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.

Phillygenin Suppresses Glutamate Exocytosis in Rat Cerebrocortical Nerve Terminals (Synaptosomes) through the Inhibition of Cav2.2 Calcium Channels.

Glutamate is a major excitatory neurotransmitter that mediates neuronal damage in acute and chronic brain disorders. The effect and mechanism of phillygenin, a natural compound with neuroprotective potential, on glutamate release in isolated nerve terminals (synaptosomes) prepared from the rat cerebral cortex were examined. In this study, 4-aminopyridine (4-AP), a potassium channel blocker, was utilized to induce the release of glutamate, which was subsequently quantified via a fluorometric assay. Our findings revealed that phillygenin reduced 4-AP-induced glutamate release, and this inhibitory effect was reversed by removing extracellular Ca2+ or inhibiting vesicular transport with bafilomycin A1. However, exposure to the glutamate transporter inhibitor dl-threo-beta-benzyl-oxyaspartate (dl-TOBA) did not influence the inhibitory effect. Moreover, phillygenin did not change the synaptosomal membrane potential but lowered the 4-AP-triggered increase in intrasynaptosomal Ca2+ concentration ([Ca2+]i). Antagonizing Cav2.2 (N-type) calcium channels blocked the inhibition of glutamate release by phillygenin, whereas pretreatment with the mitochondrial Na+/Ca2+ exchanger inhibitor, CGP37157 or the ryanodine receptor inhibitor, dantrolene, both of which block intracellular Ca2+ release, had no effect. The effect of phillygenin on glutamate release triggered by 4-AP was completely abolished when MAPK/ERK inhibitors were applied. Furthermore, phillygenin attenuated the phosphorylation of ERK1/2 and its major presynaptic target, synapsin I, a protein associated with synaptic vesicles. These data collectively suggest that phillygenin mediates the inhibition of evoked glutamate release from synaptosomes primarily by reducing the influx of Ca2+ through Cav2.2 calcium channels, thereby subsequently suppressing the MAPK/ERK/synapsin I signaling cascade.

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.

Mangiferin depresses vesicular glutamate release in synaptosomes from the rat cerebral cortex by decreasing synapsin I phosphorylation.

Mangiferin is a glucosyl xanthone that has been shown to be a neuroprotective agent against brain disorders involving excess glutamate. However, the effect of mangiferin on the function of the glutamatergic system has not been investigated. In this study, we used synaptosomes from the rat cerebral cortex to investigate the effect of mangiferin on glutamate release and identify the possible underlying mechanism. We observed that mangiferin produced a concentration-dependent reduction in the release of glutamate elicited by 4-aminopyridine with an IC50 value of 25 µM. Inhibition of glutamate release was blocked by removing extracellular calcium and by treatment with the vacuolar-type H+-ATPase inhibitor bafilomycin A1, which prevents the uptake and storage of glutamate in vesicles. Moreover, we showed that mangiferin decreased the 4-aminopyridine-elicited FM1-43 release and synaptotagmin 1 luminal domain antibody (syt1-L ab) uptake from synaptosomes, which correlated with decreased synaptic vesicle exocytosis. Transmission electron microscopy in synaptosomes also showed that mangiferin attenuated the 4-aminopyridine-elicited decrease in the number of synaptic vesicles. In addition, antagonism of Ca2+/calmodulin-dependent kinase II (CaMKII) and protein kinase A (PKA) counteracted mangiferin's effect on glutamate release. Mangiferin also decreased the phosphorylation of CaMKII, PKA, and synapsin I elicited by 4-aminopyridine treatment. Our data suggest that mangiferin reduces PKA and CaMKII activation and synapsin I phosphorylation, which could decrease synaptic vesicle availability and lead to a subsequent reduction in vesicular glutamate release from synaptosomes.

Cynarin, a caffeoylquinic acid derivative in artichoke, inhibits exocytotic glutamate release from rat cortical nerve terminals (synaptosomes).

The purpose of this study was to evaluate the effect of cynarin, a caffeoylquinic acid derivative in artichoke, on glutamate release elicited by 4-aminopyridine (4-AP) in rat cortical nerve terminals (synaptosomes). We observed that cynarin decreased 4-aminopyridine-elicited glutamate release, which was prevented by the removal of external free Ca2+ with ethylene glycol bis (ß-aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA) or the blockade of P/Q-type calcium channels with ω-agatoxin IVA. Molecular docking also revealed that cynarin formed a hydrogen bond with the P/Q-type Ca2+ channel, indicating a mechanism of action involving Ca2+ influx inhibition. Additionally, the inhibitory effect of cynarin on glutamate release is associated with a change in the available synaptic vesicles, as cynarin decreased 4-AP-elicited FM1-43 release or hypertonic sucrose-evoked glutamate release from synaptosomes. Furthermore, the suppression of protein kinase A (PKA) prevented the effect of cynarin on 4-AP-elicited glutamate release. 4-AP-elicited PKA and synapsin I or synaptosomal-associated protein of 25 kDa (SNAP-25) phosphorylation at PKA-specific residues were also attenuated by cynarin. Our data indicate that cynarin, through the suppression of P/Q-type Ca2+ channels, inhibits PKA activation and attenuates synapsin I and SNAP-25 phosphorylation at PKA-specific residues, thus decreasing synaptic vesicle availability and contributing to glutamate release inhibition in cerebral cortex terminals.

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.

The Benefits of Molnupiravir Treatment in Healthcare Facilities Patients with COVID-19.

Background: Molnupiravir (MOL) is an oral antiviral medication that has recently been treated for COVID-19. Objectively: We perform a prospective and observational study to elucidate the efficacy and safety of MOL in healthcare patients with COVID-19. Materials and Methods: A observational, non-randomized study of patients diagnosed with COVID-19 in 46 healthcare facilities and treated with MOL started within 5 days after the onset of signs or symptoms. We recorded data for all patients, including demographic data, clinical features, and symptoms. Treatment response was classified into cure, stable, hospitalization and death. Multivariate analysis was performed with stepwise logistic regression for hospitalization and death risk factors. Results: In total, 856 patients were diagnosed as having COVID-19 and treated with MOL during the study period. Of those, 496 patients (57.9%) were cured, 256 patients (29.9%) in stable condition, 104 patients (12.2%) hospitalized, and 22 patients (2.6%) died, respectively. There was significant effectiveness (87.8%) in COVID-19 patients using MOL. Multivariate analysis was performed to confirm the risk factors for hospitalization and death and included elder age (>80 years old) (odds ratio (OR) 2.2, 95% confidence interval (CI): 1.1-6.9), old cerebrovascular accident (CVA) (OR=4.1, 95% CI: 1.3-9.9), the presence of diabetes mellitus (DM) (OR=2.6, 95% CI: 1.2-9.1) and chronic respiratory diseases (OR=2.4, 95% (CI): 1.3-8.1). Limitations: This is an observational study, neither randomized study nor control group study. Conclusion: Initial treatment with MOL has the treatment benefits and is well tolerated for patients with COVID-19 in healthcare facilities. Older age, old CVA, DM, and chronic respiratory diseases were independent risk factors for hospitalization and mortality. The results demonstrate there are important clinical benefits of MOL beyond the reduction in hospitalization or death for these patients with more comorbidities in Taiwan.

Impact of Recurrent Mitral Regurgitation on Left Ventricular Mass Regression and Cardiac Events following Mitral Valve Repair.

BACKGROUND: Mitral valve regurgitation results in volume overload, followed by left ventricular remodeling. Variation of reverse remodeling following mitral repair influences the clinical outcomes. We aimed to evaluate the association between recurrent mitral regurgitation and mass regression following mitral valve repair and the impact on major adverse cardiovascular events. METHODS: A retrospective cohort study was conducted on 164 consecutive patients with severe mitral regurgitation who underwent elective mitral valve repair. Subgroups were classified based on the presence of recurrent mitral regurgitation exceeding moderate severity. The hemodynamic parameters were evaluated according to geometry, mass, and function with Doppler echocardiography before and after surgery. Cox regression analysis was performed to evaluate the association between hemodynamics and mass regression and clinical outcomes. RESULTS: The results for MR indicated 110 cases with non-recurrent MR and 54 with recurrent MR, along with 31 major adverse cardiovascular events. The tracked echocardiographic results revealed less reduction in dimension and volume, along with less mass regression in the recurrent MR subgroup. Significant differences were revealed in the relative change of the LV end-diastolic volume index and relative mass regression between subgroups. The relative change in the LVEDVI was proportionally correlated with relative mass regression. Cox regression analysis identified correlations with major adverse cardiovascular events, including suture annuloplasty, recurrent mitral regurgitation, tracked LV mass, relative LV mass regression, and systolic dysfunction. CONCLUSION: LV mass regression and relative change of the LV end-diastolic volume could be risk predictors of recurrent mitral regurgitation. The extent of LV mass regression is correlated with adverse cardiac events.

Extent of Left Ventricular Mass Regression and Impact of Global Left Ventricular Afterload on Cardiac Events and Mortality after Aortic Valve Replacement.

Patient-prosthesis mismatch (PPM) causes a high transvalvular pressure gradient and residual left ventricular (LV) hypertrophy, consequently influencing long-term results. This study aimed to find the relationships between hemodynamic parameters and LV mass regression and determine the risk predictors of major adverse cardiovascular and cerebral events (MACCE) after aortic valve replacement (AVR) for aortic stenosis. Methods and Results: Preoperative and postoperative Doppler echocardiography data were evaluated for 120 patients after AVR. The patients' mean age was 67.7 years; 55% of the patients were male. Forty-four (37%) patients suffered from MACCE during a mean follow-up period of 3.6 ± 2 years. The following hemodynamic parameters at follow-up were associated with lower relative indexed LV mass (LVMI) regression: lower postoperative indexed effective orifice area, greater mean transvalvular pressure gradient (MPG), greater stroke work loss (SWL), and concentric or eccentric LV remodeling mode. The following hemodynamic parameters at follow-up were associated with a higher risk of MACCE: higher valvuloarterial impedance (ZVA), greater SWL, greater MPG, greater relative wall thickness, greater LVMI, and hypertrophic LV remodeling mode. Lower relative LVMI regression was associated with a higher risk of MACCE (hazard ratio, 1.01: 95% confidence interval, 1.003-1.03). The corresponding cutoff of relative LVMI regression was -14%. Conclusions: Changes in hemodynamic parameters were independently associated with relative LVMI regression. Impaired reverse remodeling and persistent residual LV hypertrophy were independent risk predictors of MACCE. An LVMI regression lower than 14% indicated higher MACCE. A postoperative ZVA greater than 3.5 mmHg/mL/m2 was an independent risk predictor of cardiac events and mortality after AVR. Preventive strategies should be used at the time of the operation to avoid PPM.

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.

Lappaconitine inhibits glutamate release from rat cerebrocortical nerve terminals by suppressing Ca2+ influx and protein kinase A cascade.

The inhibition of the excessive release of glutamate in the brain has emerged as a promising new option for developing therapeutic strategies for neurodegenerative disorders. This study investigated the effect and mechanism of lappaconitine, a diterpenoid alkaloid found in species of Aconitum, on glutamate release in rat cerebral cortex nerve terminals (synaptosomes). Here, we report that in the rat cortical synaptosomal preparation, lappaconitine reduced the K+ channel blocker 4-aminopyridine (4-AP)-evoked Ca2+-dependent release of glutamate. The inhibitory effect of lappaconitine on the evoked glutamate release was blocked by the vesicular transporter inhibitor bafilomycin A1 and calcium-chelating agent ethylene glycol tetraacetic acid (EGTA), but was unaffected by exposure to the glutamate transporter inhibitor dl-threo-beta-benzyloxyaspartate (dl-TBOA). The depolarization-induced elevation of cytosolic calcium concentration ([Ca2+]c) was inhibited by lappaconitine, while the 4-AP-mediated depolarization of the synaptosomal membrane potential was not affected. The inhibition of glutamate release by lappaconitine was markedly decreased in synaptosomes pretreated with the Cav2.3 (R-type) channel blocker SNX-482 or the protein kinase A inhibitor H89. Nevertheless, the lappaconitine-mediated inhibition of glutamate release was not abolished by the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Lappaconitine also significantly decreased the 4-AP-induced phosphorylation of PKA and SNAP-25, a presynaptic substrate for PKA. Our data suggest that lappaconitine reduces Ca2+ influx through R-type Ca2+ channels, subsequently reducing the protein kinase A cascade to inhibit the evoked glutamate release from rat cerebral cortex nerve terminals.

Anticonvulsive and Neuroprotective Effects of Eupafolin in Rats Are Associated with the Inhibition of Glutamate Overexcitation and Upregulation of the Wnt/ß-Catenin Signaling Pathway.

Several plant compounds have been found to possess neuroactive properties. The aim of this study was to investigate the anticonvulsant effect of eupafolin, a major active component extracted from Salvia plebeia, a herb used in traditional medicine for its anti-inflammatory properties. To this end, we assessed the anticonvulsant effects of eupafolin in rats intraperitoneally (i.p.) injected with kainic acid (KA) to elucidate this mechanism. Treatment with eupafolin (i.p.) for 30 min before KA administration significantly reduced behavioral and electrographic seizures induced by KA, similar to carbamazepine (i.p.), a widely used antiepileptic drug. Eupafolin treatment also significantly decreased KA seizure-induced neuronal cell death and glutamate elevation in the hippocampus. In addition, eupafolin notably reversed KA seizure-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR2, glutamate decarboxylase 67 (GAD67, GABAergic enzyme), and Wnt signaling-related proteins, including porcupine, Wnt1, phosphorylated-glycogen synthase kinase-3ß, ß-catenin, and Bcl-2 in the hippocampus. Furthermore, the increased level of Dickkopf-related protein 1 (Dkk-1, a Wnt signaling antagonist) and the decreased level of Disheveled1 (Dvl-1, a Wnt signaling activator) in the hippocampus of KA-treated rats were reversed by eupafolin. This study provides evidence of the anticonvulsant and neuroprotective properties of eupafolin and of the involvement of regulation of glutamate overexcitation and Wnt signaling in the mechanisms of these properties. These findings support the benefits of eupafolin in treating epilepsy.

The impact of dental therapy timelines and irradiation dosages on osteoradionecrosis in oral cancer patients: A population-based cohort study.

OBJECTIVES: This study aimed to investigate how different timelines of various dental therapies were related to osteoradionecrosis development under consideration of radiotherapy dosage in patients with oral cancer. MATERIALS AND METHODS: A total of 7,107 oral cancer patients were enrolled, including 88 osteoradionecrosis patients treated with low radiotherapy dosages (<60 Gy) or high radiotherapy dosages (≥60 Gy), from the Longitudinal Health Insurance Database for Catastrophic Illness Patients of Taiwan. Cox proportional hazard regression was used to compare the osteoradionecrosis risk of various dental treatment timelines under different irradiation dosages. RESULTS: In the oral cancer population with low irradiation dosages (<60 Gy), performing periodontal therapy combined with irradiation significantly raised the risk of osteoradionecrosis by 2.21-fold. Starting radiotherapy within three months after dental surgery greatly increased the risk of developing osteoradionecrosis by 1.87-fold. The oral cancer patients treated with high radiation doses (≥60 Gy) receiving dental surgery within one month prior to radiotherapy had a significantly raised osteoradionecrosis occurrence by 1.60-fold. While the dental surgery was performed during the radiotherapy course, the risk of osteoradionecrosis was greatly increased by 2.21-fold. CONCLUSION: For oral cancer patients, performing dental surgery within three months before radiotherapy might significantly induce osteoradionecrosis. Patients that were treated with high irradiation dosages (≥60 Gy) had a higher tendency to develop osteoradionecrosis if they received dental surgery during radiotherapy. Those who were treated with low radiation dosages (<60 Gy) and received periodontal therapy during radiotherapy might have an increased risk in developing osteoradionecrosis.

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.