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There is compelling evidence for gradient effects of household income on school readiness. Potential mechanisms are described, yet the growth curve trajectory of maternal mental health in a child's early life has not been thoroughly investigated. We aimed to examine the relationships between household incomes, maternal mental health trajectories from antenatal to the postnatal period, and school readiness.
Prospective data from 505 mother–child dyads in a birth cohort in Singapore were used, including household income, repeated measures of maternal mental health from pregnancy to 2-years postpartum, and a range of child behavioural, socio-emotional and cognitive outcomes from 2 to 6 years of age. Antenatal mental health and its trajectory were tested as mediators in the latent growth curve models.
Household income was a robust predictor of antenatal maternal mental health and all child outcomes. Between children from the bottom and top household income quartiles, four dimensions of school readiness skills differed by a range of 0.52 (95% Cl: 0.23, 0.67) to 1.21 s.d. (95% CI: 1.02, 1.40). Thirty-eight percent of pregnant mothers in this cohort were found to have perinatal depressive and anxiety symptoms in the subclinical and clinical ranges. Poorer school readiness skills were found in children of these mothers when compared to those of mothers with little or no symptoms. After adjustment of unmeasured confounding on the indirect effect, antenatal maternal mental health provided a robust mediating path between household income and multiple school readiness outcomes (χ2 126.05, df 63, p < 0.001; RMSEA = 0.031, CFI = 0.980, SRMR = 0.034).
Pregnant mothers with mental health symptoms, particularly those from economically-challenged households, are potential targets for intervention to level the playing field of their children.
Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10−4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10−9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.
Studies have shown that mental health problems during pregnancy have adverse effects on fetal growth. The impact of depressive and anxiety symptoms during pregnancy on the fetus have not yet been examined in Singapore.
To examine the association between mental health problems during the second trimester of pregnancy on the quality of the pregnancy, reflected by birth weight and birth length of the newborn.
This study aims to understand the importance of mental health during pregnancy on the development of the child in an Asian population.
Preliminary data of a prospective cohort study of pregnant women (GUSTO), were followed from pregnancy onwards. At 26 weeks of the pregnancy, the Edinburgh Postnatal Depression Scale (EPDS), the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI) were administered. Data on birth parameters were collected from medical records.
Linear regression analyses of preliminary data show negative correlations between depressive symptoms measured with EPDS (n = 1025, P = 0.54), BDI (n = 1012, P = 0.001), and anxiety symptoms measured with STAI (n = 1023, P = 0.002) and birth length (corrected for gestational age and gender). No associations were found for birth weight.
There is an association between depressive and anxiety symptoms reported at the end of the second trimester of the pregnancy and birth length, but not birth weight, of the newborn. As it is known that fetal length increases mainly in the second trimester, it suggests that stress of the mother influences the development of the fetus during this trimester.
There is considerable variation in the prevalence of breastfeeding, which allows for investigation of factors that influence the initiation and duration of breastfeeding and its association with well being of the mother infant dyad.
To better understand factors that influence (1) maternal breastfeeding status and (2) the “effects” of breastfeeding on mothers and infants.
Participants (n = 170) derive from a longitudinal Canadian study “Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN)”, a project designed to understand the pre- and postnatal influences on maternal health and child social-emotional development. Mothers provided data on breastfeeding status, early life adversity, oxytocin gene and oxytocin gene receptor polymorphisms, depression/anxiety, infant temperament and maternal sensitivity.
Early life adversity associated with a shorter breastfeeding duration and higher maternal depression levels. The relation between mothers’ early adversity and the duration of breastfeeding was mediated by mothers’ depression level, but only in women carrying one variant of the oxytocin rs2740210 gene marker (CC genotype). Mothers who breastfeed at 3 months acted more sensitively towards their infants when they were 6 months old and they in turn had infants who at 18 months showed reduced negative affectivity.
Women who have been exposed to early adversity are “living with the past” and they are, to certain extent, protected or more vulnerable to depression, depending on their genotype. Breastfeeding associated with higher maternal sensitivity, which associated with decreased negative emotionality in the infant at 18 months. Our results help to clarify associations between early life experiences, breastfeeding, and the mother-infant relationship.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Maternal mental well being influences offspring development. Research suggests that an interplay between genetic and environmental factors underlies this familial transmission of mental disorders.
To explore an interaction between genetic and environmental factors to predict trajectories of maternal mental well being, and to examine whether these trajectories are associated with epigenetic modifications in mothers and their offspring.
We assessed maternal childhood trauma and rearing experiences, prenatal and postnatal symptoms of depression and stress experience from 6 to 72 months postpartum, and genetic and epigenetic variation in a longitudinal birth-cohort study (n = 262) (Maternal adversity, vulnerability and neurodevelopment project). We used latent class modeling to describe trajectories in maternal depressive symptoms, parenting stress, marital stress and general stress, taking polygenetic risk for major depressive disorder (MDD), a composite score for maternal early life adversities, and prenatal depressive symptoms into account.
Genetic risk for MDD associated with trajectories of maternal well being in the postpartum, conditional on the experience of early life adversities and prenatal symptoms of depression. We will explore whether these trajectories are also linked to DNA methylation patterns in mothers and their offspring. Preliminary analyses suggest that maternal early life adversities associate with offspring DNA methylation age estimates, which is mediated through maternal mental well being and maternal DNA methylation age estimates.
We found relevant gene-environment interactions associated with trajectories of maternal well being. Our findings inform research on mechanisms underlying familial transmission of vulnerability for psychopathology and might thus be relevant to prevention and early intervention programs.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Animal and human studies suggest that individual differences in maternal parenting behaviour are transmitted from one generation to the next.
This study aimed to examine potential psychosocial mechanisms underlying an intergenerational transmission of conceptualization of parenting, including affect, cognition, and parental support.
In a subsample of 201 first-time mothers participating in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project, we assessed maternal childhood rearing experiences, using the Parental Bonding Instrument and the Childhood Trauma Questionnaire. At 6 months postpartum, mothers completed questionnaires on parenting stress, symptoms of depression, internalization of maternal care regulation and current relationship with mother and father.
We found significant direct associations of maltreatment and rearing by the grandmother with parenting stress at 6 months. These associations were mediated through distinct psychosocial pathways: the association of maltreatment on higher parenting stress was fully mediated through more maternal symptoms of depression (z = 2.297; P = 022). The association between sub-optimal rearing provided by the mother and higher parenting stress was mediated through lower internalization of maternal care regulation (z = -2.155; P = 031) and to a lesser degree through more symptoms of depression (z = -1.842; P = 065). Finally, higher quality rearing by the grandfather was indirectly related to lower parenting stress through positive current relationship with the father (z = -2.617; P = 009).
There are distinct pathways by which early experiences manifest in parenting stress. By understanding the structure of dysregulated parenting, clinicians will have practical information to specifically target maternal motivation, social supports, and depressed mood to disrupt maladaptive parenting cognitions and practices.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Maternal and child health are intrinsically linked. With accumulating evidence over the past two decades supporting the developmental origins of health and diseases hypothesis, it is now widely recognised that nutrition in the first 1000 d sets the foundation for long-term health. Maternal diet before, during and after pregnancy can influence the developmental pathways of the fetus and lead to health consequences later in life. While maternal and infant mortality rates have declined significantly in the past two decades, the growing burden of obesity and chronic non-communicable diseases in women of reproductive age and children is on a rapid rise worldwide, in developed and developing countries. A key contributory factor is malnutrition, which is a consequence of consuming poor quality diets. Suboptimal macronutrient balance and micronutrient inadequacies can lead to undesirable maternal body composition and metabolism, in turn influencing the health of the mother and leading to longer-term metabolic and cognitive health consequences in the infant. The GUSTO (Growing Up in Singapore Towards healthy Outcomes) study, a mother–offspring multi-ethnic cohort study in Singapore, has contributed to this body of evidence over the past 10 years. This review will illustrate how nutritional epidemiological research through a birth cohort has illuminated the importance and urgency of maternal and child nutrition and health in a modern, industrialised setting. It underscores the importance of a number of critical nutrients during pregnancy, in combination with healthy dietary patterns and appropriate meal timing, for optimal maternal and child health.
Pro-vitamin A carotenoids namely α-, β-carotene and β-cryptoxanthin have potential roles in neurocognitive development, but current literature on these carotenoids mainly focused on preventing cognitive decline in the elderly. This study examined the associations of maternal plasma pro-vitamin A carotenoids concentrations with offspring cognitive development up to 54 months in the GUSTO mother-offspring cohort study.
Materials and Methods
Maternal plasma pro-vitamin A carotenoids concentrations at delivery were determined by ultra-performance liquid chromatography. At age 24 months, the Bayley Scales of Infant and Toddler Development (BSID-III) was used to assess children's development for the following domains: cognitive, receptive and expressive language, and fine and gross motor. At age 54 months, the Kaufman Brief Intelligence Test (KBIT-2) was used to assess children's verbal and non-verbal intelligence. Associations of maternal pro-vitamin A carotenoids with offspring cognitive development at each time point were examined in 419 mother-offspring pairs using linear regressions adjusted for confounders (e.g. maternal demographics, antenatal mental health and breastfeeding duration).
Median (IQR) maternal plasma concentrations (mg/L) were: α-carotene 0.052 (0.032–0.081), β-carotene 0.189 (0.134–0.286), and β-cryptoxanthin 0.199 (0.123–0.304). In 24 months old infants, higher maternal β-cryptoxanthin (per SD increment) were associated with higher scores in most of BSID-III domains: cognitive [β 0.18, (0.08, 0.28) SD], receptive language [β 0.17 (0.07, 0.27) SD], fine motor [β 0.16 (0.06, 0.27) SD], and gross motor [β 0.16 (0.06, 0.27) SD]. Additionally, a 1-SD increment in maternal β-carotene concentrations were associated with 0.16 SD higher scores in BSID-III cognitive domain (95%: 0.04, 0.28), which was attenuated after adjusting for breastfeeding duration. No significant associations were observed between maternal α-carotene concentrations and BSID-III in children at 24 months of age, or between maternal pro-vitamin A carotenoids and KBIT-2 in children at 54 months of age.
Our study provides novel data suggesting a role of maternal pro-vitamin A carotenoids, especially β-cryptoxanthin, in offspring early cognitive development. This adds support to the importance of consuming sufficient amounts of red- and orange-coloured fruit and vegetables (rich sources of β-cryptoxanthin and β-carotene) during pregnancy. Further studies are required in other mother-offspring cohort with larger sample sizes, and intervention trials to confirm an effect of pro-vitamin A carotenoids on neurocognitive development.
Evidence on long-term influences of maternal vitamin B12 deficiency or concentrations on infant cognition is limited. We examined associations between maternal plasma vitamin B12 and cognitive development in 24-month-old infants. Maternal plasma vitamin B12 concentrations were measured at 26–28 weeks’ gestation; infant cognitive development was assessed with the Bayley Scales of Infant and Toddler Development-III at 24 months, for 443 mother–infant pairs from the Growing Up in Singapore Towards Healthy Outcomes cohort. Linear regressions adjusted for key confounders examined associations of maternal vitamin B12 with cognitive, receptive and expressive language, fine and gross motor subscales. Co-occurrence of maternal vitamin B12 with folate or vitamin B6 insufficiencies on child’s cognition was explored. Average maternal plasma vitamin B12 concentrations was 220·5 ± 80·5 pmol/l; 15 % and 41 % of mothers were vitamin B12 deficient (<148 pmol/l) and insufficient (148–220·9 pmol/l), respectively. Infants of mothers with vitamin B12 deficiency had 0·42 (95 % CI −0·70, −0·14) sd lower cognitive scores, compared with infants of mothers with sufficient vitamin B12. Co-occurrence of maternal vitamins B12 and B6 insufficiencies was associated with 0·37 (95 % CI −0·69, −0·06) sd lower cognitive scores in infants compared with infants of mothers sufficient in both vitamins. No significant associations were observed with other subscales. Study findings suggest the possible need to ensure adequate vitamin B12 during pregnancy. The impact of co-occurrence of maternal B-vitamins insufficiencies on early cognitive development warrants further investigation.
Background: Topiramate is an antiepileptic frequently used in pediatrics with multiple mechanisms of action. This includes carbonic anhydrase inhibition, which has unclear relevance to its antiepileptic effect. Metabolic acidosis, hypocitraturia and nephrolithiasis are known side-effects of carbonic anhydrase inhibition and can limit therapeutic effect. Alkali therapy may normalize acidosis, increase urinary citrate, and reduce nephrolithiasis risk. We hypothesize that provision of sodium bicarbonate supplementation to patients with topiramate-induced acidosis will mitigate these side-effects without worsening seizure frequency or severity. Methods: Pediatric patients on antiepileptic therapy with topiramate are being recruited from outpatient pediatric neurology clinics at McMaster Children’s Hospital. We aim to recruit 20 patients with metabolic acidosis and 20 control patients. Measures include blood gas, electrolytes, urine electrolytes and citrate. Patients with metabolic acidosis will be given daily sodium bicarbonate for one month, followed by repeat bloodwork. Seizure frequency will be prospectively documented in all participants throughout the three-month period. Results: Recruitment is ongoing, and three patients (1 with acidosis) have been recruited thus far. Results will be analyzed with chi-squared and paired T tests. Conclusions: This pilot study is the first to evaluate the safety and efficacy of sodium bicarbonate supplementation in patients receiving topiramate for seizure control.
Introduction: Current data on utilization of CT imaging point to a trend of increasing overutilization of CT Angiography for the diagnosis of pulmonary embolism (CTPA) over time. Multiple educational and institution-wide interventions addressing this overutilization have been proposed, implemented and evaluated, with mixed results in terms of long-term impact on physician ordering behaviour. The objective of this study is to examine the inter-physician variability in ordering rates and diagnostic yield of CTPA, under a working hypothesis that a small number of physicians are responsible for a disproportionately high number of CTPA ordered in the ED. Methods: Data was collected on all CTPA studies ordered by ED physicians at two very high volume community hospitals and an affiliated urgent care centre during the 2-year period between January 1, 2016 and December 31, 2017. Analysis was limited to those ED physicians who had a total of greater than 500 ED visits over the course of the 2-year period. For each physician, two calculations were made: 1) CT PE ordering rate (total number of CTPA ordered divided by the total number of ED visits), and 2) CTPA diagnostic yield (total number of CTPA positive for PE divided by the total number CTPA ordered). Additional analysis was carried out in order to identify the highest orderers of CTPA and their diagnostic yield. Results: A total of 2,789 CTPA were ordered by 84 physicians for 461,045 total ED visits. Preliminary results show a great deal of variation in ordering rates, ranging from 0.9 to 22.2 CTPA per 1000 ED visit (median = 4.8, IQR = 4.5). Similarly, there was high variation in CT PE yield, ranging from 0% to 50% (median = 9.6%, IQR = 13.1%). Those physicians in the top quartile for ordering rate had a lower mean diagnostic yield, when compared to the lower quartiles (8.9% when compared to 11.5%, 11.9% and 18.2% for the physicians in the third, second, and first quartile respectively). Conclusion: The findings of this study indicate a wide degree of variability in CTPA ordering patterns and diagnostic yield among physicians working within the same clinical environment. There is some suggestion that those physicians who order disproportionately higher numbers of CTPAs have lower diagnostic yields. However, the more interesting lessons from this initial study center on the challenges in creating an audit-and-feedback program targeting CTPA ‘overutilizers’.
Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.
Introduction: Delays in transfer to an in-patient bed of admitted patients boarded in the ED has been identified as one of the chief drivers of ED overcrowding. Our study aims to replicate findings from a previous study in identifying patient characteristics associated with increased boarding time, and the impact of increased boarding time on in-patient length of stay (IPLOS). Methods: We conducted a retrospective single-centre observational study during the period between January 1, 2015 December 31, 2015 at a very high volume community hospital (~ 75,000 ED visits/year). All patients admitted from the ED to Medicine, Pediatrics, Surgery, and Critical Care were identified. The mean time to in-patient bed (TTB), as well as patient-specific and institutional factors that were associated with prolonged boarding times ( 12 hours) were identified. Mean IP LOS was calculated for those with prolonged boarding times and compared to those without prolonged boarding times. Results: There were 8,096 unique admissions during the study period. Patients admitted to the Medicine service exhibited significantly higher boarding times than those admitted to other services, with a mean boarding time of 17.4 hrs, as compared to 4.2 hrs, 5.7 hrs, and 4.0 hrs for those admitted to Surgery, Critical Care and Pediatrics respectively. Within Medicine patients, there was a statistically significant greater odds of prolonged boarding time for patients who were older, had a greater comorbidity burden, and required more specialized in-patient care (i.e. an isolation bed or telemetry bed). Medicine patients with prolonged boarding times also experienced 0.7 days longer IP LOS, even after correcting for age and comorbidity (mean adjusted IP LOS 10.6 days versus 11.3 days). Conclusion: Within our study period, older, sicker patients and those patients requiring more resource-intensive in-patient care have the longest ED boarding times. These prolonged ‘boarding’ times are associated with significantly increased IP LOS.
Cognitive remediation (CR) training has emerged as a promising approach to improving cognitive deficits in schizophrenia and related psychosis. The limited availability of psychological services for psychosis is a major barrier to accessing this intervention however. This study investigated the effectiveness of a low support, remotely accessible, computerised working memory (WM) training programme in patients with psychosis.
Ninety patients were enrolled into a single blind randomised controlled trial of CR. Effectiveness of the intervention was assessed in terms of neuropsychological performance, social and occupational function, and functional MRI 2 weeks post-intervention, with neuropsychological and social function again assessed 3–6 months post-treatment.
Patients who completed the intervention showed significant gains in both neuropsychological function (measured using both untrained WM and episodic task performance, and a measure of performance IQ), and social function at both 2-week follow-up and 3–6-month follow-up timepoints. Furthermore, patients who completed MRI scanning showed improved resting state functional connectivity relative to patients in the placebo condition.
CR training has already been shown to improve cognitive and social function in patient with psychosis. This study demonstrates that, at least for some chronic but stable outpatients, a low support treatment was associated with gains that were comparable with those reported for CR delivered entirely on a 1:1 basis. We conclude that CR has potential to be delivered even in services in which psychological supports for patients with psychosis are limited.
Faster eating rates are associated with increased energy intake, but little is known about the relationship between children’s eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and children’s BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.
Visual hallucinations are a common phenomenon, among the older adult population. They can be functional or organic in aetiology. However, new onset visual hallucinations in this population are strongly suggestive of organic brain disease. Visual impairment, cerebrovascular disease and Parkinson’s disease are three causes of visual hallucinations, considered in this case series. The evidence in the literature, for the treatment of these conditions is scant at best. There is a paucity of randomised controlled trials available concerning possible therapeutic options.
We describe three case reports of visual hallucinations due to diverse underlying aetiologies. We then discuss the aetiologies of visual hallucinations in general and then in these particular cases and finally include results of a literature search examining the available evidence for any therapeutic options proposed.
Our three cases have different, underlying aetiologies. One case is of Charles Bonnet syndrome. The next is of visual hallucinations associated with vascular dementia. The final case is of visual hallucinations associated with Parkinson’s disease. The first two cases are of particular interest due to the efficacy of Amisulpride in both clinical scenarios.
Visual hallucinations are a common phenomenon in the elderly population
They can be due to a myriad of underlying causes. There are a number of neurochemical factors and neuroanatomical structures implicated. The evidence for psychopharmacological interventions is scanty. Randomised controlled trials are lacking in the area. An interesting finding in this case series, was of the clinical utility of Amisulpiride. Given this agent’s unique psychopharmacological profile it is possible that it may be efficacious in other cases of visual hallucinations associated with particular neurochemical factors.
Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine–phosphate–guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine–phosphate–guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.
A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Sligo TCBZ-resistant fluke isolate was used for these experiments and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. In the first experiment, flukes were initially incubated for 2 h in R(+)-VPL (100 μm), then incubated in R(+)-VPL+triclabendazole sulphoxide (TCBZ.SO) (50 μg mL−1, or 133·1 μm) until flukes ceased movement (at 9 h post-treatment). In a second experiment, flukes were incubated in TCBZ.SO alone and removed from the incubation medium following cessation of motility (after 15 h). In the third experiment, flukes were incubated for 24 h in R(+)-VPL on its own. Changes to the testis tubules and vitelline follicles following drug treatment and following Pgp inhibition were assessed by means of light microscope histology and transmission electron microscopy. Incubation of the Sligo isolate in either R(+)-VPL or TCBZ.SO on their own had a limited impact on the morphology of the two tissues. Greater disruption was observed when the drugs were combined, in terms of the block in development of the spermatogenic and vitelline cells and the apoptotic breakdown of the remaining cells. Sperm formation was severely affected and abnormal. Large spaces appeared in the vitelline follicles and synthesis of shell protein was disrupted. The results of this study support the concept of altered drug efflux in TCBZ-resistant flukes and indicate that drug transporters may play a role in the development of drug resistance.
A study was carried out to investigate whether the action of triclabendazole sulphoxide (TCBZ.SO) against the liver fluke, Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for this in vitro study and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. For experiments with the Oberon isolate, flukes were incubated for 24 h with either R(+)-VPL (1×10−4m) on its own, TCBZ.SO (15 μg mL−1) alone, a combination of R(+)-VPL (1×10−4m) plus TCBZ.SO (15 μg mL−1), TCBZ.SO (50 μg mL−1) on its own, or a combination of TCBZ.SO (50 μg mL−1) plus R(+)-VPL (1×10−4m). They were also incubated in TCBZ.SO (50 μg mL−1) alone or in combination with R(+)-VPL (1×10−4m) until they became inactive; and in TCBZ.SO (50 μg mL−1) alone for a time to match that of the combination inactivity time. Flukes from the Cullompton isolate were treated with either TCBZ.SO (50 μg mL−1) alone or in combination with R(+)-VPL (1×10−4m) until they became inactive, or with TCBZ.SO (50 μg mL−1) alone time-matched to the combination inactivity time. Morphological changes resulting from drug treatment and following Pgp inhibition were assessed by means of scanning electron microscopy. Incubation in R(+)-VPL alone had a minimal effect on either isolate. TCBZ.SO treatment had a relatively greater impact on the TCBZ-susceptible Cullompton isolate. When R(+)-VPL was combined with TCBZ.SO in the incubation medium, however, the surface disruption to both isolates was more severe than that seen after TCBZ.SO treatment alone; also, the time taken to reach inactivity was shorter. More significantly, though, the potentiation of drug activity was greater in the Oberon isolate; also, it was more distinct at the higher concentration of TCBZ.SO. So, the Oberon isolate appears to be particularly sensitive to efflux pump inhibition. The results of this study suggest that enhanced drug efflux in the Oberon isolate may be involved in the mechanism of resistance to TCBZ.