Demonstrating the reliability of in vivo metabolomics based chemical grouping: towards best practice.

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography-mass spectrometry (LC-MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.

Effects of the COVID-19 pandemic on suicide attempts in a rural region in Germany, a 5-year observational study.

BACKGROUND: The COVID-19 pandemic and public life restrictions may have a negative impact on people's mental health. Therefore, we analyzed whether this condition affected the occurrence of suicide attempts (SA) over 20 months during the pandemic period. METHODS: We included patient records according to DSM-5 criteria for suicidal behavior disorders (n = 825) between Jan 1, 2017, and Dec 31, 2021. We applied interrupted time-series Poisson regression models to investigate the effect of the pandemic on SA occurrence, time trends, and seasonal patterns in the whole group of patients as well as stratified by age and gender. RESULTS: There was no significant effect of the pandemic on the occurrence of SA in the overall group. However, we observed a significant impact of the pandemic on the seasonal pattern of SA, also the variance differed significantly (pre-pandemic mean ± variance: 13.33 ± 15.75, pandemic: mean ± variance: 13.86 ± 7.26), indicating less periodic variation in SA during the pandemic. Male patients and young adults mainly contributed to this overall effect. Subgroup analysis revealed a significant difference in SA trends during the pandemic in older adults (>55 years) compared with younger adults (18-35 years); SA numbers increased in older adults and decreased in younger adults as the pandemic progressed. LIMITATIONS: A few patients may have received initial care in an emergency department after SA without being referred to psychiatry. CONCLUSIONS: In general, the COVID-19 pandemic and related measures did not significantly affect the occurrence of SA but did significantly affect the dynamics. In addition, the pandemic appeared to affect suicidal behavior differently across age groups as it progressed. Particularly for the older adult group, negative long-term effects of the pandemic on suicidal behavior can be derived from the present results, indicating the need to strengthen suicide prevention for the elderly.

QSAR Toolbox - workflow and major functionalities.

The OECD QSAR Toolbox is a software application intended to be used by governments, the chemical industry and other stakeholders in filling gaps in (eco)toxicity data needed for assessing the hazards of chemicals. The development and release of the Toolbox is a cornerstone in the computerization of hazard assessment, providing an 'all inclusive' tool for the application of category approaches, such as read-across and trend analysis, in a single software application, free of charge. The Toolbox incorporates theoretical knowledge, experimental data and computational tools from various sources into a logical workflow. The main steps of this workflow are substance identification, identification of relevant structural characteristics and potential toxic mechanisms of interaction (i.e. profiling), identification of other chemicals that have the same structural characteristics and/or mechanism (i.e. building a category), data collection for the chemicals in the category and use of the existing experimental data to fill the data gap(s). The description of the Toolbox workflow and its main functionalities is the scope of the present article.

Temporal and right frontal lobe alterations in panic disorder: a quantitative volumetric and voxel-based morphometric MRI study.

BACKGROUND: With regard to current neurobiological theories, the aim of our study was to examine possible alterations of temporal and frontal lobe volume in panic disorder (PD). METHOD: Seventeen in-patients with PD and a group of healthy control subjects (HC) matched for age and gender were investigated by quantitative volumetric magnetic resonance imaging (MRI). Structures of interest were: the temporal lobe, the amygdala-hippocampus complex (AHC) and the frontal lobe. In addition, a voxel-based morphometry (VBM) analysis implemented in Statistical Parametric Mapping 5 (SPM5) was used for a more detailed assessment of possible volume alterations. Modulated grey matter (GM) images were used to test our a priori hypotheses and to present the volumetric results. RESULTS: Quantitative volumetric MRI revealed a bilateral reduction in temporal lobe volume in patients with PD compared to HC subjects. The AHC was normal. The right frontal lobe volume was also decreased. Using VBM we detected a significant GM volume reduction in the right middle temporal gyrus [Brodmann area (BA) 21] in patients with PD. In addition, there was a reduction in GM volume in the medial part of the orbitofrontal cortex (BA 11). CONCLUSIONS: Our results of reduced temporal and frontal lobe volume in PD are in agreement with prior studies. By using a recent VBM approach we were able to assess the abnormalities more precisely. The location of GM volume reduction in the right middle temporal gyrus and medial orbitofrontal cortex lends further support to recent aetiological models of PD.

Neural stem cells from human cord blood on bioengineered surfaces--novel approach to multiparameter bio-tests.

Stem cell technology combined with emerging surface nano/micro-technologies provides a new tool for better understanding of the mechanisms involved in cell fate decisions and compound-induced adverse reactions. This article provides state-of-the-art on the development of modern multiparameter bio-tests based on interactions between neural stem cells derived from human cord blood and bioengineered surfaces. Cell growth platforms with controlled content, geometry and spatial distribution of bioactive and stem cell attractive areas were fabricated either by micro-contact printing or piezoelectric spotting of polycationic biomolecules or extracellular matrix proteins (ECM) on cell-repellent surfaces. HUCB-NSCs were shown to adhere, differentiate and respond to neurotoxic MeHgCl on functional domains in a manner dependent on protein type and concentration, cell density and serum conditions. While receptor-mediated interactions with ECM proteins under absence of serum promote neuronal differentiation, non-specific adhesion to polycationic molecules maintain cells attached to the surface in non-differentiated stage. Functional domains were further engineered to create "smart" microenvironment by immobilizing to the surface signaling molecules together with ECM proteins. Stimulation of selected intracellular pathways by molecules of Wnt, Shh, CNTF or Notch type resulted in differentiation of HUCB-NSC to either neuronal or astroglial lineage. Sensor techniques applied to HUCB-NSC included measurements of electrical activity using multielectrode array chips. Spontaneous electrical field potentials of HUCB-NSCs were dependent upon developmental stage of tested cells. Bioengineered surfaces, on protein microarrays and micro-electrode array chips provide a novel approach to the multiparameter bio-tests by adding an important information on the sensitivity of certain molecular pathways and functional cellular responses to selected neurotoxins.

Serotonin syndrome after lithium add-on medication to paroxetine.

A 59-year-old female patient was hospitalized on account of a depressive episode in the course of a long-standing bipolar disorder. On a combination of lithium (400 mg/day) and paroxetine (30 mg/day) she developed symptoms of shivering, high-frequency tremor of the upper and lower limbs, skin flush in the face, agitation, and slight impairment of mental focusing, suggestive of a serotonin syndrome. At this stage serum lithium and paroxetine levels were 0.63 mmol/l, and 693 ng/ml, respectively; the latter was six times higher than the upper concentrations seen in patients on this dosage of the drug. Consequently, the dosage of paroxetine was reduced to 10 mg/day, and lithium was continued. This regimen resulted in a steady-state paroxetine serum level of 390 ng/ml. The patient became symptom-free and the depressive episode attenuated, thus enabling us to discharge the patient.

[Acoustic hallucinations as a symptom of a REM sleep-associated parasomnia]. / Akustische Halluzinationen als Symptom einer REM-Schlaf-assoziierten Parasomnie.

This 52-year-old man suffered from auditory hallucinations that occurred during brief episodes of sleep paralysis at the end of REM sleep periods. During these episodes the patient experienced a dissociated state of consciousness with REM sleep intrusions into wakefulness. The occurrence of this mixed state, and of excessive sleep-onset REM periods during daytime polysomnography (MSLT = Multiple Sleep Latency Test), point to a disorder of REM sleep generation. The existence of narcolepsy could be ruled out. The observation of REM sleep-associated hallucinations has been reported earlier. In the presented polysomnographic sleep studies the existence of a REM sleep associated parasomnia characterised by hallucinations and sleep paralysis could be confirmed.

[Dementia-paranoid syndrome as the initial manifestation of AIDS. Case report and diagnostic overview]. / Dementiell-paranoides Syndrom als Erstmanifestation von AIDS. Kasuistik und diagnostischer Uberblick.

A 33-year-old HIV-1-positive man developed dementia and a paranoid symptomatology with auditory hallucinations as the first manifestation of AIDS. The immunodeficiency syndrome is currently represented only by the immunohistochemical findings (CD4 216/microliters; CD4/CD8 ratio 0.12); no other manifestations of the disease are present. According to the literature about 15% of patients suffering from AIDS are likely to develop dementia during the course of the disease, usually after preceding opportunistic infections, severe systemic illness, or neoplasm. The manifestation of the disease solely by dementia is a rare phenomenon and represents, particularly if the incident of infection is cryptic, a diagnostic challenge.

The trisomy 18 syndrome with an E/G translocation.

An infant with a typical Edwards syndrome and a modal chromosome number of 46 is reported. In all cells analyzed one chromosome G was missing and an additional chromosome similar to a pair No. 16 was present. The phenotype of the child indicates that the extra element is a translocation between G and 18 chromosomes as in one case described previously.