Cumulative effects of pre-pandemic vulnerabilities and pandemic-related hardship on psychological distress among pregnant individuals.

OBJECTIVE: Our primary objective was to determine whether pre-existing vulnerabilities and resilience factors combined with objective hardship resulted in cumulative (i.e., additive) effects on psychological distress in pregnant individuals during the COVID-19 pandemic. A secondary objective was to determine whether any of the effects of pandemic-related hardship were compounded (i.e., multiplicative) by pre-existing vulnerabilities. METHOD: Data are from a prospective pregnancy cohort study, the Pregnancy During the COVID-19 Pandemic study (PdP). This cross-sectional report is based upon the initial survey collected at recruitment between April 5, 2020 and April 30, 2021. Logistic regressions were used to evaluate our objectives. RESULTS: Pandemic-related hardship substantially increased the odds of scoring above the clinical cut-off on measures of anxiety and depression symptoms. Pre-existing vulnerabilities had cumulative (i.e., additive) effects on the odds of scoring above the clinical cut-off on measures of anxiety and depression symptoms. There was no evidence of compounding (i.e., multiplicative) effects. Social support had a protective effect on anxiety and depression symptoms, but government financial aid did not. CONCLUSION: Pre-pandemic vulnerability and pandemic-related hardship had cumulative effects on psychological distress during the COVID-19 pandemic. Adequate and equitable responses to pandemics and disasters may require more intensive supports for those with multiple vulnerabilities.

Diffusion tensor imaging of white matter tract evolution over the lifespan.

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.

Fear of COVID-19, mental health, and pregnancy outcomes in the pregnancy during the COVID-19 pandemic study: Fear of COVID-19 and pregnancy outcomes.

BACKGROUND: Sustained fear during pregnancy has the potential to increase psychological distress and obstetric risk. This study aimed to (1) identify factors and characteristics associated with fear of COVID-19, (2) investigate the relationship between fear of COVID-19 and maternal anxiety and depression, and (3) determine the relationship between fear of COVID-19 and pregnancy outcomes. METHODS: 9251 pregnant Canadians were recruited between April - December 2020. Participants self-reported (scale of 0-100) the degree of threat they perceived from the SARS-CoV-2 virus in relation to themselves and their unborn baby. RESULTS: Mean fear scores indicated moderate to elevated concern. In multivariable linear regression, fear of COVID-19 was associated with food insecurity, ethnicity, geographic location, history of anxiety prior to pregnancy, having a chronic health condition, pre-pregnancy BMI, parity, and stage of pregnancy at study enrollment. Higher COVID-19 fear was associated with increased odds of depression, adjusted odds ratio (aOR) = 1.75, p < 0.001, 95% CI 1.66-1.85, and anxiety, aOR=2.04, p < 0.001, 95% CI 1.94-2.15). Furthermore, fear of COVID-19 was associated with a 192-gram reduction in infant birthweight, and a 6.1-day reduction in gestational age at birth. LIMITATIONS: The sample has higher education compared to the Canadian population and cannot test causal effects. CONCLUSION: This study suggests that sociodemographic, health, and obstetric factors may contribute to increased fear of COVID-19 and associated adverse psychological and pregnancy outcomes.

Musculoskeletal ultrasound for 3D bone modeling: A preliminary study applied to lumbar vertebra.

BACKGROUND: There is no non-invasive in vivo method to assess intervertebral kinematics. Current kinematics models are based on in vitro bone reconstructions from computed tomography (CT)-scan imaging, fluoroscopy and MRIs, which are either expensive or deleterious for human tissues. Musculoskeletal ultrasound is an accessible, easy to use and cost-effective device that allows high-resolution, real-time imaging of bone structure. OBJECTIVE: The aim of this preliminary study was to compare the concordance of 3D bone modeling of lumbar vertebrae between CT-scan and ultrasound imaging and to study the intra and inter-reliability of distances measured on 3D ultrasound bone models. METHODS: CT-scan, ultrasound, and in situ data of five lumbar vertebrae from the same human specimen were used. All vertebrae were scanned by tomography and a new musculoskeletal ultrasound procedure. Then, 3D bone modeling was created from both CT-scan and ultrasound image data set. Distances between anatomical bones landmarks were measured on the 3D models and compared to in situ measurements.

The relationship between excitotoxicity and oxidative stress in the central nervous system.

Excitotoxicity and oxidative stress are two phenomena that have been repeatedly described as being implicated in a wide range of disorders of the nervous system. Such disorders include several common idiopathic neurological diseases, traumatic brain injury, and the consequences of exposure to certain neurotoxic agents. While there is evidence that metabolic derangements can lead to these adverse processes, and that these processes may synergize in their damaging effects, the degree of interdependence, and the causal relation between them is not clear. The intent of this review is to delineate potential mechanisms which may unit hyperexcitation to the excessive generation of reactive oxygen species. The degree of linkage between these events appears rather strong. It is likely that excitoxicity frequently leads to a pro-oxidant condition but that high rates of these events appears rather strong. It is likely that excitoxicity frequently leads to a pro-oxidant condition but that high rates of generation of reactive oxygen species are not invariably accompanied by a hyperexcited neuronal state Both excitoxic and 'oxidotoxic' states result from the failure of normal compensatory antiexcitatory and antioxidant mechanisms to maintain cellular homeostasis.

New aspects of brain oxidative stress induced by tert-butylhydroperoxide.

Many diseases and aging may be associated with oxidative stress in the brain. However, the effects of oxidative stress in the brain should be more clearly described, especially in terms of effects on brain reduced glutathione (GSH). This issue was addressed by intracerebroventricular injection of a direct-acting oxidative stress inducing agent, tert-butylhydroperoxide. Oxidized glutathione (GSSG) levels in the brain increased by as much as 90-fold during tert-butylhydroperoxide-induced oxidative stress. At the same time, brain GSH levels decreased. The brain appears to retain GSSG and not reduce it or export it efficiently. Vitamin E levels in the striatum increased during tert-butylhydroperoxide-induced oxidative stress. Aging alters the ability of the brain to detoxify an oxidative stress, in that 8-month-old mice retain GSSG in their brains much more than 2-month-old mice. Eight-month-old mice were much more susceptible to tert-butylhydroperoxide-induced toxicity than 2-month-old mice. This may indicate that aging makes the brain more susceptible to oxidative damage.

Effect of toluene on rat synaptosomal phospholipid methylation and membrane fluidity.

This study investigated the effects of toluene (1 g/kg, 1 hr, i.p.) on rat synaptosomal phospholipid methylation (PLM), phospholipid composition, and membrane fluidity. Toluene significantly decreased basal PLM (35%) in studies using [3H]methionine [( 3H]Met) as the methyl donor; this was reflected by similar decreases in phosphatidylmonomethylethanolamine (PME) (30%). No effects were observed in either PLM reactions that used [3H]adenosylmethionine [( 3H]AdoMet) as methyl donor, or AdoMet synthetase, suggesting that toluene preferentially affects PLM reactions that derive methyl groups from [3H]Met. Also, toluene decreased synaptosomal phosphatidylethanolamine (PE) (24%), the initial substrate for PLM, and the addition of PE back to PE-depleted synaptosomes restored methyltransferase activity. Agonist-stimulated PLM using norepinephrine (NE) demonstrated that agonist-receptor coupling returned PLM to control values in synaptosomes from toluene-treated rats. NE-stimulated PLM was also blocked by propranolol (PRO), suggesting a role for toluene in receptor-mediated events. Membrane fluidity studies demonstrated that in vivo administration of toluene increased the outer synaptosomal membrane fluidity, whereas in vitro administration of toluene had no effect. Our observations support a positive relationship between increased PLM activity and increased outer, not core, membrane fluidity. These data demonstrate that specific toluene-phospholipid interactions occur in synaptosomes, resulting in altered membrane composition, function and fluidity.

Effects of toluene and its metabolites on cerebral reactive oxygen species generation.

The effects of toluene on lipid peroxidation and rates of reactive oxygen species (ROS) formation have been studied in isolated systems and in vivo. The induction of reactive oxygen species was assayed using the probe 2',7'-dichlorofluorescin diacetate (DCFH-DA). Toluene exposure (1 g/kg, 1 hr, i.p.) did not stimulate cortical lipid peroxidation as evaluated by measurement of conjugated dienes. Exposure to toluene, however, both in vivo and in vitro, caused a significant elevation of ROS formation within cortical crude synaptosomal fractions (P2) and microsomal fractions (P3). The ROS-inducing properties of toluene were blocked in vivo in the presence of a mixed-function oxidase inhibitor, metyrapone. This suggested that a metabolite of toluene may catalyze reactive oxygen formation. Both benzyl alcohol and benzoic acid, in vitro, were found to have free radical quenching properties, while benzaldehyde exhibited significant induction of ROS generation. It appears that benzaldehyde is the metabolite responsible for the effect of toluene in accelerating reactive oxygen production within the nervous system. Benzaldehyde may also contribute to the overall neurotoxicity of toluene.

Cytological and functional aspects of telomere maintenance.

The fact that eukaryotic chromosomes are linear poses a special problem for their maintenance: the natural ends of chromosomes must be distinguished from ends generated by chromosomal breakage and somehow, the chromosome ends must also be fully replicated to maintain their integrity. Telomeres, the complex structures at the ends of chromosomes are thought to be instrumental for both of these functions. However, recent insights in telomere biology suggest that these terminal structures do much more than just fulfill these two basic functions. Cytological data demonstrate that telomeres may play leading roles in chromatin organization and nuclear architecture during mitosis and meiosis. Moreover, non-functional telomeres may lead to genetic instability, a common prelude to cancer. Here, we review the basic functions of telomeres during chromosome replication and discuss the cytological aspects of telomere function during mitosis and meiosis.

Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes.

The formation of oxygen reactive species in response to oxidative stimuli was measured in rat synaptosomes. Studies employed the non-fluorescent probe 2?,7?-dichlorofluorescin diacetate (DCFH-DA), which after de-esterification is oxidized in the presence of oxygen reactive species to the highly fluorescent 2?,7?-dichlorofluorescein (DCF). Oxygen reactive species formation, as measured by DCF fluorescence, was stimulated by ascorbate and/or FeSO(4), and xanthine/xanthine oxidase under various buffering conditions. These agents all increased DCF formation in Tris, HEPES and phosphate buffer. Ascorbate also stimulated the formation of DCF in a concentration-dependent manner. The presence of Ca(2+) in HEPES buffer did not enhance or diminish the effects of ascorbate/FeSO(4) on DCF formation. Deferoxamine inhibited the ascorbate/FeSO(4)-induced stimulation of DCF formation, but xanthine/xanthine oxidase-induced stimulation was not affected by pretreatment with superoxide dismutase. Results indicate that DCF fluorescence is a sensitive, quantitative and direct measure of oxygen reactive species formation in synaptosomes, providing a rapid method for investigating early neuronal events that occur during oxidative stress.

Persistent protein damage despite reduced oxygen radical formation in the aging rat brain.

The relation between cerebral oxygen radicals and the aging process was investigated in crude synaptosomal (P2) fractions from rats. The rate of formation of oxygen radicals was measured using the probe 2',7'-dichlorofluorescein diacetate (DCFH-DA), which is de-esterified and subsequently oxidized by oxygen radicals to a fluorescent product 2',7'-dichlorofluorescein (DCF). There was a significant age-dependent decrease in the formation rate of oxygen radicals, observed by decreased formation of DCF. No difference in oxygen radical formation was apparent between age groups following an in vitro challenge with an ascorbate/FeSO4 mixture. This age-dependent decrease in cerebral oxygen radical generation coincided with age-dependent increases in superoxide dismutase. No age-related alterations in lipid order in either the hydrophilic or lipophilic membrane regions were observed using fluorescence polarization analysis. Age-dependent losses in cerebral P2 tryptophan fluorescence (a measure of protein degradation), and increased liberation of [14C]protein fragments into the acid-soluble fraction (a measure of overall proteolytic activity) were observed. Results suggest that aging does not proceed as a result of elevated rates of generation of oxygen radicals, a finding that does not support the proposed free radical theory of aging. The observed age-dependent decrease in the formation of oxygen radicals does not effect membrane lipid order. These findings implicate modifications in proteins and activated protein catabolic pathways as major contributing factors in the normal physiological process of senescence.

Use of a rodent neurotoxicity screening battery in the preclinical safety assessment of recombinant-methionyl human brain-derived neurotrophic factor.

Recent efforts to evaluate neurobehavioral function in adult rodents as part of preclinical safety studies have typically been directed at evaluating possible environmental neurotoxicants. With considerable basic and clinical research efforts focusing on neurotrophic factors in the treatment of various neurodegenerative diseases, the application of these neurobehavioral evaluations is expected to increase. This report describes a six-month safety study of recombinant-methionyl human brain-derived neurotrophic factor (r-metHuBDNF) in rodents that included a neurotoxicity screening battery and was undertaken to evaluate safety issues that might be anticipated in the clinical setting. R-metHuBDNF was well tolerated by rats over six months of daily subcutaneous administration at doses that exceeded the highest anticipated clinical dose by 100-fold. Although statistically significant behavioral changes were noted, they were isolated and not considered to be associated with r-metHuBDNF treatment. We conclude that the inclusion of a neurotoxicity screening battery was an important study parameter in the assessment of the preclinical safety of this neurotrophin.

Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity.

Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, and hydroxyl radicals are believed to be initiators of peroxidative cell damage. This paper focused on the use of 2',7'-dichlorofluorescein-diacetate (DCFH-DA) to quantitate cerebral ROS as an index for neurotoxicity. This technique employs an assay of dichlorofluorescein (DCF), the fluorescent product of dichlorofluorescein (DCFH). Data from studies using various free radical generating systems, several iron chelators and hydroxyl radical scavengers suggest that DCFH oxidation may result in several reactive intermediates. In a biological system (synaptosomes isolated from untreated rats) DCF fluorescence was stimulated by ascorbate or FeSO4, while deferoxamine inhibited the ascorbate/FeSO4-induced stimulation of DCF formation. Two organometals, methylmercury (MeHg) and trimethyltin (TMT), known to produce neurotoxicity were tested. In vitro exposure to MeHg (10-20 microM) increased the rate of formation of ROS while TMT (5-40 microM) had no effect. In vivo, 48 hr and 1 week after a single injection of MeHg (1 mg/kg, i.p.) in mice and 1 week after a single injection of MeHg (5 mg/kg, i.p.) in rats, the rate of formation of ROS in both rat and mouse cerebellum was significantly increased. Pretreatment with deferoxamine, a potent iron-chelator, prevented MeHg-induced increase of ROS. In hippocampus and frontal cortex, ROS formation rates were also elevated 48 hr after TMT injection (3 mg/kg, i.p.) in mice. These results demonstrate that DCF fluorescence provides a good measure of overall ROS formation in synaptosomes of both in vitro as well as in vivo systems. Since ROS formation was selectively increased in areas known to be specifically vulnerable to organometals (cerebellum in the case of MeHg and hippocampus in the case of TMT), these studies further support that oxidative damage may be the primary mechanism underlying the neurotoxicity induced by these organometals.

Oxygen radicals: common mediators of neurotoxicity.

The inherent biochemical, anatomical and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the introduction of free radical-induced insult. Recently, the biochemistry of free radicals has received considerable attention. It also has become increasingly apparent that many drug and chemical-induced toxicities may be evoked via free radicals and oxidative stress. Major points addressed in this work are the regulation of neural free radical generation by antioxidants and protective enzymes, xenobiotic-induced disruption of cerebral redox status, and specific examples of neurotoxic agent-induced alterations in free radical production as measured by the fluorescent probe dichlorofluorescein. This article considers the thesis that free radical mechanisms may contribute significantly to the properties of several diverse neurotoxic agents and proposes that excess production of free radicals may be common phenomena of neurotoxicity.

Pharmacokinetic, pharmacodynamic, and pharmacotoxic profiles of recombinant-methionyl human interleukin-2[alanine-125] (r-metHuIL-2[ala-125]) following intravenous and subcutaneous administration in rats.

Comparative pharmacotoxicity studies in rats were performed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or subcutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala-125] showed high bioavailability and nonlinear concentration profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 micrograms kg-1 day-1) indicated that r-metHuIL-2[ala-125], whether given intravenously or subcutaneously, was associated with increased circulating and infiltrating levels of lymphocytes and eosinophils. Bone marrow lymphoid hyperplasia and splenic extramedullary hematopoiesis were similarly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopathologic finding described as hepatocyte single cell necrosis which was observed following both intravenous and subcutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL-2[ala-125] via intravenous administration was 6 micrograms kg-1 day-1, while that for subcutaneous administration was 30 micrograms kg-1 day-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that subcutaneous administration may be a preferred clinical route of administration.

[" Is it possible to offer innovative services in psychiatry ? The case Jean-Talon "]. / «Est-ce possible d'offrir des services innovateurs en psychiatrie? Le cas Jean-Talon¼

The authors describe their experience at the Jean-Talon Hospital. In 1975 a department of psychiatry was created according to a new model. After describing the vicissitudes of the project, the achievements and failures, the authors analyse the reasons for the failure. There are several reasons : the medical and administrative powers who refuse change, and the members of the team who do not feel prepared to assume the power.

Microstructural maturation of the human brain from childhood to adulthood.

Brain maturation is a complex process that continues well beyond infancy, and adolescence is thought to be a key period of brain rewiring. To assess structural brain maturation from childhood to adulthood, we charted brain development in subjects aged 5 to 30 years using diffusion tensor magnetic resonance imaging, a novel brain imaging technique that is sensitive to axonal packing and myelination and is particularly adept at virtually extracting white matter connections. Age-related changes were seen in major white matter tracts, deep gray matter, and subcortical white matter, in our large (n=202), age-distributed sample. These diffusion changes followed an exponential pattern of maturation with considerable regional variation. Differences observed in developmental timing suggest a pattern of maturation in which areas with fronto-temporal connections develop more slowly than other regions. These in vivo results expand upon previous postmortem and imaging studies and provide quantitative measures indicative of the progression and magnitude of regional human brain maturation.

Altered synaptosomal phospholipid metabolism after toluene: possible relationship with membrane fluidity, Na+,K(+)-adenosine triphosphatase and phospholipid methylation.

The mechanism by which toluene decreased synaptosomal phosphatidylethanolamine (PE) was investigated by studying degradative and synthetic phospholipid pathways. Toluene stimulated a PE-specific phospholipase (PLase) C both in vivo (44-75%) and in vitro (20-30%) whereas PLase A, PLase D and base exchange enzymes were unchanged. Toluene, in vivo, also increased the synthesis of PE (27%) when expressed as [3H]ethanolamine incorporation into [3H]PE, but had no effect on PE synthesis when administered in vitro. Perhaps this reflects a compensatory mechanism in synaptosomes to replace PE via increasing de novo synthesis. Phospholipid methylation, an event proposed to be related to the transduction of singals across membranes, as well as a measure of membrane function, was studied. Toluene was found to rapidly increase phospholipid methylation (43%, 15 min), followed by a significant decrease (35%, 1 hr). Another measure of membrane, as well as cell function used in these studies was ATPase activity. Toluene, both in vivo and in vitro, stimulated Na+, K(+)-adenosine triphosphatase (ATPase) activity (20-30%, 15-30 min), whereas Mg(++)-ATPase and Ca(++)-ATPase were unaffected, an indication that toluene alters neuronal cell function. Membrane fluidity studies using fluorescence polarization reported that toluene, both in vivo and in vitro, increased the outer synaptosomal membrane fluidity using the probe trimethylammonium-diphenylhexatriene, whereas no effect was observed on the central core fluidity using diphenylhexatriene. These are the first studies to demonstrate that an organic solvent effects only specific membrane region fluidities. One possibility is that early synaptic alterations resulting from toluene exposure may be preceded by increases in outer membrane fluidity.(ABSTRACT TRUNCATED AT 250 WORDS)