Enhanced charge-independent Mitochondrial Free Ca\u3csup\u3e2+\u3c/sup\u3e and Attenuated ADP-induced NADH Oxidation by Isoflurane: Implications for Cardioprotection

Modulation of mitochondrial free Ca2 + ([Ca2 +]m) is implicated as one of the possible upstream factors that initiates anesthetic-mediated cardioprotection against ischemia–reperfusion (IR) injury. To unravel possible mechanisms by which volatile anesthetics modulate [Ca2 +]m and mitochondrial bioenergetics, with implications for cardioprotection, experiments were conducted to spectrofluorometrically measure concentration-dependent effects of isoflurane (0.5, 1, 1.5, 2 mM) on the magnitudes and time-courses of [Ca2 +]m and mitochondrial redox state (NADH), membrane potential (ΔΨm), respiration, and matrix volume. Isolated mitochondria from rat hearts were energized with 10 mM Na+- or K+-pyruvate/malate (NaPM or KPM) or Na+-succinate (NaSuc) followed by additions of isoflurane, 0.5 mM CaCl2 (≈ 200 nM free Ca2 + with 1 mM EGTA buffer), and 250 μM ADP. Isoflurane stepwise: (a) increased [Ca2 +]m in state 2 with NaPM, but not with KPM substrate, despite an isoflurane-induced slight fall in ΔΨm and a mild matrix expansion, and (b) decreased NADH oxidation, respiration, ΔΨm, and matrix volume in state 3, while prolonging the duration of state 3 NADH oxidation, respiration, ΔΨm, and matrix contraction with PM substrates. These findings suggest that isoflurane\u27s effects are mediated in part at the mitochondrial level: (1) to enhance the net rate of state 2 Ca2 + uptake by inhibiting the Na+/Ca2 + exchanger (NCE), independent of changes in ΔΨm and matrix volume, and (2) to decrease the rates of state 3 electron transfer and ADP phosphorylation by inhibiting complex I. These direct effects of isoflurane to increase [Ca2 +]m, while depressing NCE activity and oxidative phosphorylation, could underlie the mechanisms by which isoflurane provides cardioprotection against IR injury at the mitochondrial level

Isoflurane Modulates Cardiac Mitochondrial Bioenergetics by Selectively Attenuating Respiratory Complexes

Mitochondrial dysfunction contributes to cardiac ischemia–reperfusion (IR) injury but volatile anesthetics (VA) may alter mitochondrial function to trigger cardioprotection. We hypothesized that the VA isoflurane (ISO) mediates cardioprotection in part by altering the function of several respiratory and transport proteins involved in oxidative phosphorylation (OxPhos). To test this we used fluorescence spectrophotometry to measure the effects of ISO (0, 0.5, 1, 2 mM) on the time-course of interlinked mitochondrial bioenergetic variables during states 2, 3 and 4 respiration in the presence of either complex I substrate K+-pyruvate/malate (PM) or complex II substrate K+-succinate (SUC) at physiological levels of extra-matrix free Ca2 + (~ 200 nM) and Na+ (10 mM). To mimic ISO effects on mitochondrial functions and to clearly delineate the possible ISO targets, the observed actions of ISO were interpreted by comparing effects of ISO to those elicited by low concentrations of inhibitors that act at each respiratory complex, e.g. rotenone (ROT) at complex I or antimycin A (AA) at complex III. Our conclusions are based primarily on the similar responses of ISO and titrated concentrations of ETC. inhibitors during state 3. We found that with the substrate PM, ISO and ROT similarly decreased the magnitude of state 3 NADH oxidation and increased the duration of state 3 NADH oxidation, ΔΨm depolarization, and respiration in a concentration-dependent manner, whereas with substrate SUC, ISO and ROT decreased the duration of state 3 NADH oxidation, ΔΨm depolarization and respiration. Unlike AA, ISO reduced the magnitude of state 3 NADH oxidation with PM or SUC as substrate. With substrate SUC, after complete block of complex I with ROT, ISO and AA similarly increased the duration of state 3 ΔΨm depolarization and respiration. This study provides a mechanistic understanding in how ISO alters mitochondrial function in a way that may lead to cardioprotection

When correction turns positive: Processing corrective prosody in Dutch

Current research on spoken language does not provide a consistent picture as to whether prosody, the melody and rhythm of speech, conveys a specific meaning. Perception studies show that English listeners assign meaning to prosodic patterns, and, for instance, associate some accents with contrast, whereas Dutch listeners behave more controversially. In two ERP studies we tested how Dutch listeners process words carrying two types of accents, which either provided new information (new information accents) or corrected information (corrective accents), both in single sentences (experiment 1) and after corrective and new information questions (experiment 2). In both experiments corrective accents elicited a sustained positivity as compared to new information accents, which started earlier in context than in single sentences. The positivity was not modulated by the nature of the preceding question, suggesting that the underlying neural mechanism likely reflects the construction of an interpretation to the accented word, either by identifying an alternative in context or by inferring it when no context is present. Our experimental results provide strong evidence for inferential processes related to prosodic contours in Dutc

Modulation of Mitochondrial Bioenergetics in the Isolated Guinea Pig Beating Heart by Potassium and Lidocaine Cardioplegia: Implications for Cardioprotection

Mitochondria are damaged by cardiac ischemia/reperfusion (I/R) injury but can contribute to cardioprotection. We tested if hyperkalemic cardioplegia (CP) and lidocaine (LID) differently modulate mitochondrial (m) bioenergetics and protect hearts against I/R injury. Guinea pig hearts (n = 71) were perfused with Krebs Ringer\u27s solution before perfusion for 1 minute just before ischemia with either CP (16 mM K+) or LID (1 mM) or Krebs Ringer\u27s (control, 4 mM K+). The 1-minute perfusion period assured treatment during ischemia but not on reperfusion. Cardiac function, NADH, FAD, m[Ca2+], and superoxide (reactive oxygen species) were assessed at baseline, during the 1-minute perfusion, and continuously during I/R. During the brief perfusion before ischemia, CP and LID decreased reactive oxygen species and increased NADH without changing m[Ca2+]. Additionally, CP decreased FAD. During ischemia, NADH was higher and reactive oxygen species was lower after CP and LID, whereas m[Ca2+] was lower only after LID. On reperfusion, NADH and FAD were more normalized, and m[Ca2+] and reactive oxygen species remained lower after CP and LID. Better functional recovery and smaller infarct size after CP and LID were accompanied by better mitochondrial function. These results suggest that mitochondria may be implicated, directly or indirectly, in protection by CP and LID against I/R injury

A Note on Venture Capital Networks: Promise and Performance

Since 1984 Informal Venture Networks (VCNs) have been formed and are currently operating in several states and Canada. However, little has been written in regard to the performance of these networks. This article presents the results of preliminary research concerning their performance. Our research reveals several factors that are presently limiting the VCNs’ success and will continue to do so until diey are changed. The limited success of the VCNs to date is primarily the result of a lack of funding. Because of small operating budgets, most VCNs have only minimal amounts available for marketing and promotion. Until the VCNs are adequately funded, their high promise will not be matched by performance

Insights into the value of the market for cocaine, heroin and methamphetamine in South Africa

The illicit drug trade generates billions of dollars and sustains transnational criminal organisations. Drug markets can destabilise governance and undermine development. Data indicate increasing drug use in South Africa. However, information on the size and value of the drug market is limited. This is the first study to estimate the market value of cocaine, heroin and methamphetamine in South Africa. People who use drugs were meaningfully involved in all aspects of implementation. We used focus group discussions, ethnographic mapping, brief interviews, and the Delphi method to estimate the number of users, volumes consumed, and price for each drug in South Africa in 2020. Nationally, we estimated there to be: 400,000 people who use heroin (probability range (PR) 215,000–425,000) consuming 146.00 tonnes (PR 78.48–155.13) with a value of US$1,898.00 million (PR US$1,020.18–US$2,016.63); 350,000 people who use cocaine (PR 250,000–475,000) consuming 18.77 tonnes (PR 13.41–25.47) with a market value of US$1,219.86 million (PR 871.33–1,655.52) and 290,000 people who use methamphetamine (PR 225,000–365,000) consuming 60.19 tonnes (PR 6.58–10.68) and a market value of US$782.51 million (PR 607.12–984.88). The combined value was calculated at US$3.5 billion. Findings can be used to stimulate engagement to reform drug policy and approaches to mitigate the impact of the illicit drug trade. Additional studies that include people who use drugs in research design and implementation are needed to improve our understanding of drug markets

Students\u27 Attitudes Toward Debt-A Study of Atkinson Faculty of Liberal and Professional Studies, York University, and Ryerson University

In Ontario, the university system has been put on notice that there will be financial consequences for those universities whose Ontario Student Assistance Plan (OSAP) default rates are greater than the norm. As a result, it is important to determine all of the factors that affect students\u27 decisions to borrow. This paper uses survey information gathered from Atkinson Faculty of Liberal and Professional Studies, York University, and Ryerson University to focus attention on the relationship between students\u27 attitudes toward going into debt to finance their university education and their actual borrowing behavior. The study found that when all else is held constant, students with positive attitudes toward debt are more likely than others to be on the OSAP