A Novel Anti-PD-L1 Antibody Exhibits Antitumor Effects on Multiple Myeloma in Murine Models via Antibody-Dependent Cellular Cytotoxicity

Multiple myeloma is a malignant cancer of plasma cells. Despite recent progress with immunomodulatory drugs and proteasome inhibitors, it remains an incurable disease that requires other strategies to overcome its recurrence and non-response. Based on the high expression levels of programmed death-ligand 1 (PD-L1) in human multiple myeloma isolated from bone marrow and the murine myeloma cell lines, NS-1 and MOPC-315, we propose PD-L1 molecule as a target of anti-multiple myeloma therapy. We developed a novel anti-PD-L1 antibody containing a murine immunoglobulin G subclass 2a (IgG2a) fragment crystallizable (Fc) domain that can induce antibody-dependent cellular cytotoxicity. The newly developed anti-PD-L1 antibody showed significant antitumor effects against multiple myeloma in mice subcutaneously, intraperitoneally, or intravenously inoculated with NS-1 and MOPC-315 cells. The anti-PD-L1 effects on multiple myeloma may be related to a decrease in the immunosuppressive myeloidderived suppressor cells (MDSCs), but there were no changes in the splenic MDSCs after combined treatment with lenalidomide and the anti-PD-L1 antibody. Interestingly, the newly developed anti-PD-L1 antibody can induce antibody-dependent cellular cytotoxicity in the myeloma cells, which differs from the existing anti-PD-L1 antibodies. Collectively, we have developed a new anti-PDL1 antibody that binds to mouse and human PD-L1 and demonstrated the antitumor effects of the antibody in several syngeneic murine myeloma models. Thus, PD-L1 is a promising target to treat multiple myeloma, and the novel anti-PD-L1 antibody may be an effective anti-myeloma drug via antibody-dependent cellular cytotoxicity effects.

Morin Hydrate Inhibits Influenza Virus entry into Host Cells and Has Anti-inflammatory Effect in Influenzainfected Mice

Influenza virus is the major cause of seasonal and pandemic flu. Currently, oseltamivir, a potent and selective inhibitor of neuraminidase of influenza A and B viruses, is the drug of choice for treating patients with influenza virus infection. However, recent emergence of oseltamivir-resistant influenza viruses has limited its efficacy. Morin hydrate (3,5,7,2′,4′-pentahydroxyflavone) is a flavonoid isolated from Morus alba L. It has antioxidant, anti-inflammatory, neuroprotective, and anticancer effects partly by the inhibition of the NF-кB signaling pathway. However, its effects on influenza virus have not been studied. We evaluated the antiviral activity of morin hydrate against influenza A/Puerto Rico/8/1934 (A/ PR/8; H1N1) and oseltamivir-resistant A/PR/8 influenza viruses in vitro. To determine its mode of action, we carried out time course experiments, and time of addition, hemolysis inhibition, and hemagglutination assays. The effects of the co-administration of morin hydrate and oseltamivir were assessed using the murine model of A/PR/8 infection. We found that morin hydrate reduced hemagglutination by A/PR/8 in vitro. It alleviated the symptoms of A/PR/8-infection, and reduced the levels of pro-inflammatory cytokines and chemokines, such as TNF-α and CCL2, in infected mice. Co-administration of morin hydrate and oseltamivir phosphate reduced the virus titers and attenuated pulmonary inflammation. Our results suggest that morin hydrate exhibits antiviral activity by inhibiting the entry of the virus.

Antiviral and Anti-Inflammatory Activities of Pochonin D, a Heat Shock Protein 90 Inhibitor, against Rhinovirus Infection

Human rhinoviruses (HRV) are one of the major causes of common cold in humans and are also associated with acute asthma and bronchial illness. Heat-shock protein 90 (Hsp90), a molecular chaperone, is an important host factor for the replication of single-strand RNA viruses. In the current study, we examined the effect of the Hsp90 inhibitor pochonin D, in vitro and in vivo, using a murine model of human rhinovirus type 1B (HRV1B) infection. Our data suggested that Hsp90 inhibition significantly reduced the inflammatory cytokine production and lung damage caused by HRV1B infection. The viral titer was significantly lowered in HRV1B-infected lungs and in Hela cells upon treatment with pochonin D. Infiltration of innate immune cells including granulocytes and monocytes was also reduced in the bronchoalveolar lavage (BAL) by pochonin D treatment after HRV1B infection. Histological analysis of the lung and respiratory tract showed that pochonin D protected the mice from HRV1B infection. Collectively, our results suggest that the Hsp90 inhibitor, pochonin D, could be an attractive antiviral therapeutic for treating HRV infection.

Development of New Preventive and Therapeutic Vaccines for Tuberculosis

Tuberculosis (TB) is a contagious disease that has been responsible for the death of one billion people in the last 200 years. Until now, the only vaccine approved for the prevention of TB is Bacillus Calmette-Guérin (BCG), which is prepared by attenuating Mycobacterium bovis. However, one of the limitations of BCG is that its preventive effect against pulmonary TB varies from person to person. Therefore, there arises a need for a new TB vaccine to replace or supplement BCG. In this review, we have summarized the findings of current clinical trials on preventive and therapeutic TB vaccine candidates. In addition, we have discussed a novel vaccination approach using the cell-based vaccine presenting early secretory antigenic target-6 (ESAT-6), which is a potent immunogenic antigen. The role of ESAT-6 in hosts has also been described.

Obstructive sleep apnea with excessive daytime sleepiness is associated with non-alcoholic fatty liver disease regardless of visceral fat

BACKGROUND/AIMS: Obstructive sleep apnea (OSA) is associated with an increased risk of obesity and non-alcoholic fatty liver disease (NAFLD), but it remains unclear whether the risk of NAFLD is independently related to OSA regardless of visceral obesity. Thus, the aim of the present study was to examine whether OSA alone or in combination with excessive daytime sleepiness (EDS) or short sleep duration was associated with NAFLD independent of visceral fat in Korean adults. METHODS: A total of 621 participants were selected from the Korean Genome and Epidemiology Study (KoGES). The abdominal visceral fat area (VFA) and hepatic fat components of the participants were assessed using computed tomography scans and they were then categorized into four groups depending on the presence of OSA and EDS. RESULTS: The proportions of NAFLD were 21.1%, 18.5%, 32.4%, and 46.7% in participants without OSA/EDS, with only EDS, with only OSA, and with both OSA and EDS, respectively. A combination of OSA and EDS increased the odds ratio (OR) for developing NAFLD (OR, 2.75; 95% confidence interval [CI], 1.21 to 6.28) compared to those without OSA/EDS, and this association remained significant (OR, 2.38; 95% CI, 1.01 to 5.59) even after adjusting for VFA. In short sleepers (< 5 hours) with OSA, the adjusted OR for NAFLD was 2.50 (95% CI, 1.08 to 5.75) compared to those sleeping longer than 5 hours without OSA. CONCLUSIONS: In the present study, OSA was closely associated with NAFLD in Korean adults. This association was particularly strong in those with EDS or short sleep duration regardless of VFA.

Prevalence and Determinants of Diabetic Nephropathy in Korea: Korea National Health and Nutrition Examination Survey

BACKGROUND: Diabetic nephropathy is a leading cause of end stage renal disease and is associated with an increased risk of cardiovascular mortality. It manifests as albuminuria or impaired glomerular filtration rate (GFR), and the prevalence of diabetic nephropathy varies with ethnicity. The prevalence of diabetic nephropathy and its determinants in Korean adults have not previously been studied at the national level. This cross-sectional study was undertaken to ascertain the prevalence and determinants of albuminuria and chronic kidney disease (CKD) in Korean patients with diabetes. METHODS: The Korea National Health and Nutrition Examination Survey (KNHANES) V, conducted in 2011, was used to define albuminuria (n=4,652), and the dataset of KNHANES IV-V (2008-2011) was used to define CKD (n=21,521). Selected samples were weighted to represent the entire civilian population in Korea. Albuminuria was defined as a spot urine albumin/creatinine ratio >30 mg/g. CKD was defined as a GFR <60 mL/min/1.73 m2. RESULTS: Among subjects with diabetes, 26.7% had albuminuria, and 8.6% had CKD. Diabetes was associated with an approximate 2.5-fold increased risk of albuminuria, with virtually no difference between new-onset and previously diagnosed diabetes. Only systolic blood pressure was significantly associated with albuminuria, and old age, high serum triglyceride levels, and previous cardiovascular disease (CVD) were related with CKD in subjects with diabetes. CONCLUSION: Korean subjects with diabetes had a higher prevalence of albuminuria and CKD than those without diabetes. Blood pressure was associated with albuminuria, and age, triglyceride level, and previous CVD were independent determinants of CKD in subjects with diabetes.

Changes in the clinical manifestations of primary aldosteronism

BACKGROUND/AIMS: Primary aldosteronism (PA) is now widely recognized to have a higher prevalence than was once thought. In view of its increasing prevalence, we compared chronological changes in clinical manifestations of PA according to different times of diagnosis. METHODS: In total, 85 patients diagnosed with PA from January 1986 through March 2012 were reviewed retrospectively, based on their medical records. During two periods-1986 to 2005 and 2006 to 2012-41 and 44 patients, respectively, were diagnosed with PA. We compared the clinical and biological characteristics of PA between these periods. RESULTS: The results demonstrate an increasing trend in the prevalence of idiopathic hyperaldosteronism (IHA; p = 0.19). In the 2006 to 2012 period, patients with PA presented with higher serum potassium levels at the time of diagnosis than in the 1986 to 2005 period (p < 0.0002). Adrenal vein sampling (AVS) was performed mostly in the latter period (82.3%) and the diagnostic accuracy of adrenal computed tomography, compared with AVS, was only 56.2%. About 78.0% versus 86.3% of patients had at least one target organ damage (TOD) in the 1986 to 2005 and 2006 to 2012 periods, respectively (p = 0.39). However, patients with TOD were older and had longer durations of hypertension than patients without, in both periods. CONCLUSIONS: PA is becoming more prevalent. There was an increasing tendency for IHA, and more PA patients presented with normokalemia than in the earlier period. Early and accurate diagnosis of PA with AVS and proper treatment should have substantial prognostic value.

Pheochromocytoma with Markedly Abnormal Liver Function Tests and Severe Leukocytosis

Pheochromocytoma is a rare neuroendocrine tumor arising from the medulla of the adrenal glands, which causes an overproduction of catecholamines. The common symptoms are headache, palpitations, and sweating; however, various other clinical manifestations might also be present. Accurate diagnosis of pheochromocytoma is important because surgical treatment is usually successful, and associated clinical problems are reversible if treated early. A 49-year-old man with a history of uncontrolled hypertension and diabetes mellitus presented with chest pain, fever, and sweating. His liver function tests and white blood cell counts were markedly increased and his echocardiography results suggested stress-induced cardiomyopathy. His abdominal computed tomography showed a 5x5-cm-sized tumor in the left adrenal gland, and laboratory tests confirmed catecholamine overproduction. After surgical resection of the left adrenal gland, his liver function tests and white blood cell counts normalized, and echocardiography showed normal cardiac function. Moreover, his previous antihypertensive regimen was deescalated, and his previously uncontrolled blood glucose levels normalized without medication.

Fatal Hypersensitivity Reactions Induced by Re-Administration of Rifampin in an Immunocompetent Patient with Tuberculous Lymphadenopathy / 대한내과학회지

A 44-year-old patient who had been diagnosed with tuberculous lymphadenopathy came to our hospital with a rash. He began to take antituberculous medications, but the next day, a rash appeared and persisted for one week. When he came to the hospital, he had already stopped the medication by his own decision. We stopped all drugs and reintroduced one drug at a time. After re-administration of rifampin, anaphylactic shock and subsequent acute renal failure and rhabdomyolysis occurred. Intensive care was performed, but the patient died 60 h after the first hypersensitive reaction that occurred due to rifampin. Anaphylaxis and subsequent rhabdomyolysis induced by rifampin is an extremely rare event. It is necessary to initially prescribe low dose rifampin in cases of re-administration.

Thyroid Dysfunction of North Korean Women Living in South Korea, Focusing on Subclinical Hypothyroidism

BACKGROUND: Thyroid function depends on ethnic and environmental factors. North Korean refugees have the same genetic background as South Koreans, but they have been exposed to different environments. This study examines the prevalence and pattern of thyroid disorders in North Korean women living in South Korea, focusing on subclinical hypothyroidism (SCH). METHODS: The intended sample was a total of 327 North Korean women residing in Seoul. Health questionnaires and medical examinations, including serum thyrotropin (thyroid stimulating hormone, TSH), free thyroxine, and thyroid autoantibodies, were conducted. RESULTS: The prevalence of SCH was 9.4%. In logistic regression analysis, smoking, menopause, length of stay in South Korea, body mass index, history of thyroid disease, and metabolic syndrome were not associated with the risk of SCH. Whereas, the positivity of autoantibodies were associated with a high risk for SCH (odds ratio [OR], 4.840; 95% confidence interval [CI], 1.80-13.017; P = 0.002), and age was associated with a low risk for SCH (OR, 0.94; 95% CI, 0.888-0.994; P = 0.031). The serum TSH levels also decreased with increasing age, and in particular, there was significant difference between 30-39 years, and over 60 years (2.33 +/- 1.51 microIU/mL vs. 1.54 +/- 0.73 microIU/mL, P = 0.028). CONCLUSION: In North Korean women, the positivity of autoantibodies was associated with a high risk for SCH. But interestingly, a younger age was associated with a high risk for SCH. Considering that they suffered from severe famine at the period of growth, and this led to malnutrition, their thyroid dysfunction might be associated with the peculiar environment that they experienced.

Effect of Eplerenone, a Selective Aldosterone Blocker, on the Development of Diabetic Nephropathy in Type 2 Diabetic Rats

BACKGROUND: Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. METHODS: Animals were divided into six groups as follows: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. RESULTS: Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-beta1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. CONCLUSION: Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.

Fatal Hypersensitivity Reactions Induced by Re-Administration of Rifampin in an Immunocompetent Patient with Tuberculous Lymphadenopathy / 대한내과학회지

A 44-year-old patient who had been diagnosed with tuberculous lymphadenopathy came to our hospital with a rash. He began to take antituberculous medications, but the next day, a rash appeared and persisted for one week. When he came to the hospital, he had already stopped the medication by his own decision. We stopped all drugs and reintroduced one drug at a time. After re-administration of rifampin, anaphylactic shock and subsequent acute renal failure and rhabdomyolysis occurred. Intensive care was performed, but the patient died 60 h after the first hypersensitive reaction that occurred due to rifampin. Anaphylaxis and subsequent rhabdomyolysis induced by rifampin is an extremely rare event. It is necessary to initially prescribe low dose rifampin in cases of re-administration.

The Influence of Gender on ProfessionalismFemale in Trainees / 한국의학교육

PURPOSE: This study aimed to analyze the experience of female trainees who were trained in hospitals after graduating from medical school, focusing on methods of representing their gender in training courses. METHODS: We interviewed 8 trainees who had been trained in a hospital in Seoul and 4 faculties from June 2010 to October 2010. We analyzed their similarities and differences and developed a vocational identity formation process to represent gender. RESULTS: Gender was represented contradictorily in their training course, affecting their choice of specialties and interactions with patients. But, female trainees did not want to their being distinguished from their male counterparts with regard to being a good doctor to be influenced by meritocracy. It was difficult for them to bear children and balance work and family life due to aspects of the training system, including long work hours and the lack of replacement workers. Consequently, they asked their parents to help with child care, because hospitals are not interested in the maternity system. Female trainees did not consider being a doctor to be a male profession. Likely, they believed that their femininity influenced their professionalism positively. CONCLUSION: The methods of representing gender are influenced by the training system, based a male-dominated apprenticeship. Thus, we will research the mechanisms that influence gender-discriminated choices in specialties, hospitals, and medical schools and prepare a maternity care system for female trainees. Strategies that maximize recruitment and retention of women in medicine should include a consideration of alternative work schedules and optimization of maternity leave and child care opportunities.

Successful Localization of Distant Metastasis in Parathyroid Carcinoma Using Intraoperative Parathyroid Hormone Assay

Intra-operative parathyroid hormone (IOPTH) assay is a useful tool to confirm complete excision of all hyper-functioning parathyroid gland tissue. In this report, we describe a case with successful localization of distant metastasis in a patient with parathyroid carcinoma using the IOPTH assay. A 53-year-old man presented to our clinic with a serum calcium level of 11.8 mg/dL and an intact PTH level of 233.3 pg/mL. He had been treated for parathyroid carcinoma eleven years ago. Two suspected metastatic lesions were detected on the chest computed tomography. Due to the vastly different surgical field necessary to excise each lesion, we preferentially removed only one lesion and we monitored the other remaining suspected lesion without resection via IOPTH assay. Six months later, the patient's serum calcium and intact PTH levels remained within their normal ranges. To the best of our knowledge, this is the first case to effectively utilize IOPTH assay for the management of metastatic parathyroid carcinoma.

The Strategies of Feedback to Improve Medical Students' Performance / 한국의학교육

No abstract available.

Analysis of the Characteristics of Discussion Materials that Promote Group Discussion in the Medical Humanities / 한국의학교육

PURPOSE: This study aims to analyze the characteristics of discussion materials that promote student participation in discussions, satisfaction with student instruction, and tutor intervention in the medical humanities. METHODS: We surveyed 117 premedical students and 7 tutors who attended 4-week group discussions in the medical humanities in 2010. We described the discussion materials using the following 4 characteristics as independent variables: material type, level of understanding, interest, and quantity. Dependent variables were: student participation in the discussion, student instruction satisfaction, and tutor intervention. Correlation analysis, multiple regression analysis, and crosstab were performed using SPSS 15.0. RESULTS: The correlation between the characteristics of the discussion materials differed by grade. When the books were chosen as the discussion material in the instruction of first-year premedical students, the correlation between level of understanding, interest, and quantity was negative. Higher levels of understanding of the material and interest in the material led to an increase in discussion participation among both first- and second-year premedical students. Higher levels of understanding and interest of the discussion material also increased student satisfaction with the instruction, regardless of grade. Finally, levels of understanding of the material affected the degree of tutor intervention. Tutors intervened more often in discussions with first-year premedical students than with second-year premedical students. CONCLUSION: Differences in grades and the understanding of the discussion material should be considered when choosing discussion materials. Further study is required to continue the development of the discussion model and improve methods of facilitate discussion among students in the medical humanities.

Hyperprolactinemia-Associated Breast Uptake of Radioiodine Following 131I Postablation Scan in Differentiated Thyroid Cancer

Scanning with whole-body 131I scintigraphy after surgery has been a valuable diagnostic modality in the surveillance of patients with differentiated thyroid cancer. Radioiodine uptake is rarely observed in non-lactating breast tissue, which mimics thyroid cancer metastasis. We now report a case of a 45-year-old female thyroid cancer patient who underwent radioiodine therapy, and in whom breast uptake of radioiodine was observed on a post-therapy whole body scan. Her serum prolactin level was elevated to 328 ng/mL at the time of the radioiodine uptake, and the hyperprolactinemia was induced by her antipsychotic medications. Six months after she discontinued that medication, her serum prolactin level was normalized to 12.6 ng/mL and breast uptake of iodine was no longer present in a follow-up whole body scan.

The Relationship of the Severity of Sleep Apnea Syndrome to the Resting Energy Expenditure and Leptin / 결핵

BACKGROUND: Obesity is present in the majority of adult patients with obstructive sleep apnea(OSA) and is considered to be a major risk factor for its development. A reduction in body weight has been associated with substantial improvement in the severity of apnea. However, a variety of treatment strategies for obesity have yielded limited sucess. This study was done to determine resting energy expenditure(REE) in patients with obstructive sleep apnea and the correlation between the severity of sleep apnea and REE, and to investigate whether leptin influences REE and correlated with the severity of sleep apnea in 39 patients with OSA and 45 controls matched for obesity. METHOD: Overnight polysomnography was performed on all subjects using standard techniques. Measurements of REE were made using a Sensormedic Vmax 229 and a canopy system. Serum leptin concentration was measured by human leptin RIA kit of LINCO Reasearch INC. RESULTS: REE was greater in patients with OSA compared with controls, but there was no differences between the two groups on REE%. And also there was no significant correlation between anthropometric data, polysomnographic data and REE%. Serum leptin was linearly related to body mass index(BMI), apnea index, apnea hypopnea index and lowest arterial oxygen saturation(SaO2) but not related to REE%. CONCLUSION: This study suggests the following firstly patients with sleep apnea have a pattern of obesity characterized by energy homeostasis at an elevated body weight set-point. In order to achieve a lower body weight in these patients, it may be necessary to increase energy expenditure by increasing physical activity. Secondly leptin levels was not correlated with REE, suggesting that leptin may predominantly regulate body fat by altering eating behavior rather than calorigenesis. Lastly leptin level was significantly correlated with the severity of sleep apnea. These elevated levels of leptin in patients of sleep apnea may be related to the obesity, however it needs further studies to determine the relationship between the severity of sleep apnea and serum leptin.

Polycythemia vera combined with coagulation disorder: A case report / 영남의대학술지

We report a case of polycythemia vera combined with coagulation disorder. The patient was 54 years old man who complained of continuous bleeding after incision of skin abscess 20days ago. Laboratory tests were revealed prolonged aPTT and slightly prolonged PT. Coagulation factor, I, VIII, IX, XI and fibrinogen decreased, however FDP did not increased. It appears that patient with polycythemia vera have chronic activation of coagulation system, probably initiated by activation of factor XII. Platelet aggregation test to ADP, collagen, epinephrine was also revealed poor response.

One Case of Insulinoma / 영남의대학술지

Insulinoma is a rare tumor, occurring more often in women and in the older age range. Eighty percent of patients have a single benign tumor, usually 2 cm in diameter, located with about equal frequency in body, head or tail of pancreas and amenable to surgical cure. About 10% have multiple tumors. The remaining 10% of patients have metastatic malignant insulinoma. The symptom of insulinoma is characterized by the periodic attack of hypoglycemia of blood sugar level below 50mg%, by fasting or exertion, and rapid relief of symptom by oral or intravenous administration of glucose. Symptom often lead to misdiagnosis as a neurologic or psychiatric disorder. A case described by authors was 44-year old female with the chief complaints of the loss of consciousness, epileptic seizure although she has been treated by anticonvulsants. Serum blood sugar and insulin level during fasting suggested insulinoma but abdominal computed tomography shows no definitive mass in pancreas. Celiac angiography revealed insulinoma. She transferred to the department of General Surgery and was performed enucleation. Microscopic findings shows the islet cell tumor of pancreas. A brief review of the literature was made.