Diabetic retinopathy remains a leading cause of irreversible blindness. A critical early pathology in the disease is the adhesion of leukocytes to the retinal vasculature, a process that occurs, in part, via intercellular adhesion molecule-1. Once leukocyte adhesion occurs, endothelial cell injury ensues, as does blood-retinal barrier breakdown. Here we show that angiopoietin-1 can prevent and reverse these diabetic retinal vascular changes in both new and established diabetes. Angiopoietin-1, when given intravitreally to newly diabetic rats, normalized retinal vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 mRNA and protein levels, leading to reductions in leukocyte adhesion, endothelial cell injury, and blood-retinal barrier breakdown. When an adenovirus coding for angiopoietin-1 was given systemically to mice with established diabetes, it similarly inhibited leukocyte adhesion and endothelial cell injury and blood-retinal barrier breakdown. These changes coincided with reductions in retinal eNOS, nitric oxide, Akt (protein kinase B), and MAP kinase activity, known mediators of VEGF bioactivity and leukocyte adhesion. When endogenous VEGF bioactivity was inhibited with a soluble Flt-1/Fc chimera, retinal Akt kinase activity was significantly reduced in vivo. Taken together, these data document new vascular and anti-inflammatory bioactivities for angiopoietin-1 and identify it as the first naturally occurring protein that directly protects the retinal vasculature in diabetes.

Abstract-Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (nϭ10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-␤ protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications. (Hypertension. 2008;51:1218-1224.)Key Words: diabetes Ⅲ kidney Ⅲ sex hormones Ⅲ glomerulosclerosis Ⅲ tubulointerstitial fibrosis E pidemiological studies show that the incidence and the rate of progression of nondiabetic renal disease are greater in men compared with age-matched women. 1,2 These observations lead to the belief that the male sex is a risk factor and/or that the female sex is a protective factor against the development of renal disease. In the setting of diabetes, however, this relationship is not so clear. Although some studies indicate that the male sex is still a risk factor for the development of diabetic nephropathy and progression to end-stage renal disease, 3,4 other studies suggest either no difference 5,6 or that females progress at a faster rate. 7,8 The actual truth is that the existing data are inadequate for the precise determination of whether sex differences, which clearly exist in nondiabetic renal disease, exist or "disappear" in the setting of diabetes.Our previous studies have shown that diabetes is associated with reduced plasma levels of estradiol in the female streptozotocin (STZ)-induced diabetic rat. 9 Supplementation of estradiol in these animals either from the onset 10,11 or 2 months after the induction of diabetes 12 attenuates the development of renal disease. Clinical studies indicate that diabetes is associated with decreased testosterone levels in men with diabetes, 13,14 suggesting that testosterone deficiency may contribute or at least be associated with the development of diabetic renal disea...

The impact of elevated ammonium nitrate concentrations onthe survival and development of common toad (Bufo bufo) tadpoles wasinvestigated in the laboratory. 1,704 mg/L and 1,637 mg/L nitrate (equivalentto 2,198.7 mg/L and 2,112.3 mg/L ammonium nitrate) were recorded as 96 h and168 h LC50s respectively. These are well above field levels (10-250 mg/L)observed in freshwater in Britain. The exposure of tadpoles to nominalconcentration of 100 mg/L nitrate for 24, 48, and 72 h caused a significantdecrease in their activity but no clear reduction in food consumption ordelay of the development. In subchronic exposures at the nominalconcentrations of 50 and 100 mg/L nitrate, the metamorphosis started earlierand took less time to complete than in the control. However, some of theresults were equivocal, at 50 mg NO3/L the metamorphs weresignificantly larger than the controls, while at 100 mg NO3/Lmetamorphs were not significantly different from the controls. Certaindeformities and unusual swimming patterns were also found in tadpoles exposedto various concentrations of ammonium nitrate.

Our previous studies have shown that diabetes in the male streptozotocin (STZ)-induced diabetic rat is characterized by a decrease in circulating testosterone and concomitant increase in estradiol levels. Interestingly, this increase in estradiol levels persists even after castration, suggesting extra-testicular origins of estradiol in diabetes. The aim of the present study was to examine whether other target organs of diabetes may be sources of estradiol. The study was performed in male Sprague-Dawley non-diabetic (ND), STZ-induced diabetic (D) and STZ-induced diabetic castrated (Dcas) rats (n=8-9/group). 14 weeks of diabetes was associated with decreased testicular (ND, 26.3±4.19; D, 18.4±1.54; P<0.05), but increased renal (ND, 1.83±0.92; D, 7.85±1.38; P<0.05) and ocular (D, 23.4±3.66; D, 87.1±28.1; P<0.05) aromatase activity. This increase in renal (Dcas, 6.30±1.25) and ocular (Dcas, 62.7±11.9) aromatase activity persisted after castration. The diabetic kidney also had increased levels of tissue estrogen (ND, 0.31 ±0.01; D, 0.51±0.11; Dcas, 0.45±0.08) as well as estrogen receptor alpha protein expression (ND, 0.63±0.09; D, 1.62±0.28; Dcas, 1.38±0.20). These data suggest that in male STZ-induced diabetic rats, tissues other than the testis may become sources of estradiol. In particular, the diabetic kidney appears to produce estradiol following castration, a state that is associated with a high degree or renal injury. Overall, our data provides evidence for the extra-testicular source of estradiol that in males, through an intracrine mechanism, may contribute to the development and/or progression of end-organ damage associated with diabetes.

We recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine whether these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin-induced diabetic rats treated with 0 mg/day DHT (DHT(0)), 0.75 mg/day DHT (DHT(0.75)), or 2.0 mg/day DHT (DHT(2.0)) for 14 wk. Treatment with 0.75 mg/day DHT attenuated castration-associated increases in urine albumin excretion (DHT(0), 81.2 +/- 18.1; DHT(0.75), 26.57 +/- 5.8 mg/day; P < 0.05), glomerulosclerosis (DHT(0), 1.1 +/- 0.79; DHT(0.75), 0.43 +/- 0.043 arbitrary units; P < 0.001), tubulointerstitial fibrosis (DHT(0), 1.3 +/- 0.12; DHT(0.75), 1.1 +/- 0.096 AU; P < 0.05), collagen type IV [DHT(0), 3.2 +/- 0.11; DHT(0.75), 2.1 +/- 0.070 relative optical density (ROD); P < 0.01], transforming growth factor-beta (DHT(0), 3.2 +/- 0.16; DHT(0.75), 2.1 +/- 0.060 ROD; P < 0.01), IL-6 (DHT(0), 0.37 +/- 0.011; DHT(0.75), 0.27 +/- 0.014 ROD; P < 0.05), and protein expression and reduced CD68-positive cell abundance (DHT(0), 17 +/- 0.86; DHT(0.75), 4.4 +/- 0.55 cells/mm(2); P < 0.001). In contrast, treatment with 2.0 mg/day DHT exacerbated all these parameters. These data suggest that the detrimental effects of castration in the diabetic kidney can be attenuated with low doses of DHT, whereas high doses augment the adverse effects of castration, and these effects appear to be influenced by estradiol. We conclude that the effects of DHT are dose dependent but caution should be taken when DHT supplementation is considered in the treatment of diabetic renal disease.

Background-The incidence of chronic renal disease in women increases with aging especially after menopause suggesting that the loss of sex hormones contributes to the development and progression of renal disease. However, the mechanisms by which sex hormones, estrogens in particular, contribute to the disease process are unclear.

Background:Injurious inflammatory response is critical to the development of lung ischemia/reperfusion injury (LIRI). The cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert an anti-inflammatory effect on the cardiovascular system. We therefore cytochrome hypothesized that CYP2J2 overexpression and pretreatment with exogenous EETs may have the potential to reduce LIRI. Methods:A rat model was used to mimic the condition of LIRI by clamping the left pulmonary hilum for 60 minutes, followed by reperfusion for 2 hours. Moreover, we developed a cell model using human pulmonary artery endothelial cells by anoxia for 8 hours, followed by reoxygenation for 16 hours to determine the anti-inflammatory effect and mechanism of CYP2J2 overexpression and exogenous 11,12-EET. Results:Lung ischemia/reperfusion increased lung wet/dry and lung weight/body weight ratios, protein concentration in bronchoalveolar lavage fluid and concentrations of pro-inflammatory, including mediators in serum IL-1ß, IL-8, TNF-a, sP- and sE-selectin, and decreased concentration of anti-inflammatory mediator IL-10. Ischemia/reperfusion also leaded to pulmonary edema and inflammation under light microscopy. Furthermore, activation of NF-γB p65 and degradation of IγBa were remarkably increased in ischemia/reperfusion lung tissues. While CYP2J2 overexpression significantly inhibited the above effects (p<0.05). In vitro data further confirmed the anti-inflammatory effect of CYP2J2 overexpression and 11,12-EET, an effect that may probably be mediated by PPARγ activation. Conclusion:CYP2J2 overexpression and administration of exogenous EETs can protect against LIRI via anti-inflammatory effects. This can be a novel potential strategy for prevention and treatment of LIRI.

Cultural influences on anatomy teaching and learning have been investigated by application of a questionnaire to medical students in British and Chinese Medical Schools. Results from the responses from students of the two countries were analyzed. Both groups found it easier to understand anatomy in a clinical context, and in both countries, student learning was driven by assessment. Curriculum design differences may have contributed to the British view wherein students were less likely to feel time pressure and enjoyed studying anatomy more than their Chinese counterparts. Different teaching approaches resulted in British students being more likely to recite definitions to learn, and the Chinese students found learning from cross-sectional images easy. Cultural differences may account for the observation that British students were more inclined to ask questions in class, and the preference of Chinese students to study in small groups. The findings give evidence to show how 'cultures of learning' influence students' approaches and indicate the importance of cultural influences as factors amongst international and home learner groups.