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1.
Analysis of Drug Effects on iPSC Cardiomyocytes with Machine Learning.
Juhola, M, Penttinen, K, Joutsijoki, H, Aalto-Setälä, K
Annals of biomedical engineering. 2021;(1):129-138
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Abstract
Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an attractive experimental platform to investigate cardiac diseases and therapeutic outcome. In this study, iPSC-CMs were utilized to study their calcium transient signals and drug effects by means of machine learning, a central part of artificial intelligence. Drug effects were assessed in six iPSC-lines carrying different mutations causing catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly malignant inherited arrhythmogenic disorder. The antiarrhythmic effect of dantrolene, an inhibitor of sarcoplasmic calcium release, was studied in iPSC-CMs after adrenaline, an adrenergic agonist, stimulation by machine learning analysis of calcium transient signals. First, beats of transient signals were identified with our peak recognition algorithm previously developed. Then 12 peak variables were computed for every identified peak of a signal and by means of this data signals were classified into different classes corresponding to those affected by adrenaline or, thereafter, affected by a drug, dantrolene. The best classification accuracy was approximately 79% indicating that machine learning methods can be utilized in analysis of iPSC-CM drug effects. In the future, data analysis of iPSC-CM drug effects together with machine learning methods can create a very valuable and efficient platform to individualize medication in addition to drug screening and cardiotoxicity studies.
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2.
Infant Anaphylaxis: A Diagnostic Challenge.
Cardenas-Morales, M, Hernandez-Trujillo, V
Current allergy and asthma reports. 2021;(2):12
Abstract
PURPOSE OF REVIEW Infant anaphylaxis has been increasing in incidence; however, significant gaps in the literature remain. The aim of this article is to review the most recent literature pertaining to infant anaphylaxis and discuss recent findings related to epidemiology, diagnosis, management, and prevention. RECENT FINDINGS There is no accurate report of the incidence and prevalence of anaphylaxis in infancy. Food is the most common trigger for infant anaphylaxis reported. The diagnosis of anaphylaxis in infants is often missed, and, even when the diagnosis is made, epinephrine continues to be under-utilized. An epinephrine autoinjector with a shorter needle and lower dose is now available for infants. Concise criteria specifically focusing on infant anaphylaxis is needed to streamline its diagnosis and management. Diagnosis is underrecognized in infants leading to improper treatment. When the diagnosis is made, epinephrine continues to be under-utilized and under-prescribed in infants.
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Self-administration of adrenaline for anaphylaxis during in-hospital food challenges improves health-related quality of life.
Burrell, S, Patel, N, Vazquez-Ortiz, M, Campbell, DE, DunnGalvin, A, Turner, PJ
Archives of disease in childhood. 2021;(6):558-563
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Abstract
OBJECTIVE To assess the impact of anaphylaxis on health-related quality of life (HRQL) and self-efficacy in food-allergic patients undergoing in-hospital food challenge. DESIGN Secondary analysis of a randomised controlled trial. SETTING Specialist allergy centre. PATIENTS Peanut-allergic young people aged 8-16 years. INTERVENTIONS Double-blind, placebo-controlled food challenge to peanut, with HRQL and self-efficacy assessed using validated questionnaire, approximately 2 weeks prior to and 2 weeks after challenge. Where possible, anaphylaxis was treated with self-injected adrenaline (epinephrine). MAIN OUTCOME MEASURES Change in HRQL and self-efficacy. RESULTS 56 participants had reactions at food challenge, of whom 16 (29%) had anaphylaxis. Overall, there was an improvement in HRQL (mean 2.6 points (95% CI 0.3 to 4.8); p=0.030) and self-efficacy (mean 4.1 points (95% CI 2.4 to 5.9); p<0.0001), independent of whether anaphylaxis occurred. Parents also reported improved HRQL (mean 10.3 points (95% CI 5.9 to 14.7); p<0.0001). We found evidence of discordance between the improvement in HRQL and self-efficacy as reported by young people and that perceived by parents in their child. CONCLUSIONS Anaphylaxis at food challenge, followed by self-administration of injected adrenaline, was associated with an increase in HRQL and self-efficacy in young people with peanut allergy. We found no evidence that the occurrence of anaphylaxis had a detrimental effect. Young people should be encouraged to self-administer adrenaline using their autoinjector device to treat anaphylaxis at in-hospital challenge. TRIAL REGISTRATION NUMBER NCT02149719.
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Pupillary Light Reflex Is Not Abolished by Epinephrine and Atropine Given During Advanced Cardiac Life Support in Patients Who Achieve Return of Spontaneous Circulation.
Achamallah, N, Fried, J, Love, R, Matusov, Y, Sharma, R
Journal of intensive care medicine. 2021;(4):459-465
Abstract
INTRODUCTION Absence of pupillary light reflex (PLR) is a well-studied indicator of poor neurologic recovery after cardiac arrest. Interpretation of absent PLR is difficult in patients with hypothermia or hypotension, or who have electrolyte or acid-base disturbances. Additionally, many studies exclude patients who receive epinephrine or atropine from their analysis on the basis that these drugs are thought to abolish the PLR. This observational cohort study assessed for presence or absence of PLR in in-hospital cardiac arrest patients who received epinephrine with or without atropine during advanced cardiac life support and achieved return of spontaneous circulation (ROSC). METHODS Pupil size and reactivity were assessed in adult patients who had an in-hospital cardiac arrest, received epinephrine with or without atropine, and achieved ROSC. Measurements were taken using a NeurOptics NPi-200 infrared pupillometer. RESULTS Forty patients had pupillometry performed within 1 hour (median: 6 minutes) after ROSC. Of these only 1 (2.5%) patient had nonreactive pupils at first measurement after ROSC. The remaining 39 (97.5%) had reactive pupils. Of the 19 patients who had pupils checked within 3 minutes of ROSC, 100% had reactive pupils. Degree of pupil responsiveness was not correlated with cumulative dose of epinephrine. Ten patients received atropine in addition to epinephrine, including the sole patient with nonreactive pupils. The remaining 9 (90%) had reactive pupils. CONCLUSION Epinephrine and atropine do not abolish the PLR in patients who achieve ROSC after in-hospital cardiac arrest. Lack of pupillary response in the post-arrest patient should not be attributed to these drugs.
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FTacV study of electroactive immobilized enzyme/free substrate reactions: Enzymatic catalysis of epinephrine by a multicopper oxidase from Thermothelomyces thermophila.
Zouraris, D, Kiafi, S, Zerva, A, Topakas, E, Karantonis, A
Bioelectrochemistry (Amsterdam, Netherlands). 2020;:107538
Abstract
In the present work, a kinetic analysis is made concerning the reaction of an electroactive immobilized enzyme with a free substrate, based on a Michaelis-Menten scheme. The proposed kinetic equations are investigated numerically for conditions describing large amplitude fast Fourier transform alternating current voltammetry (FTacV), under different reaction states (transient or steady state for the reaction intermediate as well as quasi or complete reversibility of the electrochemical step). The dependence of two chief observables that occur from the analysis of the results of the method, that is, the maximum of the harmonics and the potential shift of the corresponding dominant peaks, on substrate concentration is presented. The FTacV method is applied experimentally for an immobilized laccase-like multicopper oxidase from Thermothelomyces thermophila, TtLMCO1, and its reaction with epinephrine. From the experimental findings it is shown that the intrinsic characteristics of the system do not lead to the extraction of the desired kinetic data although indications on the relation between the kinetic constants is revealed. Finally, the response of the third harmonic for the first additions of epinephrine at subnanomolarity range can be exploited for the detection of epinephrine at rather low concentrations.
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The effects of moderate alterations in adrenergic activity on acute appetite regulation in obese women: A randomised crossover trial.
Tsofliou, F, Pitsiladis, YP, Lara, J, Hadjicharalambous, M, Macdonald, IA, Wallace, MA, Lean, MEJ
Nutrition and health. 2020;(4):311-322
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Abstract
BACKGROUND Previous evidence has demonstrated that serum leptin is correlated with appetite in combination with, but not without, modest exercise. AIM: The present experiments investigated the effects of exogenous adrenaline and α/β adrenoceptor blockade in combination with moderate exercise on serum leptin concentrations, appetite/satiety sensations and subsequent food intake in obese women. METHODS A total of 10 obese women ((mean ± SEM), age: 50 (1.9) years, body mass index 36 (4.1) kg/m2, waist 104.8 (4.1) cm) participated in two separate, double-blind randomised experimental trials. Experiment 1: moderate exercise after α/β adrenergic blocker (labetalol, 100 mg orally) versus moderate exercise plus placebo; experiment 2: adrenaline infusion for 20 minutes versus saline infusion. Appetite/satiety and biochemistry were measured at baseline, pre- and immediately post-intervention, then 1 hour post-intervention (i.e., before dinner). Food intake was assessed via ad libitum buffet-style dinner. RESULTS No differences were found in appetite/satiety, subsequent food intake or serum leptin in any of the studies (experiment 1 or experiment 2). In experiment 1, blood glucose was higher (p < 0.01) and plasma free fatty acids lower (p = 0.04) versus placebo. In experiment 2, plasma free fatty acids (p < 0.05) increased after adrenaline versus saline infusion. CONCLUSIONS Neither inhibition of exercise-induced adrenergic activity by combined α/β adrenergic blockade nor moderate increases in adrenergic activity induced by intravenous adrenaline infusion affected acute appetite regulation.
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Understanding the Solution Behavior of Epinephrine in the Presence of Toxic Cations: A Thermodynamic Investigation in Different Experimental Conditions.
Crea, F, De Stefano, C, Irto, A, Lando, G, Materazzi, S, Milea, D, Pettignano, A, Sammartano, S
Molecules (Basel, Switzerland). 2020;(3)
Abstract
The interactions of epinephrine ((R)-(-)-3,4-dihydroxy-α-(methylaminomethyl)benzyl alcohol; Eph-) with different toxic cations (methylmercury(II): CH3Hg+; dimethyltin(IV): (CH3)2Sn2+; dioxouranium(VI): UO22+) were studied in NaClaq at different ionic strengths and at T = 298.15 K (T = 310.15 K for (CH3)2Sn2+). The enthalpy changes for the protonation of epinephrine and its complex formation with UO22+ were also determined using isoperibolic titration calorimetry: HHL = -39 ± 1 kJ mol-1, HH2L = -67 ± 1 kJ mol-1 (overall reaction), HML = -26 ± 4 kJ mol-1, and HM2L2(OH)2 = 39 ± 2 kJ mol-1. The results were that UO22+ complexation by Eph- was an entropy-driven process. The dependence on the ionic strength of protonation and the complex formation constants was modeled using the extended Debye-Hückel, specific ion interaction theory (SIT), and Pitzer approaches. The sequestering ability of adrenaline toward the investigated cations was evaluated using the calculation of pL0.5 parameters. The sequestering ability trend resulted in the following: UO22+ >> (CH3)2Sn2+ > CH3Hg+. For example, at I = 0.15 mol dm-3 and pH = 7.4 (pH = 9.5 for CH3Hg+), pL0.5 = 7.68, 5.64, and 2.40 for UO22+, (CH3)2Sn2+, and CH3Hg+, respectively. Here, the pH is with respect to ionic strength in terms of sequestration.
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Norepinephrine release may play a critical role in the Warburg effect: an integrative model of tumorigenesis.
Fitzgerald, PJ
Neoplasma. 2020;(5):947-957
Abstract
Many cancer cells share the property of carrying out markedly elevated rates of glycolysis to generate energy even in the presence of sufficient oxygen, and this is known as the Warburg effect. In recent years, there has been a resurgence of interest in the Warburg effect, as the field of oncology has amassed evidence that cellular metabolism may play a prominent role in many neoplasms. Largely in the past decade, another prominent and perhaps surprising factor has emerged in the cancer literature: the catecholamine molecules, epinephrine (adrenaline) and norepinephrine (noradrenaline), appear to play a role in tumorigenesis and metastasis. The drug propranolol, which blocks beta adrenergic receptors, may be therapeutic in human angiosarcoma, melanoma, and ovarian cancer. The current paper synthesizes these older and more recent findings, in an attempt to unify the major factors that contribute to tumorigenesis. This paper suggests that in addition to the direct interaction of catecholamine signaling with genetic risk factors (including mutagenesis), it interacts with environmental factors such as hypertension, obesity, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress, to promote the Warburg effect by facilitating glucose availability through suppression of pancreatic insulin release. Further, it proposes that many cancer cells synthesize and release catecholamines to activate their own receptors in an autocrine fashion. In summary, catecholamines are an important "new" factor in cancer that may interface with both genetics and environmental factors to alter the Warburg effect and modulate tumorigenesis.
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Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation.
Fälker, K, Ljungberg, LU, Kardeby, C, Lindkvist, M, Sirsjö, A, Grenegård, M
Cellular signalling. 2019;:96-109
Abstract
The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.
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Anaphylaxis management in Australian schools: Review of guidelines and adrenaline autoinjector use.
Vale, S, Netting, MJ, Ford, LS, Tyquin, B, McWilliam, V, Campbell, DE
Journal of paediatrics and child health. 2019;(2):143-151
Abstract
Food allergy and anaphylaxis is increasing in Australian children, and anaphylaxis is relatively common in Australian schools. This review aims to provide an overview of current policies and practices for anaphylaxis management in Australian schools, including approaches to risk mitigation and anaphylaxis training. We reviewed literature related to anaphylaxis training in the school setting published between 2010 and 2018. Current anaphylaxis policies/guidelines were obtained from Australian education and health departments, and reports of suspected anaphylaxis and adrenaline autoinjector (AAI) use for 2016-2017 were obtained from education departments where available. Our review of policies/guidelines across Australian jurisdictions indicates inconsistent approaches to anaphylaxis management training. Almost half of Australian school anaphylaxis events required a general-use AAI, administered to students not identified as at risk of anaphylaxis. Development of clear, evidence-based, consistent guidelines related to anaphylaxis management and training in the school setting is imperative to minimise risk.