Despite the various medications used in clinics, the efforts to develop more effective treatments for depression continue to increase in the past decades mainly because of the treatment-resistant population, and the testing of several hypotheses- and target-based treatments. Undesirable side effects and unresponsiveness to current medications fuel the drive to solve this top global health problem. In this study, we focused on neuroinflammatory response-mediated depression which represents a cluster of depression etiology both in animal models and humans. Several meta-analyses reported that proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were increased in major depressive disorder patients. Inflammatory mediators implicated in depression include type-I interferon and inflammasome pathways. To elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression, we introduced hycanthone, an antischistosomal drug, to check whether it can counteract depressive-like behaviors in vivo and normalize the inflammation-induced changes in vitro. Lipopolysaccharide (LPS) treatment increased proinflammatory cytokine expression in the murine microglial cells as well as the stimulation of type I interferon-related pathways that are directly or indirectly regulated by Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. Hycanthone treatment attenuated those changes possibly by inhibiting the JAK-STAT pathway and inflammasome activation. Hycanthone also ameliorated depressive-like behaviors by LPS. Taken together, we suggest that the inhibitory action of hycanthone against the interferon pathway leading to attenuation of depressive-like behaviors can be a novel therapeutic mechanism for treating depression.

Autism spectrum disorder (ASD) having core characteristics of social interaction problems and repetitive behaviors and interests affects individuals at varying degrees and comorbidities, making it difficult to determine the precise etiology underlying the symptoms. Given its heterogeneity, ASD is difficult to treat and the development of therapeutics is slow due to the scarcity of animal models that are easy to produce and screen with. Based on the theory of excitation/inhibition imbalance in the brain with ASD which involves glutamatergic and/or GABAergic neurotransmission, a pharmacologic agent to modulate these receptors might be a good starting point for modeling. N-methyl-D-aspartic acid (NMDA) is an amino acid derivative acting as a specific agonist at the NMDA receptor and therefore imitates the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA selectively binds to and regulates the NMDA receptor, but not other glutamate receptors such as AMPA and kainite receptors. Given this role, we aimed to determine whether NMDA administration could result in autistic-like behavior in adolescent mice. Both male and female mice were treated with saline or NMDA (50 and 75 mg/kg) and were tested on various behavior experiments. Interestingly, acute NMDA-treated mice showed social deficits and repetitive behavior similar to ASD phenotypes. These results support the excitation/inhibition imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model of ASD-like behaviors.

Neurodevelopmental disorders are complex conditions that pose difficulty in the modulation of proper motor, sensory and cognitive function due to dysregulated neuronal development. Previous studies have reported that an imbalance in the excitation/ inhibition (E/I) in the brain regulated by glutamatergic and/or GABAergic neurotransmission can cause neurodevelopmental and neuropsychiatric behavioral deficits such as autism spectrum disorder (ASD). NMDA acts as an agonist at the NMDA receptor and imitates the action of the glutamate on that receptor. NMDA however, unlike glutamate, only binds to and regulates the NMDA receptor subtypes and not the other glutamate receptors. This study seeks to determine whether NMDA administration in mice i.e., over-activation of the NMDA system would result in long-lasting behavioral deficits in the adolescent mice. Both gender mice were treated with NMDA or saline at early postnatal developmental period with significant synaptogenesis and synaptic maturation. On postnatal day 28, various behavioral experiments were conducted to assess and identify behavioral characteristics. NMDAtreated mice show social deficits, and repetitive behavior in both gender mice at adolescent periods. However, only the male mice but not female mice showed increased locomotor activity. This study implies that neonatal exposure to NMDA may illicit behavioral features similar to ASD. This study also confirms the validity of the E/I imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model for ASD. Future studies may explore the mechanism behind the gender difference in locomotor activity as well as the human relevance and therapeutic significance of the present findings.

OBJECTIVE: Ubiquitin-specific peptidase 46 gene (USP46) polymorphisms is part of ubiquitin-proteasome system, which is responsible for dynamic cellular processes such as the regulation of cell cycle. USP46 has been reported to be associated with major depressive disorder. The objective of the present study was to investigate the association of USP46 polymorphisms with affective temperamental traits in healthy subjects. METHODS: A total of 557 Korean healthy volunteers were recruited, and 545 subjects (328 male, 217 female) were included in the final analysis. The DNA of the subjects was isolated from saliva samples. Two single-nucleotide polymorphisms (SNPs) rs346005, rs2244291 in USP46 were genotyped. Affective temperaments were assessed using the Korean version of Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). RESULTS: A significant association was found between rs346005 genotypes and TEMPS-A only in male subjects. In particular, subjects with the CC genotype of rs346005 showed a more depressive temperament than subjects with AA or CA genotypes in males. For rs2244291, there were no associations between the rs2244291 genotypes and TEMPS-A scores. CONCLUSION: Some affective temperaments may serve as a genetic predisposing factors for affective disorders, such as depressive disorder, via vulnerability genes related to the ubiquitin-proteasome system.
Causality ; Cell Cycle ; Depressive Disorder ; Depressive Disorder, Major ; DNA ; Genetic Association Studies ; Genotype ; Healthy Volunteers ; Humans ; Male ; Mood Disorders ; Saliva ; Temperament ; Volunteers

BACKGROUND/AIMS: This study was conducted to clarify the sustained virological response (SVR) prediction ability of baseline and treatment-related factors in patients with chronic hepatitis C virus (HCV) infection. METHODS: This retrospective study collected data at four tertiary referral hospitals between June 2004 and July 2012. Out of 476 patients, 330 treatment-naïve patients with chronic HCV infection were recruited. Pegylated interferon α-2a/-2b plus ribavirin was administered for either 24 or 48 weeks depending on the HCV genotype. The baseline and treatment-related predictive factors of SVR were evaluated by analyzing data measured before treatment (i.e., baseline) and during treatment. RESULTS: SVR rates for genotypes 1 and 2 were 63% (97/154) and 79.5% (140/176), respectively (p = 0.001). Multivariate analysis for baseline factors revealed that young age (p = 0.009), genotype 2 (p = 0.001), HCV RNA level of < 800,000 IU/mL (p < 0.001), and a baseline platelet count of > 150 × 10³/µL (p < 0.001) were significant SVR predictors, regardless of the genotype. In particular, predictive accuracy for achievement of SVR was 87.3% for a baseline platelet count of > 150 × 10³/µL. In multivariate analysis for treatment-related factors, SVR was associated with achievement of a rapid virological response (RVR; p < 0.001), treatment adherence of ≥ 80/80/80 (p < 0.001). CONCLUSIONS Young age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. In addition, platelet count was an independent predictive factor for SVR. Therefore, platelet count could be used to develop individualized treatment regimens and to optimize treatment outcomes in patients with chronic HCV infection.

BACKGROUND/AIMS: The aim of this study was to investigate parameters that predict radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to identify the clinical significance of RILD. METHODS: We retrospectively reviewed the medical records of 117 HCC patients who were treated by SBRT from March 2011 to February 2015. RILD was defined as elevated liver transaminases more than five times the upper normal limit or a worsening of Child-Pugh (CP) score by 2 within 3 months after SBRT. All patients were assessed at 1 month and every 3 months after SBRT. RESULTS: Median follow-up was 22.5 months (range, 3 to 56) after SBRT. RILD was developed in 29 of the 117 patients (24.7%). On univariate analysis, significant predictive factors of RILD were pretreatment CP score (p < 0.001) and normal liver volume (p = 0.002). Multivariate analysis showed that CP score was a significant predictor of RILD (p < 0.001). The incidence of RILD increased above a CP score of 6 remarkably. The rate of recovery from RILD decreased significantly above a CP score of 8. Survival analysis showed that CP score was an independent prognostic factor of overall survival (p = 0.001). CONCLUSIONS: CP score is a significant factor to predict RILD in patients with chronic liver disease. RILD can be tolerated by patients with a CP score ≤ 7. However, careful monitoring of liver function is needed for patients with a CP score 7 after SBRT.
Carcinoma, Hepatocellular* ; Follow-Up Studies ; Humans ; Incidence ; Liver Diseases* ; Liver* ; Medical Records ; Multivariate Analysis ; Radiosurgery ; Retrospective Studies ; Transaminases

BACKGROUND AND OBJECTIVES: The present study evaluated the results of skin prick test using 55 allergens at 20 centers in the Republic of Korea in 2006, 2010, and 2014–2015. The aim was to assess changes in the positive rate of allergens according to temporal, regional, and environmental factors. MATERIALS AND METHODS: In total, 20 hospitals were selected based on the population distribution in the Republic of Korea. A skin prick test panel comprising 55 aeroallergens was distributed to 18 hospitals for this prospective study. The 2006 and 2010 skin prick test results were collected and analyzed retrospectively from 20 hospitals, while the 2014/2015 skin prick test results (from June 2014 to May 2015) were collected prospectively from 18 hospitals. RESULTS: A total of 14,897 SPT test results were analyzed: 4,319 in 2006, 7,431 in 2010, and 1,852 in 2014/2015. The overall rate of skin prick test positivity to more than two allergens was significantly higher in males than females. The positive rates of alder pollens and birch, oak and ragweed pollen positivity were increased in older patients. Several positive rates were increased according to the temperature in spring. The positive rates for beech pollen, birch pollen, hazel pollen, oak pollen, Tyrophagus putrescentiae, mugwort, cat, Acarus siro, Lepidoglyphus destructor and Tyrophagus putrescentiae were significantly increased, while those of Cult rye pollen and dandelion were significantly decreased over the three test periods. The overall positive rate for allergens in Jeju province varied significantly from Seoul and other cities. CONCLUSION: Change in the positive rate of multiple aeroallergens was evaluated in the Republic of Korea over time. Our findings can be used to recommend aeroallergens suitable for inclusion in skin prick test panels in the Republic of Korea and will facilitate further investigation of changes in the patterns of allergic diseases.
Allergens* ; Alnus ; Ambrosia ; Animals ; Artemisia ; Betula ; Cats ; Demography ; Fagus ; Female ; Humans ; Korea* ; Male ; Mites ; Pollen ; Prospective Studies ; Republic of Korea ; Retrospective Studies ; Secale ; Seoul ; Skin* ; Taraxacum

No abstract available.

Hepatocellular carcinoma (HCC) is well known malignancy with poor prognosis, even after resection of the primary tumor. Sorafenib is the first-line treatment in advanced HCC, but the disease control rate of sorafenib is only 43%. Pulmonary metastasectomy in patients with pulmonary metastasis from HCC has been reported to increase long-term survival compared with systemic chemotherapy. Video-assisted thoracic surgery is considered a reliable approach to the diagnosis and treatment of pulmonary diseases with low complication rate. Pulmonary metastasectomy is not universally accepted because of frequent local recurrence, an uncontrollable primary tumor, and frequent multiple pulmonary metastases in HCC, but outcome of pulmonary metastasectomy and adjuvant sorafenib therapy has not been studied. We experienced a patient who had advanced HCC with pulmonary oligometastasis and received surgical resection of the metastatic pulmonary nodule and sorafenib chemotherapy. In advanced HCC with pulmonary oligometastasis, surgical resection of pulmonary metastasis and sorafenib chemotherapy should be considered.
Carcinoma, Hepatocellular* ; Diagnosis ; Drug Therapy ; Humans ; Lung Diseases ; Metastasectomy ; Neoplasm Metastasis* ; Prognosis ; Recurrence ; Thoracic Surgery, Video-Assisted

BACKGROUND/AIMS: The optimal timing for discontinuing oral antiviral therapy in patients with HBeAg-positive chronic hepatitis B (CHB) is unclear. The aim of our study was to investigate sustained remission after stopping antiviral therapy in patients with HBeAg-positive CHB. METHODS: We analyzed the medical records of 58 patients who were HBeAg-positive and had discontinued antiviral therapy. Antiviral therapy was discontinued after HBeAg seroconversion and HBV DNA negativity for 6-12 months with consolidation therapy. Virologic relapse was defined as an increase in serum HBV DNA >2,000 IU/mL. RESULTS: No difference was observed between the virologic non-relapse and virologic relapse groups in baseline HBV DNA level (p=0.441) or duration of seroconversion (p=0.070). Time-to-undetectable HBV DNA during treatment was shorter in the virologic non-relapse group (29 patients) compared to the relapse group (29 patients) (4.9+/-2.6 vs. 13.2+/-12.7 months; p<0.01). Cumulative relapse rates were 12.7 in month 3, 32.7 in month 6, 47.3 in month 12, and 52.7% in month 18. We determined by multivariate analysis that the consolidation period (> or =18 months, p=0.020) and early virologic response (HBV DNA <20 IU/mL) at six months during antiviral therapy (p=0.017) were significant predictors for sustained remission. CONCLUSIONS: A consolidation period of at least 18 months and early virological response at six months during antiviral therapy were associated with sustained remission in patients with HBeAg-positive CHB after treatment.
Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis ; Female ; Hepatitis B e Antigens/*blood ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Proportional Hazards Models ; Recurrence ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Withholding Treatment