesia.</AbstractText>The objective of this study was to evaluate the efficacy of racemic bupivacaine 0.0625% and 0.1% of ropivacaine both mixed with 2 μg/ml of fentanyl for epidural labor analgesia in parturients with spontaneous labor and normal fetal heart rate tracing.</AbstractText>Sixty parturients requesting for labor analgesia were divided into two groups. Group B (n</i> = 30) received racemic bupivacaine (0.0625%) and fentanyl 2 μg/ml of 10 ml and Group R (n</i> = 30) received ropivacaine (0.1%) and fentanyl 2 μg/ml. In both groups, the drug was given in 5 ml fractionated doses at 5 min interval. Parturients not experiencing analgesia within 15 min of initial bolus were supplemented with additional 5 ml of the same concentration of the solution. Epidural analgesia was maintained by timed top ups at the end of 90 min with the dosage equal to the initial dose of the drug. Duration of labor analgesia, motor block, visual analog scale, maternal hemodynamic parameters, mode of delivery, and maternal satisfaction was assessed.</AbstractText>Data were analyzed with odds variance, unpaired t</i>-test, and Chi-square tests. P</i> < 0.05 was considered statistically significant.</AbstractText>In our study, results indicate that both drugs were equally effective clinically. Maternal demographic characteristics were comparable. There were no statistically significant differences in visual analog pain score, highest sensory block, maternal satisfaction, mode of delivery, total dose of LAs during labor and motor block at delivery between the groups.</AbstractText>In our study, both the drugs produced equivalent analgesia for labor at low concentration when used with highly lipid soluble opioid such as fentanyl.</AbstractText>
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2,335,143 |
Validation of highly accelerated real-time cardiac cine MRI with radial k-space sampling and compressed sensing in patients at 1.5T and 3T.
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To validate an optimal 12-fold accelerated real-time cine MRI pulse sequence with radial k-space sampling and compressed sensing (CS) in patients at 1.5T and 3T.</AbstractText>We used two strategies to reduce image artifacts arising from gradient delays and eddy currents in radial k-space sampling with balanced steady-state free precession readout. We validated this pulse sequence against a standard breath-hold cine sequence in two patient cohorts: a myocardial infarction (n = 16) group at 1.5T and chronic kidney disease group (n = 18) at 3T. Two readers independently performed visual analysis of 68 cine sets in four categories (myocardial definition, temporal fidelity, artifact, noise) on a 5-point Likert scale (1 = nondiagnostic, 2 = poor, 3 = adequate or moderate, 4 = good, 5 = excellent). Another reader calculated left ventricular (LV) functional parameters, including ejection fraction.</AbstractText>Compared with standard cine, real-time cine produced nonsignificantly different visually assessed scores, except for the following categories: 1) temporal fidelity scores were significantly lower (P = 0.013) for real-time cine at both field strengths, 2) artifacts scores were significantly higher (P = 0.013) for real-time cine at both field strengths, and 3) noise scores were significantly (P = 0.013) higher for real-time cine at 1.5T. Standard and real-time cine pulse sequences produced LV functional parameters that were in good agreement (e.g., absolute mean difference in ejection fraction <4%).</AbstractText>This study demonstrates that an optimal 12-fold, accelerated, real-time cine MRI pulse sequence using radial k-space sampling and CS produces good to excellent visual scores and relatively accurate LV functional parameters in patients at 1.5T and 3T. Magn Reson Med 79:2745-2751, 2018. © 2017 International Society for Magnetic Resonance in Medicine.</AbstractText>© 2017 International Society for Magnetic Resonance in Medicine.</CopyrightInformation>
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Intravenous dexamethasone as an adjunct to improve labor analgesia: A randomized, double-blinded, placebo controlled clinical trial.
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To study the role of intravenous (i.v.) dexamethasone as an analgesic adjunct in labor analgesia.</AbstractText>Double-blinded randomized controlled trial.</AbstractText>Labor analgesia in a tertiary-care teaching hospital.</AbstractText>Eighty consenting ASA I-II parturients, age>18year, nulliparous, single gestation, cephalic presentation at ≥36 wk. of gestation, in early spontaneous labor (cervical dilatation≤5cm) requesting epidural analgesia.</AbstractText>The patients were randomized to two groups. The Dexa group received 8mg of dexamethasone i.v. in 50ml normal saline approximately 45min before the procedure. Placebo group patients received 50ml normal saline only. All patients underwent epidural labor analgesia per hospital protocol. After an initial bolus, they received continuous background infusion of 5ml/h of 0.1% of levobupivacaine with 2μg/ml of fentanyl, with the provision of patient controlled boluses of 5ml of the same drug combination with a lockout interval of 12min if needed.</AbstractText>Primary outcome measure: hourly average consumption of neuraxially administered levobupivacaine-fentanyl combination. Secondary outcomes and observations: pain score, maternal satisfaction, sensory and motor block characteristics, hemodynamic parameters of mother, fetal heart rate, duration of second stage of labor, mode of delivery, Apgar scores at 1 and 5min, and adverse effects.</AbstractText>Average hourly drug consumption was significantly lower in Dexa group as compared to Placebo group (10.34±1.79ml/h vs. 11.34±1.83ml/h; mean difference 1.007, 95% CI 0.199-1.815; P=0.015). The median number of bolus doses was 4 (interquartile-range [IQR] 3-5.75) and 5 (IQR 3-6) in the Dexa and Placebo groups, respectively (P=0.162). There was no significant difference between groups with regard to pain scores, maternal satisfaction and hemodynamics, mode of delivery, and adverse effects.</AbstractText>I.v. dexamethasone significantly decreased hourly average drug consumption of levobupivacaine-fentanyl combination through the epidural route, demonstrating the epidural drug dose sparing effect during labor analgesia.</AbstractText>Copyright © 2017 Elsevier Inc. All rights reserved.</CopyrightInformation>
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Temporary Left Ventricular Pacing: A Desperate Life-saving Measure in Emergency Situation.
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Transcutaneous or transvenous pacing of the right ventricle is performed as a routine practice for patients received with symptomatic bradycardia or complete heart block with relative ease in cath lab. However, more and more patients are received with multiple comorbidities, critical condition, and difficult vascular access. In this article, we describe a patient with difficult venous access with tricuspid regurgitation and displaced the right ventricular pacemaker temporary lead undergoing coronary angiography who was managed with emergent nonconventional left ventricular pacing.
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2,335,146 |
An Analysis of the Relationship Between Preclinical and Clinical QT Interval-Related Data.
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There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase.
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2,335,147 |
Effective Heart Disease Detection Based on Quantitative Computerized Traditional Chinese Medicine Using Representation Based Classifiers.
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At present, heart disease is the number one cause of death worldwide. Traditionally, heart disease is commonly detected using blood tests, electrocardiogram, cardiac computerized tomography scan, cardiac magnetic resonance imaging, and so on. However, these traditional diagnostic methods are time consuming and/or invasive. In this paper, we propose an effective noninvasive computerized method based on facial images to quantitatively detect heart disease. Specifically, facial key block color features are extracted from facial images and analyzed using the Probabilistic Collaborative Representation Based Classifier. The idea of facial key block color analysis is founded in Traditional Chinese Medicine. A new dataset consisting of 581 heart disease and 581 healthy samples was experimented by the proposed method. In order to optimize the Probabilistic Collaborative Representation Based Classifier, an analysis of its parameters was performed. According to the experimental results, the proposed method obtains the highest accuracy compared with other classifiers and is proven to be effective at heart disease detection.
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2,335,148 |
The impact of the advanced practice nursing role on quality of care, clinical outcomes, patient satisfaction, and cost in the emergency and critical care settings: a systematic review.
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The prevalence of chronic illness and multimorbidity rises with population aging, thereby increasing the acuity of care. Consequently, the demand for emergency and critical care services has increased. However, the forecasted requirements for physicians have shown a continued shortage. Among efforts underway to search for innovations to strengthen the workforce, there is a heightened interest to have nurses in advanced practice participate in patient care at a great extent. Therefore, it is of interest to evaluate the impact of increasing the autonomy of nurses assuming advanced practice roles in emergency and critical care settings on patient outcomes.</AbstractText>The objectives of this study are to present, critically appraise, and synthesize the best available evidence on the impact of advanced practice nursing on quality of care, clinical outcomes, patient satisfaction, and cost in emergency and critical care settings.</AbstractText>A comprehensive and systematic search of nine electronic databases and a hand-search of two key journals from 2006 to 2016 were conducted to identify studies evaluating the impact of advanced practice nursing in the emergency and critical care settings. Two authors were involved selecting the studies based on the inclusion criteria. Out of the original search yield of 12,061 studies, 15 studies were chosen for appraisal of methodological quality by two independent authors and subsequently included for analysis. Data was extracted using standardized tools.</AbstractText>Narrative synthesis was undertaken to summarize and report the findings. This review demonstrates that the involvement of nurses in advanced practice in emergency and critical care improves the length of stay, time to consultation/treatment, mortality, patient satisfaction, and cost savings.</AbstractText>Capitalizing on nurses in advanced practice to increase patients' access to emergency and critical care is appealing. This review suggests that the implementation of advanced practice nursing roles in the emergency and critical care settings improves patient outcomes. The transformation of healthcare delivery through effective utilization of the workforce may alleviate the impending rise in demand for health services. Nevertheless, it is necessary to first prepare a receptive context to effect sustainable change.</AbstractText>
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2,335,149 |
Fatigue-related changes in technique emerge at different timescales during repetitive training.
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Training consisting of numerous repetitions performed as closely as possible to ideal techniques is common in sports and every-day tasks. Little is known about fatigue-related technique changes that emerge at different timescales when repeating complex actions such as a karate front kick. Accordingly, 15 karatekas performed 600 kicks (1 pre-block and 9 blocks). The pre-block comprised 6 kicks (3 with each leg) at maximum intensity (K-100%). Each block comprised 60 kicks (10 with each leg) at 80% of their self-perceived maximum intensity (K-80%) plus 6 K-100%. In between blocks, the participants rested for 90 seconds. Right leg kinematics (peak joint angles, peak joint angular velocities, peak joint linear resultant velocities, and time of occurrence of peaks) and kick duration corresponding to the K-80% were measured resulting in numerous variations with fatigue. At the timescale of tens of seconds, the changes involved variables that were related to velocity of execution (slowed down), while variables related to movement form were hardly affected. At the timescale of tens of minutes, the opposite results were observed. These findings challenge the long-standing rationale underlying repetitive training, suggesting instead that such involuntary variations in technique might play a crucial role in motor skill training.
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2,335,150 |
Anti-Ro52 antibody level is an important marker of fetal congenital heart block risk in anti-Ro/SSA antibody positive pregnancy.
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The aims of this study are to determine the incidence of congenital heart block (CHB) in the Japanese population and identify maternal factors predicting fetal CHB in anti-Ro/SSA antibody positive pregnancy.</AbstractText>A retrospective study was performed using 52,147 clinical records of pregnancies followed in a single center. For 183 anti-Ro/SSA antibody-positive women, anti-Ro52 and Ro60 antibodies were measured, and the odds of CHB in relation to maternal clinical features were calculated by multivariate analysis. The receiver-operating characteristic (ROC) curves for predicting CHB were constructed for the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies.</AbstractText>Fetal CHB occurred in two pregnancies among those without known risks such as positive anti-Ro/SSA antibody or previous CHB-affected pregnancy, suggesting an incidence similar to that in Caucasian populations. As for the anti-Ro/SSA antibody positive pregnancies, the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies were independent risk factors for fetal CHB and the use of corticosteroids before 18 gestational weeks was an independent protective factor. The area under the ROC was 0.84, 0.73 and 0.74 for anti-Ro52, anti-Ro60 and anti-Ro/SSA antibodies, respectively.</AbstractText>CHB occurred in two among approximately 50,000 pregnancies without known risks such as positive anti-Ro/SSA antibody or previous delivery of CHB-affected babies. Measurement of anti-Ro52 antibody levels may be helpful in extracting a risk group of delivering CHB infants in the anti-Ro/SSA antibody positive pregnancy.</AbstractText>
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2,335,151 |
Modeling conditional dependence among multiple diagnostic tests.
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When multiple imperfect dichotomous diagnostic tests are applied to an individual, it is possible that some or all of their results remain dependent even after conditioning on the true disease status. The estimates could be biased if this conditional dependence is ignored when using the test results to infer about the prevalence of a disease or the accuracies of the diagnostic tests. However, statistical methods correcting for this bias by modelling higher-order conditional dependence terms between multiple diagnostic tests are not well addressed in the literature. This paper extends a Bayesian fixed effects model for 2 diagnostic tests with pairwise correlation to cases with 3 or more diagnostic tests with higher order correlations. Simulation results show that the proposed fixed effects model works well both in the case when the tests are highly correlated and in the case when the tests are truly conditionally independent, provided adequate external information is available in the form of fixed constraints or prior distributions. A data set on the diagnosis of childhood pulmonary tuberculosis is used to illustrate the proposed model.
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2,335,152 |
The feasibility of a heart block with an electron compensation as an alternative whole breast radiotherapy technique in patients with underlying cardiac or pulmonary disease.
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We aimed to evaluate the feasibility of the heart block with electron compensation (HBE) technique, based on three-dimensional conformal radiotherapy (3D-CRT) in left-sided breast cancer patients with underlying cardiac or pulmonary disease.</AbstractText>Twenty patients with left-sided breast cancer who were treated with whole breast radiotherapy (WBRT) were included in this study. Intensity-modulated radiotherapy (IMRT), 3D-CRT, and HBE treatment plans were generated for each patient. Based on the 3D-CRT plan, the HBE plan included a heart block from the medial tangential field to shield the heart and added an electron beam to compensate for the loss in target volume coverage. The dosimetric parameters for the heart and lung and the target volume between the three treatment types were compared.</AbstractText>Of the three plans, the HBE plan yielded the most significant reduction in the doses received by the heart and lung (heart Dmean: 5.1 Gy vs. 12.9 Gy vs. 4.0 Gy and lung Dmean: 11.4 Gy vs. 13.2 Gy vs. 10.5 Gy, for 3D-CRT, IMRT, and HBE, respectively). Target coverage with all three techniques was within the acceptable range (Dmean 51.0 Gy vs. 51.2 Gy vs. 50.6 Gy, for 3D-CRT, IMRT, and HBE, respectively).</AbstractText>The HBE plan effectively reduced the amount of radiation exposure to the heart and lung. It could be beneficial for patients who are vulnerable to radiation-related cardiac or pulmonary toxicities.</AbstractText>
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2,335,153 |
What Is the Relationship Between Dairy Intake and Blood Pressure in Black and White Children and Adolescents Enrolled in a Weight Management Program?
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The DASH (Dietary Approaches to Stop Hypertension) clinical trials and other studies have demonstrated a relationship between diet and cardiovascular outcomes in adults, yet little is known of this relationship in children. Childhood obesity has reached epidemic proportions in the United States, with similar increases in hypertension among this population. The purpose of our study was to examine the association between dairy intake and blood pressure (BP) in a cohort of children and adolescents (aged 4-17 years) enrolled in a weight management program.</AbstractText>Dietary intake was assessed using the Block Kids 2004 food frequency questionnaire in a cross-sectional sample of participants enrolled in the Pediatric Metabolic Syndrome Study at the Children's Hospital (Charleston, SC). BP and other anthropometrics were obtained at baseline. Only children with complete baseline data and food frequency questionnaires were included in this analysis (n=117). Associations between food group/nutrient intake and BP were examined across race and sex using ANOVA and Pearson correlations. Linear regression models were controlled for body mass index and age. In the total sample, a significant inverse relationship was found between the intake of dairy and systolic BP (r</i>=-0.24, P</i>=0.009). The effect of dairy on systolic BP, however, differed by race. We observed a decrease of 11.2 mm Hg for each serving of dairy consumed by white children, and no decrease in systolic BP in black children (P</i>=0.001 for the race-dairy serving interaction).</AbstractText>Nutrition professionals must consider nonnutrition factors contributing to childhood hypertension, as current dietary recommendations appear to have differential outcomes across races.</AbstractText>© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.</CopyrightInformation>
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2,335,154 |
Interleukin-18 Enhances Vascular Calcification and Osteogenic Differentiation of Vascular Smooth Muscle Cells Through TRPM7 Activation.
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Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a key mechanism of VC. Recent studies show that IL-18 (interleukin-18) favors VC while TRPM7 (transient receptor potential melastatin 7) channel upregulation inhibits VC. However, the relationship between IL-18 and TRPM7 is unclear. We questioned whether IL-18 enhances VC and osteogenic differentiation of VSMCs through TRPM7 channel activation.</AbstractText>Coronary artery calcification and serum IL-18 were measured in patients by computed tomographic scanning and enzyme-linked immunosorbent assay, respectively. Primary rat VSMCs calcification were induced by high inorganic phosphate and exposed to IL-18. VSMCs were also treated with TRPM7 antagonist 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA to block TRPM7 channel activity and expression. TRPM7 currents were recorded by patch-clamp. Human studies showed that serum IL-18 levels were positively associated with coronary artery calcium scores (r</i>=0.91; P</i><0.001). In VSMCs, IL-18 significantly decreased expression of contractile markers α-smooth muscle actin, smooth muscle 22 α, and increased calcium deposition, alkaline phosphatase activity, and expression of osteogenic differentiation markers bone morphogenetic protein-2, Runx2 (runt-related transcription factor 2), and osteocalcin (P</i><0.05). IL-18 increased TRPM7 expression through ERK1/2 (extracellular signal-regulated kinase 1/2) signaling activation, and TRPM7 currents were augmented by IL-18 treatment. Inhibition of TRPM7 channel by 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA prevented IL-18-enhanced osteogenic differentiation and VSMCs calcification.</AbstractText>These findings suggest that coronary artery calcification is associated with increased IL-18 levels. IL-18 enhances VSMCs osteogenic differentiation and subsequent VC induced by β-glycerophosphate via TRPM7 channel activation. Accordingly, IL-18 may contribute to VC in proinflammatory conditions.</AbstractText>© 2017 American Heart Association, Inc.</CopyrightInformation>
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2,335,155 |
Effects of <i>CYP3A4</i> polymorphisms on efficiency of general anesthesia combined with epidural block in patients undergoing cardiac valve replacement.
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This study aims to investigate the effects of <i>CYP3A4</i> polymorphisms (*4, *5 and *6) on efficiency of general anesthesia (GA) combined with epidural block (EB) in patients undergoing cardiac valve replacement. From January 2014 to October 2015, a total of 511 patients undergoing cardiac valve replacement (case group) and 503 healthy individuals (control group) were selected for the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied for genotyping of <i>CYP3A4</i> gene. Central venous pressure (CVP), mean arterial pressure (MAP), heart rate (HR), pulse oximetry (SPO<sub>2</sub>), extubation and duration of intensive care unit (ICU) stay during the surgery were observed and recorded. A nine-month follow-up was conducted. Genotype and allele frequency of <i>CYP3A4*4</i> were significantly different between the case and control groups (all <i>P</i> < 0.05). Compared with wild-type *1*1 patients with heterozygous *1*4 of <i>CYP3A4*4</i> showed significant difference in HR, MAP, SPO<sub>2</sub> and CVP and in the time of extubation and ICU stay. <i>CYP3A4*4</i> polymorphism may be associated with the effect of GA combined with EB in cardiac surgery. These results demonstrate that <i>CYP3A4*4</i> polymorphism is correlated with the effects of GA combined with EB in cardiac surgery. <i>CYP3A4</i> polymorphisms increase the risk of GA combined with EB among patients undergoing cardiac valve replacement.
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2,335,156 |
A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions.
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Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures to form dyads within which calcium-induced-calcium-release occurs. The organisation of these structures tightly controls intracellular calcium dynamics. In this study, we present a computational model of intracellular calcium cycling in three-dimensions (3-D), which incorporates high resolution reconstructions of these key regulatory structures, attained through imaging of tissue taken from the sheep left ventricle using serial block face scanning electron microscopy. An approach was developed to model the sarcoplasmic reticulum structure at the whole-cell scale, by reducing its full 3-D structure to a 3-D network of one-dimensional strands. The model reproduces intracellular calcium dynamics during control pacing and reveals the high-resolution 3-D spatial structure of calcium gradients and intracellular fluxes in both the cytoplasm and sarcoplasmic reticulum. We also demonstrated the capability of the model to reproduce potentially pro-arrhythmic dynamics under perturbed conditions, pertaining to calcium-transient alternans and spontaneous release events. Comparison with idealised cell models emphasised the importance of structure in determining calcium gradients and controlling the spatial dynamics associated with calcium-transient alternans, wherein the probabilistic nature of dyad activation and recruitment was constrained. The model was further used to highlight the criticality in calcium spark propagation in relation to inter-dyad distances. The model presented provides a powerful tool for future investigation of structure-function relationships underlying physiological and pathophysiological intracellular calcium handling phenomena at the whole-cell. The approach allows for the first time direct integration of high-resolution images of 3-D intracellular structures with models of calcium cycling, presenting the possibility to directly assess the functional impact of structural remodelling at the cellular scale.
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2,335,157 |
A combination of levobupivacaine and lidocaine for paravertebral block in breast cancer patients undergoing quadrantectomy causes greater hemodynamic oscillations than levobupivacaine alone.
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To test for differences in hemodynamic and analgesic properties in patients with breast cancer undergoing quadrantectomy with paravertebral block (PVB) induced with a solution of either one or two local anesthetics.</AbstractText>A prospective, single-center, randomized, double-blinded, controlled trial was conducted from June 2014 until September 2015. A total of 85 women with breast cancer were assigned to receive PVB with either 0.5% levobupivacaine (n=42) or 0.5% levobupivacaine with 2% lidocaine (n=43). Hemodynamic variables of interest included intraoperative stroke volume variation (SVV), mean arterial pressure, heart rate, cardiac output, episodes of hypotension, use of crystalloids, and use of inotropes. Analgesic variables of interest were time to block onset, duration of analgesia, and postoperative serial pain assessment using a visual analogue scale.</AbstractText>Although the use of 0.5% levobupivacaine with 2% lidocaine solution for PVB decreased the mean time-to-block onset (14 minutes; P<0.001), it also caused significantly higher SVV values over the 60 minutes of monitoring (mean difference: 4.33; P<0.001). Furthermore, the patients who received 0.5% levobupivacaine with 2% lidocaine experienced shorter mean duration of analgesia (105 minutes; P=0.006) and more episodes of hypotension (17.5%; P=0.048) and received more intraoperative crystalloids (mean volume: 550 mL; P<0.001).</AbstractText>The use of 0.5% levobupivacaine in comparison with 0.5% levobupivacaine with 2% lidocaine solution for PVB had a longer time-to-block onset, but it also reduced hemodynamic disturbances and prolonged the analgesic effect.</AbstractText>
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2,335,158 |
Maternal hyperglycemia in singleton pregnancies conceived by IVF may be modified by first-trimester BMI.
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Does IVF independently increase the risk of gestational diabetes mellitus (GDM) and is this increase in risk modified by maternal body mass index?</AbstractText>IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women (BMI > 25 kg/m2).</AbstractText>IVF has been associated with increased risk of GDM, but most previous studies did not adequately assess confounding or effect modification by other risk factors.</AbstractText><AbstractText Label="STUDY DESIGN, SIZE, DURATION">Cross-sectional study using data from 1089 women with singleton pregnancies who participated in a Singaporean birth cohort study (GUSTO) and received a 75 g oral glucose tolerance test (OGTT) at 26-28 weeks gestation.</AbstractText><AbstractText Label="PARTICIPANTS/MATERIALS, SETTING, METHODS">A total of 1089 women (n = 1013 conceived spontaneously, n = 76 conceived through IVF) with singleton pregnancies received a 75 g OGTT at 26-28 weeks gestation. Fasting and 2 h postprandial blood glucose levels were assayed. World Health Organization criteria (1999) standard criteria were used to classify GDM: ≥7.0 mmol/L for fasting and/or ≥7.8 mmol/L for 2-h postprandial plasma glucose levels, which was the clinical guideline in use during the study.</AbstractText>IVF pregnancies had nearly double the odds of GDM (OR = 1.83, 95% CI: 1.03-3.26) and elevated fasting (mean difference = 0.12 mmol/L, 95% CI: 0.00-0.24) and OGTT 2-h blood glucose levels (mean difference = 0.64 mmol/L, 95% CI: 0.27-1.01), after adjusting for commonly recognized risk factors for GDM. After stratification by first-trimester BMI, these increased risks of GDM (OR = 3.54, 95% CI: 1.44-8.72) and elevated fasting (mean difference = 0.39 mmol/L, 95% CI: 0.13-0.65) and 2-h blood (mean difference = 1.24 mmol/L, 95% CI: 0.56-1.91) glucose levels were significant only in the IVF group who is also overweight or obese (BMI > 25 kg/m2).</AbstractText>One limitation of our study is the absence of a 1 h post-OGTT plasma glucose sample, as we were using the 1999 WHO diagnostic criteria (the clinical guideline in Singapore) at the time of our study, instead of the revised 2013 WHO diagnostic criteria. Our cohort may not be representative of the general Singapore obstetric population, although participants were recruited from the two largest maternity hospitals in the country and include both private and subsidized patients.</AbstractText>IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women. Our findings reinforce the need to advise overweight or obese women contemplating IVF to lose weight before the procedure to reduce their risk of GDM and hyperglycemia-related adverse outcomes arising therefrom. In settings where universal GDM screening is not routine, overweight or obese women who conceive by IVF should be screened.</AbstractText><AbstractText Label="STUDY FUNDING/COMPETING INTEREST(S)">This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Program and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore (NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR). K.M.G. and Y.S.C. have received lecture fees from Nestle Nutrition Institute and Danone, respectively. K.M.G., Y.S.C. and S.Y.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors have nothing to disclose. The other authors have nothing to disclose.</AbstractText>N/A.</AbstractText>© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.</CopyrightInformation>
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Poly (Ethylene Glycol)-Block-Brush Poly (L-Lysine) Copolymer as an Efficient Nanocarrier for Human Hepatocyte Growth Factor with Enhanced Bioavailability and Anti-Ischemia Reperfusion Injury Efficacy.
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<AbstractText Label="BACKGROUND/AIMS" NlmCategory="OBJECTIVE">The aim of this study was to assess the effect of human hepatocyte growth factor (hHGF)-loaded poly (ethylene glycol)-b-brush poly (l-lysine) (PEG-b-P(ELG-g-PLL)) copolymer on ischemia/reperfusion (I/R) injury to different organs.</AbstractText>The isoelectric point (pI) of hHGF is 5.5, and hHGF combined with PEG-b-P(ELG-g-PLL) copolymer via electrostatic interactions at pH 7.4. The synthesized PEG-b-P(ELG-g-PLL) copolymer was analyzed using 1H nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). The hHGF/PEG-b-P(ELG-g-PLL) complex was evaluated using a nanoparticle size instrument and transmission electron microscopy (TEM). In addition, vivo performance of hHGF/PEG-b-P(ELG-g-PLL) complex was evaluated using plasma hHGF concentration and different organs ischemia reperfusion injury in rats.</AbstractText>An in vitro investigation showed that PEG-b-P(ELG-g-PLL) could serve as a potential hHGF nanocarrier with efficient encapsulation and sustained release. An additional in vivo investigation revealed that the hHGF/PEG-b-P(ELG-g-PLL) complex could prolong increases in plasma hHGF concentration and protect different organs (the brain, heart and kidney) against I/R injury.</AbstractText>Poly (ethylene glycol)-block-brush poly (l-lysine) copolymer as an efficient nanocarrier for human hepatocyte growth factor with enhanced bioavailability and anti-ischemia reperfusion injury efficacy.</AbstractText>© 2017 The Author(s). Published by S. Karger AG, Basel.</CopyrightInformation>
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2,335,160 |
IRF2BP2-deficient microglia block the anxiolytic effect of enhanced postnatal care.
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Enhanced postnatal care (EPC) increases resilience to adversity in adulthood. Since microglia participate in shaping neural circuits, we asked how ablation of an inflammation-suppressing factor IRF2BP2 (Interferon Regulatory Factor 2 Binding Protein 2) in microglia would affect the responses to EPC. Mice lacking IRF2BP2 in microglia (KO) and littermate controls (WT) were subjected to EPC during the first 3 weeks after birth. EPC reduced anxiety in WT but not KO mice. This was associated with reduced inflammatory cytokine expression in the hypothalamus. Whole genome RNAseq profiling of the hypothalamus identified 101 genes whose expression was altered by EPC: 95 in WT, 11 in KO, with 5 in common that changed in opposite directions. Proteoglycan 4 (Prg4), prostaglandin D2 synthase (Ptgds) and extracellular matrix protease inhibitor Itih2 were suppressed by EPC in WT but elevated in KO mice. On the other hand, the glutamate transporter VGLUT1 (Slc17a7) was increased by EPC in WT but not KO mice. Prostaglandin D2 (PGD2) is known to enhance microglial inflammation and promote Gfap expression. ELISA confirmed reduced PGD2 in the hypothalamus of WT mice after EPC, associated with reduced Gfap expression. Our study suggests that the anxiety-reducing effect of EPC operates by suppressing microglial inflammation, likely by reducing neuronal prostaglandin D2 production.
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2,335,161 |
Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes.
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Side effects on cardiac ion channels are one major reason for new drugs to fail during preclinical evaluation. Herein we propose a simple optogenetic screening tool measuring extracellular field potentials (FP) from paced cardiomyocytes to identify drug effects over the whole physiological heart range, which is essential given the rate-dependency of ion channel function and drug action. Human induced pluripotent stem cell-derived cardiomyocytes were transduced with an adeno-associated virus to express Channelrhodopsin2 and plated on micro-electrode arrays. Global pulsed illumination (470 nm, 1 ms, 0.9 mW/mm<sup>2</sup>) was applied at frequencies from 1 to 2.5 Hz, which evoked FP simultaneously in all cardiomyocytes. This synchronized activation allowed averaging of FP from all electrodes resulting in one robust FP signal for analysis. Field potential duration (FPD) was ~25% shorter at 2.5 Hz compared to 1 Hz. Inhibition of hERG channels prolonged FPD only at low heart rates whereas Ca<sup>2+</sup> channel block shortened FPD at all heart rates. Optogenetic pacing also allowed analysis of the maximum downstroke velocity of the FP to detect drug effects on Na<sup>+</sup> channel availability. In principle, the presented method is well scalable for high content cardiac toxicity screening or personalized medicine for inherited cardiac channelopathies.
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2,335,162 |
Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription.
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Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged "block and lock" approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4<sup>+</sup> T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.
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2,335,163 |
PR interval prolongation in coronary patients or risk equivalent: excess risk of ischemic stroke and vascular pathophysiological insights.
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Whether PR prolongation independently predicts new-onset ischemic events of myocardial infarction and stroke was unclear. Underlying pathophysiological mechanisms of PR prolongation leading to adverse cardiovascular events were poorly understood. We investigated the role of PR prolongation in pathophysiologically-related adverse cardiovascular events and underlying mechanisms.</AbstractText>We prospectively investigated 597 high-risk cardiovascular outpatients (mean age 66 ± 11 yrs.; male 67%; coronary disease 55%, stroke 22%, diabetes 52%) for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and cardiovascular death. Vascular phenotype was determined by carotid intima-media thickness (IMT).</AbstractText>PR prolongation >200 ms was present in 79 patients (13%) at baseline. PR prolongation >200 ms was associated with significantly higher mean carotid IMT (1.05 ± 0.37 mm vs 0.94 ± 0.28 mm, P = 0.010). After mean study period of 63 ± 11 months, increased PR interval significantly predicted new-onset ischemic stroke (P = 0.006), CHF (P = 0.040), cardiovascular death (P < 0.001), and combined cardiovascular endpoints (P < 0.001) at cut-off >200 ms. Using multivariable Cox regression, PR prolongation >200 ms independently predicted new-onset ischemic stroke (HR 8.6, 95% CI: 1.9-37.8, P = 0.005), cardiovascular death (HR 14.1, 95% CI: 3.8-51.4, P < 0.001) and combined cardiovascular endpoints (HR 2.4, 95% CI: 1.30-4.43, P = 0.005). PR interval predicts new-onset MI at the exploratory cut-off >162 ms (C-statistic 0.70, P = 0.001; HR: 8.0, 95% CI: 1.65-38.85, P = 0.010).</AbstractText>PR prolongation strongly predicts new-onset ischemic stroke, MI, cardiovascular death, and combined cardiovascular endpoint including CHF in coronary patients or risk equivalent. Adverse vascular function may implicate an intermediate pathophysiological phenotype or mediating mechanism.</AbstractText>
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Evaluation of a modified infraorbital approach for a maxillary nerve block for rhinoscopy with nasal biopsy of dogs.
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OBJECTIVE To determine whether a maxillary nerve block via a modified infraorbital approach, applied before rhinoscopy and nasal biopsy of dogs, would decrease procedural nociception, minimize cardiorespiratory anesthetic effects, and improve recovery quality. ANIMALS 8 healthy adult hound-type dogs PROCEDURES In a crossover study, dogs received 0.5% bupivacaine (0.1 mL/kg) or an equivalent volume of saline (0.9% NaCl) solution as a maxillary nerve block via a modified infraorbital approach. A 5-cm, 20-gauge over-the-needle catheter was placed retrograde within each infraorbital canal, and bupivacaine or saline solution was administered into each pterygopalatine region. Rhinoscopy and nasal biopsy were performed. Variables monitored included heart rate, systolic arterial blood pressure (SAP), mean arterial blood pressure (MAP), diastolic arterial blood pressure (DAP), plasma cortisol and norepinephrine concentrations, purposeful movement, and pain scores. After a 14-day washout period, the other treatment was administered on the contralateral side, and rhinoscopy and nasal biopsy were repeated. RESULTS SAP, MAP, and DAP were significantly higher for the saline solution treatment than for the bupivacaine treatment, irrespective of the time point. Plasma cortisol concentrations after saline solution treatment were significantly higher 5 minutes after nasal biopsy than at biopsy. Heart rate, norepinephrine concentration, purposeful movement, and pain score were not significantly different between treatments. CONCLUSIONS AND CLINICAL RELEVANCE Maxillary nerve block via a modified infraorbital approach prior to rhinoscopy and nasal biopsy reduced procedural nociception as determined on the basis of blood pressures and plasma cortisol concentrations during anesthesia. These findings warrant further evaluation in dogs with nasal disease.
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Novel Magnetic-Luminescent Janus Nanoparticles for Cell Labeling and Tumor Photothermal Therapy.
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Magnetic-luminescent nanocomposites have multiple uses including multimodal imaging, magnetic targeted drug delivery, and cancer imaging-guided therapies. In this work, dumbbell-like MnFe<sub>2</sub> O<sub>4</sub> -NaYF<sub>4</sub> Janus nanoparticles are synthesized via a two-step thermolysis approach. These synthesized nanoparticles exhibit stability in aqueous solutions and very low cytotoxicity after poly(acryl amide) modification. High cellular uptake efficiency is observed for the folic acid-conjugated MnFe<sub>2</sub> O<sub>4</sub> -NaYF<sub>4</sub> in human esophagus carcinoma cells (Eca-109) due to the upconversion luminescence properties as well as the folate targeting potential. The MnFe<sub>2</sub> O<sub>4</sub> -NaYF<sub>4</sub> also strongly absorbs light in the near-infrared range and rapidly converts to heat energy. It is demonstrated that Eca-109 cells incubated with MnFe<sub>2</sub> O<sub>4</sub> -NaYF<sub>4</sub> are killed with high efficiency after 808 nm laser irradiation. Furthermore, the growth of tumors in mice (grown from Eca-109 cells) is highly inhibited by the photothermal effects of MnFe<sub>2</sub> O<sub>4</sub> -NaYF<sub>4</sub> efficiently. Histological analysis reveals no pathological change and inflammatory response in heart, liver, spleen, lung, or kidney. The low toxicity, excellent luminescence, and highly efficient photothermal therapy properties of MnFe<sub>2</sub> O<sub>4</sub> -NaYF<sub>4</sub> Janus nanoparticles illustrated in this work support their vast potential for nanomedicine and cancer therapy.
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Cardiorespiratory effects of epidural anesthesia using lidocaine with morphine or dexmedetomidine in capuchin monkeys (Sapajus sp.) undergoing bilateral tubal ligation surgery, anesthetized with isoflurane.
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Epidural anesthesia is indicated to decrease other anesthetic requirements, prolong analgesia, and reduce side effects. In primates, its use has been scarcely described. The aim was to evaluate the cardiorespiratory effects of epidural anesthesia with lidocaine and dexmedetomidine (DEX) or morphine (MOR).</AbstractText>Ten female capuchin monkeys (Sapajus sp.) received epidural anesthesia with lidocaine and DEX or MOR under general anesthesia.</AbstractText>There was a significant decrease in heart rate with DEX and in blood pressure in all groups, with no changes in SpO2</sub> . There was a significant reduction in rectal temperature over time. A stable cardiac rhythm was observed; however, there was a prolonged QT interval with DEX.</AbstractText>Epidural anesthesia with access to the lumbosacral space was safe and easy to perform. DEX decreased heart rate. All groups promoted a decrease in rectal temperature with respiratory and cardiac rhythm stability; however, hypotension should be considered.</AbstractText>© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</CopyrightInformation>
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Autophagy was involved in the protective effect of metformin on hyperglycemia-induced cardiomyocyte apoptosis and Connexin43 downregulation in H9c2 cells.
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<b>Background:</b> Increased cardiomyocyte apoptosis under high glucose condition contributes to diabetic cardiomyopathy. Degradation of cardiac Connexin43 (Cx43) has been associated with cardiac dysfunction in diabetic heart. Clinical and experimental studies suggested that metformin (Met) exhibits cardioprotective properties against diabetes. <b>Aim:</b> The aim of this study was to investigate the effect and underlying signaling mechanisms of metformin on apoptosis and Cx43 expression in H9c2 cells presenting with hyperglycemia conditions. <b>Methods:</b> In the present study, H9c2 cardiac cells were incubated with 5.5 mM glucose, 33.3 mM glucose, 33.3 mM glucose with metformin at two dose (100 μM, 1 mM) for 96 hours, and 1 mM metformin with chloroquine (50 μM) in 33.3 mM glucose medium. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) cell survival assay. Cytotoxicity was determined by the release of lactate dehydrogenase (LDH). The expression of Cx43, autophagic maker protein (LAMP-1, Beclin-1, p62 and LC3) and apoptosis maker protein (Bcl-2 and Bax) were determined by western blot. <b>Results:</b> The results showed that high glucose increased apoptosis and decreased Cx43 expression. Interestingly, metformin attenuated hyperglycemia-increased apoptosis and restored Cx43 expression. Moreover, this treatment caused autophagy as well, which indicated by up-regulation of autophagy-related proteins LAMP-1, Beclin-1, p62 and reduction in the ratio of LC3-II/LC3-I. In addition, administration autophagy inhibitor chloroquine (CQ) did not block the effect of metformin on Cx43 expression while increasing Cx43 content, together with an increased apoptosis. <b>Conclusion:</b> Administration metformin can protect the H9c2 cells against hyperglycemia-induced apoptosis and Cx43 down-regulation, in part, mediated through the induction of autophagy pathway.
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2,335,168 |
Antioxidation Role of Different Lateral Stellate Ganglion Block in Isoproterenol-Induced Acute Myocardial Ischemia in Rats.
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To determine whether stellate ganglion block (SGB) treatment exerts protective effects against isoproterenol (ISO)-induced acute myocardial ischemia (AMI) due to its antioxidant effects, we aimed to evaluate the protective effects of different lateral SGB agents on the tissue antioxidant status in ISO-induced AMI in male Sprague-Dawley rats.</AbstractText>The AMI model received an acute ISO overdose to make cardiac ischemia damage at a single dose of 110 mg/kg injected subcutaneously into the rats. The rats in the SGB groups received SGB 15 minutes after ISO treatment. The data were recorded at the following time points: 0 minutes (T0) and 15 minutes after SGB (T1). The levels of cardiac troponin T and cardiac troponin I and the ST-segment depression in lead III were measured at T0 and T1. The values of oxidative production and antioxidative enzymes in the SG and heart were tested.</AbstractText>Stellate ganglion block significantly reduced serum cardiac troponin I and cardiac troponin T levels and mitigated the ST-segment depression and oxidative production levels, but it increased the antioxidative enzymes levels. Right SGB effect was more effective than that of left SGB, in the reduced nitric oxide and malonaldehyde levels, and in the increased superoxide dismutase, glutathione peroxidase, catalase, neuronal nitric oxide synthase, and endothelial nitric oxide synthase levels.</AbstractText>These findings suggest that SGB could have antioxidative effects against AMI, and the protective effect of right SGB was more effective than that of left SGB. Thus, the right SGB could be an effective and safe method of local anesthesia to protect against cardiac damage due to oxidative stress.</AbstractText>
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2,335,169 |
HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner.
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Laterality is a basic characteristic of all life forms, from single cell organisms to complex plants and animals. For many metazoans, consistent left-right asymmetric patterning is essential for the correct anatomy of internal organs, such as the heart, gut, and brain; disruption of left-right asymmetry patterning leads to an important class of birth defects in human patients. Laterality functions across multiple scales, where early embryonic, subcellular and chiral cytoskeletal events are coupled with asymmetric amplification mechanisms and gene regulatory networks leading to asymmetric physical forces that ultimately result in distinct left and right anatomical organ patterning. Recent studies have suggested the existence of multiple parallel pathways regulating organ asymmetry. Here, we show that an isoform of the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of ion channels (hyperpolarization-activated cyclic nucleotide-gated channel 4, HCN4) is important for correct left-right patterning. HCN4 channels are present very early in <i>Xenopus</i> embryos. Blocking HCN channels (<i>I<sub>h</sub></i> currents) with pharmacological inhibitors leads to errors in organ situs. This effect is only seen when HCN4 channels are blocked early (pre-stage 10) and not by a later block (post-stage 10). Injections of <i>HCN4-DN</i> (dominant-negative) mRNA induce left-right defects only when injected in both blastomeres no later than the 2-cell stage. Analysis of key asymmetric genes' expression showed that the sidedness of <i>Nodal</i>, <i>Lefty</i>, and <i>Pitx2</i> expression is largely unchanged by HCN4 blockade, despite the randomization of subsequent organ situs, although the area of <i>Pitx2</i> expression was significantly reduced. Together these data identify a novel, developmental role for HCN4 channels and reveal a new <i>Nodal-Lefty-Pitx2</i> asymmetric gene expression-independent mechanism upstream of organ positioning during embryonic left-right patterning.
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2,335,170 |
Modeling hypothermia induced effects for the heterogeneous ventricular tissue from cellular level to the impact on the ECG.
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Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27°C to 37°C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial), the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP) of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG) was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia.
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2,335,171 |
Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation.
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Nucleation processes are at the heart of a large number of phenomena, from cloud formation to protein crystallization. A recently emerging area where nucleation is highly relevant is the initiation of filamentous protein self-assembly, a process that has broad implications in many research areas ranging from medicine to nanotechnology. As such, spontaneous nucleation of protein fibrils has received much attention in recent years with many theoretical and experimental studies focussing on the underlying physical principles. In this paper we make a step forward in this direction and explore the early time behaviour of filamentous protein growth in the context of nucleation theory. We first provide an overview of the thermodynamics and kinetics of spontaneous nucleation of protein filaments in the presence of one relevant degree of freedom, namely the cluster size. In this case, we review how key kinetic observables, such as the reaction order of spontaneous nucleation, are directly related to the physical size of the critical nucleus. We then focus on the increasingly prominent case of filament nucleation that includes a conformational conversion of the nucleating building-block as an additional slow step in the nucleation process. Using computer simulations, we study the concentration dependence of the nucleation rate. We find that, under these circumstances, the reaction order of spontaneous nucleation with respect to the free monomer does no longer relate to the overall physical size of the nucleating aggregate but rather to the portion of the aggregate that actively participates in the conformational conversion. Our results thus provide a novel interpretation of the common kinetic descriptors of protein filament formation, including the reaction order of the nucleation step or the scaling exponent of lag times, and put into perspective current theoretical descriptions of protein aggregation.
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2,335,172 |
Effectiveness of transtracheal lidocaine as an adjunct to general anesthesia in providing patient immobility during total parotidectomy: A comparison with dexmedetomidine infusion.
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Dexmedetomidine and propofol infusions are increasingly being used to ensure intraoperative patient immobility in the absence of muscle relaxants during parotidectomy. The primary aim of our study was to assess the effectiveness of transtracheal block as an adjunct to general anesthesia in providing patient immobility during total parotidectomy, as compared to dexmedetomidine infusion.</AbstractText>This prospective, randomized study was conducted in 58 patients. Group A patients received a transtracheal injection of 4 ml of 4% lidocaine before induction whereas in Group B, dexmedetomidine 1 mcg/kg was administered intravenously. Following induction and intubation, anesthesia was maintained with oxygen, nitrous oxide, and isoflurane and dexmedetomidine was administered in Group B at a rate of 0.7 mcg/kg/h. In both the groups, if the patient moved, bucked, or if there were signs of inadequate depth of anesthesia, plane of anesthesia was deepened with a bolus of propofol 0.5 mg/kg intravenously. Mann-Whitney U-test and Fisher's exact test were used for statistical analysis.</AbstractText>The number of patients who moved in the transtracheal group was significantly less as compared to dexmedetomidine group (3 vs. 11). Mean heart rates (HRs) were comparable in both groups till 10 min, but between 15 and 180 min, Group B had significantly low HR. Systolic blood pressure (SBP) was significantly high at 10 min following dexmedetomidine bolus in Group B. Though Group B showed low SBP</i> values as compared to Group A from 10 min following induction, the difference became significant between 45 and 180 min. Changes in mean arterial blood pressures followed a similar trend as with SBP.</AbstractText>Transtracheal lidocaine ensured patient immobility with hemodynamic stability during total parotidectomy with nerve stimulation studies as compared to intraoperative dexmedetomidine infusion.</AbstractText>
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2,335,173 |
Psoas compartment and sacral plexus block via electrostimulation for pelvic limb amputation in dogs.
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To assess the efficacy of psoas compartment and sacral plexus block for pelvic limb amputation in dogs.</AbstractText>Prospective clinical study.</AbstractText>A total of 16 dogs aged 8±3 years and weighing 35±14 kg (mean±standard deviation).</AbstractText>Dogs were administered morphine (0.5 mg kg-1</sup>) and atropine (0.02 mg kg-1</sup>); anesthesia was induced with propofol and maintained with isoflurane. Regional blocks were performed before surgery in eight dogs with bupivacaine (2.2 mg kg-1</sup>) and eight dogs were administered an equivalent volume of saline. The lumbar plexus within the psoas compartment was identified using electrolocation lateral to the lumbar vertebrae at the fourth-fifth, fifth-sixth and sixth-seventh vertebral interspaces. The sacral plexus, ventrolateral to the sacrum, was identified using electrolocation. Anesthesia was monitored using heart rate (HR), invasive blood pressure, electrocardiography, expired gases, respiratory frequency and esophageal temperature by an investigator unaware of the group allocation. Pelvic limb amputation by coxofemoral disarticulation was performed. Dogs that responded to surgical stimulation (>10% increase in HR or arterial pressure) were administered fentanyl (2 μg kg-1</sup>) intravenously for rescue analgesia. Postoperative pain was assessed at extubation; 30, 60 and 120 minutes; and the morning after surgery using a visual analog scale (VAS).</AbstractText>The number of intraoperative fentanyl doses was fewer in the bupivacaine group (2.7±1.1 versus 6.0±2.2; p<0.01). Differences in physiologic variables were not clinically significant. VAS scores were lower in bupivacaine dogs at extubation (0.8±1.9 versus 3.8±2.5) and at 30 minutes (1.0±1.4 versus 4.3±2.1; p<0.05).</AbstractText>Psoas compartment (lumbar plexus) and sacral plexus block provided analgesia during pelvic limb amputation in dogs.</AbstractText>Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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Cumulative effects of single TMS pulses during beta-tACS are stimulation intensity-dependent.
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Single transcranial magnetic stimulation (TMS) pulses activate different components of the motor cortex neural circuitry in a stimulation intensity-dependent way and may lead to a cumulative increase of corticospinal excitability (CSE) during the same stimulation session. Furthermore, transcranial alternating current stimulation (tACS) has been shown to increase in a frequency-specific way the level of CSE probed by single-pulse TMS. The interaction of these two phenomena, i.e. cumulative increases and baseline shifts of CSE, and the involved neural circuitry has not been studied yet.</AbstractText>The aim of this study was to investigate stimulation intensity-specific online effects of simultaneous TMS and tACS on CSE.</AbstractText>Single-pulse TMS was applied concurrent to 20 Hz tACS over the left primary motor cortex of thirteen healthy subjects to probe CSE indexed by motor evoked potentials (MEPs) recorded from the contralateral extensor carpi radialis muscle of the right hand during rest. Six different TMS intensities (90%, 100%, 110%, 120%, 130%, and 140% of resting motor threshold, RMT) were studied in a randomized blocked design. In each block, 40 pulses were applied with an inter-stimulus interval of 5 s and a jitter of ±0.5 s, i.e. at a stimulation frequency of 0.2-0.25 Hz.</AbstractText>Beta-tACS has a general facilitatory effect on CSE across the tested TMS intensities. The results of the block wise regression of the MEP amplitudes show a more specific effect. Combining tACS and TMS leads to a cumulative increase in CSE for the stimulation intensity of 120% RMT only (p = 0.0004).</AbstractText>CSE increases due to beta-tACS and cumulative TMS pulses may be mediated by different neuronal mechanisms.</AbstractText>Copyright © 2017 Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,335,175 |
Pre- and post-exercise electrocardiogram pattern modifications in apparently healthy school adolescents in Cameroon.
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Background Physical Education and Sport (PES) is compulsory in Cameroonian education system. Cardiac accidents and sudden cardiac deaths (SCD) have been reported during PES examinations. This study aimed to contribute in the prevention of these cardiac accidents by studying pre- and post-exercise electrocardiogram (ECG) pattern modifications in apparently healthy school adolescents. Methods One hundred school adolescents without apparent heart disease [aged 18 ± 2 years; body mass index (BMI): 21.9 ± 2.3] were included. Participants performed two intermittent sprint-endurance tests. The test consisted in walking 2000 m as warm-up, followed by sprint and endurance races. A 12-leads ECG was performed before and in 5 min after the tests. ECG patterns changes were studied with particular attention to abnormalities that could be associated with risk of SCD. Results At rest, ECG patterns variants consisted of bradycardia (30%), sinus arrhythmia (9%), posterior hemi post-block (2%), and early repolarization (3%). which disappeared after exercise in all participants. QTc (ms) and heart rate (HR) increased after exercise (p < 0.001); and RR (ms) decreased post-exercise (p < 0.001). Other changes includes the appearance of the T-waves reversed in precordial leads (V2-V4) (p < 0.001), ventricular (6%), atrial and other supraventricular premature beats (2%) in the post-exercise ECG. Left ventricular hypertrophy (2%), right auricular enlargement (2%), short PR (2%) appeared at the end of the tests. Conclusion This study suggests that an intermittent exercise can induce cardiac abnormalities able to provoke cardiac accidents and SCD in apparently healthy school adolescents.
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2,335,176 |
Endogenous and Agonist-induced Opening of Mitochondrial Big Versus Small Ca2+-sensitive K+ Channels on Cardiac Cell and Mitochondrial Protection.
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Both big (BKCa) and small (SKCa) conductance Ca-sensitive K channels are present in mammalian cardiac cell mitochondria (m). We used pharmacological agonists and antagonists of BKCa and SKCa channels to examine the importance of endogenous opening of these channels and the relative contribution of either or both of these channels to protect against contractile dysfunction and reduce infarct size after ischemia reperfusion (IR) injury through a mitochondrial protective mechanism. After global cardiac IR injury of ex vivo perfused Guinea pig hearts, we found the following: both agonists NS1619 (for BKCa) and DCEB (for SKCa) improved contractility; BKCa antagonist paxilline (PAX) alone or with SKCa antagonist NS8593 worsened contractility and enhanced infarct size; both antagonists PAX and NS8593 obliterated protection by their respective agonists; BKCa and SKCa antagonists did not block protection afforded by SKCa and BKCa agonists, respectively; and all protective effects by the agonists were blocked by scavenging superoxide anions (O2) with Mn(III) tetrakis (4-benzoic acid) porphyrin (TBAP). Contractile function was inversely associated with global infarct size. In in vivo rats, infusion of NS8593, PAX, or both antagonists enhanced regional infarct size while infusion of either NS1619 or DCEB reduced infarct size. In cardiac mitochondria isolated from ex vivo hearts after IR, combined SKCa and BKCa agonists improved respiratory control index and Ca retention capacity compared with IR alone, whereas the combined antagonists did not alter respiratory control index but worsened Ca retention capacity. Although the differential protective bioenergetics effects of endogenous or exogenous BKCa and SKCa channel opening remain unclear, each channel likely responds to different sensing Ca concentrations and voltage gradients over time during oxidative stress-induced injury to individually or together protect cardiac mitochondria and myocytes.
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2,335,177 |
An evaluation of involving family caregivers in the self-care of heart failure patients on hospital readmission: Randomised controlled trial (the FAMILY study).
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The prevalence of heart failure is increasing in Lebanon but to date there is no systematic evaluation of a disease management intervention.</AbstractText>The aim of this study was to evaluate the effect of involving family caregivers in the self-care of patients with heart failure on the risk of hospital readmission.</AbstractText>A multi-site, block randomised controlled trial.</AbstractText>The study was conducted over a 13-month period in three tertiary medical centres in Beirut and Mount Lebanon, Lebanon.</AbstractText>Adult patients presenting for an exacerbation of heart failure to one of the study centres were included. Patients with limited life expectancy or physical functionality, planned cardiac bypass or valve replacement surgery, living alone or in nursing homes, or aged less than 18 years were excluded.</AbstractText>Patients allocated to the intervention group and their family caregivers were provided with a comprehensive, culturally appropriate, educational session on self-care maintenance and symptom management along with self-care resources. The usual care group received the self-care resources only. Follow-up phone calls were conducted 30days following discharge by a research assistant blinded to treatment assignment. The primary outcome was hospital readmission and the secondary outcomes were self-care, quality of life, major vascular events and healthcare utilization.</AbstractText>The final sample included 256 patients hospitalized for heart failure randomised into control (130 patients) and intervention (126 patients) groups. The mean age was 67 (SD=8)years, and the majority (55%) were male. Readmission at 30days was significantly lower in the intervention group compared to the control group (n=10, 9% vs. n=20, 19% respectively, OR=0.40, 95% CI=0.02, 0.10, p=0.02). Self-care scores improved in both groups at 30days, with a significantly larger improvement in the intervention group than the control group in the maintenance and confidence sub-scales, but not in the self-care management sub-scale. No differences were seen in quality of life scores or emergency department presentations between the groups. More patients in the control group than in the intervention group visited health care facilities (n=24, 23% vs. n=12, 11% respectively, OR=0.39, 95% CI=0.18, 0.83, p=0.01).</AbstractText>The trial results confirmed the potential of the family-centred self-care educational intervention under evaluation to reduce the risk of readmission in Lebanese patients suffering from exacerbated heart failure. Further research is needed to validate these findings with longer periods of follow-up and to identify the intervention components and intensity required to induce sustained benefits on patients' self-care management and quality of life.</AbstractText>Copyright © 2017 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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Systemic delivery of the anticancer agent arenobufagin using polymeric nanomicelles.<Pagination><StartPage>4981</StartPage><EndPage>4989</EndPage><MedlinePgn>4981-4989</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.2147/IJN.S139128</ELocationID><Abstract><AbstractText>Arenobufagin (ABG) is a major active component of toad venom, a traditional Chinese medicine used for cancer therapy. However, poor aqueous solubility limits its pharmacological studies in vivo due to administration difficulties. In this study, we aimed to develop a polymeric nanomicelle (PN) system to enhance the solubility of ABG for effective intravenous delivery. ABG-loaded PNs (ABG-PNs) were prepared with methoxy poly (ethylene glycol)-block-poly (d,l-lactic-co-glycolic acid) (mPEG-PLGA) using the solvent-diffusion technique. The obtained ABG-PNs were 105 nm in size with a small polydispersity index of 0.08. The entrapment efficiency and drug loading were 71.9% and 4.58%, respectively. Cellular uptake of ABG-PNs was controlled by specific clathrin-mediated endocytosis. In addition, ABG-PNs showed improved drug pharmacokinetics with an increased area under the curve value (a 1.73-fold increase) and a decreased elimination clearance (37.8% decrease). The nanomicelles showed increased drug concentrations in the liver and lung. In contrast, drug concentrations in both heart and brain were decreased. Moreover, the nanomicelles enhanced the anticancer effect of the pure drug probably via increased cellular uptake of drug molecules. In conclusion, the mPEG-PLGA-based nanomicelle system is a satisfactory carrier for the systemic delivery of ABG.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yuan</LastName><ForeName>Xue</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xie</LastName><ForeName>Qian</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Keyu</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Zhijie</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>International Ocular Surface Research Centre and Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dong</LastName><ForeName>Dong</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>International Ocular Surface Research Centre and Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Baojian</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>07</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>New Zealand</Country><MedlineTA>Int J Nanomedicine</MedlineTA><NlmUniqueID>101263847</NlmUniqueID><ISSNLinking>1176-9114</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002018">Bufanolides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004337">Drug Carriers</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008823">Micelles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011091">Polyesters</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C558447">methoxypolyethyleneglycol-poly(lactic-co-glycolic acid)</NameOfSubstance></Chemical><Chemical><RegistryNumber>1SIA8062RS</RegistryNumber><NameOfSubstance UI="D000077182">Polylactic Acid-Polyglycolic Acid Copolymer</NameOfSubstance></Chemical><Chemical><RegistryNumber>26009-03-0</RegistryNumber><NameOfSubstance UI="D011100">Polyglycolic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>33X04XA5AT</RegistryNumber><NameOfSubstance UI="D019344">Lactic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>3WJQ0SDW1A</RegistryNumber><NameOfSubstance UI="D011092">Polyethylene Glycols</NameOfSubstance></Chemical><Chemical><RegistryNumber>464-74-4</RegistryNumber><NameOfSubstance UI="C055393">arenobufagin</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002018" MajorTopicYN="N">Bufanolides</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName><QualifierName UI="Q000493" MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004337" MajorTopicYN="N">Drug Carriers</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016503" MajorTopicYN="N">Drug Delivery Systems</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D065546" MajorTopicYN="N">Drug Liberation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D056945" MajorTopicYN="N">Hep G2 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019344" MajorTopicYN="N">Lactic Acid</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008823" MajorTopicYN="N">Micelles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049329" MajorTopicYN="N">Nanostructures</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010316" MajorTopicYN="N">Particle Size</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011091" MajorTopicYN="N">Polyesters</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011092" MajorTopicYN="N">Polyethylene Glycols</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011100" MajorTopicYN="N">Polyglycolic Acid</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000077182" MajorTopicYN="N">Polylactic Acid-Polyglycolic Acid Copolymer</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012995" MajorTopicYN="N">Solubility</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014018" MajorTopicYN="N">Tissue Distribution</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">arenobufagin</Keyword><Keyword MajorTopicYN="N">bufanolide steroid</Keyword><Keyword MajorTopicYN="N">mPEG-PLGA</Keyword><Keyword MajorTopicYN="N">nanomicelles</Keyword></KeywordList><CoiStatement>Disclosure The authors report no conflicts of interest in this work.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>10</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28761339</ArticleId><ArticleId IdType="pmc">PMC5516778</ArticleId><ArticleId IdType="doi">10.2147/IJN.S139128</ArticleId><ArticleId IdType="pii">ijn-12-4981</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Yang Q, Zhou X, Zhang M, et al. 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Arenobufagin (ABG) is a major active component of toad venom, a traditional Chinese medicine used for cancer therapy. However, poor aqueous solubility limits its pharmacological studies in vivo due to administration difficulties. In this study, we aimed to develop a polymeric nanomicelle (PN) system to enhance the solubility of ABG for effective intravenous delivery. ABG-loaded PNs (ABG-PNs) were prepared with methoxy poly (ethylene glycol)-block-poly (d,l-lactic-co-glycolic acid) (mPEG-PLGA) using the solvent-diffusion technique. The obtained ABG-PNs were 105 nm in size with a small polydispersity index of 0.08. The entrapment efficiency and drug loading were 71.9% and 4.58%, respectively. Cellular uptake of ABG-PNs was controlled by specific clathrin-mediated endocytosis. In addition, ABG-PNs showed improved drug pharmacokinetics with an increased area under the curve value (a 1.73-fold increase) and a decreased elimination clearance (37.8% decrease). The nanomicelles showed increased drug concentrations in the liver and lung. In contrast, drug concentrations in both heart and brain were decreased. Moreover, the nanomicelles enhanced the anticancer effect of the pure drug probably via increased cellular uptake of drug molecules. In conclusion, the mPEG-PLGA-based nanomicelle system is a satisfactory carrier for the systemic delivery of ABG.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yuan</LastName><ForeName>Xue</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xie</LastName><ForeName>Qian</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Keyu</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Zhijie</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>International Ocular Surface Research Centre and Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dong</LastName><ForeName>Dong</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>International Ocular Surface Research Centre and Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Baojian</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>07</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>New Zealand</Country><MedlineTA>Int J Nanomedicine</MedlineTA><NlmUniqueID>101263847</NlmUniqueID><ISSNLinking>1176-9114</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002018">Bufanolides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004337">Drug Carriers</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008823">Micelles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011091">Polyesters</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C558447">methoxypolyethyleneglycol-poly(lactic-co-glycolic acid)</NameOfSubstance></Chemical><Chemical><RegistryNumber>1SIA8062RS</RegistryNumber><NameOfSubstance UI="D000077182">Polylactic Acid-Polyglycolic Acid Copolymer</NameOfSubstance></Chemical><Chemical><RegistryNumber>26009-03-0</RegistryNumber><NameOfSubstance UI="D011100">Polyglycolic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>33X04XA5AT</RegistryNumber><NameOfSubstance UI="D019344">Lactic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>3WJQ0SDW1A</RegistryNumber><NameOfSubstance UI="D011092">Polyethylene Glycols</NameOfSubstance></Chemical><Chemical><RegistryNumber>464-74-4</RegistryNumber><NameOfSubstance UI="C055393">arenobufagin</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002018" MajorTopicYN="N">Bufanolides</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName><QualifierName UI="Q000493" MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004337" MajorTopicYN="N">Drug Carriers</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016503" MajorTopicYN="N">Drug Delivery Systems</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D065546" MajorTopicYN="N">Drug Liberation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D056945" MajorTopicYN="N">Hep G2 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019344" MajorTopicYN="N">Lactic Acid</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008823" MajorTopicYN="N">Micelles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049329" MajorTopicYN="N">Nanostructures</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010316" MajorTopicYN="N">Particle Size</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011091" MajorTopicYN="N">Polyesters</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011092" MajorTopicYN="N">Polyethylene Glycols</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011100" MajorTopicYN="N">Polyglycolic Acid</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000077182" MajorTopicYN="N">Polylactic Acid-Polyglycolic Acid Copolymer</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012995" MajorTopicYN="N">Solubility</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014018" MajorTopicYN="N">Tissue Distribution</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">arenobufagin</Keyword><Keyword MajorTopicYN="N">bufanolide steroid</Keyword><Keyword MajorTopicYN="N">mPEG-PLGA</Keyword><Keyword MajorTopicYN="N">nanomicelles</Keyword></KeywordList><CoiStatement>Disclosure The authors report no conflicts of interest in this work.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>10</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28761339</ArticleId><ArticleId IdType="pmc">PMC5516778</ArticleId><ArticleId IdType="doi">10.2147/IJN.S139128</ArticleId><ArticleId IdType="pii">ijn-12-4981</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Yang Q, Zhou X, Zhang M, et al. 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Toxicol Lett. 2010;199:234–238.</Citation><ArticleIdList><ArticleId IdType="pubmed">20837118</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">28760938</PMID><DateRevised><Year>2019</Year><Month>11</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1524-4563</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2017</Year><Month>Jul</Month><Day>31</Day></PubDate></JournalIssue><Title>Hypertension (Dallas, Tex. : 1979)</Title><ISOAbbreviation>Hypertension</ISOAbbreviation></Journal><ArticleTitle>Vasorelaxation to the Nitroxyl Donor Isopropylamine NONOate in Resistance Arteries Does Not Require Perivascular Calcitonin Gene-Related Peptide.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">HYPERTENSIONAHA.117.09737</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1161/HYPERTENSIONAHA.117.09737</ELocationID><Abstract>Nitroxyl (HNO) donors offer considerable therapeutic potential for the treatment of hypertension-related cardiovascular disorders, particularly heart failure, as they combine an inotropic action with peripheral vasodilation. Angeli's salt is the only HNO donor whose mechanism has been studied in depth, and recently, Angeli's salt vasodilation was suggested to be indirect and caused by calcitonin gene-related peptide (CGRP) released from perivascular nerves after HNO activates TRPA1 (transient receptor potential cation channel subfamily A member 1) channels. We investigated resistance artery vasorelaxation to the HNO donor, isopropylamine NONOate (IPA/NO), one of the structures providing a template for therapeutic development. Wire myography in combination with measurements of smooth muscle membrane potential was used to characterize the effect of IPA/NO in mesenteric resistance arteries. Immunohistochemistry was assessed in pressurized arteries. IPA/NO concentration dependently hyperpolarized and relaxed arteries precontracted with the α<sub>1</sub>-adrenoreceptor agonist, phenylephrine. These effects were blocked by the soluble guanylyl cyclase inhibitor, ODQ (1<i>H</i>-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but not by the K<sub>ATP</sub> channel inhibitor, glibenclamide. Vasorelaxation persisted in the presence of raised [K<sup>+</sup>]<sub>o</sub>, used to block hyperpolarization, capsaicin to deplete perivascular CGRP, or HC030031 (2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7<i>H</i>-purin-7-yl)-<i>N</i>-(4 isopropylphenyl) acetamide) to block TRPA1 receptors. Without preconstriction, hyperpolarization to IPA/NO was suppressed by glibenclamide, capsaicin, or HC030031. Hyperpolarization but not vasorelaxation to exogenous CGRP was inhibited with glibenclamide. Thus, vascular hyperpolarization is not necessary for vasorelaxation to the HNO donor IPA/NO, even though both effects are cGMP dependent. The reduced hyperpolarization after depletion of perivascular CGRP or block of TRPA1 receptors indicates some release of CGRP, but this does not contribute to HNO vasorelaxation. Therefore, HNO-TRPA1-CGRP signaling does not seem important for vasodilation to IPA/NO in resistance arteries.
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Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B-Selective NMDA Receptor Antagonists with a Benzo[7]annulen-7-amine Scaffold.
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Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO<sub>2</sub> (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (K<sub>i</sub> =1.6-3.6 nm). Docking studies revealed the same binding poses for benzo[7]annulen-7-amines and ifenprodil at the interface of GluN1b and GluN2B subunits. The large 2-OBn moiety of 22 c occupies a previously unrecognized subpocket, which explains its high GluN2B affinity (K<sub>i</sub> =3.6 nm). In two-electrode voltage clamp experiments and cytoprotection assays, the high-affinity GluN2B ligands 7 c, 15 c, and 22 c could not inhibit the glutamate-/glycine-evoked current and cytotoxic effects. However, the analogous phenols 16 c ((3-phenylpropyl)amino moiety) and 16 d ((4-phenylbutyl)amino moiety) with 10-fold lower GluN2B affinity (K<sub>i</sub> =28 and 21 nm, respectively) showed promising inhibition of glutamate-/glycine-evoked effects in both assays. The presence of a phenolic hydroxy group seems to be essential for inducing conformational changes of the receptor protein, which finally results in closure of the ion conduction pathway.
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2,335,180 |
A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure.
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Endoplasmic reticulum stress is an evolutionarily conserved cell stress response associated with numerous diseases, including cardiac hypertrophy and heart failure. The major endoplasmic reticulum stress signaling pathway causing cardiac hypertrophy involves endoplasmic reticulum stress sensor PERK (protein kinase-like kinase) and eIF2α-ATF4-CHOP signaling. Here, we describe a non-canonical, AGGF1-mediated regulatory system for endoplasmic reticulum stress signaling associated with increased p-eIF2α and ATF4 and decreased sXBP1 and CHOP. Specifically, we see a reduced AGGF1 level consistently associated with induction of endoplasmic reticulum stress signaling in mouse models and human patients with heart failure. Mechanistically, AGGF1 regulates endoplasmic reticulum stress signaling by inhibiting ERK1/2 activation, which reduces the level of transcriptional repressor ZEB1, leading to induced expression of miR-183-5p. miR-183-5p post-transcriptionally downregulates CHOP and inhibits endoplasmic reticulum stress-induced apoptosis. AGGF1 protein therapy and miR-183-5p regulate endoplasmic reticulum stress signaling and block endoplasmic reticulum stress-induced apoptosis, cardiac hypertrophy, and heart failure, providing an attractive paradigm for treatment of cardiac hypertrophy and heart failure.Endoplasmic reticulum (ER) stress promotes cardiac dysfunction. Here the authors uncover a pathway whereby AGGF1 blocks ER stress by inhibiting ERK1/2 activation and the transcriptional repressor ZEB1, leading to induction of miR-183-5p and down-regulation of CHOP, and show that AGGF1 can effectively treat cardiac hypertrophy and heart failure.
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2,335,181 |
Using Planar Phi29 pRNA Three-Way Junction to Control Size and Shape of RNA Nanoparticles for Biodistribution Profiling in Mice.
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RNA is rapidly emerging as a versatile building block for nanoparticle assembly due to its simplicity in base pairing, while exhibiting diversity in function such as enzymatic activity similar to some proteins. Recent advances in RNA nanotechnology have generated significant interests in applying RNA nanoparticles for various applications in nanotechnology and nanomedicine. In particular, assessing the effect of size and shape on cell entry and intracellular trafficking as well as in vivo biodistribution of nanoparticles is challenging due to the lack of nanoparticles rich in structure while varying in size and shape. RNA nanotechnology exemplified by the packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor has provided a different prospect in nanoparticle designs. Of note, there is a robust three-way junction (3WJ) motif in pRNA which can serve as an adaptable scaffold to construct thermodynamically stable 2D planar and 3D globular RNA architectures with tunable shapes and sizes, and harboring various targeting, therapeutic, and imaging modules. This chapter focuses on the methods for constructing pRNA-3WJ based nanoparticles with controllable sizes and shapes, and assessment of their biodistribution profiles in cancer mouse models after systemic injection and ocular mouse models following subconjunctival injection.
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2,335,182 |
Comparison of the release of microRNAs and extracellular vesicles from platelets in response to different agonists.
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On activation platelets release microRNAs and extracellular vesicles (EV) into circulation. The release of EV from platelets has been shown to be dependent on the agonist; in this study, we investigated whether the microRNA profile or EV released from platelets was also agonist specific. Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (Glycoprotein VI (GPVI)), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block cyclooxygenase-1 and apyrase to remove ADP. The released microRNAs were profiled using TaqMan microRNA microarray cards. Platelet-derived EV (pdEV) were characterized by size (Nanoparticle Tracking Analysis, NTA), for procoagulant activity (Annexin-V binding and support of thrombin generation), and for the EV markers CD63 and HSP70. Platelet activation triggered the release of 57-79 different microRNAs, dependent upon agonist, with a core of 46 microRNAs observed with all agonists. There was a high level of correlation between agonists (r<sup>2</sup> > 0.98; p < 0.0001 for all), and with the microRNA content of the parent platelets (r<sup>2</sup> > 0.98; p < 0.0001). The 46 microRNAs seen in all samples are predicted to have significant effects on the translation of proteins involved in endocytosis, cell cycle control, and differentiation. MiR-223-3p was the most abundant in all samples and has previously been implicated in myeloid lineage development and demonstrated to have anti-inflammatory effects. Stimulation through GPVI produced a pdEV population with significantly more procoagulant activity than the other agonists. Apyrase significantly reduced microRNA and pdEV release, while aspirin had little effect. These data suggest that all tested agonists trigger the release of a similar microRNA profile while the procoagulant activity of the pdEV was agonist dependent. ADP was shown to play an important role in the release of both microRNAs and pdEV.
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2,335,183 |
Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes.
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Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an attractive novel therapeutic option for the treatment of type 2 diabetes. They block the reabsorption of filtered glucose in kidneys, mainly in proximal renal tubules, resulting in increased urinary glucose excretion and correction of the diabetes-related hyperglycemia. Beyond improving glucose control, SGLT2 inhibitors offer potential benefits by reducing body weight and blood pressure. On the basis of the efficacy demonstrated in clinical trials, SGLT2 inhibitors are recommended as second- or third-line agents for the management of patients with type 2 diabetes. Beneficial effects on kidney disease progression, cardiovascular and all-cause mortality, and hospitalization for heart failure have also been demonstrated with one SGLT2 inhibitor (empagliflozin). Potential adverse events resulting from their mechanism of action or related to concomitant therapies are reviewed. A treatment algorithm for the adjustment of concomitant therapies after initiating SGLT2 inhibitors is also proposed.
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2,335,184 |
Clinical and pathologic implications of extending the spectrum of maternal autoantibodies reactive with ribonucleoproteins associated with cutaneous and now cardiac neonatal lupus from SSA/Ro and SSB/La to U1RNP.
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While the relationship between maternal connective tissue diseases and neonatal rashes was described in the 1960s and congenital heart block in the 1970s, the "culprit" antibody reactivity to the SSA/Ro-SSB/La ribonucleoprotein complex was not identified until the 1980s. However, studies have shown that approximately 10-15% of cases of congenital heart block are not exposed to anti-SSA/Ro-SSB/La. Whether those cases represent a different disease entity or whether another antibody is associated has yet to be determined. Moreover, the cutaneous manifestations of neonatal lupus have also been identified in infants exposed only to anti-U1RNP antibodies. In this review, we describe what we believe to be the first case of congenital heart block exposed to maternal anti-U1RNP antibodies absent anti-SSA/Ro-SSB/La. The clinical and pathologic characteristics of this fetus are compared to those typically seen associated with SSA/Ro and SSB/La. Current guidelines for fetal surveillance are reviewed and the potential impact conferred by this case is evaluated.
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2,335,185 |
Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference.
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Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled "Challenges in the Conduct of Clinical Trials in Nephrology" to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.
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2,335,186 |
The DNA damage response pathway in normal hematopoiesis and malignancies.
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In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations. Besides favoring tumor formation and progression, molecular defects that directly or indirectly inactivate certain DDR pathways can provide a therapeutic opportunity, since a reduced ability to repair DNA lesions renders hemopoietic malignancies vulnerable to genotoxic drugs acting also through synthetic lethal interactions. Here, we discuss the essential role of DDR in HSC maintenance and protection against leukemogenesis, and how acquired DDR dysfunctions or pharmacological agents that block this pathway can be effectively exploited for the treatment of various hematopoietic malignancies.
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2,335,187 |
Pathway analysis of systemic transcriptome responses to injected polystyrene particles in zebrafish larvae.
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Microplastics are a contaminant of emergent concern in the environment, however, to date there is a limited understanding on their movement within organisms and the response of organisms. In the current study zebrafish embryos at different development stages were exposed to 700nm fluorescent polystyrene (PS) particles and the response pathway after exposure was investigated using imaging and transcriptomics. Our results show limited spreading of particles within the larvae after injection during the blastula stage. This is in contrast to injection of PS particles in the yolk of 2-day old embryos, which resulted in redistribution of the PS particles throughout the bloodstream, and accumulation in the heart region. Although injection was local, the transcriptome profiling showed strong responses of zebrafish embryos exposed to PS particle, indicating a systemic response. We found several biological pathways activated which are related to an immune response in the PS exposed zebrafish larvae. Most notably the complement system was enriched as indicated by upregulation of genes in the alternative complement pathway (e.g. cfhl3, cfhl4, cfb and c9). The fact that complement pathway is activated indicates that plastic microparticles are integrated in immunological recognition processes. This was supported by fluorescence microscopy results, in which we observed co-localisation of neutrophils and macrophages around the PS particles. Identifying these key events can be a first building block to the development of an adverse outcome pathway (AOP). These data subsequently can be used within ecological and human risk assessment.
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2,335,188 |
Phase transitions during compression and decompression of clots from platelet-poor plasma, platelet-rich plasma and whole blood.
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Blood clots are required to stem bleeding and are subject to a variety of stresses, but they can also block blood vessels and cause heart attacks and ischemic strokes. We measured the compressive response of human platelet-poor plasma (PPP) clots, platelet-rich plasma (PRP) clots and whole blood clots and correlated these measurements with confocal and scanning electron microscopy to track changes in clot structure. Stress-strain curves revealed four characteristic regions, for compression-decompression: (1) linear elastic region; (2) upper plateau or softening region; (3) non-linear elastic region or re-stretching of the network; (4) lower plateau in which dissociation of some newly made connections occurs. Our experiments revealed that compression proceeds by the passage of a phase boundary through the clot separating rarefied and densified phases. This observation motivates a model of fibrin mechanics based on the continuum theory of phase transitions, which accounts for the pre-stress caused by platelets, the adhesion of fibrin fibers in the densified phase, the compression of red blood cells (RBCs), and the pumping of liquids through the clot during compression/decompression. Our experiments and theory provide insights into the mechanical behavior of blood clots that could have implications clinically and in the design of fibrin-based biomaterials.</AbstractText>The objective of this paper is to measure and mathematically model the compression behavior of various human blood clots. We show by a combination of confocal and scanning electron microscopy that compression proceeds by the passage of a front through the sample that separates a densified region of the clot from a rarefied region, and that the compression/decompression response is reversible with hysteresis. These observations form the basis of a model for the compression response of clots based on the continuum theory of phase transitions. Our studies may reveal how clot rheology under large compression in vivo due to muscle contraction, platelet retraction and hydrodynamic flow varies under various pathophysiological conditions and could inform the design of fibrin based biomaterials.</AbstractText>Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,335,189 |
Mathematical modelling of the maternal cardiovascular system in the three stages of pregnancy.
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In this study, a mathematical model of the female circulation during pregnancy is presented in order to investigate the hemodynamic response to the cardiovascular changes associated with each trimester of pregnancy. First, a preliminary lumped parameter model of the circulation of a non-pregnant female was developed, including the heart, the systemic circulation with a specific block for the uterine district and the pulmonary circulation. The model was first tested at rest; then heart rate and vascular resistances were individually varied to verify the correct response to parameter alterations characterising pregnancy. In order to simulate hemodynamics during pregnancy at each trimester, the main changes applied to the model consisted in reducing vascular resistances, and simultaneously increasing heart rate and ventricular wall volumes. Overall, reasonable agreement was found between model outputs and in vivo data, with the trends of the cardiac hemodynamic quantities suggesting correct response of the heart model throughout pregnancy. Results were reported for uterine hemodynamics, with flow tracings resembling typical Doppler velocity waveforms at each stage, including pulsatility indexes. Such a model may be used to explore the changes that happen during pregnancy in female with cardiovascular diseases.
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2,335,190 |
Clinical effects of long-term cardiac contractility modulation (CCM) in subjects with heart failure caused by left ventricular systolic dysfunction.<Pagination><StartPage>893</StartPage><EndPage>904</EndPage><MedlinePgn>893-904</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1007/s00392-017-1135-9</ELocationID><Abstract><AbstractText Label="INTRODUCTION" NlmCategory="BACKGROUND">Heart failure is a major cause of morbidity and mortality throughout the world. Despite advances in therapy, nearly half of patients receiving guideline-directed medical therapy remain limited by symptoms. Cardiac contractility modulation (CCM) can improve symptoms in this population, but efficacy and safety in prospective studies has been limited to 12 months of follow-up. We report on the first 2 year multi-site evaluation of CCM in patients with heart failure.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">One hundred and forty-three subjects with heart failure and reduced ejection fraction were followed via clinical registry for 24 months recording NYHA class, MLWHFQ score, 6 min walk distance, LVEF, and peak VO<sub>2</sub> at baseline and 6 month intervals as clinically indicated. Serious adverse events, and all cause as well as cardiovascular mortality were recorded. Data are presented stratified by LVEF (all subjects, LVEF <35%, LVEF ≥35%).</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">One hundred and six subjects from 24 sites completed the 24 month follow-up. Baseline parameters were similar among LVEF groups. NYHA and MLWHFQ improved in all 3 groups at each time point. LVEF in the entire cohort improved 2.5, 2.9, 5.0, and 4.9% at 6, 12, 18, and 24 months, respectively. Insufficient numbers of subjects had follow-up data for 6 min walk or peak VO<sub>2</sub> assessment, precluding comparative analysis. Serious adverse events (n = 193) were observed in 91 subjects and similarly distributed between groups with LVEF <35% and LVEF ≥35%, and similar to other device trials for heart failure. Eighteen deaths (7 cardiovascularly related) over 2 years. Overall survival at 2 years was 86.4% (95% confidence intervals: 79.3, 91.2%).</AbstractText><AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">Cardiac contractility modulation provides safe and effective long-term symptomatic and functional improvement in heart failure. These benefits were independent of baseline LVEF and were associated with a safety profile similar to published device trials.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Müller</LastName><ForeName>D</ForeName><Initials>D</Initials><Identifier Source="ORCID">0000-0003-2814-7867</Identifier><AffiliationInfo><Affiliation>Heart and Vascular Center (HGZ), Bad Bevensen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Remppis</LastName><ForeName>A</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Heart and Vascular Center (HGZ), Bad Bevensen, Germany. [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schauerte</LastName><ForeName>P</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>University Hospital Aachen RWTH, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schmidt-Schweda</LastName><ForeName>S</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Georg August University of Gottingen, Gottingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Burkhoff</LastName><ForeName>D</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Columbia University, New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rousso</LastName><ForeName>B</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Impulse Dynamics, Hod Hasharon, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gutterman</LastName><ForeName>D</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Medical College of Wisconsin, Milwaukee, WI, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Senges</LastName><ForeName>J</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Institut für Herzinfarktforschung, Ludwigshafen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hindricks</LastName><ForeName>G</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Heart Center Leipzig, Leipzig, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kuck</LastName><ForeName>K-H</ForeName><Initials>KH</Initials><AffiliationInfo><Affiliation>Asklepios Klinik St. Georg, Hamburg, Germany.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016448">Multicenter Study</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>07</Month><Day>06</Day></ArticleDate></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Clin Res Cardiol</MedlineTA><NlmUniqueID>101264123</NlmUniqueID><ISSNLinking>1861-0684</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002304" MajorTopicYN="Y">Cardiac Pacing, Artificial</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002423" MajorTopicYN="N">Cause of Death</DescriptorName><QualifierName UI="Q000639" MajorTopicYN="N">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017079" MajorTopicYN="Y">Exercise Tolerance</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005500" MajorTopicYN="N">Follow-Up Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005858" MajorTopicYN="N">Germany</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006333" MajorTopicYN="N">Heart Failure</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName><QualifierName UI="Q000401" MajorTopicYN="N">mortality</QualifierName><QualifierName UI="Q000503" MajorTopicYN="Y">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007557" MajorTopicYN="N">Israel</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009200" MajorTopicYN="N">Myocardial Contraction</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011446" MajorTopicYN="N">Prospective Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011788" MajorTopicYN="N">Quality of Life</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013318" MajorTopicYN="N">Stroke Volume</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015996" MajorTopicYN="N">Survival Rate</DescriptorName><QualifierName UI="Q000639" MajorTopicYN="N">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013997" MajorTopicYN="N">Time Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016896" MajorTopicYN="N">Treatment Outcome</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014481" MajorTopicYN="N">United States</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018487" MajorTopicYN="N">Ventricular Dysfunction, Left</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="Y">complications</QualifierName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016277" MajorTopicYN="N">Ventricular Function, Left</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">CCM</Keyword><Keyword MajorTopicYN="N">Clinical</Keyword><Keyword MajorTopicYN="N">Electrical stimulation</Keyword><Keyword MajorTopicYN="N">Heart failure</Keyword><Keyword MajorTopicYN="N">Human</Keyword><Keyword MajorTopicYN="N">LVEF</Keyword><Keyword MajorTopicYN="N">MLWHFQ</Keyword><Keyword MajorTopicYN="N">NYHA</Keyword><Keyword MajorTopicYN="N">Registry</Keyword><Keyword MajorTopicYN="N">Survival</Keyword></KeywordList><CoiStatement>DISCLOSURES: Rousso is employed by Impulse Dynamics, Burkhoff and Gutterman are consults for Impulse Dynamics. Support for this study was provided by Impulse Dynamics. INFORMED CONSENT: All subject provided informed consent. Participating investigators and associated clinical research sites in Germany include: C Restle, C Menz, J Stockinger—Bad Krozingen; Sperzel J, Bruder O, Blank E, Waidelich L, Keinhorst J, Reuter V, Schmitz D, Steffen M—Essen; Frommhold M, Meiland R, Wagner A—Bad Berka; Muller S, Schmidt-Schweda S—Worbis; Schmidt T, Scholl C, Obergfoll M—Heilbronn; Bucholz M, Gebhardt S, Spencker S, Atmowihardjo I, Forster S, Szczesnlak S, Stoeckicht Y, Huseyin I—Berlin; Reith S, Zink M, Heuer G—Aachen; Hohn A, Schwartzmann L, Hornlein C, Schertel-Grunler B, Brachmann J, Denninger P—Coburg; Siems M,Latzko C, Müller D, Nickling E—Bad Bevensen; Maroto Y Jarvinen S, Block M, von Bodman G—Munchen; Beauport J, Hofmann W, Antz M—Oldenburg; Zander-Wiegmann M, Bittlinsky A, Prull M—Herne; Andreas K, Przibille O—Frankfurt; Frohlich-Grimm F, Danschel W—Chemnitz; Aydin A, Wilke I, Schnapp A—Reinbek; Haacke K, Gunther M—Dresden; Mletzko R—Hamburg; Karosiene Z, Bernard L, Willms-Weirich N—Ludenscheid; Brilla K, Minden H—Hennigsdorf; Over M, Hugl B, Findeisen Z, Haufe A, Wessling P—Neuwied.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>12</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>6</Month><Day>30</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>7</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2018</Year><Month>9</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>7</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28685207</ArticleId><ArticleId IdType="pmc">PMC5655601</ArticleId><ArticleId IdType="doi">10.1007/s00392-017-1135-9</ArticleId><ArticleId IdType="pii">10.1007/s00392-017-1135-9</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M and Document R (2016) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. 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Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration. Heart rhythm: Off J Heart Rhythm Soc. 2006;3:1140–1147. doi: 10.1016/j.hrthm.2006.06.031.</Citation><ArticleIdList><ArticleId IdType="doi">10.1016/j.hrthm.2006.06.031</ArticleId><ArticleId IdType="pubmed">17018340</ArticleId></ArticleIdList></Reference><Reference><Citation>Nagele H, Behrens S, Eisermann C. Cardiac contractility modulation in non-responders to cardiac resynchronization therapy. Eur: Eur Pacing, Arrhythm Card Electrophysiol: J Work Groups Card Pacing, Arrhythm, Card Cell Electrophysiol Eur Soc Cardiol. 2008;10:1375–1380.</Citation><ArticleIdList><ArticleId IdType="pubmed">18776196</ArticleId></ArticleIdList></Reference><Reference><Citation>Salama G, Kanai A, Efimov IR. Subthreshold stimulation of Purkinje fibers interrupts ventricular tachycardia in intact hearts. Experimental study with voltage-sensitive dyes and imaging techniques. Circ Res. 1994;74:604–619. doi: 10.1161/01.RES.74.4.604.</Citation><ArticleIdList><ArticleId IdType="doi">10.1161/01.RES.74.4.604</ArticleId><ArticleId IdType="pubmed">8137497</ArticleId></ArticleIdList></Reference><Reference><Citation>Lawo T, Borggrefe M, Butter C, Hindricks G, Schmidinger H, Mika Y, Burkhoff D, Pappone C, Sabbah HN. Electrical signals applied during the absolute refractory period: an investigational treatment for advanced heart failure in patients with normal QRS duration. J Am Coll Cardiol. 2005;46:2229–2236. doi: 10.1016/j.jacc.2005.05.093.</Citation><ArticleIdList><ArticleId IdType="doi">10.1016/j.jacc.2005.05.093</ArticleId><ArticleId IdType="pubmed">16360051</ArticleId></ArticleIdList></Reference><Reference><Citation>Fichtner S, Senges J, Hochadel M, Tilz R, Willems S, Eckardt L, Deneke T, Lewalter T, Dorwarth U, Reithmann C, Brachmann J, Steinbeck G, Kaab S, German Ablation R. Safety and efficacy in ablation of premature ventricular contraction: data from the German ablation registry. Clin Res Cardiol. 2017;106:49–57. doi: 10.1007/s00392-016-1022-9.</Citation><ArticleIdList><ArticleId IdType="doi">10.1007/s00392-016-1022-9</ArticleId><ArticleId IdType="pubmed">27484499</ArticleId></ArticleIdList></Reference><Reference><Citation>Hurlimann D, Schmidt S, Seifert B, Saguner AM, Hindricks G, Luscher TF, Ruschitzka F, Steffel J. Outcome of super-responders to cardiac resynchronization therapy defined by endpoint-derived parameters of left ventricular remodeling: a two-center retrospective study. Clin Res Cardiol. 2015;104:136–144. doi: 10.1007/s00392-014-0763-6.</Citation><ArticleIdList><ArticleId IdType="doi">10.1007/s00392-014-0763-6</ArticleId><ArticleId IdType="pubmed">25301085</ArticleId></ArticleIdList></Reference><Reference><Citation>Oldenburg O, Spiesshofer J, Fox H, Bitter T, Horstkotte D. Cheyne-Stokes respiration in heart failure: friend or foe? Hemodynamic effects of hyperventilation in heart failure patients and healthy volunteers. Clin Res Cardiol. 2015;104:328–333. doi: 10.1007/s00392-014-0784-1.</Citation><ArticleIdList><ArticleId IdType="doi">10.1007/s00392-014-0784-1</ArticleId><ArticleId IdType="pubmed">25373383</ArticleId></ArticleIdList></Reference><Reference><Citation>Poss J, Ukena C, Kindermann I, Ehrlich P, Fuernau G, Ewen S, Mahfoud F, Kriechbaum S, Bohm M, Link A. Angiopoietin-2 and outcome in patients with acute decompensated heart failure. Clin Res Cardiol. 2015;104:380–387. doi: 10.1007/s00392-014-0787-y.</Citation><ArticleIdList><ArticleId IdType="doi">10.1007/s00392-014-0787-y</ArticleId><ArticleId IdType="pubmed">25408112</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedBookArticle><BookDocument><PMID Version="1">31643610</PMID><ArticleIdList><ArticleId IdType="bookaccession">NBK548287</ArticleId></ArticleIdList><Book><Publisher><PublisherName>National Institute of Diabetes and Digestive and Kidney Diseases</PublisherName><PublisherLocation>Bethesda (MD)</PublisherLocation></Publisher><BookTitle book="livertox">LiverTox: Clinical and Research Information on Drug-Induced Liver Injury</BookTitle><PubDate><Year>2012</Year></PubDate><BeginningDate><Year>2012</Year></BeginningDate><Medium>Internet</Medium></Book><ArticleTitle book="livertox" part="Anticholinergics">Anticholinergic Agents
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Anticholinergics are agents that decrease or block the actions of acetylcholine on its parasympathetic nervous system receptors on smooth muscle cells, glands and the central nervous system. Cholinergic receptors are usually categorized as nicotinic or muscarinic. Anticholinergics often demonstrate differential antagonism for different receptors types and subtypes, accounting in part for their variety of actions and clinical usefulness for different conditions. The anticholinergics in clinical use include natural, semisynthetic and synthetic compounds that demonstrate a multitude of actions on smooth muscle cells and the parasympathetic nervous system. Anticholinergics have antisecretory activities and decrease nasal and bronchial secretions, salivation, lacrimation, sweating and gastric acid production, and can be used to decrease secretions in allergic and inflammatory diseases. Anticholinergics relax smooth muscle in the gastrointestinal tract, bladder and lung and can be used for gastrointestinal, urological or respiratory conditions associated with spasm and dysmotility. Some anticholinergics have antiemetic properties and are used to prevent nausea and vomiting from motion sickness or during the perioperative period. Anticholinergics increase heart rate and can be used to treat bradycardia. They are also used to reverse cholinergic overstimulation caused by cholinesterase inhibitors and neuromuscular blockers in anesthesia. The common side effects of anticholinergic agents are largely those of parasympathetic stimulation and include dryness of the mouth and eyes, decreased sweating and hyperthermia, headache, visual blurring, constipation, urinary retention, impotence, tachycardia and palpitations, anxiety, restlessness and in some instances agitation and delusions. Anticholinergics rarely cause liver injury. Their relative safety probably relates to their use in low doses for short periods of time only. Most anticholinergics are metabolized in the liver via the cytochrome P450 system.
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2,335,191 |
Bilateral thoracic Paravertebral block for immediate postoperative pain relief in the PACU: a prospective, observational study.
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To investigate the feasibility, effectiveness and safety of bilateral thoracic paravertebral block (TPVB) in the post anesthesia care unit (PACU) for pain relief in participants after laparotomy.</AbstractText>A single shot of bilateral TPVB with 25 ml of 0.2% ropivacaine and 5 mg dexamethasone in combination for both sides at the 8th thoracic transverse level (T8) was performed on 201 participants who complained moderate to severe pain on arrival to PACU after laparotomy. The visual analog scale (VAS) pain scores at rest and on cough, heart rate, blood pressure, and pulse oximetry before and after bilateral TPVB for up to 1 h were recorded. The VAS Pain scores at rest and on cough at 24 h after bilateral TPVB were also recorded.</AbstractText>Bilateral TPVB was carried out successfully in all participants. The VAS pain scores at rest and on cough were 7.9 ± 1.6 and 8.7 ± 1.3 respectively pre-bilateral TPVB. The VAS pain scores at rest and on cough were significantly decreased to 1.1 ± 1.2 and 2.1 ± 1.6 respectively (P < 0.001) at 60 min after bilateral TPVB and to 2.1 ± 1.7 and 3.8 ± 1.9 at rest and on cough respectively ((P < 0.001) at 24 h after bilateral TPVB. At 10 min post-bilateral TPVB, only systolic blood pressure was reduced from 122 ± 19 mmHg to 111 ± 18 mmHg (P = 0.007) but then gradually became stable. No complications related to bilateral TPVB were observed.</AbstractText>Bilateral TPVB can be provided for pain relief to the participants who suffer from moderate to severe pain after upper laparotomy in the PACU.</AbstractText>Chinese Clinical Trial Registry: ChiCTR-ONN-16009229 , Registered on 10 September 2016.</AbstractText>
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2,335,192 |
Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury.
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This study aimed to investigate the effects of regulating autonomic nervous system (ANS) homeostasis by inhibiting sympathetic hyperactivity and/or enhancing parasympathetic activity on pulmonary inflammation and functional disturbance.</AbstractText>An animal model of acute lung injury (ALI) was established in rabbits by an intratracheal injection of hydrochloric acid (HCl) in rabbits. Animals in control groups were received saline or HCl only, and the others received both HCl and followed treatments: vagus nerve stimulation (VNS), intravenous injection of tetrahydroaminoacridine (THA), or stellate ganglion block (SGB). The effects of different treatments on the changes in autonomic nervous system homeostasis, pulmonary and systemic inflammation, and functional disturbance were detected.</AbstractText>Sympathetic nervous activity was higher than parasympathetic nervous activity in rabbits after HCl aspiration, as demonstrated by the significant changes in the discharge frequency of cervical sympathetic/vagus trunk, and heart rate variability. VNS, THA and SGB could significantly alleviate the changes of ANS induced by HCl aspiration and improved the pulmonary function, especially for SGB treatment.</AbstractText>The disturbance of ANS homeostasis is attributed to a predominance of SNS activity. Administration of VNS, THA and SGB are capable to regulate disequilibrium of the ANS in rabbits with HCl-induced ALI and SGB is supposed to be the most effective approach.</AbstractText>
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2,335,193 |
[Effects of different doses of dexmedetomidine combined with ropivacaine for brachial plexus nerve block in children undergoing polydactyly surgery].
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To observe the anesthetic effect and safety of different doses of dexmedetomidine combined with ropivacaine for brachial plexus nerve block in children undergoing polydactyly surgery.</AbstractText>Eighty children undergoing polydactyly surgery were randomized into 4 groups to receive brachial plexus nerve block with dexmedetomidine at 0.25, 0.50 or 0.75 µg/kg combined with 0.25% ropivacaine (0.20 mL/kg) (D1, D2, and D3 groups, respectively) or with 0.25% ropivacaine (0.20 mL/kg) only (control group). The onset time, duration of brachial plexus nerve block, awakening time, success rate, and incidence of complications were compared among the groups. Results In D2 and D3 groups, the onset time and awakening time were shorter and anesthesia lasted longer than those in the control group. The onset time and awakening time were shorter and anesthesia maintenance time was longer in D3 group than in D1 group. The success rates of brachial plexus nerve block were significantly higher in D1-3 groups than in the control group (P<0.05). Hematoma was found in one of the patients. In each of the 4 groups, laryngeal nerve block occurred in 1 child and respiratory depression in another; 2 or 3 patients had Horner syndrome, and 1 patient in D3 group experienced an episode of lowered heart beat to below 70 min-1</sup>. All the complications were managed properly and the patients all recovered uneventfully.</AbstractText>Brachial plexus nerve block with 0.5 µg/kg dexmedetomidine combined with 0.25% ropivacaine (0.20 mL/kg) is safe for effective anesthesia in children undergoing surgery for polydactyly.</AbstractText>
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2,335,194 |
Comparing the Efficacy of Caudal with Intravenous Dexamethasone in the Management of Pain Following Lumbosacral Spine Surgeries: A Randomized Double Blinded Controlled Study.
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The challenge in providing analgesia for spine surgeries is to provide extended postoperative pain relief and simultaneously allow early neurological assessment and mobilization. Our study aimed to evaluate the analgesic efficacy of intravenous versus caudal dexamethasone in lumbosacral spine surgeries.</AbstractText>In this prospective double-blind study, a total of 96 patients undergoing lumbosacral spine surgery were randomized into three groups to receive 25 ml of preemptive caudal epidural injection of either injection ropivacaine 0.2% (Group A, n</i> = 32), a 25 ml of injection ropivacaine 0.2%, and intravenous injection dexamethasone 8 mg (Group B, n</i> = 32) or 25 ml mixture of injection ropivacaine 0.2% with injection dexamethasone 8 mg (Group C, n</i> = 32) under general anesthesia. Visual analog scale (VAS), heart rate, blood pressures, blood sugar levels, and time to rescue analgesia were recorded at regular intervals for the first 24 h. Time to discharge was noted. Analysis of variance has been used to find the significance of study parameters between the groups of patients. Statistical software, namely, SAS 9.2 and SPSS 15.0, have been used for the analysis of the data.</AbstractText>The mean VAS was significantly lower in the Group C for up to 24 h following the caudal block. No significant hemodynamic changes were noted in any of the groups. The intravenous dexamethasone group showed higher blood glucose levels at 24 h but was not clinically relevant.</AbstractText>These results suggest that injection dexamethasone is a safe adjunct to caudal ropivacaine in lumbosacral spine surgeries.</AbstractText>
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2,335,195 |
Comparison of Epidural Butorphanol with Neostigmine and Epidural Sufentanyl with Neostigmine for First Stage of Labor Analgesia: A Randomized Controlled Trial.
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Epidural administration of neostigmine appears to be safe in the obstetric population. Recently, few studies have concluded 10 μg sufentanil to be an effective adjuvant with epidural neostigmine in providing labor analgesia. However, no study has evaluated the analgesic effect of epidural butorphanol with neostigmine for the same.</AbstractText>The parturients were randomly allocated to one of the three study groups - Group A (n</i> = 30) received butorphanol 1 mg and neostigmine 7 μg/kg. Group B (n</i> = 30) received sufentanil 10 μg and neostigmine 7 μg/kg. Group C (n</i> = 30) received neostigmine 7 μg/kg and 0.9% normal saline. Maternal hemodynamic parameters and fetal heart rate (FHR) were continuously monitored. The level of sensory and motor block, and visual analog scale (VAS) pain score were recorded at designated time points. In addition, the total duration of analgesia, duration of labor, mode of delivery, and any maternal or fetal adverse effects were also recorded.</AbstractText>A one-way analysis of variance (ANOVA) with post hoc</i> Tukey's test was used to compare mean value among the three groups for age, height, weight, gestational age, and cervical dilatation. Repeated measure ANOVA was used to compare mean difference among the time points and also the trend among the various time points for hemodynamic parameters, VAS pain score, and FHR. For inter-group comparison among the groups, post hoc</i> Tukey test was used.</AbstractText>There was a statistically significant longer effect of analgesic drug in Group B with respect to Group A and C (P</i> < 0.001); however, the parturient in Group C had minimum duration of analgesia. Epidural neostigmine combined with sufentanil produces effective analgesia in early labor (VAS <30 within 10 min in 63.3% of parturient and within 15 min in 83.3% parturient) with average duration of 111.67 ± 24.51 min without motor block or other side effect in mother and fetus. No significant effect was observed in the duration of labor and mode of delivery in-between the two groups, and none of the patients in any group had any maternal or fetal side effects.</AbstractText>Epidural combination of sufentanil with neostigmine provided better pain relief in terms of the total duration of analgesia and the reduction in VAS pain scores at various time points in the initial 30 min of epidural administration of drugs during the first stage of labor in parturient when compared to the epidural combination of butorphanol with neostigmine.</AbstractText>
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2,335,196 |
Comparison between Epidural Ropivacaine versus Ropivacaine with Clonidine in Patients Undergoing Abdominal Hysterectomy: A Randomized Study.
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Regional anesthesia has emerged as one of the preferred and convenient modes for intra- and post-operative management owing to its advantage of not interfering with the metabolic functions, better tolerability, and decrease in reflex activity. In recent years, ropivacaine has increasingly replaced bupivacaine as a preferred local anesthetic because of its similar analgesic properties, lesser motor blockade, and decreased propensity of cardiotoxicity. Neuraxial adjuvant such as clonidine used in epidural anesthesia offers advantage by augmenting the local anesthetic effect and reducing the anesthetic and analgesic requirement.</AbstractText>Comparison of onset, duration of sensory and motor block, and any adverse effects between 0.5% ropivacaine with normal saline versus 0.5% ropivacaine with clonidine (75 μg/kg).</AbstractText>This prospective randomized study was carried out in 50 patients (25 in each group) of American Society of Anesthesiologist Grade 1 and 2 scheduled for abdominal hysterectomy under epidural block. Group-1 (ropivacaine-clonidine [RC]): Epidural ropivacaine 20 ml (0.5%) with 0.75 μg/kg clonidine. Group-2 (ropivacaine [R]): Epidural ropivacaine 20 ml (0.5%) with normal saline. Onset, duration of sensory-motor block, heart rate, blood pressure, oxygen saturation, and respiratory rate were recorded.</AbstractText>The statistical analysis was done using Statistical Package for Social Sciences version 15.0. Chi-square test, ANOVA, Student's t</i>-test, and paired t</i>-test were used.</AbstractText>Groups were comparable with regard to demographic data and hemodynamic stability. Onset of sensory and motor blockade was faster in RC group as compared to R group. Duration of postoperative analgesia was significantly prolonged in RC group. No potential side effect was seen in either group.</AbstractText>On account of faster onset, hemodynamic stability, and prolonged postoperative analgesia, ropivacaine with clonidine is a better option than ropivacaine alone.</AbstractText>
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2,335,197 |
No Additional Benefits of Block- Over Evenly-Distributed High-Intensity Interval Training within a Polarized Microcycle.
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<b>Introduction:</b> The current study aimed to investigate the responses to block- versus evenly-distributed high-intensity interval training (HIT) within a polarized microcycle. <b>Methods:</b> Twenty well-trained junior cross-country skiers (10 males, age 17.6 ± 1.5 and 10 females, age 17.3 ± 1.5) completed two, 3-week periods of training (EVEN and BLOCK) in a randomized, crossover-design study. In EVEN, 3 HIT sessions (5 × 4-min of diagonal-stride roller-skiing) were completed at a maximal sustainable intensity each week while low-intensity training (LIT) was distributed evenly around the HIT. In BLOCK, the same 9 HIT sessions were completed in the second week while only LIT was completed in the first and third weeks. Heart rate (HR), session ratings of perceived exertion (sRPE), and perceived recovery (pREC) were recorded for all HIT and LIT sessions, while distance covered was recorded for each HIT interval. The recovery-stress questionnaire for athletes (RESTQ-Sport) was completed weekly. Before and after EVEN and BLOCK, resting saliva and muscle samples were collected and an incremental test and 600-m time-trial (TT) were completed. <b>Results:</b> Pre- to post-testing revealed no significant differences between EVEN and BLOCK for changes in resting salivary cortisol, testosterone, or IgA, or for changes in muscle capillary density, fiber area, fiber composition, enzyme activity (CS, HAD, and PFK) or the protein content of VEGF or PGC-1α. Neither were any differences observed in the changes in skiing economy, [Formula: see text] or 600-m time-trial performance between interventions. These findings were coupled with no significant differences between EVEN and BLOCK for distance covered during HIT, summated HR zone scores, total sRPE training load, overall pREC or overall recovery-stress state. However, 600-m TT performance improved from pre- to post-training, irrespective of intervention (<i>P</i> = 0.003), and a number of hormonal and muscle biopsy markers were also significantly altered post-training (<i>P</i> < 0.05). <b>Discussion:</b> The current study shows that well-trained junior cross-country skiers are able to complete 9 HIT sessions within 1 week without compromising total work done and without experiencing greater stress or reduced recovery over a 3-week polarized microcycle. However, the findings do not support block-distributed HIT as a superior method to a more even distribution of HIT in terms of enhancing physiological or performance adaptions.
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2,335,198 |
Optimal Dose of Epidural Dexmedetomidine Added to Ropivacaine for Epidural Labor Analgesia: A Pilot Study.
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Dexmedetomidine combined with local anesthetics can decrease the concentration of epidural ropivacaine. However, the optimal dose of epidural dexmedetomidine combined with ropivacaine for labor analgesia is still uncertain. This study investigated the effect of adding different dose of epidural dexmedetomidine to ropivacaine during epidural labor analgesia.</AbstractText>One hundred women were randomly assigned to one of the four groups (Groups A, B, C, and D received 0.25, 0.5, 0.75, and 1 μ</i>g/ml of dexmedetomidine plus 0.1% ropivacaine, resp.). The onset of epidural anesthesia and stages of labor were studied, and pain was assessed using a visual analogue scale (VAS). Hemodynamic parameters and fetal heart rate were monitored. Apgar scores and umbilical artery pH were recorded. The side effects, if any, were recorded also.</AbstractText>The addition of 0.25, 0.5, and 0.75 μ</i>g/ml of dexmedetomidine to 0.1% ropivacaine provided safe and effective analgesia, but 1 μ</i>g/ml of dexmedetomidine resulted in increasing incidence of motor block. The hemodynamic parameters were similar between groups (P</i> > 0.05). Side effects in Group D were significantly higher than those in the other three groups (P</i> < 0.05).</AbstractText>When dexmedetomidine is combined with 0.1% ropivacaine, the optimal concentration of dexmedetomidine is 0.5 μ</i>g/ml for epidural labor analgesia (this trial is registered with ChiCTR-OPC-16008548).</AbstractText>
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2,335,199 |
Comparison of ultrasound and anatomical landmark-guided technique for superior laryngeal nerve block to aid awake fibre-optic intubation: A prospective randomised clinical study.
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Ultrasonography has emerged as a novel, portable, non-invasive tool encouraging airway assessment and procedural interventions. This study assesses the feasibility of ultrasound for block of internal branch of superior laryngeal nerve (ibSLN) block during upper airway anaesthesia to aid awake fibre-optic intubation.</AbstractText>Forty American Society of Anesthesiologists' physical status I-II patients, aged 18-60 years, deemed to have a difficult airway (modified Mallampati class III-IV or inter-incisor distance <2.5 cm) and planned for awake fibre-optic intubation were randomised to either landmark group (L, n</i> = 20) or ultrasound group (U, n</i> = 20). All patients received nebulised 4% lignocaine (3 mL) and transtracheal injection 3 mL 2% lignocaine. Group L received landmark-guided bilateral ibSLN block with 1 mL 2% lignocaine. Group U received bilateral ibSLN block with 1 mL 2% lignocaine using a high-frequency ultrasound transducer to define the SLN space. The primary objective was assessment of quality of airway anaesthesia. Secondary objectives were time for intubation, haemodynamic parameters and patient perception of discomfort during procedure.</AbstractText>The quality of anaesthesia was significantly better in Group U than in Group L (P</i> < 0.001). The mean time for intubation was shorter in Group U (71.05 ± 9.57 s) compared to Group L (109.05 ± 30.09 s, P</i> < 0.001). Heart rate, mean arterial pressure and patient perception of discomfort were significantly increased in Group L.</AbstractText>Ultrasound for ibSLN block as a part of preparation for awake fibre-optic intubation improves quality of airway anaesthesia and patient tolerance.</AbstractText>
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