Acid-labile protein-adducted heterocyclic aromatic amines in human blood are not viable biomarkers of dietary exposure: A systematic study.

Heterocyclic aromatic amines (HCA) are carcinogenic mutagens formed during cooking of protein-rich foods. HCA residues adducted to blood proteins have been postulated as biomarkers of HCA exposure. However, the viability of quantifying HCAs following hydrolytic release from adducts in vivo and correlation with dietary intake are unproven. To definitively assess the potential of labile HCA-protein adducts as biomarkers, a highly sensitive UPLC-MS/MS method was validated for four major HCAs: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) and 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx). Limits of detection were 1e5 pg/ml plasma and recoveries 91e115%. Efficacy of hydrolysis was demonstrated by HCA-protein adducts synthesised in vitro. Plasma and 7-day food diaries were collected from 122 fasting adults consuming their habitual diets. Estimated HCA intakes ranged from 0 to 2.5 mg/day. An extensive range of hydrolysis conditions was examined for release of adducted HCAs in plasma. HCA was detected in only one sample (PhIP, 9.7 pg/ml), demonstrating conclusively for the first time that acid-labile HCA adducts do not reflect dietary HCA intake and are present at such low concentrations that they are not feasible biomarkers of exposure. Identification of biomarkers remains important. The search should concentrate on stabilised HCA peptide markers and use of untargeted proteomic and metabolomic approaches.

Impaired orthostatic blood pressure recovery and cognitive performance at two-year follow up in older adults: The Irish Longitudinal Study on Ageing

Background: Prospective investigations of the association between impaired orthostatic blood pressure (BP) regulation and cognitive decline in older adults are limited, and findings to-date have been mixed. The aim of this study was to determine whether impaired recovery of orthostatic BP was associated with change in cognitive function over a 2-year period, in a population based sample of community dwelling older adults. 

Methods: Data from the first two waves of the Irish Longitudinal Study on Ageing were analysed. Orthostatic BP was measured during a lying to standing orthostatic stress protocol at wave 1 using beat-to-beat digital plethysmography, and impaired recovery of BP at 40 s post stand was investigated. Cognitive function was assessed at wave 1 and wave 2 (2 years later) using the Mini-Mental State Exam (MMSE), verbal fluency and word recall tasks. 

Results: After adjustment for measured, potential confounders, and multiple imputation for missing data, the change in the number of errors between waves on the MMSE was 10 % higher [IRR (95 % CI) = 1.10 (0.96, 1.26)] in those with impaired recovery at 40 s. However, this was not statistically significant (p = 0.17). Impaired BP recovery was not associated with change in performance on any of the other cognitive measures. 

Conclusions: There was no clear evidence for an association between impaired recovery of orthostatic BP and change in cognition over a 2-year period in this nationally representative cohort of older adults. Longer follow-up and more detailed cognitive testing would be advantageous to further investigate the relationship between orthostatic BP and cognitive decline.

Urinary thrombomodulin levels were significantly higher following occupational exposure to chemicals, in the presence of dipstick protein, but not in the presence of dipstick blood

Currently, there are no biomarkers which can identify patients with an increased risk of developing urothelial cancer as a result of occupational chemical exposure. The aim of this study was to evaluate the relationships between final diagnosis and 22 biomarkers measured in urine, serum and plasma collected from 156 hematuric patients. Fourteen of the 80 patients (17.5%) with urothelial cancer and 13/76 (17.1%) of the controls were deemed to have a history of chemical exposure. We applied Fisher's exact tests to explore associations between chemical exposure and final diagnosis, and tumor stage and grade, where applicable; ANOVA and t-test to compare age across patients with and without chemical exposure; and Zelen's exact test to evaluate relationships across final diagnosis, chemical exposure and smoking. Following pre-selection of biomarkers using Lasso, we identified biomarkers with differential levels across patients with and without chemical exposure using Welch's t-test. Using a one-sided t-test and considering multiple testing using FDR, we observed that TM levels in urine were significantly higher in samples from patients with a history of chemical exposure regardless of their diagnosis as control or urothelial cancer (one-sided t-test, p_UC = 0.014 and p_CTL = 0.043); in the presence of dipstick protein and when urinary pH levels ≤ 6 (p = 0.003), but not in the presence of dipstick blood (p = 0.115). Urothelial cancer patients with a history of chemical exposure were significantly younger (64.1 years) than those without chemical exposure (70.2 years) (one-sided t-test p-value = 0.012); and their tumors were higher grade (Fisher's exact test; p = 0.008). There was a strong association between a history of chemical exposure and smoking in urothelial cancer patients (Zelen's exact test; p = 0.025). Elevated urinary thrombomodulin levels could have the potential to identify chemical exposure in hematuric patients at high risk of developing urothelial cancer.