Heavy metals and trace elements in maternal blood and prevalence of congenital limb abnormalities among newborns: the Japan Environment and Children's Study.

BACKGROUND: Heavy metals such as lead (Pb) and cadmium (Cd) have been associated with adverse pregnancy and developmental outcomes, including congenital abnormalities. This study investigated the association between exposure to heavy metals and trace elements during fetal life and congenital limb abnormalities in infants. METHODS: This study is based on a prospective ongoing nationwide birth cohort from the Japan Environment and Children's Study (JECS). The concentrations of Cd, Pb, mercury (Hg), selenium (Se), and manganese (Mn) were measured in maternal blood collected during the mid-late trimesters. Inclusion criteria were available from questionnaires filled in during pregnancy, including information about congenital limb abnormalities at birth or at one month. To examine the associations with limb anomalies and individual chemicals, logistic regression models were applied following log-transformation or division into quartiles of Cd, Pb, Hg, Se, and Mn concentrations. To assess the associations with the heavy metals and trace elements mixture, quantile g-computation was employed. All models were adjusted for age, maternal smoking history, maternal alcohol intake, history of smoking, and infant sex. RESULTS: Data from 90,163 participants were included in the analysis, of whom 369 had congenital limb abnormalities in any of the collected information, and 89,794 had none. Among the 369 cases of congenital limb abnormalities, there were 185 and 142 cases of polydactyly and syndactyly, respectively. The median concentrations of Pb, Cd, Hg, Se, and Mn were 5.85, 0.66, 3.64, 168, and 15.3 ng/g, respectively. There were no associations between maternal blood concentrations of Pb [adjusted odd ratio = 0.83; 95% confidence interval = 0.61, 1.11], Cd [0.87; 0.68, 1.10], Hg [0.88; 0.73, 1.07], Se [1.07; 0.44, 2.59], and Mn [0.91; 0.64, 1.30] with congenital limb abnormalities. No significant association was observed between the mixture of heavy metals and trace elements [0.85; 0.72, 1.02] and any congenital limb abnormalities. Moreover, there was no association with all polydactylies and all syndactylies, or any type of abnormality as a subdivision. CONCLUSION: At the maternal exposure levels of Cd, Pb, Hg, Se, and Mn assessed in the present study, no association was identified with the risk of developing congenital limb abnormalities in children.

Hokkaido birth cohort study in Japan on the growth trajectory of children born with low birth weight until 7 years of age.

BACKGROUND: Low birth weight (LBW) is a significant global health concern with potential health risks and developmental implications for infants. Catch-up growth, an accelerated growth following an inhibition period, may partially compensate for growth deficits in LBW children. AIMS: This study investigated the prevalence of LBW and catch-up growth in height, weight, and body mass index (BMI) among LBW children in Japan, identified factors associated with LBW, and explored the potential for catch-up growth at different ages up to seven years. STUDY DESIGN AND SUBJECTS: The Hokkaido birth cohort study included 20,926 pregnant Japanese women recruited during their first trimester from 37 hospitals and clinics. Follow-up assessments were conducted in children up to seven years of age, tracking LBW children's growth and development using the Maternal and Child Health Handbook, and providing valuable insights into catch-up growth patterns. OUTCOME MEASURES: LBW was defined as a neonatal birth weight of <2500 g. The primary outcomes were catch-up growth in height, weight, and BMI at different ages. Z-scores were calculated to assess growth parameters with catch-up growth, defined as a change in z-score (> 0.67) between two time points. RESULTS AND CONCLUSIONS: A LBW was prevalent in 7.6 % of the cohort, which was lower than that reported in other Japanese studies. Among LBW children, 19.3 % achieved catch-up growth in height by age seven, and 10.6 % in weight. Catch-up growth in LBW children could partially offset these deficits. Further research will help understand the long-term outcomes and inform interventions for healthy development.

The association between prenatal per-and polyfluoroalkyl substance levels and Kawasaki disease among children of up to 4 years of age: A prospective birth cohort of the Japan Environment and Children's study.

Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children's Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence.

Suicidality in civilian women with PTSD: Possible link to childhood maltreatment, proinflammatory molecules, and their genetic variations.

Background: Posttraumatic stress disorder (PTSD) is a robust risk factor for suicide. Studies have suggested an association between suicide and elevated inflammatory markers, although such evidence in PTSD is scarce. Suicide risk, PTSD, and inflammatory molecules are all shown to be associated with childhood maltreatment and genetic factors. Methods: We examined the association between suicidal ideation/risk and inflammatory markers in 83 civilian women with PTSD, and explored the possible influence of childhood maltreatment and inflammatory genes. Suicidal ideation and risk were assessed using the Beck Depression Inventory-II and the Mini-International Neuropsychiatric Interview. Childhood maltreatment history was assessed with the Childhood Trauma Questionnaire (CTQ). Blood levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and high-sensitivity tumor necrosis factor-α were measured. Genetic polymorphisms of CRP rs2794520 and IL6 rs1800796 were genotyped. Results: Suicidal ideation was significantly positively correlated with hsCRP (p = 0.002) and IL-6 (p = 0.015) levels. Suicide risk weighted score was significantly positively correlated with hsCRP (p = 0.016) levels. The risk alleles of CRP rs2794520 and IL6 rs1800796 leading to increased respective protein levels were dose-dependently associated with higher risk of suicide (p = 0.007 and p = 0.029, respectively). The CTQ total score was significantly correlated with suicidal ideation and risk, but not with inflammatory marker levels. Furthermore, a multivariate regression analysis controlling for PTSD severity and potential confounders revealed that rs2794520 and rs1800796, but not hsCRP or IL-6 levels, significantly predicted suicidal ideation (p < 0.001) and risk (p = 0.007), respectively. Conclusion: Genetic variations within inflammatory genes might be useful in detecting PTSD patients at high risk of suicide.

Impact of prenatal exposure to mercury and selenium on neurodevelopmental delay in children in the Japan environment and Children's study using the ASQ-3 questionnaire: A prospective birth cohort.

Neurodevelopmental delay is associated with neurodevelopmental disorders. Prenatal metal exposure can potentially cause neurodevelopmental delays in children. This study examines whether prenatal exposure to mercury (Hg) and selenium (Se) is associated with the risk of neurodevelopmental delays in children up to 4 years of age. Children enrolled in a prospective birth cohort of the Japan Environment and Children's Study were examined. Hg and Se levels in maternal (nchild = 48,731) and cord (nchild = 3,083) blood were analyzed by inductively coupled plasma-mass spectrometry. Neurodevelopmental delays were assessed in children between the ages of 0.5 to 4 years using the Ages and Stages Questionnaires, Third Edition. The association between exposure and outcomes was examined using the generalized estimation equation models. In maternal blood, compared to participants with Se levels in the first quartile (83.0 to < 156 ng/g), the odds ratio (95 % confidence intervals) for problem-solving ability in children of mothers in the third (168 to < 181 ng/g) and fourth quartiles (181 to 976 ng/g) were 1.08 (1.01 to 1.14) and 1.10 (1.04 to 1.17), respectively. Furthermore, communication, gross and fine motor skills, and problem-solving delays were also observed. However, prenatal Hg levels in maternal and cord blood and Se levels in the latter were not associated with neurodevelopmental delays in children. Thus, the findings of this study suggest an association between Se levels in maternal blood and slightly increased risks of neurodevelopmental delays in children up to the age of 4 years.

Association between maternal caffeine intake during pregnancy and child development at 6 and 12 months: The Japan Environment and Children's Study.

BACKGROUND: Caffeine intake by pregnant women may have neurodevelopmental effects on the fetus due to adenosine antagonism. However, there are insufficient data and inconsistent results from epidemiological studies on the effect of maternal caffeine intake on child development. AIMS: This study examined the association between mothers' estimated caffeine intake during pregnancy and their children's score on the Japanese version of the Ages & Stages Questionnaires™ (J-ASQ) at 6 and 12 months of age. STUDY DESIGN: The study is a part of nationwide prospective birth-cohort study: the Japan Environment and Children's Study. SUBJECTS: In total, 87,106 participants with the Food Frequency Questionnaire (FFQ) data and J-ASQ at 6 or 12 months of age were included in the study. OUTCOME MEASURES: The data were analyzed by logistic regression analysis to determine whether the scores of the five subscales on the J-ASQ were below the cutoff point as the dependent variable. RESULTS: The results showed that children born to mothers who consumed >300 mg caffeine per day had a 1.11-fold increased odds of gross motor developmental delay at 12 months of age (adjusted odds ratio [AOR] = 1.114 [95 % CI: 1.013-1.226]). CONCLUSIONS: Issues in gross motor development can emerge prior to future developmental issues. Therefore, further studies on developmental outcomes in older children, including the future outcomes of the children who participated in this study, are needed.

Hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system in adulthood PTSD and childhood maltreatment history.

Accumulated evidence shows that psychological trauma and posttraumatic stress disorder (PTSD) are associated with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis. Besides the HPA axis hormones, recent evidence suggests that the renin-angiotensin-aldosterone (RAA) system and genetic factors may be involved in trauma/PTSD as well as in HPA axis regulation. This study attempted to better understand the HPA axis function in relation to PTSD and childhood maltreatment by simultaneously examining RAA system and genetic polymorphisms of candidate genes. Here we studied 69 civilian women with PTSD and 107 healthy control women without DSM-IV-based traumatic experience. Childhood maltreatment history was assessed with the Childhood Trauma Questionnaire. PTSD severity was assessed with the Posttraumatic Diagnostic Scale. Functional disability was assessed with the Sheehan Disability Scale. HPA axis was examined by measuring blood levels of cortisol, adrenocorticotropic hormone, and dehydroepiandrosterone-sulphate (DHEA-S). RAA system was examined by measuring blood renin and aldosterone levels. The FKBP5 rs1360780 and CACNA1C rs1006737 polymorphisms were genotyped. No significant differences were seen between patients and controls in any of the five hormone levels. DHEA-S levels were significantly negatively correlated with overall PTSD severity (p = 0.003) and functional disability (p = 0.008). A two-way analysis of variance with diagnostic groups and genotypes as fixed factors revealed that patients with the rs1006737 A-allele had significantly lower DHEA-S levels than patients with the GG genotype (p = 0.002) and controls with the A-allele (p = 0.006). Childhood maltreatment history was not significantly correlated with any of the five hormone levels. These results were generally unchanged after controlling for the potentially confounding effect of age, depression, and anxiety. Our findings suggest that lower DHEA-S levels could indicate more severe subtype of PTSD, the association of which might be partly modified by the CACNA1C polymorphism.

Association between the Concentrations of Metallic Elements in Maternal Blood during Pregnancy and Prevalence of Abdominal Congenital Malformations: The Japan Environment and Children's Study.

Abdominal congenital malformations are responsible for early mortality, inadequate nutrient intake, and infant biological dysfunction. Exposure to metallic elements in utero is reported to be toxic and negatively impacts ontogeny. However, no prior study has sufficiently evaluated the effects of exposure to metallic elements in utero on abdominal congenital malformations. The aim of the present study was to evaluate associations between metallic elements detected in maternal blood during pregnancy and congenital abdominal malformations. Data from participants in the Japan Environment and Children's Study was used in the present study, and contained information on singleton and live birth infants without congenital abnormalities (control: n = 89,134) and abdominal malformations (case: n = 139). Heavy metals such as mercury (Hg), lead (Pb), cadmium (Cd), and trace elements of manganese (Mn) and selenium (Se) were detected in maternal serum samples during mid- and late-gestation. Infant congenital abnormalities were identified from delivery records at birth or one month after birth by medical doctors. In a multivariate analysis adjusted to account for potential confounders, quartiles of heavy metals and trace elements present in maternal blood were not statistically correlated to the prevalence of abdominal congenital malformations at birth. This study is the first to reveal the absence of significant associations between exposure levels to maternal heavy metals and trace elements in utero and the prevalence of abdominal congenital malformations in a large cohort of the Japanese population. Further studies are necessary to investigate the impact of exposure to heavy metals and trace elements via maternal blood in offspring after birth.

Hypertensive Disorders during Pregnancy and Anthropometric Measurement of Children up to 7 Years of Age: The Hokkaido Birth Cohort Study in Japan.

Hypertensive disorders during pregnancy (HDP) increase the risk of offspring with a low birth weight, preterm birth and small-for-gestational age; however, evidence of the anthropometric measurements during early childhood remains limited. We aimed to understand the associations between maternal HDP and anthropometric measurements of children aged up to seven years in a Japanese cohort. In total, 20,926 mother-infant pairs participated in the Hokkaido Study on Environment and Children's Health, Japan, from 2002 to 2013. Medical reports were used to confirm HDP exposure, while weight, height, height z score, and weight z score were the outcomes. The prevalence of HDP in the study population was 1.7%. The birth height of male children born to HDP mothers was smaller as compared to those born to non-HDP mothers. When adjusted with covariates, the linear regressions showed significant changes in birth weight (ß: -79.3; 95% confidence interval [CI]: -154.8, -3.8), birth height (-0.67; 95% CI: -1.07, -0.26), weight at seven years (1.21; 95% CI: 0.13, 2.29), and weight gain between four and seven years (1.12; 95% CI: 0.28, 1.96) of male children exposed to HDP. Differences were more significant in male children than female. Our study showed that despite low birth weight, male children exposed to HDP caught up with their growth and gained more weight by seven years of age compared with male children not exposed to HDP, whereas no such differences were observed in female children; however, this finding requires replication.

Hokkaido birth cohort study on environment and children's health: cohort profile 2021.

BACKGROUND: The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco. METHODS: The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures. RESULTS: The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies. CONCLUSIONS: Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.

Hypertensive Disorders during Pregnancy (HDP), Maternal Characteristics, and Birth Outcomes among Japanese Women: A Hokkaido Study.

Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children's health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA (2.13; 95% Confidence Interval (CI): 1.57, 2.88), PTB (3.48; 95%CI: 2.68, 4.50), LBW (3.57; 95%CI: 2.83, 4.51) than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions.

The efficacy of memantine in the treatment of civilian posttraumatic stress disorder: an open-label trial.

Background: Currently, there is a paucity of pharmacological treatment options for posttraumatic stress disorder (PTSD), and the development of a novel pharmacotherapeutic approach has become a matter of great interest. Objective: We conducted a 12-week open-label clinical trial to examine the efficacy and safety of memantine, an N-methyl-D-aspartate receptor antagonist, in the treatment of civilian PTSD. Method: Thirteen adult patients with DSM-IV PTSD, all civilian women, were enrolled. They were monitored at an ambulatory care facility every week until 4 weeks and then every 4 weeks until 12 weeks. Memantine was added to each patient's current medication, with the initial dosage of 5 mg/day and then titrated. Concomitant medications were essentially kept unchanged during the trial. The primary outcome was PTSD diagnosis and severity assessed with the Posttraumatic Diagnostic Scale (PDS). Results: Of the 13 cases, one dropped out and two were discarded due to the protocol deviation, and the analysis was done for the remaining 10. Mean PDS total scores decreased from 32.3 ± 9.7 at baseline to 12.2 ± 7.9 at endpoint, which was statistically significant with a large effect (paired t-test: p = .002, d = 1.35); intrusion, avoidance, hyperarousal symptoms were all significantly improved from baseline to endpoint. Six patients no longer fulfilled the diagnostic criteria of PTSD at endpoint. Some adverse, but not serious, effects possibly related to memantine were observed, including sleep problems, sleepiness, sedation, weight change and hypotension. Conclusions: Memantine significantly reduced PTSD symptoms in civilian female PTSD patients and the drug was well tolerated. Future randomized controlled trials are necessary to verify the efficacy and safety of memantine in the treatment of PTSD.

Antecedentes: Actualmente, hay escasez de opciones de tratamiento farmacológico para el trastorno de estrés postraumático (TEPT), y el desarrollo de un enfoque farmacoterapéutico nuevo se ha transformado en materia de gran interés.Objetivo: Llevamos a cabo un ensayo clínico abierto de 12 semanas para examinar la eficacia y seguridad de memantina, un antagonista del receptor de N-metil-d-aspartato, en el tratamiento del TEPT en civiles.Método: Se inscribieron trece pacientes adultas con TEPT según DSM-IV, todas mujeres civiles. Fueron monitoreadas en un centro de atención ambulatoria semanalmente por 4 semanas, y luego cada 4 semanas hasta las 12 semanas. Se agregó memantina al tratamiento farmacológico actual de cada paciente, con dosis inicial de 5 mg/día y titulación posterior. Los fármacos concomitantes fueron mantenidos esencialmente sin cambios durante el estudio. El objetivo primario fue el diagnóstico de TEPT y su severidad, evaluada con la Escala de Diagóstico Postraumático (PDS, por su sigla en inglés).Resultados: De los 13 casos, uno abandonó y 2 fueron descartados debido a desvío del protocolo, y el análisis fue realizado con los 10 restantes. El puntaje total promedio de PDS disminuyó de 32.3 ± 9.7 en el basal a 12.2 ± 7.9 al término, lo que fue estadísticamente significativo con un tamaño de efecto grande (prueba t pareada: p=.002, d=1.35); los síntomas de intrusión, evitación e hiperactivación mejoraron todos en forma al término respecto a la basal. Seis pacientes dejaron de cumplir los criterios de TEPT al término. Se observaron algunos efectos adversos, pero no serios, posiblemente relacionados a memantina, que incluyeron problemas del sueño, somnolencia, sedación, cambios en el peso e hipotensión.Conclusiones: La memantina redujo significativamente los síntomas de TEPT en pacientes mujeres civiles con TEPT y el fármaco fue bien tolerado. Se requieren ensayos controlados aleatorizados en el futuro para verificar la eficacia y seguridad de la memantina en el tratamiento del TEPT.

Childhood maltreatment history and attention bias variability in healthy adult women: role of inflammation and the BDNF Val66Met genotype.

Childhood maltreatment has been associated with greater attention bias to emotional information, but the findings are controversial. Recently, a novel index of attention bias, i.e., attention bias variability (ABV), has been developed to better capture trauma-related attentional dysfunction. However, ABV in relation to childhood trauma has not been studied. Here, we examined the association of childhood maltreatment history with attention bias/ABV in 128 healthy adult women. Different types of childhood maltreatment were assessed with the Childhood Trauma Questionnaire. Attention bias/ABV was measured by the dot-probe task. Possible mechanisms whereby childhood maltreatment affects attention bias/ABV were also explored, focusing on blood proinflammatory markers and the BDNF Val66Met polymorphism. We observed a significant positive correlation between childhood emotional abuse and ABV (P = 0.002). Serum high-sensitivity tumor necrosis factor-α levels were significantly positively correlated with ABV (P < 0.001), but not with childhood maltreatment. Jonckheere-Terpstra trend test showed a significant tendency toward greater ABV with increasing numbers of the BDNF Met alleles (P = 0.021). A two-way analysis of variance further revealed that the genotype-by-emotional abuse interaction for ABV was significant (P = 0.022); individuals with the Val/Met and Met/Met genotypes exhibited even greater ABV when childhood emotional abuse was present. These results indicate that childhood emotional abuse can have a long-term negative impact on emotional attention control. Increased inflammation may be involved in the mechanism of ABV, possibly independently of childhood maltreatment. The BDNF Met allele may dose-dependently increase ABV by interacting with childhood emotional abuse.

Association of CRP genetic variation with symptomatology, cognitive function, and circulating proinflammatory markers in civilian women with PTSD.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with increased inflammation. C-reactive protein (CRP) is a marker of systemic inflammation, and recently, single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with increased blood CRP protein levels and illness severity in PTSD patients. However, the mechanism by which the CRP SNPs are involved in PTSD remains unclear. Here we investigated the association of CRP genetic variation with blood proinflammatory protein levels, symptomatology, and cognitive function, and further explored the moderating effect of childhood maltreatment history, in adult patients with PTSD. METHODS: Fifty-seven Japanese civilian women with PTSD and 73 healthy control women were enrolled. Three SNPs in the CRP gene, namely rs2794520, rs1130864, and rs3093059, were genotyped, and analyses focused on rs2794520 (T/C). Serum levels of high-sensitivity CRP (hsCRP), high-sensitivity tumor necrosis factor-α (hsTNF-α), and interleukin-6 were measured. PTSD symptoms were evaluated by the Posttraumatic Diagnostic Scale. Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status. Childhood maltreatment history was assessed by the Childhood Trauma Questionnaire. RESULTS: Patients with the rs2794520 CC/CT genotype, compared to those with the TT genotype, showed significantly higher levels of hsCRP (p=0.009) and hsTNF-α (p=0.001), more severe PTSD symptoms (p=0.036), and poorer cognitive function (p=0.018). A two-way analysis of variance revealed a significant genotype-by-maltreatment interaction for more severe PTSD avoidance symptom (p=0.012). LIMITATIONS: The relatively small sample size limited our findings. CONCLUSIONS: These findings may provide an insight into the etiology of PTSD from the inflammatory perspective.

Possible Long-Term Effects of Childhood Maltreatment on Cognitive Function in Adult Women With Posttraumatic Stress Disorder.

Accumulated evidence shows that individuals with posttraumatic stress disorder (PTSD) have compromised cognitive function. PTSD is associated with childhood maltreatment, which also can negatively affect cognitive function. It is therefore possible that cognitive dysfunction in adult patients with PTSD can be due at least partly to childhood maltreatment, although little is documented on this issue. Here we aimed to examine the possible effect of childhood maltreatment on cognitive function in adult patients with PTSD. A total of 50 women with DSM-IV PTSD and 94 healthy control women were enrolled. Most of the patients developed PTSD after experiencing interpersonal violence during adulthood. History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ). Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Compared to controls, patients reported significantly more experiences of all types of childhood maltreatment as assessed by the CTQ and showed significantly poorer performance on immediate memory, language, attention, and the total score of RBANS. In patients, sexual abuse scores were significantly negatively correlated with RBANS language (p < 0.001) and total score (p = 0.005). Further analyses revealed that PTSD patients with childhood sexual abuse had even poorer cognitive function than those without the abuse. In controls, no significant correlation was found between CTQ and RBANS scores. These results suggest that childhood maltreatment, specifically sexual abuse, may lead to persistent cognitive impairment in individuals with PTSD. Our findings might underscore the importance of early detection and intervention of childhood maltreatment, which will be achieved by careful observation of, and listening to, maltreated children in education and welfare scenes as well as clinical settings.

The BDNF Val66Met polymorphism affects negative memory bias in civilian women with PTSD.

Memory abnormalities are considered a core feature of posttraumatic stress disorder (PTSD). Studies attempting to quantify such memory dysfunction in PTSD have reported that individuals with this disorder exhibit selective memory bias toward negative material. The low expression Met allele of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with the aetiology of PTSD and with memory abnormalities. It is therefore possible that the BDNF Val66Met polymorphism can moderate the relationship between PTSD and memory bias. Here we examined this association in 50 civilian women with PTSD and 70 non-trauma-exposed healthy control women. All subjects were genotyped for the BDNF Val66Met (rs6265) polymorphism. Negative memory bias was assessed using a recognition memory task. Patients showed significantly greater negative memory bias compared to controls. In patients, negative memory bias significantly increased with increasing numbers of Met alleles; while no significant relationship was seen in controls. Further pairwise analyses revealed that patients with the Met allele had significantly greater negative memory bias than controls. These results suggest that the relationship between PTSD and negative memory bias can be moderated by the BDNF Val66Met polymorphism. More studies are needed to further clarify the relationship between this polymorphism and memory abnormalities in PTSD.

Proinflammatory status-stratified blood transcriptome profiling of civilian women with PTSD.

Etiology of posttraumatic stress disorder (PTSD) remains largely unknown. Studies have shown that a significant subset of patients with PTSD exhibit increased inflammation, suggesting that the understanding of this disorder could be facilitated by classifying these patients by inflammatory status. Here we performed a microarray-based blood transcriptome analysis on proinflammatory status-stratified Japanese civilian women with PTSD most of whom developed the disorder after experiencing interpersonal violence. By utilizing our previously identified cut-off serum interleukin-6 (IL-6) level that approximately corresponded to the median IL-6 level of our PTSD patients, we classified patients into those with high IL-6 levels and those with normal IL-6 levels (n = 16 for each). Transcriptome profiles of these 2 groups were compared with the profile of 16 age-matched healthy control women. Differentially expressed genes between high IL-6 patients and controls showed significant enrichment in a number of gene ontology terms and pathways primarily involved in immune/inflammatory responses, and their protein-protein interaction network was significantly enriched. In contrast, differentially expressed genes between normal IL-6 patients and controls showed significant enrichment in several gene ontology terms related to ion transport and neural function. The microarray data were confirmed by reverse transcription quantitative PCR. These findings illustrate the heterogeneous molecular mechanisms of PTSD within this relatively homogeneous sample in terms of sex, trauma type, and ethnicity, suggesting that peripheral proinflammatory status such as IL-6 levels could be a useful subtyping marker for this disorder. With further research, it is hoped that our findings will be translated into personalized medicine.

Relationships of blood proinflammatory markers with psychological resilience and quality of life in civilian women with posttraumatic stress disorder.

Individuals with posttraumatic stress disorder (PTSD) show low resilience and impaired quality of life (QOL). Accumulating evidence shows that PTSD is associated with increased inflammation. Studies suggest that inflammation can be a key mechanism underlying low resilience/QOL, but this relationship has been understudied in individuals with PTSD. Here, we investigated the association of blood proinflammatory markers with self-reported resilience and QOL in civilian women with PTSD. Fifty-six women with PTSD and 73 healthy control women participated in this study. Resilience was assessed using the Connor-Davidson Resilience Scale. QOL was assessed using the World Health Organization Quality of Life-BREF. Blood samples were collected for the measurement of three proinflammatory markers including interleukin-6 (IL-6), high-sensitivity tumor necrosis factor-α, and high-sensitivity C-reactive protein (hsCRP). Compared to controls, patients showed significantly higher IL-6 levels and lower resilience and QOL. In patients, IL-6 levels were significantly negatively correlated with resilience, and hsCRP levels were significantly negatively correlated with psychological QOL. These results show that increased levels of proinflammatory markers including IL-6 and hsCRP are associated with lower psychological resilience and QOL in PTSD patients. Our findings suggest that interventions and treatments targeting inflammation may aid in the recovery from PTSD and lead to better prognosis.

Memory bias and its association with memory function in women with posttraumatic stress disorder.

BACKGROUND: Memory abnormalities are among a central feature of posttraumatic stress disorder (PTSD). It is suggested that individuals with PTSD exhibit memory bias; while evidence shows poor memory function in these individuals. We aimed to examine memory bias in PTSD patients relative to controls and to explore an association between memory bias and memory function. METHODS: Forty-six women with DSM-IV PTSD, most of whom developed the disorder after interpersonal violence, and 68 non-trauma-exposed healthy control women were studied. Memory bias was assessed by a recognition memory task using negative, neutral, and positive words. Memory function was assessed by a standardized neuropsychological test battery. Depression and anxiety symptoms were assessed by self-report measures. RESULTS: Compared to controls, patients showed significantly greater negative bias scores (i.e., correctly recognized rates for negative words minus those for neutral words) and poorer memory function. Negative bias scores were significantly correlated with worse memory function in patients. When patients were divided into those with lower vs. normal memory function, the former patients had significantly greater negative bias than the latter patients and controls. Memory bias scores in patients were not significantly correlated with depression or anxiety symptoms, nor were they significantly different between patients with comorbid major depressive disorder and those without. LIMITATIONS: The cross-sectional design and absence of the trauma-exposed non-PTSD group limited our findings. CONCLUSIONS: PTSD patients have greater negative memory bias, which can be associated with poorer memory function. Our findings may provide an insight into the nature of memory abnormalities in PTSD.

Inflammatory markers and their possible effects on cognitive function in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) has been associated with increased inflammation, albeit with some controversy. Another key feature of PTSD is compromised function in wide-ranging cognitive domains. Increased peripheral inflammation can contribute to cognitive dysfunction, although this relationship has not been studied in patients with PTSD. Here, we examined blood inflammatory markers in adult patients with PTSD compared to healthy controls taking account of potentially confounding effects of childhood maltreatment and comorbid major depressive disorder (MDD), and explored the association between inflammation and cognition. We enrolled 40 women with PTSD, most of whom developed the disorder after interpersonal violence during adulthood, and 65 healthy control women. Diagnoses were made based on DSM-IV. History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Blood samples were collected for the measurement of 5 inflammatory markers including interleukin-6 (IL-6), soluble IL-6 receptor, interleukin-1ß, high-sensitivity tumor necrosis factor-α, and high-sensitivity C-reactive protein. Compared to controls, patients with PTSD showed significantly higher IL-6 levels (p = 0.009) and lower scores on all RBANS domains (all p < 0.01). IL-6 levels in patients were not significantly associated with the presence/absence of comorbid MDD or CTQ scores. IL-6 levels in patients were significantly negatively correlated with RBANS visuospatial construction (p = 0.046), language (p = 0.008), attention (p = 0.036) and total score (p = 0.008). These results suggest that elevated IL-6 is associated with PTSD and that the lower cognitive function in PTSD may be due at least partly to increased inflammation.