First snapshot on behavioral characteristics and related factors of patients with chronic kidney disease in SouthKorea during the COVID-19 pandemic (June to October 2020)

The recent novel coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented changes in behavior. We evaluated the current status of precautionary behavior and physical activity in chronic kidney disease (CKD) patients during the COVID-19 pandemic. Methods: A population of CKD patients (n = 306) registered in the Study on Kidney Disease and Environmental Chemicals (SKETCH, Clinical Trial No. NCT04679168) cohort recruited from June 2020 to October 2020 was included in the study. We conducted a questionnaire survey related to risk perception of COVID-19, precautionary behavior, and physical activity. Results: There were 187 patients (61.1%) with estimated glomerular filtration rate of <45 mL/min/1.73 m2 . This population showed a higher degree of risk perception for COVID-19 than the general population. Age was the most significant determinant of risk perception among CKD patients. During the pandemic, social distancing and hygiene-related behavior were significantly increased (p < 0.001). The frequency of exercise was decreased only in those who took regular exercise, without diabetes, or with a lower Charlson comorbidity index (CCI) (p < 0.001), with no change among the other groups. Socioeconomic status and comorbidities significantly affected behavioral characteristics regardless of the category. Education and income were significantly associated with precautionary behaviors such as staying at home and hand sanitizer use. Patients with higher CCI status significantly increased frequency of exercise (adjusted odds ratio, 2.10; 95% confidence interval, 1.01–4.38). Conclusion: CKD patients showed higher risk perception with active precautionary behavioral changes than the general population. Healthcare providers should be aware of the characteristics to comprise precautionary behavior without reducing physical activity.

DEHP Down-Regulates Tshr Gene Expression in Rat Thyroid Tissues and FRTL-5 Rat Thyrocytes: A Potential Mechanism of Thyroid Disruption

Background@#Di-2-ethylhexyl phthalate (DEHP) is known to disrupt thyroid hormonal status. However, the underlying molecular mechanism of this disruption is unclear. Therefore, we investigated the direct effects of DEHP on the thyroid gland. @*Methods@#DEHP (vehicle, 50 mg/kg, and 500 mg/kg) was administered to Sprague-Dawley rats for 2 weeks. The expression of the thyroid hormone synthesis pathway in rat thyroid tissues was analyzed through RNA sequencing analysis, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining. DEHP was treated to FRTL-5 rat thyroid cells, and an RT-PCR analysis was performed. A reporter gene assay containing the promoter of thyroid stimulating hormone receptor (TSHR) in Nthy-ori 3-1 human thyroid cells was constructed, and luciferase activity was determined. @*Results@#After DEHP treatment, the free thyroxine (T4) and total T4 levels in rats significantly decreased. RNA sequencing analysis of rat thyroid tissues showed little difference between vehicle and DEHP groups. In the RT-PCR analysis, Tshr expression was significantly lower in both DEHP groups (50 and 500 mg/kg) compared to that in the vehicle group, and IHC staining showed that TSHR expression in the 50 mg/kg DEHP group significantly decreased. DEHP treatment to FRTL-5 cells significantly down-regulated Tshr expression. DEHP treatment also reduced luciferase activity in a reporter gene assay for TSHR. @*Conclusion@#Although overall genetic changes in the thyroid hormone synthesis pathway are not clear, DEHP exposure could significantly down-regulate Tshr expression in thyroid glands. Down-regulation of Tshr gene appears to be one of potential mechanisms of thyroid disruption by DEHP exposure.

DEHP Down-Regulates Tshr Gene Expression in Rat Thyroid Tissues and FRTL-5 Rat Thyrocytes: A Potential Mechanism of Thyroid Disruption

Background@#Di-2-ethylhexyl phthalate (DEHP) is known to disrupt thyroid hormonal status. However, the underlying molecular mechanism of this disruption is unclear. Therefore, we investigated the direct effects of DEHP on the thyroid gland. @*Methods@#DEHP (vehicle, 50 mg/kg, and 500 mg/kg) was administered to Sprague-Dawley rats for 2 weeks. The expression of the thyroid hormone synthesis pathway in rat thyroid tissues was analyzed through RNA sequencing analysis, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining. DEHP was treated to FRTL-5 rat thyroid cells, and an RT-PCR analysis was performed. A reporter gene assay containing the promoter of thyroid stimulating hormone receptor (TSHR) in Nthy-ori 3-1 human thyroid cells was constructed, and luciferase activity was determined. @*Results@#After DEHP treatment, the free thyroxine (T4) and total T4 levels in rats significantly decreased. RNA sequencing analysis of rat thyroid tissues showed little difference between vehicle and DEHP groups. In the RT-PCR analysis, Tshr expression was significantly lower in both DEHP groups (50 and 500 mg/kg) compared to that in the vehicle group, and IHC staining showed that TSHR expression in the 50 mg/kg DEHP group significantly decreased. DEHP treatment to FRTL-5 cells significantly down-regulated Tshr expression. DEHP treatment also reduced luciferase activity in a reporter gene assay for TSHR. @*Conclusion@#Although overall genetic changes in the thyroid hormone synthesis pathway are not clear, DEHP exposure could significantly down-regulate Tshr expression in thyroid glands. Down-regulation of Tshr gene appears to be one of potential mechanisms of thyroid disruption by DEHP exposure.

Clinical Spectrum of Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G-Associated Disease in Korean Children

Background@#and Purpose: The myelin oligodendrocyte glycoprotein (MOG) antibody is detected at a high rate in childhood acquired demyelinating syndrome (ADS). This study aimed to determine the diagnostic value of the MOG antibody in ADS and the spectrum of MOGantibody-positive demyelinating diseases in children. @*Methods@#This study included 128 patients diagnosed with ADS (n=94) or unexplained encephalitis (n=34). The MOG antibody in serum was tested using an in-house live-cell-based immunofluorescence assay. @*Results@#The MOG antibody was detected in 48 patients (46 ADS patients and 2 encephalitis patients, comprising 23 males and 25 females). Acute disseminated encephalomyelitis (ADEM) (35.4%) was the most-common diagnosis, followed by the unclassified form (17.4%), isolated optic neuritis (ON) (15.2%), neuromyelitis optica spectrum disorder (13.0%), multiple sclerosis (MS) (10.8%), other clinically isolated syndromes [monophasic event except ADEM, isolated ON, or transverse myelitis (TM)] (8.7%), and unexplained encephalitis (4.3%). At the initial presentation, 35 out of the 46 patients with ADS had brain lesions detected in magnetic resonance imaging, and 54% of these 35 patients had encephalopathy. Nine of the 11 patients without brain lesions exhibited only ON. Thirty-nine percent of the patients experienced a multiphasic event during the mean follow-up period of 34.9 months (range 1.4–169.0 months). Encephalopathy at the initial presentation was frequently confirmed in the monophasic group (p= 0.011). @*Conclusions@#MOG antibodies were identified in all pediatric ADS phenotypes except for monophasic TM. Therefore, the MOG antibody test is recommended for all pediatric patients with ADS, especially before a diagnosis of MS and for patients without a clear diagnosis.

Failure of a Rotation Control Gamma 3 Lag Screw Used to Treat a Trochanteric Fracture / 대한고관절학회지

Gamma 3 rotation control lag screws (U-blade) are particularly useful when treating rotational and unstable fractures of the proximal femur. A 93-year-old woman who underwent closed reduction of a trochanteric fracture and internal fixation with a Gamma 3 nail rotation control lag screw. The patient presented with metal failure and U-blade bending following a fall occurring 4 weeks after surgery. Here, we present a case report summarizing removal of the failed lag screw.

Perfluoroalkyl substances exposure and thyroid hormones in humans: epidemiological observations and implications

Thyroid hormones play crucial roles in normal neurodevelopment of fetus and child. Many chemicals can affect control and homeostasis of thyroid hormones, and eventually lead to various adverse health effects including neurodevelopmental disorders. Perfluoroalkyl substances (PFASs) are among the thyroid disrupting chemicals that can be encountered among general human population. Due to their unique physicochemical characteristics, PFASs have been used as surfactants and surface coating materials in many applications. Therefore, PFASs have been frequently detected in humans and environment worldwide. In cross-sectional studies using nationally representative general human populations of United States, several PFASs have shown significant associations with thyroid hormones. Moreover, among pregnant women and their infants, not only major PFASs such as perfluorooctane sulfonic acid and perfluorooctanoic acid, but also those with shorter or longer carbon chains showed significant associations with thyroid hormones. Often demographic characteristics such as sex, age, and disease status appear to influence the associations between PFASs exposure and thyroid hormones. In general, major PFASs showed hypothyroidism effects among pregnant women and infants. As 8 carbon based PFASs have been phased out, those with shorter or longer carbon chains have been used in growing amount as replacement. However, only limited information is available for their occurrences and toxicity among humans. Further investigations on these substituting PFASs are required. In addition, efforts are warranted to identify sources of and mitigate exposure to these thyroid disrupting chemicals especially during pregnancy and early stages of life.

Large-Scale in-House Cell-Based Assay for Evaluating the Serostatus in Patients with Neuromyelitis Optica Spectrum Disorder Based on New Diagnostic Criteria

BACKGROUND AND PURPOSE: The detection of aquaporin 4-IgG (AQP4-IgG) is now a critical diagnostic criterion for neuromyelitis optica spectrum disorder (NMOSD). To evaluate the serostatus of NMOSD patients based on the 2015 new diagnostic criteria using a new in-house cell-based assay (CBA). METHODS: We generated a stable cell line using internal ribosome entry site-containing bicistronic vectors, which allow the simultaneous expression of two proteins (AQP4 and green fluorescent protein) separately from the same RNA transcript. We performed in-house CBA using serum from 386 patients: 178 NMOSD patients diagnosed according to the new diagnostic criteria without AQP4-IgG, 63 high risk NMOSD patients presenting 1 of the 6 core clinical characteristics of NMOSD but not fulfilling dissemination in space, and 145 patients with other neurological diseases, including 66 with multiple sclerosis. The serostatus of 111 definite and high risk NMOSD patients were also tested using a commercial CBA kit with identical serum to evaluate the correlation between the 2 methods. All assays were performed by two independent and blinded investigators. RESULTS: Our in-house assay yielded a specificity of 100% and sensitivities of 80% (142 of 178) and 76% (48 of 63) when detecting definite- and high risk NMOSD patients, respectively. The comparison with the commercial CBA kit revealed a correlation for 102 of the 111 patients: no correlation was present in 7 patients who were seronegative using the commercial method but seropositive using the in-house method, and in 2 patients who were seropositive using the commercial method but seronegative using the in-house method. CONCLUSIONS: These results demonstrate that our in-house CBA is a highly specific and sensitive method for detecting AQP4-IgG in NMOSD patients.

CTLA4-CD28 chimera gene modification of T cells enhances the therapeutic efficacy of donor lymphocyte infusion for hematological malignancy

Donor lymphocyte infusion (DLI) followed by hematopoietic stem cell transplantation has served as an effective prevention/treatment modality against the relapse of some hematologic tumors, such as chronic myeloid leukemia (CML). However, the therapeutic efficacies of DLI for other types of leukemia, including acute lymphocytic leukemia (ALL), have been limited thus far. Therefore, we examined whether increasing the reactivity of donor T cells by gene modification could enhance the therapeutic efficacy of DLI in a murine model of ALL. When a CTLA4-CD28 chimera gene (CTC28) in which the intracellular signaling domain of CTLA4 was replaced with the CD28 signaling domain was introduced into CD4 and CD8 T cells in DLI, the graft-versus-tumor (GVT) effect was significantly increased. This effect was correlated with an increased expansion of donor CD8 T cells in vivo, and the depletion of CD8 T cells abolished this effect. The CD8 T cell expansion and the enhanced GVT effect were dependent on the transduction of both CD4 and CD8 T cells with CTC28, which emphasizes the role of dual modification in this therapeutic effect. The CTC28-transduced T cells that expanded in vivo also exhibited enhanced functionality. Although the potentiation of the GVT effect mediated by the CTC28 gene modification of T cells was accompanied by an increase of graft-versus-host disease (GVHD), the GVHD was not lethal and was mitigated by treatment with IL-10 gene-modified third-party mesenchymal stem cells. Thus, the combined genetic modification of CD4 and CD8 donor T cells with CTC28 could be a promising strategy for enhancing the therapeutic efficacy of DLI.

Enhanced Anti-tumor Reactivity of Cytotoxic T Lymphocytes Expressing PD-1 Decoy

Programmed death-1 (PD-1) is a strong negative regulator of T lymphocytes in tumor-microenvironment. By engaging PD-1 ligand (PD-L1) on tumor cells, PD-1 on T cell surface inhibits anti-tumor reactivity of tumor-infiltrating T cells. Systemic blockade of PD-1 function using blocking antibodies has shown significant therapeutic efficacy in clinical trials. However, approximately 10 to 15% of treated patients exhibited serious autoimmune responses due to the activation of self-reactive lymphocytes. To achieve selective activation of tumor-specific T cells, we generated T cells expressing a dominant-negative deletion mutant of PD-1 (PD-1 decoy) via retroviral transduction. PD-1 decoy increased IFN-γ secretion of antigen-specific T cells in response to tumor cells expressing the cognate antigen. Adoptive transfer of PD-1 decoy-expressing T cells into tumor-bearing mice potentiated T cell-mediated tumor regression. Thus, T cell-specific blockade of PD-1 could be a useful strategy for enhancing both efficacy and safety of anti-tumor T cell therapy.

The effects of midazolam and sevoflurane on the GABAA receptors with alternatively spliced variants of the gamma2 subunit / 대한마취과학회지

BACKGROUND: Emergence agitation after sevoflurane anesthesia in children can be prevented by midazolam. Alternative splicing of the GABAA receptor changes with age. Therefore, we hypothesized that alternative splicing of the gamma2 subunit affects the GABA current when applying sevoflurane and midazolam. METHODS: We performed the whole-cell patch clamp technique on human embryonic kidney 293 cells that were transfected with alpha1beta2gamma2L or alpha1beta2gamma2S. The concentration-response relations were recorded for midazolam and sevoflurane, and the co-application responses were measured at concentrations of 1.5 nM, 15 nM and 300 nM of midazolam and 0.5%, 2.0% and 4.0% of sevoflurane. Each GABA current was compared with that produced by 5 microM of GABA. RESULTS: The concentration-response relationships for midazolam and sevoflurane were dose-dependent without any differences between the alpha1beta2gamma2L and alpha1beta2gamma2S subtypes. 1.5 nM and 15 nM of midazolam did not significantly enhance the current after treatment with 0.5% sevoflurane for both subtypes. The current after treatment with 2.0% sevoflurane was enhanced by 1.5 nM midazolam for the alpha1beta2gamma2S subtype, but not for the alpha1beta2gamma2L subtype. In the case of 2.0% sevoflurane with 15 nM of midazolam, and 4.0% sevoflurane with 300 nM of midazolam, the GABA currents were significantly enhanced for both subtypes. CONCLUSIONS: These results show that the difference in the gamma2 subunit cannot explain the emergence agitation after sevoflurane anesthesia in children in vitro. This suggests that co-application of sevoflurane and midazolam enhances the GABA current according to the alternative splicing of the gamma2 subunit and the concentration of both drugs.

Differential alternative splicing of human transglutaminase 4 in benign prostate hyperplasia and prostate cancer

Transglutaminase 4 is a member of enzyme family that catalyzes calcium-dependent posttranslational modification of proteins. Although transglutaminase 4 has been shown to have prostate-restricted expression pattern, little is known about the biological function of transglutaminase 4 in human. To gain insight into its role in prostate, we analyzed the expression status of human transglutaminase 4 in benign prostate hyperplasia (BPH) and prostate cancer (PCa). Unexpectedly, RT-PCR and nucleotide sequence analysis showed four alternative splicing variants of transglutaminase 4: transglutaminase 4-L, -M (-M1 and -M2) and -S. The difference between transglutaminase 4-M1 and -M2 is attributed to splicing sites, but not nucleotide size. The deduced amino acid sequences showed that transglutaminase 4-L, -M1 and -M2 have correct open reading frames, whereas transglutaminase 4-S has a truncated reading frame. RT-PCR analysis of clinical samples revealed that transglutaminase 4-M and -S were detected in all tested prostate tissue (80 BPH and 48 PCa). Interestingly, transglutaminase 4-L was found in 56% of BPH (45 out of 80) and only in 15% of PCa (7 out of 48). However, transglutaminase 4-L expression did not correlate with serum prostate-specific antigen (PSA) level, prostate volumes or PSA densities. These results will provide a clue to future investigation aiming at delineating physiological and pathological roles of human transglutaminase 4.

Investigation on Health Effects of an Abandoned Metal Mine

To investigate potential health risks associated with exposure to metals from an abandoned metal mine, the authors studied people living near an abandoned mine (n=102) and control groups (n=149). Levels of cadmium, copper, arsenic, lead, and zinc were measured in the air, soil, drinking water, and agricultural products. To assess individual exposure, biomarkers of each metal in blood and urine were measured. beta2-microglobulin, alpha1-microglobulin, and N-acetyl-beta-glucosaminidase and bone mineral density were measured. Surface soil in the study area showed 2-10 times higher levels of metals compared to that of the control area. Metal concentrations in the groundwater and air did not show any notable differences between groups. Mean concentrations of cadmium and copper in rice and barley from the study area were significantly higher than those of the control area (p<0.05). Geometric means of blood and urine cadmium in the study area were 2.9 microgram/L and 1.5 microgram/g Cr, respectively, significantly higher than those in the control area (p<0.05). There were no differences in the levels of urinary markers of early kidney dysfunction and bone mineral density. The authors conclude that the residents near the abandoned mine were exposed to higher levels of metals through various routes.

Usefulness of Color Vision Test for Early Detection of Neurological Damages by Neurotoxic Substances / 예방의학회지

This paper reviews the published literature that is concerned with color vision impairment from industrial and environmental exposure to neurotoxic substances, and we evaluated whether testing for color vision impairment could be an affordable procedure for assessing these neurotoxic effects. In general, most cases of congenital color vision impairment are red-green, and blue-yellow impairment is extremely rare. However, most of the acquired color vision impairment that is related to age, alcohol or environmental factors is blue-yellow impairment. Therefore, many studies have been performed to identify this relationship between exposure to neurotoxic substances, such as organic solvents and heavy metals, and the prevalence of blueyellow color vision impairment. The test for color vision impairment is known to be very sensitive to the early signs of nervous system dysfunction and this can be useful for making the early diagnosis of neurotoxic effects from exposure to very low concentrations of toxic substances.