A Novel Immunomodulatory Mechanism Dependent on Acetylcholine Secreted by Human Bone Marrow-derived Mesenchymal Stem Cells

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.

Surgical Outcomes of Dacryocystorhinostomy in Lacrimal Drainage Obstruction after Systemic Chemotherapy or Radioactive Iodine Therapy

PURPOSE: To compare the outcomes of endonasal dacryocystorhinostomy in patients with secondary lacrimal drainage obstruction associated with systemic chemotherapy or radioactive iodine therapy. METHODS: We retrospectively reviewed the clinical records of patients diagnosed with secondary lacrimal drainage obstruction after systemic chemotherapy or radioactive iodine therapy for thyroid disease and surgical treatment by endonasal dacryocystorhinostomy between January 2009 and January 2015. The control group included randomly selected patients who underwent endonasal dacryocystorhinostomy after diagnosis of primary lacrimal drainage obstruction. RESULTS: Patients were separated into a chemotherapy group (13 eyes of 9 patients), a radioactive iodine therapy group (44 eyes of 32 patients), and a control group (50 eyes of 40 patients). Duration from the onset of systemic chemotherapy or radioactive iodine to the first epiphora symptom was shorter in the chemotherapy group than the radioactive iodine therapy group (p < 0.001). There was no significant difference between the three groups in success rate of endonasal dacryocystorhinostomy. CONCLUSIONS: Most patients with secondary lacrimal drainage obstruction associated with systemic chemotherapy or radioactive iodine therapy had successful outcome of endonasal dacryocystorhinostomy. The success rate of dacryocystorhinostomy was comparable to that in patients with primary lacrimal drainage obstruction.

Reversal of Hypoglycemia Unawareness with a Single-donor, Marginal Dose Allogeneic Islet Transplantation in Korea: A Case Report

Pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus. Here, we describe the first reported case of successful allogeneic islet transplantation alone, using single-donor, marginal-dose islets in a Korean patient. A 59-yr-old patient with type 1 diabetes mellitus, who suffered from recurrent severe hypoglycemia, received 4,163 islet equivalents/kg from a single brain-death donor. Isolated islets were infused intraportally without any complications. The immunosuppressive regimen was based on the Edmonton protocol, but the maintenance dosage was reduced because of mucositis and leukopenia. Although insulin independence was not achieved, the patient showed stabilized blood glucose concentration, reduced insulin dosage and reversal of hypoglycemic unawareness, even with marginal dose of islets and reduced immunosuppressant. Islet transplantation may successfully improve endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus.

A Case of Cystoid Macular Edema Associated with Paclitaxel Chemotherapy

We encountered a patient with cystoid macular edema (CME) secondary to paclitaxel use. A 57-year-old man presented with gradual decreased bilateral vision. His chemotherapeutic regimen consisted of bevacizumab, paclitaxel (175 mg/m2 for 5 months), and carboplatin. Optical coherence tomography imaging revealed bilateral CME greater than 500 microm. However, one year later, visual acuity was improved, best-corrected Snellen visual acuity was 40 / 80 in each eye, and CME was spontaneously improved. Our study confirmed that macular edema associated with paclitaxel use shows spontaneous resolution and improvement of visual acuity after a change of chemotherapeutic regimen.

Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells

BACKGROUND: A limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells. METHODS: Adult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice. RESULTS: The adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells. CONCLUSION: These data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.

A Study of Different Aspects of Blowout Fracture Between Preoperative CT and Intraoperative Images

PURPOSE: To analyze the morphologic differences in blowout fracture seen on preoperative CT images compared to intraoperative images. METHODS: The present study included 63 patients (63 eyes) with orbital fractures that were repaired by orbital reconstruction between January 2009 and April 2010. We assessed the medial, inferior, and inferomedial orbital fractures and excluded superior and lateral wall fractures. We captured intraoperative blowout fracture images using a camera or endoscope and compared the fracture type (fracture size, fracture surface) seen on intraoperative images with that observed on the preoperative CT images. RESULTS: The study consisted of patients between 20 and 50 years of age with a mean age of 27.76 years (men: 49 eyes, women: 14 eyes). The proportions of small fractures and medium fractures were similar on the preoperative CT images; however, large fractures were observed more frequently on the intraoperative images. The proportions of mono-fragment fractures and multi-fragment fractures were similar on the preoperative CT images, but multi-fragment fractures, especially inferior orbital fractures, were more frequent on the intraoperative images. Features of the trapdoor fracture differed most between images in terms of fracture size and surface. CONCLUSIONS: The morphology of blowout fractures, especially trapdoor fractures, differed between preoperative CT images and intraoperative images.

Effects of Anti-Vascular Endothelial Growth Factor (VEGF) on Pancreatic Islets in Mouse Model of Type 2 Diabetes Mellitus / 당뇨병

BACKGROUND: Vascular endothelial growth factor (VEGF) is associated with the development of diabetic complications. However, it is unknown whether systemic VEGF treatment has any effects on the pancreatic islets in an animal model of type 2 diabetes mellitus. METHODS: Anti-VEGF peptide (synthetic ATWLPPR, VEGF receptor type 2 antagonist) was injected into db/db mice for 12 weeks. We analyzed pancreatic islet morphology and quantified beta-cell mass. Endothelial cell proliferation and the severity of islet fibrosis were also measured. VEGF expression in isolated islets was determined using Western blot analysis. RESULTS: When anti-VEGF was administered, db/db mice exhibited more severe hyperglycemia and associated delayed weight gain than non-treated db/db mice. Pancreas weight and pancreatic beta-cell mass were also significantly decreased in the anti-VEGF-treated group. VEGF and VEGF receptor proteins (types 1 and 2) were expressed in the pancreatic islets, and their expression was significantly increased in the db/db group compared with the db/dm group. However, the elevated VEGF expression was significantly reduced by anti-VEGF treatment compared with the db/db group. The anti-VEGF-treated group had more prominent islet fibrosis and islet destruction than db/db mice. Intra-islet endothelial cell proliferation was also remarkably reduced by the anti-VEGF peptide. CONCLUSION: Inhibition of VEGF action by the VEGF receptor 2 antagonist not only suppressed the proliferation of intra-islet endothelial cells but also accelerated pancreatic islet destruction and aggravated hyperglycemia in a type 2 diabetes mouse model. Therefore, the potential effects of anti-VEGF treatment on pancreatic beta cell damage should be considered.

The Effects of Exendin-4 on IRS-2 Expression and Phosphorylation in INS-1 Cells / 당뇨병

BACKGROUND: Insulin receptor substrate 2 (IRS-2) is a key regulator of beta cell proliferation and apoptosis. This study was aimed to investigate effect of the glucolipotoxicity on apoptosis in INS-1 cell, and the effect of Exendin-4, a GLP-1 receptor agonist, on IRS-2 expression in the glucolipotoxicity induced INS-1 cell. The goal was to discover the new action mechanism and function of Exendin-4 in beta cell apoptosis. METHOD: INS-1 cells were cultured in glucolipotoxic condition for 2, 4 or 6 days and were categorized as G groups. Another group in which 50 nM Exendin-4 was added to INS-1 cells, cultured in glucolipotoxic condition, were named as Ex-4 groups. We investigated the expression of IRS-2 by RT-PCR, phosphorylated IRS-2 and phosphorylated Akt protein levels by western blot. We measured the apoptosis ratio of INS-1 cell in glucolipotoxic condition by TUNEL staining in both groups. RESULT: IRS-2 expression of INS-1 cells decreased with correlation to the time of exposure to glucolipotoxic condition. pIRS-2 and pAkt protein levels decreased in the similar pattern in glucolipotoxicity group. However, this effect of glucolipotoxicity on INS-1 cell was inhibited by the Exendin-4 treatment. In the Ex-4 groups, IRS-2 expression, pIRS-2 and pAkt protein levels remained at the similar level to low glucose condition state. Also, apoptosis induced by glucolipotoxicity was suppressed by Exendin-4 treatment significantly. CONCLUSION: We showed that the long-term treatment of Exendin-4 inhibited the apoptosis of beta cells significantly in glucolipotoxic condition and that this effect of Exendin-4 was related with IRS-2 and Akt among the beta cell's intracellular signal transduction pathway.

Motor Involvement in Herpes Zoster Using EMG Study

Herpes zoster(HZ) is well known as a benign viral infection affecting the sensory nerves. That this disease may also cause motor paralysis is less well known. We performed this study to evaluate the exact prevalence of motor involvement and to compare the extent of EMG abnormality with that of skin lesions. Ninety patients with HZ who did not sho w clinical motor weakness except 4 patients with Ramsay-Hunt syndrome were studied prospectively for 2 years using EMG which is generally known to be very sensitive method for detection of motor involvement. The results turned out as follows. I.. In patients with Herpes zoster, motor involvement(denervation m EMG study) is 56.67%(51/90 patients) and subclinical motor involvement is 54.65%(47/86 patients). 2. There was no statistically significant difference m the rates of motor involvement among the cranial, cervical, thoracic & lumbosacral regions. 3. There was no statistically significant difference in the rates of motor involvement between the male and female, although the positivity were higher in male. 4. The subclnical motor involvement was gradually increased by aging, as seen in clinical motor paralysis of other report. 5. There was significant statistic difference between the number of dermatome involved by skin lesion(mean 1.88) and that of myotome with motor involvement (mean 2.55). In conclusion, it is suggested that subclnical motor involvement in Herpes zoster is rather frequent and extensive than generally expected.