Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Learning a high-precision locomotor task in patients with Parkinson's disease.

We evaluated the acquisition and performance of a high-precision locomotor task in patients with Parkinson's disease (PD) and healthy subjects. All subjects walked on a treadmill and had to step repetitively as low as possible over an obstacle without touching it. During blocks 1 and 2, the subjects had full vision and received additional acoustic warning and feedback signals. During block 3, vision became restricted. Changes in foot clearance and the number of obstacle hits were evaluated. Initially, PD patients performed poorer and improved foot clearance slower. After task repetition, the groups performed similarly. Restricting vision deteriorated performance in both groups. The similar performance of PD patients after task repetition might indicate that adequate training could improve adaptive locomotor behavior in PD patients.     

全膝关节置换术后的骨溶解：胫骨盘表面的修饰及聚乙烯衬垫灭菌方法对其的影响术 后5至10年的报告

背景：从关节和胫骨假体聚乙烯衬垫后表面转移磨损碎屑，是全膝关节置换术后假体周围骨溶解的主要原因。全膝人工关节假体设计随时问而发生变化，例如对胫骨盘近端表面的粗糙度和聚乙烯衬垫的灭菌方法。我们假设胫骨盘表面抛光和采用空气中γ射线照射之外的其他方法对衬垫灭菌，可降低骨溶解的发生率。方法：从1987年至1998年，我们采用后十字韧带保留型的解剖型组配式全膝人工关节假体系列。对300名患者施行365例全膝关节置换术。术后5至10年，对这些患者的膝关节摄正、侧位X线片。由两位关节置换专家对X线片上的骨溶解状况进行单独评定（骨溶解的界定标准为假体周围存在边缘清晰的非线性松质骨丢失区）。结果：在粗糙表面的胫骨盘的242例膝关节中，使用空气中γ射线照射灭菌的衬垫固定，有34％（82例）骨溶解阳性。用惰性气体中γ射线照射或没有照射的衬垫与抛光表面连接的98例膝关节中，有9％（9例）骨溶解阳性。骨溶解与六项因素相关，这些因素为：一项与患者（男性）相关、一项与胫骨盘（近端表面抛光）相关、三项与聚乙烯衬垫（加工的原材料、灭菌方法及存放时间）相关及一项与手术技术（股骨假体与胫骨假体间的过伸）相关。结论：在这类假体设计中，胫骨盘近端表面采用抛光及衬垫采用更为先进的灭菌方法（不用空气中γ射线照射灭菌）能显著减少骨溶解的发生率，但不能避免骨溶解。     

Occupational exposure to hazardous substances and risk of cancer in the area of the mouth cavity, oropharynx, hypopharynx and larynx. A case-control study

A case-control study of squamous cell carcinoma of the upper aerodigestive tract conducted in Heidelberg and Giessen (FRG) provided information on occupational factors in 200 patients and 800 controls (adjusted to sex, age and area of living; 4:1 matched design). The number of subjects exposed to wood dusts, organic chemicals, coal products or to cement was significantly elevated in the tumour group. An increased risk for head and neck cancer was observed after exposition to wood dust (RR = 2,2), organic compounds (RR = 2,4), coal products (RR = 2,7) and especially to cement (RR = 4,4). The cancer risk due to cement exposition showed a positive correlation to the duration of exposition and remained significantly elevated after adjustment for alcohol and tobacco consumption.     

Use of CO2 to move structures as an aid to percutaneous procedures

By injecting small amounts of CO2 through a needle, one can move bowel or bladder from the intended path of instruments during interventional procedures. The technique worked well in six of seven cases in the pelvis and retroperitoneum; it was not effective in the mediastinum or midabdomen (n = 6).     

Ultrastructural changes in the blood-brain barrier after nimodipine treatment and induced hypertension

Fourty-four narcotized rats were split into two equal groups, one being treated with nimodipine and the other with a placebo. By use of norfenefrine the blood pressure was raised to values of 150 and 180 mm Hg within the limits of the autoregulation of brain perfusion and under continuous measurement. Fifteen minutes after application of the standard tracer, horseradish peroxidase, the animals were exsanguinated using a saline perfusion and then perfusion-fixed with Karnovsky's solution. After development of the peroxidase staining the brain sections were evaluated and then allocated to their respective groups. In brain tissues from the experimental group significantly more frequent perivascular accumulations of horseradish peroxidase reaction product were found (P less than 0.001). In electron micrographs it could be seen that the tight junctions were intact and that there was a neuroendothelial transport, with horseradish peroxidase-filled vesicles, in the endothelium, muscle cells, and brain parenchyma. These vesicles represent a medium of transport for all proteins of high molecular weight and can therefore result in brain edema. It is concluded that nimodipine damages the blood-brain barrier by disturbance of the autoregulation of the cerebral blood flow.     

Primary tuberculous nasal polypi—A case report

Primary tuberculous pathology in nasolpolypi is a rare condition. A case of bilateral ethmoidal polypi with tubercular lesion diagnosed on histopathologlcal examination is being reported and the available relevant literature has been reviewed.     

Asymmetric space closure

In a vertically slotted 0.022 X 0.028 inch edgewise system, the use of a two-dimensional ribbon arch--0.022 X 0.016 inch from lateral incisor to lateral incisor and 0.016 X 0.022 inch from the canine to the molars--plus an uprighting spring on the canine maintained incisor position while unilaterally protracting a molar-premolar unit by means of sliding mechanics. Five degrees of labial crown torque was placed in the incisor portion of the wire and the uprighting spring exerted a force of 200 to 250 g. The intra-arch force applied to protract the molar--premolar unit was 300 to 350 g.     

Anleitung für eine vollständige Kehlkopfpräparation

Zusammenfassung Anhand von 9 Abbildungen wird eine Methode zur Kehlkopfpräparation beschrieben, bei der sämtliche Knorpel, Gelenke und Muskeln dargestellt werden. Nach Ablösung des Schildknorpels und des Hypopharynx werden die Mm. postici und arytaenoidei isoliert, die Cricoarytaenoidgelenke sowie die Arytaenoidknorpel präpariert und die Mm. laterales eingeschnitten. Ein Horizontalschnitt durch den Ringknorpel und die median-sagittale Spaltung des proximalen Fragmentes liefern schließlich den Zugang zu den inneren Kehlkopfweichteilen.