Impact of National Public-Private Mix and Medical Expense Support Program to Control Tuberculosis in South Korea: An Interrupted Time Series Analysis.

Tuberculosis (TB) remains a major threat to global public health. Various measures at the national level have been implemented to control TB, and no evidence with long-term effectiveness has yet been evaluated on TB control programs. We confirmed the long-term effectiveness of the TB control programs in reducing overall burden in South Korea using interrupted time series analysis. Our finding suggests that, along with the public-private mix, relieving the economic burden of people with TB may complement achieving the End TB Strategy. For countries currently developing strategies for TB control, results may provide important insights in effective TB control.

Risk of encephalitis and meningitis after COVID-19 vaccination in South Korea: a self-controlled case series analysis.

BACKGROUND: Several neurological manifestations shortly after a receipt of coronavirus infectious disease 2019 (COVID-19) vaccine have been described in the recent case reports. Among those, we sought to evaluate the risk of encephalitis and meningitis after COVID-19 vaccination in the entire South Korean population. METHODS: We conducted self-controlled case series (SCCS) analysis using the COVID-19 immunization record data from the Korea Disease Control Agency between February 2021 and March 2022, linked with the National Health Insurance Database between January 2021 and October 2022. We retrieved all medical claims of adults aged 18 years or older who received at least one dose of COVID-19 vaccines (BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S), and included only those who had a diagnosis record for encephalitis or meningitis within the 240-day post-vaccination period. With day 0 defined as the date of vaccination, risk window was defined as days 1-28 and the control window as the remainder period excluding the risk windows within the 240-day period. We used conditional Poisson regression to estimate the incidence rate ratios (IRR) with 95% confidence intervals (CI), stratified by dose and vaccine type. RESULTS: From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 251 and 398 cases of encephalitis and meningitis during the risk window, corresponding to 1.9 and 3.1 cases per 1 million doses, respectively. Overall, there was an increased risk of encephalitis in the first 28 days of COVID-19 vaccination (IRR 1.26; 95% CI 1.08-1.47), which was only significant after a receipt of ChAdOx1-S (1.49; 1.03-2.15). For meningitis, no increased risk was observed after any dose of COVID-19 vaccine (IRR 1.03; 95% CI 0.91-1.16). CONCLUSIONS: Our findings suggest an overall increased risk of encephalitis after COVID-19 vaccination. However, the absolute risk was small and should not impede COVID-19 vaccine confidence. No significant association was found between the risk of meningitis and COVID-19 vaccination.

Adverse Events Following COVID-19 Vaccination in Adolescents: Insights From Pharmacovigilance Study of VigiBase.

BACKGROUND: During coronavirus disease 2019 (COVID-19) pandemic, several COVID-19 vaccines were licensed with fast-track procedures. Although these vaccines have demonstrated high immunogenicity, there has been concerns on the serious adverse events (AEs) following COVID-19 vaccination among adolescents. We aimed to analyze comparative safety of COVID-19 vaccination in adolescents. METHODS: In this pharmacovigilance study, we performed a disproportionality analysis using VigiBase, the World Health Organization's global individual case safety report (ICSR) database. To compare serious AEs reported following COVID-19 vaccines vs. all other vaccines in adolescents aged 12-17 years, ICSRs following any vaccines on adolescents aged 12-17 years were included, defining cases as reports with the AEs of interest, with all other AEs as non-cases. The AEs of interest were myocarditis/pericarditis, multisystem inflammatory syndrome/Kawasaki disease (MIS/KD), anaphylaxis, Guillain-Barré syndrome (GBS), and immune thrombocytopenia (ITP). We conducted a disproportionality analysis to estimate reporting odds ratio (ROR) with 95% confidence interval (CI) for each AE of interest, adjusted for sex by using logistic regression. RESULTS: Of 99,735 AE reports after vaccination in adolescents, 80,018 reports were from COVID-19 vaccinated adolescents (52.9% females; 56.3% America). The AEs of interest were predominantly reported as serious AE (76.1%) with mRNA vaccines (99.4%). Generally, higher reporting odds for the AEs were identified following COVID-19 vaccination in adolescents; myocarditis/pericarditis (2,829 reports for the COVID-19 vaccine vs. 35 for all other vaccines, adjusted ROR [aROR], 19.61; 95% CI, 14.05-27.39), and MIS/KD (104 vs. 6, aROR, 4.33; 95% CI, 1.89-9.88). The reporting odds for anaphylaxis (515 vs. 165, aROR, 0.86; 95% CI, 0.72-1.02), GBS (94 vs. 40, aROR, 0.64; 95% CI, 0.44-0.92) and ITP (52 vs. 12, aROR, 1.12; 95% CI, 0.59-2.09) were not significantly higher following COVID-19 vaccination. CONCLUSION: In this study, there were disproportionate reporting of immune-related AEs following COVID-19 vaccination. While awaiting definitive evidence, there is a need to closely monitor for any signs of immune-related AEs following COVID-19 vaccination among adolescents.

Predictors, mortality, and health outcomes of intensive phase non-adherence to a regimen in patients with drug-susceptible tuberculosis: a nationwide linkage database.

OBJECTIVES: The clinical importance of adhering to the regimen in tuberculosis patients has been widely investigated, but most studies were conducted in controlled settings and in limited populations. We aimed to measure the level of real-world adherence during intensive phase and investigate the predictors and the risk of mortality and health outcomes of intensive phase non-adherence in tuberculosis patients. STUDY DESIGN: We conducted a nationwide cohort study by linking the Korean National Tuberculosis Surveillance System and the National Health Information Database. METHODS: We included all incident drug-susceptible tuberculosis patients who initiated the regimens recommended by the World Health Organization from 2013 to 2018. Adherence was measured using the proportion of days covered (poor [<50%], moderate [50%-79%], and high [≥80%]). We used logistic regression model to assess predictors and the Cox proportional hazard model to evaluate the risk of mortality and health outcomes with intensive phase non-adherence. RESULTS: Of 46,818 patients, there were 8% and 11% with poor and moderate adherent groups, respectively. Age ≥45 years, insulin use, and history of renal failure were predictors of non-adherence. Compared with high adherent group, poor and moderate adherent groups were associated with a substantial risk of mortality (poor: hazard ratio, 2.14 [95% confidence interval, 1.95-2.34]; moderate: 1.76 [1.62-1.92]). Similar trends were observed for health outcomes. Stratified analyses showed a higher risk of mortality in patients with medical aid, low income, and history of renal failure, systematic corticosteroids, and immunomodulators. CONCLUSIONS: Non-adherence during intensive phase increased mortality risk by twofold, underscoring targeted intervention for high-risk population, including advanced diabetes, and immunocompromised patients.

The Influence of Tacrolimus on Cellular Morphology, Cellular Viability, Osteogenic Differentiation, and mRNA Expression within Stem Cell Spheroids.

Background and Objectives: Tacrolimus is a macrolide lactone compound derived from the bacterium Streptomyces tsukubensis, widely known as an immunosuppressant. In basic research, the effects of tacrolimus on osteogenic differentiation have been tested using mesenchymal stem cells. In this study, tacrolimus's effects on the cellular survival and osteogenic differentiation of stem cell spheroids were investigated. Materials and Methods: Concave microwells were used to form stem cell spheroids in the presence of tacrolimus at final concentrations of 0 µg/mL, 0.1 µg/mL, 1 µg/mL, 10 µg/mL, and 100 µg/mL. A microscope was used to test cellular vitality qualitatively, and an assay kit based on water-soluble tetrazolium salt was used to measure cellular viability quantitatively. Alkaline phosphatase activity and an anthraquinone dye test for measuring calcium deposits were used to assess osteogenic differentiation. To assess the expression of osteogenic differentiation, a quantitative polymerase chain reaction, Western blot, and RNA sequencing were performed. Results: Spheroids across all concentrations maintained a relatively uniform and spherical shape. Cell viability assay indicated that tacrolimus, up to a concentration of 100 µg/mL, did not significantly impair cell viability within spheroids cultured in osteogenic media. The increase in calcium deposition, particularly at lower concentrations of tacrolimus, points toward an enhancement in osteogenic differentiation. There was an increase in COL1A1 expression across all tacrolimus concentrations, as evidenced by the elevated mean and median values, which may indicate enhanced osteogenic activity. Conclusions: This study showed that tacrolimus does not significantly impact the viability of stem cell spheroids in osteogenic media, even at high concentrations. It also suggests that tacrolimus may enhance osteogenic differentiation, as indicated by increased calcium deposition and COL1A1 expression. These findings advance our understanding of tacrolimus's potential roles in tissue repair, regeneration, and stem cell-based therapeutic applications.

Trends of polypharmacy among older people in Asia, Australia and the United Kingdom: a multinational population-based study.

BACKGROUND: Polypharmacy among older people represents a global challenge due to its association with adverse drug events. The reported prevalence of polypharmacy varies widely across countries, and is particularly high in Asian countries. However, there is no multinational study using standardised measurements exploring variations in prescribing trends. OBJECTIVE: To compare polypharmacy trends in older people in Asia, Australia and the United Kingdom. DESIGN: Multinational, retrospective, time-trend, observational study using a common study protocol. SETTING: Outpatient and community settings. SUBJECTS: All individuals aged ≥ 65 years between 2013 and 2016. METHODS: We defined polypharmacy as the concomitant use of ≥5 medications for ≥45 days per year. We estimated the annual prevalence of polypharmacy and calculated average annual percentage change (AAPC) to assess the time trends. RESULTS: A total of 1.62 million individuals were included in this study. The highest prevalence of polypharmacy was observed in Hong Kong (46.4%), followed by Taiwan (38.8%), South Korea (32.0%), the United Kingdom (23.5%) and Australia (20.1%) in 2016. For the time trend, the Asian region showed a steady increase, particularly in Hong Kong and South Korea (AAPC: Hong Kong, 2.7%; South Korea, 1.8%; Taiwan, 1.0%). However, Australia and the United Kingdom showed a decreasing trend (Australia, -4.9%; the United Kingdom, -1.1%). CONCLUSIONS: Polypharmacy prevalence in older people was higher in Hong Kong, Taiwan and South Korea, with an increasing trend over time, compared with Australia and the United Kingdom. Our findings underline the necessity to monitor polypharmacy among older people in Asia by conducting government-level interventions and introducing medicine-optimisation strategies.

Predictors of COVID-19 Vaccine Hesitancy Among Parents of Children Aged 5-11 Years in Korea.

This was a cross-sectional study using the data collected from a nationwide survey between November and December 2022 to explore factors associated with hesitancy towards coronavirus disease 2019 (COVID-19) vaccination for children. Among 3,011 participants with child aged 5-11 years, 82.5% demonstrated hesitancy towards vaccinating their child. This was more common among mothers (odds ratio 1.84 [95% confidence interval 1.46-2.31]), those residing outside metropolitan area (urban: 2.46 [1.89-3.20]; rural: 2.87 [2.09-3.93]) or with history of COVID-19 diagnosis (2.22 [1.78-2.76]). Parents were also hesitant if their child recently had COVID-19 (3.41 [2.67-4.37]). Conversely, they were less likely to be hesitant if they had three or more children (0.66 [0.46-0.94]) or if their child has underlying medical condition(s) (0.54 [0.41-0.71]). Our findings highlight high prevalence of parental hesitancy towards COVID-19 vaccination for children, and call for targeted outreach efforts from the stakeholders to facilitate the vaccine uptake in this pediatric population.

Incidence and Healthcare Burden of Pertussis among Older Adults with and without Pre-Existing Chronic Obstructive Pulmonary Disease or Asthma in South Korea.

A retrospective cohort study was conducted to examine trends in the incidence and burden of pertussis among adults ≥50 years in South Korea, with/without pre-existing chronic obstructive pulmonary disease (COPD) or asthma. The nationwide Health Insurance Review and Assessment Service (HIRA) database was used to identify patients ≥50 years diagnosed with pertussis (2009-2018). Mean annual incidence of pertussis per 100 000 persons and overall mean incidence rate ratios (IRR) were calculated for patients with pre-existing COPD or asthma versus those with neither. Incremental healthcare costs (all-cause and pertussis-related) and healthcare utilisation (number of outpatient visits, emergency room visits, and number and length of hospitalisations) up to 12 months after, compared to 3 months before pertussis diagnosis, were also measured for each group (matched on sex, age, and Charlson Comorbidity Index). Of 1011 pertussis cases, 175 had asthma, 96 had COPD (not mutually exclusive), and 796 had neither. Overall mean pertussis incidence was 2.5, 3.4, and 0.5 for adults with pre-existing COPD, asthma, and those with neither. IRR (95% confidence interval) of pertussis for adults with pre-existing COPD and asthma was 4.9 (4.0-|6.1) and 6.7 (5.7-7.9). Both COPD-pertussis and asthma-pertussis groups had higher mean incremental all-cause costs and length of hospitalisations than the general-pertussis group 3 months following pertussis diagnosis. In conclusion, individuals ≥50 years in South Korea with pre-existing COPD or asthma were at an increased risk of being diagnosed with pertussis and had higher healthcare resource utilisation than those without these conditions.

Impact of 17ß-Estradiol on the Shape, Survival, Osteogenic Transformation, and mRNA Expression of Gingiva-Derived Stem Cell Spheroids.

Background and Objectives: Mesenchymal stem cells hold promise for tissue regeneration, given their robust growth and versatile differentiation capabilities. An analysis of bone marrow-sourced mesenchymal stem cell proliferation showed that 17ß-estradiol could enhance their growth. This study aims to investigate the influence of 17ß-estradiol on the shape, survival, osteogenic differentiation, and mineralization of human mesenchymal stem cells. Materials and Methods: Spheroids made from human gingiva-derived stem cells were cultivated with varying concentrations of 17ß-estradiol: 0, 0.01, 0.1, 1, and 10 nM. Morphology was assessed on days 1, 3, and 5. The live/dead kit assay was employed on day 3 for qualitative cell viability, while cell counting kit-8 was used for quantitative viability assessments on days 1, 3, and 5. To evaluate the osteogenic differentiation of the spheroids, a real-time polymerase chain reaction assessed the expressions of RUNX2 and COL1A1 on day 7. Results: The stem cells formed cohesive spheroids, and the inclusion of 17ß-estradiol did not noticeably alter their shape. The spheroid diameter remained consistent across concentrations of 0, 0.01, 0.1, 1, and 10 nM of 17ß-estradiol. However, cellular viability was boosted with the addition of 1 and 10 nM of 17ß-estradiol. The highest expression levels for RUNX2 and COL1A1 were observed with the introduction of 17ß-estradiol at 0.1 nM. Conclusions: In conclusion, from the results obtained, it can be inferred that 17ß-estradiol can be utilized for differentiating stem cell spheroids. Furthermore, the localized and controlled use, potentially through localized delivery systems or biomaterials, can be an area of active research. While 17ß-estradiol holds promise for enhancing stem cell applications, any clinical use requires a thorough understanding of its mechanisms, careful control of its dosage and delivery, and extensive testing to ensure safety and efficacy.

Mad2B forms a complex with Cdc20, Cdc27, Rev3 and Rev1 in response to cisplatin-induced DNA damage.

Mitotic arrest deficient 2 like 2 (Mad2L2, also known as Mad2B), the human homologue of the yeast Rev7 protein, is a regulatory subunit of DNA polymerase ζ that shares high sequence homology with Mad2, the mitotic checkpoint protein. Previously, we demonstrated the involvement of Mad2B in the cisplatin-induced DNA damage response. In this study, we extend our findings to show that Mad2B is recruited to sites of DNA damage in human cancer cells in response to cisplatin treatment. We found that in undamaged cells, Mad2B exists in a complex with Polζ-Rev1 and the APC/C subunit Cdc27. Following cisplatin-induced DNA damage, we observed an increase in the recruitment of Mad2B and Cdc20 (the activators of the APC/C), to the complex. The involvement of Mad2B-Cdc20-APC/C during DNA damage has not been reported before and suggests that the APC/C is activated following cisplatin-induced DNA damage. Using an in vitro ubiquitination assay, our data confirmed Mad2B-dependent activation of APC/C in cisplatin-treated cells. Mad2B may act as an accelerator for APC/C activation during DNA damage response. Our data strongly suggest a role for Mad2B-APC/C-Cdc20 in the ubiquitination of proteins involved in the DNA damage response.

Survival outcomes of patients with nonsmall cell lung cancer concomitantly receiving proton pump inhibitors and immune checkpoint inhibitors.

Recent evidence suggests that gut microbiota dysbiosis adversely affects the efficacy of immune checkpoint inhibitors (ICIs). Our objective was to investigate the association between concomitant use of proton pump inhibitors (PPIs) and ICIs, and poor prognosis in patients with nonsmall cell lung cancer (NSCLC). We conducted a cohort study using a completely enumerated lung cancer cohort from a nationwide healthcare database in South Korea. We identified 2963 patients treated with ICIs as second-line or later therapy for stage ≥IIIB NSCLC. PPI use was ascertained within 30-days before and on the date of ICI initiation, and nonuse was defined as no prescription of PPIs during this period. Using national vital statistics in South Korea, we assessed the risk of all-cause mortality associated with concomitant PPI use through a propensity score-matched Cox proportional hazard model. Among 1646 patients included after 1:1 propensity score-matching, concomitant PPI use was associated with a 28% increased risk of all-cause mortality, compared to nonuse (adjusted hazard ratio [HR] 1.28; 95% confidence intervals [CIs], 1.13-1.46). We observed an increased risk when we restricted the analysis to new users of PPI (adjusted HR = 1.64; 95% CI = 1.25-2.17). Subgroup analysis showed that PPI use was associated with high mortality risk among patients with viral hepatitis (adjusted HR = 2.72; 95% CI = 1.54-4.78; Pinteraction = .048). Our study indicates that PPI use is associated with poor prognosis in NSCLC patients treated with ICIs. Further prospective studies are required to determine the risk-benefit balance of concomitant use of PPIs and ICIs.

Treatment pattern in postmenopausal women with osteoporosis: a population-based cohort study in South Korea.

INTRODUCTION: The treatment landscape of postmenopausal osteoporosis (OP) in an Asian population is yet to be explored. MATERIALS AND METHODS: We conducted a retrospective cohort study to explore treatment patterns and characteristics associated with treatment interruption in postmenopausal women diagnosed with OP between 2008 and 2014. Treatment pattern assessment included the initial distribution of OP medications and treatment interruption rate according to the treatment groups during a 3-year follow-up period. We used multivariate logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) to identify factors associated with treatment interruption. RESULTS: Of 21,813 patients, 87.9% initiated oral bisphosphonates (BP), followed by ibandronate intravenous (IV; 5.4%), selective estrogen receptor modulators (SERMs; 5.2%), pamidronate IV (1.4%) and zoledronic acid (0.06%). Treatment interruption was most notable in the first year of treatment, with cumulative treatment interruption rates highest for oral BP (76.3%) and lowest for pamidronate IV (50.5%). Compared to oral BP users, users of ibandronate IV (OR 0.34, 95% CI 0.30-0.39), pamidronate IV (0.49, 0.39-0.63), zoledronic acid (0.26, 0.09-0.77), and SERMs (0.50, 0.44-0.57) were less likely to interrupt treatment. Of characteristics assessed, presence of rheumatoid arthritis increased the odds of treatment interruption in ibandronate IV group (3.94, 2.12-7.33), and concomitant use of glucocorticoids for oral BP (1.11, 1.03-1.19) and pamidronate IV (2.04, 1.06-3.93) groups, respectively. CONCLUSION: Given the frequent treatment interruptions across all OP medications, our findings on the factors associated with treatment interruption will serve to implement targeted interventions in reinforcing persistence to OP treatment.

Association between tramadol use and seizures: A nationwide case-case-time-control study.

PURPOSE: Tramadol may lower the seizure threshold; however, there is no conclusive evidence to confirm this. This study aimed to determine whether the use of tramadol is associated with the occurrence of seizures. METHODS: We conducted a case-case-time-control (CCTC) study by identifying patients who had received tramadol and seizure diagnosis in a nationwide healthcare database in South Korea between 2003 and 2015. Each case was matched for age and sex to one future case to adjust for time trends in exposure without selection bias from the use of an external control group. The use of tramadol was assessed during a risk period of 1-30 days, and two reference periods, 61-90 days and 91-120 days, preceding the first diagnosis of seizures. We calculated the adjusted odds ratio (aOR) by dividing the OR in cases (case-crossover) by the OR in future cases (control-crossover). We performed a dose-response analysis using the average daily dose. RESULTS: We identified 2523 incident cases with matched future cases (mean age, 45.4 years; 50% men). The aOR for seizure with tramadol use was 0.94 (95% confidence interval [CI], 0.98-1.43) in the CCTC analysis, with a case-crossover OR of 1.19 (0.98-1.43) and control-crossover OR of 1.27 (1.03-1.56). The dose-response analysis showed a similar trend in the main analysis: a low-dose aOR of 0.80 (0.50-1.28) and a high-dose aOR of 0.92 (0.41-2.11). CONCLUSION: We could not identify a significant association between transient use of tramadol and incidence of seizures in clinical practice.

Comparison of Pore Structures of Cellulose-Based Activated Carbon Fibers and Their Applications for Electrode Materials.

This study presents the first investigation of cellulose-based activated carbon fibers (RACFs) prepared as electrode materials for the electric double-layer capacitor (EDLC) in lieu of activated carbon, to determine its efficacy as a low-cost, environmentally friendly enhancement alternative to nanocarbon materials. The RACFs were prepared by steam activation and their textural properties were studied by Brunauer-Emmett-Teller and non-localized density functional theory equations with N2/77K adsorption isotherms. The crystallite structure of the RACFs was observed by X-ray diffraction. The RACFs were applied as an electrode material for an EDLC and compared with commercial activated carbon (YP-50F). The electrochemical performance of the EDLC was analyzed using galvanostatic charge/discharge curves, cyclic voltammetry, and electrochemical impedance spectroscopy. The results show that the texture properties of the activated carbon fibers were influenced by the activation time. Crucially, the specific surface area, total pore volume, and mesopore volume ratio of the RACF with a 70-min activation time (RACF-70) were 2150 m2/g, 1.03 cm3/g and 31.1%, respectively. Further, electrochemical performance analysis found that the specific capacitance of RACF-70 increased from 82.6 to 103.6 F/g (at 2 mA/cm2). The overall high specific capacitance and low resistance of the RACFs were probably influenced by the pore structure that developed outstanding impedance properties. The results of this work demonstrate that RACFs have promising application value as performance enhancing EDLC electrode materials.

Exposure to long-term evolution radiofrequency electromagnetic fields decreases neuroblastoma cell proliferation via Akt/mTOR-mediated cellular senescence.

The aim of this study was to examine the potential effects of long-term evolution (LTE) radiofrequency electromagnetic fields (RF-EMF) on cell proliferation using SH-SY5Y neuronal cells. The growth rate and proliferation of SH-SY5Y cells were significantly decreased upon exposure to 1760 MHz RF-EMF at 4 W/kg specific absorption rate (SAR) for 4 hr/day for 4 days. Cell cycle analysis indicated that the cell cycle was delayed in the G0/G1 phase after RF-EMF exposure. However, DNA damage or apoptosis was not involved in the reduced cellular proliferation following RF-EMF exposure because the expression levels of histone H2A.X at Ser139 (γH2AX) were not markedly altered and the apoptotic pathway was not activated. However, SH-SY5Y cells exposed to RF-EMF exhibited a significant elevation in Akt and mTOR phosphorylation levels. In addition, the total amount of p53 and phosphorylated-p53 was significantly increased. Data suggested that Akt/mTOR-mediated cellular senescence led to p53 activation via stimulation of the mTOR pathway in SH-SY5Y cells. The transcriptional activation of p53 led to a rise in expression of cyclin-dependent kinase (CDK) inhibitors p21 and p27. Further, subsequent inhibition of CDK2 and CDK4 produced a fall in phosphorylated retinoblastoma (pRb at Ser807/811), which decreased cell proliferation. Taken together, these data suggest that exposure to RF-EMF might induce Akt/mTOR-mediated cellular senescence, which may delay the cell cycle without triggering DNA damage in SH-SY5Y neuroblastoma cells.

Exposure to RF-EMF Alters Postsynaptic Structure and Hinders Neurite Outgrowth in Developing Hippocampal Neurons of Early Postnatal Mice.

Exposure to radiofrequency electromagnetic fields (RF-EMFs) has increased rapidly in children, but information on the effects of RF-EMF exposure to the central nervous system in children is limited. In this study, pups and dams were exposed to whole-body RF-EMF at 4.0 W/kg specific absorption rate (SAR) for 5 h per day for 4 weeks (from postnatal day (P) 1 to P28). The effects of RF-EMF exposure on neurons were evaluated by using both pups' hippocampus and primary cultured hippocampal neurons. The total number of dendritic spines showed statistically significant decreases in the dentate gyrus (DG) but was not altered in the cornu ammonis (CA1) in hippocampal neurons. In particular, the number of mushroom-type dendritic spines showed statistically significant decreases in the CA1 and DG. The expression of glutamate receptors was decreased in mushroom-type dendritic spines in the CA1 and DG of hippocampal neurons following RF-EMF exposure. The expression of brain-derived neurotrophic factor (BDNF) in the CA1 and DG was significantly lower statistically in RF-EMF-exposed mice. The number of post-synaptic density protein 95 (PSD95) puncta gradually increased over time but was significantly decreased statistically at days in vitro (DIV) 5, 7, and 9 following RF-EMF exposure. Decreased BDNF expression was restricted to the soma and was not observed in neurites of hippocampal neurons following RF-EMF exposure. The length of neurite outgrowth and number of branches showed statistically significant decreases, but no changes in the soma size of hippocampal neurons were observed. Further, the memory index showed statistically significant decreases in RF-EMF-exposed mice, suggesting that decreased synaptic density following RF-EMF exposure at early developmental stages may affect memory function. Collectively, these data suggest that hindered neuronal outgrowth following RF-EMF exposure may decrease overall synaptic density during early neurite development of hippocampal neurons.

The Protective Effects of EMF-LTE against DNA Double-Strand Break Damage In Vitro and In Vivo.

With the rapid growth of the wireless communication industry, humans are extensively exposed to electromagnetic fields (EMF) comprised of radiofrequency (RF). The skin is considered the primary target of EMFs given its outermost location. Recent evidence suggests that extremely low frequency (ELF)-EMF can improve the efficacy of DNA repair in human cell-lines. However, the effects of EMF-RF on DNA damage remain unknown. Here, we investigated the impact of EMF-long term evolution (LTE, 1.762 GHz, 8 W/kg) irradiation on DNA double-strand break (DSB) using the murine melanoma cell line B16 and the human keratinocyte cell line HaCaT. EMF-LTE exposure alone did not affect cell viability or induce apoptosis or necrosis. In addition, DNA DSB damage, as determined by the neutral comet assay, was not induced by EMF-LTE irradiation. Of note, EMF-LTE exposure can attenuate the DNA DSB damage induced by physical and chemical DNA damaging agents (such as ionizing radiation (IR, 10 Gy) in HaCaT and B16 cells and bleomycin (BLM, 3 µM) in HaCaT cells and a human melanoma cell line MNT-1), suggesting that EMF-LTE promotes the repair of DNA DSB damage. The protective effect of EMF-LTE against DNA damage was further confirmed by attenuation of the DNA damage marker γ-H2AX after exposure to EMF-LTE in HaCaT and B16 cells. Most importantly, irradiation of EMF-LTE (1.76 GHz, 6 W/kg, 8 h/day) on mice in vivo for 4 weeks reduced the γ-H2AX level in the skin tissue, further supporting the protective effects of EMF-LTE against DNA DSB damage. Furthermore, p53, the master tumor-suppressor gene, was commonly upregulated by EMF-LTE irradiation in B16 and HaCaT cells. This finding suggests that p53 plays a role in the protective effect of EMF-LTE against DNA DSBs. Collectively, these results demonstrated that EMF-LTE might have a protective effect against DNA DSB damage in the skin, although further studies are necessary to understand its impact on human health.

Anti-inflammatory effects of DA-9601, an extract of Artemisia asiatica, on aceclofenac-induced acute enteritis.

DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4+ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6 , IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1ß, GMCSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ+ Th1 cells, IL-4+ Th2 cells, IL-9+ Th9 cells, IL-17+ Th17 cells, and Foxp3+ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.

Coenzyme Q10 alleviates tacrolimus-induced mitochondrial dysfunction in kidney.

The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q10, (CoQ10) a potent antioxidant, can reduce Tac-induced nephrotoxicity via improving mitochondrial function. In an in vitro study, CoQ10 reduced the production of Tac-induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function revealed that CoQ10 decreased oxygen consumption and mitochondrial respiration rate increased by Tac, suggesting improvement of mitochondrial function to synthesize ATP with CoQ10 treatment. The effect of the CoQ10in vitro study was observed in an experimental model of chronic Tac-induced nephropathy. CoQ10 attenuated Tac-induced oxidative stress and was accompanied by function and histologic improvement. On electron microscopy, addition of CoQ10 increased not only the number but also the volume of mitochondria compared with Tac treatment only. Our data indicate that CoQ10 improves Tac-induced mitochondrial dysfunction in kidney. Supplementary CoQ10 treatment may be a promising approach to reduce Tac-induced nephrotoxicity.-Yu, J. H., Lim, S. W., Luo, K., Cui, S., Quan, Y., Shin, Y. J., Lee, K. E., Kim, H. L., Ko, E. J., Chung, B. H., Kim, J. H., Chung, S. J., Yang, C. W. Coenzyme Q10 alleviates tacrolimus-induced mitochondrial dysfunction in kidney.