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Background: It is unclear whether glycemic variability (GV) is a risk factor for diabetic peripheral neuropathy (DPN), and whether control of GV is beneficial for DPN. The purpose of this study was to investigate the effect of GV on peripheral nerve damage by inducing glucose fluctuation in streptozotocin-induced diabetic rats.Methods: Rats were divided into four groups: normal (normal glucose group [NOR]), diabetes without treatment (sustained severe hyperglycemia group; diabetes mellitus [DM]), diabetes+once daily insulin glargine (stable hyperglycemia group; DM+LAN), and diabetes+once daily insulin glargine with twice daily insulin glulisine (unstable glucose fluctuation group; DM+Lantus [LAN]+Apidra [API]). We measured anti-oxidant enzyme levels and behavioral responses against tactile, thermal, and pressure stimuli in the plasma of rats. We also performed a quantitative comparison of cutaneous and sciatic nerves according to glucose fluctuation.Results: At week 24, intraepidermal nerve fiber density was less reduced in the insulin-administered groups compared to the DM group (P0.05; 16.2±1.6, 12.4±2.0, 14.3±0.9, and 13.9±0.6 for NOR, DM, DM+LAN, and DM+LAN+API, respectively). The DM group exhibited significantly decreased glutathione levels compared to the insulin-administered groups (2.64±0.10 μmol/mL, DM+LAN; 1.93±0.0 μmol/mL, DM+LAN+API vs. 1.25±0.04 μmol/mL, DM; P

Background Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM). Methods From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated. Results In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, −1.1%±1.2%; P

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

Partially purified ginsenoside extract (PGE) and compound K enriched extract (CKE) were prepared from ginseng sprouts, and their antioxidant, anti-inflammatory and antithrombotic effects were investigated. Compared to the 6-year-old ginseng roots, ginseng sprouts were found to have a higher content of phenolic compounds, saponin and protopanaxadiol-type ginsenoside by about 56%, 36% and 43%, respectively. PGE was prepared using a macroporous adsorption resin, and compound K(CK) was converted and enriched from the PGE by enzymatic hydrolysis with a conversion rate of 75%. PGE showed higher effects than CKE on radical scavenging activity in antioxidant assays. On the other hand, CKE reduced nitric oxide levels more effectively than PGE in RAW 264.7 cells. CKE also reduced pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β and IL-6 than PGE. Tail bleeding time and volume were investigated after administration of CKE at 70–150 mg/kg/day to mice. CKE administered group showed a significant increase or increased tendency in bleeding time than the control group. Bleeding volume in the CKE group increased than the control group, but not as much as in the aspirin group. In conclusion, ginseng sprouts could be an efficient source of ginsenoside, and CKE converted from the ginsenosides showed antioxidant, anti-inflammatory and antithrombotic effects. However, it was estimated that the CKE might play an essential role in anti-inflammatory effects rather than antioxidant effects.

Background Real-world data analysis is useful for identifying treatment patterns. Understanding drug prescription patterns of type 2 diabetes mellitus may facilitate diabetes management. We aimed to analyze treatment patterns of type 2 diabetes mellitus using Observational Medical Outcomes Partnership Common Data Model based on electronic health records. Methods This retrospective, observational study employed electronic health records of patients who visited Jeonbuk National University Hospital in Korea during January 2000–December 2019. Data were transformed into the Observational Medical Outcomes Partnership Common Data Model and analyzed using R version 4.0.3 and ATLAS ver. 2.7.6. Prescription frequency for each anti-diabetic drug, combination therapy pattern, and prescription pattern according to age, renal function, and glycated hemoglobin were analyzed. Results The number of adults treated for type 2 diabetes mellitus increased from 1,867 (2.0%) in 2000 to 9,972 (5.9%) in 2019. In the early 2000s, sulfonylurea was most commonly prescribed (73%), and in the recent years, metformin has been most commonly prescribed (64%). Prescription rates for DPP4 and SGLT2 inhibitors have increased gradually over the past few years. Monotherapy prescription rates decreased, whereas triple and quadruple combination prescription rates increased steadily. Different drug prescription patterns according to age, renal function, and glycated hemoglobin were observed. The proportion of patients with HbA1c ≤ 7% increased from 31.1% in 2000 to 45.6% in 2019, but that of patients visiting the emergency room for severe hypoglycemia did not change over time. Conclusion Medication utilization patterns have changed significantly over the past 20 years with an increase in the use of newer drugs and a shift to combination therapies. In addition, various prescription patterns were demonstrated according to the patient characteristics in actual practice. Although glycemic control has improved, the proportion within the target is still low, underscoring the need to improve diabetes management., Graphical Abstract

Observational Health Data Sciences and Informatics is an international collaboration created an international data network of researchers (Observational Medical Outcomes Partnership Common Data Model, OMOP-CDM). This retrospective, observational study was aim to analyze treatment patterns of type 2 diabetes mellitus (T2DM) using HIRA national patient sample (NPS) from 2012 to 2017 transformed into OMOP-CDM. ATLAS ver. 2.7.6, an OHDSI’s open-source software is publicly available, was used for analysis. HIRA-NPS contain about 1.4 million patients. The proportion of adult patients treated for T2DM increased from 78,581 (5.5%) in 2012 to 101,710 (7.0%) in 2017. Ages 50-69 were the most common (47.7% in 2017), and T2DM was most noticeably increased from 28.7% to 44.9% among those aged 70 and over for 5 years. Metformin was the most prescribed drug (82.8%) followed by sulfornylurea (SU) (62.4%), DPP-4 inhibitor (29.5%) in 2012. In 2017, metformin was still the most prescribed (87.0%), and DPP-4 inhibitor prescription increased rapidly up to 62.7%, while the SU prescription rate decreased to 46.5%. Prescription of the most recently approved SGLT2 inhibitors also continued to increase, reaching 7.2% in 2017. The rate of insulin prescription decreased from 20.2% to 17.5%. Over time, mono and dual therapy decreased while triple and quadruple combinations steadily increased. Dual combination was the most common with metformin and DPP-4 inhibitor, triple combination was the most with metformin, SU, and DPP-4 inhibitor in 2017. Drug prescriptions for hypertension remained unchanged from 71.2% in 2012 to 70.0% in 2017, while prescriptions for dyslipidemia increased from 50.7% in 2012 to 68.4% in 2017. Antiplatelet drugs prescriptions decreased slightly from 47.3% to 42.6%. T2DM is constantly increasing, and medication utilization patterns have changed significantly over the past 5 years with a shift towards newer drugs. Disclosure K. Lee: None. H. Jin: None. Y. Kim: None. T. Park: None.

Herein, we report a case of rupture of nonfunctional adrenal adenoma treated by nonsurgical supportive management due to high risk for operation. A patient with end stage renal disease (ESRD) who was on hemodialysis visited our emergency room and complained of a sudden abdominal pain after a fall. A retroperitoneal hemorrhage with hematoma formation around the adrenal adenoma, which was caused by rupture of the adrenal adenoma, was detected by abdominal computed tomography (CT). Supportive management was performed, with serial CT follow-up instead of surgical adrenalectomy treatment because of high operative risk, due to hemodialysis. After 1 week, the patient’s vital signs stabilized and the patient did not further complain about abdominal symptoms. However, supportive embolization was performed and the size of hematoma was more decreased. We report a case of a patient on hemodialysis who experienced a rupture of a nonfunctioning adrenal adenoma, which was caused by low-energy trauma. The patient’s conditions improved with nonsurgical supportive management including embolization. Physicians should consider both surgical and nonsurgical management for the rupture of adrenal adenomas, depending on the patient situation. Therefore, nonsurgical supportive management such as embolization can be one therapeutic option for treating nonfunctioning adrenal adenoma rupture caused by low-energy trauma in a patient who has risks for operation due to combined comorbidities.

Aim: Cardiac autonomic neuropathy (CAN) is a common and important chronic complication in diabetic patients. Heart failure resulting from cardiomyopathy is also a lethal complication in diabetic pa...

In this review, we consider the diverse risk factors in diabetes patients beyond hyperglycemia that are being recognized as contributors to diabetic peripheral neuropathy (DPN). Interest in such alternative mechanisms has been encouraged by the recognition that neuropathy occurs in subjects with metabolic syndrome and pre-diabetes and by the reporting of several large clinical studies that failed to show reduced prevalence of neuropathy after intensive glucose control in patients with type 2 diabetes. Animal models of obesity, dyslipidemia, hypertension, and other disorders common to both pre-diabetes and diabetes have been used to highlight a number of plausible pathogenic mechanisms that may either damage the nerve independent of hyperglycemia or augment the toxic potential of hyperglycemia. While pathogenic mechanisms stemming from hyperglycemia are likely to be significant contributors to DPN, future therapeutic strategies will require a more nuanced approach that considers a range of concurrent insults derived from the complex pathophysiology of diabetes beyond direct hyperglycemia.

The effect of sodium-glucose cotransporter 2 inhibitors on peripheral nerves and kidneys in diabetes mellitus (DM) remains unexplored. Therefore, this study aimed to explore the effect of empagliflozin in diabetic rats. DM in rats was induced by streptozotocin injection, and diabetic rats were treated with empagliflozin 3 or 10 mg/kg. Following 24-week treatment, response thresholds to four different stimuli were tested and found to be lower in diabetic rats than in normal rats. Empagliflozin significantly prevented hypersensitivity (P

The effects of rutin and rutin glycoside with different solubility were compared on antioxidant activity and anti-inflammatory effects in vitro and the effects on platelet aggregation and blood coagulation in vitro and in vivo. Rutin glycoside (consisting of rutin mono-glucoside and rutin di-glucoside) was prepared via enzymatic transglycosylation from rutin. Rutin glycoside showed a higher effect than rutin on radical scavenging activity in antioxidant assays. Rutin showed a higher toxicity than rutin glycoside in murine macrophage RAW264.7 cells. They had similar effects on the levels of nitric oxide (NO), prostaglandin E (PGE) 2 and pro-inflammatory cytokines (such as tumor necrosis factor (TNF)-α, and interleukin (IL)-6) in the cells. Both rutin and rutin glycosides similarly reduced the rate of platelet aggregation compared to controls in vitro. They also similarly delayed prothrombin time (PT) and activated partial thromboplastin time (APTT) in an in vitro blood coagulation test. The effect of repeated administration of rutin and rutin glycoside was evaluated in vivo using SD rats. The platelet aggregation rate of rutin and the rutin glycoside administered group was significantly decreased compared to that of the control group. On the other hand, PT and APTT of rutin and rutin glycoside group were not significantly delayed in vivo blood coagulation test. In conclusion, rutin and rutin glycoside showed differences in antioxidant activities in vitro, while they were similar in the reduction of NO, PGE2, TNF-α and IL-6 in vitro. Rutin and rutin glycoside also showed similar platelet aggregation rates, and blood coagulation both in vitro and in vivo condition. Comparing in vitro and in vivo, rutin and rutin glycoside were effective on platelet aggregation both in vitro and in vivo, but only in vitro on blood coagulation.

Analyzing the treatment patterns of type 2 diabetes (T2DM) in real practice helps to understand the flow of diabetes management and establish further management plans. Observational Health Data Sciences and Informatics (OHDSI) is an international collaboration created an international data network (Observational Medical Outcomes Partnership Common Data Model, OMOP-CDM). This study was aim to analyze treatment patterns of T2DM using the OMOP-CDM based on electronic health record (EHR) data and to assess whether CDM analysis was feasible to diabetes research. This is a retrospective, observational study using the EHR data of Jeonbuk National University Hospital (JNUH) transformed into OMOP-CDM. The data consisted of medical records of patients visits from January 2000 to December 2019. ATLAS ver. 2.7.6, an OHDSI’s open-source software is publicly available, was used for analysis. The 20 year old EHR data of a JNUH contain about 1.5 million patients. The proportion of adult patients treated for T2DM increased from 1,867 (1.6%) in 2000 to 9,972 (5.1%) in 2019. Sulfonylurea (SU) was the most prescribed drug (73%) followed by metformin (55%) in 2000. On the other hand, in 2019, metformin was the most prescribed (64%), and DPP-4 inhibitor prescription increased rapidly up to 55%, while the SU prescription rate decreased to 36%. The rate of insulin treatment ranged from 16% to 24%, which is higher than national surveyed based on health insurance data. Over time, monotherapy decreased while dual, triple, and quadruple combinations steadily increased. Dual combination was the most common with metformin and DPP-4 inhibitor, triple combination was the most with metformin, SU, and DPP-4 inhibitor in 2019. In analysis of annual HbA1c trends, the proportion of patients with HbA1c of 7% or lower increased (from 32.8% 2000 to 50.2% in 2019). Proportion of patients with HbA1c of 9% or more decreased from 30% to 12%. However, it was found that about half of T2DM patients still had HbA1c values above the target range. In addition, the number of patients who visited our emergency room for severe hypoglycemia did not decrease. Present study revealed that CDM analysis was feasible for diabetes research. Medication utilization patterns have changed significantly over the past 20 years with a shift towards newer drugs. Despite these changes and clinical efforts, improvement in glycemic control is still a challenge and hypoglycemic is still a problem to overcome.

Background: Nonfunctioning pituitary adenomas (NFPAs) are most common pituitary tumors, and primary pituitary gland malignancies are extremely rare. Most malignant pituitary gland lesions metastasize from other sites. Primary malignant lesions, such as sarcomas, usually develop after radiotherapy or chemotherapy for other diseases. We report a rare case of primary sellar leiomyosarcoma (LMS) without prior therapy that arose concurrently with a pituitary adenoma. Clinical Case: A 56-year-old woman with ptosis of the right eye, headache, and progressive visual deficits visited our neurosurgery department. She had no medical history besides hypertension. Twelve months ago, she was referred to us because of decreased visual acuity and a 3.5×3.6-cm-sized pituitary mass detected on brain MRI. Normal pituitary functions with mild hyperprolactinemia suggested a nonfunctioning pituitary mass with stalk compression. After transsphenoidal surgery, histopathology revealed a pituitary adenoma; MRI immediately post-surgery revealed no grossly remnant lesion. However, during the current visit, sellar MRI revealed a re-growing mass in the pituitary fossa extending to the sphenoid sinus and compressing the optic chiasm with a suprasellar extension. Functional endoscopic sinus surgery was performed, and histopathology revealed a composite tumor, i.e., a mesenchymal tumor with a pituitary adenoma. On immunohistochemical staining, smooth muscle actin, synaptophysin, and chromagranin were positive; tumor cell mitosis was observed at 7/10 high-power fields. Finally, a composite tumor of myxoid leiomyosarcoma and pituitary adenoma was diagnosed. Hence, systemic chemotherapy with radiotherapy was planned for the remnant lesion. Hormonal replacement therapy with hydrocortisone and thyroxine was also started for subsequent hypopituitarism. Conclusion: NFPA is benign and has good prognosis if it is not grow in size or is completely resected. Conversely, primary sarcomas, such as LMS, show rapid extension and aggressive local invasion. Although their incidence is extremely rare, few primary pituitary sarcoma cases with or without pituitary adenoma have been reported. In the former case, initial diagnosis of pituitary adenoma may lead to delayed diagnosis of combined malignant lesions. Thus, clinicians should consider this possibility and high index of suspicion is required when diagnosing a pituitary mass.

Objective: The aim was to investigate the glucose profiles and compare the degree of glycemic variability between kidney and liver transplantation patients during the early postoperative period. Methods: The continuous glucose monitoring (CGM) data of 31 patients including 24 with kidney transplantation (KT) and seven with liver transplantation (LT) were analyzed. Results: Post-transplantation diabetes mellitus (PTDM) occurred in 42.1% (8/19) and 16.7% (1/6) of KT and LT patients, respectively, during this early period after transplantation, except for patients with preexisting diabetes (5 KT, 1 LT). Glycemic variability after LT was better than that in KT patients. The average mean amplitude of glycemic excursion (MAGE) and mean absolute glucose (MAG) levels were 91.18±26.51 vs. 65.66±22.55 (P Conclusion: The transplanted organ is also an important factor affecting glucose control and the occurrence of PTDM in patients who receive transplantation. Further studies involving CGM follow-up at regular intervals in PTDM or preexisting diabetic patients after KT or LT may clarify the role of transplanted organs in glucose control in recipients of organ transplants. Disclosure H. Jin: None. Y. Kim: None. K. Lee: None. T. Park: None.

Background: The most common cause of hypopituitarism is pituitary adenoma. In recent years there is increased reporting of rare causes of hypopituitarism acquired in adulthood, such as other sellar and parasellar masses, brain damage, vascular lesions, infiltrative/immunological/inflammatory diseases and infectious diseases. We report an unusual case of hypopituitarism associated with simultaneously occurring suprasellar tumor and meningitis. Clinical case: A 45-year-old man was brought to the Emergency Department after being found collapsed at his home with a reduced level of consciousness. About 1 week ago, the patient was complaint headache, nausea and vomiting. He had no significant medical history. His initial assessment showed a blood pressure of 130/70 mmHg, heart rate 133/min, and body temperature 38.5 ºC. Initial laboratory finding revealed serum sodium level of 149 mmol/L (135-150), potassium level of 4.3 mmol/L (3.5-5.5), serum osmolality 292 mOsm/Kg (275-295) and urine osmolality 504 mOsm/Kg (400-800). His random cortisol level was 31.8 ug/dl, TSH 0.568 uIu/ml (0.55-4.78), and free T4 10.75 pmol/L (11.5-22.7). From clinical examination and initial investigations, he was diagnosed as having meningitis or encephalitis and was promptly commenced on empirical i.v. antibiotics. The magnetic resonance imaging (MRI) of the brain revealed diffuse leptomeningeal enhancement in both cerebral hemisphere and 1.8*1.5*1.1cm sized, oval-shaped mass in suprasellar portion, which combined peripheral edema. Examination of the cerebrospinal fluid (CSF) following lumbar puncture confirmed meningitis, antibiotics and antiviral agent were continued. After 2 weeks, he suddenly underwent hypotension and polyuria, despite inflammatory markers of blood were improved. Laboratory finding showed serum osmolality 337 mOsm/Kg, urine osmolality 271 mOsm/Kg, serum sodium 153 mmol/L, random cortisol 1.3 ug/dl, and free T4 5.19 uIu/ml. When coupled with the initial results of the brain imaging, this result helped to confirm a hypopituitarism associated with suprasellar tumor and meningitis. The patient's clinical status promptly improved with intravenous hydrocortisone and desmopressin. After that, levothyroxine supplement was started. He had good response to hormone replacement. Conclusion: Hypopituitarism may develop rapidly or slowly depending on the underlying etiology and may involve one, multiple, or all of the pituitary hormones. The clinical presentations of hypopituitarism are usually nonspecific and the recognition of these patients remains the challenge. We emphasize the importance of careful clinical assessment and focused investigations, including cranial imaging and pituitary hormone profiling to establish the underlying diagnosis.

Objective. This study used a continuous glucose monitoring system (CGMS) to investigate the glucose profiles and assess the degree of hyperglycemic excursion after kidney or liver transplantation during the early period after operation. Methods. Patients to whom a CGMS was attached during a postoperative period of approximately one month after transplantation were included. The CGM data of 31 patients including 24 with kidney transplantation (KT) and seven with liver transplantation (LT) were analyzed. Results. Hyperglycemia over 126 mg/dL (fasting) or 200 g/dL (postprandial) occurred in 42.1% (8/19) and 16.7% (1/6) of KT and LT patients, respectively, during this early period after transplantation, except for patients with preexisting diabetes (5 KT, 1 LT). The average mean amplitude of glycemic excursion (MAGE) and mean absolute glucose (MAG) levels were 91.18±26.51 vs. 65.66±22.55 (P<0.05) and 24.62±7.78 vs. 18.18±7.07 (P<0.05) in KT vs. LT patients, respectively, in patients without preexisting DM or PTDM patients who showed normal glucose levels. Average increase from the lowest level to the peak glucose value was higher in KT patients than LT patients (P<0.05). Conclusions. The transplanted organ also needs to be considered as an important factor affecting glucose control and the occurrence of more severe glucose excursions in patients who receive transplantation although immunosuppression agents are well-known important factors; however, our study was limited to the early posttransplantation period. Further studies involving CGM follow-up at regular intervals based on the time since transplantation are needed.

Although diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are different disease entities, they share similar neuropathic symptoms that impede quality of life for these patients. Despite having very similar downstream effects, there have been no direct comparisons between DPN and CIPN with respect to symptom severity and therapeutic responses. We compared peripheral nerve damage due to hyperglycemia with that caused by paclitaxel (PAC) treatment as represented by biochemical parameters, diverse sensory tests, and immunohistochemistry of cutaneous and sciatic nerves. The therapeutic effects of alpha-lipoic acid and DA-9801 were also compared in the two models. Animals were divided into seven groups (n = 7-10) as follows: normal, diabetes (DM), DM + alpha-lipoic acid 100 mg/kg (ALA), DM + DA-9801 (100 mg/kg), paclitaxel-treated rat (PAC), PAC + ALA (100 mg/kg), and PAC + DA-9801 (100 mg/kg). The sensory thresholds of animals to mechanical, heat, and pressure stimuli were altered by both hyperglycemia and PAC when compared with controls, and the responses to sensory tests were different between both groups. There were no significant differences in the biochemical markers of blood glutathione between DM and PAC groups (p .05). Quantitative comparisons of peripheral nerves by intraepidermal nerve fiber density (IENFD) analysis indicated that the DM and PAC groups were similar (6.18 ± 1.03 vs. 5.01 ± 2.57). IENFD was significantly improved after ALA and DA-9801 treatment in diabetic animals (7.6 ± 1.28, 7.7 ± 1.28, respectively, p .05) but did not reach significance in the PAC-treated groups (6.05 ± 1.76, 5.66 ± 1.26, respectively, p .05). Sciatic nerves were less damaged in the PAC-treated groups compared with the DM groups with respect to axonal diameter and area (8.60 ± 1.14 μm vs. 6.66 ± 1.07 μm, and 59.04 ± 15.16 μm

Mean glucose values alone cannot explain the patterns of morbidity and mortality due to dysglycemia in diabetes. Development of continuous glucose monitoring systems has improved the analysis and interpretation of glycemic variability. The roles of glycemic components other than constant hyperglycemia in diabetic complications must be investigated because large clinical studies have indicated that risk factors besides the average glucose value of HbA1c are involved in chronic macrocomplications/microcomplications of diabetes. Among these complications, the pathogenesis of diabetic peripheral neuropathy is particularly complex, and several factors related to glucose and nonglucose pathways have been suggested as risk factors. There is little information regarding the effect of glycemic variability on diabetic peripheral neuropathy, unlike other microvascular complications of retinopathy and nephropathy, and whether glycemic variability causes harmful effects is still a matter of debate. In this review, we discuss the relationships between glycemic variability and diabetic peripheral neuropathy, focusing on somatosensory peripheral neuropathies rather than autonomic neuropathies.

Objective Although bariatric surgery including gastrectomy has recently emerged as a useful treatment for type 2 DM with obesity, it is not clear whether gastrectomy itself can have beneficial effects on glucose metabolism. Therefore, in this study, we investigated changes in blood glucose in patients with and without diabetes who underwent gastrectomy. Methods From Jan 2010 to May 2014, 77 patients with diabetes and 77 patients without diabetes who underwent gastrectomy at Chonbuk National University Hospital, South Korea, were included. We compared fasting plasma glucose levels and HbA1c value before and after gastric surgery. Results After gastrectomy, 59 patients (38.3%) showed reduced fasting plasma glucose levels at the 1 year point, and 80 patients (51.9%) exhibited reduced fasting plasma glucose at 3 years, irrespective of their diabetes status. Among 77 patients with diabetes, decreased fasting plasma glucose was observed in 22 (28.6%) and 46 patients (59.7%) 1 and 3 years after gastrectomy, respectively. In patients who exhibited reduced fasting plasma glucose after gastrectomy, the degree of reduced glucose was as follows: 56.4±48.5 vs 23.2±16.1 mg/dL after 1 year, 58.3±52.3 vs 18.4±13.7 mg/dL after 3 years, in DM and non-DM patient respectively. Conclusions Although there was a significant drop in mean fasting glucose after gastrectomy, not all patients experienced a drop in fasting glucose. Gastrectomy did not show a consistent association with glucose reduction in patients with and without diabetes, and in about half of the patients, fasting plasma glucose levels increased after gastrectomy. Therefore, bariatric surgery including gastrectomy needs to be performed with care in diabetes, and glucose monitoring including oral glucose tolerance tests should be done for assessing or prediction of the glucose state after gastric surgery in non-DM patients.

Disorders of the endocrine system including hormone hyperfunction and hypofunction have multiple effects on cardiovascular system. However, in clinical practice, there are many cases of delayed or overlooked diagnosis of underlying endocrine dysfunction in patients presenting chest pain or other cardiac symptoms. Herein, we report three cases of endocrine hyperfunction presenting as coronary spasm; Graves’ hyperthyroidism, pheochromocytoma, and primary hyperparathyroidism. Chest pains disappear after treatment for these endocrine diseases. Endocrine hyperfunctions such as the three cases described above should be considered as possible diagnosis in patients with complaint of chest pain. High index of suspicion are needed.

Background:While salivary gland ultrasound (SGUS) has widely used for evaluating Sjögren’s syndrome, information on SGUS findings of systemic sclerosis (SSc) is limited.Objectives:We aimed to evaluate the salivary gland involvement in patients with SSc using SGUS.Methods:We consecutively included patients with SSc fulfilling American College of Rheumatology/European League against Rheumatism (ACR/EULAR) 2013 classification criteria, primary Sjögren’s syndrome (pSS) fulfilling ACR/EULAR 2016 classification criteria, and idiopathic sicca syndrome. All patients underwent SGUS examination using the Outcome Measures in Rheumatology (OMERACT) definition of a SGUS scoring system. The hyperechoic bands using 0-3 scoring system (none/50%) and intraglandular power Doppler signal (PDS) were assessed. Hocevar scoring system (0-48) comprising parenchymal echogenicity, homogeneity, hypoechoic areas, hyperechogenic reflections, and clearness of posterior borders were also evaluated.Results:A total of 147 patients were included in the study: SSc (n=59), pSS (n=56), and idiopathic sicca syndrome (n=32). The proportion of the highest OMERACT grades among the four glands≥ 2 were significantly higher in SSc (54.2%) and pSS (62.5%) than idiopathic sicca syndrome (3.1%). Total OMERACT SGUS scores, total fibrosis scores, Hocevar score were significantly higher in SSc and pSS compared to idiopathic sicca syndrome (Table 1). The proportion of the highest fibrosis grades among the four glands ≥2 were significantly higher in SSc (79.7%) than pSS (62.5%) and idiopathic sicca syndrome (46.9%). There were no significant differences in PDS among 3 groups. Twenty-one patients (65.6%) of 32 SSc patients with OMERACT grade ≥2 were anti-centromere antibody (ACA)-positive compared with 9/27 (33.3%) SSc patients with scores of 0–1. The positivity of anti-Ro-60/SSA were also significantly higher in SSc patients with SGUS grade ≥2 (37.5%) than those with SGUS scores of 0–1 (3.7%). In SSc group, there was no significant difference in auto-antibody profile and organ involvement between patients with fibrosis scores ≥2 and those with scores 0-1.Table 1.Characteristics of the study population included in the studySSc(n =59)pSS(n =56)Idiopathic sicca syndrome(n =32)P- value(SSc vs pSS)P- value(SSc vs idiopathic sicca)P- value(pSS vs idiopathic sicca)Age, mean (SD), years54.8 (12.1)60.5 (11.9)62 (11.2)0.0130.0060.559Female, n (%)53 (89.8)56 (100)28 (87.5)0.0280.7370.015Anti-Ro-60/SSA, n (%)13 (22.0)39 (69.6)7 (21.9)0.986ACA, n (%)30 (30.8)8 (14.3)2 (6.3)0.238Anti-topoisomerase, n (%)16 (27.1)0 (0)0 (0)1.000Max OMERACT US grade ≥ 2, n (%)32 (54.2)35 (62.5)1 (3.1)0.369Total SGUS scores, median (IQR)4.0 (6)7.0 (8)0 (1)0.231Max fibrosis US grade ≥ 2, n (%)47 (79.7)35 (62.5)15 (46.9)0.0420.0040.263Total fibrosis scores, median (IQR)6 (3)6 (6)4 (4)0.674< 0.0010.006PDS sum scores of four salivary glands, median (IQR)2 (5)0 (4)0 (2)0.1310.1521.000Conclusion:Based on OMERACT definitions for SGUS, more than half of the patients with SSc, especially those with ACA, had salivary gland involvement. Salivary glandular fibrosis is more prominent in patients with SSc than those with pSS and idiopathic sicca syndrome.References:[1]Jousse-Joulin S, et al. Video clip assessment of a salivary gland ultrasound scoring system in Sjogren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Ann Rheum Dis. 2019;78(7):967-73.Disclosure of Interests:None declared

Background:In the diagnosis of primary Sjogren’ syndrome (SS), salivary gland ultrasound is useful tool. Until now, there is no data for ultasonographic changes of major salivary glands over time.Objectives:This study aimed to evaluate the changes in abnormalities of salivary gland ultrasound (SGUS) over time in patients with pSS.Methods:Patients with pSS (n=70) and idiopathic sicca syndrome (n=18) underwent SGUS twice at baseline and 2 years later. The semi-quantitative SGUS score (0-48) was used, which comprises five parameters: parenchymal echogenicity, homogeneity, hypoechoic areas, hyperechogenic reflections, and clearness of posterior borders. The intraglandular power Doppler signal (PDS) was also assessed. The changes of these SGUS variables were compared in patients with pSS and idiopathic sicca syndrome.Results:The median (interquartile range) total SGUS scores at baseline was 27 (14) in patients with and 4 (3) in those with idiopathic sicca syndrome (pp=0.013 andp=0.011, respectively). Homogeneity and hypoechoic areas were the domain to show statistically significant progression of SGUS scores. None of the SGUS scores changed significantly in the patients with idiopathic sicca syndrome. In patients with pSS, baseline and follow-up PDS sum scores of four salivary glands were significant higher in worsening SGUS group (n=13) than no change/improvement SGUS group (n=55/2).Conclusion:The structural abnormalities in major salivary glands assessed using SGUS scores progressed significantly in patients with pSS. In pSS group, 18.6% patients had worsening SGUS scores during 2 years. Intra-glandular hypervascularity was associated with worsening of salivary gland abnormalities.References:[1]Delli K, Dijkstra PU, Stel AJ, Bootsma H, Vissink A, Spijkervet FK. Diagnostic properties of ultrasound of major salivary glands in Sjogren’s syndrome: a meta-analysis. Oral diseases. 2015;21(6):792-800.[2]Jousse-Joulin S, Devauchelle-Pensec V, Cornec D, Marhadour T, Bressollette L, Gestin S, et al. Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjogren’s Syndrome. Arthritis & rheumatology (Hoboken, NJ). 2015;67(6):1623-8.[3]Gazeau P, Cornec D, Jousse-Joulin S, Guellec D, Saraux A, Devauchelle-Pensec V. Time-course of ultrasound abnormalities of major salivary glands in suspected Sjogren’s syndrome. Joint, bone, spine: revue du rhumatisme. 2018;85(2):227-32.[4]Lee KA, Lee SH, Kim HR. Diagnostic and predictive evaluation using salivary gland ultrasonography in primary Sjogren’s syndrome. Clinical and experimental rheumatology. 2018;36 Suppl 112(3):165-72.Acknowledgments: :This work was funded by the Konkuk University Medical Center Research Grant 2019.Disclosure of Interests:None declared

This study evaluated the effect of jupcheong (soaking in syrup) with/without ginger on lipids and antioxidants of yakgwa (Korean deep-fried confection) during storage. Yakgwa was prepared with a dough consisting of wheat and rice flour (1:1, w/w), sesame oil, and sugar syrup. Shaped dough pieces were consecutively deep-fried in soybean oil at 90 and 150 °C, soaked in syrup with/without ginger powder, and stored at 30 °C in the dark for 8 weeks. Lipid oxidation was evaluated by peroxide and p-anisidine values, and antioxidants were determined spectrophotometrically. Jupcheong reduced lipid oxidation and antioxidant degradation during yakgwa storage, and increased stability by jupcheong was higher in lignans or tocopherols than polyphenols. The results suggest that jupcheong especially with ginger could improve the lipid oxidative stability of yakgwa by higher protection of tocopherols and lignans than polyphenols from degradation, and tocopherols were the most important antioxidants in reducing lipid oxidation of yakgwa.

Strict glucose control is a well-proven therapeutic approach for peripheral neuropathies in patients with diabetes. Alpha lipoic acid (ALA) has also been accepted as a therapeutic agent for diabetic peripheral neuropathy (DPN) in the respect of pathogenesis. However, the potential of ALA as a treatment for DPN in comparison to that of glucose control is unclear. In this study, we compared the neuroprotective potential of glucose control and ALA. Animals were divided into 6 groups based on the intervention used, as follows: normal, diabetes (DM), DM+racemic form of ALA, DM+R form of ALA, DM+once daily insulin glargine, and DM+once daily insulin glargine with twice daily insulin glulisine. Various sensory tests were performed after 12 weeks of treatment, and immunohistochemistry of nerve fibers obtained from the sciatic and cutaneous nerves was performed after 24 weeks of treatment. There were no significant differences between the ALA-treated and insulin-treated DM groups in the sensory tests or in antioxidant activity. The axonal diameters and myelin sheath area of the sciatic nerves and the cutaneous small nerves, as assessed based on intraepidermal nerve fiber density, were similar in the ALA-treated and insulin-treated animals, although there was a non-significant trend for a mild increase in the both basal and rapid-acting insulin group compared with non-treated DM group. In conclusion, our results suggest that the neuroprotective benefits of ALA and insulin-based glucose control may be similar, although glucose control may have had slightly more beneficial effects in this animal model of diabetes. Of note, glucose levels should be strictly controlled, including corrections for fluctuations in the glucose level, to obtain therapeutic benefits in DPN.

Metastasis to the pituitary gland from systemic cancer is a rare condition. The breast and lung are the most common sites of primary tumor metastasis. Most often, they occur in the setting of widespread metastatic disease, which most frequently occurs in elderly patients. However, an increase in the incidence of solitary pituitary metastasis of breast cancer as the first recurrence has been reported. Diabetes insipidus is the most frequent symptom at presentation, and visual field defects or cranial nerve deficits are common symptoms of pituitary metastasis. Unlikely these symptoms, deficiencies of anterior pituitary hormones may only become evident in critical situation because symptoms are of an insidious onset and sometimes nonspecific. We report here on a rare case of solitary pituitary metastasis from breast cancer presenting as hyponatremia without other symptoms.

Background: The Survey of Autonomic Symptom (SAS) scale was reported as an easy instrument to assess the autonomic symp toms in patients with early diabetic neuropathy. In this study, we investigated the relationship between the SAS scale and the parameters of cardiac autonomic neuropathy (CAN) in Korean patients with diabetic peripheral neuropathy (DPN). Methods: The SAS scale was tested in 30 healthy controls and 73 patients with DPN at Chonbuk National University Hospital, in Korea. The SAS score was compared to the parameters of the CAN test and the total symptom score (TSS) for DPN in patients with DPN. Results: The SAS symptom score and total impact score were increased in patients with DPN compared to the control group (P=0.01), particularly in sudomotor dysfunction (P=0.01), and vasomotor dysfunction (P=0.01). The SAS score was increased in patients with CAN compared to patients without CAN (P

The exact effectiveness of supportive care activities, such as exercise, in diabetes patients has yet to be elucidated in the diabetic peripheral neuropathy (DPN) field. Therefore, this study was designed to investigate the effect of regular exercise on the peripheral nerves of streptozotocin-induced diabetic rats. The animals were divided as follows into six groups according to exercise combination and glucose control: Normal group, normal group with exercise (EXE), diabetic group (DM), DM group with EXE, DM + glucose control with insulin (INS), and DM + INS + EXE. Animals in the exercise groups were made to walk on a treadmill machine everyday for 30 min at a setting of 8 m/min without inclination. After 8 weeks, sensory parameters were evaluated, and after 16 weeks, biochemicals and peripheral nerves were quantified by immunohistochemistry and compared among experimental groups. The resulting data showed that fasting blood glucose levels and HbA1c levels were not influenced significantly by exercise in normal and DM groups. However, the current perception threshold and the von Frey stimulation test revealed higher thresholds in the DM + INS + EXE group than in the DM + INS group (P

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

There are controversial reports about the effect of granulocyte colony-stimulating factor (G-CSF) in peripheral nerve protection. Therefore, the present study aimed to investigate the effect of G-CSF on peripheral nerves in streptozotocin (STZ) induced diabetic rats. After STZ or vehicle injection, rats were divided into five groups (n=6) as follows: normal+vehicle, normal+G-CSF (50 µg/kg for 5 days), diabetes mellitus (DM)+vehicle, DM+G-CSF (50 µg/kg for 5 days), and DM+G-CSF extension (50 µg/kg for 5 days and followed by two injections per week up to 24 weeks). Our results showed that the current perception threshold was not significantly different among experimental groups. G-CSF treatment inhibited the loss of cutaneous nerves and gastric mucosal small nerve fibers in morphometric comparison, but statistical significance was not observed. The present results demonstrated that G-CSF has no harmful but minimal beneficial effects with respect to peripheral nerve preservation in diabetic rats.

Hesperidin, a flavanone present in citrus fruits, has been studied as potential therapeutic agents that have anti-tumor activity and apoptotic effects in several cancers, but there is no report about the apoptotic effect of hesperidin in human malignant pleural mesothelioma through the specificity protein 1 (Sp1) protein. We investigated whether hesperidin inhibited cell growth and regulated Sp1 target proteins by suppressing the levels of Sp1 protein in MSTO-211H cells. The IC50 value of hesperidin was determined to be 152.3 μM in MSTO-211H cells for 48 h. Our results suggested that hesperidin (0-160 μM) decreased cell viability, and induced apoptotic cell death. Hesperidin increased Sub-G1 population in MSTO-211H cells. Hesperidin significantly suppressed mRNA/protein level of Sp1 and modulated the expression level of the Sp1 regulatory protein such as p27, p21, cyclin D1, Mcl-1, and survivin in mesothelioma cells. Also, hesperidin induced apoptotic signaling including: cleavages of Bid, caspase-3, and PARP, upregulation of Bax, and down-regulation of Bcl-xl in mesothelioma cells. These results show that hesperidin suppressed mesothelioma cell growth through inhibition of Sp1. In this study, we demonstrated that Sp1 acts as a novel molecular target of hesperidin in human malignant pleural mesothelioma.

BACKGROUND AND PURPOSE Glucagon-like peptide-1 (GLP-1) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation. The aim of this study was to investigate the effect of the GLP-1 pathway on peripheral nerves in streptozotocin-induced diabetic rats. EXPERIMENTAL APPROACH Diabetic and nondiabetic rats were treated with the GLP-1 receptor agonist, synthetic exendin-4 (i.p., 1 nmol·kg−1·day−1) or placebo for 24 weeks, and current perception threshold values, cAMP levels and nerve fibre size in the sciatic nerve were measured. We also investigated GLP-1 receptor expression, quantitative changes in PGP9.5-positive intraepidermal nerve fibres and cleaved caspase 3–stained Schwann cells by immunohistochemistry. KEY RESULTS GLP-1 receptor expression was detected in the sciatic nerve and skin. After exendin-4 treatment, the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced. Also, the decrease in myelinated fibre size or axon/fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated. These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the cAMP level in exendin-4-treated diabetic rats, compared with placebo-treated animals. CONCLUSION AND IMPLICATIONS Synthetic exendin-4 may prevent peripheral nerve degeneration induced by diabetes in an animal model, supporting the hypothesis that GLP-1 may be useful in peripheral neuropathy. The neuroprotection is probably attributable to GLP-1 receptor activation, antiapoptotic effects and restoration of cAMP content.

Background Lichen-derived glucans have been known to stimulate the functions of immune cells. However, immunostimulatory activity of glucan obtained from edible lichen, Umbilicaria esculenta, has not been reported. Thus we evaluated the phenotype and functional maturation of dendritic cells (DCs) following treatment of extracted glucan (PUE). Methods The phenotypic and functional maturation of PUE-treated DCs was assessed by flow cytometric analysis and cytokine production, respectively. PUE-treated DCs was also used for mixed leukocyte reaction to evaluate T cell-priming capacity. Finally we detected the activation of MAPK and NF-κB by immunoblot. Results Phenotypic maturation of DCs was shown by the elevated expressions of CD40, CD80, CD86, and MHC class I/II molecules. Functional activation of DCs was proved by increased cytokine production of IL-12, IL-1β, TNF-α, and IFN-α/β, decreased endocytosis, and enhanced proliferation of allogenic T cells. Polymyxin B, specific inhibitor of lipopolysaccharide (LPS), did not affect PUE activity, which suggested that PUE was free of LPS contamination. As a mechanism of action, PUE increased phosphorylation of ERK, JNK, and p38 MAPKs, and enhanced nuclear translocation of NF-κB p50/p65 in DCs. Conclusion These results indicate that PUE induced DC maturation via MAPK and NF-κB signaling pathways.

Background Clinical experience with the continuous glucose monitoring systems (CGMS) is limited in Korea. The objective of this study is to evaluate the accuracy of the CGMS and the correlation between interstitial fluid and venous plasma glucose level in Korean healthy male subjects. Methods Thirty-two subjects were served with glucose solution contained same amount of test food's carbohydrate and test foods after separate overnight fasts. CGMS was performed over 3 days during hopitalization for each subjects. Venous plasma glucose measurements were carried out during 4 hours (0, 0.25, 0.5, 0.75, 1, 2, 4 hours) just before and after glucose solution and test food load. The performance of the CGMS was evaluated by comparing its readings to those obtained at the same time by the hexokinase method using the auto biochemistry machine (Hitachi 7600-110). Also, correlations between glucose recorded with CGMS and venous plasma glucose value were examined. Results CGMS slightly underestimated the glucose value as compared with the venous plasma glucose level (16.3 ± 22.2 mg/dL). Correlation between CGMS and venous plasma glucose values throughout sensor lifetime is 0.73 (regression analysis: slope = 1.08, intercept = 8.38 mg/dL). Sensor sensitivity can deteriorate over time, with correlations between venous blood glucose and CGMS values dropping from 0.77 during 1st day to 0.65 during 2nd and 3rd day. Conclusion The accuracy of data provided by CGMS may be less than expected. CGMS sensor sensitivity is decreased with the passage of time. But, from this study, CGMS can be used for glucose variability tendency monitoring conveniently to the Korean.

A 59-year-old man was admitted with numbness, pain, and a tingling sensation in both lower legs. He was initially diagnosed with diabetic peripheral neuropathy based on a symptom questionnaire and a quantitative sensory test. Despite symptomatic treatment of diabetic neuropathy, he complained of worsening sensory symptoms and additional motor weakness in both lower extremities. As the motor weakness of both extremities became more aggravated over time, brain and spine imaging tests and a nerve conduction test were performed. The nerve conduction study revealed motor and sensory axonal neuropathy. In his cerebrospinal analysis, albumino-cytologic dissociation, which is compatible to the Gillian-Barre syndrome, was found. Cerebrospinal fluid analysis showed albumino-cytologic dissociation. He was treated with intravenous immunoglobulin and his neurologic deficits were gradually improved.

Present study investigated the morphologic changes of autonomic nerves in the adipose tissue in diabetic animal model. Male obese type 2 diabetic db/db mice and age matched non-diabetic db/m control mice were used. Epididymal adipose tissue from diabetic db/db mice with that from control heterozygous db/m mice was compared using confocal microscopy-based method to visualize intact whole adipose tissue. Immunohistochemistry with tyrosine hydroxylase for sympathetic (SP), choline acetyltransferase for parasympathetic (PSP), and protein gene product 9.5 (PGP 9.5) for whole autonomic nerves was performed. The quantity of immunostained portion of SP, PSP, and PGP 9.5 stained nerve fibers showed decreased trend in diabetic group; however, the ratio of SP/PSP of adipose tissue was higher in diabetic group compared with control group as follows (0.70±0.30 vs. 0.95±0.25, P

Mitomycin C (MMC) is used fairly widely as an anticancer drug, as it possesses mechanisms of action which are preferable to other chemotherapeutic compounds, including cisplatin, docetaxel, and lovastatin. In the previous study, we established the RSV-luc promoter analysis system, which is used to screen drugs against cervical carcinomas caused by HPV infection. We then demonstrated the repression of HPV E6-activated RSV promoter activity by anticancer agents such as carboplatin (CA), cisplatin (CIS), and MMC. In these studies, we focused on the investigation of apoptotic mechanisms in MMC-treated cervical carcinoma cell lines, most notably SiHa/pRSV-luc (KCTC 0427BP) and SiHa. DNA fragmentation assays and TUNEL staining revealed that MMC and CIS, but not CA, resulted in apoptosis. MMC treatment induced a reduction in the expressions of the E6 oncogene and IL-18, in a p53-independent manner. MMC also increased FasL expression and induced the processing of caspases-8 and -3. Our results indicated that MMC induced apoptosis in SiHa/pRSV-luc and SiHa cells via caspase-8 and -3 processing, in a Fas/FasL-dependent manner. MMC also suppressed the expression of IL-18 in the same cells. MMC also down-regulated IkappaB expression, and up-regulated p65 expression. These results suggest that MMC induces apoptosis, not only through caspase-8 and -3 dependent Fas/FasL pathway, but also via the regulation of NF-kappaB activity and IL-18 expression.

Our previous studies showed that the down-modulation of IL-18-induced immune response caused by oncoproteins E6 and E7 as one of the mechanisms underlying immune escape in HPV-induced cervical cancer cells. E42 residue of IL-18 also appears to be critical in the activity of IL-18. Single point mutation E42 in IL-18 show promise in the study of IL-18 binding motifs for HPV oncoproteins. We attempted to ascertain whether site-specific IL-18 mutant E42A would modulate the inhibitory effects of IL-18-induced immune responses via the HPV 16 E6 and E7 oncoproteins. Compared to wild type IL-18, E42A-induced IFN-gamma production was not inhibited by HPV 16 E6 and E7. In vitro and in vivo binding assays have also revealed that E6 and E7 do not result in the inhibition of the binding of E42A to its IL-18 receptor alpha chain. There were no effects on the E42A-induced phosphorylations of p38 and JNK observed in the presence of E6 or E7. The degradation of IkappaB by E42A was not affected by E6 or E7 in NK0 cells. Moreover, E42A-induced NF-kappaB activation was also not inhibited by these oncoproteins. These results suggest that E42A is a stronger activator than wild type IL-18, and is not susceptible to inhibition by the HPV oncoproteins E6 and E7. Thus, it is suggested that E42A could be used in immunotherapy for patients with cervical cancer.