Medical expenses and its determinants in female patients with urological disorder.

BACKGROUND: The rising older adult population has led to an increase in the prevalence of chronic diseases and medical expenses. Women tend to have a longer healthy life expectancy than men and are more likely to be exposed to urological disorders around the age of 50, resulting in substantial healthcare expenses throughout their lifetime. Urological disorders often require continuous treatment owing to their high risk of recurrence, contributing to an increased financial burden from medical costs. This study aimed to identify factors influencing medical expense in female patients with urological disorders and propose strategies to alleviate the associated financial burden. METHODS: We used data from the Korea Health Panel Survey conducted from 2011 to 2016. The final sample comprised 2,932 patients who visited hospitals for urological disorders. To identify the factors influencing medical expense among female patients with urological disorders, we employed a generalized estimating equation model. RESULTS: The results indicated that younger people and patients with middle-income levels tended to incur higher medical expenses. Furthermore, patients receiving treatment at tertiary hospitals and those enrolled in National Health Insurance also incurred higher health expenses. CONCLUSIONS: This study suggests that effective management of medical expenses related to urological disorders in women requires improvements in healthcare accessibility to facilitate early detection and continuous disease management. In addition, the findings highlight the potential benefits of digital health and non-face-to-face treatments in addressing these needs.

53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity.

p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.

Low-calorie sweeteners cause only limited metabolic effects in mice.

There are widespread concerns that low-calorie sweeteners (LCSs) cause metabolic derangement. These concerns stem in part from prior studies linking LCS consumption to impaired glucose tolerance in humans and rodents. Here, we examined this linkage in mice. In experiment 1, we provided mice with chow, water, and an LCS-sweetened solution (saccharin, sucralose, or acesulfame K) for 28 days and measured glucose tolerance and body weight across the exposure period. Exposure to the LCS solutions did not impair glucose tolerance or alter weight gain. In experiment 2, we provided mice with chow, water, and a solution containing saccharin, glucose, or a mixture of both for 28 days, and tested for metabolic changes. Exposure to the saccharin solution increased the insulinemic response of mice to the glucose challenge, and exposure to the saccharin + glucose solution increased the rate of glucose uptake during the glucose challenge. However, neither of these test solutions altered glucose tolerance, insulin sensitivity, plasma triglycerides, or percent body fat. In contrast, exposure to the glucose solution increased glucose tolerance, early insulin response, insulin sensitivity, and percent body fat. We conclude that whereas the LCS-containing solutions induced a few metabolic changes, they were modest compared with those induced by the glucose solution.

Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL).

BACKGROUND: A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF. METHODS: Patients received bendamustine 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine. RESULTS: Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669 ng/mL and 0.397 ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four-compartment model with first-order elimination of drug from central plasma and CSF compartments. CONCLUSIONS: R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03392714 ; retrospectively registered January 8, 2018.

Obox4-silencing-activated STAT3 and MPF/MAPK signaling accelerate nuclear membrane breakdown in mouse oocytes.

Mouse oocytes begin to mature in vitro once liberated from ovarian follicles. Previously, we showed that oocyte-specific homeobox 4 (Obox4) is critical for maintaining the intact nuclear membrane of the germinal vesicle (GV) in oocytes and for completing meiosis at the metaphase I-II (MI-MII) transition. This study further examines the molecular mechanisms of OBOX4 in regulating GV nuclear membrane breakdown. Maturation-promoting factor (MPF) and MAPK are normally inactive in GV stage oocytes but were activated prematurely in arrested GV stage oocytes by 3-isobutyl-1-metyl-xanthine (IBMX) in vitro after Obox4 RNA interference (RNAi). Furthermore, signal transducer and activator of transcription 3 (STAT3) was significantly activated by Obox4 RNAi. We confirmed that this Obox4 RNAi-induced premature STAT3 and MPF/MAPK activation at the GV stage provoked subsequent GV breakdown (GVBD) despite the opposing force of high cAMP in the IBMX-supplemented medium to maintain intact GV. When cumulus-oocyte complexes were exposed to interferon α (IFNA), a STAT3 activator, oocytes matured and cumulus cells expanded to resume nuclear maturation in IBMX-supplemented medium, suggesting that STAT3 activation is sufficient for stimulating the continuation of meiosis. Using Stattic, a specific STAT3 inhibitor, we confirmed that GVBD involves STAT3 activation in Obox4-silenced oocytes. Based on these findings, we concluded that i) Obox4 is an important upstream regulator of MPF/MAPK and STAT3 signaling, and ii) Obox4 is a key regulator of the GV arrest mechanism in oocytes.

Anti-inflammatory and antipruritic effects of luteolin from Perilla (P. frutescens L.) leaves.

Perilla (Perilla frutescens L.) leaves have shown therapeutic efficacy in the treatment of inflammatory disorders, allergies, bronchial asthma, and systemic damage due to free radicals. In the present study we analyzed the active constituents in perilla leaves using high-performance liquid chromatography (HPLC) and isolated luteolin, a polyphenolic flavonoid. We investigated the anti-inflammatory and antipruritic properties of luteolin. Luteolin inhibited the secretion of inflammatory cytokines such as interleukin-1ß (IL-1 ß) and tumor necrosis factor-α (TNF-α) from human mast cells (HMC-1) stimulated with phorbol myristate acetate plus calcium ionophore A23187 in a dose-dependent manner. Luteolin also significantly reduced the histamine release from rat peritoneal mast cells stimulated by compound 48/80, a potent histamine liberator. Furthermore, the administration of luteolin markedly inhibited the scratching behavior and vascular permeability induced by pruritogens, such as compound 48/80 or serotonin, in ICR mice. These results suggested that luteolin has potential as a therapeutic agent against inflammation and itch-related skin diseases.

Association of weekend catch-up sleep ratio and subjective sleep quality with depressive symptoms and suicidal ideation among Korean adolescents.

Circadian misalignment caused by differences in sleep duration between weekends and weekdays may be associated with adolescent mental health and sleep quality may be able to compensate for this problem. This study aimed to investigate the association between weekend catch-up sleep (CUS) ratio and sleep quality with depressive symptoms and suicidal ideation among South Korean adolescents. We used data from the Korea Youth Risk Behavior Web-based Survey 2015-2019 involving 270,619 adolescents. The weekend CUS ratio was calculated by dividing the average weekend sleep duration by the average weekday sleep duration (< 1.00, 1.00 ≤ CUS < 1.50, or ≥ 1.50). Subjective sleep quality was categorized as poor, moderate, or good. Multiple logistic regression analyses were performed. A weekend CUS ratio of < 1.00 and poor sleep quality was significantly associated with mental health. Absolutely short sleep duration (CUS < 1.00 and weekday sleep duration < 5 h) was most associated with depressive symptoms and suicidal ideation. Furthermore, adolescents with a CUS ratio of ≥ 1.50 showed increased odds of depressive symptoms despite having good sleep quality. Appropriate weekend CUS may benefit adolescents' mental health. When investigating the relationship between adolescents' sleep and mental health, a weekend CUS ratio should be considered in addition to sleep quality and duration.

Identification of an autosomal dominant locus for intracranial aneurysm through a model-based family collection in a geographically limited area.

Intracranial aneurysm (IA) is characterized by an abnormal bulging of one of the arteries in the brain and is heavily affected by genetic factors. Although IA is a very serious disease because of its severity and prevalence in the general public, the gene causing IA has not yet been identified due mainly to the lack of definitive genetic loci for the disease. Following a model-based family collection that recruited families from a geographically limited area that inherited IA as an autosomal dominant trait, we conducted a genome-wide linkage analysis. Significant evidence of linkage to IA was found on chromosome 8p22.2 with a maximum two-point logarithm of the odds ratio score of 3.61 under an autosomal dominant model of inheritance. The methods described in this study could be applied to localize disease-causing genes of other complex diseases through either a genome-wide linkage analysis or a genome-wide association study.

Obox4 critically regulates cAMP-dependent meiotic arrest and MI-MII transition in oocytes.

Extra follicular oocytes spontaneously resume meiosis in vitro, but the intact germinal vesicle (GV) is retained if the oocytes are cultured in medium containing phosphodiesterase (PDE) inhibitors or cAMP analogues. On the basis of our finding that Obox4 is prominently expressed in oocytes, the present study was conducted to determine the functional role of the homeodomain-containing factor Obox4 during in vitro oocyte maturation. After microinjection of Obox4 dsRNA into the cytoplasm of GV oocytes cultured in M16 medium, oocytes were arrested at metaphase I (MI, 77.7%) and metaphase II (MII, 22.3%). Surprisingly, however, 89% of Obox4 RNAi-treated oocytes resumed meiosis and developed to MI and MII when cultured in medium containing 0.2 mM 3-isobutyl-1-methyl-xanthine (IBMX), in which untreated oocytes maintain intact GVs. Spindles were aberrant, and chromosomes were severely aggregated with decreased MPF and MAP kinase activities in arrested MI oocytes after exposure to Obox4 RNAi. Oocytes overexpressing Obox4 retained intact GVs when cultured in M16 medium. Taken together, for the first time to our knowledge, these findings indicate that Obox4 plays a key role in the cAMP-dependent signaling cascades that maintain GV arrest. Oocytes not expressing Obox4 failed to maintain intact GVs in IBMX-supplemented medium, while GVs remained intact when oocytes were kept in plain medium and overexpressing Obox4, suggesting that Obox4 plays a critical role in cAMP-dependent cascade for maintaining intact GVs.

Correction: miR146a-mediated targeting of FANCM during inflammation compromises genome integrity.

[This corrects the article DOI: 10.18632/oncotarget.10275.].

Wild boar harbouring African swine fever virus in the demilitarized zone in South Korea, 2019.

The African swine fever virus (ASFV) was first detected in wild boar in the Demilitarized Zone, a bordered area between South and North Korea, on 2 October 2019. Phylogenetic analyses of ASFV genes encoding p72 and CD2v indicated that the causative strain belongs to genotype II and serogroup 8, respectively, and contained additional tandem repeat sequences between the I73R and the I329L protein genes.

Role of Bcl2-like 10 (Bcl2l10) in Regulating Mouse Oocyte Maturation.

Previously, we have shown that Bcl2l10 is highly expressed in metaphase II (MII)-stage oocytes. The objective of this study was to characterize Bcl2l10 expression in ovaries and to examine the function of Bcl2l10 in oocyte maturation using RNA interference. Bcl2l10 transcript expression was ovary and oocyte specific. Bcl2l10 was highly expressed in oocytes and pronuclear-stage embryos; however, its expression decreased at the two-cell stage and dramatically disappeared thereafter. Microinjection of Bcl2l10 double-stranded RNA into the cytoplasm of germinal vesicle oocytes resulted in a marked decrease in Bcl2l10 mRNA and protein and metaphase I (MI) arrest (78.9%). Most MI-arrested oocytes exhibited abnormalities in their spindles and chromosome configurations. Bcl2l10 RNA interference had an obvious effect on the activity of maturation-promoting factor but not on that of mitogen-activated protein kinase. We concluded that the role of Bcl2l10 is strongly associated with oocyte maturation, especially at the MI-MII transition.

Zap70 and downstream RanBP2 are required for the exact timing of the meiotic cell cycle in oocytes.

In previous studies, we observed that Zeta-chain-associated protein kinase 70 (Zap70) regulates spindle assembly and chromosome alignment in mouse oocyte and that Ran binding protein 2 (RanBP2) is a highly associated gene with Zap70 based on a microarray analysis. Because RanBP2 is related to nuclear envelope breakdown (NEBD) during mitosis, the aim of the present study was to elucidate the molecular mechanism of Zap70 with respect to RanBP2 in the germinal vesicle breakdown (GVBD) of oocytes. Results indicated that RanBP2 expression was regulated by Zap70 and that depletion of RanBP2 using RanBP2 RNAi manifested comparable phenotypes to those observed in Zap70 RNAi-treated oocytes, which presented faster processing of GVBD. Additionally, Zap70 RNAi-treated oocytes showed faster meiotic resumption with premature activation of maturation-promoting factor (MPF), premature division of chromosomes at approximately 6-8 h and more rapid degradation of securin. In conclusion, we report that Zap70 is a crucial factor for controlling the exact timing of meiotic progression in mouse oocytes.

miR146a-mediated targeting of FANCM during inflammation compromises genome integrity.

Inflammation is a potent inducer of tumorigenesis. Increased DNA damage or loss of genome integrity is thought to be one of the mechanisms linking inflammation and cancer development. It has been suggested that NF-κB-induced microRNA-146 (miR146a) may be a mediator of the inflammatory response. Based on our initial observation that miR146a overexpression strongly increases DNA damage, we investigated its potential role as a modulator of DNA repair. Here, we demonstrate that FANCM, a component in the Fanconi Anemia pathway, is a novel target of miR146a. miR146a suppressed FANCM expression by directly binding to the 3' untranslated region of the gene. miR146a-induced downregulation of FANCM was associated with inhibition of FANCD2 monoubiquitination, reduced DNA homologous recombination repair and checkpoint response, failed recovery from replication stress, and increased cellular sensitivity to cisplatin. These phenotypes were recapitulated when miR146a expression was induced by overexpressing the NF-κB subunit p65/RelA or Helicobacter pylori infection in a human gastric cell line; the phenotypes were effectively reversed with an anti-miR146a antagomir. These results suggest that undesired inflammation events caused by a pathogen or over-induction of miR146a can impair genome integrity via suppression of FANCM.

MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1.

MDC1 is critical component of the DNA damage response (DDR) machinery and orchestrates the ensuring assembly of the DDR protein at the DNA damage sites, and therefore loss of MDC1 results in genomic instability and tumorigenicity. However, the molecular mechanisms controlling MDC1 expression are currently unknown. Here, we show that miR-22 inhibits MDC1 translation via direct binding to its 3' untranslated region, leading to impaired DNA damage repair and genomic instability. We demonstrated that activated Akt1 and senescence hinder DDR function of MDC1 by upregulating endogenous miR-22. After overexpression of constitutively active Akt1, homologous recombination was inhibited by miR-22-mediated MDC1 repression. In addition, during replicative senescence and stress-induced premature senescence, MDC1 was downregulated by upregulating miR-22 and thereby accumulating DNA damage. Our results demonstrate a central role of miR-22 in the physiologic regulation of MDC1-dependent DDR and suggest a molecular mechanism for how aberrant Akt1 activation and senescence lead to increased genomic instability, fostering an environment that promotes tumorigenesis.

RNA Polymerase II Inhibitor, α-Amanitin, Affects Gene Expression for Gap Junctions and Metabolic Capabilities of Cumulus Cells, but Not Oocyte, during in vitro Mouse Oocyte Maturation.

A specific inhibitor of RNA polymerase II, α-amanitin is broadly used to block transcriptional activities in cells. Previous studies showed that α-amanitin affects in vitro maturation of cumulus-oocyte-complex (COC). In this study, we evaluated the target of α-amanitin, and whether it affects oocytes or cumulus cells (CCs), or both. We treated α-amanitin with different time period during in vitro culture of denuded oocytes (DOs) or COCs in comparison, and observed the changes in morphology and maturation status. Although DOs did not show any change in morphology and maturation rates with α-amanitin treatment, oocytes from COCs were arrested at metaphase I (MI) stage and CCs were more scattered than control groups. To discover causes of meiotic arrest and scattering of CCs, we focused on changes of cumulus expansion, gap junctions, and cellular metabolism which to be the important factors for the successful in vitro maturation of COCs. Expression of genes for cumulus expansion markers (Ptx3, Has2, and Tnfaip6) and gap junctional proteins (Gja1, Gja4, and Gjc1) decreased in α-amanitin-treated CCs. However, these changes were not observed in oocytes. In addition, expression of genes related to metabolism (Prps1, Rpe, Rpia, Taldo1, and Tkt) decreased in α -amanitin-treated CCs but not in oocytes. Therefore, we concluded that the transcriptional activities of CCs for supporting suitable transcripts, especially for its metabolic activities and formation of gap junctions among CCs as well as with oocytes, are important for oocytes maturation in COCs.

Thioredoxin-interacting protein regulates glucose metabolism and affects cytoplasmic streaming in mouse oocytes.

Thioredoxin-interacting protein (Txnip) regulates intracellular redox state and prompts oxidative stress by binding to and inhibiting Thioredoxin (Trx). In addition, via a Trx-independent mechanism, Txnip regulates glucose metabolism and thus maintains intracellular glucose levels. Previously, we found Txnip mRNA highly expressed in immature germinal vesicle (GV) oocytes, but currently there is no report describing the role of Txnip in oocytes. Therefore, we conducted the present study to determine the function of Txnip in mouse oocytes' maturation and meiosis by using RNA interference (RNAi) method. Upon specific depletion of Txnip, 79.5% of oocytes were arrested at metaphase I (MI) stage. Time-lapse video microscopy analysis revealed that the formation of granules in the oocyte cytoplasm increased concurrent with retarded cytoplasmic streaming after Txnip RNAi treatment. Txnip RNAi-treated oocytes had upregulated glucose uptake and lactate production. To confirm the supposition that mechanism responsible for these observed phenomena involves increased lactate in oocytes, we cultured oocytes in high lactate medium and observed the same increased granule formation and retarded cytoplasmic streaming as found by Txnip RNAi. The MI-arrested oocytes exhibited scattered microtubules and aggregated chromosomes indicating that actin networking was disturbed by Txnip RNAi. Therefore, we conclude that Txnip is a critical regulator of glucose metabolism in oocytes and is involved in maintaining cytoplasmic streaming in mouse oocytes.

Creation of resveratrol-enriched rice for the treatment of metabolic syndrome and related diseases.

Resveratrol has been clinically shown to possess a number of human health benefits. As a result, many attempts have been made to engineer resveratrol production in major cereal grains but have been largely unsuccessful. In this study, we report the creation of a transgenic rice plant that accumulates 1.9 µg resveratrol/g in its grain, surpassing the previously reported anti-metabolic syndrome activity of resveratrol through a synergistic interaction between the transgenic resveratrol and the endogenous properties of the rice. Consumption of our transgenic resveratrol-enriched rice significantly improved all aspects of metabolic syndrome and related diseases in animals fed a high-fat diet. Compared with the control animals, the resveratrol-enriched rice reduced body weight, blood glucose, triglycerides, total cholesterol, and LDL-cholesterol by 24.7%, 22%, 37.4%, 27%, and 59.6%, respectively. The resveratrol-enriched rice from our study may thus provide a safe and convenient means of preventing metabolic syndrome and related diseases without major lifestyle changes or the need for daily medications. These results also suggest that future transgenic plants could be improved if the synergistic interactions of the transgene with endogenous traits of the plant are considered in the experimental design.

Changes in gene expression associated with oocyte meiosis after Obox4 RNAi.

OBJECTIVE: Previously, we found that oocyte specific homeobox (Obox) 4 plays significant role in completion of meiosis specifically at meiosis I-meiosis II (MI-MII) transition. The purpose of this study was to determine the mechanism of action of Obox4 in oocyte maturation by evaluating downstream signal networking. METHODS: The Obox4 dsRNA was prepared by in vitro transcription and microinjected into the cytoplasm of germinal vesicle oocytes followed by in vitro maturation in the presence or absence of 0.2 mM 3-isobutyl-1-metyl-xanthine. Total RNA was extracted from 200 oocytes of each group using a PicoPure RNA isolation kit then amplified two-rounds. The probe hybridization and data analysis were used by Affymetrix GeneChip® Mouse Genome 430 2.0 array and GenPlex 3.0 (ISTECH, Korea) software, respectively. RESULTS: Total 424 genes were up (n=80) and down (n=344) regulated after Obox4 RNA interference (RNAi). Genes mainly related to metabolic pathways and mitogen-activated protein kinase (MAPK) signaling pathway was changed. Among the protein kinase C (PKC) isoforms, PKC-alpha, beta, gamma were down-regulated and especially the MAPK signaling pathway PKC-gamma was dramatically decreased by Obox4 RNAi. In the cell cycle pathway, we evaluated the expression of genes involved in regulation of chromosome separation, and found that these genes were down-regulated. It may cause the aberrant chromosome segregation during MI-MII transition. CONCLUSION: From the results of this study, it is concluded that Obox4 is important upstream regulator of the PKC and anaphase-promoting complex action for maintaining intact germinal vesicle.