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.     

Ritanserin in the treatment of alcohol dependence – a multi-center clinical trial

Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT₂ receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects’ QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence. Received: 30 April 1996/Final version: 3 July 1996     

The pattern evoked response in disorders of the optic nerve

The pattern evoked electroretinogram (PERG) was investigated in 11 patients with unilateral optic nerve disease and in a series of age-matched controls. The visually evoked potential (VEP) was also measured. The PERG showed a similar reduction to the VEP in optic nerve disease. Serial studies indicate that the PERG may not be affected immediately in some instances but may show a gradual decline over several months.     

Repair of large midline incisional hernias with polypropylene mesh: Comparison of three operative techniques

Polypropylene mesh is widely used for the reconstruction of incisional hernias that cannot be closed primarily. Several techniques have been advocated to implant the mesh. The objective of this study was to evaluate, retrospectively, early and late results of three different techniques, onlay, inlay, and underlay. The records of 53 consecutive patients with a large midline incisional hernia — 25 women and 28 men, mean age 60.4 (range 28–94) — were reviewed. Polypropylene mesh was implanted using the onlay technique in 13 patients, inlay in 23 patients, and underlay in 17 patients. Either the greater omentum or a polyglactin mesh was interponated between the mesh and the viscera. The records of these 53 patients were reviewed with respect to: size and cause of the hernia, pre- and postoperative mortality and morbidity, with special attention to wound complications. Patients were invited to attend the outpatient clinic at least 12 months after implantation of the mesh for physical examination of the abdominal wall. Postoperative complications occurred in 14 (26.4%) patients. The onlay technique had significantly more complications, as compared to both other techniques. Reherniation occurred in 15 (28.3%) patients. The reherniation rate of the inlay technique was significantly higher than after the underlay technique (44% vs 12%, P=0.03) and tended to be higher than the onlay technique (44% vs 23%, P=0.22). Repair of large midline incisional hernias with the use of a polypropylene mesh carries a high risk of complications and has a high reherniation rate. The underlay technique seems to be the better technique.     

Achilles tendon overuse injuries.

Overuse injuries of the Achilles tendon are common in patients engaging in recreational athletics. Achilles tendon overuse injuries exist as a spectrum of diseases ranging from inflammation of the paratendinous tissue (paratenonitis), to structural degeneration of the tendon (tendinosis), and finally tendon rupture. Factors known to predispose patients to Achilles tendinitis include inadequate stretching, training errors, mechanical malalignment of the lower extremities, rigid training surfaces, and occasionally systemic disease. Treatment of the patient with paratenonitis and tendinosis is initially conservative, emphasizing passive stretching, concentric and eccentric strengthening, correction of training errors, and restoration of normal limb alignment. Patients resistant to this protocol often exhibit a more advanced degree of tendon change. A high percentage of these patients can benefit from surgical debridement of the involved tendon, and they can anticipate successful return to recreational athletics. Steroid injections should not be routinely used in patients with Achilles tendinitis. Rupture of the Achilles tendon following intratendinous injection has been reported.     

Effect of a blood transfusion protocol and low dose steroid regime on renal transplant survival

The effects of introduction of a low steroid regime and pre-transplant blood transfusion were evaluated. The kidney and patient survival rates for the period before such a policy was adopted were compared with the period after this policy. There has been a highly significant rise in patient survival rates to the present level of 95 per cent at three years. There was a similar rise in three year graft survival rates from less than 40 per cent to 66 per cent.