School Greenness and Student-Level Academic Performance: Evidence From the Global South.

Greenspace in schools might enhance students' academic performance. However, the literature-dominated by ecological studies at the school level in countries from the Northern Hemisphere-presents mixed evidence of a beneficial association. We evaluated the association between school greenness and student-level academic performance in Santiago, Chile, a capital city of the Global South. This cross-sectional study included 281,695 fourth-grade students attending 1,498 public, charter, and private schools in Santiago city between 2014 and 2018. Student-level academic performance was assessed using standardized test scores and indicators of attainment of learning standards in mathematics and reading. School greenness was estimated using Normalized Difference Vegetation Index (NDVI). Linear and generalized linear mixed-effects models were fit to evaluate associations, adjusting for individual- and school-level sociodemographic factors. Analyses were stratified by school type. In fully adjusted models, a 0.1 increase in school greenness was associated with higher test scores in mathematics (36.9 points, 95% CI: 2.49; 4.88) and in reading (1.84 points, 95% CI: 0.73; 2.95); as well as with higher odds of attaining learning standards in mathematics (OR: 1.20, 95% CI: 1.12; 1.28) and reading (OR: 1.07, 95% CI: 1.02; 1.13). Stratified analysis showed differences by school type, with associations of greater magnitude and strength for students attending public schools. No significant associations were detected for students in private schools. Higher school greenness was associated with improved individual-level academic outcomes among elementary-aged students in a capital city in South America. Our results highlight the potential of greenness in the school environment to moderate educational and environmental inequalities in urban areas.

Critical windows of susceptibility for the effects of prenatal exposure to heat and heat variability on gestational growth.

BACKGROUND: Studies have shown that prenatal heat exposure may impact fetal growth, but few studies have examined the critical windows of susceptibility. As extreme heat events and within season temperature variability is expected to increase in frequency, it is important to understand how this may impact gestational growth. OBJECTIVES: We investigated associations between various measures of weekly prenatal heat exposure (mean and standard deviation (SD) of temperature and heat index (HI), derived using temperature in °C and dew point) and term birthweight or odds of being born small for gestational age (SGA) to identify critical windows of susceptibility. METHODS: We analyzed data from mother-child dyads (n = 4442) in the Boston-based Children's HealthWatch cohort. Birthweights were collected from survey data and electronic health records. Daily temperature and HI values were obtained from 800 m gridded spatial climate datasets aggregated by the PRISM Climate Group. Distributed lag-nonlinear models were used to assess the effect of the four weekly heat metrics on measures of gestational growth (birthweight, SGA, and birthweight z-scores). Analyses were stratified by child sex and maternal homelessness status during pregnancy. RESULTS: HI variability was significantly associated with decreased term birthweight during gestational weeks 10-29 and with SGA for weeks 9-26. Cumulative effects for these time periods were -287.4 g (95% CI: -474.1 g, -100.8 g for birthweight and 4.7 (95% CI: 1.6, 14.1) for SGA. Temperature variability was also significantly associated with decreased birthweight between weeks 15 and 26. The effects for mean heat measures on term birthweight and SGA were not significant for any gestational week. Stratification by sex revealed a significant effect on term birthweight in females between weeks 23-28 and in males between weeks 9-26. Strongest effects of HI variability on term birthweight were found in children of mothers who experienced homelessness during pregnancy. Weekly HI variability was the heat metric most strongly associated with measures of gestational growth. The effects observed were largest in males and those who experienced homelessness during pregnancy. DISCUSSION: Given the impact of heat variability on birthweight and risk of SGA, it is important for future heat warnings to incorporate measure of heat index and temperature variability.

Host gut resistome in Gulf War chronic multisymptom illness correlates with persistent inflammation.

Chronic multisymptom illness (CMI) affects a subsection of elderly and war Veterans and is associated with systemic inflammation. Here, using a mouse model of CMI and a group of Gulf War (GW) Veterans' with CMI we show the presence of an altered host resistome. Results show that antibiotic resistance genes (ARGs) are significantly altered in the CMI group in both mice and GW Veterans when compared to control. Fecal samples from GW Veterans with persistent CMI show a significant increase of resistance to a wide class of antibiotics and exhibited an array of mobile genetic elements (MGEs) distinct from normal healthy controls. The altered resistome and gene signature is correlated with mouse serum IL-6 levels. Altered resistome in mice also is correlated strongly with intestinal inflammation, decreased synaptic plasticity, reversible with fecal microbiota transplant (FMT). The results reported might help in understanding the risks to treating hospital acquired infections in this population.

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals.

Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelopmental outcomes in offspring. US federal risk assessments rely almost exclusively on apical endpoints in animal models for deriving points of departure (PODs). New approach methodologies (NAMs) such as high-throughput screening (HTS) and mechanistically informative in vitro human cell-based systems, combined with in vitro to in vivo extrapolation (IVIVE), supplement in vivo studies and provide an alternative approach to calculate/determine PODs. We examine how parameterization of IVIVE models impacts the comparison between IVIVE-derived equivalent administered doses (EADs) from thyroid-relevant in vitro assays and the POD values that serve as the basis for risk assessments. Pesticide chemicals with thyroid-based in vitro bioactivity data from the US Tox21 HTS program were included (n = 45). Depending on the model structure used for IVIVE analysis, up to 35 chemicals produced EAD values lower than the POD. A total of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVE-derived EAD values and the in vivo-derived POD values is highly dependent on model parameterization. Here, we derive a range of potentially thyroid-relevant doses that incorporate uncertainty in modeling choices and in vitro assay data.

Neuropsychological effects in children exposed to anticonvulsant monotherapy during gestation: Phenobarbital, carbamazepine, and phenytoin.

OBJECTIVE: Usage during pregnancy of the antiseizure medication (ASM), phenobarbital (PB), carbamazepine (CBZ), and phenytoin (PHT), has been associated with adverse pregnancy outcomes. While morphological effects on offspring are well-documented, inconsistent findings have been reported on neuropsychological development, possibly due to differences in attention to maternal demographics, and other design characteristics. Herein, we report the results of a carefully designed protocol used to examine the effects of gestational monotherapy with PB, CBZ, or PHT upon children's general mental abilities, when compared to age- and gender- matched children born to unexposed women of similar age, education, and socioeconomic status. METHODS: For each ASM, we selected qualifying cases from children born to PB, CBZ, or PHT monotherapy-exposed and unexposed women. Following the application of inclusion, exclusion, and matching criteria, our sample included 34 PB-exposed, 40 PHT-exposed, and 41 CBZ-exposed children along with matched unexposed children for each drug group. Criteria were applied through examination of maternal medical and educational histories, parental socioeconomic characteristics, and child's age and gender. Each child's physical and neuropsychological characteristics were examined, using standardized protocols. We report on the cognitive performance of the children as assessed by the Wechsler Intelligence Scale for Children - III (WISC-III), the leading measure of mental ability in the U.S. RESULTS: An overall mixed model ANOVA of the adjusted performance of the children across all groups controlling for maternal IQ revealed significant effects on verbal IQ, but not full-scale IQ or performance IQ. In the individual drug and unexposed group comparisons, only reduced verbal and full-scale IQ scores in PB-exposed versus matched unexposed children were found. Comparisons between drug groups revealed a significant reduction in verbal IQ and full-scale IQ in PB-exposed versus PHT-exposed children, but not in other drug-drug comparisons. SIGNIFICANCE: These results demonstrate effects on children's mental ability due to prenatal PB exposure, such that analyses adjusted for maternal IQ scores, revealed reduced verbal mental abilities and reduced full-scale IQ scores when scores in exposed children were compared to scores from children of the same age and sex born to demographically similar, healthy unexposed women. When comparisons were made between drug groups, children exposed prenatally to PB performed significantly worse than prenatally PHT-exposed children, but CBZ-exposed children's scores were not significantly different from those of PB or PHT-exposed groups. In light of shared effects on structural teratogenicity, these findings suggest that use of PB monotherapy for the management of seizures during pregnancy may be associated with increased risk in comparison to PHT when neurobehavioral functioning is considered, and that only PB-exposed children have reduced performance compared to matched controls. Attention to these effects is critical in the developing world where use of these older medications remains predominant, and prudent choices can be made to reduce impact on cognitive development.

Pre-pregnancy body mass index and parent and teacher-reported behavioral outcomes among offspring in childhood.

OBJECTIVE: Pre-pregnancy obesity has been linked to childhood neurodevelopmental outcomes, including autism and attention-deficit hyperactivity disorder. The aim of our study was to examine the association between pre-pregnancy body mass index (BMI) and scores on behavioral scales according to both mother and teacher report. METHODS: We conducted a longitudinal study of 469 mother-child pairs. Information on pre-pregnancy body mass index (BMI) was collected from standardized maternal interviews conducted after delivery and assessment of childhood behavioral problems was measured at 5-12 years of age according to maternal-report using the Child Behavior Checklist (CBCL) and teacher-report using the Teacher Report Form (TRF). Using normal pre-pregnancy BMI (18.5-24.9 kg/m2) as the reference (n = 305), we calculated adjusted mean differences (MD) for t-scores on broadband and syndrome scales of behavior for children of mothers with pre-pregnancy overweight (n = 101) or obese (n = 63) BMI. We also examined associations with scores in the clinical range using risk ratios (RR) and compared results across informants. To account for loss to follow-up between the initial interview and the childhood behavioral assessment, we weighted models using stabilized inverse probability weights. RESULTS: Pre-pregnancy obesity was associated with a mean increase in child's total behavior problem t-scores according to both mother and teacher report, after adjustment for confounders and weighted for loss to follow-up (MD: 0.7, 95% CI: -2.2, 3.6 on CBCL; MD: 3.1, 95% CI: 0.5, 5.7 on TRF), indicating poorer behavioral outcomes. Comparing the magnitude of associations between mother and teacher-report, mean differences for pre-pregnancy obesity and most behavioral problem scales were larger for teacher-reported outcomes than mother-reported outcomes. Pre-pregnancy obesity was associated with increased risks of externalizing behaviors in the clinical range regardless of informant (CBCL RR: 1.6, 95% CI: 0.8, 3.2 and TRF RR: 1.7, 95% CI: 0.8, 3.5). Pre-pregnancy obesity was also associated with increased risks of internalizing behaviors according to teacher-report (TRF RR: 2.6, 95% CI:1.5, 4.6). CONCLUSIONS: Pre-pregnancy obesity, compared to pre-pregnancy normal weight, is associated with generally higher scores on both mother and teacher reported childhood behavioral assessments, indicating an increased likelihood of behavioral problems.

Brain-Immune Interactions as the Basis of Gulf War Illness: Clinical Assessment and Deployment Profile of 1990-1991 Gulf War Veterans in the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990-1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S. sites that included clinical assessments, brain imaging, neuropsychological testing, and analyses of a broad range of immune and immunogenetic parameters. GWI cases were similar to controls on most demographic, military, and deployment characteristics although on average were two years younger, with a higher proportion of enlisted personnel vs. officers. Results of physical evaluation and routine clinical lab tests were largely normal, with few differences between GWI cases and healthy controls. However, veterans with GWI scored significantly worse than controls on standardized assessments of general health, pain, fatigue, and sleep quality and had higher rates of diagnosed conditions that included hypertension, respiratory and sinus conditions, gastrointestinal conditions, and current or lifetime depression and post-traumatic stress disorder. Among multiple deployment experiences/exposures reported by veterans, multivariable logistic regression identified just two significant GWI risk factors: extended use of skin pesticides in theater (adjusted OR = 3.25, p = 0.005) and experiencing mild traumatic brain injury during deployment (OR = 7.39, p = 0.009). Gulf War experiences associated with intense stress or trauma (e.g., participation in ground combat) were not associated with GWI. Data and samples from the GWIC project are now stored in a repository for use by GWI researchers. Future reports will present detailed findings on brain structure and function, immune function, and association of neuroimmune measures with characteristics of GWI and Gulf War service.

Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk.

Gulf War Illness (GWI) is a chronic multi-symptomatic illness that is associated with fatigue, pain, cognitive deficits, and gastrointestinal disturbances and presents a significant challenge to treat in clinics. Our previous studies show a role of an altered Gut-Brain axis pathology in disease development and symptom persistence in GWI. The present study utilizes a mouse model of GWI to study the role of a labdane diterpenoid andrographolide (AG) to attenuate the Gut-Brain axis-linked pathology. Results showed that AG treatment in mice (100 mg/kg) via oral gavage restored bacteriome alterations, significantly increased probiotic bacteria Akkermansia, Lachnospiraceae, and Bifidobacterium, the genera that are known to aid in preserving gut and immune health. AG also corrected an altered virome with significant decreases in virome families Siphoviridae and Myoviridae known to be associated with gastrointestinal pathology. AG treatment significantly restored tight junction proteins that correlated well with decreased intestinal proinflammatory mediators IL-1ß and IL-6 release. AG treatment could restore Claudin-5 levels, crucial for maintaining the BBB integrity. Notably, AG could decrease microglial activation and increase neurotrophic factor BDNF, the key to neurogenesis. Mechanistically, microglial conditioned medium generated from IL-6 stimulation with or without AG in a concentration similar to circulating levels found in the GWI mouse model and co-incubated with neuronal cells in vitro, decreased Tau phosphorylation and neuronal apoptosis. In conclusion, we show that AG treatment mitigated the Gut-Brain-Axis associated pathology in GWI and may be considered as a potential therapeutic avenue for the much-needed bench to bedside strategies in GWI.

Perchloroethylene and Dry Cleaning: It's Time to Move the Industry to Safer Alternatives.

Perchloroethylene (PERC) is the most common solvent used for dry cleaning in the United States. PERC is a reproductive toxicant, neurotoxicant, potential human carcinogen, and a persistent environmental pollutant. The Environmental Protection Agency is evaluating PERC under the Frank R. Lautenberg Chemical Safety for the 21st Century Act, which amended the Toxic Substances Control Act (amended TSCA), and has mandated that PERC dry cleaning machines be removed from residential buildings. Some local and state programs are also requiring or facilitating transitions to alternative cleaning technologies. However, the potential for these alternatives to harm human health and the environment is not well-understood. This review describes the issues surrounding the use of PERC and alternative solvents for dry cleaning while highlighting the lessons learned from a local government program that transitioned PERC dry cleaners to the safest current alternative: professional wet cleaning. Implications for future public health research and policy are discussed: (1) we must move away from PERC, (2) any transition must account for the economic instability and cultural aspects of the people who work in the industry, (3) legacy contamination must be addressed even after safer alternatives are adopted, and (4) evaluations of PERC alternatives are needed to determine their implications for the long-term health and sustainability of the people who work in the industry.

Urinary Isoflavones Levels in Relation to Serum Thyroid Hormone Concentrations in Female and Male Adults in the U.S. General Population.

Isoflavones are phytoestrogens found in plant-based foods and nutritional supplements. Experimental studies show a positive association between isoflavones and hypothyroidism, but epidemiological findings are conflicting. We used multivariable linear regression to examine the association between urinary isoflavone concentrations and serum thyroid hormone concentrations in the National Health and Nutrition Examination Survey (2007-2010). In this study, we found that Daidzein and O-DMA associations with free T4 were stronger among women: a 10-fold increase in daidzein was associated with a 3.2% (95% CI: 1.9%, 4.5%) increase in women and a 0.6% (95% CI: -1.7%, 0.6%) decrease in men and a 10-fold increase in O-DMA was related to a 2.0% (95% CI: 1.1%, 2.9%) increase in women and a 0.3% (95% CI: -1.2%, 0.5%) decrease in men. In this study, selected urinary isoflavone concentrations were associated with serum thyroid hormone concentration in a sex-dependent fashion.

Neuroimaging Markers for Studying Gulf-War Illness: Single-Subject Level Analytical Method Based on Machine Learning.

Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed that the severity of these symptoms often remain unchanged even years after the GW, and these veterans with GWI continue to have poorer general health and increased chronic medical conditions than their non-deployed counterparts. For better management and treatment of this condition, there is an urgent need for developing objective biomarkers that can help with simple and accurate diagnosis of GWI. In this study, we applied multiple neuroimaging techniques, including T1-weighted magnetic resonance imaging (T1W-MRI), diffusion tensor imaging (DTI), and novel neurite density imaging (NDI) to perform both a group-level statistical comparison and a single-subject level machine learning (ML) analysis to identify diagnostic imaging features of GWI. Our results supported NDI as the most sensitive in defining GWI characteristics. In particular, our classifier trained with white matter NDI features achieved an accuracy of 90% and F-score of 0.941 for classifying GWI cases from controls after the cross-validation. These results are consistent with our previous study which suggests that NDI measures are sensitive to the microstructural and macrostructural changes in the brain of veterans with GWI, which can be valuable for designing better diagnosis method and treatment efficacy studies.

Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model.

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1ß in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1ß, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.

Alterations in high-order diffusion imaging in veterans with Gulf War Illness is associated with chemical weapons exposure and mild traumatic brain injury.

The complex etiology behind Gulf War Illness (GWI) has been attributed to the combined exposure to neurotoxicant chemicals, brain injuries, and some combat experiences. Chronic GWI symptoms have been shown to be associated with intensified neuroinflammatory responses in animal and human studies. To investigate the neuroinflammatory responses and potential causes in Gulf War (GW) veterans, we focused on the effects of chemical/biological weapons (CBW) exposure and mild traumatic brain injury (mTBI) during the war. We applied a novel MRI diffusion processing method, Neurite density imaging (NDI), on high-order diffusion imaging to estimate microstructural alterations of brain imaging in Gulf War veterans with and without GWI, and collected plasma proinflammatory cytokine samples as well as self-reported health symptom scores. Our study identified microstructural changes specific to GWI in the frontal and limbic regions due to CBW and mTBI, and further showed distinctive microstructural patterns such that widespread changes were associated with CBW and more focal changes on diffusion imaging were observed in GW veterans with an mTBI during the war. In addition, microstructural alterations on brain imaging correlated with upregulated blood proinflammatory cytokine markers TNFRI and TNFRII and with worse outcomes on self-reported symptom measures for fatigue and sleep functioning. Taken together, these results suggest TNF signaling mediated inflammation affects frontal and limbic regions of the brain, which may contribute to the fatigue and sleep symptoms of the disease and suggest a strong neuroinflammatory component to GWI. These results also suggest exposures to chemical weapons and mTBI during the war are associated with different patterns of peripheral and central inflammation and highlight the brain regions vulnerable to further subtle microscale morphological changes and chronic signaling to nearby glia.

TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model.

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive. Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1ß and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro. Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.

Host Akkermansia muciniphila Abundance Correlates With Gulf War Illness Symptom Persistence via NLRP3-Mediated Neuroinflammation and Decreased Brain-Derived Neurotrophic Factor.

Neurological disorders are commonly reported among veterans who returned from the Gulf war. Veterans who suffer from Gulf War illness (GWI) complain of continued symptom persistence that includes neurological disorders, muscle weakness, headaches, and memory loss, that developed during or shortly after the war. Our recent research showed that chemical exposure associated microbial dysbiosis accompanied by a leaky gut connected the pathologies in the intestine, liver, and brain. However, the mechanisms that caused the symptoms to persist even 30 years after the war remained elusive to investigators. In this study, we used a rodent model of GWI to investigate the persistence of microbiome alterations, resultant chronic inflammation, and its effect on neurotrophic and synaptic plasticity marker BDNF. The results showed that exposure to GW chemicals (the pesticide permethrin and prophylactic drug pyridostigmine bromide) resulted in persistent pathology characterized by the low relative abundance of the probiotic bacteria Akkermansia muciniphila in the gut, which correlated with high circulatory HMGB1 levels, blood-brain barrier dysfunction, neuroinflammation and lowered neurotrophin BDNF levels. Mechanistically, we used mice lacking the NLRP3 gene to investigate this inflammasome's role in observed pathology. These mice had significantly decreased inflammation and a subsequent increase in BDNF in the frontal cortex. This suggests that a persistently low species abundance of Akkermansia muciniphila and associated chronic inflammation due to inflammasome activation might be playing a significant role in contributing to chronic neurological problems in GWI. A therapeutic approach with various small molecules that can target both the restoration of a healthy microbiome and decreasing inflammasome activation might have better outcomes in treating GWI symptom persistence.

Correction to: Occurrence of mental illness following prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study.

Following publication of the original article [1], the author reported that, because of a programming error, incorrect sentences and incorrect Table 3 has been published. The correct sentences and Table 3 are shown below.

Reproductive and developmental health effects of prenatal exposure to tetrachloroethylene-contaminated drinking water.

Tetrachloroethylene (PCE) is a common contaminant in both occupational and community settings. High exposure levels in the workplace have been shown to have adverse impacts on reproduction and development but few epidemiological studies have examined these effects at the lower levels commonly seen in community settings. We were presented with a unique opportunity to examine the reproductive and developmental effects of prenatal exposure to PCE-contaminated drinking water resulting from the installation of vinyl-lined water pipes in Massachusetts and Rhode Island from the late 1960s through 1980. This review describes the methods and findings of two community-based epidemiological studies, places their results in the context of the existing literature, and describes the strengths and challenges of conducting epidemiological research on a historical pollution episode. Our studies found that prenatal exposure to PCE-contaminated drinking water is associated with delayed time-to-pregnancy, and increased risks of placental abruption, stillbirths stemming from placental dysfunction, and certain birth defects. No associations were observed with pregnancy loss, birth weight, and gestational duration. Important strengths of this research included the availability of historical data on the affected water systems, a relatively high exposure prevalence and wide range of exposure levels, and little opportunity for recall bias and confounding. Challenges arose mainly from the retrospective nature of the exposure assessments. This research highlights the importance of considering pregnant women and their developing fetuses when monitoring, regulating, and remediating drinking water contaminants.

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology.

About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100ß/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence.

The Gut-Microbiome in Gulf War Veterans: A Preliminary Report.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting the central nervous system (CNS), immune and gastrointestinal (GI) systems of Gulf War veterans (GWV). We assessed the relationships between GWI, GI symptoms, gut microbiome and inflammatory markers in GWV from the Boston Gulf War Illness Consortium (GWIC). Three groups of GWIC veterans were recruited in this pilot study; GWV without GWI and no gastrointestinal symptoms (controls), GWV with GWI and no gastrointestinal symptoms (GWI-GI), GWV with GWI who reported gastrointestinal symptoms (GW+GI). Here we report on a subset of the first thirteen stool samples analyzed. Results showed significantly different gut microbiome patterns among the three groups and within the GWI +/-GI groups. Specifically, GW controls had a greater abundance of firmicutes and the GWI+GI group had a greater abundance of the phyla bacteroidetes, actinobacteria, euryarchaeota, and proteobacteria as well as higher abundances of the families Bacteroidaceae, Erysipelotrichaceae, and Bifidobacteriaceae. The GWI+GI group also showed greater plasma levels of the inflammatory cytokine TNF-RI and they endorsed significantly more chemical weapons exposure during the war and reported significantly greater chronic pain, fatigue and sleep difficulties than the other groups. Studies with larger samples sizes are needed to confirm these initial findings.

The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury.

The Gulf War Illness Consortium (GWIC) was designed to identify objective biomarkers of Gulf War Illness (GWI) in 1991 Gulf War veterans. The symptoms of GWI include fatigue, pain, cognitive problems, gastrointestinal, respiratory, and skin problems. Neurotoxicant exposures during deployment, such as pesticides, sarin, and pyridostigmine bromide pills have been identified as contributors to GWI. We have also found an association between mild traumatic brain injury (mTBI) and increased rates of GWI. However, the combined impact of these physical and chemical exposures has not yet been explored in GWI. The objective of this study was to examine both self-reported mTBI and exposure to chemical/biological weapons (CBW) as a multiple or two hit model for increased risk of GWI and other chronic health conditions. The study population included 125 Gulf War (GW) veterans from the Boston GWIC. Exposure to CBW was reported in 47.2% of the study population, and 35.2% reported sustaining a mTBI during the war. Results confirmed that those with both exposures (mTBI and CBW) had higher rates of comorbid chronic health conditions while rates of GWI were equivalent for mTBI and CBW or mTBI alone. The timing of exposure to mTBI was found to be strikingly different between those with GWI and those without it. Correspondingly, 42.3% of GWI cases reported experiencing a mTBI during military service while none of the controls did (p = 0.0002). Rates of mTBI before and after the war did not differ between the cases and controls. In addition, 54% of cases compared to 14.3% of controls (p = <0.001) reported being exposed to CBW during military service. The current study examined the relation of the separate and combined effects of exposure to mTBI and CBW in 1991 GW veterans. The findings from this study suggest that both exposure to mTBI and CBW are associated with the development of GWI and multiple chronic health conditions and that combined exposure appears to lead to higher risk of chronic health effects.