Do False Tendons Prevent Adverse Left Ventricular Remodeling After Anterior Wall Myocardial Infarction? An Echocardiographic Strain Imaging Study.

The role of muscular left ventricular (LV) false tendons (FTs) is poorly understood. To gain insight into their pathophysiologic significance, we adapted echocardiographic LV strain imaging software to measure LVFT longitudinal strain in subjects with normal left ventricles and in patients who sustained previous anterior wall myocardial infarction (AWMI). GE EchoPAC software was used to measure longitudinal strain in LVFTs ≥0.3 cm in diameter. Tendinous strain was measured in 11 patients with LVFTs confined to the left anterior descending artery territory (connecting the anteroseptum or anterior wall to the apex) ≥6 months after AWMI (myocardial infarction [MI]+FT+ group) and in 25 patients with normal hearts containing LVFTs (MI-FT+ group). We also compared the indexed LV end-diastolic volumes in the MI+FT+ group to that of 25 patients with previous AWMI without LVFTs (MI+FT- group). The mean LVFT strain in MI+FT+ group was 5.5 ± 6.2% and -28.9 ± 4.7% in the MI-FT+ group (p <0.0001). The indexed LV end-diastolic volume in the MI+FT+ group did not differ from the MI+FT- group (88.4 ± 17.8 vs 87.9 ± 17 ml/m2, p = 0.90). In conclusion, the negative strain (contraction) developed by LVFTs in the MI-FT+ group may help maintain normal LV size and shape by generating inward restraining forces. The development of positive strain (stretch) in LVFTs in patients in the MI+FT+ group suggests they become infarcted after AWMI. This implies that they are incapable of generating inward restraining forces that might otherwise mitigate adverse remodeling. Of note, LV volumes after AWMI do not differ whether or not LVFTs are present.

Masked autoencoders with handcrafted feature predictions: Transformer for weakly supervised esophageal cancer classification.

BACKGROUND AND OBJECTIVE: Esophageal cancer is a serious disease with a high prevalence in Eastern Asia. Histopathology tissue analysis stands as the gold standard in diagnosing esophageal cancer. In recent years, there has been a shift towards digitizing histopathological images into whole slide images (WSIs), progressively integrating them into cancer diagnostics. However, the gigapixel sizes of WSIs present significant storage and processing challenges, and they often lack localized annotations. To address this issue, multi-instance learning (MIL) has been introduced for WSI classification, utilizing weakly supervised learning for diagnosis analysis. By applying the principles of MIL to WSI analysis, it is possible to reduce the workload of pathologists by facilitating the generation of localized annotations. Nevertheless, the approach's effectiveness is hindered by the traditional simple aggregation operation and the domain shift resulting from the prevalent use of convolutional feature extractors pretrained on ImageNet. METHODS: We propose a MIL-based framework for WSI analysis and cancer classification. Concurrently, we introduce employing self-supervised learning, which obviates the need for manual annotation and demonstrates versatility in various tasks, to pretrain feature extractors. This method enhances the extraction of representative features from esophageal WSI for MIL, ensuring more robust and accurate performance. RESULTS: We build a comprehensive dataset of whole esophageal slide images and conduct extensive experiments utilizing this dataset. The performance on our dataset demonstrates the efficiency of our proposed MIL framework and the pretraining process, with our framework outperforming existing methods, achieving an accuracy of 93.07% and AUC (area under the curve) of 95.31%. CONCLUSION: This work proposes an effective MIL method to classify WSI of esophageal cancer. The promising results indicate that our cancer classification framework holds great potential in promoting the automatic whole esophageal slide image analysis.

WS-MTST: Weakly Supervised Multi-Label Brain Tumor Segmentation With Transformers.

Brain tumor segmentation is a key step in brain cancer diagnosis. Segmentation of brain tumor sub-regions, including necrotic, enhancing, and edematous regions, can provide more detailed guidance for clinical diagnosis. Weakly supervised brain tumor segmentation methods have received much attention because they do not require time-consuming pixel-level annotations. However, existing weakly supervised methods focus on the segmentation of the entire tumor region while ignoring the challenging task of multi-label segmentation for the tumor sub-regions. In this article, we propose a weakly supervised approach to solve the multi-label brain tumor segmentation problem. To the best of our knowledge, it's the first end-to-end multi-label weakly supervised segmentation model applied to brain tumor segmentation. With well-designed loss functions and a contrastive learning pre-training process, our proposed Transformer-based segmentation method (WS-MTST) has the ability to perform segmentation of brain tumor sub-regions. We conduct comprehensive experiments and demonstrate that our method reaches the state-of-the-art on the popular brain tumor dataset BraTS (from 2018 to 2020).

Interaction between GPR110 (ADGRF1) and tight junction protein occludin implicated in blood-brain barrier permeability.

Activation of adhesion receptor GPR110 by the endogenous ligand synaptamide promotes neurogenesis, neurite growth, and synaptogenesis in developing brains through cAMP signal transduction. However, interacting partners of GPR110 and their involvement in cellular function remain unclear. Here, we demonstrate using chemical crosslinking, affinity purification, and quantitative mass spectrometry that GPR110 interacts with the tight junction adhesion protein occludin. By removing non-specific partners by comparing the binding proteins of GPR110 WT and an inactive mutant exhibiting impaired surface expression, occludin was distinguished as a true binding partner which was further confirmed by reciprocal co-immunoprecipitation assay. Deletion of GPR110 in mice led to the disruption of blood-brain barrier (BBB) and reduced occludin phosphorylation at Y285 in the brain. The Y285 phosphorylation increased upon the ligand-induced activation of GPR110. These data suggest an important role of GPR110-occludin interaction in BBB function and association of previously unknown GPR110-dependent occludin phosphorylation at Y285 with BBB integrity.

Wide Complex Tachycardia: The Answer Is in Front of You.

Supraventricular tachycardia with aberrancy and ventricular tachycardia can often be differentiated on the basis of subtle findings. We present an electrocardiogram with findings of Coumel's sign, which is diagnostic of atrioventricular re-entrant tachycardia using an accessory pathway. (Level of Difficulty: Advanced.).

Impact of complex percutaneous coronary intervention features on clinical outcomes in patients with or without chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) are at higher risk of ischemic and bleeding events after percutaneous coronary intervention (PCI). Complex PCI (CPCI) is associated with higher rates of ischemic complications. Whether CPCI confers an additive risk of adverse events in CKD patients is unclear. METHODS: Patients who underwent PCI at a single tertiary-care-center between 2012 and 2019 were stratified by CKD status and CPCI. The primary outcome was major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), and target-vessel revascularization (TVR) at 1-year follow-up. Secondary outcomes included the individual components of the primary outcome and major bleeding. RESULTS: Out of 15,071 patients, 4537 (30.1%) had CKD and 10,534 (69.9%) had no CKD. Patients undergoing CPCI were 1151 (25.4%) and 2983 (28.3%) in the two cohorts, respectively. At one year, CPCI compared with no CPCI was associated with higher risk of MACE in both CKD (Adj. HR 1.72, 95% confidence interval [CI] 1.45-2.06, p < 0.001) and no-CKD patients (Adj. hazard ratios [HR] 2.19, 95% CI 1.91-2.51, p < 0.001; p of interaction 0.057), determined by an excess of death, MI and TVR in CKD patients and of TVR and MI only in no-CKD. CPCI was related with a consistent increase of major bleeding in the CKD (Adj. HR 1.49, 95% CI 1.18-1.87, p < 0.001) and no-CKD group (Adj. HR 1.23, 95% CI 0.98-1.54, p = 0.071, p of interaction 0.206). CONCLUSION: At 1-year follow-up, CPCI was associated with higher risk of MACE and major bleeding irrespective of concomitant CKD. CPCI predicted mortality in CKD patients only.

Cardiac Imaging for Diagnosis and Management of Infective Endocarditis.

Imaging is central to the care of patients with infective endocarditis. Although transthoracic and transesophageal echocardiography are the principal imaging techniques, additional modalities including positron emission tomography and cardiac computed tomography, and to a lesser extent intracardiac echocardiography, play an increasing role. This review discusses the role of cardiac imaging in establishing the diagnosis of endocarditis, in predicting its embolic risk, and in making decisions regarding the need for and timing of surgery.

Human-Body-Temperature Triggerable Phase Transition of W-VO2@PEG Nanoprobes with Strong and Switchable NIR-II Absorption for Deep and Contrast-Enhanced Photoacoustic Imaging.

The immense potential of temperature-responsive nanomaterials for use as contrast agents has propelled much recent research and development in the field of photoacoustic (PA) imaging, while the exorbitant transition temperature exceeding the human-tolerable range and the low reversibility of the reported temperature-sensitive nanosystems are still two severe issues that hinder effective imaging and long-term monitoring in practical applications. Herein, we propose a high-performing thermoresponsive polyethylene glycol-coated tungsten-doped vanadium dioxide (W-VO2@PEG) nanoprobe (NP) with strong and switchable optical absorption in the near-infrared-II (NIR-II) biowindow (1000-1700 nm) near human-body temperature, to achieve deep and contrast-enhanced PA imaging. Our study shows that the PA signal amplitude of W-VO2@PEG NPs at 1064 nm increases up to 260% when the temperature increases from 35 °C to 45 °C, with a signal fluctuation of less than 10% after 10 temperature cycles, therefore enabling great potential of "off-to-on" dynamic contrast-enhanced imaging capability in deep-seated tissues. Experiments on tissue-mimicking phantoms and in vitro chicken breast showed that, by levering the prepared W-VO2@PEG NPs and dynamically modulating the temperature field with an external NIR optical stimulus, contrast-enhanced PA images of the target can be obtained with an imaging depth up to 1.5 cm. Furthermore, in vivo potential of the prepared thermoresponsive NPs for the detection and identification of deep-seated tumors by directly comparing to conventional "always on" NPs has been demonstrated. Our work will offer feasible guidance for the development of smart temperature-activatable PA NPs with improved imaging depth and imaging contrast.

GPR110 ligands reduce chronic optic tract gliosis and visual deficit following repetitive mild traumatic brain injury in mice.

BACKGROUND: Repetitive mild traumatic brain injury (mTBI) can result in chronic visual dysfunction. G-protein receptor 110 (GPR110, ADGRF1) is the target receptor of N-docosahexaenoylethanolamine (synaptamide) mediating the anti-neuroinflammatory function of synaptamide. In this study, we evaluated the effect of an endogenous and a synthetic ligand of GPR110, synaptamide and (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-hydroxy-2-methylpropyl) docosa-4,7,10,13,16,19-hexaenamide (dimethylsynaptamide, A8), on the mTBI-induced long-term optic tract histopathology and visual dysfunction using Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), a clinically relevant model of mTBI. METHODS: The brain injury in wild-type (WT) and GPR110 knockout (KO) mice was induced by CHIMERA applied daily for 3 days, and GPR110 ligands were intraperitoneally injected immediately following each impact. The expression of GPR110 and proinflammatory mediator tumor necrosis factor (TNF) in the brain was measured by using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in an acute phase. Chronic inflammatory responses in the optic tract and visual dysfunction were assessed by immunostaining for Iba-1 and GFAP and visual evoked potential (VEP), respectively. The effect of GPR110 ligands in vitro was evaluated by the cyclic adenosine monophosphate (cAMP) production in primary microglia isolated from adult WT or KO mouse brains. RESULTS: CHIMERA injury acutely upregulated the GPR110 and TNF gene level in mouse brain. Repetitive CHIMERA (rCHIMERA) increased the GFAP and Iba-1 immunostaining of glia cells and silver staining of degenerating axons in the optic tract with significant reduction of N1 amplitude of visual evoked potential at up to 3.5 months after injury. Both GPR110 ligands dose- and GPR110-dependently increased cAMP in cultured primary microglia with A8, a ligand with improved stability, being more effective than synaptamide. Intraperitoneal injection of A8 at 1 mg/kg or synaptamide at 5 mg/kg significantly reduced the acute expression of TNF mRNA in the brain and ameliorated chronic optic tract microgliosis, astrogliosis, and axonal degeneration as well as visual deficit caused by injury in WT but not in GPR110 KO mice. CONCLUSION: Our data demonstrate that ligand-induced activation of the GPR110/cAMP system upregulated after injury ameliorates the long-term optic tract histopathology and visual impairment caused by rCHIMERA. Based on the anti-inflammatory nature of GPR110 activation, we suggest that GPR110 ligands may have therapeutic potential for chronic visual dysfunction associated with mTBI.

From Lab Formulation Development to CTM Manufacturing of KO-947 Injectable Drug Products: a Case Study and Lessons Learned.

Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at -20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial.

Higher n-3 Polyunsaturated Fatty Acid Diet Improves Long-Term Neuropathological and Functional Outcome after Repeated Mild Traumatic Brain Injury.

Repeated mild traumatic brain injury (TBI) can cause persistent neuropathological effects and is a major risk factor for chronic traumatic encephalopathy. PUFAs (n-3 polyunsaturated fatty acids) were shown to improve acute TBI outcomes in single-injury models in most cases. In this study, we demonstrate positive effects of dietary n-3 PUFA on long-term neuropathological and functional outcome in a clinically relevant model of repeated mild TBI using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Adult mice, reared on n-3 PUFA adequate (higher n-3 PUFA) or deficient (lower n-3 PUFA) diets, were given a mild CHIMERA daily for 3 consecutive days. At 2 months after injury, visual function and spatial memory were evaluated. Glia cell activation was assessed by immunostaining using antibodies of ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein, and axonal damage was examined using silver staining. Repeated CHIMERA (rCHIMERA)-induced gliosis was significantly suppressed in the optic tract, corpus callosum, and hippocampus of mice fed the n-3 PUFA adequate diet compared to the deficient diet group. Considerable axonal damage was detected in the optic tract after rCHIMERA, but the adequate diet group displayed less axonal damage compared to the deficient diet group. rCHIMERA induced a drastic reduction in N1 amplitude of the visual evoked potential in both diet groups and the a-wave amplitude of the electroretinogram in the deficient diet group. However, reduction of N1 and a-wave amplitude were less severe in the adequate diet group. The Morris water maze probe test indicated a significant decrease in the number of platform crossings in the deficient diet group compared to the adequate group. In summary, dietary n-3 PUFA can attenuate persistent glial cell activation and axonal damage and improve deficits in visual function and spatial memory after repeated mild TBI. These data support the neuroprotective potential of a higher n-3 PUFA diet in ameliorating the adverse outcome of repeated mild TBI.

Investigation of the effect of dietary intake of omega-3 polyunsaturated fatty acids on trauma-induced white matter injury with quantitative diffusion MRI in mice.

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.

Multiple Mild Traumatic Brain Injuries Lead to Visual Dysfunction in a Mouse Model.

Visual dysfunction is a common occurrence after traumatic brain injury (TBI). We investigated in this study effects of single or multiple mild TBI on visual function in mice using a closed head injury model that permits unconstrained head movement after impact. Adult mice were briefly anesthetized with isoflurane and given one or three mild TBI with the closed head injury by mechanically engineered rotational acceleration (CHIMERA) device with an interinjury interval of 24 h. Mice were then tested in the Morris water maze, visual cliff, and open field tests from day 19 to day 32 and for visual evoked potential at 5 weeks after the last injury and euthanized. Mice with multiple TBI showed impaired performance in the visible platform water maze test and had increased errors in the visual cliff test. Further, there was a graded difference in visual evoked potential, with the single injury mice showing modest reduction in N1 amplitude whereas the multiple injuries produced significant reduction compared to sham and single injury groups. The optic tract of the injured mice showed increases in glial cell immunostaining. The increase in glial fibrillary acid protein immunostaining reached statistical significance for both injured groups whereas the ionized calcium binding adaptor molecule 1 immunostaining was only significantly increased in the optic tract of repeatedly injured mice. These results indicate that multiple injuries using CHIMERA may result in visual deficits, which can affect certain behavioral performances. The change in vision may be a useful marker when monitoring repeated TBI outcome and screening for protective agents from TBI.

Incidence, predictors and impact of stroke on mortality among patients with acute coronary syndromes following percutaneous coronary intervention-Results from the PROMETHEUS registry.

BACKGROUND: Stroke represents a potentially calamitous complication among patients with acute coronary syndrome (ACS) undergoing percutaneous intervention (PCI). Data on the distribution of stroke occurrence post-PCI and its impact on mortality are scarce. OBJECTIVES: We sought to determine the incidence, predictors and impact of stroke on mortality in ACS patients undergoing PCI. METHODS: A total of 19,914 ACS patients underwent PCI in the PROMETHEUS multicenter observational study. We calculated the cumulative stroke incidence at 30 days and 1 year using the Kaplan Meier method. We also compared the distribution of stroke, myocardial infarction (MI), and bleeding across time and evaluated their overlap. Predictors of stroke were identified through multivariable Cox-regression. Stroke, MI, and bleeding were assessed as time-updated covariates to estimate how each impacts subsequent mortality. RESULTS: We found that 244 patients had a stroke within 1 year, a cumulative incidence of 1.5%. Previous cerebrovascular disease was the strongest predictor for post-PCI stroke, followed by ST-elevation MI presentation, hypertension, non-ST-elevation MI presentation, smoking, female sex, and age. Mortality risk was significantly higher among those who had a stroke versus those who did not (adjusted HR 4.84, p < .0001). However, the association attenuated over time with a much larger effect in the first 30 days of its occurrence (adjusted HR 17.7; 95% CI: 12.3-25.4, p < .0001) versus beyond 30 days (adjusted HR 1.22; 95% CI: 0.6-2.46, p = .58). CONCLUSIONS: Stroke occurrence within 1 year was not uncommon for ACS patients undergoing PCI. When compared with MI and bleeding, stroke had a substantial impact on mortality that attenuated rapidly over time.

GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine.

BACKGROUND: Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. METHODS: For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. RESULTS: Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1ß in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. CONCLUSION: Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.

Photoacoustic thermorelaxation microscopy for thermal diffusivity measurement.

Thermal diffusivity is one of the main parameters to characterize the thermo-physical properties of materials, and advances in its measurement technique will have significant impact on materials science and related applications. Here a photoacoustic (PA) thermorelaxation microscopy is proposed as a new noncontact method to measure the thermal diffusivity. By delivering co-focused heating/probing laser pulse pairs with tunable time delays, the sample's in situ thermal relaxation behavior after the heating pulse excitation can be photoacoustically monitored based on the temperature-dependent property of the Grueneisen parameter. We theoretically deduced the dependence of the obtained PA thermorelaxation time on the thermal diffusivity, and the results coincided well with simulations. The feasibility of this method was validated by various industrial and biological samples. This method provides a new strategy for high-resolution thermal diffusivity measurement with flexible measurement conditions, prefiguring great potential for material and biological applications.

Optimal duration of dual antiplatelet therapy after PCI: integrating procedural complexity, bleeding risk and the acuteness of clinical presentation.

INTRODUCTION: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor constitutes the standard of care to prevent major adverse cardiac events in patients who undergo percutaneous coronary intervention (PCI) with drug-eluting stents (DES). However, the anti-ischemic benefits of DAPT are counterbalanced by an increased risk of hemorrhagic complications, which are known to be associated with increased morbidity and mortality. While the efficacy of DAPT in patients presenting with acute coronary syndrome (ACS) has been well established, the risk-benefit balance of DAPT in other subsets of patients remain controversial. As a result, multiple risk scores to inform optimal duration of DAPT have been developed recently for individuals with various degrees of coronary artery disease. Areas covered: Authors summarize the current evidence and guideline recommendations on the optimal duration and intensity of DAPT across the spectrum of coronary artery disease including those who undergo complex PCI and recapitulated the recently developed risk scores to inform clinical decision on the optimal duration of DAPT. Expert commentary: Clinical decision-making for upfront duration of DAPT after PCI with DES should consider the individual bleeding risk profile, the initial clinical presentation and the complexity of coronary stenting.

Repetitive Closed-Head Impact Model of Engineered Rotational Acceleration Induces Long-Term Cognitive Impairments with Persistent Astrogliosis and Microgliosis in Mice.

Repeated mild traumatic brain injury (rmTBI) has been identified by epidemiology as a high-risk factor for dementia at a later stage in life. Animal models to replicate complex features of human rmTBI and/or to evaluate long-term effects on brain function have not been established. In this study, we used a novel closed-head impact model of engineered rotational acceleration (CHIMERA) to investigate the long-term neuropathological and cognitive functional consequences of rmTBI. Adult C57BL/6 male mice were subjected to CHIMERA for 3 consecutive days 24 h apart. Functional outcomes were assessed by the beam walk and Morris water maze tests. Neuropathology was evaluated by immunostaining of glial fibrillary acidic protein (GFAP), amyloid precursor protein (APP), and ionizing calcium-binding adaptor molecule-1 (Iba-1), and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blotting of GFAP, Iba-1, and tumor necrosis factor (TNF)-α. Repeated CHIMERA (rCHIMERA) resulted in motor deficits at 3 days, and in learning and memory impairments that were sustained up to 6 months post injury. GFAP and TNF-α gene expression was increased within a week, whereas astrogliosis and microgliosis were induced starting from day 1 up to 6.5 months after rCHIMERA with upregulated GFAP and Iba-1 protein levels. rCHIMERA also induced APP deposition from day 1 to day 7, but this diminished by 1 month. In conclusion, rCHIMERA produces long-lasting cognitive impairments with astrogliosis and microgliosis in mice, suggesting that rCHIMERA can be a useful animal model to study the long-term complications, as well as the cellular and molecular mechanisms, of human rmTBI.

N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling.

BACKGROUND: Brain inflammation has been implicated as a critical mechanism responsible for the progression of neurodegeneration and characterized by glial cell activation accompanied by production of inflammation-related cytokines and chemokines. Growing evidence also suggests that metabolites derived from docosahexaenoic acid (DHA) have anti-inflammatory and pro-resolving effects; however, the possible role of N-docosahexaenoylethanolamine (synaptamide), an endogenous neurogenic and synaptogenic metabolite of DHA, in inflammation, is largely unknown. (The term "synaptamide" instead of "DHEA" was used for N-docosahexaenoylethanolamine since DHEA is a widely used and accepted term for the steroid, dehydroepiandrosterone.) In the present study, we tested this possibility using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo. METHODS: For in vitro studies, we used P3 primary rat microglia and immortalized murine microglia cells (BV2) to assess synaptamide effects on LPS-induced cytokine/chemokine/iNOS (inducible nitric oxide synthase) expression by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). To evaluate in vivo effects, mice were intraperitoneally (i.p.) injected with LPS followed by synaptamide, and expression of proinflammatory mediators was measured by qPCR and western blot analysis. Activation of microglia and astrocyte in the brain was examined by Iba-1 and GFAP immunostaining. RESULTS: Synaptamide significantly reduced LPS-induced production of TNF-α and NO in cultured microglia cells. Synaptamide increased intracellular cAMP levels, phosphorylation of PKA, and phosphorylation of CREB but suppressed LPS-induced nuclear translocation of NF-κB p65. Conversely, adenylyl cyclase or PKA inhibitors abolished the synaptamide effect on p65 translocation as well as TNF-α and iNOS expression. Administration of synaptamide following LPS injection (i.p.) significantly reduced neuroinflammatory responses, such as microglia activation and mRNA expression of inflammatory cytokines, chemokine, and iNOS in the brain. CONCLUSIONS: DHA-derived synaptamide is a potent suppressor of neuroinflammation in an LPS-induced model, by enhancing cAMP/PKA signaling and inhibiting NF-κB activation. The anti-inflammatory capability of synaptamide may provide a new therapeutic avenue to ameliorate the inflammation-associated neurodegenerative conditions.