Reduction of adenovirus 36-induced obesity and inflammation by mulberry extract.

Adenovirus 36 (Ad36) is known to be associated with human obesity and to trigger inflammation in murine models. However, to date no clinical drugs for treating virus-induced obesity have been developed. Therefore, in this study, the anti-obesity and anti-inflammation effects of mulberry extract on Ad36 were evaluated in mice. The mulberry extract-fed group showed a reduction in total body weight and in epidermal fat pads. A combination of various mulberry components (1-deoxynojirimycin, kuromanin chloride and resveratrol) and a mulberry extract prevented viral replication by 50% and 70%, respectively, compared with an untreated Ad36-infected group. Moreover, the extract decreased both concentrations of proinflammatory cytokines, such as MCP-1 and TNF-α, and the numbers of infiltrating immune cells and macrophages in epidermal fat pads. In conclusion, dietary mulberry extract might offer an avenue for the development of therapeutic approaches for treating or preventing virus-induced obesity and inflammation-related metabolic diseases.

A pilot study of adrenal suppression after dexamethasone therapy as an antiemetic in cancer patients.

PURPOSE: Dexamethasone has a high therapeutic index when used to prevent chemotherapy-induced nausea and vomiting. However, the chronic use of glucocorticoids has been associated with suppression of the hypothalamic-pituitary-adrenal axis. Therefore, the authors designed this pilot study to assess the incidence of adrenal insufficiency after dexamethasone therapy as an antiemetic in cancer patients receiving chemotherapy. METHODS: The rapid adrenocorticotropic hormone (ACTH) stimulation test was performed in 103 cancer patients, who had been treated with high-dose dexamethasone as an antiemetic for more than 3 months. When response to the rapid ACTH stimulation test was abnormal, the patient received corticosteroid replacement by prednisolone 7.5 mg daily for 1-2 weeks and after prednisolone replacement, changes in symptoms associated with adrenal insufficiency were investigated using a visual analog scale. RESULTS: Forty-five of the 103 patients (43.7%) showed a suppressed adrenal response to the rapid ACTH stimulation test, and the incidence of adrenal suppression was found to be significantly affected by megestrol acetate use (P = 0.035). Thirty-three patients with a suppressed adrenal function achieved an improvement in quality of life after prednisolone replacement, as determined using a self-report questionnaire (22.9 ± 14.7 to 14.8 ± 11.0, P < 0.001). CONCLUSIONS: We suggest that suppression of adrenal response is common after antiemetic dexamethasone therapy in cancer patients receiving chemotherapy.

Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model.

The chemotherapeutic agent temozolomide (TMZ) and the anti-angiogenic agent thalidomide (THD) have both demonstrated anti-tumor activity in patients with recurrent malignant glioma. Combination treatment with TMZ and THD in patients with glioblastoma multiforme (GBM) appears to be more effective than treatment with either drug alone. To investigate the mechanism of this anti-tumor effect, we examined the combined effects of TMZ and THD in a rat glioma xenograft model. We found that combination treatment markedly inhibited the growth of tumors that were orthotopically implanted into rat brains. Using proliferating cell nuclear antigen (PCNA) staining, we observed a significant decrease in cell proliferation in these tumors. CD31 staining of the microvasculature revealed a significant decrease in angiogenesis. We also found increased apoptosis in treated tumors by terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. We further demonstrated that the expression of angiogenic factors, such as vascular endothelial cell growth factor (VEGF) and basic fibroblastic growth factor (bFGF), were inhibited by THD. THD also decreased the number of ED1-positive, activated macrophages or microglial cells, which produce pro-angiogenic molecules around the glioma. Taken together, these results suggest that combination treatment with TMZ and THD inhibits tumor growth via the induction of apoptosis and the inhibition of angiogenesis in a rat model and may be a promising therapy for malignant gliomas.

A Pilot Study Evaluating Steroid-Induced Diabetes after Antiemetic Dexamethasone Therapy in Chemotherapy-Treated Cancer Patients.

PURPOSE: Dexamethasone is a mainstay antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting. The aim of this pilot study was to assess the incidence of and factors associated with steroid-induced diabetes in cancer patients receiving chemotherapy with dexamethasone as an antiemetic. MATERIALS AND METHODS: Non-diabetic patients with newly diagnosed gastrointestinal cancer who received at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Fasting plasma glucose levels, 2-hour postprandial glucose levels, and hemoglobin A1C tests for the diagnosis of diabetes were performed before chemotherapy and at 3 and 6 months after the start of chemotherapy. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as an index for measurement of insulin resistance, defined as a HOMA-IR ≥ 2.5. RESULTS: Between January 2012 and November 2013, 101 patients with no history of diabetes underwent laboratory tests for assessment of eligibility; 77 of these patients were included in the analysis. Forty-five patients (58.4%) were insulin resistant and 17 (22.1%) developed steroid-induced diabetes at 3 or 6 months after the first chemotherapy, which included dexamethasone as an antiemetic. Multivariate analysis showed significant association of the incidence of steroid-induced diabetes with the cumulative dose of dexamethasone (p=0.049). CONCLUSION: We suggest that development of steroid-induced diabetes after antiemetic dexamethasone therapy occurs in approximately 20% of non-diabetic cancer patients; this is particularly significant for patients receiving high doses of dexamethasone.

High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association criteria.

OBJECTIVE: The incidence of posttransplantation diabetes mellitus (PTDM) has been reported to vary according to different study populations or different definitions. In this study, using American Diabetes Association criteria, the incidence and clinical characteristics of PTDM in Korean renal allograft recipients undergoing tacrolimus-based immunosuppression were examined. RESEARCH DESIGN AND METHODS: A total of 21 patients taking tacrolimus as primary immunosuppressant were recruited and tested with a serial 75-g oral glucose tolerance test at 0, 1, 3, and 6 months after renal transplantation. RESULTS: The cumulative incidence of PTDM was 52.4% at 1 month and 57.1% at 3 and 6 months. The baseline characteristics of the PTDM group were old age (especially >40 years), a high BMI, a high fasting glucose level, a high plasma insulin level, and increased insulin resistance. Among these parameters, old age was the only independent risk factor. The insulin secretory capacity in the PTDM group was maximally suppressed 3 months after transplantation. Thereafter, it was gradually restored along with dose reduction of tacrolimus. CONCLUSIONS: Routine screening for PTDM is necessary in patients over 40 years of age who are undergoing a relatively higher dose tacrolimus therapy during the early course of postrenal transplantation.

Tracking Study About Adenovirus 36 Infection: Increase of Adiposity.

This study investigated the cross-sectional and longitudinal association between adenovirus 36 (Ad36) and obesity in 79 Korean adolescent boys over 1 year. We analyzed the changes in body composition and metabolic risk factors according to the presence of Ad36 antibodies. Ad36 antibodies in serum were detected using the constant virus-decreasing serum method. We found that the fat percentage and fasting insulin in the Ad36-seropositive group were greater than the Ad36-seronegative group. These results suggest that Ad36 infection is associated with an increase of adiposity, and the experience of Ad36 infection may affect the future fat gain of adolescents.

Tracheal gas isufflation-aided mechanical ventilation during carbon dioxide-induced pneumoperitoneum in rabbits.

Despite numerous benefits of laparoscopic procedures, the serious hypercapnia and respiratory acidosis in hypercapnic patients with decreased pulmonary compliance during carbon dioxide-induced pneumoperitoneum (CDP) may be developed. Tracheal gas insufflation (TGI) has been shown to be a useful adjunct to controlled mechanical hypoventilation. This study was undertaken to identify whether TGI superimposed on controlled mechanical ventilation (CMV) improve ventilatory efficiency during CDP in rabbits. Sixteen paralyzed and anesthetized rabbits were used. The animals were assigned to two groups-CMV group: CMV alone; TGI group: CMV superimposed by TGI with flow rate of 2L/min. The animals were insufflated to intra-abdominal pressure of 8 mmHg with CO2 gas. Then, tidal volume (V(T)) was changed to maintain the set peak inspiratory pressure (PIP) value, while other ventilatory settings were kept constant. The set PIP value corresponding to 30, 60, and 90 min after the start of peritoneal insufflation of CO2 were 15, 22, and 25 cm H2O, respectively. During CDP with TGI, PaCO2 decreased significantly (p<0.01) from CMV without TGI of 82.1 +/- 14.1 to 47.5 +/- 5.5, 58.1 +/- 9.9 to 40.0 +/- 4.6, 47.1 +/- 9.4 to 32.7 +/- 5.1 mmHg at PIP of 15, 22, and 25 cm H2O, respectively. The inspired V(T) decreased significantly (p<0.05) from CMV without TGI of 18.4 +/- 3.9 to 12.8 +/- 2.8 ml at PIP of 15 cm H2O. TGI superimposed on CMV is more effective than CMV alone in enhancing ventilatory efficiency during CDP in rabbits.

Obesity-induced chronic inflammation is associated with the reduced efficacy of influenza vaccine.

The relationship between obesity and vaccine efficacy is a serious issue. Previous studies have shown that vaccine efficacy is lower in the obese than in the non-obese. Here, we examined the influence of obesity on the efficacy of influenza vaccination using high fat diet (HFD) and regular fat diet (RFD) mice that were immunized with 2 types of influenza virus vaccines-cell culture-based vaccines and egg-based vaccines. HFD mice showed lower levels of neutralizing antibody titers as compared with RFD mice. Moreover, HFD mice showed high levels of MCP-1 in serum and adipocytes, and low level of influenza virus-specific effector memory CD8(+) T cells. After challenge with influenza virus, the lungs of HFD mice showed more severe inflammatory responses as compared with the lungs of RFD mice, even after vaccination. Taken together, our data suggested that the inflammatory condition in obesity may contribute to the suppressed efficacy of influenza vaccination.

Impact of hyperglycemia on survival and infection-related adverse events in patients with metastatic colorectal cancer who were receiving palliative chemotherapy.

PURPOSE: Non-metastatic colorectal cancer patients with diabetes have poor overall survival than those without diabetes. However, the effect of hyperglycemia on survival after diagnosis of metastatic colorectal cancer (CRC) has not been assessed. Therefore, we assessed the impact of hyperglycemia on the survival and infection-related adverse events (AEs) in patients with metastatic CRC. MATERIALS AND METHODS: We reviewed the records of 206 patients with newly diagnosed metastatic CRC who were treated with palliative chemotherapy from March 2000 to December 2012 at Chungbuk National University Hospital. The mean glucose level of each patient was calculated using all available glucose results. RESULTS: The mean glucose levels ranged between 76.8 and 303.5 mg/dL, and patients were categorized into quartiles in accordance to their mean glucose level: group 1 (< 106.7 mg/dL), group 2 (106.7-117.2 mg/dL), group 3 (117.3-142.6 mg/dL), and group 4 (> 142.6 mg/dL). The median overall survival for patients in groups 1, 2, 3, and 4 were 22.6, 20.1, 18.9, and 17.9 months, respectively; however, this difference was not statistically significant (p=0.643). Compared with patients in group 1, those in groups 2, 3, and 4 were at a higher risk of infection-related AEs, according to a multivariate analysis (p=0.002). CONCLUSION: Hyperglycemia was not associated with shorter survival; however, it was associated with infection-related AEs in patients with newly diagnosed metastatic CRC receiving palliative chemotherapy.

Poorly differentiated neuroendocrine carcinoma in a perigastric lymph node from an unknown primary site.

Neuroendocrine carcinomas from an unknown primary site are uncommon. The authors report on a case of neuroendocrine carcinoma in a perigastric lymph node (LN) with no primary site. A 52-year-old male patient with early gastric adenocarcinoma underwent treatment by endoscopic submucosal dissection, and, six months later, findings on a computed tomographic scan of the abdomen revealed a LN enlargement measuring 2.0 cm in the perigastric region. The patient underwent subtotal gastrectomy and regional LN dissection under a suggestive preoperative diagnosis of gastric adenocarcinoma with LN metastasis. However, microscopically, no residual tumor was found in the stomach, and the perigastric LN showed poorly differentiated neuroendocrine carcinoma (PDNEC). After an extensive workup, no primary site was identified. The patient also received four cycles of etoposide and cisplatin. Despite its extremely rare incidence, this case suggests that PDNEC of an unknown primary site is limited to a single site, and that resection should be considered in combination with chemotherapy.

Metastatic renal cell carcinoma in a supraclavicular lymph node with no known primary: a case report.

Although metastasis is relatively frequent in cases of renal cell carcinoma (RCC), metastasis in the cervical or supraclavicular lymph node (LN) is relatively rare. Moreover, cases of metastatic RCC with a non-identifiable kidney mass are extremely rare. Here, the authors report a case of metastatic RCC in a supraclavicular LN without a primary kidney lesion. A 69-year-old man presented with a progressively enlarging right supraclavicular mass. Incisional biopsy of the affected supraclavicular LN was performed, and histological examination revealed metastatic RCC. However, no tumor was found in either kidney, despite various examinations. The patient was treated with radiotherapy followed by sunitinib. After three months on sunitinib, a follow-up computed tomography scan revealed that the supraclavicular LN had markedly decreased, and after 20 months, the disease had not progressed. This case suggests that, even when there is no primary kidney lesion, clinicians must consider the possibility of metastatic RCC when evaluating patients with clear cell carcinoma with an unknown primary site.

Coating with paclitaxel improves graft survival in a porcine model of haemodialysis graft stenosis.

BACKGROUND: Most commonly resulting from intimal hyperplasia at the venous anastomosis, stenosis leading to thrombosis is a major cause of failure of polytetrafluoroethylene (PTFE) dialysis grafts. We recently reported that coating haemodialysis grafts with paclitaxel could reduce neointimal hyperplasia. This study tested whether paclitaxel-coating could prolong graft survival in a porcine model. METHODS: PTFE grafts were double-coated with paclitaxel. Bilateral grafts were created between the carotid arteries and the external jugular veins, and we evaluated graft survival by weekly measurements of blood flow for 12 weeks. RESULTS: We successfully implanted four pairs of paclitaxel-coated grafts and four pairs of control grafts in eight Landrace pigs. One control pig had to be euthanized at 4 weeks after graft placement. The grafts in the other three controls and four paclitaxel pigs survived until harvesting of the grafts. All paclitaxel-coated grafts remained patent for 12 weeks without decrease of blood flow. Median blood flow was 702 ml/min at three weeks and 818 ml/min at 12 weeks after placement. In contrast, the four control grafts lost luminal patency at 5, 6, 6 and 8 weeks, respectively. In Kaplan-Meier analysis, paclitaxel-coated grafts showed better survival than uncoated grafts (P = 0.011). CONCLUSIONS: Double-coating with paclitaxel improved graft survival. Coated PTFE grafts may be effective for the prevention of graft failure in patients on haemodialysis.

Mouse orthotopic lung cancer model induced by PC14PE6.

PURPOSE: This study was undertaken to investigate in detail the xenograft mouse orthotopic lung cancer model induced by PC14PE6 adenocarcinoma cells. MATERIALS AND METHODS: Three cell doses (0.5x10(6); 1x10(6); 2x10(6)) of PC14PE6 cells were injected into the lungs of male BALB/c nude mice by the intrathoracic injection method. The lung and other organs, including brain, liver, spleen, kidney, muscle, adrenal gland, and lymph node on knee, were removed and stained with H/E to detect the presence of tumor cells. RESULTS: The reliable tumorigenicity time in the PC14PE6 adenocarcinoma cell-inoculated BALB/c nude mouse was 10 days after intrathoracic injection. The average life span of the three groups after inoculation was 14 days in the 2x10(6) cells inoculum group; 25 days in the 1x10(6) cells inoculum group; and 32 days in the 0.5x10(6) cells inoculum group. The PC14PE6 adenocarcinoma cells induced orthotopic lung cancer limited within the thorax. CONCLUSIONS: This orthotopic lung cancer model is an efficient cancer model with easy inoculation methods, rapid and high tumorigenicity, and simple monitoring methods for metastasis.

Paclitaxel-coated expanded polytetrafluoroethylene haemodialysis grafts inhibit neointimal hyperplasia in porcine model of graft stenosis.

BACKGROUND: The main pathology of haemodialysis graft stenosis is venous neointimal hyperplasia at graft-venous anastomoses. Neointimal hyperplasia is also observed in cases of coronary artery in-stent restenosis. Paclitaxel is a chemotherapeutic agent used to treat cancer, and has been proven to inhibit neointimal hyperplasia of coronary artery in-stent restenosis. In this study, we examined whether a paclitaxel-coated haemodialysis graft could inhibit neointimal hyperplasia and prevent stenosis. METHODS: We dip-coated paclitaxel on expanded polytetrafluoroethylene (ePTFE) grafts at a dose density of 0.59 microg/mm(2). In vitro release tests showed an initial paclitaxel burst followed by a long-term slow release. Using ePTFE grafts with (coated group, n = 8) or without a paclitaxel coating (control group, n = 11), we constructed arteriovenous (AV) grafts connecting the common carotid artery and the external jugular vein in Landrace pigs. RESULTS: After excluding seven pigs for technical failure, cross-sections of graft-venous anastomoses obtained 6 weeks after placing the AV grafts were analysed. Percentage luminal stenosis, ratios of intima to media in whole cross-sections, areas of intima in the peri-junctional areas (within 2 mm above and 2 mm below the graft-venous junction), and the mean thickness of intima within venous sides of cross-sections, were 60.5% (range, 41.5-60.7), 13.0 (range, 8.6-20.4), 23.7 mm(2) (range, 10.8-32.1) and 2.1 mm (range, 1.1-3.0), respectively, in the control group, whereas corresponding median values in the coated group were 10.4% (range, 1.0-17.8), 1.0 (range, 0.7-5.1), 1.6 mm(2) (range, 0.2-8.0) and 0.3 mm (range, 0.1-2.2). All parameters were significantly different between the two groups (P<0.05 by Mann-Whitney test). CONCLUSION: Paclitaxel-coated ePTFE grafts could prevent neointimal hyperplasia and the stenosis of AV haemodialysis grafts.

Neuroprotective effects of 3,5-dicaffeoylquinic acid on hydrogen peroxide-induced cell death in SH-SY5Y cells.

Oxidative stress plays an important role in the pathological processes of a variety of neurodegenerative diseases. The neuroprotective effects of 3,5-diCQA and 3,4-diCQA, two caffeoylquinic acid derivatives present in Dipsacus asper, on hydrogen peroxide (H2O2)-induced neuronal cell damage were evaluated in this study.SH-SY5Y cells treated with H2O2 exhibited a decrease in survival and intracellular glutathione and also an increase in the caspase-3 activity. However, pretreatment of cells with 3,5-diCQA attenuated the neuronal death and caspase-3 activation induced by H2O2. In addition, 3,5-diCQA restored H2O2-induced depletion of intracellular glutathione. 3,5-diCQA showed significant protective effects although it could not completely suppress H2O2-induced cell injury to control levels. The data suggest that 3,5-diCQA might be a potential therapeutic agent for treating or preventing neurodegenerative diseases implicated with oxidative stress.