Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix GeneChip® Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.
Acetaminophen ; Animals ; Drug-Induced Liver Injury ; Genetic Variation ; Incidence ; Lipoprotein Lipase* ; Lipoproteins* ; Liver ; Methods ; Mice ; Microarray Analysis ; Real-Time Polymerase Chain Reaction ; Receptors, GABA-A* ; Toxicogenetics ; Transcriptome

Objective To investigate the therapeutic effects and mechanisms of interleukin-10 (IL-10) gene-modified dendritic cells (DC-IL-10) in mice with liver fibrosis. Methods DC-IL-10 was constructed in vitro, the phenotype and function of which were evaluated by flow cytometry. BALB/c mice were treated with intraperitoneal injection of carbon tetrachloride(CCl4)to establish liver fibrotic model. DC-IL-10 was administrated via tail vein. Animals were divided into 4 groups including normal dendritic cell (DC) control , liver fibrosis only, negative lentiviral transfection DC (DC-mock) and DC-IL-10. Liver function, cytokine secretion, T lymphocyte differentiation and liver histomorphology were tested. Real-time PCR and western blot were used to analyze the effect of DC-IL-10 on Wnt/β-catenin signaling pathway and its role in liver fibrosis. Results When compared with DC control and DC-mock, the expression of DC-IL-10 surface stimulating molecules (major histocompatibity complex-Ⅱ, CD80, CD86) were significantly decreased (F=14.708, 22.503, 12.595, respectively, all P<0.05), and DC-IL-10 significantly inhibited T lymphocyte proliferation (F=50.295, P<0.05). When compared with liver fibrosis group, serum alanine aminotransferase and aspartate transaminase were decreased in DC-IL-10 treated group (all P<0.05), other parameters including inflammatory factors (tumor necrosis factor α, IL-6, IL-1β) reduced (all P<0.05), the proportion of regulatory T cells (Treg) increased (F=6.742, P<0.05), pathological damage improved, the expression of Wnt3a, α-SMA and β-catenin mRNA and protein significantly reduced in DC-IL-10 treatment group(all P<0.001). Conclusions DC-IL-10 induces elevation of Treg for immune tolerance, as well as inhibition of inflammatory response, block of Wnt/β-catenin signaling pathway, which translates into improvement of liver fibrosis.

BACKGROUND: Multiple studies have been reported regarding preeclampsia as a possible risk factor of cerebrovascular disease (CVD). However, the correlation of preeclampsia and CVD, whether it is a cause-effect relationship or they are sharing common predisposing condition, is not well understood. Therefore, the aim of this study was to investigate the association between the preeclampsia during pregnancy and development of postpartum CVD. METHODS: A total of 1,384,550 Korean women who had a delivery between January 1, 2010 and December 31, 2012, were enrolled. Women with the risk of CVD within 1 year prior to pregnancy were excluded based on the Charlson comorbidity index. Primary endpoint was the event of CVD within a year from delivery. After exclusion, 1,075,061 women were analyzed. RESULTS: During the follow-up of 1 year postpartum, there were 25,577 preeclampsia out of 1,072,041 women without postpartum CVD (2.39%), and 121 of 3,020 women with postpartum CVD had preeclampsia before delivery (4.01%). In multivariate logistic regression analysis, women who had preeclampsia during pregnancy showed a higher risk for postpartum CVD (odds ratio, 1.64; 95% confidence interval, 1.37–1.98). CONCLUSION: The incidence of CVD after delivery was higher in women who had preeclampsia during pregnancy.
Cerebrovascular Disorders ; Comorbidity ; Female ; Follow-Up Studies ; Humans ; Incidence ; Insurance Claim Reporting ; Korea ; Logistic Models ; Postpartum Period ; Pre-Eclampsia ; Pregnancy ; Risk Factors

Purpose: In Korea, since the Act on Hospice and Palliative Care and Decisions on LifeSustaining Treatment for Patients at the End of Life was implemented in February 2018, advance directives (ADs) have become legally effective and should be documented after sufficient explanation by a registered counselor. However, little is known regarding the adequacy of current AD counseling. This qualitative study aimed to explore the barriers to AD counseling based on counselors’ experiences. Methods: We conducted focus group interviews using purposive sampling. Seven counselors working at hospitals, community health institutions, and non-profit organizations participated in this study. They were asked about the challenges and problems they encountered during AD counseling. Results: Three themes emerged from this study; 1) issues regarding consistency in AD counseling, 2) issues regarding AD counselors’ competency and work environment, and 3) issues regarding the adequacy of the service system. The interviewees stated that the lack of a manual for standardized service made AD counseling inconsistent. The limited competency and poor work environment of counselors were pointed out as major barriers. The interviewees also stated that a proper service system considering individual circumstances is absent. Conclusion The goals of AD counseling should be clarified and guidance should be implemented for providing standardized services. Further efforts to enhance the competency of AD counselors and to improve their working conditions are needed. Establishing an integrated framework for an adequate service system is also essential to overcome systematic barriers to AD counseling.

BACKGROUND: A considerable amount of research has shown that knowledge and appropriate awareness are essential for encouraging positive behaviors and promoting health. In Korea, the roles that behavioral changes play in the prevention of cancer have been an important issue since the introduction of the 10 codes for cancer prevention in 2006. Thus, the present study investigated the associations of tobacco-related knowledge with awareness and attitudes towards positive smoking-cessation behaviors. METHODS: The present study analyzed data from the 2010 national questionnaire survey (n = 1,006). This study evaluated sociodemographic characteristics, smoking status, self-rated health status, health-related interests, and the accuracy of 12 tobacco-related statements to determine knowledge level and to investigate its impact on awareness and behaviors related to smoking. These parameters were examined and staged using the Precaution Adoption Process Model. RESULTS: A higher level of tobacco-related knowledge was significantly associated with a positive attitude towards smoking cessation (5–8 correct answers: odds ratio [OR], 2.53; 95% confidence interval [CI], 1.57–4.08; ≥ 9 correct answers: OR, 3.90; 95% CI, 2.22–6.82; reference: ≤ 4 correct answers). Interestingly, among current smokers, only those who correctly responded to ≥ 9 of 12 tobacco-related statements were significantly associated with a positive attitude towards smoking cessation. CONCLUSION: This study found that having a higher level of tobacco-related knowledge had a significant impact on positive attitudes towards smoking cessation. This suggests that there is a need to disseminate appropriate knowledge to the general population to encourage positive attitudes and promote healthful behaviors in terms of smoking.
Korea ; Odds Ratio ; Smoke* ; Smoking Cessation ; Smoking*

Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current in vivo liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.

Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains ( Animals ; Ceramides ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Epidermis ; Fatty Acids, Nonesterified ; Humans ; Hyperglycemia ; Kidney ; Liver ; Mice ; Receptors, Cytoplasmic and Nuclear ; Skin ; Stearoyl-CoA Desaturase ; Subcutaneous Fat

Purpose: Life-sustaining treatment (LST) decisions for patients and caregivers at the end-of-life (EOL) process are supported by the “Act on Hospice and Palliative Care and Decisions on LST for Patients at the EOL,” enforced in February 2018. Itremains unclearwhetherthe act changes EOL decisions and LST implementation in clinical practice. For this study, we investigated patients’ decision-making regarding LSTs during the EOL process since the act’s enforcement. Materials and Methods: Retrospective reviews were conducted on adult patients who were able to decide to terminate LST and died at Seoul National University Hospital between February 5, 2018, and February 5, 2019. We examined demographics, who made the decisions, the type and date of documentation confirming patient's LST, and whether the LST was withheld or withdrawn. Results: Of 809 patients who were enrolled, 29% (n=231) completed forms regarding LST themselves, and 71% (n=578) needed family members to decide. The median time from confirmation of the EOL process to death and from the Advance Statement to death were 2 and 5 days, respectively (both ranges, 0 to 244). In total, 90% (n=727) of patients withheld treatment, and 10% (n=82)withdrewit. We found a higherwithdrawalratewhen family members made the decisions (13.3% vs. 1.7%, p < 0.001). Conclusion After the act’s enforcement, withdrawing LSTs became lawful and self-determination rates increased. Family members still make 71% of decisions regarding LSTs, but these are often inconsistent with the patients’ wishes; thus, further efforts are needed to integrate the new act into clinical practice.

Background: Basiliximab is used as an alternative to tacrolimus in patients with decreased renal function. However, studies on basiliximab as a maintenance immunosuppressant, particularly in patients with lung transplantation, are limited. Therefore, here, we investigated the efficacy and safety of basiliximab in patients with lung transplantation. Methods: Adult patients with acute kidney injury (AKI) who received lung transplantation at a single general hospital between July 1, 2014 and June 30, 2018, were selected and classified in tacrolimus and basiliximab groups. Both groups received a triple-drug regimen (tacrolimus, mycophenolate mofetil, and steroids). However, tacrolimus was discontinued in the basiliximab group when AKI occurred, and two or more repeat basiliximab doses were administered within 3 months after transplantation. The electronic medical records were analyzed retrospectively. Results: Of the 85 patients who met the selection criteria, 61 and 24 were assigned to the tacrolimus and basiliximab groups, respectively. Significant improvement in renal function was observed in the basiliximab group (p <0.001).However, there were no differences in acute and chronic rejection rates in both the groups. No difference was observed in the incidence rate of complications between the groups, except for chronic kidney disease, which showed higher incidence in the basiliximab group (25.0% vs. 4.9%; p =0.013). Conclusions We suggest the use of basiliximab as an immunosuppressant alternative to tacrolimus in patients with acute renal failure after lung transplantation. Basiliximab demonstrated effectiveness as an immunosuppressant and improved renal function. Therefore, basiliximab can be used in patients with decreased renal function.

In the era of coronavirus disease 2019 (COVID-19), social distancing and strict visitation policies at hospitals have made it difficult for medical staff to provide high-quality endof-life (EOL) care to dying patients and their families. There are various issues related to EOL care, including psychological problems of patients and their families, difficulties in EOL decision-making, the complicated grief of the bereaved family, moral distress, and exhaustion of medical staff. In relation to these issues, we aimed to discuss practical considerations in providing high-quality EOL care in the COVID-19 pandemic. First, medical staff should discuss advance care planning as early as possible and use the parallel planning strategy. Second, medical staff should play a role in facilitating patient-family communication. Third, medical staff should actively and proactively evaluate and alleviate dying patients’ symptoms using non-verbal communication. Lastly, medical staff should provide care for family members of the dying patient, who may be particularly vulnerable to postbereavement problems in the COVID-19 era. Establishing a system of screening highrisk individuals for complicated grief and connecting them to bereavement support services might be considered. Despite the challenging and limited environment, providing EOL care is essential for patients to die with dignity in peace and for the remaining family to return to life after the loved one’s death. Efforts considering the practical issues faced by all medical staff and healthcare institutions caring for dying patients should be made.