Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition

Background@#Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors. @*Methods@#Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice. @*Results@#Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus. @*Conclusion@#This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.

Cathelicidin-related Antimicrobial Peptide Contributes to Host Immune Responses Against Pulmonary Infection with Acinetobacter baumannii in Mice

Acinetobacter baumannii is known for its multidrug antibiotic resistance. New approaches to treating drug-resistant bacterial infections are urgently required. Cathelicidin-related antimicrobial peptide (CRAMP) is a murine antimicrobial peptide that exerts diverse immune functions, including both direct bacterial cell killing and immunomodulatory effects. In this study, we sought to identify the role of CRAMP in the host immune response to multidrug-resistant Acinetobacter baumannii. Wild-type (WT) and CRAMP knockout mice were infected intranasally with the bacteria. CRAMP−/− mice exhibited increased bacterial colony-forming units (CFUs) in bronchoalveolar lavage (BAL) fluid after A. baumannii infection compared to WT mice. The loss of CRAMP expression resulted in a significant decrease in the recruitment of immune cells, primarily neutrophils. The levels of IL-6 and CXCL1 were lower, whereas the levels of IL-10 were significantly higher in the BAL fluid of CRAMP−/− mice compared to WT mice 1 day after infection. In an in vitro assay using thioglycollate-induced peritoneal neutrophils, the ability of bacterial phagocytosis and killing was impaired in CRAMP−/− neutrophils compared to the WT cells. CRAMP was also essential for the production of cytokines and chemokines in response to A. baumannii in neutrophils. In addition, the A. baumannii-induced inhibitor of κB-α degradation and phosphorylation of p38 MAPK were impaired in CRAMP−/− neutrophils, whereas ERK and JNK phosphorylation was upregulated. Our results indicate that CRAMP plays an important role in the host defense against pulmonary infection with A. baumannii by promoting the antibacterial activity of neutrophils and regulating the innate immune responses.

Frequency and Severity of Hypoglycemia in Type 2 Diabetes Mellitus Patients Treated with a Sulfonylurea-Based Regimen at University-Affiliated Hospitals in Korea: The Naturalistic Evaluation of Hypoglycemic Events in Diabetic Subjects Study / 가정의학회지

BACKGROUND: We assessed the frequency and severity of hypoglycemia in type 2 diabetes mellitus patients treated with sulfonylurea monotherapy or sulfonylurea+metformin. METHODS: We conducted a retrospective, observational, cross-sectional study in 2011 and 2012 including patients with type 2 diabetes mellitus aged ≥30 years who were treated with ≥6 months of sulfonylurea monotherapy or sulfonylurea+metformin at 20 university-affiliated hospitals in Korea. At enrollment, glycated hemoglobin (HbA1c) was assessed; participants completed self-reported questionnaires describing hypoglycemia incidents over the past 6 months. A review of medical records up to 12 months before enrollment provided data on demographics, disease history, comorbidities, laboratory results, and drug usage. RESULTS: Of 726 enrolled patients, 719 were included (55.6% male); 31.7% and 68.3% were on sulfonylurea monotherapy and sulfonylurea+metformin, respectively. Mean±standard deviation age was 65.9±10.0 years; mean HbA1c level was 7.0%±1.0%; 77.8% of patients had hypertension (89.4% used antihypertensive medication); 60.5% had lipid disorders (72.5% used lipid-lowering medication); and 52.0% had one or more micro- or macrovascular diseases. Among patients with A1c measurement (n=717), 56.4% achieved therapeutic goals (HbA1c <7.0%); 42.4% (305/719) experienced hypoglycemia within 6 months of enrollment; and 38.8%, 12.9%, 12.7%, and 3.9% of patients experienced mild, moderate, severe, and very severe hypoglycemia symptoms, respectively. Several reported hypoglycemia frequency as 1–2 times over the last 6 months. The mean number of very severe hypoglycemia episodes was 3.5±5.5. CONCLUSION: Among type 2 diabetes mellitus patients treated with sulfonylurea-based regimens, glycemic levels were relatively well controlled but hypoglycemia remained a prevalent side effect.

A Putative Adverse Outcome Pathway Relevant to Carcinogenicity Induced by Sulfuric Acid in Strong Inorganic Acid Mists

Based on epidemiological studies, an International Agency for Research on Cancer Working Group determined that strong inorganic acid mists containing sulfuric acid are carcinogenic to human even though, sulfuric acid, per se, is not. Accumulative studies indicate that there is a link between chronic occupational exposure to sulfuric acid mists and an increased risk of laryngeal cancer. Unintended, acute exposure to sulfuric acid mists can cause corrosive damage to target tissues depending on the route of exposure. This review compares the toxicity and carcinogenicity of sulfuric acid mists compared to other strong inorganic acid mists. It also examines the routes and duration of exposure (short-term, prolonged, and long-term). In vivo evidence does not support or refute the carcinogenicity of sulfuric inorganic mists even though its co-carcinogenic or promoting potential has been considered. On the basis of existing evidence on sulfuric acid mist toxicity, we suggested a putative adverse outcome pathway (AOP) relevant to carcinogenicity caused by mists containing sulfuric acid. A possible key factor involved in sulfuric acid mist carcinogenesis is the genotoxic effects of low pH since it can increase instability in chromosomes and DNA. A putative AOP for sulfuric acid mist carcinogenicity would help generate better risk assessments and more accurate predictions regarding the risk of developing cancer due to prolonged exposure. Establishing an AOP would also be useful for future studies examining the carcinogenicity of other strong inorganic mists.

Application of the Adverse Outcome Pathway Framework to Risk Assessment for Predicting Carcinogenicity of Chemicals

As industry develops in modern society, many chemicals are being used. The safety of chemicals is an important issue because humans are constantly exposed to chemicals throughout their daily life. Through a risk assessment, the hazardous human effects of chemicals can be identified. Recently, the adverse outcome pathway (AOP) framework has been used to predict the adverse effects of chemicals. As a conceptual framework for organizing existing biological knowledge, the AOP consists of a molecular initiating event, key events, and an adverse outcome. These independent elements represent biological responses and are connected by key event relationships. This AOP framework provides intuitive hazard identification that can be helpful for carcinogenic risk assessment of chemicals. In this review, we introduce the application of the AOP framework to risk assessment for predicting carcinogenicity of chemicals and illustrate the utility of this approach for cancer prevention.

Establishment of Effective Mouse Model of Premature Ovarian Failure Considering Treatment Duration of Anticancer Drugs and Natural Recovery Time

OBJECTIVES: This study was aimed to establish the most effective premature ovarian failure (POF) mouse model using Cyclophosphamide (CTX), busulfan (Bu), and cisplatin considering treatment duration of anticancer drugs and natural recovery time. METHODS: POF was induced by intraperitoneally injecting CTX (120 mg/kg)/Bu (12 mg/kg) for 1 to 4 weeks or cisplatin (2 mg/kg) for 3 to 14 days to C57BL/6 female mice aged 6 to 8 weeks. Controls were injected with equal volume of saline for the same periods. Body weight was measured every week, and ovarian and uterine weights were measured after the last injection of anticancer drug. To assess ovarian function, POF-induced mice were superovulated with pregnant mare serum gonadotropin and human chorionic gonadotropin, and then mated with male. After 18 hours, zygotes were retrieved and cultured for 4 days. Finally, the mice were left untreated for a period of times after the final injection of anticancer drug, and the time for natural recovery of ovarian function was evaluated. RESULTS: After 2 weeks of CTX/Bu injection, ovarian and uterine weights, and ovarian function were decreased sharply. Cisplatin treatment for 10 days resulted in a significant decrease in ovarian and uterine weight, and ovarian function. When POF was induced for at least 2 weeks for CTX/Bu and for at least 10 days for cisplatin, ovarian function did not recover naturally for 2 weeks and 1 week, respectively. CONCLUSIONS: These results suggest that CTX/Bu should be treated for at least 2 weeks and cisplatin for at least 10 days to establish the most effective primary ovarian insufficiency mouse model.

Corn silk extract improves benign prostatic hyperplasia in experimental rat model

BACKGROUND/OBJECTIVES: This study was conducted to investigate the effect of a corn silk extract on improving benign prostatic hyperplasia (BPH). MATERIALS/METHODS: The experimental animals, 6-week-old male Wistar rats, were divided into sham-operated control (Sham) and experimental groups. The experimental group, which underwent orchiectomy and received subcutaneous injection of 10 mg/kg of testosterone propionate to induce BPH, was divided into a Testo Only group that received only testosterone, a Testo+Fina group that received testosterone and 5 mg/kg finasteride, a Testo+CSE10 group that received testosterone and 10 mg/kg of corn silk extract, and a Testo+CSE100 group that received testosterone and 100 mg/kg of corn silk extract. Prostate weight and concentrations of dihydrotestosterone (DHT), 5α-reductase 2 (5α-R2), and prostate specific antigen (PSA) in serum or prostate tissue were determined. The mRNA expressions of 5α-R2 and proliferating cell nuclear antigen (PCNA) in prostate tissue were also measured. RESULTS: Compared to the Sham group, prostate weight was significantly higher in the Testo Only group and decreased significantly in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups (P < 0.05), results that were consistent with those for serum DHT concentrations. The concentrations of 5α-R2 in serum and prostate as well as the mRNA expression of 5α-R2 in prostate were significantly lower in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups than that in the Testo Only group (P < 0.05). Similarly, the concentrations of PSA in serum and prostate were significantly lower in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups (P < 0.05) than in the Testo Only group. The mRNA expression of PCNA in prostate dose-independently decreased in the Testo+CSE-treated groups (P < 0.05). CONCLUSIONS: BPH was induced through injection of testosterone, and corn silk extract treatment improved BPH symptoms by inhibiting the mRNA expression of 5α-R2 and decreasing the amount of 5α-R2, DHT, and PSA in serum and prostate tissue.

Erratum: Correction of Figure: Clinical Implications of Various Criteria for the Biochemical Diagnosis of Insulinoma

In the original article, the legend of Fig. 1 was incorrect. The solid line was noninsulinoma, and the dotted line was insulinoma.

Neutrophil-to-lymphocyte Ratio in Diagnosis of Systemic Sclerosis for Prediction of Interstitial Lung Disease

OBJECTIVE: The neutrophil-to-lymphocyte ratio (NLR) is elevated in inflammatory diseases, but its clinical significance in systemic sclerosis (SSc) is unclear. This study evaluated NLR in diagnosing SSc and in predicting lung involvement such as interstitial lung disease (ILD). METHODS: The medical records of 88 patients with SSc and 50 healthy controls were reviewed. Exclusion criteria included active infection or the presence of any hematological, cardiovascular, or metabolic disorder. The NLR was compared between patients with SSc and healthy controls, and associations between NLR and lung involvement were analyzed. RESULTS: The NLR was significantly higher in patients with SSc compared to healthy controls (NLR, 3.95±6.59 vs. 2.00±1.07, p<0.01). Patients with SSc and ILD had higher NLR levels than those without ILD (p<0.01, p<0.05). NLR was negatively associated with forced vital capacity (r=−0.341, p<0.01), but not with diffusing capacity for carbon monoxide. Receiver-operating characteristics analysis of NLR to predict ILD in patients with SSc showed that the area under the curve was 0.763. The cut-off NLR value for prediction of lung involvement was determined to be 2.59 (sensitivity, 0.700; specificity, 0.729; p<0.01). CONCLUSION: NLR may be a promising marker that reflects ILD in patients with SSc, and values greater than 2.59 were useful in predicting ILD.

High maysin corn silk extract reduces body weight and fat deposition in C57BL/6J mice fed high-fat diets

BACKGROUNG/OBJECTIVES: The study was performed to investigate the effects and mechanisms of action of high maysin corn silk extract on body weight and fat deposition in experimental animals. MATERIALS/METHODS: A total of 30 male C57BL/6J mice, 4-weeks-old, were purchased and divided into three groups by weight using a randomized block design. The normal-fat (NF) group received 7% fat (diet weight basis), the high-fat (HF) group received 25% fat and 0.5% cholesterol, and the high-fat corn silk (HFCS) group received high-fat diet and high maysin corn silk extract at 100 mg/kg body weight through daily oral administration. Body weight and body fat were measured, and mRNA expression levels of proteins involved in adipocyte differentiation, fat accumulation, fat synthesis, lipolysis, and fat oxidation in adipose tissue and the liver were measured. RESULTS: After experimental diet intake for 8 weeks, body weight was significantly lower in the HFCS group compared to the HF group (P < 0.05), and kidney fat and epididymal fat pad weights were significantly lower in the HFCS group compared to the HF group (P < 0.05). In the HFCS group, CCAAT/enhancer binding protein-β, peroxisome proliferator-activated receptor-γ1 (PPAR-γ1), and PPAR-γ2 mRNA expression levels were significantly reduced (P < 0.05) in the epididymal fat pad, whereas cluster of differentiation 36, lipoprotein lipase, acetyl-CoA carboxylase-1, sterol regulatory element binding protein-1c, pyruvate dehydrogenase kinase, isozyme-4, glucose-6-phosphate dehydrogenase, and stearoyl-CoA desaturase-1 mRNA expression levels were significantly decreased in liver and adipose tissues (P < 0.05). In the HFCS group, mRNA expression levels of AMP-activated protein kinase, hormone-sensitive lipase, and carnitine palmitoyltransferase-1 were elevated (P < 0.05). CONCLUSIONS: It can be concluded that high maysin corn silk extract inhibits expression of genes involved in adipocyte differentiation, fat accumulation, and fat synthesis as well as promotes expression of genes involved in lipolysis and fat oxidation, further inhibiting body fat accumulation and body weight elevation in experimental animals.

A Case of Gastric Langerhans Cell Histiocytosis with Spontaneous Regression

A 44-year-old male was followed-up with esophagogastroduodenoscopy due to an esophageal submucosal tumor. On the lesser curvature of the gastric low body, a 0.5 cm sized round elevated lesion with hyperemia was noticed. Two pieces of biopsy were taken from this lesion for histopathologic examination. Histology showed Langerhans cell infiltration. Immunohistochemical staining was positive for CD1a antigen, which confirmed the diagnosis of Langerhans cell histiocytosis. There was no evidence of other organ involvement. The lesions spontaneously disappeared 4 months later without any treatment. We report a very rare case of gastric Langerhans cell histiocytosis.

Intrathoracic Desmoid Tumor Presenting as Multiple Lung Nodules 13 Years after Previous Resection of Abdominal Wall Desmoid Tumor / 결핵및호흡기질환

Desmoid tumors are rare soft tissue tumors considered to have locally infiltrative features without distant metastasis until now. Although they are most commonly intraabdominal, very few cases have extra-abdominal locations. The origin of intrathoracic desmoid tumors is predominantly the chest wall with occasional involvement of pleura. True intrathoracic primary desmoid tumors with no involvement of the chest wall or pleura are extremely rare. We recently experienced a case of true intrathoracic desmoid tumor presenting as multiple lung nodules at 13 years after resection of a previous intraabdominal desmoid tumor.

A Case of Incidentally Detected Asymptomatic Emphysematous Pyelonephritis / 대한내과학회지

Emphysematous pyelonephritis (EPN) is a severe gas-forming infection of the renal parenchyma and surrounding tissues. Patients with EPN commonly present with high fever, chills, and flank pain. These symptoms mimic a simple urinary tract infection, such that diagnosis is often delayed. Because of its life-threatening fulminant course, the early detection of EPN and its prompt treatment with intravenous antibiotics with or without percutaneous drainage are critical. Here we describe a case of a 63-year-old Korean female with diabetes mellitus who had no specific symptoms or signs of EPN. A chest computed tomography (CT) scan to assess a right pleural effusion incidentally detected an abnormal gas shadow in the renal parenchyma. An abdominal CT scan performed 5 days later showed increased gas within the kidney parenchyma, but the patient still had no symptoms of EPN. She was treated with intravenous antibiotics alone. A follow-up abdominal CT scan revealed the complete disappearance of the features of EPN.

A Case of MELAS Syndrome Presenting with Type 1 Diabetes Mellitus / 대한내과학회지

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome presents with various clinical features, including seizures, stroke-like episodes, encephalopathy, myopathy, cardiac involvement, and diabetes. However, due to its clinical heterogeneity, the diagnosis of MELAS syndrome is complex and difficult. The present report describes an 18-year-old male who was diagnosed with MELAS syndrome following the onset of type 1 diabetes. The patient had suffered from ataxia, mental retardation, and recurrent headaches for several years; following hospitalization for loss of consciousness, he was treated for cerebellar atrophy and Wolf-Parkinson-White (WPW) syndrome. Although the patient had no history of lactic acidosis, the recent onset of type 1 diabetes and his medical history of encephalopathy and WPW syndrome suggested MELAS syndrome. The diagnosis of MELAS syndrome was confirmed by molecular genetic testing, which revealed a point mutation (A3243G) in the patient's mitochondrial DNA.

Clinical Implications of Various Criteria for the Biochemical Diagnosis of Insulinoma

BACKGROUND: Among the various diagnostic criteria for insulinoma, the ratio criteria have been controversial. However, the amended insulin-glucose ratio exhibited excellent diagnostic performance in a recent retrospective cohort study, although it has not yet been validated in other patient cohorts. We examined the diagnostic performance of the current criteria of the Endocrine Society, insulin-glucose ratio, C-peptide-glucose ratio, and amended ratios in terms of differentiating insulinomas. METHODS: We reviewed the medical records of patients who underwent evaluation for hypoglycemia from 2000 to 2013. Fourteen patients with histopathologically confirmed insulinoma and 18 patients without clinical evidence of insulinoma were included. The results of a prolonged fast test were analyzed according to the abovementioned criteria. RESULTS: Fulfilling all three Endocrine Society criteria-plasma levels of glucose ( or =8 pmol/L), and C-peptide (> or =0.2 nmol/L)-exhibited 100% sensitivity and 89% specificity. Fulfilling the glucose and C-peptide criteria showed 100% sensitivity and 83% specificity, while fulfilling the glucose and insulin criteria showed 100% sensitivity and 72% specificity. Among the ratio criteria, the insulin-glucose ratio [>24.0 (pmol/L)/(mmol/L)] gave the highest area under the receiver operating characteristic curve, with 93% sensitivity and 94% specificity. CONCLUSION: Fulfilling the glucose, insulin, and C-peptide criteria of the Endocrine Society guidelines exhibited the best diagnostic performance for insulinoma. Nonetheless, the insulin-glucose ratio may still have a role in the biochemical diagnosis of insulinoma.

Case Report of Everolimus-Associated DKA in a Patient with Metastatic Renal Cell Carcinoma / 대한내과학회지

Everolimus, an inhibitor of the mammalian target of the rapamycin (mTOR) pathway, is widely used as an immunosuppressant for the prevention of organ rejection following transplant and to treat metastatic clear-cell type renal cell carcinoma (RCC), breast cancer, and pancreatic neuroendocrine tumors. Everolimus commonly induces metabolic abnormalities such as hyperglycemia, hypercholesterolemia, and hypertriglyceridemia due to concomitant increases in blood glucose levels via the induction of insulin resistance and a decrease in beta cell function, which both lead to insulin deficiency. Although abnormal blood glucose levels are observed in more than 50% of patients treated with Everolimus, hyperglycemia exceeding 500 mg/dL is not common and there have been no reports of Everolimus-induced acute hyperglycemic crisis conditions. Here, a novel case of Everolimus-associated diabetic ketoacidosis (DKA) in a patient with RCC is reported.

Successful Fecal Transplantation by Enema for Recurrent and Refractory Clostridium difficile Infection

Clostridium difficile infection (CDI) is a common cause of antibiotic-associated diarrhea with an increase in severity and frequency in the recent times. CDI can be refractory and relapses, especially in the elderly or patients with significant comorbidities. Conventional treatments with antibiotics often fail to cure the infection. Even when successfully treated, recurrent infection is common. Some studies have reported that fecal transplantation may be effective and safe for the treatment of recurrent and intractable CDI. We present two CDI cases (one recurrent and one refractory) which were treated successfully by fecal transplantation using enema.

Endobronchial Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation / 대한내과학회지

Myeloid sarcoma is an uncommon extramedullary tumor of immature myeloid cells or myeloblasts. It may occur alone or concurrently with an underlying hematological malignancy. Although it can develop anywhere in the body, common sites include bones, particularly the skull and vertebra, soft tissues, and lymph nodes. However, there have been few reports of myeloid sarcoma occurring in the respiratory system, especially the large airways. We describe a case of endobronchial relapse of acute myeloid leukemia in a patient who achieved complete remission after allogeneic stem cell transplantation. To our knowledge, this is the first such report in Korea.

A Case of Thymoma with Immunodeficiency (Good's Syndrome) with Disseminated Tuberculosis / 대한내과학회지

Good's syndrome is the rare association of immunodeficiency with thymoma, characterized by hypogammaglobulinemia, depleted B-cells, diminished T-cells and inversion of the CD4/CD8 ratio. Thymectomy does not usually improve hypogammaglobulinemia; thus, the patient remains prone to infections. Infections affect primarily the sinopulmonary and gastrointestinal system. Here we present a case of a 71-year-old woman with common manifestations of Good's syndrome who succumbed to disseminated tuberculosis. Serum immunoglobulin levels should be measured for patients with thymoma and susceptibility to infection.

Comparative Analysis of Laparoscopic Versus Open Appendectomy for Perforated Appendicitis in Children Under 12 Years Old at a Single Institute

PURPOSE: The purpose of this study is to evaluate the outcome of laparoscopic (LA) vs. open appendectomy (OA) in children under 12 years old with perforated appendicitis. METHODS: We reviewed the medical files of 156 children who underwent LA (n=96), OA (n=59), and conversion (CO) (n=1), and compared duration of operation, length of hospital stay, incidence of wound infection, mechanical ileus, intra-abdominal abscess (IAA), and re-admission. RESULTS: Compared to OA, LA resulted in longer duration of operation (58.32+/-17.105 min vs. 44.27+/-18.735 min; p=0.001), but fewer wound infections (2.1% vs. 10.2%; p=0.054), and fewer cases of mechanical ileus (0% vs. 5.1%; p=0.053). No differences in the length of hospital stay (5.85+/-1.824 days vs. 6.10+/-3.027 days; p=0.526), IAA (2.1% vs. 1.7%; p=1.000), or re-admissions (2.1% vs. 5.1%; p=0.369) were observed. CONCLUSION: We report that although LA showed an association with longer duration of operation compared to OA, it is superior to OA with regard to incidence of wound infection and mechanical ileus.