Understanding the importance of low-molecular weight (ethylene oxide- and propylene oxide-induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions

The interpretation and significance of DNA adduct data, their causal relationship to mutations, and their role in risk assessment have been debated for many years. An extended effort to identify key questions and collect relevant data to address them was focused on the ubiquitous low MW N7-alkyl/hydroxyalkylguanine adducts. Several academic, governmental, and industrial laboratories collaborated to gather new data aimed at better understanding the role and potential impact of these adducts in quantifiable genotoxic events (gene mutations/micronucleus). This review summarizes and evaluates the status of dose–response data for DNA adducts and mutations from recent experimental work with standard mutagenic agents and ethylene oxide and propylene oxide, and the importance for risk assessment. This body of evidence demonstrates that small N7-alkyl/hydroxyalkylguanine adducts are not pro-mutagenic and, therefore, adduct formation alone is not adequate evidence to support a mutagenic mode of action. Quantitative methods for dose–response analysis and derivation of thresholds, benchmark dose (BMD), or other points-of-departure (POD) for genotoxic events are now available. Integration of such analyses of genetox data is necessary to properly assess any role for DNA adducts in risk assessment. Regulatory acceptance and application of these insights remain key challenges that only the regulatory community can address by applying the many learnings from recent research. The necessary tools, such as BMDs and PODs, and the example datasets, are now available and sufficiently mature for use by the regulatory community. Environ. Mol. Mutagen. 60: 100–121, 2019. © 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.     

Clinical course of chronic periodontitis. II. Incidence, characteristics and time of occurrence of the initial periodontal lesion

AIM: The purpose of this study was to assess the initiation and progression of periodontal disease during adult life. MATERIALS AND METHODS: In a 26-year longitudinal investigation of the initiation and progression of chronic periodontitis that started in 1969 and included 565 men of Norwegian middle class, 223 who had participated in some, but not all, intermediate examinations presented at the last survey in 1995. Fifty-four individuals were available for examination in all seven surveys. RESULTS: Covering the age range from 16 to 60 years, the study showed that at 16 years of age, 5% of the participants had initial loss of periodontal attachment (ILA > or = 2 mm) at one or more sites. Both the subject incidence and the site incidence increased with time, and by 32 years of age, all individuals had one or more sites with loss of attachment. As age progressed, new lesions affected sites, so that as these men approached 60 years of age approximately 50% of all available sites had ILA. An assessment of the intraoral distribution of the first periodontal lesion showed that, regardless of age, molars and bicuspids were most often affected. At and before the age of 40 years, the majority of ILA was found in buccal surfaces in the form of gingival recession. By 50 years, however, a greater proportion of sites presented with attachment loss attributed to pocket formation or a combination of pocket formation and gingival recession. As individuals neared 60 years of age, approximately half of the interproximal areas in posterior teeth had these lesions. CONCLUSION: This investigation has shown that, in a well-maintained population who practises oral home care and has regular check-ups, the incidence of incipient periodontal destruction increases with age, the highest rate occurs between 50 and 60 years, and gingival recession is the predominant lesion before 40 years, while periodontal pocketing is the principal mode of destruction between 50 and 60 years of age.     

Clinical course of chronic periodontitis. I. Role of gingivitis

OBJECTIVES: The purpose of this study was to determine the influence of long-standing gingival inflammation on periodontal attachment loss. On the basis of repeated examinations, the present report describes the influence of gingival inflammation on the initiation of periodontitis from 16 to 59 years of age. MATERIAL AND METHODS: The data originated from a 26-year longitudinal study of Norwegian males, who practiced daily oral home care and received state-of-the-art dental care. The initial examination included 565 individuals. Subsequent examinations took place in 1971, 1973, 1975, 1981, 1988 and 1995. Thus, the study covers the age range of 16-59 years. All tooth sites were divided into four categories according to their history of gingival inflammation over the entire observation period: sites always scoring GI = 0, GI = 1 and GI = 2 sites (GI = gingival index). Sites disclosing various GI scores at different observation periods were not considered. RESULTS: The mean cumulative attachment loss for non-inflamed (GI = 0) sites in individuals approaching 60 years of age was 1.94 mm. Sites always scoring GI = 1 yielded 2.42 mm, and sites that always scored GI = 2 exhibited 3.31 mm of periodontal attachment loss. At interproximal sites of all three groups where gingival trauma was assumed to be minimal or non-existent, only very few sites expressed attachment loss due to gingival recession (2-4%). At interproximal sites always scoring GI = 0, 20% loss of attachment was in the form of pocket formation by 59 years of age. The GI = 1 and the GI = 2 cohorts exhibited attachment loss with pocket formation in 28% and 54%, respectively. CONCLUSION: This study has shown that, as men approach 60 years of age, gingival sites that throughout the 26 years of observation bled on probing had approximately 70% more attachment loss than sites that were consistently non-inflamed (GI = 0). Before 40 years of age, there was a slight increase in periodontal attachment loss due to pocket formation, but after this, the frequency increased significantly. Loss of attachment due to gingival recession was very small in all three groups.The fact that sites with non-inflamed gingiva also exhibited some loss of attachment and pocket formation may be explained by fluctuation in the variations of tissue status during long observation intervals combined with the presence of subclinical inflammation.     

Sucralfate versus placebo treatment in duodenal and prepyloric ulcer: a clinical endoscopic, double-blind controlled investigation

Sucralfate, which has cytoprotective, pepsinostatic, antacid and bile acid-binding properties, was studied in a therapeutic trial against a placebo in patients with duodenal and prepyloric ulcer. The investigation was designed as a double-blind controlled study. Thirty-five patients with endoscopically verified ulcers were observed during 8 weeks of treatment. In 14 out of 17 (82%) patients treated with sucralfate the ulcers healed, as compared with 7 out of 18 (39%) in the placebo group, as compared with 7 out of 18 (39%) in the placebo group. In approximately 60% of sucralfate-treated patients all symptoms disappeared, as compared with approximately 30% in the placebo group. No significant side effects were detected, and compliance was good. Consequently, sucralfate represents as effective and safe treatment for duodenal ulcer.     

Comparison of insulins detemir and glargine: effects on glucose disposal, hepatic glucose release and the central nervous system

Aims: The effects of insulins detemir (Det) and glargine (Glar) on endogenous glucose production (EGP) and net hepatic glucose output (NHGO) were compared. Methods: Arteriovenous difference and tracer ([3‐³H]glucose) techniques were employed during a two‐step hyperinsulinemic euglycaemic clamp in conscious dogs (6 groups, n = 5–6/group). After equilibration and basal sampling (0–120 min), somatostatin was infused and basal glucagon was replaced intraportally. Det or Glar was infused via portal vein (Po), peripheral vein (IV), or bilateral carotid and vertebral arteries (H) at 0.1 and 0.3 mU/kg/min (low Insulin; Glar vs. Det, respectively, 120–420 min) and 4× the low insulin rate (high insulin; 420–540 min). Results: NHGO and EGP were suppressed and glucose R_d and infusion rate were stimulated similarly by Det and Glar at both Low and high insulin with each infusion route. Non‐esterified fatty acid (NEFA) concentrations during low insulin were 202 ± 37 versus 323 ± 75 µM in DetPo and GlarPo (p < 0.05) and 125 ± 39 versus 263 ± 48 µM in DetIV and GlarIV, respectively (p < 0.05). In DetH versus GlarH, pAkt/Akt (1.7 ± 0.2 vs. 1.0 ± 0.2) and pSTAT3/STAT3 (1.4 ± 0.2 vs. 1.0 ± 0.1) were significantly increased in the liver but not in the hypothalamus. Conclusions: Det and Glar have similar net effects on acute regulation of hepatic glucose metabolism in vivo regardless of delivery route. Portal and IV detemir delivery reduces circulating NEFA to a greater extent than glargine, and head detemir infusion enhances molecular signalling in the liver. These findings indicate a need for further examination of Det's central and hepatic effects.     

Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial

BACKGROUND: A poor outcome after stroke is associated independently with high blood pressure during the acute phase; however, relationships with other haemodynamic measures [heart rate (HR), pulse pressure (PP), rate-pressure product (RPP)] remain less clear. METHODS: The Tinzaparin in Acute Ischaemic Stroke Trial is a randomised, controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR measurements taken immediately prior to randomization were averaged, and the mid-blood pressure (MBP), PP, mean arterial pressure (MAP), pulse pressure index, and RPP were calculated. The relationship between these haemodynamic measures and functional outcome (death or dependency, modified Rankin Scale > 2) and early recurrent stroke, were studied with adjustment for baseline prognostic factors and treatment group. Odds ratios (OR) and 95% confidence intervals (CI) refer to a change in haemodynamic measure by 10 points. RESULTS: A poor functional outcome was associated with SBP (adjusted OR; 1.11; 95% CI, 1.03-1.21), HR (adjusted OR; 1.15; 95% CI, 1.00-1.31), MBP (adjusted OR; 1.15, 95% CI, 1.03-1.29), PP (adjusted OR; 1.14; 95% CI, 1.02-1.26), MAP (adjusted OR; 1.15; 95% CI, 1.02-1.31) and RPP (adjusted OR; 1.01; 95% CI, 1.00-1.02). Early recurrent stroke was associated with SBP, DBP, MBP and MAP. CONCLUSIONS: A poor outcome is independently associated with elevations in blood pressure, HR and their derived haemodynamic variables, including PP and the RPP. Agents that modify these measures may improve functional outcome after stroke.