The Mediator subunit MED20 organizes the early adipogenic complex to promote development of adipose tissues and diet-induced obesity.

MED20 is a non-essential subunit of the transcriptional coactivator Mediator complex, but its physiological function remains largely unknown. Here, we identify MED20 as a substrate of the anti-obesity CRL4-WDTC1 E3 ubiquitin ligase complex through affinity purification and candidate screening. Overexpression of WDTC1 leads to degradation of MED20, whereas depletion of WDTC1 or CUL4A/B causes accumulation of MED20. Depleting MED20 inhibits adipogenesis, and a non-degradable MED20 mutant restores adipogenesis in WDTC1-overexpressing cells. Furthermore, knockout of Med20 in preadipocytes abolishes development of brown adipose tissues. Removing one allele of Med20 in preadipocytes protects mice from diet-induced obesity and reverses weight gain in Cul4a- or Cul4b-depleted mice. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that MED20 organizes the early adipogenic complex by bridging C/EBPß and RNA polymerase II to promote transcription of the central adipogenic factor, PPARγ. Our findings have thus uncovered a critical role of MED20 in promoting adipogenesis, development of adipose tissue and diet-induced obesity.

DDB1 binds histone reader BRWD3 to activate the transcriptional cascade in adipogenesis and promote onset of obesity.

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity. Although typically recognized as a component of the CUL4-RING E3 ubiquitin ligase complex, DDB1 stimulates adipogenesis independently of CUL4. A DDB1 mutant that does not bind CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient cells. Ddb1+/- mice show delayed postnatal development of white adipose tissues and are protected from diet-induced obesity. Mechanistically, by interacting with BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of ELK1 downstream immediate early response genes and facilitates the release of paused RNA polymerase II, thereby activating the transcriptional cascade in adipogenesis. Our findings have uncovered a CUL4-independent function of DDB1 in promoting the transcriptional cascade of adipogenesis, development of adipose tissues, and onset of obesity.

Coexistence of ovarian serous papillary cystadenofibroma and type A insulin resistance syndrome in a 14-year-old girl: A case report.

BACKGROUND: Type A insulin resistance syndrome is a rare disorder caused by mutations in the gene encoding the insulin receptor. Its coexistence with ovarian serous papillary cystadenofibroma is even rarer. CASE SUMMARY: A 14-year-old girl developed type A insulin resistance syndrome and showed high fasting insulin, glucose, and hemoglobin A1c (HbA1c) levels. The girl suffered from ovarian serous papillary cystadenofibroma. The laboratory results were as follows: fasting insulin was 2624.90 pmol/L and HbA1c was 8.5%. A heterozygous missense mutation on exon 20 of the insulin receptor gene (c.3601C>T, Arg1201Trp) was observed. The histopathological diagnosis was a cystic lesion that extended to the upper right uterus, indicating a right ovarian serous papillary cystadefibroma accompanied by focal interstitial hyperplasia. The patient was treated with metformin for over 6 mo. Additionally, laparoscopic resection (bilateral) of the ovarian lesion and laparoscopic intestinal adhesiolysis were performed under general anesthesia. Diet therapy combined with exercise was then initiated. The patient had an uneventful recovery. The patient also showed improved blood glucose control, with reduced levels of fasting insulin (857.84 pmol/L) and HbA1c (7.0%). CONCLUSION: Insulin resistance may play a significant role in the induction of tumors. It is important to investigate further the association between insulin resistance and tumors and the underlying mechanism.

Risk of tuberculosis in patients with immune-mediated diseases on biological therapies: a population-based study in a tuberculosis endemic region.

OBJECTIVE: Real-world epidemiological data on the risk of tuberculosis (TB) in patients with immune-mediated diseases treated with biologics are scarce in TB endemic areas. We investigated the incidence of TB in a population-based setting and stratified the risk of TB among different biological therapies. METHODS: We collected medical data from a territory-wide computerized database in Hong Kong. We reported the incidence of TB in patients treated with various classes of biologics, and calculated standardized incidence ratio by comparing with the general population. Subgroup analyses were performed based on disease subtypes and biological drugs. RESULTS: Among 2485 subjects with immune-mediated diseases (82.5% rheumatology diseases; 10.6% IBD; 6.9% dermatology diseases), 54 subjects developed active TB during 6921 person-years of follow-up. The mean age (±s.d.) was 43 (14) years, and the median follow-up duration was 24.9 months (interquartile range 4.9-45.0). The overall standardized incidence ratio of TB was 10.91 (95% CI 8.00-13.82), and patients treated with infliximab had a nearly 26 times increased risk of TB compared with the general population (standardized incidence ratio 25.95; 95% CI 17.23-34.67). The risk of TB with TNF inhibitor was higher than with a non-TNF biologic (hazard ratio 4.34; 95% CI 1.31-14.39), while the risk of infliximab was higher than etanercept and adalimumab (hazard ratio: 4.10 and 2.08, respectively). CONCLUSION: The risk of TB is much higher in patients with immune-mediated diseases on biological therapy compared with the general population, and infliximab is associated with the highest risk of TB among the biologics analysed.

Serum uric acid is independently and linearly associated with risk of nonalcoholic fatty liver disease in obese Chinese adults.

The present study aimed to explore the independent association and potential pathways between serum uric acid (SUA) and nonalcoholic fatty liver disease (NAFLD). 1365 community-living obese Chinese adults who received hepatic ultrasonography scanning were included. The prevalence rates of NAFLD were 71.5% for men and 53.8% for women. Compared with controls, NAFLD subjects showed significantly increased SUA levels (333.3 ± 84.9 v.s. 383.4 ± 93.7 µmol/L) and prevalence rate of hyperuricemia (HUA) (25.7% v.s. 47.3%, p < 0.001). After adjustment for insulin resistance (IR), components of metabolic syndrome (MetS) and other potential confounders, elevated SUA is independently associated with increased risk of NAFLD, with the adjusted OR of 1.528-2.031 (p < 0.001). By using multivariable fractional polynomial (MFP) modeling, the best FP transformation model shows that SUA was independently and linearly associated with risk of NAFLD. The one-pathway model by using structural equation modeling (SEM) about the relationships among SUA, IR, components of metabolic syndrome and NAFLD fits well (χ2 = 57.367, p < 0.001; CFI = 0.998; TLI = 0.992; and RMSEA = 0.048) and shows SUA might increase the risk of NAFLD directly besides of the indirect effects through increasing fasting insulin, blood pressure, triglyceride and decreasing HDL-C levels. Our results imply that elevated SUA may play an important role in NAFLD pathogenesis.

Severe Henoch-Schönlein purpura with infliximab for ulcerative colitis.

Infliximab (IFX) is an anti-tumor necrosis factor chimeric antibody that is effective for treatment of autoimmune disorders such as Crohn's disease and ulcerative colitis (UC). IFX is well tolerated with a low incidence of adverse effects such as infections, skin reactions, autoimmunity, and malignancy. Dermatological manifestations can appear as infusion reaction, vasculitis, cutaneous infections, psoriasis, eczema, and skin cancer. Here, we present an unusual case of extensive and sporadic subcutaneous ecchymosis in a 69-year-old woman with severe UC, partial colectomy and cecostomy, following her initial dose of IFX. The reaction occurred during infliximab infusion, and withdrawal of IFX led to gradual alleviation of her symptoms. We concluded that Henoch-Schönlein purpura, a kind of leukocytoclastic vasculitis, might have contributed to the development of the bruising. Although the precise mechanisms of the vasculitis are still controversial, such a case highlights the importance of subcutaneous adverse effects in the management of UC with IFX.

Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. The exact etiology and pathology of IBD remain unknown. Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals. Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules including cytokines. On the other hand, besides T helper (Th) 1 and Th2 cell immune responses, other subsets of T cells, namely Th17 and regulatory T cells, are likely associated with disease progression. Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.

Inhibition of Wnt/ß-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma.

The development of multi-drug resistance (MDR) represents a major obstacle in the successful treatment of cancers. However, the factors and mechanisms that lead to MDR in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remain unclear. In this study, we established a human MDR CCA cell line QBC939/5-FU. Compared with QBC939 cells, a rounder shape, a higher nuclear-cytoplasmic ratio, a shorter cell cycle, faster growth and resistance to chemotherapeutics are major characteristics of QBC939/5-FU cells. P-glycoprotein (P-gp) and ß-catenin were upregulated in QBC939/5-FU cells. Furthermore, the drug susceptibility of QBC939 cells to common chemotherapeutics was significantly decreased after Wnt3a treatment, whereas inhibition of Wnt/ß-catenin pathway by ß-catenin siRNA reversed the MDR of QBC939/5-FU cells to chemotherapeutics. Molecular study revealed that activation of Wnt/ß-catenin pathway resulted in upregulation of P-gp and contributed to MDR of QBC939/5-FU cells. Extraction of Siamese Crocodile 3 (ESC-3) bile enhanced the drug sensitivity of QBC939/5-FU cells to 5-FU, paralleled with downregulation of ß-catenin and P-gp. The association of Wnt/ß-catenin pathway and P-gp was further confirmed by the clinical data for CCA tissues. Our study represents the first implication of Wnt/ß-catenin activation in the MDR of CCA, which may be a beneficial target for the clinical treatment of CCA.

Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves ß-cell mass and function in ZDF rats.

We reported earlier that ß-cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of ß-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent ß-cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA1c levels with no effects on body weight. Ebselen doubled ß-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal ß-cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on ß-cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of ß-cell mass and function in humans undergoing the onset of type 2 diabetes.

Comparative evaluation of intragastric bile acids and hepatobiliary scintigraphy in the diagnosis of duodenogastric reflux.

AIM: To assess the diagnostic value of a combination of intragastric bile acids and hepatobiliary scintigraphy in the detection of duodenogastric reflux (DGR). METHODS: The study contained 99 patients with DGR and 70 healthy volunteers who made up the control group. The diagnosis was based on the combination of several objective arguments: a long history of gastric symptoms (i.e., nausea, epigastric pain, and/or bilious vomiting) poorly responsive to medical treatment, gastroesophageal reflux symptoms unresponsive to proton-pump inhibitors, gastritis on upper gastrointestinal (GI) endoscopy and/or at histology, presence of a bilious gastric lake at > 1 upper GI endoscopy, pathologic 24-h intragastric bile monitoring with the Bilitec device. Gastric juice was aspirated in the GI endoscopy and total bile acid (TBA), total bilirubin (TBIL) and direct bilirubin (DBIL) were tested in the clinical laboratory. Continuous data of gastric juice were compared between each group using the independent-samples Mann-Whitney U-test and their relationship was analysed by Spearman's rank correlation test and Fisher's linear discriminant analysis. Histopathology of DGR patients and 23 patients with chronic atrophic gastritis was compared by clinical pathologists. Using the Independent-samples Mann-Whitney U-test, DGR index (DGRi) was calculated in 28 patients of DGR group and 19 persons of control group who were subjected to hepatobiliary scintigraphy. Receiver operating characteristic curve was made to determine the sensitivity and specificity of these two methods in the diagnosis of DGR. RESULTS: The group of patients with DGR showed a statistically higher prevalence of epigastric pain in comparison with control group. There was no significant difference between the histology of gastric mucosa with atrophic gastritis and duodenogastric reflux. The bile acid levels of DGR patients were significantly higher than the control values (Z: TBA: -8.916, DBIL: -3.914, TBIL: -6.197, all P < 0.001). Two of three in the DGR group have a significantly associated with each other (r: TBA/DBIL: 0.362, TBA/TBIL: 0.470, DBIL/TBIL: 0.737, all P < 0.001). The Fisher's discriminant function is followed: Con: Y = 0.002TBA + 0.048DBIL + 0.032TBIL - 0.986; Reflux: Y = 0.012TBA + 0.076DBIL + 0.089TBIL - 2.614. Eighty-four point zero five percent of original grouped cases were correctly classified by this method. With respect to the DGR group, DGRi were higher than those in the control group with statistically significant differences (Z = -5.224, P < 0.001). Twenty eight patients (59.6%) were deemed to be duodenogastric reflux positive by endoscopy, as compared to 37 patients (78.7%) by hepatobiliary scintigraphy. CONCLUSION: The integrated use of intragastric bile acid examination and scintigraphy can greatly improve the sensitivity and specificity of the diagnosis of DGR.

Chinese lacto-vegetarian diet exerts favorable effects on metabolic parameters, intima-media thickness, and cardiovascular risks in healthy men.

BACKGROUND: To investigate whether the Chinese lacto-vegetarian diet has protective effects on metabolic and cardiovascular disease (CVD). METHODS: One hundred sixty-nine healthy Chinese lacto-vegetarians and 126 healthy omnivore men aged 21-76 years were enrolled. Anthropometric indexes, lipid profile, insulin sensitivity, pancreatic ß cell function, and intima-media thickness (IMT) of carotid arteries were assessed and compared. Cardiovascular risk points and probability of developing CVD in 5-10 years in participants aged 24-55 years were calculated. RESULTS: Compared with omnivores, lacto-vegetarians had remarkably lower body mass index, systolic and diastolic blood pressure, and serum levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, γ-glutamyl transferase, serum creatinine, uric acid, fasting blood glucose, as well as lower total cholesterol/high-density lipoprotein cholesterol ratio. Vegetarians also had higher homeostasis model assessment ß cell function and insulin secretion index and thinner carotid IMT than the omnivores did. These results corresponded with lower cardiovascular risk points and probability of developing CVD in 5-10 years in vegetarians 24-55 years old. CONCLUSIONS: In healthy Chinese men, the lacto-vegetarian diet seems to exert protective effects on blood pressure, lipid profiles, and metabolic parameters and results in significantly lower carotid IMT. Lower CVD risks found in vegetarians also reflect the beneficial effect of the Chinese lacto-vegetarian diet.

Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro.

The endothelin B2 (ET(B2)) receptors are induced in vascular smooth muscle cells (VSMCs) in cardiovascular diseases. We tested if in vitro short-term exposure to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) could up-regulate ET(B2) receptors in rat mesenteric arteries, and if this effect is through activation of intracellular nuclear factor-κB (NF-κB) pathway. The mesenteric arteries were dissected from male Sprague-Dawley rats and the endothelium was removed. The arteries were co-incubated with TNF-α in serum-free Dulbecco's modified Eagle's medium. Real-time reverse transcription-PCR, Western blot and immunohistochemical staining were employed to assess the mRNA/protein expression of ET(B2) receptors and activation of NF-κB pathway. The results showed that, during organ culture, TNF-α concentration-dependently enhanced ET(B2) receptors expression at both mRNA and protein levels, paralleled with activation of NF-κB pathway in VSMC. The up-regulated ET(B2) receptor expression and NF-κB activation could be effectively suppressed by general transcriptional inhibitor actinomycin D, or either of the selective IκB kinase inhibitors wedelolactone and IMD-0354. Conclusively, the activation of intracellular NF-κB pathway is responsible for the up-regulation of ET(B2) receptors induced by short-term exposure to TNF-α. This could partly explain the toxic effects of TNF-α on VSMCs that account for cardiovascular diseases.

Relationship of carotid intima-media thickness and duration of vegetarian diet in Chinese male vegetarians.

OBJECTIVE: Many studies have shown that vegetarian diet has beneficial effects on the prevention of cardiovascular diseases. However, the effect of vegetarian diet on carotid intima-media thickness (IMT), as well as the association between IMT and duration of vegetarian diet, are still unclear. The present study aims to investigate the influence of duration of vegetarian diet on cardiovascular risk factors, and more importantly on IMT among Chinese vegetarians. METHODS: One hundred and seventy-one Chinese male vegetarians were screened for metabolic profile, cardiovascular risk and carotid IMT. They were compared with 129 age-matched omnivores recruited from a community-based health project. The effects of confounding factors were adjusted by stepwise logistic regression analysis. RESULTS: Compared to the omnivores, the vegetarians had lower BMI, weight, systolic blood pressure and diastolic blood pressure. Also, the levels of triglyceride, total cholesterol, HDL-Cholesterol, LDL-Cholesterol, ApoA1, ApoB, uric acid, albumin and γ-glutamyltransferase were significantly reduced in vegetarians. Omnivores had significantly higher fasting blood glucose than that of vegetarians. However, there were no differences in fasting insulin, C-reactive protein and HOMA-IR between the two groups. IMT was thinner in the vegetarian group than in the omnivore group (0.59 ± 0.16 vs. 0.63 ± 0.10 cm, P < 0.05). The vegetarians were divided according to duration of vegetarian diet (< 6 years, 6 to ≤ 11 years, > 11 years), those in tertile 1 (< 6 years) and tertile 2 (6 to ≤ 11 years) had shown thinner IMT as compared to the omnivores, and tertile 3 had shown no reduction. CONCLUSION: A decrease in multiple cardiovascular risk factors such as BMI, blood pressure and lipid profile was associated with vegetarian diet. Moreover, taking a low-calorie, low-protein, or vegetarian diet might have great beneficial effects on IMT through improved lipid profile, and the beneficial effects appeared to be correlated with the duration of vegetarian diet.

Metabolic disorders in newly diagnosed young adult female patients with simple virilizing 21-hydroxylase deficiency.

Classical congenital adrenal hyperplasia (CAH) is characterized by the defects in cortisol and aldosterone secretion, and accompanied with adrenal hyperandrogenism. It is likely that the impaired adrenocortical function and intermittent treatment-related hypercortisolism may predispose patients to the development of metabolic syndrome in adulthood. Our aim was to assess the impact of hyperandrogenism on metabolic profiles in CAH women without glucocorticosteroid treatment. We evaluated the clinical characteristics and metabolic profiles in 30 untreated Chinese female adults with simple virilizing congenital adrenal hyperplasia (SV-CAH). Mutation analysis was performed by sequencing the entire 21-hydroxylase gene (CYP21A2). As compared with the controls, CAH patients had higher BMI (BMI, 21.5±2.1 vs. 20.0±1.8 kg/m2, P<0.05), higher 2 h post-load plasma glucose levels (6. 35±1.74 vs. 5. 35±1.17 mmol/l, P<0.05), higher serum triglycerides (TG) (1.12±0.64 vs. 0.63±0.15 mmol/l, P<0.01), and lower high-density lipoprotein cholesterol (HDL-c) (1.30±0.39 vs. 1.67±0.29 mmol/l, P<0.01). Moreover, CAH patients had higher fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (1.81±0.99 vs. 1.24±0.50, P<0.05), while ΔIns30/ΔGlu30 showed no statistically significant difference in two groups. In addition, a marked reduction of serum adiponectin levels were observed in CAH patients (7.0±3.3 vs. 13.2±4.8 µg/ml, P<0.001), however, serum CRP levels were not different between patients and the controls. Further regression analysis showed that higher serum testosterone concentrations were associated with metabolic disorder indexes and reduction of serum adiponectin. Our study demonstrates that untreated CAH patients are prone to have metabolic disorders in association with elevated serum testosterone levels and reduced insulin insensitivity.

Puerarin improves insulin resistance and modulates adipokine expression in rats fed a high-fat diet.

The link between obesity and insulin resistance largely accounts for the pathogenesis of metabolic syndrome and diabetes mellitus, in which adipokine expression plays a key role. Puerarin, a major active isoflavone extracted from the traditional Chinese medicine Radix Puerariae, has been studied for its comprehensive biological actions. However, its effect on high-fat diet (HFD)-induced insulin resistance and adipokine expression in rat has not been well investigated. In the present study, male Sprague-Dawley rats were fed on a normal control diet (NCD) or HFD for 6 weeks, followed by administration of puerarin (100 and 200 mg/kg) for up to 8 weeks. Compared to NCD, HFD feeding for 6 weeks led to increased body weight gain and impaired glucose/insulin tolerance manifested by oral glucose/intraperitoneal insulin tolerance tests in rats. These exacerbations prolonged through HFD feeding, but were effectively reversed by puerarin administration. Enzyme-linked immunosorbent assay demonstrated that, serum levels of leptin and resistin, but not that of adiponectin, were markedly augmented by HFD and retarded by puerarin treatment. Real-time reverse transcription polymerase chain reaction results showed that, in agreement with the circulating levels, mRNA expression of leptin and resistin in epididymal white adipose tissue was modified by HFD and improved by puerarin in the same pattern. Collectively, we revealed that puerarin could improve body weight gain, glucose/insulin intolerance and adipokine expression in HFD-induced insulin resistant rats, indicating its potential value for treatment of metabolic syndrome.

Immediate but not long-term administration of nicardipine inhibits tolbutamide-induced insulin secretion from rat pancreatic beta cells.

OBJECTIVES: Calcium channel blockers alter glucose homeostasis, but sufficient data regarding this effect in healthy animals have not been provided. We test the effect of nicardipine on beta cell function in healthy rats. METHODS: Islets from Sprague-Dawley rats were coincubated with nicardipine, tolbutamide, or their combination for 1 hour. Insulin secretion was measured by radioimmunoassay. The rats were given nicardipine, tolbutamide, or their combination by intravenous injection. Intravenous glucose tolerance tests were performed after the first drug administration and 4 weeks later. Pancreata were excised for assessment of insulin content and immunohistochemical staining in the end. RESULTS: Nicardipine markedly inhibited not only the insulin secretion by islets per se but also that enhanced by tolbutamide in vitro. Blood glucose was reduced by tolbutamide in vivo but elevated by nicardipine abruptly in parallel with retarded insulin secretion. Long-term administration of nicardipine altered neither fasting blood glucose level nor fasting serum insulin level, whereas pancreatic insulin content was unmodified despite that nicardipine caused shrunken islets with weak immunoreactivity of beta cells by immunohistochemistry. CONCLUSIONS: In healthy rats, immediate administration of nicardipine inhibits insulin secretion of beta cells both in vitro and in vivo but does not exert a deleterious effect in vivo after long-term treatment.

Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma.

PURPOSE: To centrally assess the safety, efficacy, and 6-year follow-up of recombinant adenovirus-p53 (rAd-p53) combined with radiotherapy (RT) for patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: A randomized controlled clinical study on rAd-p53 combined with RT in 42 patients with NPC was compared with a control group of 40 patients with NPC treated with RT alone. In the group receiving rAd-p53 combined with RT, rAd-p53 was intratumorally injected once a week for 8 weeks. Concurrent RT (70 Gy in 35 fractions) was given to the nasopharyngeal tumor and neck lymph node. Patients and tumors were monitored for adverse events and responses. RESULTS: rAd-p53-specific p53 mRNA was detected in postinjection of rAd-p53 biopsies from 16 (94.1%) of 17 patients. Upregulation of p21/WAF1 and Bax and downregulation of vascular endothelial growth factor were observed in postinjection tumor biopsy. Complete response rate in the group receiving rAd-p53 combined with RT was observed at 2.73 times that of the group receiving RT alone (66.7% v 24.4%). Six-year follow-up data showed that rAd-p53 significantly increased the 5-year locoregional tumor control rate by 25.3% for patients with NPC treated with irradiation (P = .002). The 5-year overall survival rate and 5-year disease-free survival rate of the group receiving rAd-p53 combined with RT were 7.5% (P = .34) and 11.7% (P = .21) higher than those of the group receiving RT alone. No dose-limiting toxicity or adverse events appeared, except for transient fever after rAd-p53 administration. CONCLUSION: In patients with NPC, rAd-p53 was safe and biologically active. Our results indicated that rAd-p53 improves radiotherapeutic tumor control and survival rate in patients with NPC.

Expression of motilin in the hypothalamus and the effect of central erythromycin on gastric motility in diabetic rats.

OBJECTIVE: To investigate the expression of motilin-immunoreactive neurons in the hypothalamus and the effect of central administration of erythromycin (EM) on the regulation of gastric motility in diabetic rats. METHODS: The motilin immunoreactive neurons in the hypothalamus and the hippocampus were detected by immunohistochemistry with rabbit anti-motilin polyclonal antibody. To measure the gastric motility, force transducers were surgically affixed to the gastric serosa. A microinjection syringe was connected via a plastic tube to an injection cannula, which was connected with a stainless steel guide cannula. The syringe was inserted into the right lateral cerebral ventricle for microinjecting the chemicals. RESULTS: Diabetic mellitus was successfully induced in cohorts of rats. Motilin-immunoreactive neurons significantly increased in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in the diabetic rats. Intracerebroventricular (i.c.v.) administration of EM, a motilin receptor agonist, stimulated the gastric motility of diabetic rats. EM (91.56 nmol, i.c.v.) dose-dependently increased the amplitude by (174.82 +/- 48.62)% (P<0.05), and increased the frequency by (70.43 +/- 27.11)% (P < 0.05) in 5 min. The stimulatory effect lasted more than 15 min to the end of the measurement, and can be blocked partially by the prior treatment of motilin receptor antagonist GM-109. CONCLUSION: Motilin-immunoreactive neurons are increased in the PVN and SON of the hypothalamus in diabetic rats. Centrally administered EM may regulate gastric motility by binding to the central motilin receptors, and central motilin might be involved in regulation of gastric motility in diabetic rats.

[Association of a polymorphism in MDR1 C3435T with response to antiepileptic drug treatment in ethic Han Chinese children with epilepsy].

OBJECTIVE: P-glycoprotein 170 (P-gp) is a plausible biologic candidate for pharmacoresistance in epilepsy. The expression and efflux efficiency of P-gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). The CC genotype at the MDR1 C3435T polymorphism was reported to be associated with the response to antiepileptic drug treatment. This study attempted to replicate this finding by examining the association of this genetic polymorphism with response to antiepileptic drug treatment in ethnic Han Chinese children with epilepsy. METHODS: Two hundred and fourteen ethnic Han Chinese children with epilepsy were classified based on the response to antiepileptic drug treatment: drug-nonresponsive and drug-responsive. DNA samples were obtained from the patients. Genotypes of the C3435T polymorphism were determined by traditional polymerase chain reaction followed by restriction digestion (PCR-RFLP). The frequency of genotypes and alleles between the two groups was compared by Chi-square test. RESULTS: Of the 214 patients, 164 were drug-responsive and 50 were drug-nonresponsive. There were no significant differences in the allele frequency and genotype frequency between the two groups. CONCLUSIONS: There is no an association between the CC genotype or C allele at the locus of C3435T in MDR1 gene and response to antiepileptic drug treatment in ethnic Han Chinese children with epilepsy.

Effects of ghrelin on hypothalamic glucose responding neurons in rats.

Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R) with potent stimulatory effects on food intake. The aim of the present study was to investigate the effects of ghrelin on neuronal activity of hypothalamic glucose responding neurons. Single unit discharges in the lateral hypothalamic area (LHA), the ventromedial hypothalamic nucleus (VMH), and the parvocellular part of the paraventricular nucleus(pPVN) were recorded extracellularly by means of four-barrel glass micropipettes in anesthetized rats. The activity of glucose-sensitive neurons (GSNs) in the LHA, pPVN, and of glucoreceptor neurons (GRNs) in the VMH modulated by administration of ghrelin was analyzed. In the LHA, the majority of GSNs (17/25) increased in frequency due to ghrelin. Whereas the majority of VMH-GRNs (27/33) and pPVN-GSNs (9/13) was inhibited. The responses to ghrelin were abolished by pretreatment of [D-Lys-3]-GHRP-6, ghrelin receptor antagonist. These data indicate that the glucose responding neurons in the LHA, VMH, and pPVN are also involved in the orexigenic actions of ghrelin in the hypothalamic circuits, although AgRP/NPY neurons in the arcuate nucleus (ARC) are the primary targets of ghrelin.