Ischemic preconditioning modulates mitochondrial respiration, irrespective of the employed signal transduction pathway

We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69%+/-2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48%+/-4%). Cardioprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K(+)(ATP)-channel opening. In contrast, cardioprotection by 3 cycles of 3-min coronary occlusions (infarct size 27%+/-5% of the area at risk) involved the release of reactive oxygen species, which was followed by protein kinase C and tyrosine kinase activation, but was independent of adenosine receptor stimulation and K(+)(ATP)-channel activation. However, both pathways decreased respiratory control index (RCI; state-3/state-2, using succinate as complex-II substrate) from 3.1+/-0.2 in mitochondria from sham-treated hearts to 2.4+/-0.2 and 2.5+/-0.1 in hearts subjected to a single 15-min and triple 3-min coronary occlusions, respectively (both P<0.05). The decreases in RCI were due to an increase in state-2 respiration, whereas state-3 respiration was unchanged. Abolition of cardioprotection by blockade of either signal transduction pathway was paralleled by a concomitant abolition of mitochondrial uncoupling. These observations are consistent with the concept that mild mitochondrial uncoupling contributes to infarct size limitation by various ischemic preconditioning stimuli, despite using different signal transduction pathways. In conclusion, in the in vivo rat heart, different ischemic preconditioning (IPC) stimuli can activate highly different signal transduction pathways, which seem to converge at the level of the mitochondria where they increase state-2 respiration.     

Normal brachial plexus: MR imaging

Magnetic resonance (MR) imaging of the brachial plexus was performed in the axial, coronal, and sagittal planes in seven volunteers. Normal structures were delineated by comparison with axial and sagittal cadaver sections and with gross dissection. Differentiation of soft tissues with MR imaging enabled the brachial plexus to be defined from surrounding muscle and vascular structures. Multiplanar imaging demonstrated anatomic detail not previously demonstrated with other radiologic modalities and provided excellent delineation of the components of the brachial plexus from the ventral rami to the peripheral nerve branches.     

Critical appraisal of the literature—its role in CPD

The information explosion has affected the medical as well as the lay press. Sources of literature have never been so diverse, and freedom of information legislation globally has empowered all and sundry to voice their views on all matters. This freedom is exercised with regard to medical literature in general and Women’s Health publications in particular. The implicit requirement for clinical practice to be informed by evidence (evidence-based medicine) has placed the onus on the readership of clinical literature to acquire skills in appraising such literature. The need to sift out relevant information from the burgeoning obstetrics and gynaecology literature has mandated the acquisition of skills in critical literature appraisal. This review outlines how to critically appreciate and evaluate literature generally, and as it relates to obstetrics and gynaecology.     

Preoperative right heart hemodynamics predict postoperative acute kidney injury after heart transplantation

Purpose

Acute kidney injury (AKI) frequently occurs after heart transplantation (HTx), but its relation to preoperative right heart hemodynamic (RHH) parameters remains unknown. Therefore, we aimed to determine their predictive properties for postoperative AKI severity within 30 days after HTx.

Methods

From 1984 to 2016, all consecutive HTx recipients (n?=?595) in our tertiary referral center were included and analyzed for the occurrence of postoperative AKI staged by the kidney disease improving global outcome criteria. The effects of preoperative RHH parameters on postoperative AKI were calculated using logistic regression, and predictive accuracy was assessed using integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under the receiver operating characteristic curves (AUC).

Results

Postoperative AKI occurred in 430 (72%) patients including 278 (47%) stage 1, 66 (11%) stage 2, and 86 (14%) stage 3 cases. Renal replacement therapy (RRT) was administered in 41 (7%) patients. Patients with higher AKI stages had also higher baseline right atrial pressure (RAP; median 7, 7, 8, and in RRT 11 mmHg, p trend?=?0.021), RAP-to-pulmonary capillary wedge pressure ratio (median 0.37, 0.36, 0.40, 0.47, p trend?=?0.009), and lower pulmonary artery pulsatility index (PAPi) values (median 2.83, 3.17, 2.54, 2.31, p trend?=?0.012). Higher RAP and lower PAPi values independently predicted AKI severity [adjusted odds ratio (OR) per doubling of RAP 1.16 (1.02–1.32), p?=?0.029; of PAPi 0.85 (0.75–0.96), p?=?0.008]. Based on IDI, NRI, and delta AUC, inclusion of these parameters improved the models’ predictive accuracy.

Conclusions

Preoperative PAPi and RAP strongly predict the development of AKI early after HTx and can be used as early AKI predictors.

     

Review article: Safety aspects of anesthesia in under-resourced locations

Purpose

Improving patient safety during anesthesia and surgery is the focus of much effort worldwide. Major advances have occurred since the 1980s, especially in economically advantaged areas. This paper is a review of some of the challenges that face those who work in resource-poor areas of the world.

Principal findings

There is a shortage of trained anesthesia providers, both physician and non-physician, and this is particularly acute outside urban areas. Anesthesia is still sometimes delivered by unqualified people, which results in expected high rates of morbidity and mortality. Residency training programs in low-income countries ought to increase their output as anesthesiologists must be available to supervise non-physician providers. All groups require continuing medical education. In addition, increased efforts are needed to recruit trainees into the specialty of anesthesia and to retain them locally. There is a well-recognized shortage of resources for anesthesia. Consequently, concerted efforts are necessary to ensure reliable supplies of drugs, and attention should be paid to the procurement of anesthesia equipment appropriate for the location. Biomedical support must also be developed. Lifebox is a charitable foundation dedicated to supplying pulse oximeters to low- and middle-income countries. Adoption of the World Health Organization’s Surgical Safety Checklist could further reduce morbidity and mortality.

Conclusions

Much time, effort, planning, and resources are required to ensure that anesthesia in low-income areas can reach internationally accepted standards. Such investment in anesthesia would result in wider access to surgical and obstetrical care, and the quality and safety of that care would be much improved.     

Polymersome nanoparticles for delivery of Wnt-activating small molecules

Spatiotemporal control of drug delivery is important for a number of medical applications and may be achieved using polymersome nanoparticles (PMs). Wnt signalling is a molecular pathway activated in various physiological processes, including bone repair, that requires precise control of activation. Here, we hypothesise that PMs can be stably loaded with a small molecule Wnt agonist, 6-bromoindirubin-3′-oxime (BIO), and activate Wnt signalling promoting the osteogenic differentiation in human primary bone marrow stromal cells (BMSCs). We showed that BIO-PMs induced a 40% increase in Wnt signaling activation in reporter cell lines without cytotoxicity induced by free BIO. BMSCs incubated with BIO-PMs showed a significant up-regulation of the Wnt target gene AXIN2 (14?±?4 fold increase, P?<?0.001) and a prolonged activation of the osteogenic gene RUNX2. We conclude that BIO-PMs could represent an innovative approach for the controlled activation of Wnt signaling for promoting bone regeneration after fracture.     

The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels

Vanadate has been shown to inhibit tyrosine phosphatase, leading to an increased tyrosine phosphorylation state. The latter has been demonstrated to be involved in the signal transduction pathway of ischemic preconditioning, the most potent endogenous mechanism to limit myocardial infarct size. Furthermore, there is evidence that phosphatase inhibition may be cardioprotective when given late after the onset of ischemia, but the mechanism of protection is unknown. We tested the hypothesis that the organic vanadate compound bis(maltolato)oxovanadium (BMOV) limits myocardial infarct size by attenuating reperfusion injury and investigated the underlying mechanism. Myocardial infarction was produced in 112 anesthetized rats by a 60-min coronary artery occlusion, and infarct size was determined histochemically after 180 min of reperfusion. Intravenous infusion of BMOV in doses of 3.3, 7.5, and 15 mg/kg i.v. decreased infarct size dose-dependently from 70 +/- 2% of the area at risk in vehicle-treated rats down to 41 +/- 5% (P < 0.05 versus control), when administered before occlusion. Administration of the low dose just before reperfusion was ineffective, but administration of the higher doses was equally cardioprotective as compared with administration before occlusion. The cardioprotection by BMOV was abolished by the tyrosine kinase inhibitor genistein and by the ATP-sensitive potassium (K(+)(ATP)) channel blocker glibenclamide but was not affected by the ganglion blocker hexamethonium. We conclude that BMOV afforded significant cardioprotection principally by limiting reperfusion injury. The mode of action appears to be by opening of cardiac K(+)(ATP) channels via increased tyrosine phosphorylation.