Identification of focal epilepsy by diffusion tensor imaging using machine learning.

OBJECTIVE: The aim of this study was to evaluate the feasibility of machine learning based on diffusion tensor imaging (DTI) measures to distinguish patients with focal epilepsy versus healthy controls and antiseizure medication (ASM) responsiveness. METHODS: This was a retrospective study performed at a tertiary hospital. We enrolled 456 patients with focal epilepsy, who underwent DTI and were taking ASMs. We enrolled 100 healthy subjects as a control. We obtained the conventional DTI measures and structural connectomic profiles from the DTI. RESULTS: The support vector machine (SVM) classifier based on the conventional DTI measures revealed an accuracy of 76.5% and an area under curve (AUC) of 0.604 (95% Confidence interval (CI), 0.506-0.695). Another SVM classifier combined with structural connectomic profiles demonstrated an accuracy of 82.8% and an AUC of 0.701 (95% CI, 0.606-0.784). Of the 456 patients with epilepsy, 242 patients were ASM good responders, whereas 214 patients were ASM poor responders. In the classification of the ASM responders, an SVM classifier based on the conventional DTI measures revealed an accuracy of 54.9% and an AUC of 0.551 (95% CI, 0.443-0.655). Another SVM classifier combined with structural connectomic profiles demonstrated an accuracy of 59.3% and an AUC of 0.594 (95% CI, 0.485-0.695). CONCLUSION: DTI using a machine learning is useful for differentiating patients with focal epilepsy from healthy controls, but it cannot classify ASM responsiveness. Combining structural connectomic profiles results in a better classification performance than the use of conventional DTI measures alone for identifying focal epilepsy and ASM responsiveness.

Characteristics of Perfusion Computed Tomography Imaging in Patients with Seizures Mimicking Acute Stroke.

INTRODUCTION: Seizures as acute stroke mimics are a diagnostic challenge. OBJECTIVE: The aim of the study was to characterize the perfusion patterns on perfusion computed tomography (PCT) in patients with seizures masquerading as acute stroke. METHODS: We conducted a study on patients with acute seizures as stroke mimics. The inclusion criteria for this study were patients (1) initially presenting with stroke-like symptoms but finally diagnosed to have seizures and (2) with PCT performed within 72 h of seizures. The PCT of seizure patients (n = 27) was compared with that of revascularized stroke patients (n = 20) as the control group. RESULTS: Among the 27 patients with seizures as stroke mimics, 70.4% (n = 19) showed characteristic PCT findings compared with the revascularized stroke patients, which were as follows: (1) multi-territorial cortical hyperperfusion {(73.7% [14/19] vs. 0% [0/20], p = 0.002), sensitivity of 73.7%, negative predictive value (NPV) of 80%}, (2) involvement of the ipsilateral thalamus {(57.9% [11/19] vs. 0% [0/20], p = 0.007), sensitivity of 57.9%, NPV of 71.4%}, and (3) reduced perfusion time {(84.2% [16/19] vs. 0% [0/20], p = 0.001), sensitivity of 84.2%, NPV of 87%}. These 3 findings had 100% specificity and positive predictive value in predicting patients with acute seizures in comparison with reperfused stroke patients. Older age was strongly associated with abnormal perfusion changes (p = 0.038), with a mean age of 66.8 ± 14.5 years versus 49.2 ± 27.4 years (in seizure patients with normal perfusion scan). CONCLUSIONS: PCT is a reliable tool to differentiate acute seizures from acute stroke in the emergency setting.

Which Factors Are the Most Important for Predicting Sleep Quality in Obstructive Sleep Apnea Patients with Obesity?

BACKGROUND: Both obstructive sleep apnea (OSA) and obesity are associated with poor sleep quality. However, there have been no studies investigating sleep quality in OSA patients with obesity. The aims of this study were to (1) evaluate the sleep quality in OSA patients with obesity and (2) identify the parameters most related to sleep quality in OSA patients with obesity. METHODS: Of the patients with polysomnography (PSG), OSA patients with obesity (body mass index [BMI] ≥25) were enrolled and then divided into 2 groups based on the Pittsburg Sleep Questionnaire Index (PSQI): patients with good sleep quality (PSQI ≤5, good sleepers) and those with poor sleep quality (PSQI >5, poor sleepers). In addition, we enrolled OSA patients without obesity as a disease control group. RESULTS: Eighty-two OSA patients with obesity met the inclusion criteria (28 were good sleepers, whereas 54 were poor sleepers). We found that the BMI of the poor sleepers was significantly higher than that of the good sleepers, whereas the N-stage sleep ratio of good sleepers was higher than that of poor sleepers. Logistic -regression analysis also showed that a high BMI and low -N-stage sleep ratio were independently associated with poor sleep quality. In addition, BMI and N-stage sleep ratio were significantly correlated with PSQI. However, in 56 OSA patients (n = 56) without obesity, there were no differences of demographic/clinical characteristics and PSG parameters between the good (n = 18) and poor sleepers (n = 38). DISCUSSIONS: About two-thirds of OSA patients with obesity show poor sleep quality. The sleep quality of these patients was more affected by the severity of obesity, but not the severity of OSA. Thus, we recommend weight loss in OSA patients with obesity to improve sleep quality as well as the severity of OSA.

Dissipation Kinetics and the Pre-Harvest Residue Limits of Acetamiprid and Chlorantraniliprole in Kimchi Cabbage Using Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.

The dissipation behaviors of acetamiprid and chlorantraniliprole in kimchi cabbages were studied under open-field conditions. A simple and rapid analytical method was developed using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The multiple reaction monitoring (MRM) conditions of two pesticides were optimized to quantify and identify the pesticide residues. Sample preparation was performed by the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method. Average recovery rates at the different spiked levels (0.05 and 0.25 mg/kg) were in the range of 103.6-113.9% (acetamiprid) and 80.8-91.2% (chlorantraniliprole), and the relative standard deviations were ≤4.3% for all. The dissipation kinetics were assessed using first-order equations after spraying acetamiprid and chlorantraniliprole individually on kimchi cabbages. The biological half-lives in field 1 and 2 were 5.2 and 6.3 days (acetamiprid) and 10.0 and 15.2 days (chlorantraniliprole), respectively. Based on the dissipation equations, the pre-harvest residue limits (PHRLs) corresponding to each day before harvest were suggested as the guidelines to meet the MRL on harvest day. It was also predicted that the terminal residues observed after multiple sprayings (three and seven days) would be below the MRL when harvested, in compliance with the established pre-harvest intervals.

Pyroelectric and Piezoelectric Properties of (1-x)Na0.5K0.5NbO3-xBiScO3 Lead-Free Ceramics.

In this research, the pyroelectric and piezoelectric properties of (1 - x)Na0.5K0.5NbO3-xBiScO3 ceramics were investigated and analyzed. (Na, K)NbO3 based (1 - x)Na0.5K0.5NbO3-xBiScO3 ceramics were prepared by a conventional mixed oxide method. As the substituent, BiScO3 material enhanced the sintering mechanism of NKN ceramic, which improved the density, pyroelectric and piezoelectric properties, without any structural distortion. In this study, the structural dependent improved piezoelectric properties of (1 - x)Na0.5K0.5NbO3-xBiScO3 ceramics were investigated with various sintering temperatures. Also, the pyroelectric properties of (1 - x)Na0.5K0.5NbO3-xBiScO3 ceramics were observed up to 200 °C for the devices applications. The crystalline structures of the (1-x)Na0.5K0.5NbO3-x BiScO3 ceramics were measured by X-ray diffraction (XRD). The microstructure was examined by field emission scanning electron microscopy (FE-SEM). In addition, piezo-electric charge coefficient d33 and pyroelectric coefficient will be discussed.

Efficacy and safety of gemigliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus inadequately controlled with combination treatment of metformin and sulphonylurea: a 24-week, multicentre, randomized, double-blind, placebo-controlled study (TROICA study).

AIMS: To assess the efficacy and safety of gemigliptin, a dipeptidyl peptidase-4 inhibitor, added to metformin and sulphonylurea in patients with type 2 diabetes (T2DM). MATERIALS AND METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 219 Korean patients inadequately controlled with metformin and glimepiride. Participants were randomized to gemigliptin 50 mg once daily or placebo added to metformin and glimepiride. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. RESULTS: The baseline HbA1c was 8.2% in both groups. The addition of gemigliptin to metformin and glimepiride significantly reduced HbA1c levels at week 24 compared with placebo (between-group difference in adjusted mean change -0.87%, 95% confidence interval [CI] -1.09% to -0.64%). Fasting plasma glucose level was also significantly reduced with gemigliptin (-0.93 mmol/L, 95% CI -1.50 to -0.35 mmol/L), and a higher proportion of participants achieved an HbA1c level of <7% (39.3% vs 5.5%; P <.001) in the gemigliptin group than in the placebo group. Total cholesterol and LDL cholesterol were modestly but significantly reduced in the gemigliptin group compared with the placebo group (-0.21 mmol/L, 95% CI -0.38 to -0.03 mmol/L for total cholesterol, -0.18 mmol/L, 95% CI -0.34 to -0.01 mmol/L for LDL cholesterol). The incidence of hypoglycaemia was 9.4% in the gemigliptin group and 2.7% in the placebo group. CONCLUSIONS: Gemigliptin significantly improved glycaemic control in patients with T2DM inadequately controlled with metformin and sulphonylurea. The incidence of hypoglycaemia was higher with gemigliptin than with placebo, which highlights the importance of optimal dose adjustment for sulphonylurea.

Organophosphate Detection in Animal-Derived Foods Using a Modified Quick, Easy, Cheap, Effective, Rugged, and Safe Method with Liquid Chromatography-Mass Spectrometry.

Organophosphates are widely used in the livestock industry. In this study, we developed a method for detecting 27 organophosphate insecticides in animal-derived foods, including beef, pork, chicken, milk, and eggs, using liquid chromatography-tandem mass spectrometry. A modified QuEChERS method was optimized for sample pretreatment. A mixture of acetonitrile and acetone was used as the extraction solvent, and MgSO4 and NaCl were used as salts. Among the five different dispersive solid-phase extraction systems, MgSO4, primary secondary amines, and C18 were selected for purification because they had the highest recovery rates and least matrix effects. The matrix-dependent limit of quantitation was 0.0005-0.005 mg/kg, and the correlation coefficient of the matrix-matched calibration curve was >0.99, which was acceptable for quantifying residues below 0.01 mg/kg-the default maximum residue limit in a positive list system. The recovery efficiencies ranged from 71.9 to 110.5%, with standard deviations ranging from 0.2% to 12.5%, satisfying the SANTE guidelines. The established analytical method was used to monitor organophosphates in animal-derived foods obtained from a local market, and no pesticides were detected. With respect to industry standards, our proposed method is recommended for practical organophosphate detection in animal-derived foods.

Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea.

Background: Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans. Methods: A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness. Conclusion: A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.

Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

BACKGRUOUND: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. RESULTS: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. CONCLUSION: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Analysis of the layering pattern of the apparent diffusion coefficient (ADC) for differentiation of radiation necrosis from tumour progression.

OBJECTIVES: To evaluate the added value of diffusion-weighted imaging (DWI) to perfusion-weighted imaging (PWI) for differentiating tumour progression from radiation necrosis. METHODS: Sixteen consecutive patients who underwent removal of a metastatic brain tumour that increased in size after stereotactic radiosurgery were retrospectively reviewed. The layering of the ADC was categorised into three patterns. ADC values were measured on each layer, and the maximum rCBV was measured. rCBV and the layering pattern of the ADC of radiation necrosis and tumour progression were compared. RESULTS: Nine cases of radiation necrosis and seven cases of tumour progression were pathologically confirmed. Radiation necrosis (88.9 % vs. 14.3 %) showed a three-layer pattern of ADC with a middle layer of minimum ADC more frequently. If rCBV larger than 2.6 was used to differentiate radiation necrosis and tumour progression, the sensitivity was 100 % but specificity was 56 %. If the lesions with the three-layer pattern of ADC with moderately increased rCBV (2.6-4.1) were excluded from tumour progression, the sensitivity and specificity increased to 100 %. CONCLUSIONS: The three-layer pattern of ADC shows high specificity in diagnosing radiation necrosis; therefore, combined analysis of the ADC pattern with rCBV may have added value in the correct differentiation of tumour progression from radiation necrosis.

Correlation Between Quantitative Background Suppression on EEG and Serum NSE in Patients With Hypoxic-ischemic Encephalopathy.

PURPOSE: We evaluated the correlation between quantitative background activities on electroencephalography (EEG) and serum neuron specific enolase (NSE) in patients with hypoxic-ischemic encephalopathy as well as a diagnostic value of prognostication. METHODS: This retrospective cohort study enrolled patients with return of spontaneous circulation after cardiac arrest from March 2010 to March 2020. The inclusion criteria were (1) older than the age of 16 years and (2) patients who had both EEG and NSE. The median time for EEG and NSE were 3 days (interquartile range 2-5 days) and 3 days (interquartile range 2-4 days), respectively. The quantification of background activity was conducted with the suppression ratio (SR). We used a machine learning (eXtreme Gradient Boosting algorithm) to evaluate whether the SR could improve the accuracy of prognostication. RESULTS: We enrolled 151 patients. The receiver operating characteristic analysis revealed a cut-off value of serum NSE and the SR for poor outcome, serum NSE (>31.9 µg/L, area under curve [AUC] = 0.88), and the SR (>21.5%, AUC = 0.75 in the right hemisphere, >34.4%, AUC = 0.76 in the left hemisphere). There was a significant positive correlation between the severity of SR and the level of NSE (ρ = 0.57, p < 0.0001 for the right hemisphere, ρ = 0.58, p < 0.0001 for the left hemisphere). The SR showed an excellent diagnostic value for predicting poor outcome (93% specificity, 60% sensitivity in the right hemisphere and 93% specificity, 58% sensitivity in the left hemisphere). With machine learning analysis, there was an increment in distinguishing the neurological outcome by adding SR on clinical factors. CONCLUSIONS: The SR showed a positive correlation with the level of serum NSE. The diagnostic value of the SR for predicting poor outcome was excellent, suggesting that it can be a possible biomarker for neuroprognostication in patients with hypoxic-ischemic encephalopathy.

Exendin-4 protects against sulfonylurea-induced ß-cell apoptosis.

Sulfonylurea is one of the commonly used anti-diabetic drugs that stimulate insulin secretion from ß-cells. Despite their glucose lowering effects in type 2 diabetes mellitus, long-term treatment brought on secondary failure characterized by ß-cell exhaustion and apoptosis. ER stress induced by Ca(2+) depletion in endoplasmic reticulum (ER) is speculated be one of the causes of secondary failure, but it remains unclear. Glucagon like peptide-1 (GLP-1) has anti-apoptotic effects in ß-cells after the induction of oxidative and ER stress. In this study, we examined the anti-apoptotic action of a GLP-1 analogue in ß-cell lines and islets against ER stress induced by chronic treatment of sulfonylurea. HIT-T15 and dispersed islet cells were exposed to glibenclamide for 48 h, and apoptosis was evaluated using Annexin/PI flow cytometry. Expression of the ER stress-related molecules and sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) 2/3 was determined by real-time PCR and western blot analysis. Chronic exposure to glibenclamide increased apoptosis by depletion of ER Ca(2+) concentration through reduced expression of SERCA 2/3. Pretreatment with Exendin-4 had an anti-apoptotic role through ER stress modulation and ER Ca(2+) replenishing by SERCA restoration. These findings will further the understanding of one cause of glibenclamide-induced ß-cell loss and therapeutic availability of GLP-1-based drugs in secondary failure by sulfonylurea during treatment of diabetes.

Exendin-4 Protects Against Sulfonylurea-Induced ß-Cell Apoptosis.

Sulfonylurea is one of the commonly used anti-diabetic drugs that stimulate insulin secretion from ß-cells. Despite their glucose lowering effects in type 2 diabetes mellitus, long-term treatment brought on secondary failure characterized by ß-cell exhaustion and apoptosis. ER stress induced by Ca2+ depletion in endoplasmic reticulum (ER) is speculated be one of the causes of secondary failure, but it remains unclear. Glucagon like peptide-1 (GLP-1) has anti-apoptotic effects in ß-cells after the induction of oxidative and ER stress. In this study, we examined the antiapoptotic action of a GLP-1 analogue in ß-cell lines and islets against ER stress induced by chronic treatment of sulfonylurea. HIT-T15 and dispersed islet cells were exposed to glibenclamide for 48 h, and apoptosis was evaluated using Annexin/PI flow cytometry. Expression of the ER stress-related molecules and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2/3 was determined by real-time PCR and western blot analysis. Chronic exposure to glibenclamide increased apoptosis by depletion of ER Ca2+ concentration through reduced expression of SERCA 2/3. Pretreatment with Exendin-4 had an anti-apoptotic role through ER stress modulation and ER Ca2+ replenishing by SERCA restoration. These findings will further the understanding of one cause of glibenclamide-induced ß-cell loss and therapeutic availability of GLP-1-based drugs in secondary failure by sulfonylurea during treatment of diabetes.

Simultaneous Determination of Pyrethroid Insecticides in Foods of Animal Origins Using the Modified QuEChERS Method and Gas Chromatography-Mass Spectrometry.

Pyrethroid insecticides are used in agriculture to treat parasites in livestock. This study developed a simultaneous residue analysis method to measure seventeen pyrethroid insecticides in foods of animal origin, including beef, pork, chicken, milk, and eggs. The method, which comprises instrumental analysis using gas chromatography-tandem mass spectrometry and a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method for pretreatment, was optimized to verify the applicability of the method. A mixture of acetonitrile, ethyl acetate, and original salt (MgSO4 4 g, NaCl 1 g) was used as the extraction solvent and salt. MgSO4 (150 mg) primary secondary amine (25 mg) and graphitized carbon black (25 mg) were selected for dispersive solid phase extraction (d-SPE). The method limit of quantitation was 0.01 mg/L, and the linearity of the matrix-matched calibration curves was reasonable (R2 > 0.99). Recovery tests were performed at three concentrations (LOQ, 10 LOQ, and 50 LOQ). Good recoveries (75.2109.8%) and reproducibility (coefficient of variation <10%) were obtained. The matrix effects were in the range of −35.8 to 56.0%. The established method was fully validated and can be used as an official analytical method for quantifying pyrethroid insecticides in animal commodities.

Chronic administration of ezetimibe increases active glucagon-like peptide-1 and improves glycemic control and pancreatic beta cell mass in a rat model of type 2 diabetes.

Ezetimibe is a cholesterol-lowering agent targeting Niemann-Pick C1-like 1, an intestinal cholesterol transporter. Inhibition of intestinal cholesterol absorption with ezetimibe may ameliorate several metabolic disorders including hepatic steatosis and insulin resistance. In this study, we investigated whether chronic ezetimibe treatment improves glycemic control and pancreatic beta cell mass, and alters levels of glucagon-like peptide-1 (GLP-1), an incretin hormone involved in glucose homeostasis. Male LETO and OLETF rats were treated with vehicle or ezetimibe (10 mg kg(-1)day(-1)) for 20 weeks via stomach gavage. OLETF rats were diabetic with hyperglycemia and significant decreases in pancreatic size and beta cell mass compared with LETO lean controls. Chronic treatment of OLETF rats with ezetimibe improved glycemic control during oral glucose tolerance test compared with OLETF controls. Moreover, ezetimibe treatment rescued the reduced pancreatic size and beta cell mass in OLETF rats. Interestingly, ezetimibe significantly decreased serum dipeptidyl peptidase-4 activity and increased serum active GLP-1 in OLETF rats without altering serum total GLP-1. These findings demonstrated that chronic administration of ezetimibe improves glycemic control and pancreatic beta cell mass, and increases serum active GLP-1 levels, suggesting possible involvement of GLP-1 in the ezetimibe-mediated beneficial effects on glycemic control.

Notch1 Has an Important Role in ß-Cell Mass Determination and Development of Diabetes.

BACKGROUND: Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). METHODS: Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and ß-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. RESULTS: NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and ß-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice. CONCLUSION: Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and ß-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in ß-cell mass determination and diabetes.

Notch signaling in pancreatic endocrine cell and diabetes.

Recent studies have improved our understanding of the physiological function of Notch signaling pathway and now there is compelling evidence demonstrating that Notch is a key regulator of embryonic development and tissue homeostasis. Although further extensive studies are necessary to illustrate the molecular mechanisms, new insights into the role of Notch signaling in pancreas development and diabetes have been achieved. Importantly, the ability to regulate Notch signaling intensity both positively and negatively may have therapeutic relevance for diabetes. Thus, this paper reviews the current knowledge of the roles of Notch signaling in the pancreatic endocrine cell system.

Transferrin fusion technology: a novel approach to prolonging biological half-life of insulinotropic peptides.

Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic beta-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.

Single-session endovascular treatment for symptomatic lower extremity deep vein thrombosis: a feasibility study.

BACKGROUND: The risk of complications and discomfort in patients who undergo prolonged infusion of a thrombolytic agent is significant when conventional catheter-directed thrombolysis is used to treat lower extremity deep vein thrombosis (DVT). PURPOSE: To evaluate the feasibility and safety of single-session endovascular treatment for symptomatic lower extremity DVT. MATERIAL AND METHODS: Single-session endovascular treatment for lower extremity DVT was performed on 29 limbs in 26 patients diagnosed with acute DVT in our institution. Nine patients were male and 17 female, with a mean age of 64 years (range 28-82 years). At 5-10 min after the locoregional injection of the thrombolytic agent (urokinase) via a 5-Fr catheter to soften the thrombus, aspiration thrombectomy was performed with a large-bore sheath. In patients with an underlying anatomical stenosis or obstruction, combined angioplasty with or without stent placement was performed immediately after the complete removal of the thrombus. We then evaluated the technical and clinical outcomes of the procedure, along with any complications or recurrences of DVT. RESULTS: Technical success was achieved in 24 procedures (82.8%) of single-session endovascular treatment for lower extremity DVT, and clinical success was achieved in 22 (75.9%) of these single-session procedures. Additional catheter-directed thrombolysis procedures were performed on five limbs after repeated aspiration thrombectomies failed to completely remove thrombi in those limbs. Stenotic or occlusive lesions were revealed in 24 limbs and percutaneous angioplasty procedures with or without stent placement were performed in these cases. No major complications resulted from the procedure. CONCLUSION: Single-session endovascular treatment is a feasible technique that provides acceptable technical and clinical success with excellent safety for treating symptomatic lower extremity DVT.

Exendin-4 protects oxidative stress-induced ß-cell apoptosis through reduced JNK and GSK3ß activity.

Oxidative stress induced by chronic hyperglycemia in type 2 diabetes plays a crucial role in progressive loss of ß-cell mass through ß-cell apoptosis. Glucagon like peptide-1 (GLP-1) has effects on preservation of ß-cell mass and its insulin secretory function. GLP-1 possibly increases islet cell mass through stimulated proliferation from ß-cell and differentiation to ß-cell from progenitor cells. Also, it probably has an antiapoptotic effect on ß-cell, but detailed mechanisms are not proven. Therefore, we examined the protective mechanism of GLP-1 in ß-cell after induction of oxidative stress. The cell apoptosis decreased to ~50% when cells were treated with 100 µM H(2)O(2) for up to 2 hr. After pretreatment of Ex-4, GLP-1 receptor agonist, flow cytometric analysis shows 41.7% reduction of ß-cell apoptosis. This data suggested that pretreatment of Ex-4 protect from oxidative stress-induced apoptosis. Also, Ex-4 treatment decreased GSK3ß activation, JNK phosphorylation and caspase-9, -3 activation and recovered the expression of insulin2 mRNA in ß-cell lines and secretion of insulin in human islet. These results suggest that Ex-4 may protect ß-cell apoptosis by blocking the JNK and GSK3ß mediated apoptotic pathway.