Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.     

Switching to Sulphonylureas in Children With iDEND Syndrome Caused by KCNJ11 Mutations Results in Improved Cerebellar Perfusion

OBJECTIVE

Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the K_ATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide.

RESEARCH DESIGN AND METHODS

To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed.

RESULTS

Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of K_ATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5′-triphosphate inhibition were associated with the most severe neurologic symptoms.

CONCLUSIONS

We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.Approximately 50% of cases of permanent neonatal diabetes mellitus are caused by mutations in the genes encoding either the pore-forming (Kir6.2, KCNJ11) or regulatory (SUR1, ABCC8) subunits of the ATP-sensitive K⁺ (K_ATP) channel (1). In some patients with these mutations, neurologic symptoms such as mental retardation, impaired motor development, and hypotonia coexist with neonatal diabetes (iDEND syndrome); if epilepsy is also present, then the condition is called DEND syndrome (2). Previous studies have shown that it is possible to alleviate diabetes and some of the neurologic symptoms by substituting insulin therapy with orally ingested sulphonylurea (SU) drugs (3). In one patient, the improvement in neurologic function was associated with enhanced perfusion of the brain, particularly of the cerebellum, as measured by single-photon emission computed tomography (SPECT). To determine if this effect is common to patients treated with SU, we performed SPECT in patients with different mutations in KCNJ11 and varying clinical phenotypes.     

Women's experiences of increasing subjective well-being in CFS/ME through leisure-based arts and crafts activities: A qualitative study

Purpose. To understand the meanings of art-making among a group of women living with the occupational constraints and stigma of CFS/ME. The study explored their initial motives for art-making, and then examined how art-making had subsequently influenced their subjective well-being.

Method. Ten women with CFS/ME were interviewed; three provided lengthy written accounts to the interview questions.

Findings. Illness had resulted in devastating occupational and role loss. Participants took many years to make positive lifestyle changes. Art-making was typically discovered once participants had accepted the long-term nature of CFS/ME, accommodated to illness, and reprioritized occupations. Several factors then attracted participants specifically to art-making. It was perceived as manageable within the constraints of ill-health. Participants also tended to be familiar with craft skills; had family members interested in arts and crafts, and some desired a means to express grief and loss. Once established as a leisure activity, art-making increased subjective well-being mainly through providing increased satisfaction in daily life, positive self-image, hope, and contact with the outside world. Participants recommended provision of occupational/recreational counselling earlier in the illness trajectory.

Conclusions. Creative art-making occurred as part of a broader acceptance and adjustment process to CFS/ME, and allowed some psychological escape from a circumscribed lifeworld.     

Family practitioner committee records — a neglected resource. 1. An information service for general practitioners based on claims for fees

Data held by a London family practitioner committee for the purpose of paying general practitioners' capitation and item of service fees were analysed every quarter for one year to provide an information service for general practices in the area. Each practice received a quarterly printout showing the age structure of its patient population, the numbers of new registrations and removals and data about items of service. These were expressed as rates which could be compared with those of the area as a whole, and with the highest and lowest rates found in individual practices. A survey at the end of the year showed that the service was welcomed and found useful by the practices. A fully computerized family practitioner committee could provide a similar service without great difficulty, and could make it more informative by linking items of service to specific age groups; data about prescribing and use of hospital and district services could also be incorporated when the relevant agencies are fully computerized too.     

Transient apical breakdown and its relation to color and sensibility changes after luxation injuries to teeth

Abstract In examining a population of 637 luxated permanent teeth, it was found that 27 teeth (4.2%) demonstrated apical breakdown in the form of either a pronounced radiolucency which appeared spontaneously some time after injury, or a persistent expansion of the periodontal ligament space (PDL) over an extended interval after injury, which at later follow-up controls had either returned to normal without further radiographic change or was accompanied by surface resorption and/or pulp canal obliteration without intervening treatment. Two of the 27 teeth demonstrated radiographic change alone, while the remaining 25 demonstrated color and/or electrometric sensibility-changes as well. Twenty-three teeth had fully-formed roots whose apices were either closed or half-closed at the time of injury. Five had roots which were fully formed, but with an open apex; the remaining tooth had three-quarter root formation. The injuries were moderate, the majority being extrusion or lateral luxation, affecting both pulpal and periodontal structures. Based on clinical findings, the following hypothesis is proposed: Transient apical breakdown appears to be a phenomenon linked to the repair processes in the traumatized pulp or pulp and periodontium of luxated mature teeth which returns to normal when repair is complete. Whether this is related to a transitory infection and/ or removal of necrotic traumatized tissue cannot be evaluated from the material available.     

Evaluating the importance of information sources for preventive health care in rural Australia

Abstract: Health promotion and prevention are critical elements of public health programs designed to improve health status and extend life chances. The pattern of mortality and morbidity in rural Australia suggests a particularly important role for health promotion and preventive measures in country areas. However, the importance of preventive health measures and how people access health-related information is not well understood. This study examines which sources of health-related information are most valued by rural residents and whether the importance attributed to different sources varies according to age, sex and geographic location. The results demonstrate the overwhelming importance of the general practitioner and pharmacist in provision of preventive health information for all rural people. There is a need to ensure that the work carried out by all those involved with health promotion is closely integrated with that of rural general practitioners.