Principles of studying low-level neurotoxic exposures in children: using the Seychelles Child Development Study of methyl mercury as a prototype

Epidemiological studies to determine the impact of low level toxic exposure on child development are important in guiding clinical and public health action. However, carrying out such studies and interpreting their findings presents a number of significant challenges to the investigators. First, they must find a cohort with suitable exposure, select a biomarker that will accurately determine the level of exposure and determine the endpoints that are most likely to detect subtle differences in neurodevelopment. Following that, the logistics of the study must be organised and collaboration established with the local population and health authorities. To accurately interpret the data, they must also accurately determine covariates that impact child development. After the data are collected, interpreting the findings presents a further challenge. Throughout this process, the study must adhere to fundamental epidemiological principles and clearly defined statistical approaches. This paper discusses those principles and uses the Seychelles Child Development Study to show how one epidemiological study addressed them.     

The Seychelles Child Development Study of methyl mercury from fish consumption: analysis of subscales from the Child Behaviour Checklist at age 107 months in the main cohort

Methyl mercury (MeHg) is neurotoxic and all fish contain at least trace amounts. Consequently, prenatal or fetal exposure occurs when pregnant women consume fish and children are exposed postnatally when they breastfeed or consume fish. However, the level of exposure at which toxicity occurs is presently unknown. Since behavioural endpoints can be sensitive indicators of toxic exposure, we administered the Child Behaviour Checklist (CBCL) to measure behaviour as part of a prospective, longitudinal, double blind study (n = 779) of prenatal MeHg exposure, the Seychelles Child Development Study (SCDS). The CBCL Total T score was a primary endpoint at 66 and 107 month evaluations of the cohort and showed no association with prenatal or postnatal MeHg exposure. This paper reports the results of a secondary analysis of the CBCL subscales to see if specific aspects of behaviour might show associations. The SCDS main cohort was enrolled in 1989-90 and evaluated on five occasions through 107 months of age. The child's primary caregiver completed the CBCL at the 107 month evaluation. Prenatal exposure was determined by measuring total mercury (THg) in maternal hair growing during pregnancy and recent postnatal exposure by analysing the child's hair taken at the 107 month evaluation. Analysis included linear and nonlinear multiple regression models. For prenatal MeHg exposure, the Social Problems subscale was significantly associated and the Somatic Complaints subscale was marginally associated. Both were beneficial associations. For postnatal exposure the Thought Problems subscale was associated in an adverse direction. This secondary analysis identified a small number of subtle beneficial and adverse associations with prenatal and postnatal MeHg exposure for specific CBCL subscales. These analyses provide no evidence for an adverse effect of prenatal exposure. The adverse postnatal association is difficult to interpret because we measured only recent (about one month) exposure and no adjustment was made for the multiplicity of endpoints.     

小儿病毒性脑炎继发癫痫的EEG影像学及临床分析

目的探讨儿童病毒性脑炎继发癫痫(PEE)的脑电图(EEG)及影像学特点,进一步探讨其临床高危因素。方法以明确诊断的34例PEE患儿为观察组,选取同时期就诊的同年龄段病毒性脑炎未继发癫痫(no-PEE)患儿102例为对照组。收集患儿病毒性脑炎(VE)急性期临床资料,并进行随访。结果单因素分析得出2组病脑急性期痫性发作≥2次、癫痫持续状态(SE)、昏迷,EEG癫痫样放电、广泛或弥漫性慢波,影像学单纯皮层受损、皮层及皮层下受损、丘脑基底节受损差异有统计学意义(P<0.05)。多因素Logistic回归分析显示,病毒性脑炎急性期痫性发作≥2次、SE、昏迷、EEG癫痫样放电、影像学皮层及皮层下同时受损差异有统计学意义(P<0.05),为PEE危险因素。2组患儿随访期间智力发育落后差异有统计学意义(P<0.001)。结论病毒性脑炎急性期EEG癫痫样放电、影像学皮层及皮层下同时受损、痫性发作≥2次、SE、昏迷为PEE危险因素。PEE患儿远期多有智力发育落后,应密切随访,及时干预治疗。     

Subtle sex differences in vasopressin mRNA expression in the embryonic mouse brain

Arginine vasopressin (AVP) is a neuropeptide which acts centrally to modulate numerous social behaviors. One receptor subtype through which these effects occur is the AVP 1a receptor (AVPR1A). The modulatory effects of Avp via the AVPR1A varies by species as well as sex, since both AVP and the AVPR1A tend to be expressed more prominently in males. Beyond these neuromodulatory effects there are also indications that the AVP system may play a role in early development to, in part, organize sex‐specific neural circuitry that is important to sexually dimorphic social behaviors in adulthood. However, to date, AVP's role in early development is poorly understood, particularly with respect to its differential effect on males and females. In order to determine the timing and distribution of the AVP system in early brain development, we examined the brains of male and female C57BL/6J mice between embryonic day (E) 12.5 and postnatal day (P) 2 and quantified Avp and Avpr1a mRNA using qPCR and AVPR1A protein using receptor autoradiography. The mRNA for Avp was measurable in males and females starting at E14.5, with males producing more than females, while Avpr1a mRNA was found as early as E12.5, with no difference in expression between sexes. AVPR1A binding was observed in both sexes starting at E16.5, and while there were no observed sex differences, binding density and the number of neuroanatomical areas did increase over time. These data are significant as they provide the first whole‐brain characterization of the vasopressin system in the embryonic mouse. Further, these findings are consistent with data from other species, that have documented a sex difference in the vasopressin system during early brain formation.     

“Rapid actions of the neurosteroid allopregnanolone on ovarian and hypothalamic steroidogenesis: Central and peripheral modulation”

The present study aimed to determine whether an i.c.v. administration of allopregnanolone (ALLO) rapidly modifies the hypothalamic and ovarian 3β‐hydroxysteroid dehydrogenase (3β‐HSD) enzymatic activity and gene expression in in vivo and ex vivo systems in pro‐oestrus (PE) and dioestrus I (DI) rats. Animals were injected with vehicle, ALLO, bicuculline or bicuculline plus ALLO and were then killed. In the in vivo experiment, the hypothalamus, ovaries and serum were extracted and analysed. In the ex vivo experiment, the superior mesenteric ganglion ‐ ovarian nerve plexus ‐ ovary system was extracted and incubated during 120 minutes at 37 ºC. The serum and ovarian compartment fluids were used to determine progesterone by radioimmunoanalysis. In the in vivo experiments, ALLO caused a decrease in hypothalamic and ovarian 3β‐HSD enzymatic activity during PE. During DI, ALLO increased hypothalamic and ovarian 3β‐HSD activity and gene expression. The ovarian 3β‐HSD activity increased in both stages in the ex vivo system; gene expression increased only during DI. ALLO induced an increase in serum progesterone only in D1 and in the ovarian incubation liquids in both stages. All findings were reversed by an injection of bicuculline before ALLO. Ovarian steroidogenic changes could be attributed to signals coming from ganglion neurones, which are affected by the acute central neurosteroid stimulation. The i.c.v. administration of ALLO via the GABAergic system altered 3β‐HSD activity and gene expression, modulating the neuroendocrine axis. The present study reveals the action that ALLO exerts on the GABAA receptor in both the central and peripheral nervous system and its relationship with hormonal variations. ALLO is involved in the “fine tuning” of neurosecretory functions as a potent modulator of reproductive processes in female rats.     

Epigenomic control of gonadotrophin‐releasing hormone neurone development and hypogonadotrophic hypogonadism

Mammalian reproductive success depends on gonadotrophin‐releasing hormone (GnRH) neurones to stimulate gonadotrophin secretion from the anterior pituitary and activate gonadal steroidogenesis and gametogenesis. Genetic screening studies in patients diagnosed with Kallmann syndrome (KS), a congenital form of hypogonadotrophic hypogonadism (CHH), identified several causal mutations, including those in the fibroblast growth factor (FGF) system. This signalling pathway regulates neuroendocrine progenitor cell proliferation, fate specification and cell survival. Indeed, the GnRH neurone system was absent or abrogated in transgenic mice with reduced (ie, hypomorphic) Fgf8 and/or Fgf receptor (Fgfr) 1 expression, respectively. Moreover, we found that GnRH neurones were absent in the embryonic olfactory placode of Fgf8 hypomorphic mice, the putative birthplace of GnRH neurones. These observations, together with those made in human KS/CHH patients, indicate that the FGF8/FGFR1 signalling system is a requirement for the ontogenesis of the GnRH neuronal system and function. In this review, we discuss how epigenetic factors control the expression of genes such as Fgf8 that are known to be critical for GnRH neurone ontogenesis, fate specification, and the pathogenesis of KS/CHH.     

Could self-locking stand-alone cage reduce adjacent-level ossification development after aneterior cervical discectomy and fusion?

Numerous studies have shown that cervical arthrodesis is associated with the adjacent-segment pathology (ASP), such as adjacent-level ossification development (ALOD). However, it still remains largely unclear whether the self-locking stand-alone implant system can reduce the incidence of ALOD. In the present study, we prospectively recruited 120 patients with cervical degenerative disc disease (CDDD) who were treated by anterior cervical discectomy and fusion (ACDF). These patients were randomly and evenly divided into the ROI-C group and plate group. Clinical and radiologic follow-up was performed at 3, 6, 12, 24 and 36 months after surgery. Clinical evaluation included preoperative and postoperative assessments of Japanese Orthopaedic Association (JOA) score and Neck Disability Index (NDI) score. The presence and severity of ALOD, as well as the C2-7 Cobb angle, were assessed on the lateral cervical films during follow-up. There were no significant differences in JOA and NDI scores at each time point during the follow-up period between the two groups. ALOD occurred in 8.8% of 58 patients and 6.7% of 104 levels in the cage group. Moreover, ALOD occurred in 20.1% of 57 patients and 17.8% of 101 levels in the plate group. The ALOD was more serious in the plate group compared with the cage group. The C2-7 Cobb angle was significantly improved compared with that before the operation and could be maintained during the follow-up in both groups. The self-locking stand-alone cage was efficacious for ACDF, and it could reduce the incidence of ALOD compared with anterior plate and cage.     

Research Recommendations on the Effects of Postpartum Depression and Pain on Infant Care and Development

Postpartum depression is one of the most common complications of childbirth, and another is pain. A growing body of research shows that the severity and duration of postpartum pain can increase a woman’s risk for postpartum depression. Postpartum depression and pain negatively affect maternal well-being, and postpartum depression has been associated with adverse outcomes in children. However, there is a dearth of information about the effects of postpartum depression and pain on infant care and development. The objectives of this commentary were to highlight the need to address this gap in the literature, offer a preliminary conceptual model to advance the field, and ignite new lines of inquiry to inform infant care and development.     

Increased risk of eating disorders in women with polycystic ovary syndrome: a case-control study

Abstract

Data on eating disorders in women with PCOS is insufficient. The objective of this case study was to examine the hypothesis that women with PCOS exhibit more impaired eating than healthy women. Women diagnosed with PCOS under the 2003 Rotterdam Diagnostic Criteria (n?=?40) were compared with a healthy control group (n?=?40). The groups also were divided into two as normal body weight and overweight/obese. The Eating Disorders Assessment Questionnaire (EDE-Q) and the Three Factor Eating Questionnaire (TFEQ-R21), were completed by all participants in order to evaluate eating behaviors in addition to eating disorders. Among the overweight/obese group, the average total and subscale scores of the EDE-Q as well as the total and sub-factor scores of the TFEQ-R21 were higher in women with PCOS compared to controls (p?<?.05). However, this statistically significant result was not shown among the women with normal weight (p?>?.05). In comparison to the controls, the PCOS women displayed higher values of the tool scores indicating abnormal restraint eating, body shape concern and weight concern subscale scores (p?<?.05). This result suggests that the evaluation of eating disorders should be added to routine screening and the monitoring of women with PCOS.