TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-β signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-β signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-β signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-β signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-β signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-β signaling. These results implicate constitutive TGF-β signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-β signaling in vasoproliferative and vascular degenerative retinal diseases.     

西班牙渗出性老年性黄斑变性的相关流行病学因素(英文)

目的:报告在西班牙Castilla-Leo地区患有渗出性老年性黄斑变性(AMD)的样本人群的流行病学特点,并与一组来自同一地区和相同年龄人群进行比较。方法:在本次观察性前瞻性调查中,我们访问了在一家地区性诊所接受光动力学疗法的AMD患者。患者报告了高血压、高血脂、吸烟的病史,检查患者虹膜颜色并分为浅色(绿色、蓝色、灰色)和深色(淡褐色、褐色、黑色)。结果:共有343名患者接受了访问,平均年龄为74.9岁(55~93岁),其中64.5%为女性,35.5%为男性,有45.1%的患者虹膜颜色被划为浅色。这些患者中,有50%有动脉性高血压,15.3%接受高胆固醇血症治疗,30.2%吸烟或者已经戒烟(女性中占80.9%)。结论:在渗出性AMD患者中,虹膜颜色为浅色的频率较高。在我们的调查中,其他渗出性AMD其他的风险因素有男性的吸烟习惯、未接受高胆固醇血症治疗、患者为女性身份等。     

Effects of constitutive deletion of opioid receptors on the basal densities of Fas and Fas-associated protein with death domain (FADD) in the mouse brain: a delta-opioid tone inhibits FADD.

The acute effects of opiate drugs and opiate addiction have been associated with modulation of Fas/FADD (Fas-Associated protein with Death Domain) signaling complex in the rat brain. This study investigated the possible existence of endogenous opioid tones regulating the basal activities of Fas receptor forms and FADD in the brain, using gene-targeted mice lacking mu-, delta- or kappa-opioid peptide receptors (KO mice). In mu-KO mice, but not in delta- or kappa-KO mice, the basal immunodensity of native Fas (35 kDa monomeric form) was decreased in the cerebral cortex (33%) when compared with WT littermates. In delta-KO mice, but not in mu- or kappa-KO mice, the basal content of 120 kDa Fas aggregates (complexes of monomers relevant in Fas signaling) was markedly increased in the cortex (93%). In contrast, no differences between genotypes were observed in the basal expression of glycosylated Fas (51/48/45 kDa forms). Notably, the basal content of FADD (the adaptor protein that couples Fas to caspases and transmits the death signal) was increased in the cerebral cortex of delta-KO mice (48%), but not in mu- or kappa-KO mice. In addition, the basal content of phosphorylated FADD at Ser191 (the relevant species of FADD implicated in nonapoptotic signals) was also upregulated in the cortices of delta-opioid receptor KO mice (6.5-11.0-fold). The results suggest that mu-receptors tonically stimulate (through endogenous opioid peptides) the activation of native Fas, whereas delta-receptors tonically inhibit the expression of Fas aggregates and that of FADD and phosphorylated FADD (Ser191) in the mouse brain. These data are in line with the acute opposite modulation of Fas and FADD induced by mu- and delta-opiate agonists, and strongly support the notion of an anti-apoptotic delta-opioid tone that restrains Fas signaling.     

Diminished concentrations of insulin-like growth factor I in cystic fibrosis

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean (-2 SD to +2 SD) IGF-I SD score was -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females. Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females. In patients who were still in the growth period a significant correlation of IGF-I SD score to height SD score (r = 0.28, p < 0.001) was found. The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.     

Cerebral gigantism associated with Wilms' tumor

Two children had cerebral gigantism in unique association with Wilms' tumor. An increased incidence of neoplasms has been reported in cerebral gigantism, as well as in Beckwith-Wiedemann syndrome. We report similarities and differences between these disorders.     

Function of neutrophilic polymorphonuclear leukocytes in pediatric patients with intrinsic and extrinsic asthma during the intercrisis period

Polymorphonuclear leukocyte function: chemotaxis, NBT and myeloperoxidases activity, was investigated in a group of asthmatic pediatric patients, 26 with intrinsic and 27 with extrinsic asthma, during intercrisis. There was no difference between the extrinsic asthma group and the control one while the group with intrinsic asthma showed an increase of chemotaxis activity (p less than 0.001) and NBT reduction (p less than 0.01); myeloperoxidases activity was similar to the control group. The comparative study of the two types of asthma shows a significant increase of NBT reduction (p less than 0.02) and chemotaxis activity (p less than 0.001) in the intrinsic group. These findings demonstrate that polymorphonuclear function is different in the two main types of asthma during the asymptomatic period.