Blast-induced axonal degeneration in the rat cerebellum in the absence of head movement.

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or permitted in the lateral plane. Blast was found to produce axonal injury even with strict prevention of head movement. This axonal injury was restricted to the cerebellum, with the exception of injury in visual tracts secondary to ocular trauma. The cerebellar axonal injury was increased in rats in which blast-induced head movement was permitted, but the pattern of injury was unchanged. These findings support the contentions that blast per se, independent of head movement, is sufficient to induce axonal injury, and that axons in cerebellar white matter are particularly vulnerable to direct blast-induced injury.

Cost-Effectiveness Analysis of Robotic-assisted Lobectomy for Non-Small Cell Lung Cancer.

BACKGROUND: Robot-assisted thoracic surgery has emerged as an alternative to video-assisted thoracic surgery (VATS) for treating patients with resectable non-small cell lung cancer. The objective of this study was to evaluate the cost effectiveness of robotic-assisted lobectomy (RAL) compared with VATS and open lobectomy for adults with NSCLC. METHODS: A decision analysis model was employed to compare the cost effectiveness of RAL, VATS, and open lobectomy with 1-year time horizon from both health care and societal perspectives. Health care costs (2020$) and quality-adjusted life-years were compared between the approaches. The incremental cost-effectiveness ratio was calculated in terms of cost per quality-adjusted life-years gained. Sensitivity analyses were performed to identify variables driving cost effectiveness across several willingness-to-pay thresholds. RESULTS: Open thoracotomy was not cost effective compared with both RAL and VATS lobectomy. From the health care sector perspective, RAL was $394.97 more expensive per case than VATS resulting in an incremental cost-effectiveness ratio of $180 755.10 per quality-adjusted life-year. From the societal perspective, RAL was $247.77 more expensive per case than VATS, resulting in an incremental cost-effectiveness ratio of $113 388.80 per quality-adjusted life-years. Robotic-assisted lobectomy becomes cost effective with marginally lower robotic instrument costs, shorter operating room times, lower conversion rates, shorter lengths of stay, higher hospital volumes, and improved quality of life. Robotic-assisted lobectomy is also cost effective if surgeons can increase the proportion of minimally invasive lobectomies using robotic technology. CONCLUSIONS: Compared with VATS, RAL is not cost effective for lung cancer lobectomy at lower willingness-to-pay thresholds. However, several factors may drive RAL to emerge as the more cost-effective approach for minimally invasive lung cancer resection.

Cofilin-actin rod formation in neuronal processes after brain ischemia.

Functional impairment after brain ischemia results in part from loss of neuronal spines and dendrites, independent of neuronal death. Cofilin-actin rods are covalently linked aggregates of cofilin-1 and actin that form in neuronal processes (neurites) under conditions of ATP depletion and oxidative stress, and which cause neurite degeneration if not disassembled. ATP depletion and oxidative stress occur with differing severity, duration, and time course in different ischemic conditions. Here we evaluated four mouse models of brain ischemia to define the conditions that drive formation of cofilin-actin rods. Three of the models provide early reperfusion: transient middle cerebral artery occlusion (MCAo), transient bilateral common carotid artery occlusion (CCAo), and cardiac arrest / cardiopulmonary resuscitation (CA/CPR). Early reperfusion restores ATP generating capacity, but also induces oxidative stress. The fourth model, photothrombotic cortical infarction, does not provide reperfusion. Cofilin-actin rods were formed in each of these models, but with differing patterns. Where acute reperfusion occurred, rod formation was maximal within 4 hours after reperfusion. Where infarction occurred, rods continued to form for at least 24 hours after ischemic onset, and extended into the adjacent non-ischemic tissue. Interventions that limit cofilin-actin rod formation may help to preserve integrity of neuronal processes in permanent ischemia.

Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig.

The inflammation response induced by brain trauma can impair recovery. This response requires several hours to develop fully and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. We evaluated delayed treatment with veliparib, a poly(ADP-ribose) polymerase inhibitor, currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI). In rats, CCI induced a robust inflammatory response at the lesion margins, scattered cell death in the dentate gyrus, and a delayed, progressive loss of corpus callosum axons. Pre-determined measures of cognitive and motor function showed evidence of attentional deficits that resolved after three weeks and motor deficits that recovered only partially over eight weeks. Veliparib was administered beginning 2 or 24 h after CCI and continued for up to 12 days. Veliparib suppressed CCI-induced microglial activation at doses of 3 mg/kg or higher and reduced reactive astrocytosis and cell death in the dentate gyrus, but had no significant effect on delayed axonal loss or functional recovery. In pigs, CCI similarly induced a perilesional microglial activation that was attenuated by veliparib. CCI in the pig did not, however, induce detectable persisting cognitive or motor impairment. Our results showed veliparib suppression of CCI-induced microglial activation with a delay-to-treatment interval of at least 24 h in both rats and pigs, but with no associated functional improvement. The lack of improvement in long-term recovery underscores the complexities in translating anti-inflammatory effects to clinically relevant outcomes.

Targeted myocardial gene expression in failing hearts by RNA sequencing.

BACKGROUND: Myocardial recovery with left ventricular assist device (LVAD) therapy is highly variable and difficult to predict. Next generation ribonucleic acid (RNA) sequencing is an innovative, rapid, and quantitative approach to gene expression profiling in small amounts of tissue. Our primary goal was to identify baseline transcriptional profiles in non-ischemic cardiomyopathies that predict myocardial recovery in response to LVAD therapy. We also sought to verify transcriptional differences between failing and non-failing human hearts. METHODS: RNA was isolated from failing (n = 16) and non-failing (n = 8) human hearts. RNA from each patient was reverse transcribed and quantitatively sequenced on the personal genome machine (PGM) sequencer (Ion torrent) for 95 heart failure candidate genes. Coverage analysis as well as mapping the reads and alignment was done using the Ion Torrent Browser Suite™. Differential expression analyses were conducted by empirical analysis of digital gene expression data in R (edgeR) to identify differential expressed genes between failing and non-failing groups, and between responder and non-responder groups respectively. Targeted cardiac gene messenger RNA (mRNA) expression was analyzed in proportion to the total number of reads. Gene expression profiles from the PGM sequencer were validated by performing RNA sequencing (RNAseq) with the Illumina Hiseq2500 sequencing system. RESULTS: The failing sample population was 75% male with an average age of 50 and a left ventricular ejection fraction (LVEF) of 16%. Myosin light chain kinase (MYLK) and interleukin (IL)-6 genes expression were significantly higher in LVAD responders compared to non-responders. Thirty-six cardiac genes were expressed differentially between failing and non-failing hearts (23 decreased, 13 elevated). MYLK, Beta-1 adrenergic receptor (ADRB1) and myosin heavy chain (MYH)-6 expression were among those significantly decreased in failing hearts compared to non-failing hearts. Natriuretic peptide B (NPPB) and IL-6 were significantly elevated. Targeted gene expression profiles obtained from the Ion torrent PGM sequencer were consistent with those obtained from Illumina HiSeq2500 sequencing system. CONCLUSIONS: Heart failure is associated with a network of transcriptional changes involving contractile proteins, metabolism, adrenergic receptors, protein phosphorylation, and signaling factors. Myocardial MYLK and IL-6 expression are positively correlated with ejection fraction (EF) response to LVAD placement. Targeted RNA sequencing of myocardial gene expression can be utilized to predict responders to LVAD therapy and to better characterize transcriptional changes in human heart failure.

Cardiac magnetic resonance imaging for the assessment of the myocardium after doxorubicin-based chemotherapy.

OBJECTIVES: Doxorubicin is associated with a cumulative dose-dependent nonischemic cardiomyopathy. Cardiac magnetic resonance imaging (cMRI) is able to examine both structural and functional components of the myocardium. Our aim was to assess the myocardial changes in non-Hodgkin lymphoma patients undergoing doxorubicin-based chemotherapy using cMRI. MATERIALS AND METHODS: cMRI examination was performed before and 3 months after chemotherapy. Experienced investigators interpreted each cMRI, and were blinded to all data. Left ventricular ejection fractions (LVEF), cardiac deformation, and delayed gadolinium enhancement (GD-DE) were quantified for each cMRI. The change between LVEF, GD-GE, and cardiac deformation parameters were compared between the 2 cMRI studies. A Δ LVEF≥10% was considered clinically relevant. The findings of GD-GE or changes in myocardial strain were analyzed as independent variables. RESULTS: All 10 patients enrolled received a cumulative dose of doxorubicin of 300 mg/m. A comparison of pretreatment and posttreatment cMRI demonstrated 5 (50%) patients with a ≥10% decrease in LVEF (median, -8.4%; range, 1% to -17%; P=0.004). Three patients had at least 1 new or progressive segment of GD-DE. The global circumferential strain was significantly lower in patients after treatment, as compared with values before treatment (P=0.018) and to normal controls (P=0.046). Patients after treatment also had significantly lower global longitudinal strain than controls (P=0.035), and longitudinal strain values that tended to decrease compared with pretreatment values (P=0.073). DISCUSSION: Our data suggests that cMRI has the ability to assess both early structural and functional myocardial changes in association with doxorubicin-based chemotherapy.

Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors.

Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents.