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.     

Communication Between HIV Patients and Their Providers: A Qualitative Preference Match Analysis

Since the introduction of cART (combination antiretroviral therapy), HIV has evolved into a chronic disease such that it requires lifelong medical treatment to which patients must adhere. Communication with health care providers is pivotal in supporting patients to adapt to having HIV and adhering to treatment, in order to maintain health and quality of life. Previous research indicates that communication is optimal when it matches patient preferences for information exchange, relationship establishment, and involvement in treatment decisions. The aim of the present study is to explore HIV patient communication preferences as well as patient experiences with their providers (not) matching their preferences. A second aim is to explore provider beliefs about patient preferences and provider views on optimal communication. Data were collected through interviews with 28 patients and 11 providers from two academic hospitals. Results indicate that patient preferences reflect their cognitive, emotional, and practical needs such that patients look to increase their sense of control over their HIV. Patients aim to further increase their sense of control (by proxy) through their relationship with their providers and through their decisional involvement preferences. Providers are well aware of patient communication preferences but do not explicate underlying control needs. Implications for clinical practice are discussed.     

Tauchunfälle

Notfall + Rettungsmedizin - Tauchunfälle sind vergleichsweise selten und stellen (Erst‑)Helfer vor besondere Herausforderungen. Sie müssen schnell und kompetent behandelt werden, da...     

Arrogance in the Workplace: Implications for Mental Health Nurses

Cultures of performativity may contribute to organizational and individual arrogance. Workplace organizations have individuals who at various times will display arrogance, which may manifest in behaviours, such as an exaggerated sense of self-importance, dismissiveness of others, condescending behaviors and an impatient manner. Arrogance is not a flattering label and irrespective of the reason or the position of power, in the context of organizational behaviors, may not be useful and may even be detrimental to the work environment. Thus, it is timely to reflect on the implications of arrogance in the workplace. Advocacy and empowerment can be undermined and relationships adversely impacted, including the achievement of positive consumer outcomes. This paper provides an introduction to arrogance, and then discusses arrogance to promote awareness of the potential consequences of arrogance and its constituent behaviors.     

Factors predicting tracer uptake in somatostatin receptor and MIBG scintigraphy of metastatic gastroenteropancreatic neuroendocrine tumors.

Radiolabeled octreotide analogs (Oct) and metaiodobenzylguanidine (MIBG) offer 2 different approaches for imaging and targeting metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET). Despite successful establishment of the revised World Health Organization (WHO) classification, which distinguishes between low- and high-grade malignant GEP-NET, there is a lack of scintigraphic studies comparing uptake behavior on the basis of this categorization. This study aims to define predisposing factors of tracer uptake for both imaging principles implementing the updated tumor criteria of the current WHO classification. METHODS: Fifty-seven consecutive patients with histologically confirmed metastatic GEP-NET evaluated with both 111In-pentetreotide and 123I/131I-MIBG scintigraphy were included in this study. Intensity of tracer uptake was graded according to the different metastatic regions. Patients were classified as overall positive when avid uptake in the clinically relevant tumor lesions was present. Correlation was tested between the proportion of positive patients and tumor origin, function, and malignancy. RESULTS: Overall, 52 patients (91.2%) were Oct positive and 28 patients (49.1%) were MIBG positive. The proportion of tracer-positive patients was significantly higher (P < 0.05) in low-grade malignant tumors for both tracers and in functioning as well as in gastroenteral NET for MIBG. Five patients were negative for both tracers. None of the Oct-negative patients proved to be MIBG positive. CONCLUSION: Oct affinity is observed with high frequency throughout the subgroups of metastatic GEP-NET, whereas corresponding MIBG uptake is overall less prevalent and more group dependent. Tumor differentiation significantly impacts both Oct and MIBG uptake, whereas functionality predisposes only for MIBG accumulation. Though clearly inferior to Oct-based radioimaging in most GEP-NET, MIBG achieves a remarkable rate of radioligand accumulation in functioning midgut enterochromaffin cell metastases (>80% of patients positive). These results may have implications for patient management and potentially for selection and performance of targeted therapy.     

Cognitive effects attributed to angiotensin II may result from its conversion to angiotensin IV.

This study tests the hypothesis that the facilitation of learning and improvement of memory observed after an intracerebroventricular (i.c.v.) injection of angiotensin II (Ang II) is, in fact, caused by its derivative angiotensin IV (Ang IV). We ran two memory tests as well as an auxiliary test assessing motor performance in rats injected (i.c.v., 1 nmol in 2 microl saline) with Ang II or Ang IV. There were separate groups receiving peptide or saline five, 10 and 15 minutes before testing. Ang IV significantly increased step-through latencies in a passive avoidance paradigm as well as improved discrimination between familiar and unfamiliar objects in an object recognition test in all groups showing better retrieval of memory of aversive as well as appetitive stimuli in the peptide-treated groups regardless of the time of its injection. In contrast, rats treated with Ang II demonstrated significant improvement of memory of aversive and appetitive stimuli in the same tests only 15 minutes after its i.c.v. injection, with no effect in the groups injected five minutes before testing and slight efficacy in those injected 10 minutes before the test. Numbers of crossings, rearings and bar approaches in an open field were similar both in the peptide-treated and control groups making it unlikely that changes in motor performance affected the memory tests. In line with the present views on the intracellular metabolism of Ang II, these results suggest degradation to Ang IV by aminopeptidases A and N is necessary before the cognitive effects can occur.