Indications and outcomes of elective open chest lead extractions.

BACKGROUND: Complications associated with cardiovascular implantable electronic devices may necessitate device and lead removal. An open approach to removal may be electively chosen in cases with high risk of complications or those requiring additional concomitant cardiac surgery. This study aimed to investigate outcomes of patients who underwent elective open lead extractions (OLE) at two large tertiary care centers. METHODS: The records of 29 patients undergoing elective OLE were analyzed through retrospective chart review. RESULTS: 69 total leads were extracted from 29 patients (77% completely, 23% partially). The average age of the oldest leads was 13.3 ± 11.3 years. Infective endocarditis with severe valvular insufficiency requiring valvular intervention (41%)-an infectious etiology, and tricuspid valve intervention to correct RV lead-related severe TR (38%)-a noninfectious etiology, were the most common reasons for OLE. 38% of the patients had additional co-primary or secondary indications for open extraction, such as CABG and pericardiectomies. The rate of major complications and procedural failure was 3% each (1/29). 30-day survival was 100%, and 1-year survival was 92%. The average length of hospital stay was 15 days and higher among those undergoing OLE for infectious indications. CONCLUSION: Open lead extractions offered a similar clinical success rate (97%) to transvenous extractions in this cohort and may be a viable alternative for those necessitating valvular intervention or when the risk of complications from TLE is considered very high.

Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established. METHODS: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry. RESULTS: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively. CONCLUSIONS: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry.

PURPOSE: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis. METHODS: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram. RESULTS: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057). CONCLUSION: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.

Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning.

Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge; however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received "dummy drive" implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. OBJECTIVE: To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. METHODS: A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. RESULTS: The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). CONCLUSIONS: Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy.

PURPOSE OF REVIEW: Histologic evidence of myocardial inflammatory infiltrate not secondary to an ischemic injury is required by current diagnostic criteria to reach a definite diagnosis of myocarditis. Endomyocardial biopsy (EMB) is therefore often indicated for the diagnosis of myocarditis, although it may lack sufficient sensitivity considering the limited possibility of myocardial sampling. Improving the diagnostic yield and utility of EMB is of high priority in the fields of heart failure cardiology and myocarditis in particular. The aim of the present review is to highlight indications, strengths, and shortcomings of current EMB techniques, and discuss innovations currently being tested in ongoing clinical studies, especially in the setting of acute myocarditis and chronic inflammatory cardiomyopathy. RECENT FINDINGS: EMB provides unique diagnostic elements and prognostic information which can effectively guide the treatment of myocarditis. Issues affecting the diagnostic performance in the setting of acute myocarditis and chronic inflammatory cardiomyopathies will be discussed in this review in the light of recent expert consensus documents on the management of these conditions and on indication to EMB. Recent innovations using electroanatomic mapping (EAM)-guided EMB and fluoroscopic-guided EMB during temporary mechanical circulatory support have improved the utility of the procedure. EMB remains an important diagnostic test whose results need to be interpreted in the context of (1) clinical pre-test probability, (2) timing of sampling, (3) quality of sampling (4) site of sampling, (5) histologic type of myocarditis, and (6) analytic methods that are applied. Herein we will review these caveats as well as perspectives and innovations related to the use of this diagnostic tool.

Weighted activity unit effect: evaluating the cost of diagnosis-related group coding.

BACKGROUND: Activity-based funding (ABF) is a means of healthcare reimbursement, where hospitals are allocated funding based on the number and mix of clinical activity. The ABF model is based solely on Australian refined diagnosis-related group (AR-DRG) classifications of hospital encounters. Each AR-DRG is allocated a weighted activity unit (WAU) translating to cost value to determine ongoing funding allocations for each hospital annually. AIM: We explored cost consequences of AR-DRG coding variances within our Medical Oncology department over a 6-month period. METHODS: All inpatient encounters for medical oncology from 1 January to 30 June 2014 were identified and paired with actual AR-DRG coding sheets submitted by the hospital coders. Inpatient charts were manually reviewed by a Medical Oncology Registrar to capture any changes or additional AR-DRGs, which were subsequently evaluated for total WAU value variance. Applying 1 WAU = $4676 as per the 2014 Queensland model, cost consequences were calculated. RESULTS: A total of 116 encounters was identified for 72 patients. Of 116 patients, 95 (81%) had additional diagnoses captured, leading to an AR-DRG and WAU change in 26 encounters. The total reimbursement variance for this period was $143 404.07. Cost consequences resulted from: (i) use of abbreviations in clinical notes unable to be coded; and (ii) diagnoses not documented despite treatment delivered as per medication charts. CONCLUSION: Clinical note documentation ultimately determines the future funding of our healthcare system. Appropriate communication and education of medical staff and hospital coders are vital to ensure precise documentation and accurate AR-DRG coding for optimal and appropriate reimbursement in this funding model.

Transition Radiation in Photonic Topological Crystals: Quasiresonant Excitation of Robust Edge States by a Moving Charge.

We demonstrate, theoretically and experimentally, that a traveling electric charge passing from one photonic crystal into another generates edge waves-electromagnetic modes with frequencies inside the common photonic band gap localized at the interface-via a process of transition edge-wave radiation (TER). A simple and intuitive expression for the TER spectral density is derived and then applied to a specific structure: two interfacing photonic topological insulators with opposite spin-Chern indices. We show that TER breaks the time-reversal symmetry and enables valley- and spin-polarized generation of topologically protected edge waves propagating in one or both directions along the interface. Experimental measurements at the Argonne Wakefield Accelerator Facility are consistent with the excitation and localization of the edge waves. The concept of TER paves the way for novel particle accelerators and detectors.

Generation of High-Power, Reversed-Cherenkov Wakefield Radiation in a Metamaterial Structure.

We present the first demonstration of high-power, reversed-Cherenkov wakefield radiation by electron bunches passing through a metamaterial structure. The structure supports a fundamental transverse magnetic mode with a negative group velocity leading to reversed-Cherenkov radiation, which was clearly verified in the experiments. Single 45 nC electron bunches of 65 MeV traversing the structure generated up to 25 MW in 2 ns pulses at 11.4 GHz, in excellent agreement with theory. Two bunches of 85 nC with appropriate temporal spacing generated up to 80 MW by coherent wakefield superposition, the highest rf power that metamaterial structures ever experienced without damage. These results demonstrate the unique features of metamaterial structures that are very attractive for future high-gradient wakefield accelerators, including two-beam and collinear accelerators. Advantages include the high shunt impedance for high-power generation and high-gradient acceleration, the simple and rugged structure, and a large parameter space for optimization.

Alzheimer's Disease and Cancer: When Two Monsters Cannot Be Together.

Alzheimer's disease (AD) and cancer are among the leading causes of human death around the world. While neurodegeneration is the main feature of AD, the most important characteristic of malignant tumors is cell proliferation, placing these two diseases in opposite sides of cell division spectrum. Interestingly, AD and cancer's pathologies consist of a remarkable common feature and that is the presence of active cell cycle in both conditions. In an in vitro model of primary adult neuronal culture, we previously showed that treating cell with beta amyloid forced neurons to start a cell cycle. Instead of cell division, however, neuronal cell cycle was aborted and a massive neurodegeneration was left behind as the consequence. A high level of cell cycle entry, which is a requirement for cancer pathogenesis, was reported in clinically diagnosed cases of AD, leading to neurodegeneration. The diverse clinical manifestation of a similar etiology, have puzzled researchers for many years. In fact, the evidence showed an inverse association between AD and cancer prevalence, suggesting that switching pathogenesis toward AD protects patients against cancer and vice versa. In this mini review, we discussed the possibility of involvement of cell proliferation and survival dysregulation as the underlying mechanism of neurodegeneration in AD, and the leading event to develop both disorders' pathology. As examples, the role of phosphoinositide 3 kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in cell cycle re-entry and blocking autophagy are discussed as potential common intracellular components between AD and cancer pathogenesis, with diverse clinical diagnosis.

Femoral Access for Iliac Branched Endoprosthesis Deployment in Patients with a Prior Bifurcated Aortic Stent Graft.

This series describes an innovative technique to deploy iliac branched endoprostheses (IBEs) in patients with preexisting endovascular aneurysm repair (EVAR). It demonstrates an alternative approach that may be preferred when brachial access is anatomically challenging or when access site complications are of concern. We detail a technique that uses transfemoral access to bring IBE device components up and over an infrarenal endograft bifurcation and into proper position. This series suggests that endovascular specialists should consider the advantages and disadvantages of a transfemoral approach when selecting the best method of repairing a patient's iliac artery aneurysm after prior EVAR.

A comparison of LKB1/AMPK/mTOR metabolic axis response to global ischaemia in brain, heart, liver and kidney in a rat model of cardiac arrest.

BACKGROUND: Cellular energy failure in high metabolic rate organs is one of the underlying causes for many disorders such as neurodegenerative diseases, cardiomyopathies, liver and renal failures. In the past decade, numerous studies have discovered the cellular axis of LKB1/AMPK/mTOR as an essential modulator of cell homeostasis in response to energy stress. Through regulating adaptive mechanisms, this axis adjusts the energy availability to its demand by a systematized control on metabolism. Energy stress, however, could be sensed at different levels in various tissues, leading to applying different strategies in response to hypoxic insults. METHODS: Here the immediate strategies of high metabolic rate organs to time-dependent short episodes of ischaemia were studied by using a rat model (n = 6/group) of cardiac arrest (CA) (15 and 30 s, 1, 2, 4 and 8 min CA). Using western blot analysis, we examined the responses of LKB1/AMPK/mTOR pathway in brain, heart, liver and kidney from 15 s up to 8 min of global ischaemia. The ratio of ADP/ATP was assessed in all ischemic and control groups, using ApoSENSOR bioluminescent assay kit. RESULTS: Brain, followed by kidney showed the early dephosphorylation response in AMPK (Thr172) and LKB1 (Ser431); in the absence of ATP decline (ADP/ATP elevation). Dephosphorylation of AMPK was followed by rephosphorylation and hyperphosphorylation, which was associated with a significant ATP decline. While heart's activity of AMPK and LKB1 remained at the same level during short episodes of ischaemia, liver's LKB1 was dephosphorylated after 2 min. AMPK response to ischaemia in liver was mainly based on an early alternative and a late constant hyperphosphorylation. No significant changes was observed in mTOR activity in all groups. CONCLUSION: Together our results suggest that early AMPK dephosphorylation followed by late hyperphosphorylation is the strategy of brain and kidney in response to ischaemia. While the liver seemed to get benefit of its AMPK system in early ischameia, possibly to stabilize ATP, the level of LKB1/AMPK activity in heart remained unchanged in short ischaemic episodes up to 8 min. Further researches must be conducted to elucidate the molecular mechanism underlying LKB1/AMPK response to oxygen supply.

Trends in vena cava filter insertions and "prophylactic" use.

BACKGROUND: Prophylactic vena cava filter (VCF) use in patients without venous thromboembolism is common practice despite ongoing controversy. Thorough analysis of the evolution of this practice is lacking. We describe trends in VCF use and identify events associated with changes in practice. METHODS: Using the National Inpatient Sample, we conducted a retrospective observational study of U.S. adult hospitalizations from 2000 to 2014. Trends in prophylactic VCF insertion were analyzed both across the entire study population and within subgroups according to trauma status and type of concurrent surgery. Annual percentage change (APC) was calculated, and trends were analyzed using Poisson regression. RESULTS: Among 461,904,314 adult inpatients (median [interquartile range] age, 58.1 [38.5-74.3] years; 39.6% male), the incidence of VCF insertion increased rapidly at first (from 0.19% to 0.35%; APC, 11.2%; 95% confidence interval [CI], 10.3%-12.2%; P < .001), then at a slower rate after the publication of the Prévention du Risque d'Embolie Pulmonaire par Interruption Cave 2 (PREPIC2) trial in 2005 (from 0.35% to 0.42%; APC, 4.4%; 95% CI, 2.8%-6.0%; P < .001), and it began decreasing after the 2010 Food and Drug Administration (FDA) safety alert (from 0.42% to 0.32%; APC, -5.5%; 95% CI, -6.5% to -4.6%; P < .001). The percentage of total VCFs that had a prophylactic indication increased quickly before publication of the PREPIC2 trial (APC, 19.5%; 95% CI, 17.9%-21.0%; P < .001), increased at a slower rate after publication in 2005 (APC, 4.4%; 95% CI, 2.6%-6.2%; P < .001), and dropped after the FDA safety alert, stabilizing at 18.5% for the last 3 years (APC, -0.3%; 95% CI, -2.2% to 1.7%; P = .8). Subgroups most associated with prophylactic VCF insertion were operative trauma (odds ratio [OR], 10.9; 95% CI, 10.2-11.7), orthopedic surgery (OR, 4.7; 95% CI, 4.3-5.2), and neurosurgical procedures (OR, 3.9; 95% CI, 3.6-4.2). All groups except orthopedic surgery experienced a deceleration in prophylactic VCF growth after the publication of PREPIC2. Meanwhile, the FDA safety alert was associated with a decrease in prophylactic VCF insertions for all groups except other major surgery. CONCLUSIONS: Whereas publication of the PREPIC2 trial led to a deceleration in prophylactic VCF insertion growth, the FDA alert had a bigger impact, leading to declining rates of prophylactic VCF use. Further investigations of prophylactic insertion of VCF in trauma, orthopedic, and neurosurgical patients are needed to determine whether current levels of use are justified.

Oxidative Stress and Decreased Mitochondrial Superoxide Dismutase 2 and Peroxiredoxins 1 and 4 Based Mechanism of Concurrent Activation of AMPK and mTOR in Alzheimer's Disease.

BACKGROUND: Emerging evidence supports the hypothesis that metabolism dysfunction is involved in pathogenesis of Alzheimer's disease (AD). One aspect of metabolic dysfunction includes dysregulation of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin (mTOR) metabolic axis, which is extensively present in some of the leading causes of AD such as cerebrovascular diseases, type 2 diabetes and brain ischaemic events. While the molecular basis underlying this metabolic dysregulation remains a significant challenge, mitochondrial dysfunction due to aging appears to be an essential factor to activate AMPK/mTOR signaling pathway, leading to abnormal neuronal energy metabolism and AD pathology. METHODS: Using immunofluorescent imaging by Lecia confocal microscopy, we analyzed the activation of AMPK/mTOR. Concurrently, the level of mitochondrial antioxidant enzymes of superoxide dismutase 2 (SOD2) and peroxiredoxin 1 and 4 (p1 and p4) along with protein and DANA oxidation were examined to in postmortem brains of AD (n= 8) and normal (n= 7) subjects to evaluate the metabolism dysfunction role in AD pathology. RESULTS: In spite of AMPK inhibitory control on mTOR, concurrent phosphorylation of AMPK and mTOR (p-AMPK and p-mTOR) was observed in AD brains with high colocalization with hyperphosphorylated tau. Mitochondrial antioxidant enzymes of SOD2 and p1 and p4 were substantially decreased in p-AMPK, p-mTOR and p-tau positive cells along with higher levels of DNA and protein oxidation. CONCLUSION: Collectively, we conclude that AMPK and mTOR metabolic axis is highly activated in AD brains. While the inhibitory link between AMPK and mTOR seems to be disrupted, we suggest oxidative stress as the underlying mechanism for concurrent activation of AMPK and mTOR in AD.

Compound C enhances tau phosphorylation at Serine396 via PI3K activation in an AMPK and rapamycin independent way in differentiated SH-SY5Y cells.

Aggregation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFT) is a main hallmark for Alzheimer's disease (AD). Activation of cellular metabolic axis, made of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin (mTOR) have been implicated in generating tau pathology of AD. Thus, blocking either of these two proteins or both, are suggested as the future therapeutic approaches for AD. How and to what level these approaches could be applied, however are not entirely clear. By using Compound C (CC) in this study, we showed a substantial decrease in mTOR activity in a rapamycin-independent way without blocking AMPK. This decline in mTOR activity was accompanied by an increase in phosphoinositide 3 kinase (PI3K)/Akt activity and a parallel increase in p-tau (Ser396) but not p-tau (Ser262) in differentiated SH-SY5Y neuroblastoma cells. This elevation was blocked when the cells were treated with 15 µM of LY294002, a specific PI3K inhibitor, suggesting PI3K involvement in CC-mediated tau hyperphosphorylation at Ser396. For all groups the activity levels of glycogen synthase kinase-3ß (GSK-3ß), cyclin-dependent kinase-5 (cdk5) and protein phosphatase 2A (PP2A), the other main kinases and phosphatase responsible for tau phosphorylation/dephosphorylation remained unchanged. Collectively, our results demonstrate that rapamycin-independent blocking of mTOR enhances p-tau (Ser396) in a PI3K-dependent way, suggesting the careful consideration of future therapeutic approaches for AD, which will be based on mTOR inhibition.