Variable aneuploidy mechanisms in embryos from couples with poor reproductive histories undergoing preimplantation genetic screening

BACKGROUND: Preimplantation genetic screening (PGS) is used to determine the chromosome status of human embryos from patients with advanced maternal age (AMA), recurrent miscarriage (RM) or repeated implantation failure (RIF). METHODS: Embryos from 47 such couples were investigated for chromosomes 13, 15, 16, 18, 21 and 22 using fluorescence in situ hybridization with two rounds of hybridization. The investigation included parental lymphocyte work-up, the screening of blastomeres on day 3 and full follow-up on day 5/6 of untransferred embryos. RESULTS: The outcome of 60 PGS cycles is described, in which 523 embryos were biopsied; 91% gave results, of which 18% were diploid for all the chromosomes tested and 82% were abnormal. The pregnancy rate per cycle that reached the biopsy stage was 27%, and 30% per embryo transfer. Satisfactory follow-up was obtained from 353 embryos; all those diagnosed as abnormal were confirmed as such, although two false-positives were detected in relation to specific chromosome abnormalities. Meiotic errors were identified in 16% of embryos. Between the RM, AMA and RIF groups, there was a significant difference in the distribution of embryos that were uniformly abnormal and of those with meiotic errors; with an almost 3-fold increase in meiotic errors in the first two groups compared with the RIF group. CONCLUSIONS: This complete investigation has identified significant differences between referral groups concerning the origin of aneuploidy in their embryos.     

Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease

The aim of this review is to summarize and critically discuss the complex role played by adenosine A_2A receptors (A_2ARs) in Huntington's disease (HD). Since A_2ARs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A_2AR antagonists could be neuroprotective. This was further sustained by the demonstration that A_2ARs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A_2A receptor blockade = neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating ‘bad’ responses (for example, stimulation of glutamate outflow and excessive glial activation), A_2ARs also promote ‘good’ responses (such as trophic and antinflammatory effects). This implies that A_2AR blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A_2ARs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A_2AR activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A_2ARs, and by the strikingly different effects mediated by A_2ARs expressed by different cell populations within the brain.     

Mathematical models of passive motion at the human ankle joint by equivalent spatial parallel mechanisms

The paper presents a theoretical model of the ankle joint, i.e. tibio-talar articulation, which shows how the articular surfaces and the ligaments, acting together as a mechanism, can control the passive kinematics of the joint. The authors had previously shown that, in virtually unloaded conditions, the ankle behaves as a single degree-of-freedom system, and that two ligament fibres remain nearly isometric throughout the flexion arc. Two different equivalent spatial parallel mechanisms together with corresponding kinematic models were formulated. These assumed isometricity of fibres within the calcaneal-fibular and tibio-calcaneal ligaments and rigidity of the articulating surfaces, taken as three sphere-plane contacts in one model, and as a single spherical pair in the other. Geometry parameters for the models were obtained from three specimens. Motion predictions compare quite well with the measured motion of the specimens. The differences are accounted for by the simplifications adopted to represent the complex anatomical structures, and might be reduced by future more realistic representations of the natural articular surfaces.     

Pathobiology of Lomentospora prolificans: could this species serve as a model of primary antifungal resistance?

The number of fungal isolates resistant to antifungal drugs has increased dramatically over the last few years and has become an important concern for clinicians. Among these isolates, fungi showing multidrug resistance are particularly worrying because of the difficulties associated with their treatment. These factors hamper the successful recovery of patients and drastically raise mortality rates. Antifungal resistance is multifactorial and several mechanisms in different fungi have been described. There is a need to study these mechanisms in depth; however, the study of antifungal drug resistance separately for each individual species makes progress in the field very slow and tedious. The selection of a multiresistant microorganism as a model for understanding resistance mechanisms and extrapolating the results to other species could help in the search for a solution. In this mini-review, we describe the pathobiology of Lomentospora (Scedosporium) prolificans, paying special attention to its intrinsic resistance to all currently available antifungal agents. The characteristics of L. prolificans offer several advantages: the possibility of using a single microorganism for the study of resistance to different drugs, even cases of double and triple resistance; it is biologically safe for society in general as no new genetically–modified strains are needed for the experiments; it is homologous with other fungal species, and there is repetitiveness between different strains. In conclusion, we propose L. prolificans as a candidate for consideration as a fungal model for the study of resistance mechanisms against antifungal agents.     

钠-葡萄糖共转运蛋白2抑制剂引发糖尿病酮症酸中毒机制的研究进展

糖尿病酮症酸中毒是一种以高血糖,酸中毒和酮血症为特征的复杂无序的代谢状态,通常在绝对或相对胰岛素缺乏伴拮抗激素增多时发生。糖尿病酮症酸中毒虽然可预防,但仍是糖尿病患者常见且可能危及生命的并发症。钠-葡萄糖共转运蛋白2抑制剂是一类新型的口服降糖药物,它们通过减少肾脏近端小管葡萄糖的重吸收,增加尿糖排泄来达到降低血糖水平的目的。这类药物使血清中酮酸以及胰高血糖素的产生增加,在某些个体中可导致糖尿病酮症酸中毒的发生。本文将对钠-葡萄糖共转运蛋白2抑制剂可能引发糖尿病酮症酸中毒的潜在机制进行综述,为降低其用药风险提供依据。     

慢性阻塞性肺疾病免疫调节治疗专家共识

慢性阻塞性肺疾病（简称慢阻肺）是我国重点防治的慢性呼吸系统疾病之一,深入探讨慢阻肺的免疫发病机制并对其中的关键靶点进行干预可能为慢阻肺的防治提供新办法。基于目前临床常用的慢阻肺免疫调节剂相关研究证据及具有免疫治疗作用的药物研发现状和趋势,《慢性阻塞性肺疾病免疫调节治疗专家共识》撰写组提出4条推荐意见：（1）细菌溶解产物、磷酸二酯酶抑制剂、大环内酯类药物等生物、化学制剂均可通过增强机体免疫功能和提高免疫细胞活性而发挥对慢阻肺的免疫调节作用;（2）针对流感病毒、肺炎球菌感染等进行疫苗接种可预防慢阻肺急性加重、降低患者死亡率;（3）他汀类药物及维生素D等具有免疫调节作用,对慢阻肺可能有一定的治疗作用,但二者在慢阻肺中的应用证据较少且存在一定不良反应,仍需进一步积累证据;（4）中医药复方及虫草制剂或可通过调节机体免疫功能、提高免疫细胞活性改善慢阻肺稳定期患者生活质量,减少急性加重。本专家共识旨在进一步推动我国慢阻肺免疫调节治疗的临床实践。     

青藤碱抗肿瘤作用与分子机制研究进展

肿瘤为机体在多重致瘤因子的影响下,导致局部组织细胞增生产生的病因未明的新生物,严重威胁人类生命和健康。肿瘤根据其病理性质分为良性肿瘤、交界性肿瘤、恶性肿瘤;其中恶性肿瘤统称为癌症,目前尚无特效药及可靠的治愈手段,为当前医学界研究的一大热点和难点。文献古籍中多有中草药治疗肿瘤屡建良效的记载,且现代药理研究表明,越来越多的中药活性成分已逐步凸显其对多种不同类型肿瘤的抑制作用。青风藤作为我国传统中草药治疗风湿类疾病具有悠久的历史,青藤碱为中药青风藤中含量较高的主要活性成分,具有抗炎、免疫抑制、镇痛、镇静等广泛药理作用,因微溶于水的特性故临床多应用其盐酸盐,商品名为正清风痛宁。近年研究表明,青藤碱单用或联合放化疗对多种肿瘤有显著或协同的抑制作用,被称为肿瘤抑制剂、放化疗增敏剂,其作用机制主要通过抑制肿瘤细胞增殖,诱导肿瘤细胞凋亡,阻滞肿瘤细胞周期,抑制肿瘤侵袭、转移,诱导肿瘤细胞自噬,逆转肿瘤细胞多药耐药,结合纳米材料增效减毒等。该文通过总结近年来青藤碱抗肿瘤抗癌相关实验研究成果,并根据其体内外药理作用及作用机制进行分类叙述,以期为青藤碱作为抗肿瘤治疗潜在药物提供理论依据,亦为其抗肿瘤的进一步机制研究提供参考。     

Trained immunity in organ transplantation

Consistent induction of donor‐specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen‐presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long‐term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro‐inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection.     

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

Allergic contact dermatitis (ACD) is a hypersensitivity immune response induced by small protein-reactive chemicals. Currently, the murine local lymph node assay (LLNA) provides hazard identification and quantitative estimation of sensitizing potency. Given the complexity of ACD, a single alternative method cannot replace the LLNA, but it is necessary to combine methods through an integrated testing strategy (ITS). In the development of an ITS, information regarding mechanisms and molecular processes involved in skin sensitization is crucial. The recently published adverse outcome pathway (AOP) for skin sensitization captures mechanistic knowledge into key events that lead to ACD. To understand the molecular processes in ACD, a systematic review of murine in vivo studies was performed and an ACD molecular map was constructed. In addition, comparing the molecular map to the limited human in vivo toxicogenomic data available suggests that certain processes are similarly triggered in mice and humans, but additional human data will be needed to confirm these findings and identify differences. To gain insight in the molecular mechanisms represented by various human in vitro systems, the map was compared to in vitro toxicogenomic data. This analysis allows for comparison of emerging in vitro methods on a molecular basis, in addition to mathematical predictive value. Finally, a survey of the current in silico, in chemico, and in vitro methods was used to indicate which AOP key event is modeled by each method. By anchoring emerging classification methods to the AOP and the ACD molecular map, complementing methods can be identified, which provides a cornerstone for the development of a testing strategy that accurately reflects the key events in skin sensitization.     

The role of water and mineral–collagen interfacial bonding on microdamage progression in bone

Microdamage would be accumulated in bone due to high‐intensity training or even normal daily activity, which may consequently cause fragility fracture or stress fracture. On the other hand, microdamage formation serves as a toughening mechanism in bone. However, the mechanisms that control microdamage initiation and accumulation in bone are still poorly understood. Our previous finite element model indicated that different interfacial properties between mineral and collagen in bone may lead to distinct patterns of microdamage accumulation. Therefore, the current study was designed to examine such prediction and to investigate the role of water and mineral–collagen interactions on microdamage accumulation in bone. To address these issues, 48 mice femurs were divided randomly into four groups. These groups were dehydrated or treated with perfluorotripropylamine (PFTA) or NaF solution to change water distribution and mineral–collagen interfacial bonding in bone. After three‐point bending fatigue tests, the types of microdamage (i.e., linear microcracks or diffuse damage) formed in bone were compared between different groups. The results suggested that (1) bone tissues with strong mineral–collagen interfacial bonding facilitate the formation of linear microcraks, and (2) water has little contribution to the growth of microcracks. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:217–223, 2014.