Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.

OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.

A Collaborative Classroom Investigation of the Evolution of SABATH Methyltransferase Substrate Preference Shifts over 120 My of Flowering Plant History.

Next-generation sequencing has resulted in an explosion of available data, much of which remains unstudied in terms of biochemical function; yet, experimental characterization of these sequences has the potential to provide unprecedented insight into the evolution of enzyme activity. One way to make inroads into the experimental study of the voluminous data available is to engage students by integrating teaching and research in a college classroom such that eventually hundreds or thousands of enzymes may be characterized. In this study, we capitalize on this potential to focus on SABATH methyltransferase enzymes that have been shown to methylate the important plant hormone, salicylic acid (SA), to form methyl salicylate. We analyze data from 76 enzymes of flowering plant species in 23 orders and 41 families to investigate how widely conserved substrate preference is for SA methyltransferase orthologs. We find a high degree of conservation of substrate preference for SA over the structurally similar metabolite, benzoic acid, with recent switches that appear to be associated with gene duplication and at least three cases of functional compensation by paralogous enzymes. The presence of Met in active site position 150 is a useful predictor of SA methylation preference in SABATH methyltransferases but enzymes with other residues in the homologous position show the same substrate preference. Although our dense and systematic sampling of SABATH enzymes across angiosperms has revealed novel insights, this is merely the "tip of the iceberg" since thousands of sequences remain uncharacterized in this enzyme family alone.

Information enhanced model selection for Gaussian graphical model with application to metabolomic data.

In light of the low signal-to-noise nature of many large biological data sets, we propose a novel method to learn the structure of association networks using Gaussian graphical models combined with prior knowledge. Our strategy includes two parts. In the first part, we propose a model selection criterion called structural Bayesian information criterion, in which the prior structure is modeled and incorporated into Bayesian information criterion. It is shown that the popular extended Bayesian information criterion is a special case of structural Bayesian information criterion. In the second part, we propose a two-step algorithm to construct the candidate model pool. The algorithm is data-driven and the prior structure is embedded into the candidate model automatically. Theoretical investigation shows that under some mild conditions structural Bayesian information criterion is a consistent model selection criterion for high-dimensional Gaussian graphical model. Simulation studies validate the superiority of the proposed algorithm over the existing ones and show the robustness to the model misspecification. Application to relative concentration data from infant feces collected from subjects enrolled in a large molecular epidemiological cohort study validates that metabolic pathway involvement is a statistically significant factor for the conditional dependence between metabolites. Furthermore, new relationships among metabolites are discovered which can not be identified by the conventional methods of pathway analysis. Some of them have been widely recognized in biological literature.

Examining the role of community resilience and social capital on mental health in public health emergency and disaster response: a scoping review.

The ability of the public to remain psychologically resilient in the face of public health emergencies and disasters (such as the COVID-19 pandemic) is a key factor in the effectiveness of a national response to such events. Community resilience and social capital are often perceived as beneficial and ensuring that a community is socially and psychologically resilient may aid emergency response and recovery. This review presents a synthesis of literature which answers the following research questions: How are community resilience and social capital quantified in research?; What is the impact of community resilience on mental wellbeing?; What is the impact of infectious disease outbreaks, disasters and emergencies on community resilience and social capital?; and, What types of interventions enhance community resilience and social capital?A scoping review procedure was followed. Searches were run across Medline, PsycInfo, and EMBASE, with search terms covering both community resilience and social capital, public health emergencies, and mental health. 26 papers met the inclusion criteria.The majority of retained papers originated in the USA, used a survey methodology to collect data, and involved a natural disaster. There was no common method for measuring community resilience or social capital. The association between community resilience and social capital with mental health was regarded as positive in most cases. However, we found that community resilience, and social capital, were initially negatively impacted by public health emergencies and enhanced by social group activities.Several key recommendations are proposed based on the outcomes from the review, which include: the need for a standardised and validated approach to measuring both community resilience and social capital; that there should be enhanced effort to improve preparedness to public health emergencies in communities by gauging current levels of community resilience and social capital; that community resilience and social capital should be bolstered if areas are at risk of disasters or public health emergencies; the need to ensure that suitable short-term support is provided to communities with high resilience in the immediate aftermath of a public health emergency or disaster; the importance of conducting robust evaluation of community resilience initiatives deployed during the COVID-19 pandemic.

Correcting for digital image correlation speckle inversion at high temperature using color cameras.

Digital image correlation (DIC) is a popular, noncontacting technique to measure full-field deformation by using cameras to track the motion of an applied surface pattern. Because it is noncontacting, DIC can be performed for extreme temperature applications (e.g., hot-fire rocket testing of carbon composite rocket nozzles) under harsh conditions during which bonded gauges are damaged. Speckle pattern inversion is a phenomenon that sometimes occurs while performing high-temperature DIC. During speckle pattern inversion, portions of the surface pattern that were initially darker at room temperature (e.g., graphite) may emit more light due to blackbody radiation than the portions that were initially paler, thereby producing images in which the pattern appears inverted at high temperature relative to the initial pattern at room temperature. This phenomenon can prevent the correlation algorithm from being able to resolve the displacements between images. This work compares three methods to mitigate speckle pattern inversion: (A) the subtraction method, a recently-published technique in which two high-temperature images are subtracted to remove unwanted light; (B) the filtering method, a popular technique in which optical bandpass filters screen out unwanted light; and (C) the histogram rescaling method, a proposed new method that pairs a color camera with a blue light source and uses information from the green sensor of the camera to correct against inversion in the blue sensor through postprocessing. The histogram rescaling method is shown to successfully eliminate speckle pattern inversion and has the added advantages that it does not require quasi-static loading to be able to compensate for speckle pattern inversion, nor does it impose thick-glass distortions caused by the optical filter.

Social and psychological impact of the COVID-19 pandemic on people with Parkinson's disease: a scoping review.

OBJECTIVES: The COVID-19 pandemic caused countries across the globe to impose restrictions to slow the spread of the virus, with people instructed to stay at home and reduce contact with others. This reduction in social contact has the potential to negatively impact mental health and well-being. The restrictions are particularly concerning for people with existing chronic illnesses such as Parkinson's disease, who may be especially affected by concerns about the pandemic and associated reduction of social contact. The aim of this review was to synthesise published literature on the impact of the COVID-19 pandemic on the social and psychological well-being of people with Parkinson's disease. STUDY DESIGN: The design of this study is a scoping review. METHODS: We searched five electronic databases for English language articles containing primary data on this topic. RESULTS: Thirty-one relevant studies were found and included in the review. Six main themes were identified: impact of the pandemic on physical and mental health; COVID-19 concerns; access to health care; impact on daily and social activities; impact on physical activity and impact on caregivers. Levels of perceived risk of COVID-19 differed across studies, but most participants had adopted preventive measures such as staying at home and reducing social contacts. Participants in many studies reported a discontinuation of regular healthcare appointments and physiotherapy, as well as concerns about being able to obtain medication. Loss of daily activities and social support was noted by many participants. There was mixed evidence on the impact of the pandemic on physical exercise, with some studies finding no change in physical activity and others reporting a reduction; generally, participants with reduced physical activity had poorer mental health and greater worsening of symptoms. Caregivers of people with Parkinson's disease were more likely to be negatively affected by the pandemic if they cared for people with complex needs such as additional mental health problems. CONCLUSIONS: The COVID-19 pandemic has had negative effects on the physical and mental health of people with Parkinson's disease, perhaps due to disruption of healthcare services, loss of usual activities and supports and reduction in physical activity. We make recommendations for policy, practice and future research.

Mental health of staff working in intensive care during Covid-19.

BACKGROUND: Staff working in intensive care units (ICUs) have faced significant challenges during the COVID-19 pandemic which have the potential to adversely affect their mental health. AIMS: To identify the rates of probable mental health disorder in staff working in ICUs in nine English hospitals during June and July 2020. METHODS: An anonymized brief web-based survey comprising standardized questionnaires examining depression, anxiety symptoms, symptoms of post-traumatic stress disorder (PTSD), well-being and alcohol use was administered to staff. RESULTS: Seven hundred and nine participants completed the surveys comprising 291 (41%) doctors, 344 (49%) nurses and 74 (10%) other healthcare staff. Over half (59%) reported good well-being; however, 45% met the threshold for probable clinical significance on at least one of the following measures: severe depression (6%), PTSD (40%), severe anxiety (11%) or problem drinking (7%). Thirteen per cent of respondents reported frequent thoughts of being better off dead, or of hurting themselves in the past 2 weeks. Within the sample used in this study, we found that doctors reported better mental health than nurses across a range of measures. CONCLUSIONS: We found substantial rates of probable mental health disorders, and thoughts of self-harm, amongst ICU staff; these difficulties were especially prevalent in nurses. Whilst further work is needed to better understand the real level of clinical need amongst ICU staff, these results indicate the need for a national strategy to protect the mental health, and decrease the risk of functional impairment, of ICU staff whilst they carry out their essential work during COVID-19.

An investigation of the effect of temperature on the oxidation processes of metallic diesel engine fuel system materials and B100 biodiesel from used cooking oil in exposure testing.

Biodiesel is increasingly being used in automotive and other engine applications because of its potential to contribute to the reduction of CO2 and other harmful emissions. However, biodiesel is known to be more corrosive in contact with metallic components than petroleum diesel. This work explores the corrosion of aluminium, steel, brass and copper metallic coupons exposed to B100 biodiesel at 25, 80, 90, 100, 110 and 120 °C. The metals that were chosen are commonly found in automotive engines. The B100 in each experiment was sampled at 48, 100, 150, 200 and 270 h and examined by GCMS to determine compositional changes. It was found that corrosion rates for copper were 10x faster than brass and approximately 100x faster than for mild steel, Al7075 and Al1050. Activation energies for corrosion were calculated from mass loss and ICP, with good correlation between the two methods for Cu containing samples. By mass loss, the activation energies for Cu, Brass, Al7075 and Al1050 were calculated to be -47.9 kJ mol-1, -85.4 kJ mol-1, -86.7 kJ mol-1 and -54.4 kJ mol-1, respectively. By ICP analysis, the activation energies for Cu, Brass, and Al7075 were calculated to be -57.9 kJ mol-1, -90 kJ mol-1 and -140 kJ mol-1, respectively. Corrosion rates in brass and copper samples were faster owing to the direct reaction of copper with the fatty acid. The copper was found to cause chain scission and greater degradation of the biodiesel.

Psychological impact of infectious disease outbreaks on pregnant women: rapid evidence review.

OBJECTIVES: Infectious disease outbreaks can be distressing for everyone, especially those deemed to be particularly vulnerable such as pregnant women, who have been named a high-risk group in the current COVID-19 pandemic. This paper aimed to summarise existing literature on the psychological impact of infectious disease outbreaks on women who were pregnant at the time of the outbreak. STUDY DESIGN: The design of this study is a rapid review. METHODS: Five databases were searched for relevant literature, and main findings were extracted. RESULTS: Thirteen articles were included in the review. The following themes were identified: negative emotional states; living with uncertainty; concerns about infection; concerns about and uptake of prophylaxis or treatment; disrupted routines; non-pharmaceutical protective behaviours; social support; financial and occupational concerns; disrupted expectations of birth, prenatal care and postnatal care and sources of information. CONCLUSIONS: Pregnant women have unique needs during infectious disease outbreaks and could benefit from up-to-date, consistent information and guidance; appropriate support and advice from healthcare professionals, particularly with regards to the risks and benefits of prophylaxis and treatment; virtual support groups and designating locations or staff specifically for pregnant women.

Evaluating a pilot mental health awareness for managers' training course.

BACKGROUND: Despite the substantial personal and economic consequences of mental ill-health, and the relationship between mental ill-health and poor management provision, further work is needed to provide a robust evaluation of employment interventions to address mental ill-health in the workplace. AIMS: To provide a pilot service evaluation of a UK organization's mental health awareness for managers' training provision. METHODS: Participants were 93 employees at a UK-based organization who attended one of the three different types of, independently facilitated, half-day training courses designed to raise managers' awareness and understanding of mental health. All participants were asked to complete three questionnaires (one prior to the training session, one immediately following the training session and one 3 months after the training session). Each questionnaire contained six questions concerning participants' awareness of mental ill-health, and their confidence in dealing with mental ill-health among employees. RESULTS: Participants reported feeling more aware of mental ill-health at work and more confident in their ability to address mental ill-health among their employees after attending mental health awareness for managers' training. CONCLUSIONS: Although further work is needed to explore the efficacy of different types of training, the results of our pilot evaluation alongside the extant literature suggest that workplace interventions can have positive implications for good mental health.

Interictal epileptiform discharges impair word recall in multiple brain areas.

OBJECTIVES: Interictal epileptiform discharges (IEDs) have been linked to memory impairment, but the spatial and temporal dynamics of this relationship remain elusive. In the present study, we aim to systematically characterize the brain areas and times at which IEDs affect memory. METHODS: Eighty epilepsy patients participated in a delayed free recall task while undergoing intracranial electroencephalography (EEG) monitoring. We analyzed the locations and timing of IEDs relative to the behavioral data in order to measure their effects on memory. RESULTS: Overall IED rates did not correlate with task performance across subjects (r = 0.03, p = 0.8). However, at a finer temporal scale, within-subject memory was negatively affected by IEDs during the encoding and recall periods of the task but not during the rest and distractor periods (p < 0.01, p < 0.001, p = 0.3, and p = 0.8, respectively). The effects of IEDs during encoding and recall were stronger in the left hemisphere than in the right (p < 0.05). Of six brain areas analyzed, IEDs in the inferior-temporal, medial-temporal, and parietal areas significantly affected memory (false discovery rate < 0.05). SIGNIFICANCE: These findings reveal a network of brain areas sensitive to IEDs with key nodes in temporal as well as parietal lobes. They also demonstrate the time-dependent effects of IEDs in this network on memory.

Mixed contact methods to improve response to a postal questionnaire.

BACKGROUND: Postal questionnaires remain an important method of collecting data in trials. However, a high non-response rate can lead to biases, which may undermine the validity of the study. AIMS: To assess a simple method of trying to improve response rates in an occupational health trial evaluating an intervention to prevent hand dermatitis in nurses. METHODS: The trial employed questionnaires at t = 0, t = 1 month and t = 12 months. The t = 1 month questionnaire was posted to study participants (student and intensive care nurses) together with a free postage reply envelope. After 2 weeks, an e-mail was sent to non-responders reinforcing the need for completed questionnaires to be returned. Two weeks later, non-responders were sent another hard copy of the questionnaire, along with an accompanying letter. Six weeks after posting the initial questionnaires, non-responders were sent an SMS text message or were telephoned to remind them to return the questionnaire. RESULTS: The response rates for the 744 student nurses were 8% (no reminder), 27% (after first reminder), 22% (after second reminder) and 27% (after the third reminder), resulting in a response rate of 63%. The response rates for the 959 intensive care nurses were 9% (no reminder), 24% (after first reminder), 24% (after second reminder) and 31% (after third reminder), resulting in a final response rate of 63%. CONCLUSIONS: We found that a series of regular reminders including a third, personalized reminder by SMS text or telephone had a positive impact on non-responders.

Variation in Utilization and Need for Tympanostomy Tubes across England and New England.

OBJECTIVES: To compare rates of typmanostomy tube insertions for otitis media with effusion with estimates of need in 2 countries. STUDY DESIGN: This cross-sectional analysis used all-payer claims to calculate rates of tympanostomy tube insertions for insured children ages 2-8 years (2007-2010) across pediatric surgical areas (PSA) for Northern New England (NNE; Maine, Vermont, and New Hampshire) and the English National Health Service Primary Care Trusts (PCT). Rates were compared with expected rates estimated using a Monte Carlo simulation model that integrates clinical guidelines and published probabilities of the incidence and course of otitis media with effusion. RESULTS: Observed rates of tympanostomy tube placement varied >30-fold across English PCT (N = 150) and >3-fold across NNE PSA (N = 30). At a 25 dB hearing threshold, the overall difference in observed to expected tympanostomy tubes provided was -3.41 per 1000 child-years in England and -0.01 per 1000 child-years in NNE. Observed incidence of insertion was less than expected in 143 of 151 PCT, and was higher than expected in one-half of the PSA. Using a 20 dB hearing threshold, there were fewer tube insertions than expected in all but 2 England and 7 NNE areas. There was an inverse relationship between estimated need and observed tube insertion rates. CONCLUSIONS: Regional variations in observed tympanostomy tube insertion rates are unlikely to be due to differences in need and suggest overall underuse in England and both overuse and underuse in NNE.

A scoping review of behavioural science approaches and frameworks for health protection and emergency response.

AIMS: Rapid intervention development, implementation, and evaluation are required for emergency public health contexts, such as the recent COVID-19 pandemic. A novel Agile Co-production and Evaluation (ACE) framework has been developed to assist this endeavour in future public health emergencies. This scoping review aimed to map available behavioural science resources that can be used to develop and evaluate public health guidance, messaging, and interventions in emergency contexts onto components of ACE: rapid development and implementation, co-production with patients or the public including seldom heard voices from diverse communities, and inclusion of evaluation. METHODS: A scoping review methodology was used. Searches were run on MEDLINE, EMBASE, PsycINFO, and Google, with search terms covering emergency response and behavioural science. Articles published since 2014 and which discussed a framework or guidance for using behavioural science in response to a public health emergency were included. A narrative synthesis was conducted. RESULTS: Seventeen records were included in the synthesis. The records covered a range of emergency contexts, the most frequent of which were COVID-19 (n = 7) and non-specific emergencies (n = 4). One record evaluated existing approaches, 6 proposed new approaches, and 10 described existing approaches. Commonly used approaches included the Behavioural Change Wheel; Capability, Opportunity, and Motivation Behaviour model; and social identity theory. Three records discuss co-production with the target audience and consideration of diverse populations. Four records incorporate rapid testing, evaluation, or validation methods. Six records state that their approaches are designed to be implemented rapidly. No records cover all components of ACE. CONCLUSION: We recommend that future research explores how to create guidance involving rapid implementation, co-production with patients or the public including seldom heard voices from diverse communities, and evaluation.

A quantitative descriptive study of the prevalence of carriage (colonisation) of haemolytic streptococci groups A, B, C and G in pregnancy.

Invasive group B streptococcus (GBS) disease is a leading cause of neonatal death. There is no UK national screening programme for GBS in pregnancy, hence colonisation rates are unknown. Intrapartum antibiotic prophylaxis is given during labour to colonised women to reduce neonatal GBS transmission and subsequent invasive infection. Data about prevalence of other haemolytic streptococci in pregnancy, including group A streptococcus (GAS), are uncommon despite increasing importance. This study investigated colonisation in 100 pregnant women using conventional culture methods; 19% had GBS. This suggests that GBS carriage is common in the UK. The role of other ß-haemolytic streptococci remains undefined.

Nocardia cyriacigeorgica Brain and Lung Abscesses in 77-Year-Old Man With Diabetes.

Nocardia species are difficult to identify, saprophytic, aerobic actinomycetes that are associated with high mortality rates and primarily affect immunocompromised hosts. Recently, the number ofdiagnoses of Nocardia cyriacigeorgica has grown in the United States, yet complicated clinical diagnosis and costly identification methods presume an underestimation of its presence in patients. We describe a case of brain abscess secondary to a pulmonary infection in an elderly, diabetic, Afghani man with an extensive history of chewing tobacco use.

INFORMATION CONTENT OF HIGH-ORDER ASSOCIATIONS OF THE HUMAN GUT MICROBIOTA NETWORK.

The human gastrointestinal tract is an environment that hosts an ecosystem of microorganisms essential to human health. Vital biological processes emerge from fundamental inter- and intra-species molecular interactions that influence the assembly and composition of the gut microbiota ecology. Here we quantify the complexity of the ecological relationships within the human infant gut microbiota ecosystem as a function of the information contained in the nonlinear associations of a sequence of increasingly-specified maximum entropy representations of the system. Our paradigm frames the ecological state, in terms of the presence or absence of individual microbial ecological units that are identified by amplicon sequence variants (ASV) in the gut microenvironment, as a function of both the ecological states of its neighboring units and, in a departure from standard graphical model representations, the associations among the units within its neighborhood. We characterize the order of the system based on the relative quantity of statistical information encoded by high-order statistical associations of the infant gut microbiota.

Identification of microbial interaction network: zero-inflated latent Ising model based approach.

BACKGROUND: Throughout their lifespans, humans continually interact with the microbial world, including those organisms which live in and on the human body. Research in this domain has revealed the extensive links between the human-associated microbiota and health. In particular, the microbiota of the human gut plays essential roles in digestion, nutrient metabolism, immune maturation and homeostasis, neurological signaling, and endocrine regulation. Microbial interaction networks are frequently estimated from data and are an indispensable tool for representing and understanding the conditional correlation between the microbes. In this high-dimensional setting, zero-inflation and unit-sum constraint for relative abundance data pose challenges to the reliable estimation of microbial interaction networks. METHODS AND RESULTS: To identify the microbial interaction network, the zero-inflated latent Ising (ZILI) model is proposed which assumes the distribution of relative abundance relies only on finite latent states and provides a novel way to solve issues induced by the unit-sum and zero-inflation constrains. A two-step algorithm is proposed for the model selection of ZILI. ZILI is evaluated through simulated data and subsequently applied to an infant gut microbiota dataset from New Hampshire Birth Cohort Study. The results are compared with results from Gaussian graphical model (GGM) and dichotomous Ising model (DIS). Providing ZILI is the true data-generating model, the simulation studies show that the two-step algorithm can identify the graphical structure effectively and is robust to a range of parameter settings. For the infant gut microbiota dataset, the final estimated networks from GGM and ZILI turn out to have significant overlap in which the ZILI tends to select the sparser network than those from GGM. From the shared subnetwork, a hub taxon Lachnospiraceae is identified whose involvement in human disease development has been discovered recently in literature. CONCLUSIONS: Constrains induced by relative abundance of microbiota such as zero inflation and unit sum render the conditional correlation analysis unreliable for conventional methods such as GGM. The proposed optimal categoricalization based ZILI model provides an alternative yet elegant way to deal with these difficulties. The results from ZILI have reasonable biological interpretation. This model can also be used to study the microbial interaction in other body parts.

Alterations in glucocorticoid negative feedback following maternal Pb, prenatal stress and the combination: a potential biological unifying mechanism for their corresponding disease profiles.

Combined exposures to maternal lead (Pb) and prenatal stress (PS) can act synergistically to enhance behavioral and neurochemical toxicity in offspring. Maternal Pb itself causes permanent dysfunction of the body's major stress system, the hypothalamic pituitary adrenal (HPA) axis. The current study sought to determine the potential involvement of altered negative glucocorticoid feedback as a mechanistic basis of the effects in rats of maternal Pb (0, 50 or 150 ppm in drinking water beginning 2 mo prior to breeding), prenatal stress (PS; restraint on gestational days 16-17) and combined maternal Pb+PS in 8 mo old male and female offspring. Corticosterone changes were measured over 24 h following an i.p. injection stress containing vehicle or 100 or 300 microg/kg (females) or 100 or 150 microg/kg (males) dexamethasone (DEX). Both Pb and PS prolonged the time course of corticosterone reduction following vehicle injection stress. Pb effects were non-monotonic, with a greater impact at 50 vs. 150 ppm, particularly in males, where further enhancement occurred with PS. In accord with these findings, the efficacy of DEX in suppressing corticosterone was reduced by Pb and Pb+PS in both genders, with Pb efficacy enhanced by PS in females, over the first 6 h post-administration. A marked prolongation of DEX effects was found in males. Thus, Pb, PS and Pb+PS, sometimes additively, produced hypercortisolism in both genders, followed by hypocortisolism in males, consistent with HPA axis dysfunction. These findings may provide a plausible unifying biological mechanism for the reported links between Pb exposure and stress-associated diseases and disorders mediated via the HPA axis, including obesity, hypertension, diabetes, anxiety, schizophrenia and depression. They also suggest broadening of Pb screening programs to pregnant women in high stress environments.

Influence of low level maternal Pb exposure and prenatal stress on offspring stress challenge responsivity.

We previously demonstrated potentiated effects of maternal Pb exposure producing blood Pb(PbB) levels averaging 39microg/dl combined with prenatal restraint stress (PS) on stress challenge responsivity of female offspring as adults. The present study sought to determine if: (1) such interactions occurred at lower PbBs, (2) exhibited gender specificity, and (3) corticosterone and neurochemical changes contributed to behavioral outcomes. Rat dams were exposed to 0, 50 or 150ppm Pb acetate drinking water solutions from 2 mos prior to breeding through lactation (pup exposure ended at weaning; mean PbBs of dams at weaning were <1, 11 and 31microg/dl, respectively); a subset in each Pb group underwent prenatal restraint stress (PS) on gestational days 16-17. The effects of variable intermittent stress challenge (restraint, cold, novelty) on Fixed Interval (FI) schedule controlled behavior and corticosterone were examined in offspring when they were adults. Corticosterone changes were also measured in non-behaviorally tested (NFI) littermates. PS alone was associated with FI rate suppression in females and FI rate enhancement in males; Pb exposure blunted these effects in both genders, particularly following restraint stress. PS alone produced modest corticosterone elevation following restraint stress in adult females, but robust enhancements in males following all challenges. Pb exposure blunted these corticosterone changes in females, but further enhanced levels in males. Pb-associated changes showed linear concentration dependence in females, but non-linearity in males, with stronger or selective changes at 50ppm. Statistically, FI performance was associated with corticosterone changes in females, but with frontal cortical dopaminergic and serotonergic changes in males. Corticosterone changes differed markedly in FI vs. NFI groups in both genders, demonstrating a critical role for behavioral history and raising caution about extrapolating biochemical markers across such conditions. These findings demonstrate that maternal Pb interacts with prenatal stress to further modify both behavioral and corticosterone responses to stress challenge, thereby suggesting that studies of Pb in isolation from other disease risk factors will not reveal the extent of its adverse effects. These findings also underscore the critical need to extend screening programs for elevated Pb exposure, now restricted to young children, to pregnant, at risk, women.