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IL-10+ regulatory B (Breg) cells play a vital role in regulating the immune responses in experimental autoimmune encephalomyelitis, colitis, and contact hypersensitivity (CHS). Several stimulants such as lipopolysaccharide (LPS), CD40 ligand, and IL-21 spur the activation and maturation of IL-10+ Breg cells, while the epigenetic mechanism for the IL-10 expression remains largely unknown. It is well accepted that the histone acetylation/ deacetylation is an important mechanism that regulates the expression of IL-10. We found that entinostat, an HDAC inhibitor, stimulated the induction of IL-10+ Breg cells by LPS in vitro and the formation of IL-10+ Breg cells to suppress CHS in vivo. We further demonstrated that entinostat inhibited HDAC1 from binding to the proximal region of the IL-10 expression promoter in splenic B cells, followed by an increase in the binding of NF-κB p65, eventually enhancing the expression of IL-10 in Breg cells. [BMB Reports 2021; 54(10): 534-539].

Idiopathic intracranial hypertension (IIH) is a syndrome defined by elevated intracranial pressure without any abnormal findings. In the present study, we report a rare case of IIH in a patient after ventriculoperitoneal shunt (VPS) due to infant hydrocephalus. A 13-year-old girl with a history of VPS due to infant hydrocephalus was admitted to emergency room with the complaint of severe headache and visual disturbance. Brain computed tomography showed normal findings. However, based on the measurement by lumbar puncture, her cerebrospinal fluid (CSF) pressure was observed to be very high. The shunt function test revealed a VPS malfunction. Thus, we conducted VPS revision in this patient. All symptoms improved immediately after the revision. Thus, it is proposed that IIH should be considered for patients with visual disturbance and severe headache after VPS due to infant hydrocephalus without ventriculomegaly.

DNAJB9, a member of the heat shock protein 40 family, acts as a multifunctional player involved in the maintenance of their client proteins and cellular homeostasis. However, the mechanistic action of DNAJB9 in human malignancies is yet to be fully understood. In this study, we found that ectopic restoration of DNAJB9 inhibits the migration, invasion, in vivo metastasis, and lung colonization of triple-negative breast cancer (TNBC) cells. Mechanistically, DNAJB9 stabilizes FBXO45 protein by suppressing self-ubiquitination and reduces the abundance of ZEB1 by Lys48-linked polyubiquitination to inhibit the epithelial–mesenchymal transition (EMT) and metastasis. Clinically, the reduction of DNAJB9 expression, concomitant with decreased FBXO45 abundance in breast cancer tissues, correlates with poorer clinical outcomes of patients with breast cancer. Taken together, our results provide a novel insight into the metastasis of TNBC and define a promising therapeutic strategy for cancers with overactive ZEB1 by regulating the DNAJB9–FBXO45 signaling axis.

Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. In vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC50, ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED50, ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

Purpose Multiple independent spike foci (MISF) have been reported to be associated with hypsarrhythmia and slow spikes and waves. However, some patients with MISF demonstrate a good prognosis, such as benign focal epilepsy. This study aimed to elucidate the prognosis of epileptic children with MISF and to analyze the prognostic factors. Methods The subjects were 115 epileptic children aged 1 to 18 years who visited Pusan National University Children’s Hospital between November 2008 and July 2016 and in whom MISF were noted on electroencephalography. We excluded patients with infantile spasms, congenital metabolic diseases, neurodegenerative diseases, or post-encephalitic epilepsy. We retrospectively reviewed participants’ clinical information. Seizure control was defined as no seizures over 6 months at the last visit. Prognostic factors were analyzed in the seizure control (group A; 84 [73%]) and no seizure control (group B; 31 [27%]) groups. Results Generalized seizure (P=0.033), intellectual disability (P

Background Hemorrhage is the leading cause of maternal mortality worldwide and accounts for 56% of maternal deaths in Afghanistan. Postpartum hemorrhage (PPH) is commonly caused by uterine atony, genital tract trauma, retained placenta, and coagulation disorders. The purpose of this study is to examine the quality of prevention, detection and management of PPH in both public and private hospitals in Afghanistan in 2016, and compare the quality of care in district hospitals with care in provincial, regional, and specialty hospitals. Methods This study uses a subset of data from the 2016 Afghanistan National Maternal and Newborn Health Quality of Care Assessment. It covers a census of all accessible public hospitals, including 40 district hospitals, 27 provincial hospitals, five regional hospitals, and five specialty hospitals, as well as 10 purposively selected private hospitals. Results All public and private hospitals reported 24 h/7 days a week service provision. Oxytocin was available in 90.0% of district hospitals, 89.2% of provincial, regional and specialty hospitals and all 10 private hospitals; misoprostol was available in 52.5% of district hospitals, 56.8% of provincial, regional and specialty hospitals and in all 10 private hospitals. For prevention of PPH, 73.3% women in district hospitals, 71.2% women at provincial, regional and specialty hospitals and 72.7% women at private hospital received uterotonics. Placenta and membranes were checked for completeness in almost half of women in all hospitals. Manual removal of placenta was performed in 97.8% women with retained placenta. Monitoring blood loss during the immediate postpartum period was performed in 48.4% of women in district hospitals, 36.9% of women in provincial, regional and specialty hospitals, and 43.3% in private hospitals. The most commonly observed cause of PPH was retained placenta followed by genital tract trauma and uterine atony. Conclusion Gaps in performance of skilled birth attendants are substantial across public and private hospitals. Improving and retaining skills of health workers through on-site, continuous capacity development approaches and encouraging a culture of audit, learning and quality improvement may address clinical gaps and improve quality of PPH prevention, detection and management.

Colorectal cancer (CRC) is one of the most malignant type of cancers and its incidence is steadily increasing, due to life style factors that include western diet. Abnormal activation of canonical Wnt/β-catenin signaling pathway plays an important role in colorectal carcinogenesis. Therefore, targeting Wnt/β-catenin signaling has been considered a crucial strategy in the discovery of small molecules for CRC. In the present study, we found that Nodosin, an ent-kaurene diterpenoid isolated from Isodon serra, effectively inhibits the proliferation of human colon cancer HCT116 cells. Mechanistically, Nodosin effectively inhibited the overactivated transcriptional activity of β-catenin/T-cell factor (TCF) determined by Wnt/β-catenin reporter gene assay in HEK293 and HCT116 cells. The expression of Wnt/β-catenin target genes such as Axin2, cyclin D1, and survivin were also suppressed by Nodosin in HCT116 cells. Further study revealed that a longer exposure of Nodosin induced the G2/M phase cell cycle arrest and subsequently apoptosis in HCT116 cells. These findings suggest that the anti-proliferative activity of Nodosin in colorectal cancer cells might in part be associated with the regulation of Wnt/β-catenin signaling pathway.

Familial hypophosphatemic rickets (FHR) is a disorder characterized by phosphate wasting and hypophosphatemia due to defects in renal phosphate transport regulation. There are 4 known inherited forms of FHR that differ in their molecular causes. Very few studies have been conducted that focused on the molecular analysis of FHR in Koreans. Eighteen mutations of the PHEX gene have been identified to this date in Korea. Herein, we report the clinical case of a 24-month-old boy presenting with bowed legs and short stature. The biochemical profile showed hypophosphatemia with decreased tubular reabsorption of phosphate. Several family members were identified with short stature and genu varum. Therefore, he was diagnosed with FHR. To identify the molecular causes of FHR, we performed targeted gene panel sequencing and found a novel hemizygous missense variant, c.1949T>C (p.Leu650Pro), in the PHEX gene. This variant was also detected in the boy’s mother who exhibited genu varum and short stature.

Purpose: The purpose of this study was to identify the factors relating to commitment to a plan for exercise in the breast cancer patient following a mastectomy and to examine the relationship between these factors.Methods: This study was a correlational research and the participants were 152 patients with breast cancer. Data were collected using a structured questionnaire from June to October, 2015.Results: The final regression model showed that income, experience of exercise and current exercise were significant predictors related to commitment to a plan for exercise in patients with breast cancer and explained for 65.9% of the variance in commitment to a plan for exercise.Conclusion: The findings indicate that patients in breast cancer-oriented intervention programs have an enhancing experience of exercise. Current exercise should be provided for patients with breast cancer in order to promote health and quality of life.

Purpose Guillain-Barré syndrome (GBS) is a group of clinical syndromes involving acute polyneuropathy secondary to an immune-mediated process. Although affected children generally tend to have a good prognosis, a small subset of children experience residual symptoms that require lengthy and costly rehabilitation. Therefore, we aimed to describe the clinical findings of children with GBS and to investigate factors associated with their outcomes. Methods A retrospective study was conducted of previously healthy children ≤18 years of age diagnosed with GBS and admitted to Pusan National Children’s Hospital between 2009 and 2018. Results Of the 38 patients included in the study (23 boys [60.5%]; median age, 4.3 years [interquartile range, 2.8 to 9.7 years]), 28 (73.7%) fully recovered without any residual symptoms, while 10 (26.3%) had residual symptoms more than 6 months after the onset of GBS. The presence of autonomic dysfunction and a ≥50% decrease in compound muscle action potential (CMAP) amplitude from the lower limit of normal were associated with functional deficits at 6 months. Age, sex, type of antecedent illness, cranial nerve involvement, the need for mechanical ventilation, and the subtype of GBS were not significantly associated with functional outcomes. Post-gadolinium enhancement of nerve roots was seen in 71.1% of patients on initial spine magnetic resonance imaging (MRI). Conclusion Contrast enhancement of nerve roots on MRI was the most helpful initial finding for diagnosing GBS. The presence of autonomic dysfunction and a ≥50% decrease in CMAP from the lower limit of normal were poor prognostic factors for functional outcomes.

Purpose Recognition of cardiogenic syncope caused by acute myocarditis masquerading as febrile seizures (FS) in children can be difficult in the emergency department (ED) before a cardiac work-up. We aimed to identify clinical and laboratory characteristics of children with seizure-like activity and fever caused by myocarditis that would enable their condition to be distinguished from benign FS. Methods We identified seven children who visited the ED for paroxysmal seizure-like activity with fever and were diagnosed with acute myocarditis between 2012 and 2015, as well as 204 children who were diagnosed with benign FS during the same period. A detailed retrospective review of the medical charts of both groups was conducted. Results Age at onset of seizure-like activity was much higher in the myocarditis group than in the FS group (4.4±1.9 years vs. 2.4±1.1 years, P=0.033). Body temperature at seizure-like activity onset was significantly lower in the myocarditis group than in the FS group (37.9°C±0.2°C vs. 38.7°C±0.6°C, P

Most maternal and perinatal deaths could be prevented through timely access to skilled birth attendants. Women should access appropriate obstetric care during pregnancy, labor, and puerperium. Maternity waiting homes (MWHs) permit access to emergency obstetric care when labor starts. This study compared maternal and perinatal outcomes among MWH users and non-users through a retrospective cohort study. Data were collected through obstetric chart reviews and analyzed using STATA version 15. Of the 8144 deliveries reported between 2015 and 2019, 1305 women had high-risk pregnancies and were included in the study. MWH users had more spontaneous vaginal deliveries compared to non-users (38.6% versus 16.8%) and less cesarean sections (57.7% versus 76.7%). Maternal morbidities such as postpartum hemorrhage occurred less frequently among users than non-users (2.13% versus 5.64%). Four women died among non-users while there was no death among users. Non-users had more stillbirths than users (7.68% versus 0.91%). The MWH may have contributed to the observed differences in outcomes. However, many women with high risk pregnancies did not use the MWH, indicating a probable gap in awareness, usefulness, or their inability to stay due to other responsibilities at home. Use of MWHs at scale could improve maternal and perinatal outcomes in Rwanda.

This study aimed to investigate factors affecting blood glucose control among middle-aged and older diabetic patients taking medications or receiving insulin therapy. In 2015–2017 data obtained from the Korean National Health and Nutrition Examination Survey (KNHANES), 1257 patients with diabetes were divided into a controlled group and an uncontrolled group based on blood glucose levels (cutoff ≥126 mg/dL). After adjusting for confounding factors, the BMI, total cholesterol level, and triglycerides level of the uncontrolled group were significantly higher than the controlled group. The total amount of moderate-intensity activity in controlled patients was significantly higher than that of the controlled group. Total energy, fat, saturated fatty acids, and cholesterol intakes were found to be significantly higher in the uncontrolled than controlled group. Intakes of calcium, phosphorus, potassium, riboflavin, niacin, and vitamin C were significantly lower in the uncontrolled than controlled group. Adequate nutrition intake and physical activity of patients undergoing diabetes therapy are required for effective blood glucose management for both diabetic drug and insulin therapies.

Cold‑inducible RNA‑binding protein (CIRBP) is a cold‑shock protein comprised of an RNA‑binding motif that is induced by several stressors, such as cold shock, UV radiation, nutrient deprivation, reactive oxygen species and hypoxia. CIRBP can modulate post‑transcriptional regulation of target mRNA, which is required to control DNA repair, circadian rhythms, cell growth, telomere integrity and cardiac physiology. In addition, the crucial function of CIRBP in various human diseases, including cancers and inflammatory disease, has been reported. Although CIRBP is primarily considered to be an oncogene, it may also serve a role in tumor suppression. In the present study, the controversial roles of CIRBP in various human cancers is summarized, with a focus on the interconnectivity between CIRBP and its target mRNAs involved in tumorigenesis. CIRBP may represent an important prognostic marker and therapeutic target for cancer therapy.

Radioresistance poses a major challenge in the treatment of advanced rectal cancer. Therefore, understanding the detailed mechanisms of radioresistance may improve patient response to irradiation and the survival rate. To identify the novel targets that modulate the radiosensitivity of rectal cancer, we performed small RNA sequencing with human rectal cancer cell lines. Through bioinformatics analysis, we selected microRNA-310a (miR-130a) as a promising candidate to elucidate radioresistance. miR-130a was dramatically upregulated in radiosensitive rectal cancer cells and overexpression of miR-130a promotes rectal cancer cell radiosensitivity. Mechanically, miR-130a reversed the epithelial-mesenchymal transition phenotype of rectal cancer cells following inhibition of cell invasion upon irradiation. Moreover, miR-130a also inhibited the repair of irradiation-induced DNA damage followed by cell death. We identified that SOX4 was a direct target of miR-130a. Overexpression of SOX4 reversed the promotion activity of miR-130a on radiosensitivity. Together, our findings suggest that miR-130a functions as a radiosensitizer in rectal cancer and reveals a potential therapeutic target and preoperative prognostic marker for radiotherapy.

This study aimed to investigate cardiac electrical and autonomic function, the longitudinal changes, and the associated risk factors in children with Dravet syndrome (DS).Twenty-four children with DS (11 boys, 13 girls; mean age, 7.2 ± 2.9 years) and 21 control subjects (9 boys, 12 girls; mean age, 8.2 ± 3.0 years) were enrolled in this study. P dispersion, QTc and QTc dispersion, and heart rate variability (HRV) were evaluated using standard electrocardiography and 24-hr Holter monitoring at the initial and follow-up study of the 6-12 months intervals.The DS group had significantly higher P dispersion (p = 0.017), QT and QTc dispersion values (p 0.001 for two parameters) than the control group. Most HRV parameters, such as SDNN (p 0.001), SDANN5 (p 0.001), SDANN-index (p = 0.001), and RMSSD (p = 0.006) were all significantly lower in the DS group than in the control group. The mean values of initial QTc, QTc dispersion, and HRV parameters showed significantly increase (QTc and QTc dispersion) and decrease (HRV) in the follow-up study (mean duration: 1.2 ± 0.5 years) in 13 DS children. ± On multivariate regression analysis, epilepsy duration had an independently significant effect for the longitudinal change of QTc, QTc dispersion, and HRV.DS children had significant different values of cardiac electrical and autonomic function compared with control group. Particularly, longer duration of epilepsy was significantly negative effect on the longitudinal change of cardiac autonomic function.

PURPOSE: This study examined the effects of observing a self-video or a video of another person performing balance and gait training, followed by actual performance of the observed movements on the balance and walking ability of chronic stroke patients. METHODS: Thirty patients, who had experienced a stroke and were admitted to S rehabilitation hospital for treatment, were selected randomly and divided into three groups with 10 patients each: self-action observation (SAO) group, other-action observation (OAO) group, and treadmill walking training (TWT) group. The training program was conducted five times per week for four weeks. The GAITRite system, 10 m walking test, and timed up and go test were performed to measure the subjects’ gait and balance ability. RESULTS: The velocity, cadence, double support, and stride length were increased significantly in the SAO and OAO groups (p .05). The 10MWT decreased significantly in the OAO group (p .05). The TUG decreased significantly in the SAO and OAO groups (p .05). CONCLUSION: The self or other action observation training helps improve the balance and gait ability.

Hepatic fibrosis, characterized by persistent deposition of extracellular matrix (ECM) proteins, occurs in most types of chronic liver disease. The prevention of liver damage using extract of Dendropanax morbifera has been widely studied, but its molecular mechanism on the therapeutic efficacy of hepatic fibrosis is unclear. The aim of this study was to assess whether aquatic extract (DM) of D. morbifera ameliorates thioacetamide (TAA)-induced hepatic fibrosis. Hepatic fibrosis was induced by an intraperitoneal (i.p.) injection (150 mg/kg, twice per week) of TAA for 6 weeks. DM (50 mg/kg/day) or silymarin (50 mg/kg/day) was administered daily for 6 weeks. DM markedly reduced serum AST, ALT, ALP, and r-GTP in TAA-treated rats. DM significantly ameliorated the total glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activity in TAA-treated rats. In particular, DM significantly reduced expression of α-SMA, type I collagen, vimentin, TGF-β1 and p-Smad2/3 in hepatic fibrosis rats. The protective effects of DM on progression of hepatic fibrosis were clearly shown by detecting 4-hydroxyproline concentration and histopathological examination in the liver. Therefore, our data suggest that DM dramatically prevented hepatic fibrosis by inhibiting oxidative stress and the TGF-β1/Smads signaling pathways.

Guillain-Barré syndrome (GBS) and acute disseminated encephalomyelitis (ADEM) are demyelinating neurologic disorders with different target organs. Although they share similar pathogenetic mechanism, reports of simultaneous occurrence of the 2 disorders are rare. A 2 year 6 month old girl visited our hospital for fever, cough, and general weakness. Although the muscle power of extremities showed mild weakness and voiding difficulty, initial deep tendon reflex of both knees and ankles was normal. A nerve conduction study to evaluate the weakness revealed the absence of F waves. Cerebrospinal fluid analysis demonstrated pleocytosis with lymphocyte predominance and elevated protein levels. Magnetic resonance imaging showed abnormal T2 hyperintensity in pons, medulla and spinal cord. Serum anti-GD1b antibody was positive. Based on clinical findings, laboratory findings, nerve conduction study, and neuroimaging, the diagnosis of GBS and ADEM was made. This is the first case of GBS accompanied by ADEM in Korea.

뇌전증 환자에서 자기공명영상은 기질적인 병변을 확인하기 위해 권장된다. 그러나 청소년기 결신 발작을 포함한 특발성 전신 발작에서 이상소견은 대개 자기공명영상과 같은 뇌 영상 기법을 사용하여 확인할 수 없다. 발작기 동안 자기공명영상 이상은 뇌전증 지속증에 의한 이차성으로 가장 흔히 보고되었으며, 부분발작과 전신 강직간대 발작환자에서 거의 나타나지 않는다....

Purpose: This study was to examine the effects of treadmill gait training at different controlled inclinations on the standing balance of hemiplegic patients caused by cerebrovascular injury. Methods: The study’s subjects were 44 patients with chronic stroke, randomly divided into three experimental groups: 0° treadmill gait training (n=14), 5° treadmill gait training (n=15), and 10° treadmill gait training (n=15). In addition to conventional physical therapy, the subjects underwent gait training on a treadmill with one of three different inclinations for 30 min per session five times per week for six weeks. The Biodex balance system SD, Berg balance scale, and timed up and go tests were used to measure the postural balance of the patients. Results: This study showed that gait training on a treadmill at controlled inclinations of 0°, 5°, and 10° positively influenced the stroke patients’ standing balance. The 5° and 10° inclination gait training groups showed significantly more improvement than the 0° inclination group. Conclusion: Gait training on a treadmill with inclinations of 0°, 5°, or 10° can be said to positively affect the postural balance of hemiplegic patients due to stroke. In particular, 5° and 10° inclination gait training offered more significant improvement than the 0° inclination gait training group. When added to regular treatment routines, gait training at controlled inclinations is an effective intervention for improving hemiplegia due to postural balance.

BackgroundSubmicroscopic segmental imbalances detected by array-comparative genomic hybridization (array-CGH) were discovered to be common in chronic myeloid leukemia (CML) patients with t(9;22) as the sole chromosomal anomaly. To confirm the findings of the previous study and expand the investigation, additional CML patients with t(9;22) as the sole chromosomal anomaly were recruited and copy number variants (CNVs) were searched for.MethodsKaryotyping tests were performed on 106 CML patients during January 2010–September 2019 in our Genetics Laboratory. Eighty-four (79.2%) patients had the Philadelphia (Ph) chromosome as the sole chromosomal anomaly. Only 49(58.3%) of these 84 patients had sufficient marrow or leukemia blood materials to additionally be included in the array-CGH analysis. Fluorescence in situ hybridization (FISH) was carried out to confirm the genes covered by the deleted or duplicated regions of the CNVs.Results11(22.4%) out of the 49 patients were found to have one to three somatic segmental somatic segmental (CNVs), including fourteen deletions and three duplications. The common region associated with deletions was on 9q33.3-34.12. Identified in five (45.5%) of the 11 positive patients with segmental CNVs, the deletions ranged from 106 kb to 4.1 Mb in size. Two (18.2%) cases had a deletion in the ABL1-BCR fusion gene on der (9), while three (27.3%) cases had a deletion in the ASS1 gene. The remaining CNVs were randomly distributed on different autosomes.ConclusionSubtle genomic CNVs are relatively common in CML patients without cytogenetically visible additional chromosomal aberrations (ACAs). Long-term studies investigating the potential impact on patient prognosis and treatment outcome is underway.

[Image: see text] This study evaluated the potential use of senescence-inducing small molecules in the treatment of melanoma. We screened commercially available small-molecule libraries with high-throughput screening and high-content screening image-based technology. Our findings showed an initial hit with the embedded N-arylpiperidine-3-carboxamide scaffold-induced senescence-like phenotypic changes in human melanoma A375 cells without serious cytotoxicity against normal cells. A focused library containing diversely modified analogues were constructed and examined to evaluate the structure–activity relationship of N-arylpiperidine-3-carboxamide derivatives starting from hit 1. This work identified a novel compound with remarkable antiproliferative activity in vitro and demonstrated the key structural moieties within.

The aim of the present study was to examine the protective effect of &gamma, mangostin, a component of the mangosteen shell, against oxidative damage to nerve cells induced by excessive glutamate, a known excitatory neurotransmitter. To investigate the effect of &gamma, mangostin on apoptosis, 5 mM of glutamate was used to induce apoptotic cell death in mouse hippocampal HT22 cells. In this study, &gamma, mangostin was found to exert a stronger protection than N-acetyl cysteine against glutamate-induced cell damage. &gamma, Mangostin showed prevented glutamate-induced apoptosis in HT22 cells by reducing the production of reactive oxygen species and stimulating the expression of heme oxygenase-1 protein. In addition, glutamate significantly induced the accumulation of intracellular calcium ions, whereas treatment with &gamma, mangostin markedly reduced it. Hoechst 33342 staining showed an improvement in glutamate-induced nuclear condensation following &gamma, mangostin treatment. Furthermore, the number of annexin V-positive cells was significantly reduced following treatment with &gamma, mangostin. Western blot analysis showed the inhibition of glutamate-induced mitogen-activated protein kinase phosphorylation by &gamma, mangostin. &gamma, mangostin also inhibited the regulation of the intrinsic mitochondrial apoptotic pathway. Thus, the results of this study suggest that &gamma, mangostin is an active ingredient of mangosteen and exerts neuroprotective activities in HT22 cells.

In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M. tuberculosis H37Rv. In the present study we report the structure–activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.

Aim of the study The aim of this study was to test the anti-rheumatic effects of A. jaluense tubers in acute and chronic arthritis rats, and to assign its ingredients through UPLC-TOF/MS. Materials and methods Subcutaneous injection of carrageenan for acute arthritis and complete Freund's adjuvant (CFA) for chronic arthritis was carried out in the hind paw of SD rats. The paw volume was measured by a plethysmometer; thermal hyperalgesia was tested using a thermal plantar tester, and mechanical hyperalgesia was evaluated by ankle flexion evoked vocalizations. The expression of c-Fos in the brain hippocampus was measured with the avidin-biotin-peroxidase technique. The ingredients were assigned by UPLC-TOF/MS, chromatography was performed by UHPLC system with DAD detector and BEH C18 column, and spectroscopy was conducted by ESI-MS system. Results and discussion The 80% ethanoic extract of A. jaluense tubers showed an acute anti-inflammatory effect by suppressing the edema volume in the hind paw of carrageenan-stimulated rats. In addition, A. jaluense tubers exerted an anti-rheumatic activity by reducing the secondary swelling volume from an immunological reaction in the left hind paw of CFA-induced chronic arthritis rats. Additionally, oral treatment with the 80% ethanoic extract -showed potent analgesic effects in the arthritis rats by recovering the paw withdrawal latency stimulated by the thermal hyperalgesia and by reducing the vocalization scores evoked by ankle flexion on both hind paws. Moreover, its treatment also indicated an anti-psychiatric effect by controlling the c-Fos protein expression of the brain hippocampus in CFA-stimulated arthritis rats. These results suggested that these therapeutic effects were exhibited by less toxic monoester diterpenoid alkaloids (MDAs), and nontoxic non ester diterpenoid alkaloids (NDAs). Conclusion A. jaluense tubers may act as viable therapeutic or preventive candidates for acute and chronic arthritis, particularly, for immune-inflammatory rheumatoid arthritis to suppress the pain and psychiatric condition.

Objective: The purpose of the study was performed for effects of treadmill gait training according to different inclination influenced on the pulmonary function with hemiplegic patients caused by cerebrovascular accident. Method: The subjects of the study were 44 patients with chronic stroke and randomly divided into three group which were two experimental groups (5° treadmill gait training (n=15) and 10°treadmill gait training (n=15)) and control group (treadmill flat gait training (n=14)). Three groups received different inclination (5°, 10°, flat) treadmill gait training for 30 minutes a time while 5times per week for 6week in addition to conventional physical therapy. We performed pulmonary function test. Results: The result of this study showed that treadmill gait training controlled inclination 5°, 10°, flat plane were positive influence on stroke patients’ pulmonary function. Especially, inclination 5°, 10° gait training group showed Significant improved than flat gait training group. Conclusion: Gait training controlled inclination is an effective intervention in order to improve hemiplegia due to stroke patients’ pulmonary function. It is considered to be treadmill gait training controlled appropriate inclination when in addition to treatment time.

Background Few studies have examined the effect of atopic dermatitis (AD) on the resolution of food allergies in Asia, and the predictors of egg allergy resolution are not yet well defined. Objective We evaluated whether AD severity could predict the resolution of egg allergy. Methods This retrospective cohort study included infants under 24 months of age diagnosed with IgE-mediated egg white allergy. We included subjects who completed a 60-month follow-up. Open oral food challenges (OFCs) and serologic tests were performed at the time of initial diagnosis and at 36 ± 3 and 60 ± 3 months. Results We analyzed 68 patients (39 boys and 29 girls). OFCs were performed in 88.2% of the patients. The egg allergy remission rates were 23.5% and 47.1% by 3 and by 5 years of age, respectively. Persistent egg allergy was significantly associated with moderate to severe AD and house dust mite sensitization. Kaplan-Meier curve analysis revealed that patients with moderate to severe AD had higher persistent egg allergy rates than patients with no and mild AD (p = 0.012). Multivariable analysis identified moderate to severe AD as strongly associated with persistent egg allergy (p = 0.001). Conclusions In this study, 47.1% of infants had resolved egg white allergies at 60 months. Moderate to severe AD may be a practical and important prognostic factor for persistent egg allergy in clinical settings.

The beneficial effects of light-emitting diode (LED) irradiation have been reported in various pathologies, including cancer. However, its effect in pancreatic cancer cells remains unclear. Herein, we demonstrated that blue LED of 460 nm regulated pancreatic cancer cell proliferation and apoptosis by suppressing the expression of apoptosis-related factors, such as mutant p53 and B-cell lymphoma 2 (Bcl-2), and decreasing the expression of RAC-β serine/threonine kinase 2 (AKT2), the phosphorylation of protein kinase B (AKT), and mammalian target of rapamycin (mTOR). Blue LED irradiation also increased the levels of cleaved poly-(ADP-ribose) polymerase (PARP) and caspase-3 in pancreatic cancer cells, while it suppressed AKT2 expression and inhibited tumor growth in xenograft tumor tissues. In conclusion, blue LED irradiation suppressed pancreatic cancer cell and tumor growth by regulating AKT/mTOR signaling. Our findings indicated that blue LEDs could be used as a nonpharmacological treatment for pancreatic cancer.

Maternal deaths remain a major public health concern in low- and middle-income countries. Implementation of maternal and perinatal deaths surveillance and response (MPDSR) is vital to reduce preventable deaths. The study aimed to assess implementation of MPDSR in Rwanda. We applied mixed methods following the six-step audit cycle for MPDSR to determine the level of implementation at 10 hospitals and three health centers. Results showed various stages of implementation of MPDSR across facilities. Maternal death audits were conducted regularly, and facilities had action plans to address modifiable factors. However, perinatal death audits were not formally done. Implementation was challenged by lack of enough motivated staff, heavy workload, lack of community engagement, no linkages with existing quality improvement efforts, no guidelines for review of stillbirths, incomplete medical records, poor classification of cause of death, and no sharing of feedback among others. Implementation of MPDSR varied from facility to facility indicating varying capacity gaps. There is need to integrate perinatal death audits with maternal death audits and ensure the process is part of other quality improvement initiatives at the facility level. More efforts are needed to support health facilities to improve implementation of MPDSR and contribute to achieving sustainable development goal (SDG) 3.

Purpose Bell's palsy is characterized by sudden onset of unilateral facial weakness. The use of corticosteroids for childhood Bell's palsy is controversial. This study aimed to identify clinical characteristics, etiology, and laboratory findings in childhood Bell's palsy, and to evaluate the efficacy of corticosteroid treatment. Methods We conducted a retrospective analysis of children under 19 years of age treated for Bell's palsy between January 2009 and June 2017, and followed up for over 1 month. Clinical characteristics, neuroimaging data, laboratory findings, treatments, and outcomes were reviewed. Patients with Bell's palsy were divided into groups with (group 1) and without (group 2) corticosteroid treatment. Differences in onset age, sex, laterality, infection and vaccination history, degree of facial nerve palsy, and prognosis after treatment between the groups were analyzed. Results One hundred patients were included. Mean age at presentation was 7.4±5.62 years. A total of 73 patients (73%) received corticosteroids with or without intravenous antiviral agents, and 27 (27%) received only supportive treatment. There was no significant difference in the severity, laboratory findings, or neuroimaging findings between the groups. Significant improvement was observed in 68 (93.2%) and 26 patients (96.3%) in groups 1 and 2, respectively; this rate was not significantly different between the groups (P=0.48). Conclusion Childhood Bell's palsy showed good prognosis with or without corticosteroid treatment; there was no difference in prognosis between treated and untreated groups. Steroid therapy in childhood Bell's palsy may not significantly improve outcomes.

Background Although the cause of adenotonsillar hypertrophy remains unknown, some studies have shown that allergy may be a risk factor. Purpose This study determined the levels of allergen-specific immunoglobulin E (sIgE) in the adenotonsillar tissues of children with adenotonsillar hypertrophy and evaluated the clinical significance of local atopy in adenotonsillar tissues. Methods We measured 21 types of specific immunoglobulin E in the serum and adenotonsillar tissues of 102 children with adenotonsillar hypertrophy and compared the sensitization patterns of the serum and local tissues. The patients were divided into three groups—atopy, local atopy, and nonatopy—according to the sensitization of serum and adenotonsillar tissues, and the clinical symptoms among the groups were analyzed. Results Seventy-two (70.6%) children with adenotonsillar hypertrophy were sensitized to more than one allergen in the serum and/or adenotonsillar tissue. Thirty (29.4%) children had no IgE positivity to any allergen in both serum and adenotonsillar tissues. Fifty-five (53.9%) were sensitized to at least one allergen in the serum. Seventy (68.6%) were sensitized to at least one allergen in the adenotonsillar tissue. Seventeen (36.2%) of 47 children with specific immunoglobulin E-negative serum had specific immunoglobulin E-positive adenotonsillar tissues. The rate of specific immunoglobulin E was significantly higher in local tissues than in serum. The rate of inhalant allergen specific immunoglobulin E was significantly higher in the adenoids than in the tonsils. However, the rate of food allergen specific immunoglobulin E was significantly higher in the tonsils than adenoids. The lifetime prevalence of asthma and allergic rhinitis, recent symptoms or treatment of allergic rhinitis, and severity of nasal symptoms (rhinorrhea, sneezing, and nasal itching) were significantly higher in children with local atopy than with nonatopy. Conclusions These results confirm that allergic response may be a risk factor for adenotonsillar hypertrophy. Local allergic inflammation may play an important role in childhood adenotonsillar hypertrophy, and local atopy in adenotonsillar tissues can cause respiratory allergic symptoms in children.

Background and Purpose The aim of this study is to evaluate the prevalence of hypothyroidism and the change of thyroid hormone level in the children with epilepsy on a ketogenic diet (KD). Methods The levels of serum free thyroxine (fT4) and thyroid-stimulation hormone (TSH) were measured at the start of the KD and at 6- to 12-month intervals in children with intractable epilepsy. Hypothyroidism was defined as fT4 level < 0.8 ng/dL and TSH level > 6.0 μIU/mL. Results A total of 28 children (17 boys and 11 girls) were enrolled in the study. The mean age of onset of seizure was 1.4 ± 1.6 years, the mean age of the start of the KD was 3.2 ± 2.4 years, and the mean duration of KD was 1.9 ± 1.5 years. Overall, there was no significant longitudinal change in the mean fT4 (0.99 ± 0.25 vs. 0.94 ± 0.71 ng/dL, p = 0.28) and TSH (2.94 ± 1.32 vs. 3.18 ± 1.21 μIU/mL, p = 0.44) levels from the start of the KD to last follow-up. The patients with a younger age of seizure onset, earlier initiation of KD, and higher serum levels of cholesterol and triglyceride had a significant decrease in fT4 levels and increase in TSH levels during the KD. Sex, duration of the seizure or KD therapy, seizure types, seizure frequency, seizure outcomes, brain lesion, ratio of KD, and being overweight did not affect the longitudinal change of fT4 and TSH levels during KD. Conclusion Thyroid function had no significant longitudinal decrease in pediatric epilepsy during KD therapy. However, careful monitoring of the serum levels of fT4/TSH should be recommended in children on KDs, especially in those with earlier seizure onset, earlier start of KD, and higher levels of lipid profiles.

The potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in inducing apoptosis is a hallmark in cancer therapeutics, after which its selective ability to achieve cell death pathways against cancer cells led to hope for recombinant TRAIL in cancer therapeutics. The present data from azoxymethane-initiated, dextran sulfate sodium-promoted colitis associated cancer (CAC) model strongly indicate the potential of rTRAIL in cancer prevention rather than in cancer therapeutics. Early treatment of rTRAIL significantly reduced colitis and CAC by inhibiting the recruitment of macrophages into the damaged mucosa and activating the scavenger activity with efferocytosis and the production of several growth factors. In contrast, late administration of rTRAIL as for anti-cancer effect did not decrease the initiation and development of CAC at all. Significant cancer preventing mechanisms of rTRAIL were identified. In the CAC model, anti-inflammation, regeneration, and efferocytosis was induced by treatment of TRAIL for 6 days, significant inhibitory activity was evident at 4 weeks and anti-oxidative and anti-inflammatory induction were noted at 12 weeks. Most importantly, TRAIL promoted tissue regeneration by enhancing the resolution of pathological inflammation through the activation of the NLRP3 inflammasome pathway. The results indicate that TRAIL reduces the induction of colitis and the initiation of CAC by inhibiting pro-inflammatory signaling and promoting tissue repair to maintain intestinal homeostasis through activation of the NLRP3 inflammasome. Therefore, TRAIL can be used as a chemopreventive agent against CAC, rather than as a therapeutic drug endowing apoptosis.

Volunteerism is a global phenomenon that aids multiple generations. Considering the positive evidence of volunteering among older adults and their desire for intergenerational engagement, it is important to explore older adult volunteers’ experiences in intergenerational programs with a specific focus on the cultural and social impacts of volunteering in educational settings in later years. Using a phenomenological qualitative approach, 43 interviews with older adult volunteers (23 in Korea and 20 in the USA) in intergenerational programs were conducted. Participants were recruited from the Beautiful Story Grandma (BSG) in Korea and the Foster Grandparent Program (FGP) in the USA in 2019. Due to the prescribed nature of the BSG, all of the Korean volunteers were female. The USA volunteers from the FGP included three African Americans, one Asian, and 16 White older adults. Two FGP volunteers were male. Korean participants lived primarily in Busan Metropolitan city (mean age: 63, range: 61-73). The USA volunteers were from urban/suburban areas New York State (mean age: 74, range: 60-84). Two major themes emerged from the interviews revolving around the role of culture and other demographics in the experience of volunteering: (1) Older adults experience benefits from volunteering to support the younger generation that transcend demographic and geographic differences; and, (2) distinctive cultural views of education lead to different experiences of volunteering in the two countries. The comparative research highlights the need for development of a model for culturally responsive practice with older adult volunteers in a global context.

The pharmacokinetic (PK) change in a drug by co-administered herbal products can alter the efficacy and toxicity. In the circumstances that herb–drug combinations have been increasingly attempted to alleviate Alzheimer’s disease (AD), the PK evaluation of herb–drug interaction (HDI) is necessary. The change in systemic exposure as well as target tissue distribution of the drug have been issued in HDIs. Recently, the memory-enhancing effects of water extract of mangosteen pericarp (WMP) has been reported, suggesting a potential for the combination of WMP and donepezil (DNP) for AD treatment. Thus, it was evaluated how WMP affects the PK change of donepezil, including systemic exposure and tissue distribution in mice after simultaneous oral administration of DNP with WMP. Firstly, co-treatment of WMP and donepezil showed a stronger inhibitory effect (by 23.0%) on the neurotoxicity induced by Aβ(25–35) in SH-SY5Y neuroblastoma cells than donepezil alone, suggesting that the combination of WMP and donepezil may be more effective in moderating neurotoxicity than donepezil alone. In PK interaction, WMP increased donepezil concentration in the brain at 4 h (by 63.6%) after administration without affecting systemic exposure of donepezil. Taken together, our results suggest that WMP might be used in combination with DNP as a therapy for AD.

An estimated 15–20% of patients who are treated for pulmonary tuberculosis (TB) are culture-negative at the time of diagnosis. Recent work has focused on the existence of differentially detectable Mycobacterium tuberculosis (Mtb) bacilli that do not grow under routine solid culture conditions without the addition of supplementary stimuli. We identified a cohort of TB patients in Lima, Peru, in whom acid-fast bacilli could be detected by sputum smear microscopy, but from whom Mtb could not be grown in standard solid culture media. When we attempted to re-grow Mtb from the frozen sputum samples of these patients, we found that 10 out of 15 could be grown in a glycerol-poor/lipid-rich medium. These fell into the following two groups: a subset that could be regrown in glycerol after “lipid-resuscitation”, and a group that displayed a heritable glycerol-sensitive phenotype that were unable to grow in the presence of this carbon source. Notably, all of the glycerol-sensitive strains were found to be multidrug resistant. Although whole-genome sequencing of the lipid-resuscitated strains identified 20 unique mutations compared to closely related strains, no single genetic lesion could be associated with this phenotype. In summary, we found that lipid-based media effectively fostered the growth of Mtb from a series of sputum smear-positive samples that were not culturable in glycerol-based Lowenstein–Jensen or 7H9 media, which is consistent with Mtb’s known preference for non-glycolytic sources during infection. Analysis of the recovered strains demonstrated that both genetic and non-genetic mechanisms contribute to the observed differential capturability, and suggested that this phenotype may be associated with drug resistance.

Receptor activator of NF-kB ligand (RANKL) generates intracellular reactive oxygen species (ROS), which increase RANKL-mediated signaling in osteoclast (OC) precursor bone marrow macrophages (BMMs). Here we show that a ROS scavenging protein DJ-1 negatively regulates RANKL-driven OC differentiation, also called osteoclastogenesis. DJ-1 ablation in mice leads to a decreased bone volume and an increase in OC numbers. In vitro, the activation of RANK-dependent signals is enhanced in DJ-1-deficient BMMs as compared to wild-type BMMs. DJ-1 suppresses the activation of both RANK-TRAF6 and RANK-FcRγ/Syk signaling pathways because of activation of Src homology region 2 domain-containing phosphatase-1, which is inhibited by ROS. Ablation of DJ-1 in mouse models of arthritis and RANKL-induced bone disease leads to an increase in the number of OCs, and exacerbation of bone damage. Overall, our results suggest that DJ-1 plays a role in bone homeostasis in normal physiology and in bone-associated pathology by negatively regulating osteoclastogenesis., Osteoclasts are involved in arthritis, and their differentiation depends on RANKL signaling. The author show that the ROS-scavenging protein DJ-1 negatively regulates RANKL signaling and that its ablation increases osteoclast numbers and exacerbates bone damage in mouse models of arthritis.

Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4μ8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4μ8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4μ8C suppressed the degranulation of IgE-mediated mast cells (IC50=3.2μM) and the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in a dose-dependent manner. 4μ8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50=25.1mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4μ8C, and phosphorylation of downstream signaling molecules, such as linker for activated T cells (LAT), Akt, and the three MAP kinases, ERK, p38, and JNK, were suppressed. Mechanistic studies showed that 4μ8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4μ8C involved reduced activity of Lyn and Fyn, which is pivotal in an IgE-mediated signaling pathway. In summary, for the first time, this study shows that 4μ8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4μ8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis.

GPR119 belongs to the G protein-coupled receptor family and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycaemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.