To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

Recently, increasing evidence suggests that neuroinflammation may be a critical factor in the development of Parkinson’s disease (PD) in addition to the ratio of acetylcholine/dopamine because dopaminergic neurons are particularly vulnerable to inflammatory attack. In this study, we investigated whether botulinum neurotoxin A (BoNT-A) was effective for the treatment of PD through its anti-neuroinflammatory effects and the modulation of acetylcholine and dopamine release. We found that BoNT-A ameliorated MPTP and 6-OHDA-induced PD progression, reduced acetylcholine release, levels of IL-1β, IL-6 and TNF-α as well as GFAP expression, but enhanced dopamine release and tyrosine hydroxylase expression. These results indicated that BoNT-A had beneficial effects on MPTP or 6-OHDA-induced PD-like behavior impairments via its anti-neuroinflammation properties, recovering dopamine, and reducing acetylcholine release.

Background/Aims: Self-expandable metal stents (SEMSs) can be applied to relieve colorectal obstruction secondary to incurable primary colorectal cancer or extracolonic malignancy. We aimed to identify factors associated with clinical success and the reintervention-free survival (RFS) after palliative stenting. Methods: Cases of palliative SEMS placement between 2005 and 2019 were retrieved from the institutional database and reviewed retrospectively. Logistic regression and log-rank testing followed by Cox proportional hazard analyses were performed to investigate the predictors of the clinical success of palliative stenting and factors associated with RFS, respectively. Results: A total of 593 patients underwent palliative stenting for malignant colonic obstruction (MCO). The technical and clinical success rates were 92.9% and 83.5%, respectively. Peritoneal carcinomatosis was a predictor of clinical failure (odds ratio, 0.33; 95% confidence interval [CI], 0.17 to 0.65) in the multivariate analysis. Peritoneal carcinomatosis (hazard ratio [HR], 2.48; 95% CI, 1.69 to 3.64) and stent expansion >90% on day 1 (HR, 1.62; 95% CI, 1.05 to 2.50) were associated with a shorter RFS. Neither clinical success nor RFS was associated with extracolonic malignancy. Re-obstruction, stent migration, and perforation were responsible for most reinterventions after clinically successful palliative stenting. Conclusions In patients requiring palliative stenting for MCO, peritoneal carcinomatosis was associated with both clinical failure and short RFS. Stent expansion >90% on postprocedural day 1 was another predictor of a short RFS after clinically successful stenting. A large prospective study is warranted to establish factors associated with RFS after successful palliative stenting for MCO.

Background/Aims: Self-expandable metal stents (SEMSs) can be applied to relieve colorectal obstruction secondary to incurable primary colorectal cancer or extracolonic malignancy. We aimed to identify factors associated with clinical success and the reintervention-free survival (RFS) after palliative stenting. Methods: Cases of palliative SEMS placement between 2005 and 2019 were retrieved from the institutional database and reviewed retrospectively. Logistic regression and log-rank testing followed by Cox proportional hazard analyses were performed to investigate the predictors of the clinical success of palliative stenting and factors associated with RFS, respectively. Results: A total of 593 patients underwent palliative stenting for malignant colonic obstruction (MCO). The technical and clinical success rates were 92.9% and 83.5%, respectively. Peritoneal carcinomatosis was a predictor of clinical failure (odds ratio, 0.33; 95% confidence interval [CI], 0.17 to 0.65) in the multivariate analysis. Peritoneal carcinomatosis (hazard ratio [HR], 2.48; 95% CI, 1.69 to 3.64) and stent expansion >90% on day 1 (HR, 1.62; 95% CI, 1.05 to 2.50) were associated with a shorter RFS. Neither clinical success nor RFS was associated with extracolonic malignancy. Re-obstruction, stent migration, and perforation were responsible for most reinterventions after clinically successful palliative stenting. Conclusions In patients requiring palliative stenting for MCO, peritoneal carcinomatosis was associated with both clinical failure and short RFS. Stent expansion >90% on postprocedural day 1 was another predictor of a short RFS after clinically successful stenting. A large prospective study is warranted to establish factors associated with RFS after successful palliative stenting for MCO.

Background/Aims: Studies on long-term outcomes of adalimumab therapy in non-Caucasian patients with ulcerative colitis (UC) are lacking. Methods: We analyzed long-term outcomes of Korean UC patients treated with adalimumab at the Asan Medical Center, Seoul, Korea. Results: Between July 2013 and October 2018, adalimumab therapy was started in a total of 100 patients with UC (65 males [65.0%]; median age, 39.5 years [interquartile range, 23.3 to 49.8 years]; and median disease duration, 3.0 years [interquartile range, 1.0 to 7.0 years]). The median duration of adalimumab therapy was 13.5 months (interquartile range, 4.0 to 32.0 months). Eight of 100 patients (8.0%) received induction therapy only, four (4.0%) of whom ultimately underwent colectomy. Of 92 patients who received adalimumab maintenance therapy, 30 (30.0%) stopped adalimumab therapy due to loss of response, and one patient (1.0%) was lost to follow-up. Among the 92 patients who received adalimumab maintenance therapy, the cumulative proportions of patients remaining on adalimumab maintenance therapy were 70.0% at 1 year and 48.9% at 5 years. High partial Mayo score after 8 weeks of adalimumab therapy (hazard ratio [HR], 1.217; 95% confidence interval [CI], 1.040 to 1.425; p=0.014) and a history of exposure to two biologic agents before adalimumab therapy (HR, 4.722; CI, 1.033 to 21.586; p=0.045) were predictors of adalimumab discontinuation. Conclusions Long-term outcomes of adalimumab therapy in Korean UC patients appear to be comparable to those in previously published Western studies. Furthermore, previous exposure to multiple biologic agents before adalimumab therapy and disease activity after 8 weeks of adalimumab therapy were predictors of adalimumab discontinuation.

BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSCs) are used to treat autoimmune or inflammatory diseases. Our aim was to determine the immunomodulatory mechanisms elicited by MSCs during inflammation. METHODS AND RESULTS: We cocultured MSCs with peripheral blood mononuclear cells for a mixed lymphocyte reaction or stimulated them by phytohemagglutinin. Morphological changes of MSCs and secretion of acetylcholine (ACh) from MSCs were measured. The effects of an ACh antagonist and ACh agonist on lymphocyte proliferation and proinflammatory-cytokine production were determined. The inflammatory milieu created by immune-cell activation caused MSCs to adopt a neuronlike phenotype and induced them to release ACh. Additionally, nicotinic acetylcholine receptors (nAChRs) were upregulated in activated peripheral blood mononuclear cells. We observed that ACh bound to nAChR on activated immune cells and led to the inhibition of lymphocyte proliferation and of proinflammatory-cytokine production. MSC-mediated immunosuppression through ACh activity was reversed by an ACh antagonist called α-bungarotoxin, and lymphocyte proliferation was inhibited by an ACh agonist, ACh chloride. CONCLUSIONS: Our findings point to a novel immunomodulatory mechanism in which ACh secreted by MSCs under inflammatory conditions might modulate immune cells. This study may provide a novel method for the treatment of autoimmune diseases by means of MSCs.
Acetylcholine ; Autoimmune Diseases ; Humans ; Immunosuppression ; Inflammation ; Lymphocyte Culture Test, Mixed ; Lymphocytes ; Mesenchymal Stromal Cells ; Methods ; Phenotype ; Receptors, Nicotinic

PURPOSE: Androgen deprivation therapy (ADT) is used as a salvage treatment for men with biochemical recurrence (BCR) of prostate cancer (PCa) following initial radical prostatectomy (RP). The optimal time at which to begin salvage ADT (sADT) remains controversial. In this retrospective study, we evaluated the efficacy of initiating sADT in patients before prostate-specific antigen (PSA) values met the clinical definition of BCR. MATERIALS AND METHODS: We identified 484 PCa patients who received sADT for BCR after RP. Median follow-up was 82 months. Propensity score matching was performed based on preoperative PSA level, pathologic T stage, and Gleason score. Patients were assigned to two groups of 169 patients each, based on PSA levels at the time of sADT: Group A (without meeting of the definition of BCR) and Group B (after BCR). Kaplan-Meier survival analyses and Cox regression analyses were performed. RESULTS: The median PSA level at sADT initiation was 0.12 ng/mL in group A and 0.42 ng/mL in group B. Kaplan-Meier analyses showed that group A had favorable disease progression-free survival (DPFS) and distant metastasis-free survival (DMFS), but did not have better cancer-specific survival (CSS) than group B. In subgroup analyses, group A showed better CSS rates in the non-organ confined PCa group. In Cox regression analyses, early sADT was associated significantly with DPFS and DMFS rates, however, did not correlate with CSS (p=0.107). CONCLUSION: Early sADT after RP improved DPFS and DMFS. Furthermore, early sADT patients demonstrated better CSS in non-organ confined PCa.
Disease-Free Survival ; Follow-Up Studies ; Humans ; Male ; Neoplasm Grading ; Passive Cutaneous Anaphylaxis ; Propensity Score* ; Prostate* ; Prostate-Specific Antigen ; Prostatectomy* ; Prostatic Neoplasms* ; Recurrence ; Retrospective Studies ; Salvage Therapy

PURPOSE: To evaluate the efficacy and safety of robotic procedures performed using the da Vinci Robotic Surgical System at a single institute. MATERIALS AND METHODS: We analyzed all robotic procedures performed at Severance Hospital, Yonsei University Health System (Seoul, Korea). Reliability and mortality rates of the robotic surgeries were also investigated. RESULTS: From July 2005 to December 2013, 10267 da Vinci robotic procedures were performed in seven different departments by 47 surgeons at our institute. There were 5641 cases (54.9%) of general surgery, including endocrine (38.0%), upper (7.7%) and lower gastrointestinal tract (7.5%), hepato-biliary and pancreatic (1.2%), and pediatric (0.6%) surgeries. Urologic surgery (33.0%) was the second most common, followed by otorhinolaryngologic (7.0%), obstetric and gynecologic (3.2%), thoracic (1.5%), cardiac (0.3%), and neurosurgery (0.1%). Thyroid (40.8%) and prostate (27.4%) procedures accounted for more than half of all surgeries, followed by stomach (7.6%), colorectal (7.5%), kidney and ureter (5.1%), head and neck (4.0%), uterus (3.2%), thoracic (1.5%), and other (2.9%) surgeries. Most surgeries (94.5%) were performed for malignancies. General and urologic surgeries rapidly increased after 2005, whereas others increased slowly. Thyroid and prostate surgeries increased rapidly after 2007. Surgeries for benign conditions accounted for a small portion of all procedures, although the numbers thereof have been steadily increasing. System malfunctions and failures were reported in 185 (1.8%) cases. Mortality related to robotic surgery was observed for 12 (0.12%) cases. CONCLUSION: Robotic surgeries have increased steadily at our institution. The da Vinci Robotic Surgical System is effective and safe for use during surgery.
Head ; Kidney ; Korea* ; Lower Gastrointestinal Tract ; Mortality ; Neck ; Neurosurgery ; Prostate ; Robotic Surgical Procedures ; Stomach ; Surgeons ; Thyroid Gland ; Ureter ; Uterus