机械力学对体外骨髓间充质干细胞的影响

目的:分析力学刺激体外骨髓间充质干细胞所产生增殖分化等生物学效应的影响及其力化学信号转导途径。资料来源:因特网上检索PubMed数据库中2000-01/2006-06期间有关力学刺激对骨髓干细胞作用效应进展的英文文章,检索词“stem cel1,marrow mesenchymal stem cells,mechanical stimulation,stress”,同时检索CNKI中国知网医学文献数据库2000-01/2006-06期间的相关文章,检索词为“干细胞、骨髓间充质干细胞、机械刺激、应力”。资料选择:对资料进行筛选,选取相关文章查找全文。纳入标准:①骨髓间充质干细胞相关生物学特性。②体外细胞加载的应力分类及相应力学装置的特点。③应力对细胞影响的研究。④能获取文章的全文。排除标准:①较陈旧的文献。②重复研究。资料提炼:共收集关于86篇体外骨髓干细胞及力学干预的相关文献。其中30篇符合纳入标准。资料综合:①骨髓干细胞具有高度增殖及多向分化能力,可通过体外培养、干预作为细胞组织工程的理想种子细胞。②力学刺激是体外调节细胞生物学效应的重要途径,其中力学分类有:流体切应力、静止压应力、张应力、离心力以及单个细胞的吸吮力等,介绍各种力以及相应的力学装置的特点。③骨髓干细胞加载各种应力干预后产生的生物学效应,以及细胞应力学刺激的机制、信号转导途径。结论:力学刺激可影响骨髓间充质干细胞生物学特性,在适当的力学刺激条件下,促进细胞的增殖与分化,为骨组织工程提供新的技术手段,同时也为临床应用牵拉成骨的骨再生过程提供理论依据。     

Identification of a novel CTR9 germline mutation in a family with Wilms tumor

Germline mutations in the WT1 gene have been identified in some families with Wilms tumor. Recently, the CTR9 gene was found to be mutated in three families with Wilms tumor, thus representing a novel predisposition gene for this disease. We identified a family with a history of Wilms tumor characterized by three affected siblings, one of them presenting an aggressive bilateral tumor.Here we investigated the involvement of WT1 and CTR9 genes in this family with Wilms tumor. The involvement of WT1 was first evaluated by Next generation sequencing in leukocytes DNA from one affected family member. Subsequently, the CTR9 gene was analyzed by Sanger sequencing in DNA and RNA from patients’ leukocytes and/or tumor. No mutations were detected in WT1. However, we identified a novel CTR9 germline variant, located in a consensus splice acceptor site, which was found to segregate with Wilms tumor in this family. We found that this variant leads to the skipping of the entire exon 9 in the mRNA, which is predicted to encode a truncated CTR9 protein, strongly suggesting that it is pathogenic. Additionally, we also detected loss of heterozygosity in the index case tumor, which is consistent with CTR9 being a tumor suppressor gene, confirming also its contribution to familial Wilms tumor etiology.The identification of a novel CTR9 germline mutation will improve the present knowledge on the molecular basis of familial Wilms tumor. Importantly, it will help in the genetic counselling and may also lead to earlier diagnosis in other family members and future generations.     

Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation

Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Behçet’s disease associated with superior vena cava syndrome without thrombosis

Behçet’s disease is a multisystemic vasculitis of unknown etiology, which is characterized by recurrent urogenital ulceration, cutaneous eruptions, ocular manifestations, arthritis and vasculitis, and its diagnosis is based on clinical criteria. Superior vena cava (SVC) thrombosis is a rare but well-recognized manifestation of Behçet’s disease, whereas SVC syndrome due to vasculopathy, without evidence of thrombosis, has not yet been described in the literature. The authors report the case of a patient with Behçet’s disease, who presented SVC syndrome with reduction in the lumen of the SVC due to thickening of the vessel wall, without evidence of thrombosis upon computed tomography and magnetic angioresonance. The patient received early anticoagulant therapy, corticosteroid and monthly cyclophosphamide pulse therapy. Clinical control without recurrence was observed after 6 months of follow-up. Behçet’s disease should be suspected in young patients presenting with SVC syndrome, in the absence of thrombosis or of a hypercoagulable state.     

The Accelerating Access Initiative: experience with a multinational workplace programme in Africa

Problem

A multinational company with operations in several African countries was committed to offer antiretroviral treatment to its employees and their dependants.

Approach

The Accelerating Access Initiative (AAI), an initiative of six pharmaceutical companies and five United Nations’ agencies, offered the possibility of obtaining brand antiretroviral drugs (ARVs) at 10% of the commercial price. PharmAccess, a foundation aimed at removing barriers to AIDS treatment in Africa, helped to establish an HIV policy and treatment guidelines, and a workplace programme was rolled out from September 2001.

Local setting

Private sector employers in Africa are keen to take more responsibility in HIV prevention and AIDS care. An important hurdle for African employers remains the price and availability of ARVs.

Relevant changes

The programme encountered various hurdles, among them the need for multiple contracts with multiple companies, complex importation procedures, taxes levied on ARVs, lack of support from pharmaceutical companies in importation and transportation, slow delivery of the drugs, lack of institutional memory in pharmaceutical companies and government policies excluding the company from access to ARVs under the AAI.

Lessons learned

The launch of the AAI enabled this multinational company to offer access to ARVs to its employees and dependants. The private sector should have access to these discounted drugs under the AAI. A network of local AAI offices should be created to assist in logistics of drugs ordering, purchase and clearance. No taxes should be levied on ARVs.     

IGOB131, a novel seed extract of the West African plant Irvingia gabonensis, significantly reduces body weight and improves metabolic parameters in overweight humans in a randomized double-blind placebo controlled investigation

Background  

A recent in vitro study indicates that IGOB131, a novel seed extract of the traditional West African food plant Irvingia gabonensis, favorably impacts adipogenesis through a variety of critical metabolic pathways including PPAR gamma, leptin, adiponectin, and glycerol-3 phosphate dehydrogenase. This study was therefore aimed at evaluating the effects of IGOB131, an extract of Irvingia gabonensis, on body weight and associated metabolic parameters in overweight human volunteers.     

TAFI deficiency in liver cirrhosis: relation with plasma fibrinolysis and survival

INTRODUCTION: TAFI (thrombin-activatable fibrinolysis inhibitor) is a potent anti-fibrinolytic and anti-inflammatory factor of liver origin. It is markedly reduced in liver cirrhosis but its effect on fibrinolysis remains controversial and no data are available on its prognostic value. We evaluated the relationship of TAFI level with plasma fibrinolysis and survival in cirrhotic patients. PATIENTS AND METHODS: Sixty-five patients with liver cirrhosis were studied. TAFI antigen, plasma fibrinolysis and other laboratory variables were assayed at study entry and their association with mortality was assessed during a 3-year follow-up. RESULTS: TAFI level and fibrinolysis time were markedly reduced in liver cirrhosis as compared to healthy subjects (p<0.0001) and TAFI deficiency was strongly correlated with fibrinolysis time (p=0.0002). TAFI level at entry, but not fibrinolysis time, was significantly lower in non-survivors (n=25) than in survivors (n=40, p=0.0001). By Cox regression analysis, after adjustment for possible confounding factors, TAFI, but not fibrinolysis time, was identified as an independent predictor of mortality. TAFI assay, moreover, showed a clinically relevant accuracy in assessing patients' survival (ROC curve analysis, p<0.0001) achieving a sensitivity of 92%, a specificity of 55%, and a negative predictive value of 91.7%. CONCLUSIONS: Our data indicate that TAFI deficiency in liver cirrhosis is associated with enhanced plasma fibrinolysis. Moreover, they suggest that TAFI, but not fibrinolysis time, is a strong predictor of survival and thus TAFI assay might prove useful to select candidates for liver transplantation.