Arrhythmia induction using isoproterenol or epinephrine during electrophysiology study for supraventricular tachycardia

Background Electrophysiology study (EPS) is an important part of the diagnosis and workup for supraventricular tachycardia (SVT). Provocative medications are used to induce arrhythmias, when they are not inducible at baseline. The most common medication is the β1‐specific agonist, isoproterenol, but recent price increases have resulted in a shift toward the nonspecific agonist, epinephrine. Objective We hypothesize that isoproterenol is a better induction agent for SVT during EPS than epinephrine. Methods We created a retrospective cohort of 131 patients, who underwent EPS and required medication infusion with either isoproterenol or epinephrine for SVT induction. The primary outcome was arrhythmia induction. Results Successful induction was achieved in 71% of isoproterenol cases and 53% of epinephrine cases (P = 0.020). Isoproterenol was significantly better than epinephrine for SVT induction during EPS (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.14‐4.85; P = 0.021). There was no difference in baseline variables or complications between the two groups. Other variables associated with successful arrhythmia induction included a longer procedure duration and atrioventricular nodal re‐entry tachycardia as the clinical arrhythmia. In a multivariable model, isoproterenol remained significantly associated with successful induction (OR, 2.57; 95% CI, 1.002‐6.59; P = 0.05). Conclusions Isoproterenol was significantly better than epinephrine for SVT arrhythmia induction. However, epinephrine was safe and successfully induced arrhythmias in the majority of patients who received it. Furthermore, when atropine was added in epinephrine‐refractory cases, in a post hoc analysis there was no difference in arrhythmia induction between medications. Cost savings could thus be significant without compromising safety

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

ephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.United States. National Institutes of Health (R01- CA075576)United States. National Institutes of Health (R01-CA055042)United States. National Institutes of Health (R01-CA149261)United States. National Institutes of Health (AGSS- 3046-12)United States. National Institutes of Health (P30-ES02109)United States. National Institutes of Health (P30-CA014051

Smooth Muscle-Generated Methylglyoxal Impairs Endothelial Cell-Mediated Vasodilatation of Cerebral Microvessels in Type 1 Diabetic Rats

Background and Purpose Endothelial cell-mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia-reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs). Experimental Approach Endothelial cell-mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia-reperfusion injury were assessed in brains of male Sprague-Dawley rats with streptozotocin-induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal-degrading enzyme glyoxalase-I (Glo-I) in cSMCs. Key Results After 7–8 weeks of T1D, endothelial cell-mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF-κB activity and TNF-α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid-cerebral artery exacerbated ischaemia-reperfusion injury. In cSMCs, Glo-I protein was decreased, and the methylglyoxal-synthesizing enzyme, vascular adhesion protein 1 (VAP-1) and methylglyoxal were increased. Restoring Glo-I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP-1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia-reperfusion injury and increased microvessel perfusion. Conclusions and Implications Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia-reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D

Dynamics of membrane damage to skeletal muscle cells at supraphysiological temperatures and the role of poloxamer 188 in minimizing membrane injury

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1994.Includes bibliographical references (leaves 96-101).by Joseph T. Padanilam.M.S

A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury.

Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted--ischemia--and then restored--reperfusion--leading to a burst of reactive oxygen species (ROS) from mitochondria. It has been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies.Work in our laboratories is supported by the Medical Research Council (UK) and the British Heart Foundation. E.T.C. is supported by a Human Frontiers Science Program fellowship.This is the author accepted manuscript. The final version is available from Cell Press via http://dx.doi.org/10.1016/j.cmet.2015.12.00

Anti-Tuberculosis Drugs and Adverse Events

Anti-tuberculosis (TB) drugs can cause adverse drug reactions, particularly the older second-line drugs. Early intervention and adequate management of adverse drug reactions are important to prevent complications. Laboratory testing at baseline and during treatment, in addition to clinical monitoring, is protocolized to improve patient and treatment management. This chapter provides an overview of the most frequent and severe adverse effects caused by the first-and second-line drugs used for the treatment of tuberculosis. An approach on how to manage the adverse drugs effects is briefly described.</p

Anti-Tuberculosis Drugs and Adverse Events

Anti-tuberculosis (TB) drugs can cause adverse drug reactions, particularly the older second-line drugs. Early intervention and adequate management of adverse drug reactions are important to prevent complications. Laboratory testing at baseline and during treatment, in addition to clinical monitoring, is protocolized to improve patient and treatment management. This chapter provides an overview of the most frequent and severe adverse effects caused by the first-and second-line drugs used for the treatment of tuberculosis. An approach on how to manage the adverse drugs effects is briefly described.</p