Systemic inflammation and delirium during critical illness.

PURPOSE: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness. METHODS: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1ß), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives. RESULTS: Among 991 participants with a median age (interquartile range, IQR) of 62 [53-72] years and enrollment SOFA of 9 [7-11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4-2.3]), IL-8 (1.3 [1.1-1.5]), IL-10 (1.5 [1.2-1.8]), TNF-α (1.2 [1.0-1.4]), and TNFR1 (1.3 [1.1-1.6]) and lower concentrations of protein C (0.7 [0.6-0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1-1.7]), IFN-γ (1.3 [1.1-1.5]), IL-6 (2.3 [1.8-3.0]), IL-8 (1.8 [1.4-2.3]), and IL-10 (1.5 [1.2-2.0]) and lower concentrations of protein C (0.6 [0.5-0.8]) were associated with coma the following day. IL-1ß, IL-12, and MMP-9 were not associated with mental status. CONCLUSION: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness.

Ascorbic acid and its transporter SVCT2, affect radial glia cells differentiation in postnatal stages.

Radial glia (RG) cells generate neurons and glial cells that make up the cerebral cortex. Both in rodents and humans, these stem cells remain for a specific time after birth, named late radial glia (lRG). The knowledge of lRG and molecules that may be involved in their differentiation is based on very limited data. We analyzed whether ascorbic acid (AA) and its transporter SVCT2, are involved in lRG cells differentiation. We demonstrated that lRG cells are highly present between the first and fourth postnatal days. Anatomical characterization of lRG cells, revealed that lRG cells maintained their bipolar morphology and stem-like character. When lRG cells were labeled with adenovirus-eGFP at 1 postnatal day, we detected that some cells display an obvious migratory neuronal phenotype, suggesting that lRG cells continue generating neurons postnatally. Moreover, we demonstrated that SVCT2 was apically polarized in lRG cells. In vitro studies using the transgenic mice SVCT2+/- and SVCT2tg (SVCT2-overexpressing mouse), showed that decreased SVCT2 levels led to accelerated differentiation into astrocytes, whereas both AA treatment and elevated SVCT2 expression maintain the lRG cells in an undifferentiated state. In vivo overexpression of SVCT2 in lRG cells generated cells with a rounded morphology that were migratory and positive for proliferation and neuronal markers. We also examined mediators that can be involved in AA/SVCT2-modulated signaling pathways, determining that GSK3-ß through AKT, mTORC2, and PDK1 is active in brains with high levels of SVCT2/AA. Our data provide new insights into the role of AA and SVCT2 in late RG cells.

Microglial-specific knockdown of iron import gene, Slc11a2, blunts LPS-induced neuroinflammatory responses in a sex-specific manner.

Neuroinflammation and microglial iron load are significant hallmarks found in several neurodegenerative diseases. In in vitro systems, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and it has been shown that iron can augment cellular inflammation, suggesting a feed-forward loop between mechanisms involved in iron import and inflammatory signaling. However, it is not understood how microglial iron import mechanisms contribute to inflammation in vivo, or whether altering a microglial iron-related gene affects the inflammatory response. These studies aimed to determine the effect of knocking down microglial iron import gene Slc11a2 on the inflammatory response in vivo. We generated a novel model of tamoxifen-inducible, microglial-specific Slc11a2 knockdown using Cx3cr1Cre-ERT2 mice. Transgenic male and female mice were administered intraperitoneal saline or lipopolysaccharide (LPS) and assessed for sickness behavior post-injection. Plasma cytokines and microglial bulk RNA sequencing (RNASeq) analyses were performed at 4 h post-LPS, and microglia were collected for gene expression analysis after 24 h. A subset of mice was assessed in a behavioral test battery following LPS-induced sickness recovery. Control male, but not female, mice significantly upregulated microglial Slc11a2 at 4 and 24 h following LPS. In Slc11a2 knockdown mice, we observed an improvement in the acute behavioral sickness response post-LPS in male, but not female, animals. Microglia from male, but not female, knockdown animals exhibited a significant decrease in LPS-provoked pro-inflammatory cytokine expression after 24 h. RNASeq data from male knockdown microglia 4 h post-LPS revealed a robust downregulation in inflammatory genes including Il6, Tnfα, and Il1ß, and an increase in anti-inflammatory and homeostatic markers (e.g., Tgfbr1, Cx3cr1, and Trem2). This corresponded with a profound decrease in plasma pro-inflammatory cytokines 4 h post-LPS. At 4 h, male knockdown microglia also upregulated expression of markers of iron export, iron recycling, and iron homeostasis and decreased iron storage and import genes, along with pro-oxidant markers such as Cybb, Nos2, and Hif1α. Overall, this work elucidates how manipulating a specific gene involved in iron import in microglia alters acute inflammatory signaling and overall cell activation state in male mice. These data highlight a sex-specific link between a microglial iron import gene and the pro-inflammatory response to LPS in vivo, providing further insight into the mechanisms driving neuroinflammatory disease.

Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension.

Ligands for the serotonin 2B receptor (5-HT2B) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT2B. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia-induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT2B ligands with high potency and selectivity for the 5-HT2B receptor subtype. Next-generation 5-HT2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug-enabling studies.

Insight into What Is inside Swift Heavy Ion Latent Tracks in PET Film.

We present here a novel experimental study of changes after contact electrification in the optical transmission spectra of samples of both pristine and irradiated PET film treated with Kr+15 ions of energy of 1.75 MeV and a fluence of 3 × 1010 cm2. We used a non-standard electrification scheme for injecting electrons into the film by applying negative electrodes to both its surfaces and using the positively charged inner regions of the film itself as the positive electrode. Electrification led to a decrease in the intensity of the internal electric fields for both samples and a hypsochromic (blue) shift in their spectra. For the irradiated PET sample, electrification resulted in a Gaussian modulation of its optical properties in the photon energy range 2.3-3.6 eV. We associate this Gaussian modulation with the partial decay of non-covalent extended conjugated systems that were formed under the influence of the residual radial electric field of the SHI latent tracks. Our studies lead us to suggest the latent track in the PET film can be considered as a variband material in the radial direction. Consideration of our results along with other published experimental results leads us to conclude that these can all be consistently understood by taking into account both the swift and slow electrons produced by SHI irradiation, and that it appears that the core of a latent track is negatively charged, and the periphery is positively charged.

Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness.

Despite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity. In this Series paper, we discuss neurological, cognitive, and psychiatric sequelae in patients who have survived critical illness due to COVID-19. We review current knowledge of the epidemiology and pathophysiology of persistent neuropsychological impairments, and outline potential preventive strategies based on safe, evidence-based approaches to the management of pain, agitation, delirium, anticoagulation, and ventilator weaning during critical illness. We highlight priorities for current and future research, including possible therapeutic approaches, and offer considerations for health services to address the escalating health burden of long COVID.

What do women think about having received their breast cancer risk as part of a risk-stratified NHS Breast Screening Programme? A qualitative study.

BACKGROUND: Risk-stratified screening is being considered for national breast screening programmes. It is unclear how women experience risk-stratified screening and receipt of breast cancer risk information in real time. This study aimed to explore the psychological impact of undergoing risk-stratified screening within England's NHS Breast Screening Programme. METHODS: Individual telephone interviews were conducted with 40 women who participated in the BC-Predict study and received a letter indicating their estimated breast cancer risk as one of four risk categories: low (<2% 10-year risk), average (2-4.99%), above average (moderate; 5-7.99%) or high (≥8%). Audio-recorded interview transcriptions were analysed using reflexive thematic analysis. RESULTS: Two themes were produced: 'From risk expectations to what's my future health story?' highlights that women overall valued the opportunity to receive risk estimates; however, when these were discordant with perceived risk, this causes temporary distress or rejection of the information. 'Being a good (woman) citizen' where women felt positive contributing to society but may feel judged if they then cannot exert agency over the management of their risk or access follow-up support CONCLUSIONS: Risk-stratified breast screening was generally accepted without causing long-lasting distress; however, issues related to risk communication and access to care pathways need to be considered for implementation.

Quantifying the effects of risk-stratified breast cancer screening when delivered in real time as routine practice versus usual screening: the BC-Predict non-randomised controlled study (NCT04359420).

BACKGROUND: Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). METHODS: Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer-Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5-<8% 10-year) to have appointments to discuss prevention and additional screening. RESULTS: Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to <10% with BC-Predict only (P < 0.0001). Risk appointment attendance was highest for those at high risk (40.6%); 77.5% of those opted for preventive medication. DISCUSSION: We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. TRIAL REGISTRATION: Retrospectively registered with clinicaltrials.gov (NCT04359420).

Psychological impact of risk-stratified screening as part of the NHS Breast Screening Programme: multi-site non-randomised comparison of BC-Predict versus usual screening (NCT04359420).

BACKGROUND: Adding risk stratification to standard screening via the NHS Breast Screening Programme (NHSBSP) allows women at higher risk to be offered additional prevention and screening options. It may, however, introduce new harms such as increasing cancer worry. The present study aimed to assess whether there were differences in self-reported harms and benefits between women offered risk stratification (BC-Predict) compared to women offered standard NHSBSP, controlling for baseline values. METHODS: As part of the larger PROCAS2 study (NCT04359420), 5901 women were offered standard NHSBSP or BC-Predict at the invitation to NHSBSP. Women who took up BC-Predict received 10-year risk estimates: "high" (≥8%), "above average (moderate)" (5-7.99%), "average" (2-4.99%) or "below average (low)" (<2%) risk. A subset of 662 women completed questionnaires at baseline and at 3 months (n = 511) and 6 months (n = 473). RESULTS: State anxiety and cancer worry scores were low with no differences between women offered BC-Predict or NHSBSP. Women offered BC-Predict and informed of being at higher risk reported higher risk perceptions and cancer worry than other women, but without reaching clinical levels. CONCLUSIONS: Concerns that risk-stratified screening will produce harm due to increases in general anxiety or cancer worry are unfounded, even for women informed that they are at high risk.

Enhancement of Luminescence of PET Films after Swift Heavy Ion Irradiation.

The novelty of the study is that the ordering that occurs in a PET film under the action of SHI irradiation manifests itself as an increase in the integral intensity of intrinsic luminescence. The Urbach behaviour of the red shift of the absorption edge is used as a baseline for further analysis of experimental optical transmission spectra of PET films irradiated by swift heavy ions (SHI) previously published by the authors. Negative deviations of the experimental spectra from the Urbach baseline in the visible and UV parts of the spectrum are attributed to enhanced by SHI irradiation intrinsic luminescence. The observed dependence of the integral intensity of luminescence of irradiated PET films on the SHI fluence and ion charge provides further confirmation of the presence of SHI-induced ordering of the molecular structure in SHI latent tracks.

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial.

Importance: Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors. Objective: To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial. Design, Setting, and Participants: This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022. Interventions: The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo. Main Outcomes and Measures: Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization. Results: After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups. Conclusions and Relevance: In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Acute manganese exposure impairs glutamatergic function in a young mouse model of Alzheimer's disease.

Manganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating oxidative stress and the glutamate/glutamine cycle. Mn is typically obtained through the diet, but toxic overexposure can occur through other environmental or occupational exposure routes such as inhalation. Mn is known to accumulate in the brain following exposure and may contribute to the etiology of neurodegenerative disorders such as Alzheimer's disease (AD) even in the absence of acute neurotoxicity. In the present study, we used in vitro primary cell culture, ex vivo slice electrophysiology and in vivo behavioral approaches to determine if Mn-induced changes in glutamatergic signaling may be altered by genetic risk factors for AD neuropathology. Primary cortical astrocytes incubated with Mn exhibited early rapid clearance of glutamate compared to saline treated astrocytes but decreased clearance over longer time periods, with no effect of the AD genotype. Further, we found that in vivo exposure to a subcutaneous subacute, high dose of Mn as manganese chloride tetrahydrate (3 ×50 mg/kg MnCl2·4(H2O) over 7 days) resulted in increased expression of cortical GLAST protein regardless of genotype, with no changes in GLT-1. Hippocampal long-term potentiation was not altered in APP/PSEN1 mice at this age and neither was it disrupted following Mn exposure. Mn exposure did increase sensitivity to seizure onset following treatment with the excitatory agonist kainic acid, with differing responses between APP/PSEN1 and control mice. These results highlight the sensitivity of the glutamatergic system to Mn exposure. Experiments were performed in young adult APP/PSEN1 mice, prior to cognitive decline or accumulation of hallmark amyloid plaque pathology and following subacute exposure to Mn. The data support a role of Mn in pathophysiology of AD in early stages of the disease and support the need to better understand neurological consequences of Mn exposure in vulnerable populations.

Altered EEG, disrupted hippocampal long-term potentiation and neurobehavioral deficits implicate a delirium-like state in a mouse model of sepsis.

Sepsis and systemic inflammation are often accompanied by severe encephalopathy, sleep disruption and delirium that strongly correlate with poor clinical outcomes including long-term cognitive deficits. The cardinal manifestations of delirium are fluctuating altered mental status and inattention, identified in critically ill patients by interactive bedside assessment. The lack of analogous assessments in mouse models or clear biomarkers is a challenge to preclinical studies of delirium. In this study, we utilized concurrent measures of telemetric EEG recordings and neurobehavioral tasks in mice to characterize inattention and persistent cognitive deficits following polymicrobial sepsis. During the 24-hour critical illness period for the mice, slow-wave EEG dominance, sleep disruption, and hypersensitivity to auditory stimuli in neurobehavioral tasks resembled clinical observations in delirious patients in which alterations in similar outcome measurements, although measured differently in mice and humans, are reported. Mice were tested for nest building ability 7 days after sepsis induction, when sickness behaviors and spontaneous activity had returned to baseline. Animals that showed persistent deficits determined by poor nest building at 7 days also exhibited molecular changes in hippocampal long-term potentiation compared to mice that returned to baseline cognitive performance. Together, these behavioral and electrophysiological biomarkers offer a robust mouse model with which to further probe molecular pathways underlying brain and behavioral changes during and after acute illness such as sepsis.

Implementing Risk-Stratified Breast Screening in England: An Agenda Setting Meeting.

It is now possible to accurately assess breast cancer risk at routine NHS Breast Screening Programme (NHSBSP) appointments, provide risk feedback and offer risk management strategies to women at higher risk. These strategies include National Institute for Health and Care Excellence (NICE) approved additional breast screening and risk-reducing medication. However, the NHSBSP invites nearly all women three-yearly, regardless of risk. In March 2022, a one-day agenda setting meeting took place in Manchester to discuss the feasibility and desirability of implementation of risk-stratified screening in the NHSBSP. Fifty-eight individuals participated (38 face-to-face, 20 virtual) with relevant expertise from academic, clinical and/or policy-making perspectives. Key findings were presented from the PROCAS2 NIHR programme grant regarding feasibility of risk-stratified screening in the NHSBSP. Participants discussed key uncertainties in seven groups, followed by a plenary session. Discussions were audio-recorded and thematically analysed to produce descriptive themes. Five themes were developed: (i) risk and health economic modelling; (ii) health inequalities and communication with women; (iii); extending screening intervals for low-risk women; (iv) integration with existing NHSBSP; and (v) potential new service models. Most attendees expected some form of risk-stratified breast screening to be implemented in England and collectively identified key issues to be resolved to facilitate this.

Epigenetic remodeling by vitamin C potentiates plasma cell differentiation.

Ascorbate (vitamin C) is an essential micronutrient in humans. The severe chronic deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. From a micronutrient analysis, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique as other antioxidants failed to promote plasma cell differentiation. Ascorbate is especially critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. As a cofactor for epigenetic enzymes, ascorbate facilitates TET2/3-mediated DNA modification and demethylation of multiple elements at the Prdm1 locus. DNA demethylation augments STAT3 association at the Prdm1 promoter and a downstream enhancer, thus ensuring efficient gene expression and plasma cell differentiation. The results suggest that an adequate level of ascorbate is required for antibody response and highlight how micronutrients may regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions.

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer's Disease.

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood-brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer's disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.

Exposing the role of metals in neurological disorders: a focus on manganese.

Metals are ubiquitous chemical entities involved in a myriad of biological processes. Despite their integral role in sustaining life, overexposure can lead to deleterious neurological outcomes posing a public health concern. Excess exposure to metals has been associated with aberrant neurodevelopmental and neurodegenerative diseases and prominently contributes to environmental risk for neurological disorders. Here, we use manganese (Mn) to exemplify the gap in our understanding of the mechanisms behind acute metal toxicity and their relationship to chronic toxicity and disease. This challenge frustrates understanding of how individual exposure histories translate into preventing and treating brain diseases from childhood through old age. We discuss ways to enhance the predictive value of preclinical models and define mechanisms of chronic, persistent, and latent neurotoxicity.

Urbach Rule in the Red-Shifted Absorption Edge of PET Films Irradiated with Swift Heavy Ions.

This paper presents a new analysis of the experimental transmission spectra of polyethylene terephthalate (PET) films before and after irradiation with swift heavy ions (SHI) films, as reported previously by the authors. It is shown that the absorption edge red shift for irradiated films contains two regions of exponential form, one of which is located in the UV region and the other at lower energy, mainly in the visible part of the spectrum. The behaviour of the transmission curves under different irradiating fluences demonstrates that these two regions reflect respectively the electron-enriched core of the latent track and its electron-depleted peripheral halo. The focal point method yields a bandgap energy of 4.1 eV for the electron-enriched core of the latent track, which is similar to n-doped semiconductors, and a bandgap of about 1.3-1.5 eV for the electron-depleted halo, similar to p-doped semiconductors. The boundary between the latent track cores and halos corresponds to a conventional semiconductor p-n junction. The values of the characteristic Urbach energy determined from experimental data correspond to the nonradiative transition energy between the excited singlet and triplet levels of benzene-carboxyl complexes in repeat units of the PET chain molecule. A parallel is drawn between the SHI-induced redistribution of electrons held in structural traps in the PET film and chemical redox reactions, which involve the redistribution of electrons in chemical bonds. It is suggested that alkali etching triggers the release of excess electrons in the latent track cores, which act as a catalyst for the fragmentation of PET chain molecules along the latent tracks of the SHI irradiation.

Manganese-induced hyperactivity and dopaminergic dysfunction depend on age, sex and YAC128 genotype.

Manganese (Mn) is an essential micronutrient but is neurotoxic in excess. Environmental and genetic factors influence vulnerability to Mn toxicity, including sex, age, and the autosomal dominant mutation that causes Huntington disease (HD). To better understand the differential effects of Mn in wild-type (WT) versus YAC128 mice, we examined impacts of Mn exposure across different ages and sexes on disease-relevant behavioral tasks and dopamine dynamics. Young (3-week) and aged (12-month) WT and YAC128 mice received control (70 ppm) or high (2400 ppm) Mn diet for 8 weeks followed by a battery of behavioral tasks. In young female WT mice, high Mn diet induced hyperactivity across two independent behavioral tasks. Changes in the expression of tyrosine hydroxylase (TH) were consistent with the behavioral data in young females such that elevated TH in YAC128 on control diet was decreased by high Mn diet. Aged YAC128 mice showed the expected disease-relevant behavioral impairments in females and decreased TH expression, but we observed no significant effects of Mn diet in either genotype of the aged group. Fast-scan cyclic voltammetry recorded dopamine release and clearance in the nucleus accumbens of eight-month-old WT and YAC128 mice following acute Mn exposure (3×/1 week subcutaneous injections of 50 mg/kg MnCl[2]-tetrahydrate or saline). In WT mice, Mn exposure led to faster dopamine clearance that resembled saline treated YAC128 mice. Mn treatment increased dopamine release only in YAC128 mice, possibly indirectly correcting the faster dopamine clearance observed in saline treated YAC128 mice. The same exposure paradigm led to decreased dopamine and serotonin and metabolites (3-MT, HVA and 5-HIAA) in striatum and increased glutamate in YAC128 mice but not WT mice. These studies confirm an adverse effect of Mn in young, female WT animals and support a role for Mn exposure in stabilizing dopaminergic dysfunction and motivated behavior in early HD.