The lived experience of young adults with Fetal Valproate Spectrum Disorder, and the perspective of their parents: A qualitative study.

BACKGROUND: While research has investigated the physical and neurodevelopmental consequences following prenatal exposure to valproate, our understanding of individuals with a formal diagnosis of Fetal Valproate Spectrum Disorder (FVSD), particularly in the context of adulthood, remains limited. AIM: To investigate how symptoms and challenges of FVSD present in adulthood. METHODS: 30 people took part in the study, including 13 young adults aged between 21 and 37 years, 15 mothers, and 2 fathers. In all cases, valproate had been used for the treatment of maternal epilepsy. Data were collected using semi-structured interviews and analysed using thematic analysis. RESULTS: Six broad themes were identified: 1. Health and development, 2. Employment, 3. Daily living and independence, 4. Social skills and relationships, 5. Access to services, and 6. Impact on families. Individuals with FVSD live with an array of physical, mental, and developmental challenges that extend well beyond childhood, significantly altering their life course and that of their families. Challenges in obtaining employment, achieving independent living, and navigating social and romantic relationships become increasingly significant as individuals with FVSD age. Despite their persistent need for support, services for adults with FVSD are either limited or entirely absent. Recommendations from families were provided regarding optimized support systems. CONCLUSION: This study highlights the lifelong physical, cognitive, emotional, social and behavioural symptoms associated with FVSD. Young adults and their parents desire further research regarding the condition along with improved support and health services in adulthood.

Assessing the endometrium: An update on current and potential novel biomarkers of receptivity.

A cyclical evolvement of the endometrium into a transient state of receptivity is crucial for acceptance of the semi-allogeneic foetus, conducive to pregnancy. Despite documentation of aberrances in this process within patients experiencing repeated embryo implantation failures and miscarriages, the endometrium is often overlooked in IVF clinics as the cause for failure. Focus instead is usually given to embryo-derived factors, such as aneuploidy. Nevertheless, failure of approximately 30 % of euploid embryos to implant demonstrates that other factors such as the endometrium require clinical exploration. Here, we review both traditional and novel methods used to assess endometrial receptivity such as identifying the WOI, endometrial immune profiling and transcriptomics panel testing. Where reported, we will also discuss their clinical application, as well as novel potential biomarkers within the pre-clinical research stages which show promise in their ability to assess endometrial receptivity.

Views on chemical safety information and influences on chemical disposal behaviour in the UK.

This study examined how groups representing four tiers in the chemical supply chain (manufacturers, vendors, workers and consumers) understood safety information, and the factors that influenced disposal behaviour. Data from seven, semi-structured, focus groups was analysed both qualitatively (textual analysis) and quantitatively (network analysis). Such combined analytical methods enabled us to achieve both detailed insights into perceptions and behaviour and an objective understanding of the prevailing opinions that occurred within and between the focus group discussions. We found issues around awareness, trust, access and disposal behaviours differed between groups within the supply chain. Participants from the lower tiers perceived chemical safety information to be largely inaccessible. Labels were the main source of information on chemical risks for the middle and bottom tiers of the supply chain. Almost all of the participants were aware of the St Andrew's Cross and skull and crossbones symbols but few were familiar with the Volatile Organic Compound logo or the fish and tree symbol. Both the network and thematic analysis demonstrated that whilst frequent references to health risks associated with chemicals were made environmental risks were usually only articulated after prompting. It is clear that the issues surrounding public understanding of chemical safety labels are highly complex and this is compounded by inconsistencies in the cognitive profiles of chemical users. Substantially different cognitive profiles are likely to contribute towards communication difficulties between different tiers of the supply chain. Further research is needed to examine the most effective ways of communicating chemical hazards information to the public. The findings demonstrate a need to improve and simplify disposal guidance to members of the public, to raise public awareness of the graphic symbols in the CHIP 3.1, 2005 regulations and to improve access to disposal guidance.

Cortical differences in diverticular disease and correlation with symptom reports.

BACKGROUND: Recent studies have shown that the brain of patients with gastrointestinal disease differ both structurally and functionally from that of controls. Highly somatizing diverticular disease (HSDD) patients were also shown to differ from low somatizing (LSDD) patients functionally. This study aimed to investigate how they differed structurally. METHODS: Four diseases subgroups were studied in a cross-sectional design: 20 patients with asymptomatic diverticular disease (ADD), 18 LSDD, 16 HSDD, and 18 with irritable bowel syndrome. We divided DD patients into LSDD and HSDD using a cutoff of 6 on the Patient Health Questionnaire 12 Somatic Symptom (PHQ12-SS) scale. All patients underwent a 1-mm isotropic structural brain MRI scan and were assessed for somatization, hospital anxiety, depression, and pain catastrophizing. Whole brain volumetry, cortical thickness analysis and voxel-based morphometry were carried out using Freesurfer and SPM. KEY RESULTS: We observed decreases in gray matter density in the left and right dorsolateral prefrontal cortex (dlPFC), and in the mid-cingulate and motor cortex, and increases in the left (19, 20) and right (19, 38) Brodmann Areas. The average cortical thickness differed overall across groups (P = .002) and regionally: HSDD > ADD in the posterior cingulate cortex (P = .03), HSDD > LSDD in the dlPFC (P = .03) and in the ventrolateral PFC (P < .001). The thickness of the anterior cingulate cortex and of the mid-prefrontal cortex were also found to correlate with Pain Catastrophizing (Spearman's ρ = 0.24, P = .043 uncorrected and Spearman's ρ = 0.25, P = .03 uncorrected). CONCLUSION & INFERENCES: This is the first study of structural gray matter abnormalities in diverticular disease patients. The data show brain differences in the pain network.

Sorption behaviour of oxadiazon in tropical rice soils.

The soprtion behaviour of a pre-emergent herbicide, oxadiazon (5-tert-butyl-3-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazol-2 (3H)-one) was investigated in tropical rice soils using a batch equilibrium method. There is no information available on the fate of oxadiazon in Bangladeshi soils; Bangladesh rice soil is a unique environment. The experiment was performed using radiolabelled (14C) oxadiazon. The sorption and desorption isotherm of oxadiazon was described using the Freundlich equation. L-type sorption isotherms were observed. The correlation coefficient (r2) was 0.995 to 0.997 and the linearity of the slope was in the range 0.96-1.07. Sorption of oxadiazon was related to organic carbon. Sorption of oxadiazon by soil was a rapid process; sorption kinetics indicated that most of the sorption occurred within two hours. Changes in sorption of oxadiazon by soils was investigated by repeated application. Sorption after the first cycle was in the range 81-92% whereas sorption capacity decreased in the following cycles.

Modelling the exposure to chemicals for risk assessment: a comprehensive library of multimedia and PBPK models for integration, prediction, uncertainty and sensitivity analysis - the MERLIN-Expo tool.

MERLIN-Expo is a library of models that was developed in the frame of the FP7 EU project 4FUN in order to provide an integrated assessment tool for state-of-the-art exposure assessment for environment, biota and humans, allowing the detection of scientific uncertainties at each step of the exposure process. This paper describes the main features of the MERLIN-Expo tool. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (i) the integration of multimedia (MM) models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic (PBPK) models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (ii) the incorporation of a set of functionalities for uncertainty/sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (iii) the integration of human and wildlife biota targets with common fate modelling in the environment. MERLIN-Expo is composed of a library of fate models dedicated to non biological receptor media (surface waters, soils, outdoor air), biological media of concern for humans (several cultivated crops, mammals, milk, fish), as well as wildlife biota (primary producers in rivers, invertebrates, fish) and humans. These models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Standardized documentation for each model and training material were prepared to support an accurate use of the tool by end-users. One of the objectives of the 4FUN project was also to increase the confidence in the applicability of the MERLIN-Expo tool through targeted realistic case studies. In particular, we aimed at demonstrating the feasibility of building complex realistic exposure scenarios and the accuracy of the modelling predictions through a comparison with actual measurements.

In vivo evidence that 5-hydroxytryptamine (5-HT) neuronal firing and release are not necessarily correlated with 5-HT metabolism.

The relationship between 5-hydroxytryptamine release, metabolism and unit activity has been investigated in the anaesthetized rat. 5-Hydroxytryptamine release and metabolism were monitored in vivo by the measurement of extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the frontal cortex using in vivo voltammetry combined with nafion-coated and uncoated electrically pretreated carbon fibre electrodes. The monoamine oxidase inhibitor pargyline (100 mg/kg) increased extracellular 5-hydroxytryptamine and decreased 5-hydroxyindoleacetic acid. The 5-hydroxytryptamine releaser fenfluramine (10 mg/kg i.p.) acutely increased extracellular 5-hydroxytryptamine while having no effect on 5-hydroxyindoleacetic acid and the effect on extracellular 5-hydroxytryptamine was markedly reduced in rats pretreated (four weeks) with 5,7-dihydroxytryptamine. 8-Hydroxy-2-(di-n-propyl-amino) tetralin (10 micrograms/kg i.v.), an agonist at the 5-hydroxytryptamine1A somatodendritic autoreceptor, inhibited 5-hydroxytryptamine neuronal firing in the dorsal raphe nucleus and decreased extracellular 5-hydroxytryptamine during the period when firing was inhibited but did not alter extracellular 5-hydroxyindoleacetic acid. In contrast 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridin-4-yl) (RU 24969), which is an agonist at the terminal autoreceptor in the rat, had no effect on 5-hydroxytryptamine neuronal firing but decreased 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. The results support the view that extracellular 5-hydroxyindoleacetic acid is not a good index of 5-hydroxytryptamine release and that under specific circumstances 5-hydroxytryptamine neuronal firing, release and metabolism are independent of one another.

Effects of a selective 5-HT2 agonist, DOI, on 5-HT neuronal firing in the dorsal raphe nucleus and 5-HT release and metabolism in the frontal cortex.

Systemic administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (50 and 100 micrograms kg-1, i.v.) inhibited dorsal raphe neuronal firing. DOI (100 micrograms kg-1, i.v.) also produced a decrease in extracellular 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex measured by microdialysis. However, local administration of DOI into the frontal cortex produced no change in extracellular 5-HT and 5-HIAA at any dose given (1, 10 and 100ng). The results demonstrate that DOI is a potent inhibitor of 5-HT neuronal firing and terminal release and that the effects on release are not mediated by an action within the terminal region. The site of action and the receptor involved in the inhibition remains to be determined.

Effects of repeated treatment with 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on the autoregulatory control of dorsal raphe 5-HT neuronal firing and cortical 5-HT release.

These experiments were designed to examine the effects of repeated 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) treatment on the autoregulatory control of cortical 5-HT release and dorsal raphe nucleus (DRN) 5-HT neuronal cell firing. Repeated DOI treatment decreased the behavioural responsiveness (wet-dog shakes) of 5-HT2 receptors and attenuated the inhibitory effects of the 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), on both cortical 5-HT release and DRN 5-HT neuronal firing. In contrast, the inhibitory effect of acute DOI on cortical 5-HT release and DRN 5-HT neuronal firing was unaffected by repeated DOI treatment. The results demonstrate that changes in the responsiveness of 5-HT2 receptor function may influence the responsiveness of presynaptic 5-HT1A receptors regulating 5-HT neuronal function. The results also provide further evidence that the inhibition of cortical 5-HT release and DRN 5-HT neuronal firing produced by DOI is not mediated by 5-HT2 receptor activation.

Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?

The development of anticonvulsant tolerance with three benzodiazepines was assessed in mice using a slow intravenous infusion of pentylenetetrazol as the convulsive stimulus. Chlordiazepoxide (12.5 mg/kg b.d.) and midazolam (0.75 mg/kg b.d.) induced a slowly evolving tolerance over 15 days whereas nitrazepam (0.6 mg/kg b.d.) induced a very marked rapid tolerance which developed no further during 6 days treatment. Tolerance appeared to be incomplete with all three benzodiazepines. Possible explanations for the differences in tolerance profile are discussed and an alternative basis for the classification of benzodiazepines is suggested.

Blockade of two voltage-dependent potassium channels, mKv1.1 and mKv1.2, by docosahexaenoic acid.

The effects of the polyunsaturated fatty acid, docosahexaenoic acid, were examined on two single cloned potassium channels, mKv1.1 and mKv1.2, stably expressed in Chinese hamster ovary cells using whole-cell patch clamp techniques. Docosahexaenoic acid produced a time- and dose-dependent, reversible block of mKv1.1 and mKv1.2. Interestingly, docosahexaenoic acid increased the rate of activation of mKv1.2 leading to an enhancement of current amplitude at short intervals following activating the voltage step. This phenomenon was not seen in the case of mKv1.1. Intracellular administration of docosahexaenoic acid did not block either type of channel. These findings suggest that docosahexaenoic acid inhibits mKv1.1 and mKv1.2 channels by acting at an extracellular site and by an open-channel blocking mechanism.

Effects of idazoxan on dorsal raphe 5-hydroxytryptamine neuronal function.

The effects of the alpha 2-adrenoceptor antagonist idazoxan on 5-hydroxytryptamine (5-HT) neuronal firing and release have been investigated. Idazoxan, administered i.v. (10 micrograms/kg and 0.5 mg/kg) increased dorsal raphe nucleus (DRN)-5-HT neuronal firing rate in a dose-dependent fashion. At the higher dose, a voltammetric study revealed increases in extracellular 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels, there was no effect with the lower dose. Intra-raphe administration of idazoxan (1 ng) also elevated the firing rate of 5-HT neurones in the dorsal raphe, suggesting that idazoxan may produce the increase in firing by a direct effect in the DRN. However, microiontophoretic application of idazoxan did not increase the firing rate of 5-HT neurones in the DRN. Thus the increase in the firing rate of 5-HT neurones in the DRN observed with systemic and local administration of idazoxan is probably not due to a direct action of idazoxan on the 5-HT neurone. Possibly the idazoxan acted at alpha 2-adrenoceptors located on noradrenergic terminals thus stimulating noradrenaline release and consequently increased 5-HT activity. Chronic administration of idazoxan (0.8 mg/kg per h for 14 days), using osmotic mini-pumps, caused an elevation in basal firing rate and an attenuation of the inhibitory response of DRN 5-HT neurones to the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (10 micrograms/kg i.v.). This finding suggests that chronic infusion with idazoxan leads to desensitisation of the 5-HT1A somatodendritic autoreceptor.

Inhibition of 5-hydroxytryptamine neuronal activity by the 5-HT agonist, DOI.

Systemic, intra-raphe and microiontophoretic administration of the 5-hydroxytryptamine (5-HT)1C/5-HT2 agonist (1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane (DOI) inhibited the firing of 5-HT neurones in the dorsal raphe. DOI administered systemically and directly into the raphe also decreased the extracellular concentration of 5-hydroxytryptamine (5-HT) in the frontal cortex. In contrast, the administration of DOI directly into the frontal cortex did not significantly alter the concentration of frontal cortical extracellular 5-HT. The reduction of the firing rate of 5-HT neurons in the dorsal raphe and extracellular 5-HT concentration in the frontal cortex induced by systemic administration of DOI could not be blocked by the 5-HT2 antagonist ketanserin, ritanserin (5-HT2/5-HT1C antagonist) or the putative 5-HT1A antagonist, pindolol. These results suggest that the inhibition of 5-HT neuronal firing seen with administration of DOI is mediated via an action within the dorsal raphe and at least in close proximity to the 5-HT neurone cell bodies. The decrease in frontal cortical extracellular concentration of 5-HT release was not due to a direct action in the frontal cortex itself and may possibly be as a result of the decrease in the firing rate of the 5-HT neurones in the dorsal raphe. The mechanism of action of DOI to produce these effects is, however, unclear and warrants further investigation.

LSD has high efficacy relative to serotonin in enhancing the cationic current Ih: intracellular studies in rat facial motoneurons.

The effects of LSD (d-lysergic acid diethylamide) on rat facial motoneurons were compared to those of 5-hydroxytryptamine (5-HT) in brain slices by means of current clamp and single-electrode voltage-clamp recordings. As previously reported, 5-HT, in part by decreasing a resting potassium conductance, produced a reversible depolarization (approximately 5 mV), an increase in input resistance, and an enhancement in electrical excitability. LSD also produced an increase in electrical excitability, although with a much slower onset and longer duration. However, in contrast to 5-HT, LSD produced only a slight depolarization (1-2 mV). Moreover, in the presence of LSD the depolarizing effect of 5-HT was markedly attenuated. The 5-HT2/5-HT1C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced effects intermediate between LSD and 5-HT. The LSD-induced increase in electrical excitability was completely reversed by spiperone, a 5-HT2/5-HT1A antagonist, and by ritanserin, a 5-HT2/5-HT1C antagonist; the effects of 5-HT were also reduced by these 2 antagonists, but complete blockade did not occur at the concentrations and durations tested. Surprisingly, LSD was found to enhance the hyperpolarization-activated nonspecific cation current Ih to a greater extent than did 5-HT; this enhancement was blocked by both spiperone and ritanserin. These results indicate that, despite having low efficacy relative to 5-HT in decreasing resting potassium conductance, LSD has high efficacy in enhancing the Ih current in rat facial motoneurons; possible mechanisms for this difference are discussed.

On the mechanism of 4-aminopyridine action on the cloned mouse brain potassium channel mKv1.1.

1. This study used the whole-cell patch clamp technique to investigate the mechanism of action of the K+ channel blocker 4-aminopyridine (4-AP) on the cloned K+ channel mouse Kv1.1 (mKv1.1) expressed in Chinese hamster ovary cells. 2. Cells transfected with mKv1.1 expressed a non-inactivating, delayed rectifier-type K+ current. 4-AP induced a dose-, voltage- and use-dependent block of mKv1.1. 3. 4-AP blockade of mKv1.1 was similar whether 4-AP was administered extracellularly (IC50 = 147 microM) or intracellularly (IC50 = 117 microM). 4. Inclusion of the first twenty amino acids of the N-terminus sequence of the Shaker B K+ channel ('inactivation peptide') in the patch electrode transformed mKv1.1 into a rapidly inactivating current. The time constant of decay for the modified current was dependent on the concentration of inactivation peptide, and under these conditions extracellular 4-AP had a reduced potency (IC50 values of 471 and 537 microM for 0.5 and 2 mg ml-1 inactivation peptide, respectively). 5. A permanently charged analogue of 4-AP, 4-aminopyridine methiodide (4-APMI), was found to block mKv1.1 when applied inside the cell, but was without effect when administered externally. 6. Decreasing the intracellular pH (pHi) to 6.4 caused an increase in 4-AP potency (IC50 = 76 microM), whereas at pHi 9.0, the 4-AP potency fell (IC50 = 295 microM). Conversely, increasing extracellular pH (pHo) to 9.0 caused an increase in 4-AP potency (IC50 = 93 microM), whereas at pHo 6.4, 4-AP potency decreased (IC50 = 398 microM). 7. Taken together, these findings support the hypotheses that the uncharged form of 4-AP crosses the membrane, and that it is predominantly the cationic form which acts on mKv1.1 channels intracellularly, possibly at or near to the binding site for the inactivation peptide.