Inflammation is a common link in the pathophysiology of many neurological illnesses, including Alzheimer’s disease. Activated glial cells contribute to neuroinflammation by producing pro-inflammatory mediators. Naproxen and ibuprofen are nonsteroidal anti-inflammatory drugs with 2-aryl(s) propionic acid as a common pharmacophore. Here we designed a small series of naproxen and ibuprofen amide dimers and tested their effects on the expression of inducible nitric oxide synthase (iNOS), a neuroinflammatory enzyme in lipopolysaccharide (LPS)-stimulated BV2 mouse microglial cells. Of note, treatment with CNU 019, 020, 021, 023, 024, and 027 at 10 M markedly inhibited the LPS-induced iNOS expression in BV2 cells. CNU 024 was tested further at different concentrations to regulate the LPS-induced iNOS expression in BV2 cells. Treatment with CNU 024 at 5, 10, or 20 M dose-dependently suppressed the LPS-induced iNOS protein and mRNA expression levels in BV2 cells, in which maximal inhibition was seen at 20 M. CNU 024 treatment at doses tested further led to a concentration-dependent inhibition of the LPS-induced phosphorylation (activation) of p38 mitogen-activated protein kinase (MAPK) without influencing its total protein expression in BV2 cells, but it did not affect the LPS-induced activation of c-jun N-terminal kinase-1/2 and extracellular signal-regulated kinases-1/2 in these cells. In summary, our results demonstrate that CNU 024 inhibits the LPS-induced iNOS expression in BV2 cells, partly mediated by the inhibition of p38 MAPK. This work shows that CNU 024 could be a valuable ligand for further development as a potential drug candidate for treating neuroinflammatory pathologies.

Background: An excess of thyroid hormones in Graves’ disease (GD) has profound effects on systemic energy metabolism that are currently partially understood. In this study, we aimed to provide a comprehensive understanding of the metabolite changes that occur when patients with GD transition from hyperthyroidism to euthyroidism with methimazole treatment. Methods: Eighteen patients (mean age, 38.6±14.7 years; 66.7% female) with newly diagnosed or relapsed GD attending the endocrinology outpatient clinics in a single institution were recruited between January 2019 and July 2020. All subjects were treated with methimazole to achieve euthyroidism. We explored metabolomics by performing liquid chromatography-mass spectrometry analysis of plasma samples of these patients and then performed multivariate statistical analysis of the metabolomics data. Results: Two hundred metabolites were measured before and after 12 weeks of methimazole treatment in patients with GD. The levels of 61 metabolites, including palmitic acid (C16:0) and oleic acid (C18:1), were elevated in methimazole-naïve patients with GD, and these levels were decreased by methimazole treatment. The levels of another 15 metabolites, including glycine and creatinine, were increased after recovery of euthyroidism upon methimazole treatment in patients with GD. Pathway analysis of metabolomics data showed that hyperthyroidism was closely related to aminoacyl-transfer ribonucleic acid biosynthesis and branched-chain amino acid biosynthesis pathways. Conclusion In this study, significant variations of plasma metabolomic patterns that occur during the transition from hyperthyroidism to euthyroidism were detected in patients with GD via untargeted metabolomics analysis.

Objective: To compare the predicted and actual maximal heart rate (HRmax) values in the cardiopulmonary exercise test (CPET). Methods: We retrospectively investigated 1,060 patients who underwent a CPET between January 2016 and April 2020 at our institution’s cardiopulmonary rehabilitation center. The following patients were included: those aged >20 years, those tested with a treadmill, and those who underwent symptom-limited maximum exercise testing— reaching ≥85% of the predicted HRmax (62% if taking beta-blockers) and highest respiratory exchange ratio ≥1.1. Ultimately, 827 patients were included in this study. Data on diagnosis, history of taking beta-blockers, age, body mass index (BMI), and CPET parameters were collected. Subgroup analysis was performed according to age, betablockers, BMI (low <18.5 kg/m2, normal, and high ≥25 kg/m2), and risk classification. Results: There was a significant difference between the actual HRmax and the predicted value (p<0.001). Betablocker administration resulted in a significant difference in the actual HRmax (p<0.001). There were significant differences in the moderate-to-high-risk and low-risk groups and the normal BMI and high BMI groups (p<0.001). There was no significant difference between the elderly and younger groups. We suggest new formulae for HRmax of cardiopulmonary patients: estimated HRmax=183-0.76×age (the beta-blocker group) and etimated HRmax=210-0.91×age (the non-beta-blocker group). Conclusion Age-predicted HRmax was significantly different from the actual HRmax of patients with cardiopulmonary disease, especially in the beta-blocker group. For participants with high BMI and moderate-tosevere risk, the actual HRmax was significantly lower than the predicted HRmax.

Background and Objectives: Non-linear frequency compression (NLFC) technology compresses and shifts higher frequencies into a lower frequency area that has better residual hearing. Because consonants are uttered in the high-frequency area, NLFC could provide better speech understanding. The aim of this study was to investigate the clinical effectiveness of NLFC technology on the perception of speech and music in patients with high-frequency hearing loss. Subjects and Methods: Twelve participants with high-frequency hearing loss were tested in a counter-balanced order, and had two weeks of daily experience with NLFC set on/off prior to testing. Performance was repeatedly evaluated with consonant tests in quiet and noise environments, speech perception in noise, music perception and acceptableness of sound quality rating tasks. Additionally, two questionnaires (the Abbreviated Profile of Hearing Aid Benefit and the Korean version of the International Outcome Inventory-Hearing Aids) were administered. Results: Consonant and speech perception improved with hearing aids (NLFC on/off conditions), but there was no significant difference between NLFC on and off states. Music perception performances revealed no notable difference among unaided and NLFC on and off states. The benefits and satisfaction ratings between NLFC on and off conditions were also not significantly different, based on questionnaires, however great individual variability preferences were noted. Conclusions Speech perception as well as music perception both in quiet and noise environments was similar between NLFC on and off states, indicating that real world benefits from NLFC technology may be limited in Korean adult hearing aid users.

Background: This study was undertaken to compare the sensitivities of mice strains during tumor induction by transcription activator-like effector nucleases (TALEN)-mediated Trp53 mutant gene. Alterations of their tumorigenic phenotypes including survival rate, tumor formation and tumor spectrum, were assessed in FVB/N-Trp53 em2Hwl /Korl and C57BL/6-Trp53 em1Hwl /Korl knockout (KO) mice over 16 weeks. Results: Most of the physiological phenotypes factors were observed to be higher in FVB/N-Trp53 em2Hwl /Korl KO mice than C57BL/6-Trp53 em1Hwl /Korl KO mice, although there were significant differences in the body weight, immune organ weight, number of red blood cells, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), total bilirubin (Bil-T) and glucose (Glu) levels in the KO mice relative to the wild type (WT) mice. Furthermore, numerous solid tumors were also observed in various regions of the surface skin of FVB/N-Trp53 em2Hwl /Korl KO mice, but were not detected in C57BL/6-Trp53 em1Hwl /Korl KO mice. The most frequently observed tumor in both the Trp53 KO mice was malignant lymphoma, while soft tissue teratomas and hemangiosarcomas were only detected in the FVB/N-Trp53 em2Hwl /Korl KO mice. Conclusions Our results indicate that the spectrum and incidence of tumors induced by the TALEN-mediated Trp53 mutant gene is greater in FVB/N-Trp53 em2Hwl /Korl KO mice than C57BL/6-Trp53 em1Hwl /Korl KO mice over 16 weeks.

Purpose: Data on the distribution and impact of panel reactive antibodies (PRA) and donor specific antibodies (DSA) before lung transplantation in Asia, especially multi-center-based data, are limited. This study evaluated the prevalence of and effects of PRA and DSA levels before lung transplantations on outcomes in Korean patients using nationwide multicenter registry data. Materials and Methods: This study included 103 patients who received a lung transplant at five tertiary hospitals in South Korea between March 2015 and December 2017. Mortality, primary graft dysfunction (PGD), and bronchiolitis obliterans syndrome (BOS) were evaluated. Results: Sixteen patients had class I and/or class II PRAs exceeding 50%. Ten patients (9.7%) had DSAs with a mean fluorescence intensity (MFI) higher than 1000, six of whom had antibodies with a high MFI (≥2000). DSAs with high MFIs were more frequently observed in patients with high-grade PGD (≥2) than in those with no or low-grade (≤1) PGD. In the 47 patients who survived for longer than 9 months and were evaluated for BOS after the transplant, BOS was not related to DSA or PRA levels. One-year mortality was more strongly related to PRA class I exceeding 50% than that under 50% (0% vs. 16.7%, p=0.007). Conclusion Preoperative DSAs and PRAs are related to worse outcomes after lung transplantation. DSAs and PRAs should be considered when selecting lung transplant recipients, and recipients who have preoperative DSAs with high MFI values and high PRA levels should be monitored closely after lung transplantation.

Academies and Institutes ; Aged ; Asbestos ; Biopsy ; Compensation and Redress ; Diagnosis ; Drinking ; Drug Therapy ; Endoscopy ; Gastrectomy ; Gastrointestinal Neoplasms ; Humans ; Korea ; Middle Aged ; Occupational Exposure ; Occupational Health ; Oxygen ; Power Plants ; Rectal Neoplasms ; Ships ; Smoke ; Smoking ; Stomach Neoplasms

BACKGROUND: The Occupational Safety and Health Research Institute (OSHRI) of the Korea had not recognized gastrointestinal cancer as work-related disease during their evaluation. However, in 2018 OSHRI recognized gastric and rectal cancers as work-related disease in asbestos-exposed workers. We present 2 such cases along supportive evidence of causation.CASE PRESENTATION: Patient A: A 57-year-old man had worked for about 40 years since 1978 as an oxygen cutter at workplaces that dismantle ships, buildings, boilers, and thermal power plants. In November 2016, endoscopy and biopsy confirmed the diagnosis of advanced gastric cancer, for which he underwent subtotal gastrectomy and chemotherapy; however, he later died of the cancer. Patient B: A 71-year-old man had worked in shipbuilding and repair workplaces for approximately 49 years, being employed in pipe laying, asbestos insulation installation, grinding, and other ship repair work. In 2003, he was diagnosed of rectal cancer by abdominal computed tomography. He accordingly underwent surgical removal of the cancer. Based on the occupational history of the 2 patients and our review of the relevant literature addressing the occupational environment, we concluded that both patients had continuous exposure to high levels of asbestos while performing their jobs for 40 and 49 years, respectively. CONCLUSION Both patients had a history of smoking and drinking (non-occupational personal risk factors). However, the possibility of an increased risk of gastric and rectal cancers from asbestos exposure cannot be excluded. Therefore, we considered that occupational exposure to asbestos had contributed to the cancer diagnosis in these cases. Workers exposed to asbestos should be made aware of the possibility of gastric or rectal cancer, and should undergo monitoring and medical examinations. Appropriate compensation for gastric and rectal cancers that occur in workers exposed to asbestos are anticipated in future.

Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.

Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.