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.     

Angiolymphoid hyperplasia with eosinophilia of the orbit associated with obstructive airway disease

Two patients with angiolymphoid hyperplasia with eosinophilia isolated to the orbit had eyelid swelling, a superior orbital mass, and histories of intermittent obstructive airway disease. One patient later developed a transient peripheral blood eosinophilia as high as 36%. One lesion recurred 38 months postoperatively and responded to systemic corticosteroid therapy.     

FEASIBILITY OF CONDUCTING CARDIOVASCULAR OUTCOME RESEARCH IN AUSTRALIAN GENERAL PRACTICE: RESULTS FROM THE ANBP2 PILOT STUDY

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was 160 mmHg systolic or 90 mmHg diastolic if systolic BP was 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82 000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP 5=160/90 mmHg. Forty-seven percent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.     

Extracorporeal membrane oxygenation for pediatric cardiopulmonary failure

Extracorporeal membrane oxygenation is now standard treatment of severe respiratory failure in newborn infants in our center (200 cases) and worldwide (over 2500 cases), but there are few reports of such trials in older children. We reviewed our experience with extracorporeal membrane oxygenation in 33 children aged 1 week to 18 years between 1971 and 1989. The modality was used when all other treatment failed. Extracorporeal membrane oxygenation provided excellent cardiopulmonary support for 1 to 25 days (average 7 1/2 days). The survival rate was 25% for cardiac support patients and 47% for respiratory failure patients (36% overall survival). Mechanical complications included membrane lung failure, tubing rupture, and pump failure, all managed without mortality. Physiologic complications included bleeding, pneumothorax, cardiac arrest, renal failure, hepatic failure, and brain injury. The major cause of death was irreversible injury to lung, heart, or brain. Extracorporeal life support is a reasonable approach for children with serious but reversible cardiopulmonary failure.     

Endoscopic laser ablation of obstructing congenital duodenal webs in the newborn: a case report of limited success with criteria for patient selection.

Standard approaches to intrinsic obstructing duodenal lesions in the newborn include laparotomy with enteroenterostomy, bypassing the obstruction, or duoduodenotomy with excision. The advent of improved pediatric flexible fiberoptic endoscopes and fiberoptic laser technology makes endoscopic ablation of duodenal webs and windsocks in the newborn possible.     

Depressed pathological gamblers

Depressed gamblers (n = 14) were compared with normal controls (n = 41) for antecedent life events. The depressed gamblers had experienced significantly more life events, and undesirable or exit life events, during the 6 months before the onset of depression.