Utility of in vivo metabolomics to support read-across for UVCB substances under REACH.

Structure-based grouping of chemicals for targeted testing and read-across is an efficient way to reduce resources and animal usage. For substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs), structure-based grouping is virtually impossible. Biology-based approaches such as metabolomics could provide a solution. Here, 15 steam-cracked distillates, registered in the EU through the Lower Olefins Aromatics Reach Consortium (LOA), as well as six of the major substance constituents, were tested in a 14-day rat oral gavage study, in line with the fundamental elements of the OECD 407 guideline, in combination with plasma metabolomics. Beyond signs of clinical toxicity, reduced body weight (gain), and food consumption, pathological investigations demonstrated the liver, thyroid, kidneys (males only), and hematological system to be the target organs. These targets were confirmed by metabolome pattern recognition, with no additional targets being identified. While classical toxicological parameters did not allow for a clear distinction between the substances, univariate and multivariate statistical analysis of the respective metabolomes allowed for the identification of several subclusters of biologically most similar substances. These groups were partly associated with the dominant (> 50%) constituents of these UVCBs, i.e., indene and dicyclopentadiene. Despite minor differences in clustering results based on the two statistical analyses, a proposal can be made for the grouping of these UVCBs. Both analyses correctly clustered the chemically most similar compounds, increasing the confidence that this biological approach may provide a solution for the grouping of UVCBs.

Alexithymia and facial emotion recognition in patients with functional neurological disorder.

OBJECTIVES: Patients with functional neurological disorder (FND) are known to have difficulties recognizing and processing emotions. Problems recognizing internal emotional states (alexithymia) are common in FND, but little is known about recognizing emotions expressed by other people. This study investigates whether patients with FND have higher levels of alexithymia and reduced facial emotion recognition compared to healthy controls. METHODS: Patients with FND (n = 31, mean age=42.7 [SD=14.8] years, 54.8% women) were compared to healthy controls (n = 33, mean age=45.1 [SD=16.2] years, 63.6% women). The Bermond-Vorst Alexithymia Questionnaire (BVAQ) was used for the assessment of alexithymia and the Ekman 60 Faces Test (EFT) for facial emotion recognition. RESULTS: Patients with FND had higher levels of alexithymia than healthy controls (BVAQ=71.8 [SD=19.8] versus 59.3 [SD=20.3], p = .02, Cohen's d=0.62). Facial emotion recognition did not significantly differ between FND patients and controls (EFT total score FND: 46.1 [SD=5.9], Controls: 47.5 [SD=5.5], p = .34, Cohen's d=0.24). Only recognition of surprise differed between patients and controls (FND: 8.4 [SD=1.8], Controls: 9.2 [SD=1.0), p = .03, Cohen's d= 0.56). Higher levels of alexithymia were associated with poorer facial emotion recognition, but this relationship was not statistically significant (FND: ß= -0.20, p = .28; Controls: ß=-0.03; p = .87). CONCLUSIONS: The current data confirm prior observations that patients with FND have higher alexithymia levels than controls without FND. Difficulties recognizing emotions among patients with FND primarily involves recognition of internal emotional states rather than recognition of facially expressed emotions by others. These findings require replication in a larger and more divers sample.

Is heart rate variability related to gait impairment in patients with Parkinson's disease? A pilot study.

BACKGROUND AND PURPOSE: Impairments in gait and autonomic function are common in patients with Parkinson's disease (PD). These are likely independent symptoms, based on different etiologic mechanisms. However, a few recent reports have observed an association between motor function, in particular gait impairment, and autonomic function in PD. In those studies, the Unified Parkinson's Disease Rating Scale (UPDRS) was used to evaluate gait and motor function. The present study was performed to further examine this putative relationship using quantitative measures of autonomic function and gait in order to shed light on the underlying pathophysiology of these symptoms. METHODS: Nine healthy young, 15 healthy elderly and 18 PD patients were studied. Heart rate variability (HRV) measures were collected during rest. Gait speed, swing time and swing time variability were measured during a 1-min walk at comfortable speed. The motor portion of the UPDRS was also evaluated in all subjects. RESULTS: HRV values were highest in the young adults, intermediate in the healthy elderly controls, and lowest in the PD patients. Gait measures tended to deteriorate with age and were significantly worse in the PD patients, compared to the elderly controls. HRV was not correlated with any measure of gait performance (p>0.129) nor with the UPDRS-motor score (p>0.147). DISCUSSION AND CONCLUSIONS: The present findings support the idea that gait and autonomic function impairments co-exist in PD, but their etiology is based on distinct pathophysiological pathways, with minimal overlap.