The study aimed to investigate the role of peripheral NLR family pyrin domain-containing 3 protein (NLRP3) in inflammatory pain development in the orofacial area. Male Sprague–Dawley rats were used in experiments, with orofacial formalin-induced pain behavior and complete Freund’s adjuvant (CFA)-induced thermal hyperalgesia as chronic inflammatory pain models. Administration of 5% formalin produced biphasic nociceptive behavior, and subcutaneous pretreatment with MCC950 (50 and 100 μg/50 μL), an NLRP3 inhibitor, remarkably attenuated nociceptive behavior during the second phase. Subcutaneous CFA injection induced thermal hyperalgesia 1 day after injection, which persisted for 7 days. Five days after CFA injection, subcutaneous treatment with MCC950 (50 and 100 μg/50 μL) significantly attenuated thermal hyperalgesia. Additionally, subcutaneous injection of BMS-986299 (50 and 100 μg/50 μL), an NLRP3 agonist, induced significant nociceptive behavior for 1 hour in naïve rats. Pretreatment with an interleukin-1β (IL-1β) receptor antagonist blocked the nociceptive behavior produced by subcutaneous injection of BMS-986299 (100 μg/50 μL);however, treatment with a hypoxia-inducible factor 1α inhibitor did not. These findings suggest the involvement of the peripheral NLRP3 and IL-1β pathway in chronic inflammatory pain development in the orofacial area, highlighting the potential of blocking this pathway as a strategy for developing future inflammatory pain treatment drugs.

The aim of this study was to develop evidence-based recommendations for determining the surgical extent in patients with locally invasive differentiated thyroid cancer (DTC). Locally invasive DTC with gross extrathyroidal extension invading surrounding anatomical structures may lead to several functional deficits and poor oncological outcomes. At present, the optimal extent of surgery in locally invasive DTC remains a matter of debate, and there are no adequate guidelines. On October 8, 2021, four experts searched the PubMed, Embase, and Cochrane Library databases; the identified papers were reviewed by 39 experts in thyroid and head and neck surgery. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence, and to develop and report recommendations. The strength of a recommendation reflects the confidence of a guideline panel that the desirable effects of an intervention outweigh any undesirable effects, across all patients for whom the recommendation is applicable. After completing the draft guidelines, Delphi questionnaires were completed by members of the Korean Society of Head and Neck Surgery. Twenty-seven evidence-based recommendations were made for several factors, including the preoperative workup; surgical extent of thyroidectomy; surgery for cancer invading the strap muscles, recurrent laryngeal nerve, laryngeal framework, trachea, or esophagus; and surgery for patients with central and lateral cervical lymph node involvement. Evidence-based guidelines were devised to help clinicians make safer and more efficient clinical decisions for the optimal surgical treatment of patients with locally invasive DTC.

Background/Aims: While switching strategies of P2Y12 receptor inhibitors (RIs) have sometimes been used in acute myocardial infarction (AMI) patients, the current status of in-hospital P2Y12RI switching remains unknown. Methods: Overall, 8,476 AMI patients who underwent successful revascularization from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) were divided according to in-hospital P2Y12RI strategies, and net adverse cardiovascular events (NACEs), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding during hospitalization were compared. Results: Patients with in-hospital P2Y12RI switching accounted for 16.5%, of which 867 patients were switched from clopidogrel to potent P2Y12RI (C-P) and 532 patients from potent P2Y12RI to clopidogrel (P-C). There were no differences in NACEs among the unchanged clopidogrel, the unchanged potent P2Y12RIs, and the P2Y12RI switching groups. However, compared to the unchanged clopidogrel group, the C-P group had a higher incidence of non-fatal MI, and the P-C group had a higher incidence of TIMI major bleeding. In clinical events of in-hospital P2Y12RI switching, 90.9% of non-fatal MI occurred during pre-switching clopidogrel administration, 60.7% of TIMI major bleeding was related to pre-switching P2Y12RIs, and 71.4% of TIMI major bleeding was related to potent P2Y12RIs. Only 21.6% of the P2Y12RI switching group switched to P2Y12RIs after a loading dose (LD); however, there were no differences in clinical events between patients with and without LD. Conclusions In-hospital P2Y12RI switching occurred occasionally, but had relatively similar clinical outcomes compared to unchanged P2Y12RIs in Korean AMI patients. Non-fatal MI and bleeding appeared to be mainly related to pre-switching P2Y12RIs.

Background: Although ticagrelor is known to increase the bleeding risk compared to clopidogrel in East Asian patients, its clinical benefits in patients with acute myocardial infarction (AMI) without high bleeding risk (HBR) remains unknown. Methods: A total of 7,348 patients who underwent successful percutaneous coronary intervention (PCI) from the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), between November 2011 and December 2015, were divided into two groups according to the Academic Research Consortium for HBR criteria (KAMIR-HBR, 2,469 patients; KAMIR-non HBR, 4,879 patients). We compared in-hospital major adverse cardiovascular events (MACEs, defined as a composite of cardiac death, non-fatal myocardial infarction, or stroke), and the thrombolysis in myocardial infarction (TIMI) major bleeding between ticagrelor and clopidogrel in the KAMIR-HBR and the KAMIR-non HBR groups, respectively. Results: After propensity score matching, ticagrelor had a higher incidence of in-hospital TIMI major bleeding than clopidogrel in all patients (odds ratio [OR], 1.683; 95% confidence interval [CI], 1.010–2.805; P = 0.046) and the KAMIR-HBR group (OR, 3.460; 95% CI, 1.374–8.714; P = 0.008). However, there was no significant difference in in-hospital TIMI major bleeding between ticagrelor and clopidogrel in the KAMIR-non HBR group (OR, 1.436; 95% CI, 0.722–2.855; P = 0.303). No differences were observed in the cumulative incidences of in-hospital and 6-month MACEs between ticagrelor and clopidogrel in both groups. Conclusions The bleeding risk of ticagrelor was attenuated in Korean patients with AMI without HBR. Appropriate patient selection could reduce in-hospital bleeding complications associated with ticagrelor in Korean patients with AMI who underwent successful PCI.

Background/Aims: Minimising total ischemic time (TIT) is important for improving clinical outcomes in patients with ST-segment elevation myocardial infarction who have undergone percutaneous coronary intervention (PCI). TIT has not shown a significant improvement due to persistent pre-hospital delay. This study aimed to investigate the risk factors associated with pre-hospital delay. Methods: Individuals enrolled in the Korea Acute Myocardial Infarction Registry-National Institutes of Health between 2011 and 2015 were included in this study. The study population was analyzed according to the symptom-to-door time (STDT; within 60 or > 60 minutes), and according to the type of hospital visit (emergency medical services [EMS], non-PCI center, or PCI center). Results: A total of 4,874 patients were included in the analysis, of whom 28.4% arrived at the hospital within 60 minutes of symptom-onset. Old age (> 65 years), female gender, and renewed ischemia were independent predictors of delayed STDT. Utilising EMS was the only factor shown to reduce STDT within 60 minutes, even when cardiogenic shock was evident. The overall frequency of EMS utilisation was low (21.7%). Female gender was associated with not utilising EMS, whereas cardiogenic shock, previous myocardial infarction, familial history of ischemic heart disease, and off-hour visits were associated with utilising EMS. Conclusions Factors associated with delayed STDT and not utilising EMS could be targets for preventive intervention to improve STDT and TIT.

Background/Aims: This study investigated the prognostic power of corrected QT (QTc) interval in patients with acute heart failure (AHF) according to sex. Methods: We analyzed multicenter Korean Acute Heart Failure registry with patients with AHF admitted from 2011 to 2014. Among them, we analyzed 4,990 patients who were followed up to 5 years. Regarding QTc interval based on 12 lead electrocardiogram, patients were classified into quartiles according to sex. Results: During follow-up with median 43.7 months, 2,243 (44.9%) patients died. The relationship between corrected QT interval and all-cause mortality followed a J-curve relationship. In Kaplan-Meier analysis, both sex had lowest mortality in the second QTc quartile. There were significant prognostic differences between the second and the fourth quartiles in male (log-rank p = 0.002), but not in female (log-rank p = 0.338). After adjusting covariates, the third (hazard ratio [HR], 1.185; 95% confidence interval [CI], 1.001 to 1.404; p = 0.049) and the fourth (HR, 1.404; 95% CI, 1.091 to 1.535; p = 0.003) quartiles demonstrated increased risk of mortality compared to the second quartile in male. In female, however, there was no significant difference across quartiles. QTc interval was associated with 5-year all-cause mortality in J-shape with nadir of 440 to 450 ms in male and 470 to 480 ms in female. Conclusions QTc interval was an independent predictor of overall death in male, but its significance decreased in female. The relationship between QTc interval and all-cause mortality was J-shaped in both sex.

The present study investigated the participation of D-serine and NR2 in antinociception produced by blockade of central erythropoietin-producing hepatocellular carcinoma (Eph) A4 (EphA4) signaling in rats with trigeminal neuropathic pain. Trigeminal neuropathic pain was modeled in male Sprague-Dawley rats using mal-positioned dental implants. The left mandibular second molar was extracted under anesthesia, and a miniature dental implant was placed to induce injury to the inferior alveolar nerve. Our current findings showed that nerve injury induced by malpositioned dental implants significantly produced mechanical allodynia; additionally, the inferior alveolar nerve injury increased the expression of D-serine and NR2 subunits in the ipsilateral medullary dorsal horn (trigeminal subnucleus caudalis). Intracisternal administration of EphA4-Fc, an EphA4 inhibitor, inhibited nerve injury-induced mechanical allodynia and upregulated the expression of D-serine and NR2 subunits. Moreover, intracisternal administration of D-amino acids oxidase, a D-serine inhibitor, inhibited trigeminal mechanical allodynia. These results show that D-serine and NR2 subunit pathways participate in central EphA4 signaling after an inferior alveolar nerve injury.Therefore, blockade of D-serine and NR2 subunit pathways in central EphA4 signaling provides a new therapeutic target for the treatment of trigeminal neuropathic pain.

BACKGROUND AND OBJECTIVES: Diffuse long coronary artery disease (DLCAD) still has unfavorable clinical outcomes after successful percutaneous coronary intervention (PCI). Therefore, we aimed to evaluate the effectiveness and safety of Resolute™ zotarolimus-eluting stent (R-ZES; Resolute™ Integrity) for patients with DLCAD. METHODS: From December 2011 to December 2014, 1,011 patients who underwent PCI using R-ZES for CAD with longer than 25 mm lesion were prospectively enrolled from 21 hospitals in Korea. We assessed the clinical outcome of major adverse cardiac events (MACE) defined as the composite of cardiac death, non-fatal myocardial infarction (MI), and clinically-driven target vessel revascularization at 12 months. RESULTS: Mean age was 63.8±10.8 years, 701 (69.3%) patients were male, 572 (87.0%) patients had hypertension, 339 (33.8%) patients had diabetes, 549 (54.3%) patients diagnosed with acute MI and 545 (53.9%) patients had multi-vessel disease (MVD). A total of 1,697 stents were implanted into a total of 1,472 lesions. The mean diameter was 3.07±0.38 mm and the length was 28.27±6.97 mm. Multiple overlapping stents were performed in 205 (13.8%) lesions. A 12-month clinical follow-up was available in 1,004 patients (99.3%). The incidences of MACE and definite stent thrombosis at 12-month were 3.0% and 0.3% respectively. On multivariate Cox-regression analysis, multiple overlapping stents implantation, previous congestive heart failure, MVD, and age ≥75 years were independent predictors of one-year MACE. CONCLUSIONS: Our study shows that R-ZES has an excellent 1-year clinical outcome in Korean patients with DLCAD.
Coronary Artery Disease ; Coronary Vessels ; Death ; Drug-Eluting Stents ; Follow-Up Studies ; Heart Failure ; Humans ; Hypertension ; Incidence ; Korea ; Male ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Prospective Studies ; Stents ; Thrombosis ; Treatment Outcome

BACKGROUND AND OBJECTIVES: Diffuse long coronary artery disease (DLCAD) still has unfavorable clinical outcomes after successful percutaneous coronary intervention (PCI). Therefore, we aimed to evaluate the effectiveness and safety of Resolute™ zotarolimus-eluting stent (R-ZES; Resolute™ Integrity) for patients with DLCAD. METHODS: From December 2011 to December 2014, 1,011 patients who underwent PCI using R-ZES for CAD with longer than 25 mm lesion were prospectively enrolled from 21 hospitals in Korea. We assessed the clinical outcome of major adverse cardiac events (MACE) defined as the composite of cardiac death, non-fatal myocardial infarction (MI), and clinically-driven target vessel revascularization at 12 months. RESULTS: Mean age was 63.8±10.8 years, 701 (69.3%) patients were male, 572 (87.0%) patients had hypertension, 339 (33.8%) patients had diabetes, 549 (54.3%) patients diagnosed with acute MI and 545 (53.9%) patients had multi-vessel disease (MVD). A total of 1,697 stents were implanted into a total of 1,472 lesions. The mean diameter was 3.07±0.38 mm and the length was 28.27±6.97 mm. Multiple overlapping stents were performed in 205 (13.8%) lesions. A 12-month clinical follow-up was available in 1,004 patients (99.3%). The incidences of MACE and definite stent thrombosis at 12-month were 3.0% and 0.3% respectively. On multivariate Cox-regression analysis, multiple overlapping stents implantation, previous congestive heart failure, MVD, and age ≥75 years were independent predictors of one-year MACE. CONCLUSIONS Our study shows that R-ZES has an excellent 1-year clinical outcome in Korean patients with DLCAD.

The aim of the present study was to evaluate the central antinociceptive effects of eugenol after intraperitoneal administration. Experiments were carried out using male Sprague-Dawley rats. Subcutaneous injection of 5% formalin-induced nociceptive behavioral responses was used as the pain model. Subcutaneous injection of 5% formalin significantly produced nociceptive responses by increasing the licking time during nociceptive behavior. Subsequent intraperitoneal injection of 100 mg/kg of eugenol led to a significant decrease in the licking time. However, low dose of eugenol (50 mg/kg) did not affect the nociceptive behavioral responses produced by subcutaneous injection of formalin. Intrathecal injection of 30 µg of naloxone, an opioid receptor antagonist, significantly blocked antinociceptive effects produced by intraperitoneal injection of eugenol. Neither intrathecal injection of methysergide (30 µg), a serotonin receptor antagonist nor phentolamine (30 µg), an α-adrenergic receptor antagonist influenced antinociceptive effects of eugenol, as compared to the vehicle treatment. These results suggest that central opioid pathway participates in mediating the antinociceptive effects of eugenol.
Eugenol ; Formaldehyde ; Humans ; Injections, Intraperitoneal ; Injections, Spinal ; Injections, Subcutaneous ; Male ; Methysergide ; Naloxone ; Negotiating ; Phentolamine ; Rats, Sprague-Dawley ; Receptors, Opioid ; Serotonin