Citations

Background Renovascular hypertension ( RVH ) impairs cardiac structure and left ventricular ( LV ) function, but whether mitochondrial injury is implicated in RVH ‐induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. Methods and Results After 12 weeks of hypercholesterolemic ( HC )‐ RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial‐targeted peptide ( MTP ), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner‐membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector‐computed tomography and oxygenation by blood‐oxygen‐level–dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic‐reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert‐butyl hydroperoxide ( tBHP ) untreated or treated with MTP . Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin‐sensitive sarcoplasmic reticulum Ca 2+ ‐ ATP ase activity that declined in HC ‐ RVH normalized in MTP ‐treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP ‐treated pigs. In tBHP ‐treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. Conclusions Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC ‐ RVH , suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.

Abstract Introduction. For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. Materials and Methods. Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. Results. A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. Conclusion. Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.

Abstract There are three main patterns of complex elbow instability: posterolateral (terrible triad), varus posteromedial (anteromedial coronoid fracture with lateral collateral ligament complex disruption), and trans-olecranon fracture dislocations. Radial head fractures, in the setting of complex elbow instability, often require internal fixation or arthroplasty; the outcome of radial head replacement is dictated by adequate selection of the head diameter, correct restoration of radial length, and proper alignment and tracking. Small coronoid fractures can be ignored. Larger coronoid fractures, especially those involving the anteromedial facet, require fixation or graft reconstruction, particularly in the presence of incongruity. The lateral collateral ligament complex should be repaired whenever disrupted. Medial collateral ligament disruptions seem to heal reliably without surgical repair provided all other involved structures are addressed. The most common mistakes in the management of trans-olecranon fracture dislocations are suboptimal fixation, lack of fixation of coronoid fragments, and lack of restoration of the natural dorsal angulation of the ulna. Cite this article: Sanchez-Sotelo J, Morrey M. Complex elbow instability. EFORT Open Rev 2016;1:183-190.

The large conductance Ca2+-activated K+ (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes.

Abstract Rationale The use of tunneled indwelling pleural catheters for management of refractory pleural effusions continues to increase. Pleural space infections are among the most common and serious complication of the procedure. The risk may be higher in patients receiving immunosuppressive medications. Objectives The aim of this study was to assess the risk of infections complicating placement of a tunneled indwelling pleural catheter in patients who have received a solid organ transplant. Methods Electronic medical records were retrospectively reviewed to identify patients with prior solid organ transplant who subsequently underwent placement of a tunneled intrapleural catheter. We selected a matched sample of comparison patients without solid organ transplant who underwent the same procedure during the study period. Detailed chart abstraction was performed to compare baseline clinical information with procedure outcomes in both groups. Measurements and Main Results: Nineteen study patients underwent kidney, liver, lung, or heart transplant. Another 55 patients were included in the nontransplant comparison group. Transplant patients were taking a mean of 2.4 (range, 1–4) immunosuppressive medications. In transplant patients, the intrapleural catheter remained in place for a median of 95 days (interquartile range, 58–256 d). Two of the 19 transplant patients (16.9% 90-day Kaplan–Meier estimate) and 4 of the 55 control patients (11.0% weighted 90-day Kaplan–Meier estimate) developed a major infectious complication (not significant). There were no deaths attributed to intrapleural catheter placement in either group. Conclusions In a series of 19 patients with solid organ transplantation taking daily immunosuppressive medications who underwent placement of a tunneled intrapleural catheter, we report an 11% rate of major infectious complications over the lifetime of the catheter in the transplant group with no significant difference in 90-day estimated risk of complication between transplant and nontransplant comparison group.