Cardiopulmonary Resuscitation Without Aortic Valve Compression Increases the Chances of Return of Spontaneous Circulation in Out-of-Hospital Cardiac Arrest: A Prospective Observational Cohort Study.

OBJECTIVES: Following current cardiopulmonary resuscitation (CPR) guidelines, which recommend chest compressions at "the center of the chest," ~50% of patients experiencing out-of-hospital cardiac arrest (OHCA) undergo aortic valve (AV) compression, obstructing blood flow. We used resuscitative transesophageal echocardiography (TEE) to elucidate the impact of uncompressed vs. compressed AV on outcomes of adult patients experiencing OHCA. DESIGN: Prospective observational cohort study. SETTING: Single center. PATIENTS: This study included adult OHCA patients undergoing resuscitative TEE in the emergency department. Patients were categorized into AV uncompressed or AV compressed groups based on TEE findings. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was sustained return of spontaneous circulation (ROSC). The secondary outcomes included end-tidal co2 (Etco2) during CPR, any ROSC, survival to ICU and hospital discharge, post-resuscitation withdrawal, and favorable neurologic outcomes at discharge. Additional analyses on intra-arrest arterial blood pressure (ABP) were also conducted. The sample size was pre-estimated at 37 patients/group. From October 2020 to January 2023, 76 patients were enrolled, 39 and 37 in the AV uncompressed and AV compressed groups, respectively. Intergroup baseline characteristics were similar. Compared with the AV compressed group, the AV uncompressed group had a higher probability of sustained ROSC (53.8% vs. 24.3%; adjusted odds ratio [aOR], 4.72; p = 0.010), any ROSC (56.4% vs. 32.4%; aOR, 3.30; p = 0.033), and survival to ICU (33.3% vs. 8.1%; aOR, 6.74; p = 0.010), and recorded higher initial diastolic ABP (33.4 vs. 11.5 mm Hg; p = 0.002) and a larger proportion achieving diastolic ABP greater than 20 mm Hg during CPR (93.8% vs. 33.3%; p < 0.001). The Etco2, post-resuscitation withdrawal, and survival to discharge revealed no significant intergroup differences. No patients were discharged with favorable neurologic outcomes. Uncompressed AV seemed critical for sustained ROSC across all subgroups. CONCLUSIONS: Absence of AV compression during OHCA resuscitation is associated with an increased chance of ROSC and survival to ICU. However, its effect on long-term outcomes remains unclear.

Transformation from zero tolerance to living with COVID-19 in New Taipei City, Taiwan. Experience of the FEMH "home-hotel-hospital" care model.

In March 2022, local cases of COVID-19 infections of the Omicron variant were identified in Taiwan. In response to impending community transmission, the "Home-Hotel-Hospital" (3H) care model was implemented by the Far Eastern Memorial Hospital (FEMH). It established the first remote home care center in Taiwan and two quarantine centers in two hotels. The hospital focused on care for critical COVID-19 patients, community screening, and telehealth care. The home care call center evaluated and triaged up to 104,244 cases and provided remote home care for 96,894 cases within the first three months; in 2022, it provided home care to 107,095 patients. The two quarantine hotels admitted a total of 1834 individuals. A total of 3796 COVID-19 patients were admitted to the hospital-367 in intensive care. The telehealth outpatient clinic-including the online video clinic-served 25,775 cases; 21.5% (n = 5544) of them were prescribed oral anti-viral medications. In 2022, the FEMH prescribed oral anti-viral therapies to a total of 12,571 cases. The FEMH 3H care model not only enabled non-critical patients to recover at home, but also provided severely ill patients access to timely in-hospital care. In the future, this model will continue to play a significant role in COVID-19 management.

Acute Effect in Mechanical Efficiency by Pressure-Volume Loop Analysis after Transcatheter Aortic Valve Implantation.

Background: This study aimed to evaluate the immediate effect of transcatheter aortic valve implantation (TAVI) on mechanical efficiency. Methods: A total of 46 patients (25 females) with an average age of 83 ± 6.4 years underwent TAVI using the CoreValve system. During the same hospitalization, we conducted a comprehensive comparison of the patients before and after TAVI without inotropic support using echocardiography. The parameters encompassed left ventricular (LV) geometry, valvular load, global LV afterload and ventricular hemodynamics. The analysis using pressure-volume loops enabled the determination of load-independent contractility (Ees) and afterload, in addition to assessing potential energy, stroke work, and mechanical efficiency. Results: The immediate effect was an augmented aortic valve area accompanied by a reduction in the transvalvular pressure gradient. We observed reductions in left ventricular end-systolic volume and end-diastolic volume, and also reductions in global afterload and end-systolic meridional wall stress. The Ea index decreased, while the Ees index remained relatively stable. We noted increases in stroke volume and systemic arterial compliance, indicating more efficient blood transfer from the ventricle to aorta. These changes contributed to the normalization of ventricular-arterial coupling. In terms of mechanical work of the chamber, we observed significant decreases in potential energy, stroke work, and pressure-volume area. There was an increase in the mechanical efficiency of the chamber. Conclusions: The TAVI procedure immediately reduced global afterload and improved diastolic compliance of the chamber, resulting in enhanced ventricular function and mechanical efficiency.

Plantainoside D Reduces Depolarization-Evoked Glutamate Release from Rat Cerebral Cortical Synaptosomes.

Inhibiting the excessive release of glutamate in the brain is emerging as a promising therapeutic option and is efficient for treating neurodegenerative disorders. The aim of this study is to investigate the effect and mechanism of plantainoside D (PD), a phenylenthanoid glycoside isolated from Plantago asiatica L., on glutamate release in rat cerebral cortical nerve terminals (synaptosomes). We observed that PD inhibited the potassium channel blocker 4-aminopyridine (4-AP)-evoked release of glutamate and elevated concentration of cytosolic Ca2+. Using bafilomycin A1 to block glutamate uptake into synaptic vesicles and EDTA to chelate extracellular Ca2+, the inhibitory effect of PD on 4-AP-evoked glutamate release was prevented. In contrast, the action of PD on the 4-AP-evoked release of glutamate in the presence of dl-TBOA, a potent nontransportable inhibitor of glutamate transporters, was unaffected. PD does not alter the 4-AP-mediated depolarization of the synaptosomal membrane potential, suggesting that the inhibitory effect of PD on glutamate release is associated with voltage-dependent Ca2+ channels (VDCCs) but not the modulation of plasma membrane potential. Pretreatment with the Ca2+ channel blocker (N-type) ω-conotoxin GVIA abolished the inhibitory effect of PD on the evoked glutamate release, as did pretreatment with the protein kinase C inhibitor GF109203x. However, the PD-mediated inhibition of glutamate release was eliminated by applying the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 or dantrolene, which inhibits Ca2+ release through ryanodine receptor channels. These data suggest that PD mediates the inhibition of evoked glutamate release from synaptosomes primarily by reducing the influx of Ca2+ through N-type Ca2+ channels, subsequently reducing the protein kinase C cascade.

Referral, Diagnosis, and Pharmacological Management of Peripheral Artery Disease: Perspectives from Taiwan.

Peripheral artery disease (PAD) imposes a heavy burden of major adverse cardiovascular events that are associated with considerable mortality and morbidity, and major adverse limb events (e.g., thrombectomy, revascularization, amputation) that can substantially impact patients' daily functioning and quality of life. Global registry data have indicated that PAD is an underdiagnosed disease in Taiwan, and its associated risk factors remain inadequately controlled. This review discusses the burden of PAD in Taiwan, major guidelines on PAD management, and the latest clinical trial outcomes. Practical experience, opinions, and the latest trial data were integrated to derive a series of clinical algorithms - patient referral, PAD diagnosis, and the antithrombotic management of PAD. These algorithms can be adapted not only by physicians in Taiwan involved in the clinical management of patients with PAD but also by general practitioners in local clinics and regional hospital settings, with the ultimate aim of improving the totality of PAD patient care in Taiwan.

Neferine, an Alkaloid from Lotus Seed Embryos, Exerts Antiseizure and Neuroprotective Effects in a Kainic Acid-Induced Seizure Model in Rats.

Current anti-seizure drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective anti-seizure drugs, and medicinal plants provide an attractive source for new compounds. This study aimed to evaluate the possible anti-seizure and neuroprotective effects of neferine, an alkaloid from the lotus seed embryos of Nelumbo nucifera, in a kainic acid (KA)-induced seizure rat model and its underlying mechanisms. Rats were intraperitoneally (i.p.) administrated neferine (10 and 50 mg/kg) 30 min before KA injection (15 mg/kg, i.p.). Neferine pretreatment increased seizure latency and reduced seizure scores, prevented glutamate elevation and neuronal loss, and increased presynaptic protein synaptophysin and postsynaptic density protein 95 expression in the hippocampi of rats with KA. Neferine pretreatment also decreased glial cell activation and proinflammatory cytokine (interleukin-1ß, interleukin-6, tumor necrosis factor-α) expression in the hippocampi of rats with KA. In addition, NOD-like receptor 3 (NLRP3) inflammasome, caspase-1, and interleukin-18 expression levels were decreased in the hippocampi of seizure rats pretreated with neferine. These results indicated that neferine reduced seizure severity, exerted neuroprotective effects, and ameliorated neuroinflammation in the hippocampi of KA-treated rats, possibly by inhibiting NLRP3 inflammasome activation and decreasing inflammatory cytokine secretion. Our findings highlight the potential of neferine as a therapeutic option in the treatment of epilepsy.

An Anthranilate Derivative Inhibits Glutamate Release and Glutamate Excitotoxicity in Rats.

The neurotransmitter glutamate plays an essential role in excitatory neurotransmission; however, excessive amounts of glutamate lead to excitotoxicity, which is the most common pathogenic feature of numerous brain disorders. This study aimed to investigate the role of butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034), a synthesized anthranilate derivative, in the central glutamatergic system. We used rat cerebro-cortical synaptosomes to examine the effect of HFP034 on glutamate release. In addition, we used a rat model of kainic acid (KA)-induced glutamate excitotoxicity to evaluate the neuroprotective potential of HFP034. We showed that HFP034 inhibits 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes, and this inhibition was absent in the absence of extracellular calcium. HFP034-mediated inhibition of glutamate release was associated with decreased 4-AP-evoked Ca2+ level elevation and had no effect on synaptosomal membrane potential. The inhibitory effect of HFP034 on evoked glutamate release was suppressed by blocking P/Q-type Ca2+ channels and protein kinase C (PKC). Furthermore, HFP034 inhibited the phosphorylation of PKC and its substrate, myristoylated alanine-rich C kinase substrate (MARCKS) in synaptosomes. We also observed that HFP034 pretreatment reduced neuronal death, glutamate concentration, glial activation, and the levels of endoplasmic reticulum stress-related proteins, calpains, glucose-regulated protein 78 (GRP 78), C/EBP homologous protein (CHOP), and caspase-12 in the hippocampus of KA-injected rats. We conclude that HFP034 is a neuroprotective agent that prevents glutamate excitotoxicity, and we suggest that this effect involves inhibition of presynaptic glutamate release through the suppression of P/Q-type Ca2+ channels and PKC/MARCKS pathways.

Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex.

The inhibition of synaptic glutamate release to maintain glutamate homeostasis contributes to the alleviation of neuronal cell injury, and accumulating evidence suggests that natural products can repress glutamate levels and associated excitotoxicity. In this study, we investigated whether eupatilin, a constituent of Artemisia argyi, affected glutamate release in rat cortical nerve terminals (synaptosomes). Additionally, we evaluated the effect of eupatilin in an animal model of kainic acid (KA) excitotoxicity, particularly on the levels of glutamate and N-methyl-D-aspartate (NMDA) receptor subunits (GluN2A and GluN2B). We found that eupatilin decreased depolarization-evoked glutamate release from rat cortical synaptosomes and that this effect was accompanied by a reduction in cytosolic Ca2+ elevation, inhibition of P/Q-type Ca2+ channels, decreased synapsin I Ca2+-dependent phosphorylation and no detectable effect on the membrane potential. In a KA-induced glutamate excitotoxicity rat model, the administration of eupatilin before KA administration prevented neuronal cell degeneration, glutamate elevation, glutamate-generating enzyme glutaminase increase, excitatory amino acid transporter (EAAT) decrease, GluN2A protein decrease and GluN2B protein increase in the rat cortex. Taken together, the results suggest that eupatilin depresses glutamate exocytosis from cerebrocortical synaptosomes by decreasing P/Q-type Ca2+ channels and synapsin I phosphorylation and alleviates glutamate excitotoxicity caused by KA by preventing glutamatergic alterations in the rat cortex. Thus, this study suggests that eupatilin can be considered a potential therapeutic agent in the treatment of brain impairment associated with glutamate excitotoxicity.

The Effect of Isosaponarin Derived from Wasabi Leaves on Glutamate Release in Rat Synaptosomes and Its Underlying Mechanism.

Excessive glutamate release is known to be involved in the pathogenesis of neurological diseases, and suppression of glutamate release from nerve terminals is considered to be a treatment strategy. In this study, we investigated whether isosaponarin, a flavone glycoside isolated from wasabi leaves, could affect glutamate release in rat cerebral cortex nerve terminals (synaptosomes). The release of glutamate was evoked by the K+ channel blocker 4-aminopyridine (4-AP) and measured by an online enzyme-coupled fluorimetric assay. Isosaponarin produced a concentration-dependent inhibition of 4-AP-evoked glutamate release with a half-maximum inhibition of release value of 22 µM. The inhibition caused by isosaponarin was prevented by eliminating extracellular Ca2+ or by using bafilomycin A1, an inhibitor of synaptic vesicle exocytosis. Isosaponarin decreased intrasynaptosomal rises in Ca2+ levels that were induced by 4-AP, without affecting the synaptosomal membrane potential. The isosaponarin-induced inhibition of glutamate release was significantly prevented in synaptosomes that were pretreated with a combination of the calcium channel blockers ω-conotoxin GVIA (N-type) and ω-agatoxin IVA (P/Q-types). The protein kinase C (PKC) pan-inhibitor GF109203X and the Ca2+-dependent PKC inhibitor Go6976 abolished the inhibition of glutamate release by isosaponarin, while the Ca2+-independent PKC inhibitor rottlerin did not show any effect. The results from immunoblotting assays also showed that isosaponarin lowered PKC, PKCα, synaptosomal-associated protein of 25 kDa (SNAP-25), and myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation induced by 4-AP. In addition, FM1-43-labeled synaptic vesicles in synaptosomes showed that treatment with isosaponarin resulted in an attenuation of the 4-AP-induced decrease in fluorescence intensity that is consistent with glutamate release. Transmission electron microscopy of synaptosomes also provided evidence that isosaponarin altered the number of synaptic vesicles. These results indicate that isosaponarin suppresses the Ca2+-dependent PKC/SNAP-25 and MARCKS pathways in synaptosomes, causing a decrease in the number of available synaptic vesicles, which inhibits vesicular glutamate release from synaptosomes.

Inhibition of Glutamate Release from Rat Cortical Nerve Terminals by Dehydrocorydaline, an Alkaloid from Corydalis yanhusuo.

Excessive release of glutamate induces excitotoxicity and causes neuronal damage in several neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for preventing and treating neurological disorders. Dehydrocorydaline (DHC), an active alkaloid compound isolated from Corydalis yanhusuo, possesses neuroprotective capacity. The present study investigated the effect of DHC on glutamate release using a rat brain cortical synaptosome model. Our results indicate that DHC inhibited 4-aminopyridine (4-AP)-evoked glutamate release and elevated intrasynaptosomal calcium levels. The inhibitory effect of DHC on 4-AP-evoked glutamate release was prevented in the presence of the vesicular transporter inhibitor bafilomycin A1 and the N- and P/Q-type Ca2+ channel blocker ω-conotoxin MVIIC but not the intracellular inhibitor of Ca2+ release dantrolene or the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157. Moreover, the inhibitory effect of DHC on evoked glutamate release was prevented by the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) inhibitor PD98059. Western blotting data in synaptosomes also showed that DHC significantly decreased the level of ERK1/2 phosphorylation and synaptic vesicle-associated protein synapsin I, the main presynaptic target of ERK. Together, these results suggest that DHC inhibits presynaptic glutamate release from cerebrocortical synaptosomes by suppressing presynaptic voltage-dependent Ca2+ entry and the MAPK/ERK/synapsin I signaling pathway.

Typhaneoside Suppresses Glutamate Release Through Inhibition of Voltage-Dependent Calcium Entry in Rat Cerebrocortical Nerve Terminals.

Glutamate is the major excitatory neurotransmitter in the brain and is involved in many brain functions. In this study, we investigated whether typhaneoside, a flavonoid from Typhae angustifolia pollen, affects endogenous glutamate release from rat cortical synaptosomes. Using a one-line enzyme-coupled fluorometric assay, glutamate release stimulated by the K+ channel blocker 4-aminopyridine was monitored to explore the possible underlying mechanisms. The vesicular transporter inhibitor bafilomycin A1 and chelation of extracellular Ca2+ ions with EGTA suppressed the effect of typhaneoside on the induced glutamate release. Nevertheless, the typhaneoside activity has not been affected by the glutamate transporter inhibitor dl-threo-beta-benzyloxyaspartate. The synaptosomal plasma membrane potential was assayed using a membrane potential-sensitive dye DiSC3(5), and cytosolic Ca2+ concentrations ([Ca2+]C) was monitored by a Ca2+ indicator Fura-2. Results showed that typhaneoside did not alter the synaptosomal membrane potential but lowered 4-aminopyridine-induced increases in [Ca2+]C. Furthermore, the Cav2.2 (N-type) channel blocker ω-conotoxin GVIA blocked Ca2+ entry and inhibited the effect of typhaneoside on 4-aminopyridine-induced glutamate release. However, the inhibitor of intracellular Ca2+ release dantrolene and the mitochondrial Na+/Ca2+ exchanger blocker 7-chloro-5-(2-chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one have no effect on the suppression of glutamate release mediated by typhaneoside. Moreover, inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) prevented the inhibitory effect of typhaneoside on induced glutamate release. Typhaneoside reduced 4-aminopyridine-induced phosphorylation of ERK1/2 and the major presynaptic ERK target synapsin I, which is a synaptic vesicle-associated protein. In conclusion, these findings suggest a role for typhaneoside in modulating glutamate release by suppressing voltage-dependent Ca2+ channel mediated presynaptic Ca2+ influx and the MAPK/ERK/synapsin I signaling cascade.

The impact of timing and modalities of dental prophylaxis on the risk of 5-fluorouracil-related oral mucositis in patients with head and neck cancer: a nationwide population-based cohort study.

PURPOSE: This study investigated the impact of dental prophylaxis on 5-fluorouracil (5-FU)-related oral mucositis (OM) according to the head and neck cancer (HNC) locations and treatment times. METHODS: A total of 13,969 HNC participants, including 482 5-FU-related OM subjects and 13,487 comparisons were enrolled from the Longitudinal Health Insurance Database for Catastrophic Illness Patients of Taiwan between 2000 and 2008. All subjects were stratified into subgroups based on the times to perform chlorhexidine use, scaling, and fluoride application before 5-FU administration. The dental prophylaxis related to 5-FU-related OM was estimated by multiple logistic regression and represented with odds ratio (OR) and 95% confidence interval (CI). RESULTS: Fluoride gel application and scaling significantly impacted on OM development (p < 0.001), and the joint effect of fluoride gel and scaling induced 5-FU-related OM (OR = 3.46, 95% CI = 2.39-5.01). The risk of OM was raised 2.25-fold as scaling within 3 weeks before 5-FU-related chemotherapy (95% CI = 1.81-2.81), and a 3.22-fold increased risk of OM while fluoride gel was applied during 5-FU-related treatment (95% CI = 1.46-7.13). CONCLUSION: Dental prophylaxis significantly affected 5-FU-related OM in the HNC population. A short interval between dental scaling or fluoride application and 5-FU administration may be associated with higher prevalence of OM. Scaling simultaneously combined with chlorohexidine promoted 5-FU-related OM in specific HNC patients excluding the oral cancer and nasopharyngeal cancer population. Proper timing of the prophylactic dental treatments prior to 5-FU therapy could reduce the risk to develop 5-FU-related OM.

Inhibition of glutamatergic transmission and neuronal excitability by oxycodone in the rat hippocampal CA3 neurons.

Oxycodone, a semisynthetic opioid analgesic with actions similar to morphine, is extensively prescribed for treatment of moderate to severe acute pain. Given that glutamate plays a crucial role in mediating pain transmission, the purpose of this study was to investigate the effect of oxycodone on glutamatergic synaptic transmission in rat hippocampal CA3 area, which is associated with the modulation of nociceptive perception. Whole-cell patch-clamp recordings revealed that oxycodone effectively reduced presynaptic glutamate release, as detected by decreased frequencies of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature EPSCs (mEPSCs), without eliciting significant changes in the amplitudes of sEPSCs and mEPSCs and glutamate-evoked inward currents. The inhibitory effect of oxycodone on the frequency of sEPSCs was blocked by the nonselective opioid receptor antagonist naloxone. In addition, oxycodone suppressed burst firing induced by 4-aminopyridine and tonic repetitive firing evoked by the applied depolarizing current. These results suggest that oxycodone inhibits spontaneous presynaptic glutamate release possibly by activating opioid receptors and consequently suppressing the neuronal excitability of hippocampal CA3 neurons.

Bidirectional relationship between temporomandibular disorder and ankylosing spondylitis: a population-based cohort study.

OBJECTIVES: This study aimed to determine the relation between temporomandibular disorder (TMD) and ankylosing spondylitis (AS) bidirectionally and ascertain the important comorbidities for AS occurrence in TMD patients. MATERIALS AND METHODS: We conducted this population-based cohort study through Longitudinal Health Insurance Database, Taiwan. Study 1 investigated the risk of TMD in AS patients. Study 2 assessed the risk of AS in TMD patients. RESULTS: In total, 3204 AS patients and 12,816 age-matched and gender-matched comparisons were enrolled in study 1. The TMD incidence in the AS cohort was 2.88-fold higher when compared with the comparisons (1.54 vs. 0.53 per 10,000 person-years). After adjusting for age, gender, and comorbidity, the AS cohort had a 2.66-fold (95% CI = 1.79-3.97) increased risk of TMD occurrence (P < 0.0001). The second study recruited 4998 TMD patients and 19,991 age-matched and gender-matched comparisons. Both TMD and comparison cohorts showed similar AS risk (HR = 1.49, 95% CI = 0.91-2.43, P = 0.1108) in the adjusted model. Study 2 identified a 3.66-fold increased risk of AS occurrence in TMD patients with comorbidity, including parapsoriasis, rheumatoid arthritis, osteoporosis, Cushing's syndrome, and climacteric arthritis (P < 0.012). CONCLUSIONS: AS appears to significantly impact the occurrence of TMD. TMD might play a synergic role in AS development. CLINICAL RELEVANCE: Clinicians have to be vigilant about the increased risk of TMD in AS patients and take care of AS disease activity and prognosis. The symptoms and signs of TMD could be a predictor of AS in patients with the aforementioned comorbidities.

Enmein Decreases Synaptic Glutamate Release and Protects against Kainic Acid-Induced Brain Injury in Rats.

This study investigated the effects of enmein, an active constituent of Isodon japonicus Hara, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes) and evaluated its neuroprotective potential in a rat model of kainic acid (KA)-induced glutamate excitotoxicity. Enmein inhibited depolarization-induced glutamate release, FM1-43 release, and Ca2+ elevation in cortical nerve terminals but had no effect on the membrane potential. Removing extracellular Ca2+ and blocking vesicular glutamate transporters, N- and P/Q-type Ca2+ channels, or protein kinase C (PKC) prevented the inhibition of glutamate release by enmein. Enmein also decreased the phosphorylation of PKC, PKC-α, and myristoylated alanine-rich C kinase substrates in synaptosomes. In the KA rat model, intraperitoneal administration of enmein 30 min before intraperitoneal injection of KA reduced neuronal cell death, glial cell activation, and glutamate elevation in the hippocampus. Furthermore, in the hippocampi of KA rats, enmein increased the expression of synaptic markers (synaptophysin and postsynaptic density protein 95) and excitatory amino acid transporters 2 and 3, which are responsible for glutamate clearance, whereas enmein decreased the expression of glial fibrillary acidic protein (GFAP) and CD11b. These results indicate that enmein not only inhibited glutamate release from cortical synaptosomes by suppressing Ca2+ influx and PKC but also increased KA-induced hippocampal neuronal death by suppressing gliosis and decreasing glutamate levels by increasing glutamate uptake.

Anti-Allergic and Anti-Inflammatory Effects of Neferine on RBL-2H3 Cells.

Mast cells play a very important role in skin allergy and inflammation, including atopic dermatitis and psoriasis. In the past, it was found that neferine has anti-inflammatory and anti-aging effects on the skin, but its effect on mast cells has not yet been studied in detail. In this study, we used mast cells (RBL-2H3 cells) and mouse models to study the anti-allergic and inflammatory effects of neferine. First, we found that neferine inhibits the degranulation of mast cells and the expression of cytokines. In addition, we observed that when mast cells were stimulated by A23187/phorbol 12-myristate-13-acetate (PMA), the elevation of intracellular calcium was inhibited by neferine. The phosphorylation of the MAPK/NF-κB pathway is also reduced by pretreatment of neferine. The results of in vivo studies show that neferine can improve the appearance of dermatitis and mast cell infiltration caused by dinitrochlorobenzene (DNCB). Moreover, the expressions of barrier proteins in the skin are also restored. Finally, it was found that neferine can reduce the scratching behavior caused by compound 48/80. Taken together, our results indicate that neferine is a very good anti-allergic and anti-inflammatory natural product. Its effect on mast cells contributes to its pharmacological mechanism.

Clinical significance of quantitative assessment of glucose utilization in patients with ischemic cardiomyopathy.

BACKGROUND: The aim of this study was to prospectively quantify the rate of myocardial glucose uptake (MRGlu) in myocardium with different perfusion-metabolism patterns and determine its prognostic value in patients with ischemic cardiomyopathy. METHODS AND RESULTS: 79 patients with ischemic cardiomyopathy were prospectively enrolled for dynamic cardiac FDG PET, and then followed for at least 6 months. Perfusion-metabolism patterns were determined based on visual score analysis of 201Tl SPECT and FDG PET. MRGlu was analyzed using the Patlak kinetic model. The primary end-point was cardiovascular mortality. Significantly higher MRGlu was observed in viable compared with non-viable areas. Negative correlations were found between MRGlu in transmural match and a history of hyperlipidemia, statin usage, and triglyceride levels. Diabetic patients receiving dipeptidyl peptidase-4 inhibitors (DPP4i) had a significantly lower MRGlu in transmural match, mismatch, and reverse mismatch. Patients with MRGlu in transmural match ≥ 23.40 or reverse mismatch ≥ 36.90 had a worse outcome. CONCLUSIONS: Myocardial glucose utilization was influenced by substrates and medications, including statins and DPP4i. MRGlu could discriminate between viable and non-viable myocardium, and MRGlu in transmural match and reverse mismatch may be prognostic predictors of cardiovascular death in patients with ischemic cardiomyopathy.

Prediction of the development of acute kidney injury following cardiac surgery by machine learning.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication that results in increased morbidity and mortality after cardiac surgery. Most established prediction models are limited to the analysis of nonlinear relationships and fail to fully consider intraoperative variables, which represent the acute response to surgery. Therefore, this study utilized an artificial intelligence-based machine learning approach thorough perioperative data-driven learning to predict CSA-AKI. METHODS: A total of 671 patients undergoing cardiac surgery from August 2016 to August 2018 were enrolled. AKI following cardiac surgery was defined according to criteria from Kidney Disease: Improving Global Outcomes (KDIGO). The variables used for analysis included demographic characteristics, clinical condition, preoperative biochemistry data, preoperative medication, and intraoperative variables such as time-series hemodynamic changes. The machine learning methods used included logistic regression, support vector machine (SVM), random forest (RF), extreme gradient boosting (XGboost), and ensemble (RF + XGboost). The performance of these models was evaluated using the area under the receiver operating characteristic curve (AUC). We also utilized SHapley Additive exPlanation (SHAP) values to explain the prediction model. RESULTS: Development of CSA-AKI was noted in 163 patients (24.3%) during the first postoperative week. Regarding the efficacy of the single model that most accurately predicted the outcome, RF exhibited the greatest AUC (0.839, 95% confidence interval [CI] 0.772-0.898), whereas the AUC (0.843, 95% CI 0.778-0.899) of ensemble model (RF + XGboost) was even greater than that of the RF model alone. The top 3 most influential features in the RF importance matrix plot were intraoperative urine output, units of packed red blood cells (pRBCs) transfused during surgery, and preoperative hemoglobin level. The SHAP summary plot was used to illustrate the positive or negative effects of the top 20 features attributed to the RF. We also used the SHAP dependence plot to explain how a single feature affects the output of the RF prediction model. CONCLUSIONS: In this study, machine learning methods were successfully established to predict CSA-AKI, which determines risks following cardiac surgery, enabling the optimization of postoperative treatment strategies to minimize the postoperative complications following cardiac surgeries.

An Engineered Gene Nanovehicle Developed for Smart Gene Therapy to Selectively Inhibit Smooth Muscle Cells: An In Vitro Study.

In-stent restenosis is a serious concern for patients treated through the stenting procedure, although this can be solved using drug-eluting stents and/or drug-eluting balloon catheters. However, the chemical agents released from the drug-eluting layer for inhibiting smooth muscle cell (SMC) migration are inevitably associated with damage to vascular endothelial cell (ECs). The present in vitro study used a distinct strategy, in which a smart gene (phEGR1-PKCδ, an engineered plasmid consists of an SMC-specific promoter (human early growth response 1, hEGR1 promoter) ligated with a gene encoding apoptosis-inducing protein (protein kinase C-delta, PKCδ) was incorporated into a novel gene vehicle (Au cluster-incorporated polyethylenimine/carboxymethyl hexanoyl chitosan, PEI-Au/CHC) to form the PEI-Au/CHC/phEGR1-PKCδ complex, which was proposed for the selective inhibition of SMC proliferation. It was found that the cell viability of SMCs receiving the PEI-Au/CHC/phEGR1-PKCδ complex under simulated inflammation conditions was significantly lower than that of the ECs receiving the same treatment. In addition, the PEI-Au/CHC/phEGR1-PKCδ complex did not demonstrate an inhibitory effect on EC proliferation and migration under simulated inflammation conditions. Finally, the PEI-Au/CHC/phEGR1-PKCδ complexes coated onto a balloon catheter used in percutaneous transluminal coronary angioplasty (PTCA) could be transferred to both the ECs and the SMC layer of Sprague Dawley (SD) rat aortas ex vivo. These preliminary in vitro results suggest that the newly developed approach proposed in the present study might be a potential treatment for reducing the incidence rate of in-stent restenosis and late thrombosis in the future.

Management of Venous Thromboembolisms: Part II. The Consensus for Pulmonary Embolism and Updates.

Pulmonary embolism (PE) is a potential life-threatening condition and risk-adapted diagnostic and therapeutic management conveys a favorable outcome. For patients at high risk for early complications and mortality, prompt exclusion or confirmation of PE by imaging is the key step to initiate and facilitate reperfusion treatment. Among patients with hemodynamic instability, systemic thrombolysis improves survival, whereas surgical embolectomy or percutaneous intervention are alternatives in experienced hands in scenarios where systemic thrombolysis is not the best preferred thromboreduction measure. For patients with suspected PE who are not at high risk for early complications and mortality, the organized approach using a structured evaluation system to assess the pretest probability, the age-adjusted D-dimer cut-offs, the appropriate selection of imaging tools, and proper interpretation of imaging results is important when deciding the allocation of treatment strategies. Patients with PE requires anticoagulation treatment. In patients with cancer and thrombosis, low-molecular-weight heparin (LMWH) used to be the standard regimen. Recently, three factor Xa inhibitors collectively show that non-vitamin K oral anticoagulants (NOACs) are as effective as LMWH in four randomized clinical trials. Therefore, NOACs are suitable and preferred in most conditions. Finally, chronic thromboembolic pulmonary hypertension is the most disabling long-term complication of PE. Because of its low incidence, the extra caution should be given when managing patients with PE.