力达霉素抑制人纤维肉瘤肺转移的裸鼠活体成像观察

观察力达霉素 (LDM)、LDM与甲氨蝶呤 (MTX) 联合用药对人纤维肉瘤HT-1080^LUC实验性肺转移的抑制作用。构建稳定表达荧光素酶的HT-1080细胞株并扩增培养, 检测HT-1080^LUC细胞的荧光素酶的表达。建立裸鼠人纤维肉瘤HT-1080^LUC实验性肺转移模型, 并采用活体动物成像系统监测肿瘤的生长情况, 观察LDM和MTX的体内抗肺转移瘤活性。结果表明, HT-1080^LUC细胞荧光光子量与细胞数呈线性相关, 最小可检测的细胞数量为100个/孔。活体成像结果显示, 治疗组裸鼠的肺部荧光强度较对照组明显减弱。单独给予LDM 0.025 mg·kg⁻¹、LDM 0.05 mg·kg⁻¹或MTX 0.5 mg·kg⁻¹的肺转移抑制率分别为53.9%、75.9%和70.2%; LDM 0.025 mg·kg⁻¹与MTX 0.5 mg·kg⁻¹联合应用的肺转移抑制率为88.7%, 两药相互作用指数CDI = 0.82。研究表明, LDM对人纤维肉瘤肺转移有明显抑制作用, 与MTX联合用药对肺转移瘤的疗效明显优于单独给药。     

Mobilization of circulating endothelial progenitor cells after endovascular therapy for ruptured cerebral aneurysms

Emerging evidence shows that circulating endothelial progenitor cells (EPCs) promote regeneration of the endothelium at sites of vessel injury. This study was designed to test the hypothesis that EPCs are mobilized in patients who had ruptured cerebral aneurysm (CA) and underwent endovascular therapy. Fourteen patients with ruptured CAs were recruited and blood samples were analyzed after coil embolization surgery. Blood samples were also obtained from 18 healthy control subjects who had no evidence of CAs and did not undergo endovascular surgery. We measured the numbers of circulating EPCs, levels of plasma vascular endothelial growth factor (VEGF) and platelet counts. EPCs significantly increased in patients with ruptured CAs and underwent surgical coil embolization, reaching a peak level on day 14 post operation. The levels of plasma VEGF and platelet counts also significantly increased in parallel with the increase in EPCs, leading to significant positive correlations of circulating EPCs with VEGF in plasma (r = 0.636, P < 0.01) and platelet counts (r = 0.721, P < 0.001), respectively. The finding suggests that EPCs are mobilized upon surgery and may play a critical role in repairing injured vascular endothelium. Levels of EPCs in peripheral blood could also serve as a prognostic marker for the outcomes of ruptured cerebral aneurysms after surgical repair.     

Citrin deficiency,a perplexing global disorder

Citrin deficiency, caused by mutations in SLC25A13, can present with neonatal intrahepatic cholestasis or with adult onset neuropsychiatric, hepatic and pancreatic disease. Until recently, it had been thought to be found mostly in individuals of East Asian ancestry. A key diagnostic feature has been the deficient argininosuccinate synthetase (ASS) activity (E.C. 6.3.4.5) in liver, with normal activity in skin fibroblasts. In this series we describe the clinical presentation of 10 patients referred to our laboratories for sequence analysis of the SCL25A13 gene, including several patients who presented with elevated citrulline on newborn screening. In addition to sequence analysis performed on all patients, ASS enzyme activity, citrulline incorporation and Western blot analysis for ASS and citrin were performed on skin fibroblasts if available. We have found 5 unreported mutations including two apparent founder mutations in three unrelated French-Canadian patients. In marked contrast to previous cases, these patients have a markedly reduced ASS activity in skin fibroblasts. The presence of citrin protein on Western blot in three of our cases reduces the sensitivity of a screening test based on protein immunoblotting. The finding of citrin mutations in patients of Arabic, Pakistani, French Canadian and Northern European origins supports the concept that citrin deficiency is a panethnic disease.     

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.     

Proton magnetic resonance spectroscopy reveals an abnormality in the anterior cingulate of a subgroup of obsessive–compulsive disorder patients

Numerous neuroimaging studies have suggested that obsessive–compulsive disorder (OCD) patients had a neurobiological abnormality in the frontal-subcortical circuits. On the other hand, there are distinct differences in the responses to pharmacological treatment among OCD patients. In the present study, we measured the concentration of N-acetyl aspartate (NAA), a putative marker of neuronal viability, with proton magnetic resonance spectroscopy (MRS) in OCD patients with different pharmacological responses. Participants comprised 20 patients and 26 healthy control subjects. OCD patients were divided into three groups according to the pharmacological response; responders to a selective serotonin reuptake inhibitor (SSRI) (group A: n = 7), responders to SSRI with an atypical antipsychotic (group B: n = 8) and non-responders to either SSRI or SSRI with an atypical antipsychotic (group C: n = 5). Short echo proton MRS was used to measure NAA concentrations in the anterior cingulate, the left basal ganglia and the left prefrontal lobe of subjects. A significantly lower NAA concentration was observed only in group B compared with control subjects in the anterior cingulate. Our results suggest that a subgroup of OCD patients who respond to an SSRI with an atypical antipsychotic have distinct biological abnormalities in the anterior cingulate.     

Asymmetries of the central sulcus in young adults: Effects of gender,age and sulcal pattern

In this study, we clarified the gender and age-related asymmetries of the central sulcus (CS) in early adulthood using a parametric ribbon method. The CS was reconstructed and parameterized automatically from 3D MR images of 112 healthy right-handed subjects. The 3D anatomic morphology of the CS was presented using 5 sulcal parameters, including sulcal depth position-based profile (DPP), average depth (AD), average width (AW), top length (TL) and bottom length (BL). Asymmetry differences in DPPs were found in the medial and lateral part of the CS. In addition, significant gender differences were observed in the medial and middle parts of the right CS DPPs but scattered in the left side. We found leftward asymmetries of TL in males, but rightward asymmetries of AW in females. Males had a greater AW than females in the right hemisphere. Moreover, the females had bilateral longer TL and a longer left BL than did males. We also found significant age-related reductions in bilateral TL and increases in bilateral AW, with males presenting more obvious age-related change than females. There were sexual differences of the CS patterns, in which Type b was the most dominant sulcal pattern in males, whereas Type a was dominant in females. Three-way ANOVA revealed sexual and asymmetry changes of TL and BL among different CS patterns. Our findings indicate that the lateralization performances of the CS manifest as sexually and regionally different. In addition, it is suggested that males may undergo a faster progress of aging compared to females.