Ischemia reperfusion dysfunction changes model-estimated kinetics of myofilament interaction due to inotropic drugs in isolated hearts

BACKGROUND: The phase-space relationship between simultaneously measured myoplasmic [Ca(2+)] and isovolumetric left ventricular pressure (LVP) in guinea pig intact hearts is altered by ischemic and inotropic interventions. Our objective was to mathematically model this phase-space relationship between [Ca(2+)] and LVP with a focus on the changes in cross-bridge kinetics and myofilament Ca(2+ )sensitivity responsible for alterations in Ca(2+)-contraction coupling due to inotropic drugs in the presence and absence of ischemia reperfusion (IR) injury. METHODS: We used a four state computational model to predict LVP using experimentally measured, averaged myoplasmic [Ca(2+)] transients from unpaced, isolated guinea pig hearts as the model input. Values of model parameters were estimated by minimizing the error between experimentally measured LVP and model-predicted LVP. RESULTS: We found that IR injury resulted in reduced myofilament Ca(2+ )sensitivity, and decreased cross-bridge association and dissociation rates. Dopamine (8 μM) reduced myofilament Ca(2+ )sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 μM) reduced myofilament Ca(2+ )sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 μM) increased myofilament Ca(2+ )sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 μM) enhanced myofilament Ca(2+ )affinity and cross-bridge kinetics only after ischemia. CONCLUSION: Estimated model parameters reveal mechanistic changes in Ca(2+)-contraction coupling due to IR injury, specifically the inefficient utilization of Ca(2+ )for contractile function with diastolic contracture (increase in resting diastolic LVP). The model parameters also reveal drug-induced improvements in Ca(2+)-contraction coupling before and after IR injury

Increased reports of severe myocarditis associated with enterovirus infection in neonates, United Kingdom, 27 June 2022 to 26 April 2023

Enteroviruses are a common cause of seasonal childhood infections. The vast majority of enterovirus infections are mild and self-limiting, although neonates can sometimes develop severe disease. Myocarditis is a rare complication of enterovirus infection. Between June 2022 and April 2023, twenty cases of severe neonatal enteroviral myocarditis caused by coxsackie B viruses were reported in the United Kingdom. Sixteen required critical care support and two died. Enterovirus PCR on whole blood was the most sensitive diagnostic test. We describe the initial public health investigation into this cluster and aim to raise awareness among paediatricians, laboratories and public health specialists

Measurement of illumination exposure in postpartum women

BACKGROUND: Low levels of light exposure at critical times are thought to cause seasonal affective disorder. Investigators, in studies demonstrating the usefulness of bright light therapy, also have implicated light's role in non-seasonal depression. The precise cause of postpartum depression has not been delineated, but it seemed possible that new mothers would spend reduced time in daylight. The goal of this study was to examine the levels of illumination experienced by postpartum mothers and to discover any relationship between light exposure and mood levels experienced during the postpartum period. METHODS: Fifteen postpartum women, who did not have any baseline indication of depression, wore a wrist device (Actillume) for 72 hours to measure their exposure to light. At the end of the recording period, they completed a self-reported measure of mood. The mean light exposure of these postpartum women (expressed as the 24-hour average logarithm of illumination in lux) was compared with that of a representative sample of women of comparable age, residence, and seasonal months of recording. Mood levels were then rank-ordered and tested for correlation with light exposure levels. RESULTS: There was no significant difference between the amount of light [log(10)lux] experienced by postpartum (1.01 SD 0.236) and control women (1.06 SD 0.285). Mood was not correlated with illumination in the postpartum sample. CONCLUSIONS: Postpartum women in San Diego did not receive reduced light, nor was low mood related to low illumination

Morphine induces preconditioning via activation of mitochondrial KCa channels

PURPOSE: Mitochondrial calcium sensitive potassium (mK(Ca)) channels are involved in cardioprotection induced by ischemic preconditioning. In the present study we investigated whether morphine-induced preconditioning also involves activation of mK(Ca) channels. METHODS: Isolated rat hearts (six groups; each n = 8) underwent global ischemia for 30 min followed by a 60-min reperfusion. Control animals were not further treated. Morphine preconditioning (MPC) was initiated by two five-minute cycles of morphine 1 muM infusion with one five-minute washout and one final ten-minute washout period before ischemia. The mK(Ca) blocker, paxilline 1 muM, was administered, with and without morphine administration (MPC + Pax and Pax). As a positive control, we added an ischemic preconditioning group (IPC) alone and combined with paxilline (IPC + Pax). At the end of reperfusion, infarct sizes were determined by triphenyltetrazoliumchloride staining. RESULTS: Infarct size was (mean +/- SD) 45 +/- 9% of the area at risk in the Control group. The infarct size was less in the morphine or ischemic preconditioning groups (MPC: 23 +/- 8%, IPC: 20 +/- 5%; each P < 0.05 vs Control). Infarct size reduction was abolished by paxilline (MPC + Pax: 37 +/- 7%, P < 0.05 vs MPC and IPC + Pax: 36 +/- 6%, P < 0.05 vs IPC), whereas paxilline alone had no effect (Pax: 46 +/- 7%, not significantly different from Control). CONCLUSION: Cardioprotection by morphine-induced preconditioning is mediated by activation of mK(Ca) channel

Resveratrol Suppresses Constitutive Activation of AKT via Generation of ROS and Induces Apoptosis in Diffuse Large B Cell Lymphoma Cell Lines

BACKGROUND: We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,4', 5-trihydroxystilbene), a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL) cells in causing inhibition of cell viability and inducing apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the action of Resveratrol on DLBCL cells and found that Resveratrol inhibited cell viability and induced apoptosis by inhibition of constitutively activated AKT and its downstream targets via generation of reactive oxygen species (ROS). Simultaneously, Resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; and interestingly, co-treatment of DLBCL with sub-toxic doses of TRAIL and Resveratrol synergistically induced apoptosis via utilizing DR5, on the other hand, gene silencing of DR5 abolished this effect. CONCLUSION/SIGNIFICANCE: Altogether, these data suggest that Resveratrol acts as a suppressor of AKT/PKB pathway leading to apoptosis via generation of ROS and at the same time primes DLBCL cells via up-regulation of DR5 to TRAIL-mediated apoptosis. These data raise the possibility that Resveratrol may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway

An experimental test of host’s life history traits modulation in response to cuckoo parasitism risk

Hosts can counteract parasites through defences based on resistance and/or tolerance. The mechanistic basis of tolerance, which involve defensive mechanisms minimizing parasite damage after a successful parasitic attack, remains poorly explored in the study of cuckoo-host interactions. Here, we experimentally explore the possibility that the risk of great spotted cuckoo Clamator glandarius parasitism may induce tolerance defences in magpie Pica pica hosts through plasticity in life-history traits. We predict that magpies exposed to auditory cues indicating high parasitism risk will more likely exhibit resistance and/or modify their life-history traits to minimize parasitism costs (i.e. tolerance) compared to magpies under low parasitism risk. We found that manipulating the perceived parasitism risk did not affect host resistance (i.e. rejection of parasitic eggs) nor host life-history traits. Unexpectedly, host's egg volume increased over the season in nests exposed to auditory cues of control non-harmful hoopoes Upupa epops. Our results do not provide support for inducible defences (either based on resistance or tolerance) in response to risk of parasitism in magpie hosts. Even so, we encourage studying plastic expression of breeding strategies in response to risk of cuckoo parasitism to achieve a better understanding of the mechanistic basis of tolerance defences.This work was supported by the Spanish Ministry of Education and Science/FEDER (Projects CGL2011-27561/BOS and CGL2014-56769-P to D. P. and J.M.A.). D.P. was supported by the Government of Extremadura while writing (contract number TA13002). M.E.G. was supported by the Spanish Ministry of Economy and Competitiveness (grant number BES-2012-051898).

Low Concentrations of Methamphetamine Can Protect Dopaminergic Cells against a Larger Oxidative Stress Injury: Mechanistic Study

Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [3H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD