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Sara Razmjou, Darcy Litteljohn, Chris Rudyk, Shuaib Syed, Melanie Clarke, Rowan Pentz, Zach Dwyer, Shawn Hayley Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada Abstract: Approximately one-third of patients with major depressive disorders (MDDs) are resistant to current treatment methods, and the majority of cases relapse at some point during therapy. This has resulted in novel treatments being adopted, including subanesthetic doses of ketamine, which affects aberrant neuroplastic circuits, glutamatergic signaling, and the production of brain-derived neurotrophic factor. Ketamine rapidly relieves depressive symptoms in treatment-resistant major depressive disorder patients with effects that last for up to 2 weeks even after a single administration. However, it is also a drug with an abusive potential and can have marked side effects. Hence, this study aimed at enhancing the antidepressant-like effects of ketamine (allowing for lower dosing regimens) by coadministering magnesium hydroaspartate (Mg2+ normally affects the same receptors as ketamine) and also assessed whether an Mg2+-deficient diet would modify the impact of ketamine. It was found that a single 15 mg/kg dose of ketamine did indeed induce rapid antidepressant-like effects in the forced swim test but did not affect brain levels of the brain-derived neurotrophic factor. Contrary to our hypothesis, magnesium administration or deficiency did not influence the impact of ketamine on these outcomes. Thus, these data do not support the use of magnesium as an adjunct agent and instead suggest that further research involving other antidepressant and animal models is required to confirm the present findings. Keywords: ketamine, depression, treatment resistance, ghrelin, BDNF, NMDA

Abstract For more than 40 years coumarin has been successfully used in the therapy of chronic venous insufficiency (CVI). The occurrence of liver injuries is rather rare and happens predominantly [...]

We investigated the acute toxic and metabolic effects of 23 aliphatic alcohols (16 saturated and 7 unsaturated) in the isolated perfused rat liver at a concentration of 65.1 mmol/l (∼0.3% ethanol). The capacity of the straight chain primary alcohols (methanol, ethanol, 1-propanol, 1-butanol and 1-pentanol) to release the enzymes glutamate-pyruvate transaminase (GTP), lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH) into the perfusate was strongly correlated with their carbon chain length. The secondary alcohols were less active in this respect whereas branching of the carbon chain did not consistently change alcohol toxicity. Unsaturation in the straight chain but not in the branched chain alcohols was accompanied by an increase in toxicity. An increased enzyme release was in general accompanied by, and correlated to, reductions in oxygen consumption, bile secretion, and perfusion flow of the isolated livers. Statistically significant correlations exist between parameters of alcohol-induced hepatotoxicity and the membrane/buffer partition coefficients of the alcohols. With the exception of methanol, all alcohols tested increased the lactate/pyruvate ratio of the perfusate, although this effect was not correlated to the degree of hepatic injury. Hepatic ATP concentrations decreased in most cases in line with hepatic injury and were particularly correlated with changes in oxygen consumption. Hepatic concentrations of reduced glutathione (GSH) were only diminished by the unsaturated alcohols, whereas an increase in hepatic oxidized glutathione (GSSG) occurred only with some of the saturated alcohols. Hepatic concentrations of malondialdehyde (MDA) increased after two saturated and three unsaturated alcohols but did not correlate with other parameters of hepatotoxicity. In conclusion, alcohol-induced hepatotoxicity is primarily due to membrane damage induced by the direct solvent properties of the alcohols. The consequences and relative contributions of alcohol metabolization to the overall hepatotoxicity of higher alcohols requires further study. [ABSTRACT FROM PUBLISHER]

The toxic effects of cadmium, mercury, and copper were compared over the range 0.01, 0.03, and 0.1 m M using the isolated perfused rat liver preparation. All metals caused similar changes in various parameters used to describe general toxicity. Thus reductions in oxygen consumption, perfusion flow, and biliary secretion were found, while lactate dehydrogenase release into the perfusate, as well as liver weight, increased also in a dose-dependent fashion. Each metal caused similar magnitudes of changes and exerted sim ilar potency. Measurement of other parameters indicating more specific injury revealed a number of differences. Although all metals reduced hepatic ATP concentration, mercury and cadmium were more potent than copper in this respect. Cadmium was the most potent at decreasing reduced glutathione levels. Mercury was most effective at increasing tissue calcium content, while copper was less so, and cadmium ineffective. Only copper significantly increased tissue malondialdehyde (MDA) content, while all metals increased its release into perfusate. Furthermore, whereas cadmium seemed the most potent metal in increasing MDA release, it was least efficacious, while copper was the most. Antioxidants such as superoxide dismutase, catalase, and Trolox C only reduced cadmium's influence on MDA in perfusate; however, they did not affect cadmium's ability to alter most other parameters of vitality. Albumin reversed the toxic effects of copper and mercury, but not cadmium. While metal-induced reductions in perfusion flow accounted for some of the toxic effects of the metals investigated, the results as a whole supported the suggestion that all metals exerted toxicity at the mitochondria, since ATP levels were reduced in a manner that could not be reproduced by perfusion flow reduction alone. Lipid peroxidation appears to play little role in determining toxicity induced by any of these metals. Furthermore, albumin may play an important physiological role in preventing hepatic injury that might otherwise be induced through acute metal intoxication. [ABSTRACT FROM AUTHOR]

Background: During the first epidemic wave, COVID-19 surveillance focused on quantifying the magnitude and the escalation of a growing global health crisis. The scientific community first assessed risk through basic indicators, such as the number of cases or rates of new cases and deaths, and later began using other direct impact indicators to conduct more detailed analyses. We aimed at synthesizing the scientific community's contribution to assessing the direct impact of the COVID-19 pandemic on population health through indicators reported in research papers., Methods: We conducted a rapid scoping review to identify and describe health indicators included in articles published between January 2020 and June 2021, using one strategy to search PubMed, EMBASE and WHO COVID-19 databases. Sixteen experts from European public health institutions screened papers and retrieved indicator characteristics. We also asked in an online survey how the health indicators were added to and used in policy documents in Europe., Results: After reviewing 3891 records, we selected a final sample of 67 articles and 233 indicators. We identified 52 (22.3%) morbidity indicators from 33 articles, 105 severity indicators (45.1%, 27 articles) and 68 mortality indicators (29.2%, 51). Respondents from 22 countries completed 31 questionnaires, and the majority reported morbidity indicators (29, 93.5%), followed by mortality indicators (26, 83.9%)., Conclusions: The indicators collated here might be useful to assess the impact of future pandemics. Therefore, their measurement should be standardized to allow for comparisons between settings, countries and different populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: Thirty-four percent of Multiple Myeloma (MM) clinical trial participants at Winship Cancer Institute (Winship) are African American (AA); however, AAs make up only 4.5 percent of myeloma clinical trial participants in the United States. Given our high enrollment, we aimed to measure AAs' trust in providers and identify if clinical trial enrollment barriers exist., Methodology: A member of the ethics research team surveyed AA patients who had consented to a MM clinical trial at Winship. Three validated surveys were used: Trust in Medical Research (TMR); Human Connection (THC) which measures how much patients feel they are heard and valued by their physicians; and the Duke Intrinsic Religiosity Scale (DUREL) which measures strength of religious engagement and belief. The survey also included questions about the impact of side effects, distance to the trial center and trial related costs on the decision to participate in clinical trial., Results: Ninety-two percent (61/67) of patients approached consented. The mean TMR score and the mean THC score were significantly higher ( P -value < 0.001) than the results obtained in key national surveys (TMR 14.9 compared to 11.65; THC 57.7 compared to 54.6). These two surveys were significantly correlated, meaning trust and human connection increase or decrease in tandem. The 3 religiosity subscale results showed high religiosity (3.84, 4.36, and 4.35 with 5 being the highest score). The mean scores of the importance of the investigational agent's side effects, trial costs, and distance to trial center on the decision to enroll in a clinical trial were also high (8.5, 7.8, and 6.5, respectively, with 10 being the most important)., Conclusion: In our study population, high trust and human connection overcame other trial participation barriers: strong religious beliefs and concerns about side effects, costs, and travel distance. We present a roadmap to guide investigators to increase human connection, and hopefully trust.

Basal forebrain cholinergic neurons (BFCNs) represent the main source of cholinergic innervation to the cortex and hippocampus and degenerate early in Alzheimer's disease (AD) progression. Phenotypic maintenance of BFCNs depends on levels of mature nerve growth factor (mNGF) and mature brain-derived neurotrophic factor (mBDNF), produced by target neurons and retrogradely transported to the cell body. Whether a reciprocal interaction where BFCN inputs impact neurotrophin availability and affect cortical neuronal markers remains unknown. To address our hypothesis, we immunolesioned the nucleus basalis (nb), a basal forebrain cholinergic nuclei projecting mainly to the cortex, by bilateral stereotaxic injection of 192-IgG-Saporin (the cytotoxin Saporin binds p75ntr receptors expressed exclusively by BFCNs) in 2.5-month-old Wistar rats. At 6 months post-lesion, Saporin-injected rats (SAP) showed an impairment in a modified version of the 5-Choice Serial Reaction Time Task (5-choice task). Postmortem analyses of the brain revealed a reduction of Choline Acetyltransferase-immunoreactive neurons compared to wild-type controls. A diminished number of cortical vesicular acetylcholine transporter-immunoreactive boutons was accompanied by a reduction in BDNF mRNA, mBDNF protein levels, markers of glutamatergic (vGluT1), and GABAergic (GAD65) neurons in the SAP-group compared to the controls. NGF mRNA, NGF precursor, and mNGF protein levels were not affected. Additionally, cholinergic markers correlated with the attentional deficit and BDNF levels. Our findings demonstrate that while cholinergic nb loss impairs cognition and reduces cortical neuron markers, it produces differential effects on neurotrophin availability, affecting BDNF but not NGF levels., (© 2022 International Society for Neurochemistry.)

Some individuals' understanding of informed consent (IC) information may improve with electronic delivery, but others may benefit from face-to-face (F2F). This randomized, multisite study explores how individuals from diverse backgrounds understand electronic IC documents versus F2F, their confidence in understanding, and enrollment in research. A total of 501 patients at two U.S. biobanks with diverse populations participated. There were no overall differences between electronic and F2F understanding, but F2F predicted higher confidence in understanding and enrollment. Ethnicity and a higher educational level predicted higher understanding and confidence. Study findings suggest that electronic consent may lead to better understanding for non-Hispanic patients of higher socioeconomic status. F2F processes may lead to better understanding and higher enrollment of patients from Hispanic and lower socioeconomic levels. Researchers should carefully consider how they implement electronic IC processes and whether to maintain an F2F process to better address the needs and limitations of some populations.