The extreme yet transient nature of glacial erosion.

Ice can sculpt extraordinary landscapes, yet the efficacy of, and controls governing, glacial erosion on geological timescales remain poorly understood and contended, particularly across Polar continental shields. Here, we assimilate geophysical data with modelling of the Eurasian Ice Sheet - the third largest Quaternary ice mass that spanned 49°N to 82°N - to decipher its erosional footprint during the entire last ~100 ka glacial cycle. Our results demonstrate extreme spatial and temporal heterogeneity in subglacial erosion, with rates ranging from 0 to 5 mm a-1 and a net volume equating to ~130,000 km3 of bedrock excavated to depths of ~190 m. A hierarchy of environmental controls ostensibly underpins this complex signature: lithology, topography and climate, though it is basal thermodynamics that ultimately regulates erosion, which can be variously protective, pervasive, or, highly selective. Our analysis highlights the remarkable yet fickle nature of glacial erosion - critically modulated by transient ice-sheet dynamics - with its capacity to impart a profound but piecemeal geological legacy across mid- and high latitudes.

Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice.

BACKGROUND: Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD. METHODS: Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months. RESULTS: We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators. CONCLUSIONS: These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.

Best practice principles for management of children with developmental coordination disorder (DCD): results of a scoping review.

BACKGROUND: Developmental coordination disorder (DCD) is a prevalent health condition that is frequently unrecognized despite the substantial evidence that has accumulated regarding how it affects children's health, education and skills. Most literature focuses on measurement of impairment and description of intervention approaches for individual children; little is known about the principles that should guide best practice and service delivery for children with DCD as a population. The purpose of this study was to identify these principles. METHODS: A scoping review was used to 'map' the information available to inform intervention and service delivery. Scholarly and grey literature written in English was identified in six databases, using a combination of keywords (e.g. guidelines, management, models and DCD); a 'snow-balling' technique was also used in Canada and the UK to access clinical protocols used in publicly funded health care systems. Over 500 documents were screened: 31 met inclusion criteria as they outlined practice principles for children with DCD as a population. Data regarding best practices were independently extracted by two reviewers and then compared with achieve consistency and consensus. RESULTS: Two over-arching themes emerged, with five principles: (1) Organizing services to efficiently meet the comprehensive needs of children (e.g. Increasing awareness of DCD and coordination; Implementing clearly defined pathways; Using a graduated/staged approach); (2) Working collaboratively to offer evidence-based services (e.g. Integration of child and family views; Evidence-based interventions fostering function, participation and prevention). CONCLUSION: Numerous documents support each of the principles, reflecting agreement across studies about recommended organization of services. While these principles may apply to many populations of children with disabilities, this review highlights how essential these principles are in DCD. Researchers, managers, clinicians, community partners and families are encouraged to work together in designing, implementing and evaluating interventions that reflect these principles.

Emerging adulthood in developmental co-ordination disorder: parent and young adult perspectives.

Recent research widely acknowledges that developmental co-ordination disorder (DCD) is a pervasive and enduring disorder, which persists into adolescence and adulthood (Cousins & Smyth, 2003; Kirby, Sugden, Beveridge, & Edwards, 2008). However, few studies have given detailed consideration to the range and level of functioning difficulties in emerging adults with DCD, and no studies to date have gained a parental perspective. Current functioning of 19 young adults with DCD was examined using the Adult Dyspraxia/DCD Checklist (ADC, Kirby, Edwards, Sugden, & Rosenblum, 2010) and parents' views of their child's current functioning was also obtained. Results suggest that whilst some motor skills such as handwriting continue to impact in emerging adulthood, not all skills are as problematic, such as self-care skills. Additionally, executive functioning, and social skills seem to be a key areas of concern for both young adults and their parents. Results provide guidance for areas of intervention that need to be considered, especially focusing on executive functioning skills. Also they highlight the need for gathering information from more than one source to gain a complete picture of functioning.

Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: a role for Nrf2 in vascular protection in diabetes.

BACKGROUND AND AIMS: Hyperglycemia and diabetes are associated with increased formation of advanced glycation end products and enhanced oxidative stress, leading to the progression of diabetic vascular disease. We have investigated the mechanisms by which AGE-modified bovine albumin (AGE-BSA) induces reactive oxygen species (ROS) generation, leading to nuclear factor-erythroid 2-related factor (Nrf2) dependent induction of the antioxidant genes heme oxygenase-1 (HO-1) and NADPH:quinone oxidoreductase 1 (NQO1) in bovine aortic endothelial cells. METHODS AND RESULTS: AGE-BSA (100 µg ml⁻¹, 0-24 h), but not native BSA, elicited time-dependent increases in ROS generation, Nrf2 nuclear translocation and enhanced mRNA and protein expression of HO-1 and NQO1, but not glutathione peroxidase-1. Inhibition of ROS production with the superoxide scavenger Tiron or inhibitors of flavoproteins (diphenylene iodonium) and NADPH oxidase (apocynin), but not eNOS (L-NAME) or mitochondria complex I (rotenone) abrogated HO-1 induction by AGE-BSA. Although AGE-BSA induced rapid phosphorylation of JNK and Akt, only inhibition of JNK abrogated HO-1 expression, implicating the involvement of the JNK signaling pathway in AGEs activation of Nrf2/ARE-linked antioxidant gene expression. CONCLUSION: Our findings establish that AGEs activate redox sensitive Nrf2-dependent antioxidant gene expression in bovine aortic endothelial cells, providing an adaptive endogenous defense against oxidative stress in diabetes.

Assistive devices and cerebral palsy: the use of assistive devices at school by children with cerebral palsy.

BACKGROUND: Although the importance of providing disabled children with assistive devices has always been highlighted, most studies in the field of assistive device research seek the participation of adult users or adult carers. Accordingly, the opinions of young users themselves seem to be overlooked. To start to address the gap, this study aimed to understand the children's perspectives regarding device use in school and to explore the factors related to their device utilization in this setting. METHODS: Semi-structured interviews were adopted as the main data collection instrument. A total of 44 participants were involved, including 15 Taiwanese children with cerebral palsy, aged between 8 and 15 years, 15 mothers and 14 teachers. RESULTS: The interview results show a high frequency of device use in school which can be attributed to children's willingness, teachers' attitudes, mothers' support, physical environmental factors and device-related features. CONCLUSIONS: The findings not only demonstrate the significance of child-environment interaction but also provide evidence that children's views may be different from those of adults because they are at a different developmental stage and act out different roles in their environment.

Assistive devices and cerebral palsy: factors influencing the use of assistive devices at home by children with cerebral palsy.

BACKGROUND: There is a growing awareness of the significance of gaining insights into device users' needs in their everyday usage in order to maximize the potential of assistive device intervention. However, current studies in this field are likely to focus more upon adult users' or adult carers' perspectives and, accordingly, the opinions of young users seem to be overlooked. In order to take the gap into consideration, this study aimed to explore the usability of assistive devices at home by children with cerebral palsy and consider the underlying factors related to the device usage in this setting mainly from the children's perspectives. METHODS: Semi-structured interviews were adopted as the main data collection instrument. A total of 30 participants were involved in the study, including 15 Taiwanese children with cerebral palsy and 15 mothers. RESULTS: The results showed a low frequency of device use at home by the participating children. Four factors leading to low device use at home were identified, including children's reluctance, mothers' perspectives, physical environmental barriers and device-related barriers. CONCLUSIONS: The results highlight the need, when considering the usability of assistive devices, to take into account three interactive factors, namely, the personal, device and environmental factors. They also demonstrate the importance of taking children's different developmental stages and unique personal experiences into consideration in understanding the influence of assistive device intervention for children with cerebral palsy.

Effect of egg turning and incubation time on carbonic anhydrase gene expression in the blastoderm of the Japanese quail (Coturnix c. japonica).

1. The gene expression of carbonic anhydrase, a key enzyme for the production of sub-embryonic fluid (SEF), was assessed in turned and unturned eggs of the Japanese quail. The plasma membrane-associated isoforms CA IV, CA IX, CA XII, CA XIV, and the cytoplasmic isoform CA II, were investigated in the extra-embryonic tissue of the blastoderm and in embryonic blood. 2. Eggs were incubated at 37.6 degrees C, c.60% RH, and turned hourly (90 degrees ) or left unturned. From 48 to 96 h of incubation mRNA was extracted from blastoderm tissue, reverse-transcribed to cDNA and quantified by real-time qPCR using gene-specific primers. Blood collected at 96 h was processed identically. 3. Blastoderm CA IV gene expression increased with the period of incubation only in turned eggs, with maxima at 84 and 96 h of incubation. Only very low levels were found in blood. 4. Blastoderm CA II gene expression was greatest at 48 and 54 h of incubation, subsequently declining to much lower levels and unaffected by turning. Blood CA II gene expression was about 25-fold greater than in the blastoderm. 5. The expression of CA IX in the blastoderm was the highest of all isoforms, yet unaffected by turning. CA XII did not amplify and CA XIV was present at unquantifiable low levels. 6. It is concluded that only gene expression for CA IV is sensitive to egg turning, and that increased CA IV gene expression could account for the additional SEF mass found at 84 to 96 h of incubation in embryos of turned eggs.

Does subtype of developmental coordination disorder count: is there a differential effect on outcome following intervention?

It is well known that developmental coordination disorder (DCD) is a heterogeneous condition in which children frequently present with co-occurring conditions in addition to their motor difficulties. This study considered whether there would be a differential effect of a group treatment program on subtypes of perceptual and movement problems or associated co-occurring conditions. A subset of children (n=43) from a larger clinical sample (n=100) with DCD participated in a 214 year cross-over intervention study which followed the cognitive orientation to daily occupational performance (CO-OP) approach. Original subtypes were determined by contrasting the current sample with previously published subtyping studies in DCD [Hoare, D. (1994). Subtypes of developmental coordination disorder. Adapted Physical Activity Quarterly, 11, 158-169; Macnab, J. J., Miller, L. T., & Polatajko, H. J. (2001). The search for subtypes of DCD: Is cluster analysis the answer? Human Movement Science, 20, 49-72]. No advantage was conferred to any subtype although children with more profound and complex difficulties at initial assessment, despite progress following intervention, were most likely to have continuing difficulties at the end of the project.

Anterior thalamic lesions produce chronic and profuse transcriptional de-regulation in retrosplenial cortex: A model of retrosplenial hypoactivity and covert pathology.

Anterior thalamic lesions are thought to produce 'covert pathology' in retrosplenial cortex, but the causes are unknown. Microarray analyses tested the hypothesis that thalamic damage causes a chronic, hypo-function of metabolic and plasticity-related pathways (Experiment 1). Rats with unilateral, anterior thalamic lesions were exposed to a novel environment for 20 minutes, and granular retrosplenial tissue sampled from both hemispheres 30 minutes, 2h, or 8h later. Complementary statistical approaches (analyses of variance, predictive patterning and gene set enrichment analysis) revealed pervasive gene expression differences between retrosplenial cortex ipsilateral to the thalamic lesion and contralateral to the lesion. Selected gene differences were validated by QPCR, immunohistochemistry (Experiment 1), and in situ hybridisation (Experiment 2). Following thalamic lesions, the retrosplenial cortex undergoes profuse cellular transcriptome changes including lower relative levels of specific mRNAs involved in energy metabolism and neuronal plasticity. These changes in functional gene expression may be largely driven by decreases in the expression of multiple transcription factors, including brd8, c-fos, fra-2, klf5, nfix, nr4a1, smad3, smarcc2, and zfp9, with a much smaller number (nfat5, neuroD1, RXRγ) showing increases. These findings have implications for conditions such as diencephalic amnesia and Alzheimer's disease, where both anterior thalamic pathology and retrosplenial cortex hypometabolism are prominent.

Design and synthesis of new N-OMe fluoro-indole melatoninergics.

The synthesis of a series of new N-OMe fluoro-indoles with melatoninergic activity in the Xenopus melanophore assay is described. All of the 4-F substituted compounds, 22a-e and 25a,b, were antagonists on the clonal Xenopus melanophore line. Conversely, the 5-F substituted analogs (15a-e) did not share the same pharmacological profile, as two of them, compounds 15d (R=c-C(3)H(5)) and 15e (R=c-C(4)H(7)), exhibited a weak agonistic and partial agonistic activity, respectively, whilst the other three (15a-c) were all agonists. It seems that in this case the nature of the response (agonist or antagonist activity) is solely dependent on the shape of the R group.

Stability and change in children with Developmental Coordination Disorder.

BACKGROUND: Children with Developmental Coordination Disorder (DCD) are a heterogeneous group who have a marked impairment in the performance of functional motor skills. Provision for these children is usually made via a paediatrician through occupational or physiotherapy; though with a prevalence rate of 5%, regular provision is rarely possible because of limited professional resources. METHODS: This study covers a period of nearly 4 years and initially examined a group of 31 children first identified as having DCD at 7-9 years of age. The children were observed and assessed before, during and after a total of 16 weeks of intervention carried out by parents and teachers. This was followed by a period of monitoring of performance for 26 of the children in the motor domain plus other abilities such as educational progress and self-concept. Individual children were tracked using a variety of qualitative and quantitative approaches, building up longitudinal whole child profiles. RESULTS: Following intervention, 14 of the 26 children have shown improvement and stability in all areas and no longer display DCD symptoms. Eight children have profiles which have shown variability, with the children moving in and out of the DCD classification, while the remaining four children have consistently scored poorly in their movement skills and in addition received ongoing support in school for academic subjects. CONCLUSIONS: The study has confirmed that children with DCD show varying profiles over a period of time and that the profiles have distinct characteristics related to events in the child's life. This approach to examining stability and change in the progressions of children's difficulties is in keeping with an ecological approach to explaining development with its multilayered influences creating changes.

Neurotrophin-3 administration alters neurotrophin, neurotrophin receptor and nestin mRNA expression in rat dorsal root ganglia following axotomy.

In the months following transection of adult rat peripheral nerve some sensory neurons undergo apoptosis. Two weeks after sciatic nerve transection some neurons in the L4 and L5 dorsal root ganglia begin to show immunoreactivity for nestin, a filament protein expressed by neuronal precursors and immature neurons, which is stimulated by neurotrophin-3 (NT-3) administration. The aim of this study was to examine whether NT-3 administration could be compensating for decreased production of neurotrophins or their receptors after axotomy, and to determine the effect on nestin synthesis. The levels of mRNA in the ipsilateral and contralateral L4 and L5 dorsal root ganglia were analyzed using real-time polymerase chain reaction, 1 day, 1, 2 and 4 weeks after unilateral sciatic nerve transection and NT-3 or vehicle administration via s.c. micro-osmotic pumps. In situ hybridization was used to identify which cells and neurons expressed mRNAs of interest, and the expression of full-length trkC and p75NTR protein was investigated using immunohistochemistry. Systemic NT-3 treatment increased the expression of brain-derived neurotrophic factor, nestin, trkA, trkB and trkC mRNA in ipsilateral ganglia compared with vehicle-treated animals. Some satellite cells surrounding neurons expressed trkA and trkC mRNA and trkC immunoreactivity. NT-3 administration did not affect neurotrophin mRNA levels in the contralateral ganglia, but decreased the expression of trkA mRNA and increased the expression of trkB mRNA and p75NTR mRNA and protein. These data suggest that systemically administered NT-3 may counteract the decrease, or even increase, neurotrophin responsiveness in both ipsi- and contralateral ganglia after nerve injury.

The influence of perturbing the working surface during reaching and grasping in children with hemiplegic cerebral palsy.

PURPOSE: To examine unimanual and bimanual reaching and grasping in children with hemiplegic cerebral palsy with particular emphasis on the nature and extent of interlimb coupling when the working surface is perturbed. METHOD: Nine children with hemiplegic cerebral palsy and 7 control children with no movement difficulties took part in the study. Children were asked to pick up a cube unimamually and bimanually when the surface it was placed on was either sloping away from the child (Experiment 1) or towards the child (Experiment 2). Both 3D kinematic data and video data were gathered and qualitative descriptions of video data were made. RESULTS: The working surface did indeed influence the nature and extent of interlimb coupling and this varied from participant to participant. Analysis of the displacement data revealed that during the bimanual condition lower trajectories were produced by both the hemiplegic and non hemiplegic sides, especially in Experiment 2. The control group showed little difference between the unimanual and bimanual condition. CONCLUSIONS: Evidence of interlimb coupling is found, these studies support the findings of our previous work that indicates that there are some benefits to performing bimanual movements in children with hemiplegic cerebral palsy.

A pilot study of psychopathology in Developmental Coordination Disorder.

BACKGROUND: This paper explores the prevalence of emotional and behavioural disorders in children referred to a Community Paediatric Occupational Therapy service for assessment and treatment of problems with development of motor skills. METHODS: Parents of 47 children from a clinical sample of children who had been identified with Developmental Coordination Disorder (DCD) returned the Strengths and Difficulties Questionnaire (SDQ)--a brief measure of the pro-social behaviour and psychopathology that can be completed by parents, teachers or youths. RESULTS: Significant emotional and behavioural problems were reported by 29 parents (62%) with a further six (13%) reporting problems in the borderline range. Seven children (15%) were without significant problems in one or more area although only four of these (9%) were outside the borderline range for all of the sub-domains of the SDQ. DISCUSSION: A significant proportion of children with DCD were reported by their parents to be at risk of psychopathology. Further research is needed to understand the relationship between motor difficulties and emotional and behavioural symptoms; however, it is recommended that interventions for children with DCD should support mental health and behavioural problems as well as motor development.

Enhanced vascular responses to adrenomedullin in mice overexpressing receptor-activity-modifying protein 2.

Adrenomedullin (AM) levels are elevated in cardiovascular disease, but little is known of the role of specific receptor components. AM acts via the calcitonin receptor-like receptor (CLR) interacting with a receptor-activity-modifying protein (RAMP). The AM1 receptor is composed of CLR and RAMP2, and the calcitonin gene-related peptide (CGRP) receptor of CLR and RAMP1, as determined by molecular and cell-based analysis. This study examines the relevance of RAMP2 in vivo. Transgenic (TG) mice that overexpress RAMP2 in smooth muscle were generated. The role of RAMP2 in the regulation of blood pressure and in vascular function was investigated. Basal blood pressure, acute angiotensin II-raised blood pressure, and cardiovascular properties were similar in wild-type (WT) and TG mice. However, the hypotensive effect of IV AM, unlike CGRP, was enhanced in TG mice (P<0.05), whereas a negative inotropic action was excluded by left-ventricular pressure-volume analysis. In aorta relaxation studies, TG vessels responded in a more sensitive manner to AM (EC50, 8.0+/-1.5 nmol/L) than WT (EC50, 17.9+/-3.6 nmol/L). These responses were attenuated by the AM receptor antagonist, AM(22-52), such that residual responses were identical in all mice. Remaining relaxations were further inhibited by CGRP receptor antagonists, although neither affected AM responses when given alone. Mesenteric and cutaneous resistance vessels were also more sensitive to AM in TG than WT mice. Thus RAMP2 plays a key role in the sensitivity and potency of AM-induced hypotensive responses via the AM1 receptor, providing evidence that this receptor is a selective target for novel therapeutic approaches.

The influence of object size on discrete bimanual co-ordination in children with hemiplegic cerebral palsy.

PURPOSE: To examine the influence of perturbation of object size on the nature and extent of interlimb coupling in children with hemiplegic cerebral palsy. METHOD: Participants completed a number of trials reaching and grasping unimanually and bimanually to a small cube (1.5 cm) and a large cube (6 cm). Both 3D kinematic data and video data were gathered and qualitative descriptions of the video data were made. RESULTS: It was found that object size did influence the nature and extent of bimanual coupling. As in previous studies this varied from participant to participant and either or a combination of temporal, spatial, or postural coupling was observed. In some cases the hemiplegic hand was influenced by the non hemiplegic hand, while in others it was the reverse. CONCLUSIONS: The influence of context and the individual nature of children with cerebral palsy observed in this paper must be considered by those in rehabilitation. Additionally, the therapist might be able to use the natural tendency to couple to assist the functional control of the hemiplegic side.

ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans.

It has previously been suggested that ACTH and ACTH-related peptides may act as paracrine modulators of insulin secretion in the islets of Langerhans. We have, therefore, examined the expression and function of the ACTH receptor (the melanocortin 2 receptor, MC2-R) in human and mouse primary islet tIssue and in the MIN6 mouse insulinoma cell line. Mouse MC2-R mRNA was detected in both MIN6 cells and mouse islet tIssue by PCR amplification of cDNA. In perifusion experiments with MIN6 pseudo-islets, a small, transient increase in insulin secretion was obtained when ACTH(1-24) (1 nM) was added to medium containing 2 mM glucose (control) but not when the medium glucose content was increased to 8 mM. Further investigations were performed using static incubations of MIN6 cell monolayers; ACTH(1-24) (1 pM-10 nM) provoked a concentration-dependent increase in insulin secretion from MIN6 monolayer cells that achieved statistical significance at concentrations of 1 and 10 nM (150 +/- 13.6% basal secretion; 187 +/- 14.9% basal secretion, P<0.01). Similar responses were obtained with ACTH(1-39). The phosphodiesterase inhibitor IBMX (100 microM) potentiated the responses to sub-maximal doses of ACTH(1-24). Two inhibitors of the protein kinase A (PKA) signaling pathway, Rp-cAMPS (500 microM) and H-89 (10 microM), abolished the insulin secretory response to ACTH(1-24) (0.5-10 nM). Treatment with 1 nM ACTH(1-24) caused a small, statistically significant increase in intracellular cAMP levels. Secretory responses of MIN6 cells to ACTH(1-24) were also influenced by changes in extracellular Ca2+ levels. Incubation in Ca2+-free buffer supplemented with 0.1 mM EGTA blocked the MIN6 cells' secretory response to 1 and 10 nM ACTH(1-24). Similar results were obtained when a Ca2+ channel blocker (nitrendipine, 10 microM) was added to the Ca2+-containing buffer. ACTH(1-24) also evoked an insulin secretory response from primary tIssues. The addition of ACTH(1-24) (0.5 nM) to perifusions of mouse islets induced a transient increase in insulin secretion at 8 mM glucose. Perifused human primary islets also showed a secretory response to ACTH(1-24) at basal glucose concentration (2 mM) with a rapid initial spike in insulin secretion followed by a decline to basal levels. Overall the results demonstrate that the MC2-R is expressed in beta-cells and suggest that activation of the receptor by ACTH initiates insulin secretion through the activation of PKA in association with Ca2+ influx into beta-cells.

Synthesis and biological evaluation of new beta,beta'-disubstituted 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl ethylamido melatoninergic ligands.

Tricyclic analogs of melatonin with alkyl and cycloalkyl moieties in the beta position of the ethylamido chain have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores. The introduction of two methyl groups in the beta position of the side-chain of the methoxyl-substituted ligands induces a synergistic effect in agonist potency, which, importantly, is maintained after the methoxyl substituent is removed. The presence of more bulky beta-substituents, regardless of the size of the R group, seems to lead to antagonism.

The effects of the phytoestrogen, coumestrol, on gonadotropin-releasing hormone (GnRH) mRNA expression in GT1-7 GnRH neurones.

Phytoestrogens can produce inhibitory effects on gonadotropin secretion in both animals and humans, although little is known about the mechanisms and the role of direct action on oestrogen receptors (ER) in this process. We examined the effect of coumestrol, alone and combined with ER antagonists, on gonadotropin-releasing hormone (GnRH) mRNA expression in GT1-7 cells. Coumestrol was found to have an inhibitory effect compared to controls, which was blocked by R,R-THC, a selective ER beta antagonist. These results suggest that ER beta is involved in the suppression of GnRH mRNA expression by coumestrol.