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Abstract Background Spinal cord injury (SCI) is a complex cause of rapid low bone mass that easily predisposes the affected individuals to osteoporosis-induced fractures. Several studies have investigated osteoporosis pathophysiology in SCI; however, those associated with its diagnosis in SCI are limited. Additionally, errors in osteoporosis diagnosis and its prevalence vary based on the bone mineral density (BMD) reference values (BMDRV), and no studies have reported BMDRV application for osteoporosis diagnosis in individuals with SCI. Therefore, this study aimed to compare the prevalence of osteoporosis among Korean adults aged ≥ 50 years with SCI according to BMDRV for diagnosing osteoporosis. Methods Overall, 855 patients with SCI who underwent BMD tests of the lumbar spine, femoral neck, and total hip at the National Rehabilitation Center (NRC) in Korea between 2010 and 2020 were included in this retrospective cross-sectional study. Osteoporosis was diagnosed in patients with SCI by comparing the differences in prevalence, diagnostic consistency, and risk factors according to the region-based BMDRV of the dual-energy x-ray absorptiometry (DXA) manufacturer and international BMDRV based on the Third National Health and Nutrition Examination Survey (NHANES III) data of females aged 20–29 years. Results The prevalence of osteoporosis according to the T-score provided by a single reference population of the NHANES III (TNHA) (PONHA) (males: 26.69%; females: 69.35%) was significantly higher in females and males than that according to the T-scores provided by the DXA manufacturer (TDXA) (PODXA) (males: 15.32%; females: 43.15%). The lumbar spine and femoral neck were major osteoporosis diagnosis sites for the PODXA and PONHA, respectively. Risk factors for osteoporosis differed based on the probability of osteoporosis (also known as the OZ ratio) according to the BMD criteria; however, the risk factors were similar according to old age, female sex, low body mass index (BMI), and long SCI period. No significant relationship was noted between the different SCI-related clinical factors (p > 0.05). Conclusions The osteoporosis diagnostic site and prevalence in SCI differed according to the regional-based TDXA and international standards of the TNHA. Therefore, further studies on BMDRV are warranted to establish accurate diagnostic criteria for osteoporosis prevention in patients with SCI.

Abstract The outbreak of novel COVID-19 disease elicited a wide range of anti-contagion and economic policies like school closure, income support, contact tracing, and so forth, in the mitigation and suppression of the spread of the SARS-CoV-2 virus. However, a systematic evaluation of these policies has not been made. Here, 17 implemented policies from the Oxford COVID-19 Government Response Tracker dataset employed in 90 countries from December 31, 2019, to August 31, 2020, were analyzed. A Poisson regression model was applied to analyze the relationship between policies and daily confirmed cases using a generalized estimating equations approach. A lag is a fixed time displacement in time series data. With that, lagging (0, 3, 7, 10, and 14 days) was also considered during the analysis since the effects of policies implemented on a given day may affect the number of confirmed cases several days after implementation. The countries were divided into three groups depending on the number of waves of the pandemic observed in each country. Through subgroup analysis, we showed that with and without lagging, contact tracing and containment policies were significant for countries with two waves, while closing, economic, and health policies were significant for countries with three waves. Wave-specific analysis for each wave showed that significant health, economic, and containment policies varied across waves of the pandemic. Emergency investment in healthcare was consistently significant among the three groups of countries, while the Stringency index was significant among all waves of the pandemic. These findings may help in making informed decisions regarding whether, which, or when these policies should be intensified or lifted.

Background : The role of interleukin-10 (IL-10) in humans is controversial because IL-10 has been proposed to exhibit both pro- and anti-inflammatory effects. We aimed to determine the relationships between the changes in these parameters in obese individuals participating in a weight-reduction program. Methods : We measured cardiometabolic parameters including lipid profile and serum IL-10 concentration before and after completion of a 12-week weight-reduction program in 63 non-diabetic obese subjects with a body mass index ≥27 kg/m2 who had comorbid hypertension or dyslipidemia. All the participants were provided with individual intervention sessions designed to implement lifestyle modifications and administered 120 mg orlistat three times daily for 12 weeks. The relationships between changes in serum IL-10 concentration and changes in cardiometabolic risk factors were analyzed. Results : Changes in serum IL-10 concentration were significantly negatively correlated with changes in total cholesterol (r=-0.377), high-density lipoprotein cholesterol (HDL-C; r=-0.377), and low-density lipoprotein cholesterol (LDL-C; r=-0.278) concentrations. However, there were no correlations between changes in serum IL-10 concentration and changes in other cardiometabolic parameters. Conclusion : Serum IL-10 concentration can increase as serum total cholesterol decreases. Additional studies are needed to explore the mechanisms linking changes in serum IL-10 with serum LDL-C and HDL-C concentrations.

Abstract Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency‐associated transcription factor, orchestrated pluripotency and cell‐cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell cycle progression, pluripotency, and differentiation. The CDK1‐TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self‐renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co‐expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer‐specific survival. These findings demonstrate the molecular and clinical significance of CDK1‐mediated TFCP2L1 phosphorylation in stem cell pluripotency and in the tumorigenic stemness features associated with BC progression.

Summary: Background: With the increase in the prevalence of overweight, percentage of overweight patients with gastric cancer has also increased. This 5-year retrospective cohort study was performed to investigate long-term changes in the metabolic and nutritional parameters of early gastric cancer (EGC) patients with overweight after gastrectomy. Methods: EGC patients who underwent gastrectomy were followed up over a 5-year period. We included 393 patients (261 men, 132 women) who had an initial body mass index (BMI) of ≥23 kg/m2, and analyzed the longitudinal changes in the metabolic and nutritional parameters. Results: Body weight and random glucose, alanine aminotransferase (ALT), hemoglobin, and serum calcium levels significantly decreased, while serum protein and albumin levels increased in both men and women after gastrectomy. The odds ratios (ORs) for BMI ≥ 25 kg/m2 (P 40 IU/dL (men; P

Background: We aimed to investigate the association between alcohol drinking patterns and the presence of impaired fasting glucose (IFG) and diabetes mellitus (DM). Methods: We used data from the Korean National Health and Nutrition Examination Survey, 2010–2014. The participants were aged ≥30 years and had no previous diagnosis of DM. High-risk drinking was defined as alcohol consumption of ≥7 glasses at a sitting for men, and ≥5 glasses for women. After adjusting for confounding factors, a polychotomous logistic regression analysis was performed to assess the association of drinking patterns with IFG and DM. Results: For men, high-risk drinking was associated with higher odds ratios (ORs) of IFG (2–4/month, OR 1.51; 95% confidence interval [CI], 1.13–2.04; 2–3/week, OR 1.79; 95% CI, 1.38–2.33; and ≥4/week, OR 2.24; 95% CI, 1.65–3.03) and of DM (2–4/month, OR 2.12; 95% CI, 1.20–3.77; 2–3/week, OR 1.78; 95% CI, 1.05–3.03; and ≥4/week, OR 2.98; 95% CI, 1.72–5.17). For women, high-risk drinking was associated with higher risk of IFG (2–4/month, OR 1.51; 95% CI, 1.04–2.21; 2–3/week, OR 3.19; 95% CI, 2.20–4.64; and ≥4/week, OR 2.23; 95% CI, 1.23–4.06), but not of DM, compared with non-high-risk drinkers who consumed alcohol ≤1 day/month. Non-high-risk drinkers who consumed alcohol ≥4 days/week had higher ORs of DM in men, but lower ORs of DM in women compared with non-high risk drinkers who consumed alcohol ≤1 day/month. Conclusions: Compared with non-high-risk alcohol drinking, even occasional high-risk alcohol drinking was associated with a higher risk of IFG in men and women, and DM in men. Nearly daily non-high-risk alcohol drinking was associated with a higher risk of DM in men and lower risk of DM in women.

Summary: The core functions of stem cells (SCs) are critically regulated by their cellular redox status. Glutathione is the most abundant non-protein thiol functioning as an antioxidant and a redox regulator. However, an investigation into the relationship between glutathione-mediated redox capacity and SC activities is hindered by lack of probe. Here, we demonstrate that cyanoacrylamide-based coumarin derivatives are ratiometric probes suitable for the real-time monitoring of glutathione levels in living SCs. These probes revealed that glutathione levels are heterogeneous among subcellular organelles and among individual cells and show dynamic changes and heterogeneity in repopulating SCs depending on oxidative stress or culture conditions. Importantly, a subpopulation of SCs with high glutathione levels exhibited increased stemness and migration activities in vitro and showed improved therapeutic efficiency in treating asthma. Our results indicate that high glutathione levels are required for maintaining SC functions, and monitoring glutathione dynamics and heterogeneity can advance our understanding of the cellular responses to oxidative stress. : By developing and characterizing new fluorescent probes enabling fast, reversible, and ratiometric reaction with glutathione, Jeong et al. reveal considerable dynamics and heterogeneity in glutathione levels in living stem cells in response to environmental stress and also show that high glutathione levels are required for maintaining stemness of murine embryonic stem cells or therapeutic potency of mesenchymal stem cells. Keywords: glutathione, fluorescent probe, real-time monitoring, stem cell, oxidative stress, heterogeneity, pluripotency, self-renewal, migration, asthma

Many studies support a stepwise continuum of morphologic changes between atypical adenomatous hyperplasia (AAH) and lung adenocarcinoma (ADC). Here we characterized gene expression patterns and the association of differentially expressed genes and immune tumor microenvironment behaviors in AAH to ADC during ADC development. Tumor tissues from nine patients with ADC and synchronous multiple ground glass nodules/lesions (GGN/Ls) were analyzed using RNA sequencing. Using clustering, we identified genes differentially and sequentially expressed in AAH and ADC compared to normal tissues. Functional enrichment analysis using gene ontology terms was performed, and the fraction of immune cell types was estimated. We identified up-regulated genes (ACSL5 and SERINC2) with a stepwise change of expression from AAH to ADC and validated those expressions by quantitative PCR and immunohistochemistry. The immune cell profiles revealed increased B cell activities and decreased natural killer cell activities in AAH and ADC. A stepwise change of differential expression during ADC development revealed potential effects on immune function in synchronous precursors and in tumor lesions in patients with lung cancer.

A Body Shape Index (ABSI) is a recently proposed index for standardizing waist circumference (WC) for body mass index (BMI) and height in adults, using 2/3 and 1/2 as scaling exponents, respectively. However, ABSI has limited applicability to children and adolescents, as the relationship between height and weight changes with age and varies according to sex. This study aimed to investigate whether ABSI can be applied to adolescents and to analyze the relationships among BMI, WC, height, weight, and body shape index (BSI) in Korean adolescents. The data of 1023 adolescents aged 10–19 years from the 2009–2012 Korea National Health and Nutrition Examination Survey were collected. Body measurements (height, weight, WC, and BMI) were analyzed to estimate the BSI using log-linear regression. The scaling exponents for standardizing WC for weight and height were estimated according to age (per year) and sex. The scaling exponents for standardizing WC for weight and height were 0.698 and −1.090 for boys and 0.646 and −0.855 for girls, respectively. The exponents also differed according to age. BSI was negatively correlated with height, weight, and BMI in boys and girls, and these correlations differed in direction from those in adults. ABSI cannot be applied to adolescents. In adolescents, the BSI is dependent on age and sex and is associated with growth and puberty. Further studies are required to evaluate the association between BSI and other biomarkers, to improve its applicability as a parameter for predicting the risk of chronic diseases in adolescents.

To reduce the prevalence of obesity and provide information on evidence-based obesity treatments, the Education Committee of the Korean Society for the Study of Obesity (KSSO) has developed and launched the first Obesity Educator Training Program (OETP). After the course, we analyzed the results of a survey from 110 participants, comprising medical doctors (n=58), nutrition specialists (n=19), exercise specialists (n=14), and students (n=6). Approximately half of the participants were recruited through the Internet (48%), followed by academic leaflets, such as conference posters (21%); the reasons for participation were to learn about evidence-based treatments for obesity (47%), to receive up-to-date knowledge on obesity treatments (39%), to obtain basic information on obesity (10%), and others (4%). More than half of the participants found the date, lecture time, process, and theme of the OETP favorable. The participants indicated that there should be an in-depth course, sharing of the presented files with attendees, a longer lecture time, and a broader OETP that includes other specialties such as nursing. To improve the OETP, the educational committee of the KSSO must develop an in-depth OETP that will reflect these participant’s feedback.

Abstract Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease characterized by severe pelvic pain and urinary frequency. Mesenchymal stem cell (MSC) therapy is a promising approach to treat incurable IC/BPS. Here, we show greater therapeutic efficacy of human embryonic stem cell (hESC)-derived multipotent stem cells (M-MSCs) than adult bone-marrow (BM)-derived counterparts for treating IC/BPS and also monitor long-term safety and in vivo properties of transplanted M-MSCs in living animals. Controlled hESC differentiation and isolation procedures resulted in pure M-MSCs displaying typical MSC behavior. In a hydrochloric-acid instillation-induced IC/BPS animal model, a single local injection of M-MSCs ameliorated bladder symptoms of IC/BPS with superior efficacy compared to BM-derived MSCs in ameliorating bladder voiding function and histological injuries including urothelium denudation, mast-cell infiltration, tissue fibrosis, apoptosis, and visceral hypersensitivity. Little adverse outcomes such as abnormal growth, tumorigenesis, or immune-mediated transplant rejection were observed over 12-months post-injection. Intravital confocal fluorescence imaging tracked the persistence of the transplanted cells over 6-months in living animals. The infused M-MSCs differentiated into multiple cell types and gradually integrated into vascular-like structures. The present study provides the first evidence for improved therapeutic efficacy, long-term safety, and in vivo distribution and cellular properties of hESC derivatives in preclinical models of IC/BPS.

Herein we review the management status of governmental financial support of bariatric surgeries in several Asia-Pacific areas of Japan, Singapore, and Australia, which were discussed in the 2016 International Congress on Obesity and Metabolic Syndrome (ICOMES). Patient’s body mass index criteria of bariatric surgery for public support are different one another in the three countries. Whereas laparoscopic sleeve gastrectomy (LSG), Rouxen Y gastric bypass (RYGB), and laparoscopic adjustable gastric banding (LAGB) are applicable in both Singapore and Australia, the coverage of insurance is limited to LSG in Japan. In addition, the surgical fees and equipment costs are not fully covered by public health insurance for performing sleeve gastrectomy in Japan, but patients with morbid obesity can still use public health insurance. In Singapore, the waiting time for surgery in public hospitals is longer on average than for private hospitals. However, patients can obtain subsidies of up to 80% of the costs of surgery in public hospitals, while particularly needy patients may even be able to obtain completely free bariatric surgery through Medifund. In Australia, bariatric surgeries in public sectors are publicly funded, but most bariatric surgeries occur in the private sector and Medicare only reimburses surgical costs in the private sector. Although certain characteristics need to be improved, the access to bariatric surgery has shown steady progress through public support in each of these countries.

Embryonic stem cell (ESC) abnormalities in genome methylation hamper the utility of their therapeutic derivatives; however, the underlying mechanisms are unknown. Here, we show that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, Sirt1, selectively prevents abnormal DNA methylation of some developmental genes in murine ESCs by antagonizing Dnmt3l. Transcriptome and DNA methylome analyses demonstrated that Sirt1-null (Sirt1−/−) ESCs repress expression of a subset of imprinted and germline genes concomitant with increased DNA methylation of regulatory elements. Dnmt3l was highly expressed in Sirt1−/− ESCs, and knockdown partially rescued abnormal DNA methylation of the Sirt1 target genes. The Sirt1 protein suppressed transcription of Dnmt3l and physically interacted with the Dnmt3l protein, deacetylating and destabilizing Dnmt3l protein. Sirt1 deficiency delayed neurogenesis and spermatogenesis. These differentiation delays were significantly or partially abolished by reintroduction of Sirt1 cDNA or Dnmt3l knockdown. This study sheds light on mechanisms that restrain DNA methylation of developmentally vital genes operating in ESCs.

Purpose To evaluate the therapeutic effect of human embryonic stem cell (hESC)-derived multipotent mesenchymal stem cells (M-MSCs) on ketamine-induced cystitis (KC) in rats. Methods To induce KC, 10-week-old female rats were injected with 25-mg/kg ketamine hydrochloride twice weekly for 12 weeks. In the sham group, phosphate buffered saline (PBS) was injected instead of ketamine. One week after the final injection of ketamine, the indicated doses (0.25, 0.5, and 1×106 cells) of M-MSCs (KC+M-MSC group) or PBS vehicle (KC group) were directly injected into the bladder wall. One week after M-MSC injection, the therapeutic outcomes were evaluated via cystometry, histological analyses, and measurement of gene expression. Next, we compared the efficacy of M-MSCs at a low dose (1×105 cells) to that of an identical dose of adult bone marrow (BM)-derived MSCs. Results Rats in the KC group exhibited increased voiding frequency and reduced bladder capacity compared to rats of the sham group. However, these parameters recovered after transplantation of M-MSCs at all doses tested. KC bladders exhibited markedly increased mast cell infiltration, apoptosis, and tissue fibrosis. Administration of M-MSCs significantly reversed these characteristic histological alterations. Gene expression analyses indicated that several genes associated with tissue fibrosis were markedly upregulated in KC bladders. However the expression of these genes was significantly suppressed by the administration of M-MSCs. Importantly, M-MSCs ameliorated bladder deterioration in KC rats after injection of a low dose (1×105) of cells, at which point BM-derived MSCs did not substantially improve bladder function. Conclusions This study demonstrates for the first time the therapeutic efficacy of hESC-derived M-MSCs on KC in rats. M-MSCs restored bladder function more effectively than did BM-derived MSCs, protecting against abnormal changes including mast cell infiltration, apoptosis and fibrotic damage.

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BACKGROUND:We examined the relationship between changes in waist circumference (WC) and the incidence of nonalcoholic fatty liver disease (NAFLD). METHODS:A cohort study of 37,130 men and women were followed-up annually or biennially. Differences in WC between baseline and subsequent measurements were categorized in quartiles: first (WC loss), second (no change in WC as the reference), third and highest quartiles (WC gain). The presence of fatty liver was determined using ultrasound. Parametric Cox modeling was used to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) of the incidence of NAFLD. RESULTS:During 127,324.4 person-years of follow-up, 6249 participants developed NAFLD. Despite adjusting for possible confounders, the risk of development of NAFLD increased with increasing quartiles of WC change in a dose-response manner (p for trend < 0.001). Compared with the reference, WC loss was associated with a lower risk of NAFLD (men: aHR 0.79 [95% CI: 0.73-0.87]; women: 0.72 [0.63-0.81]), and the highest quartile (WC gain) was associated with a higher risk of NAFLD (men: 1.30 [1.19-1.42]; women: 1.48 [1.31-1.67]). CONCLUSION:Waist gain appears to increase the risk of developing NAFLD, independently of the baseline body mass index and WC.

BACKGROUND: Modeling of short-term viral dynamics of hepatitis B with traditional biphasic model might be insufficient to explain long-term viral dynamics. The aim was to develop a novel method of mathematical modeling to shed light on the dissociation between early and long-term dynamics in previous studies. METHODS: We investigated the viral decay pattern in 50 patients from the phase III clinical trial of 24-week clevudine therapy, who showed virological response and HBsAg decline. Immune effectors were added as a new compartment in the model equations. We determined some parameter values in the model using the non-linear least square minimization method. RESULTS: Median baseline viral load was 8.526 Log(10)copies/mL, and on-treatment viral load decline was 5.683 Log(10)copies/mL. The median half-life of free virus was 24.89 hours. The median half-life of infected hepatocytes was 7.39 days. The viral decay patterns were visualized as triphasic curves with decreasing slopes over time: fastest decay in the first phase; slowest in the third phase; the second phase in between. CONCLUSIONS: In the present study, mathematical modeling of hepatitis B in patients with virological response and HBsAg decline during 24-week antiviral therapy showed triphasic viral dynamics with direct introduction of immune effectors as a new compartment, which was thought to reflect the reduction of clearance rate of infected cells over time. This modeling method seems more appropriate to describe long-term viral dynamics compared to the biphasic model, and needs further validation.

Purpose Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD). Materials and Methods We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing. Results Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR, p.L858R) were present across synchronous lesions. Conclusion Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment. [ABSTRACT FROM AUTHOR]

Airway exposure of lipopolysaccharide (LPS) is shown to regulate type I and type II helper T cell induced asthma. While high doses of LPS derive Th1-or Th17-immune responses, low LPS levels lead to Th2 responses. In this paper, we analyze a mathematical model of Th1/Th2/Th17 asthma regulation suggested by Lee et al. (S. Lee, H.J. Hwang, and Y. Kim, Modeling the role of TGF-fi in regulation of the Th17 phenotype in the LPS-driven immune system, Bull Math Biol., 76 (5), 1045-1080, 2014) and show that the system can undergo a Hopf bifurcation at a steady state of the Th17 phenotype for high LPS levels in the presence of time delays in inhibition pathways of two key regulators: IL-4/Th2 activities (H) and TGF-β levels (G). The time delays affect the phenotypic switches among the Th1, Th2, and Th17 phenotypes in response to time-dependent LPS doses via nonlinear crosstalk between H and G. An extended reaction-diffusion model also predicts coexistence of these phenotypes under various biochemical and bio-mechanical conditions in the heterogeneous microenvironment. [ABSTRACT FROM AUTHOR]

Introduction Persistent migraine aura without headache is an extremely rare condition. The International Headache Society defines various subtypes of migraines, including "persistent migraine aura without infarction" and "typical aura without headache." Case presentation We describe the case of a 21-year-old Asian woman with a history of migraine without aura who had (as her first aura episode) persistent negative visual symptoms without headache for 6 months. We detected no lesions that could cause her persistent visual symptoms. Based on the patient's history of migraine without aura and responsiveness to furosemide and lamotrigine, we concluded that the visual symptoms in this case were related to migraine visual auras. Conclusions Persistent visual aura without headache overlapped the criteria for the two migraine subtypes mentioned above and thus did not fit an exact diagnosis. Therefore, we assert that new criteria are needed to encompass uncertain visual symptoms of migraine aura. [ABSTRACT FROM AUTHOR]

In this paper, we deal with the stability problem to some mathematical models that describe chemical reaction kinetics. One is a set of ordinary differential equations induced by one reversible chemical reaction mechanism containing three chemical species. The other is a set of reaction diffusion equations based on the same chemical reaction. We show that all solutions of the model are asymptotically stable by applying the Liapunov method. We thus find that the concentration of each species has certain limits as time proceeds. [ABSTRACT FROM AUTHOR]