Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation.

The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6-/- mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.

Impacts of Tocolytics on Maternal and Neonatal Glucose Levels in Women With Gestational Diabetes Mellitus.

BACKGROUND: We investigated the impacts of tocolytic agents on maternal and neonatal blood glucose levels in women with gestational diabetes mellitus (GDM) who used tocolytics for preterm labor. METHODS: This multi-center, retrospective cohort study included women with GDM who were admitted for preterm labor from twelve hospitals in South Korea. We excluded women with multiple pregnancies, anomalies, overt DM diagnosed before pregnancy or 23 weeks of gestation, and women who received multiple tocolytics. The patients were divided according to the types of tocolytics; atosiban, ritodrine, and nifedipine group. We collected baseline maternal characteristics, pregnancy outcomes, maternal glucose levels during hospitalization, and neonatal glucose levels. We compared the frequency of maternal hyperglycemia and neonatal hypoglycemia among three groups. A multivariate logistic regression analysis was performed to evaluate the contributing factors to the occurrence of maternal hyperglycemia and neonatal hypoglycemia. RESULTS: A total of 128 women were included: 44 (34.4%), 51 (39.8%), and 33 (25.8%) women received atosiban, ritodrine, and nifedipine, respectively. Mean fasting blood glucose (FBG) (112.3, 109.6, and 89.5 mg/dL, P < 0.001) and 2-hour postprandial glucose (PPG2) levels (145.4, 148.3, and 116.5 mg/dL, P = 0.004) were significantly higher in atosiban and ritodrine group than those in nifedipine group. Even after adjusting for covariates including antenatal steroid use, gestational age at admission, and pre-pregnancy body mass index, there was an increased risk of high maternal mean FBG (≥ 95 mg/dL) and PPG2 (≥ 120 mg/dL) levels in the atosiban and ritodrine group than in nifedipine group. The atosiban and ritodrine groups are also at increased risk of neonatal hypoglycemia (< 47 mg/dL) compared to the nifedipine group with the odds ratio of 4.58 and 4.67, respectively (P < 0.05). CONCLUSION: There is an increased risk of maternal hyperglycemia and neonatal hypoglycemia in women with GDM using atosiban and ritodrine tocolytics for preterm labor compared to those using nifedipine.

Effects of Melatonin, GM-CSF, IGF-1, and LIF in Culture Media on Embryonic Development: Potential Benefits of Individualization.

The implantation of good-quality embryos to the receptive endometrium is essential for successful live birth through in vitro fertilization (IVF). The higher the quality of embryos, the higher the live birth rate per cycle, and so efforts have been made to obtain as many high-quality embryos as possible after fertilization. In addition to an effective controlled ovarian stimulation process to obtain high-quality embryos, the composition of the embryo culture medium in direct contact with embryos in vitro is also important. During embryonic development, under the control of female sex hormones, the fallopian tubes and endometrium create a microenvironment that supplies the nutrients and substances necessary for embryos at each stage. During this process, the development of the embryo is finely regulated by signaling molecules, such as growth factors and cytokines secreted from the epithelial cells of the fallopian tube and uterine endometrium. The development of embryo culture media has continued since the first successful human birth through IVF in 1978. However, there are still limitations to mimicking a microenvironment similar to the reproductive organs of women suitable for embryo development in vitro. Efforts have been made to overcome the harsh in vitro culture environment and obtain high-quality embryos by adding various supplements, such as antioxidants and growth factors, to the embryo culture medium. Recently, there has been an increase in the number of studies on the effect of supplementation in different clinical situations such as old age, recurrent implantation failure (RIF), and unexplained infertility; in addition, anticipation of the potential benefits from individuation is rising. This article reviews the effects of representative supplements in culture media on embryo development.

Development and Evaluation of a Mobile Application to Prevent Recurrent Stroke by Enhancing Self-management on Health Outcomes for Stroke Survivors.

This study aimed to develop a Mobile Application to Prevent Recurrent Stroke to prevent recurrent stroke by enhancing self-management and to evaluate its effects on stroke survivors' health outcomes. The Mobile Application to Prevent Recurrent Stroke was developed based on social cognitive theory and the model in order of analysis, design, development, implementation, and evaluation process. The Mobile Application to Prevent Recurrent Stroke consisted of health management contents such as information about stroke, its associated risk factors, and required skills to conduct self-management with tailored support and counseling. A quasi-experimental preintervention and postintervention design was used involving a total of 54 stroke survivors. The experimental group (n = 27) was provided the Mobile Application to Prevent Recurrent Stroke for 8 weeks, whereas the control group (n = 27) received an education booklet. The result revealed that medication adherence ( P = .002), healthy eating habit ( P < .001), physical activity ( P < .001), and affected-side grip strength ( P = .002) in the experimental group were significantly better than those in the control group. The systolic blood pressure ( P = .020), diastolic blood pressure ( P < .001), body mass index ( P < .001), and waist circumference ( P < .001) in the experimental group were significantly lower than those in the control group. Stroke survivors can easily use this Mobile Application to Prevent Recurrent Stroke to improve self-management. Nurses can provide tailored care based on the lifelogging data of stroke survivors to prevent recurrent stroke.

Healthcare Utilization and Costs According to Frailty Transitions After Two Years: A Korean Frailty and Aging Cohort Study.

BACKGROUND: Korea's aging population has raised several challenges, especially concerning healthcare costs. Consequently, this study evaluated the association of frailty transitions with healthcare utilization and costs for older adults aged 70 to 84. METHODS: This study linked the frailty status data of the Korean Frailty and Aging Cohort Study to the National Health Insurance Database. We included 2,291 participants who had frailty measured by Fried Frailty phenotype at baseline in 2016-2017 and follow-up in 2018-2019. We conducted a multivariate regression analysis to determine the association between their healthcare utilization and costs by frailty transition groups. RESULTS: After 2 years, changes from "pre-frail" to "frail" (Group 6) and "frail" to "pre-frail" (Group 8) were significantly associated with increased inpatient days (P < 0.001), inpatient frequency (P < 0.001), inpatient cost (P < 0.001 and P < 0.01, respectively), and total healthcare cost (P < 0.001) than "robust" to "robust" (Group 1) older adults. A transition to frailty from "pre-frail" to "frail" (Group 6) resulted in a $2,339 total healthcare cost increase, and from "frail" to "pre-frail" (Group 8), a $1,605, compared to "robust" to "robust" older adults. CONCLUSION: Frailty among community-dwelling older adults is economically relevant. Therefore, it is crucial to study the burden of medical expenses and countermeasures for older adults to not only provide appropriate medical services but also to prevent the decline in their living standards due to medical expenses.

Nationwide Treatment Outcomes of Patients With Multidrug/Rifampin-Resistant Tuberculosis in Korea, 2011-2017: A Retrospective Cohort Study (Korean TB-POST).

BACKGROUND: The treatment outcomes of patients with multidrug/rifampin-resistant (MDR/RR) tuberculosis (TB) are important indicators that reflect the current status of TB management and identify the key challenges encountered by TB control programs in a country. METHODS: We retrospectively evaluated the treatment outcomes as well as predictors of unfavorable outcomes in patients with MDR/RR-TB notified from 2011 to 2017, using an integrated TB database. RESULTS: A total of 7,226 patients with MDR/RR-TB were included. The treatment success rate had significantly increased from 63.9% in 2011 to 75.1% in 2017 (P < 0.001). Among unfavorable outcomes, the proportion of patients who failed, were lost to follow up, and were not evaluated had gradually decreased (P < 0.001). In contrast, TB-related death rate was not significantly changed (P = 0.513), while the non-TB related death rate had increased from 3.2% in 2011 to 11.1% in 2017 (P < 0.001). Older age, male sex, immigrants, low household income, previous history of TB treatment, and comorbidities were independent predictors of unfavorable outcomes. Of the 5,308 patients who were successfully treated, recurrence occurred in 241 patients (4.5%) at a median 18.4 months (interquartile range, 9.2-32.4) after completion treatment. CONCLUSION: The treatment outcomes of patients with MDR/RR-TB has gradually improved but increasing deaths during treatment is an emerging challenge for MDR-TB control in Korea. Targeted and comprehensive care is needed for vulnerable patients such as the elderly, patients with comorbidities, and those with low household incomes.

Dysregulated Liver Metabolism and Polycystic Ovarian Syndrome.

A significant fraction of couples around the world suffer from polycystic ovarian syndrome (PCOS), a disease defined by the characteristics of enhanced androgen synthesis in ovarian theca cells, hyperandrogenemia, and ovarian dysfunction in women. Most of the clinically observable symptoms and altered blood biomarker levels in the patients indicate metabolic dysregulation and adaptive changes as the key underlying mechanisms. Since the liver is the metabolic hub of the body and is involved in steroid-hormonal detoxification, pathological changes in the liver may contribute to female endocrine disruption, potentially through the liver-to-ovary axis. Of particular interest are hyperglycemic challenges and the consequent changes in liver-secretory protein(s) and insulin sensitivity affecting the maturation of ovarian follicles, potentially leading to female infertility. The purpose of this review is to provide insight into emerging metabolic mechanisms underlying PCOS as the primary culprit, which promote its incidence and aggravation. Additionally, this review aims to summarize medications and new potential therapeutic approaches for the disease.

Impact evaluation of a community nutrition and livelihood program on child nutrition in rural Bangladesh.

Given the high prevalence of child undernutrition in Bangladesh, multi-sectoral approaches involving livelihood promotion have potential to mitigate the burden of undernutrition. This study examined the impact of an economic development (ED) program providing poultry assets, gardening skills and saving training added to the Positive Deviant (PD)/Hearth program (PDH/ED), compared to PD/Hearth only (PDH). A total of 1029 children who attended PD/Hearth sessions in September-November 2018 at 6-13 months of age were enrolled in the cohort study in July-August 2019. The cohort, comprised of 532 children in the PDH/ED group and 593 children in the PDH group, was reassessed in November 2020. The program impact on child nutrition, food security, crop production, dietary quality and household income was estimated using a difference-in-differences approach accounting for the sociodemographic differences between PDH/ED and PDH groups. Compared to the PDH group, the PDH/ED group showed increases in child dietary diversity score (DDS) (+0.32), child minimum dietary diversity (13.7 percentage points [pp]), and maternal DDS (+0.28) (all p < 0.05). From 2019 to 2020, the PDH/ED households improved food security by 12.6 pp and diversified crop production (bananas (9.7 pp), papaya (11.1 pp), carrots (3.8 pp) and lemons (5.9 pp)), and increased the proportion of annual income ≥60,000 Taka by 12.4 pp and last month income ≥5000 Taka by 7.8 pp, compared to PDH group (all p < 0.05). However, there was no impact on child nutritional status, morbidity, livestock ownership and total annual/last income. Incorporating an ED program into nutrition programming could benefit food security and dietary diversity in rural Bangladesh.

Hypertensive effects of transforming growth factor-ß1 in vascular smooth muscles cells from spontaneously hypertensive rats are mediated by sulfatase 2.

Extracellular sulfatases (sulfatase 1 and sulfatase 2) mediate up- or down-regulatory effects of cytokines on angiotensin II (Ang II)-induced expression of hypertensive mediators in hypertensive cells. The overproduction of transforming growth factor-ß1 (TGF-ß1) is associated with chronic hypertension. In this study, we examined the role of extracellular sulfatases on TGF-ß1-induced effects associated with the expression of mediators related to hypertension in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). First, TGF-ß1 increased the expression of 12-lipoxygenase (12-LO) and endothelin-1 (ET-1), inhibited dimethylarginine dimethylaminohydrolase-1 (DDAH-1) expression and showed additive effects on Ang II-induced 12-LO and ET-1 expression as well as Ang II-induced inhibition of DDAH-1 expression in SHR VSMCs. However, it had no effect on the expression of 12-LO, ET-1, and DDAH-1 in VSMCs from normotensive Wistar Kyoto rats. Downregulation of sulfatase 2 (Sulf2) inhibited all of these hypertensive effects caused by TGF-ß1, while sulfatase 1 (Sulf1) had no effect on these events in SHR VSMCs. All these hypertensive effects of TGF-ß1 were dependent on the Ang II subtype 1 receptor (AT1 R) pathway, and not on Ang II subtype 2 receptor (AT2 R). In addition, downregulation of Sulf2 inhibited the expression of TGF-ß1-induced AT1 R and the additive effect of TGF-ß1 on Ang II-induced AT1 R expression. Additionally, downregulation of Sulf2, but not Sulf1, abrogated TGF-ß1-induced inhibition of AMP-activated protein kinase (AMPK) activation and the additive effect of TGF-ß1 on Ang II-induced inhibition of AMPK activation via the AT1 R pathway. Moreover, TGF-ß1-induced VSMCs proliferation and the additive effect of TGF-ß1 on Ang II-induced VSMCs proliferation were abrogated in Sulf2 siRNA-transfected SHR VSMCs, while these effects were maintained in Sulf1 siRNA-transfected SHR VSMCs. The hypertensive effects of TGF-ß1 through the AT1 R pathway were mainly dependent on Sulf2 activity in SHR VSMCs. Taken together, these results suggest that Sulf2, but not Sulf1, plays a major role in mediating the increased effects of TGF-ß1 in hypertensive VSMCs.

A Survey on Public Perceptions of Low Fertility: A Social Research Panel Study.

BACKGROUND: It was reported that South Korea showed the greatest decline in the fertility rate among the entire OECD countries over the last 30 years with the total fertility rate (TFR) of 0.84 persons in 2020. Despite the efforts of the Korean government, the TFR has decreased constantly. This study intended to analyze the perception of Koreans toward pregnancy and childbirth regarding the low fertility rate in South Korea for understanding the causes of constantly decreased low fertility. METHODS: This study carried out an online survey based on 1,002 men and women aged 19 to 59 years old for six days from October 21 to October 26 in 2021 in cooperation with Gallup Korea. This study analyzed the perception of people toward low fertility, the severity of low fertility, and level of interest in low fertility to inspect awareness of the severity of low fertility in South Korea through a survey. RESULTS: It was found that 62%, 52%, and 72% of entire participants, women, and men agreed on a question "It is better to get married". As for women's age, a positive response for this question was derived from 34.2% (20s), 43.1% (30s), 53.4% (40s), and 71.4% (50s), respectively (P < 0.001). In a question "the necessity of children", a positive response for this question was derived from 34.7% (20s), 58.3% (30s), 75.9% (40s), and 83.5% (50s) of female respondents, respectively (P < 0.001). Positive responses were shown 39.2%, 60.0%, 79.7%, and 81.5% of female participants in their 20s, 30s, 40s, and 50s agreed on the question "My children make me happy in my life", respectively (P < 0.001). CONCLUSION: This study found that a decrease in the TFR was affected mainly by the negative perception of women in their 20s and 30s toward marriage, childbirth, and the necessity of children. Therefore, further research should be conducted to develop policies that focus on these significant variables to overcome the worsening low fertility problem.

Anti-Inflammatory and Neuroprotective Mechanisms of GTS-21, an α7 Nicotinic Acetylcholine Receptor Agonist, in Neuroinflammation and Parkinson's Disease Mouse Models.

Neuroinflammation is crucial in the progression of neurodegenerative diseases. Thus, controlling neuroinflammation has been proposed as an important therapeutic strategy for neurodegenerative disease. In the present study, we examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in neuroinflammation and Parkinson's disease (PD) mouse models. GTS-21 inhibited the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary microglia. Further research revealed that GTS-21 has anti-inflammatory properties by inhibiting PI3K/Akt, NF-κB, and upregulating AMPK, Nrf2, CREB, and PPARγ signals. The effects of GTS-21 on these pro-/anti-inflammatory signaling molecules were reversed by treatment with an α7 nAChR antagonist, suggesting that the anti-inflammatory effects of GTS-21 are mediated through α7 nAChR activation. The anti-inflammatory and neuroprotective properties of GTS-21 were then confirmed in LPS-induced systemic inflammation and MPTP-induced PD model mice. In LPS-injected mouse brains, GTS-21 reduced microglial activation and production of proinflammatory markers. Furthermore, in the brains of MPTP-injected mice, GTS-21 restored locomotor activity and dopaminergic neuronal cell death while inhibiting microglial activation and pro-inflammatory gene expression. These findings suggest that GTS-21 has therapeutic potential in neuroinflammatory and neurodegenerative diseases such as PD.

RACK1 mediates rewiring of intracellular networks induced by hepatitis C virus infection.

Hepatitis C virus (HCV) is a positive-strand RNA virus replicating in a membranous replication organelle composed primarily of double-membrane vesicles (DMVs) having morphological resemblance to autophagosomes. To define the mechanism of DMV formation and the possible link to autophagy, we conducted a yeast two-hybrid screening revealing 32 cellular proteins potentially interacting with HCV proteins. Among these was the Receptor for Activated Protein C Kinase 1 (RACK1), a scaffolding protein involved in many cellular processes, including autophagy. Depletion of RACK1 strongly inhibits HCV RNA replication without affecting HCV internal ribosome entry site (IRES) activity. RACK1 is required for the rewiring of subcellular membranous structures and for the induction of autophagy. RACK1 binds to HCV nonstructural protein 5A (NS5A), which induces DMV formation. NS5A interacts with ATG14L in a RACK1 dependent manner, and with the ATG14L-Beclin1-Vps34-Vps15 complex that is required for autophagosome formation. Both RACK1 and ATG14L are required for HCV DMV formation and viral RNA replication. These results indicate that NS5A participates in the formation of the HCV replication organelle through interactions with RACK1 and ATG14L.

Sulfatase 1 mediates IL-10-induced dimethylarginine dimethylaminohydrolase-1 expression and antiproliferative effects in vascular smooth muscle cells of spontaneously hypertensive rats.

The extracellular sulfatases (exSulfs) sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2) are well-known regulators of cell signaling and metabolism. In addition, exSulfs mediate the up- or downregulatory effects of cytokines on angiotensin II (Ang II)-induced expression of hypertensive mediators in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHRs). Previously, we demonstrated that interleukin-10 (IL-10)-induced dimethylarginine dimethylaminohydrolase-1 (DDAH-1) expression was mediated by Ang II subtype 2 receptor (AT2 R) and AMP-activated protein kinase (AMPK) activation, and that IL-10-mediated inhibition of Ang II-induced proliferation of SHRs VSMC was partially associated with DDAH-1. In this study, we examined the effects of exSulfs on IL-10-induced DDAH-1 expression, abrogation of Ang II-induced DDAH-1 downregulation, and inhibition of Ang II-induced proliferation of SHRs VSMC. IL-10-induced DDAH-1 expression and abrogation of Ang II-induced DDAH-1 downregulation were attenuated in Sulf1 siRNA-transfected SHRs VSMC. However, Sulf2 did not affect IL-10-induced DDAH-1 expression and abrogation of Ang II-induced DDAH-1 downregulation. Downregulation of Sulf1 inhibited IL-10-induced AT2 R expression and the synergistic effects of IL-10 on Ang II-induced AT2 R expression. Additionally, Sulf1 downregulation inhibited IL-10-induced AMPK activity and abrogation of Ang II-induced decrease in AMPK activity. Moreover, the IL-10-mediated inhibition of Ang II-induced proliferation was not detected in Sulf1 siRNA-transfected SHRs VSMC; IL-10-mediated inhibition of Ang II-induced VSMC proliferation was mediated via the AT2 R pathway and AMPK activation. Specifically, IL-10-induced DDAH-1 expression, abrogation of Ang II-induced DDAH-1 downregulation, and inhibition of Ang II-induced proliferation, which is mediated by the AT2 R pathway and AMPK activation, are mainly mediated by Sulf1 activity in SHRs VSMC. These results suggest that Sulf1, and not Sulf2, mediates the IL-10-induced inhibition of Ang II-induced hypertensive effects in SHRs VSMC.

How to approach the rupture of tubo-ovarian abscess during pregnancy: A case report and literature review.

We present the case of a 26-year-old multiparous woman who experienced rupture of a tubo-ovarian abscess during the second trimester of pregnancy. She presented with epigastric and right lower quadrant pain at 12 + 0 weeks' gestation. There were no other specific findings on the magnetic resonance imaging images. We recommended hospitalization to observe the changes in pain, but she refused confinement. About 3 weeks later, she revisited our emergency room at 15 + 4 weeks' gestation. She complained of worsening abdominal pain with fever. She underwent right salpingo-oophorectomy and appendectomy due to uncontrollable, severe abdominal pain without any obstetric abnormal condition. There was a rupture site in the right adnexa, which was covered with pus. The rupture of tubo-ovarian abscess during pregnancy is very rare. Therefore, obstetricians should carefully monitor the adnexal masses observed during pregnancy, which should be treated with caution, whether or not the patient is symptomatic.

Cognitive Outcomes of Children with Very Low Birth Weight at 3 to 5 Years of Age.

BACKGROUND: The cognitive consequences and risk factors based long-term outcome of very-low-birth-weight (VLBW; < 1,500 g) infants in Korea has not been studied. The aim of this study was to determine the influence of perinatal and neonatal risk factors on the cognitive performance of VLBW children at 3 to 5 years of age. METHODS: We enrolled 88 VLBW infants without cystic periventricular leukomalacia for the assessment of their demographic data, cognitive performance, and development of cerebral palsy (CP) at 3 to 5 years of age. Cognitive performance was assessed using the Korean version of the Wechsler Preschool and Primary Scale of Intelligence IV. Growth data were assessed with measurements of weight, height, and head circumference (HC) at the corrected ages of 6, 12, and 18 months, and 3 to 5 years of age. RESULTS: In the VLBW group, the full-scale intelligence quotient (FSIQ) was 96.1 ± 15.2 at the mean age of 4.5 years. The incidence rate of CP was 3.4%. Overall, 17% (15/88) of the VLBW children had a below-average FSIQ (< 85). We divided the VLBW children into the abnormal FSIQ group (< 85, n = 15) and the normal FSIQ group (≥ 85, n = 73). VLBW children with intrauterine growth retardation (IUGR) was associated with a below-average FSIQ at the mean age of 4.5 years (< 85, 8/15, 53.3% vs. ≥ 85, 5/73, 6.8%; P < 0.001). After controlling for associated clinical factors, IUGR in the VLBW children was found to be associated with an abnormal FSIQ at the mean age of 4.5 years (P = 0.025). The weight, height, and HC obtained for both groups showed that normal growth was maintained at the mean age of 4.5 years with no significant difference between abnormal and normal FSIQ groups. CONCLUSION: Fifteen of 88 (17%) of the VLBW children had a below-average FSIQ (< 85). VLBW with IUGR is associated with poor cognitive outcomes at the mean age of 4.5 years.

The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson's disease mouse models.

BACKGROUND: Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Thus, the development of agents that can control neuroinflammation has been suggested as a promising therapeutic strategy for PD. In the present study, we investigated whether the phosphodiesterase (PDE) 10 inhibitor has anti-inflammatory and neuroprotective effects in neuroinflammation and PD mouse models. METHODS: Papaverine (PAP) was utilized as a selective inhibitor of PDE10. The effects of PAP on the expression of pro-inflammatory molecules were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells by ELISA, RT-PCR, and Western blot analysis. The effects of PAP on transcription factors were analyzed by the electrophoretic mobility shift assay, the reporter gene assay, and Western blot analysis. Microglial activation and the expression of proinflammatory molecules were measured in the LPS- or MPTP-injected mouse brains by immunohistochemistry and RT-PCR analysis. The effect of PAP on dopaminergic neuronal cell death and neurotrophic factors were determined by immunohistochemistry and Western blot analysis. To assess mouse locomotor activity, rotarod and pole tests were performed in MPTP-injected mice. RESULTS: PAP inhibited the production of nitric oxide and proinflammatory cytokines in LPS-stimulated microglia by modulating various inflammatory signals. In addition, PAP elevated intracellular cAMP levels and CREB phosphorylation. Treatment with H89, a PKA inhibitor, reversed the anti-inflammatory effects of PAP, suggesting the critical role of PKA signaling in the anti-inflammatory effects of PAP. We verified the anti-inflammatory effects of PAP in the brains of mice with LPS-induced systemic inflammation. PAP suppressed microglial activation and proinflammatory gene expression in the brains of these mice, and these effects were reversed by H89 treatment. We further examined the effects of PAP on MPTP-injected PD model mice. MPTP-induced dopaminergic neuronal cell death and impaired locomotor activity were recovered by PAP. In addition, PAP suppressed microglial activation and proinflammatory mediators in the brains of MPTP-injected mice. CONCLUSIONS: PAP has strong anti-inflammatory and neuroprotective effects and thus may be a potential candidate for treating neuroinflammatory disorders such as PD.

Sulfatase 2 mediates, partially, the expression of endothelin-1 and the additive effect of Ang II-induced endothelin-1 expression by CXCL8 in vascular smooth muscle cells from spontaneously hypertensive rats.

The extracellular sulfatases (Sulfs), sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2), have an important role in cell signaling by modulating the 6-O-sulfation of heparan sulfate proteoglycans (HSPGs) on the cell surface. Gene expression and enzyme activity of Sulfs are elevated in hypertensive vascular smooth muscle cells (VSMCs) compared to those in normotensive VSMCs. CXC-chemokine ligand (CXCL) 8 has a pathogenic role in the development and progression of hypertension. In this study, we investigated the effect of Sulfs on the expression of CXCL8-induced endothelin (ET)-1, a hypertensive mediator, in VSMCs from spontaneously hypertensive rats (SHR). Expression of ET-1 and elevation of angiotensin (Ang) II-induced ET-1 expression by CXCL8 were reduced in Sulf2 small interfering RNA (siRNA)-transfected SHR VSMCs. But, downregulation of Sulf1 did not affect the expression of CXCL8-induced ET-1 and additive effect of CXCL8 on Ang II-induced ET-1 expression in SHR VSMCs. CXCL8-induced ET-1 expression and the additive effect of CXCL8 on Ang II-induced ET-1 expression were dependent on the Ang II type 1 receptor (AT1 R) pathway, not the Ang II type 2 receptor (AT2 R) pathway. In addition, downregulation of Sulf2 reduced the expression of CXCL8-induced AT1 R and abrogated the additive effect of CXCL8 on Ang II-induced AT1 R expression in SHR VSMCs. Sulf2 mediated, partially, the expression of ET-1 and the additive expression of Ang II-induced ET-1 mRNA by CXCL8 via the AT1 R pathway in SHR VSMCs. These findings suggest that Sulf2 is an up-regulatory factor in the additive action of CXCL8 via the AT1 R pathway on Ang II-induced ET-1 expression in VSMCs under hypertension environment.

Early risk stratification for diffuse large B-cell lymphoma integrating interim Deauville score and International Prognostic Index.

The aim of this study was to evaluate the prognostic relevance of early risk stratification in diffuse large B-cell lymphoma (DLBCL) using interim Deauville score on positron emission tomography-computed tomography (PET-CT) scan and baseline International Prognostic Index (IPI). This retrospective study included 220 patients (median age, 64 years; men, 60%) diagnosed with DLBCL between 2007 and 2016 at our institution, treated with rituximab-based chemotherapy. Interim PET-CT was performed after three cycles of immuno-chemotherapy. Interim Deauville score was assessed as 4 or 5 in 49 patients (22.3%), and 94 patients (42.7%) had high-intermediate or high-risk IPI scores. In multivariate analysis, interim Deauville score (1-3 and 4-5) and baseline IPI (low/low-intermediate and high-intermediate/high) were independently associated with progression-free survival (for Deauville score, hazard ratio [HR], 1.00 vs. 2.96 [95% confidence interval (CI), 1.83-4.78], P < 0.001; for IPI, HR, 1.00 vs. 4.84 [95% CI, 2.84-8.24], P < 0.001). We stratified patients into three groups: low-risk (interim Deauville scores 1-3 and low/low-intermediate IPI), intermediate-risk (Deauville scores 1-3 with high-intermediate/high IPI or Deauville scores 4-5 with low/low-intermediate IPI), and high-risk (Deauville scores 4-5 and high-intermediate/high IPI). This early risk stratification showed a strong association with progression-free survival (HR, 1.00 vs. 3.98 [95% CI 2.10-7.54] vs. 13.97 [95% CI 7.02-27.83], P < 0.001). Early risk stratification using interim Deauville score and baseline IPI predicts the risk of disease progression or death in patients with DLBCL. Our results provide guidance with interim PET-driven treatment intensification strategies.

Association between dental health and obstructive coronary artery disease: an observational study.

BACKGROUND: The association between dental health and coronary artery disease (CAD) remains a topic of debate. This study aimed to investigate the association between dental health and obstructive CAD using multiple dental indices. METHODS: Eighty-eight patients (mean age: 65 years, 86% male) were prospectively enrolled before undergoing coronary CT angiography (n = 52) or invasive coronary angiography (n = 36). Obstructive CAD was defined as luminal stenosis of ≥50% for the left main coronary artery or ≥ 70% for the other epicardial coronary arteries. All patients underwent thorough dental examinations to evaluate 7 dental health indices, including the sum of decayed and filled teeth, the ratio of no restoration, the community periodontal index of treatment needs, clinical attachment loss, the total dental index, the panoramic topography index, and number of lost teeth. RESULTS: Forty patients (45.4%) had obstructive CAD. Among the 7 dental health indices, only the number of lost teeth was significantly associated with obstructive CAD, with patients who had obstructive CAD having significantly more lost teeth than patients without obstructive CAD (13.08 ± 10.4 vs. 5.44 ± 5.74, p < 0.001). The number of lost teeth was correlated with the number of obstructed coronary arteries (p < 0.001). Multiple binary logistic regression analysis revealed that having ≥10 lost teeth was independently associated with the presence of obstructive CAD (odds ratio: 8.02, 95% confidence interval: 1.80-35.64; p = 0.006). CONCLUSIONS: Tooth loss was associated with the presence of obstructive CAD in patients undergoing coronary evaluation. Larger longitudinal studies are needed to determine whether there is a causal relationship between tooth loss and CAD.

Learning to Detect Cracks on Damaged Concrete Surfaces Using Two-Branched Convolutional Neural Network.

Image sensors are widely used for detecting cracks on concrete surfaces to help proactive and timely management of concrete structures. However, it is a challenging task to reliably detect cracks on damaged surfaces in the real world due to noise and undesired artifacts. In this paper, we propose an autonomous crack detection algorithm based on convolutional neural network (CNN) to solve the problem. To this aim, the proposed algorithm uses a two-branched CNN architecture, consisting of sub-networks named a crack-component-aware (CCA) network and a crack-region-aware (CRA) network. The CCA network is to learn gradient component regarding cracks, and the CRA network is to learn a region-of-interest by distinguishing critical cracks and noise such as scratches. Specifically, the two sub-networks are built on convolution-deconvolution CNN architectures, but also they are comprised of different functional components to achieve their own goals efficiently. The two sub-networks are trained in an end-to-end to jointly optimize parameters and produce the final output of localizing important cracks. Various crack image samples and learning methods are used for efficiently training the proposed network. In the experimental results, the proposed algorithm provides better performance in the crack detection than the conventional algorithms.