Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton.

BACKGROUND: Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton. METHODS: Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology. RESULTS: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. CONCLUSIONS: Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.

Prenatal alcohol exposure (PAE) can lead to a set of lifelong cognitive, behavioural, and physical disabilities known as foetal alcohol spectrum disorder (FASD). FASD is a significant burden on healthcare, justice and education systems, which is set to worsen with rising alcohol consumption rates. FASD children have an increased risk of long bone fracture and adolescents are smaller in stature. However, sex differences and the long-term effects of PAE on the skeleton have not been investigated and was the aim of this study. Using a mouse model of PAE, we examined the function and gene expression of bone-forming cells (osteoblasts). We then analysed the skeletons of male and female mice at 12-weeks-old (adult) and 4-weeks-old (juvenile). PAE reduced osteoblast bone formation in both sexes, compared to control. Differential gene expression was predominantly observed in PAE males and largely involved genes related to blood vessel formation. High resolution x-ray imaging (micro-CT) revealed PAE had a detrimental effect on the inner trabecular bone component in 12-week-old male mice only. Analysis of the outer cortical bone revealed that whilst both male and female PAE mice were negatively affected, anatomical variations were observed. Mechanical testing also revealed differences in bone strength in PAE mice, compared to control. Interestingly, 4-week-old mice did not possess these sex differences observed in our PAE model at 12 weeks of age. Our data suggest PAE has detrimental and yet sex-dependent effects on the skeleton. Establishing these sex differences will support future policies and clinical management of FASD.

Fetal alcohol spectrum disorders: an overview of current evidence and activities in the UK.

Estimates for the UK suggest that alcohol consumption during pregnancy and prevalence of fetal alcohol spectrum disorder (FASD)-the most common neurodevelopmental condition-are high. Considering the significant health and social impacts of FASD, there is a public health imperative to prioritise prevention, interventions and support. In this article, we outline the current state of play regarding FASD knowledge and research in the UK, which is characterised by a lack of evidence, a lack of dedicated funding and services, and consequently little policy formulation and strategic direction. We highlight progress made to date, as well as current knowledge and service gaps to propose a way forward for UK research.

Decreased behavioural and neurochemical effects of angiotensin IV following prenatal alcohol exposure in the mouse.

Angiotensin IV (ang IV) is known to improve learning and memory in animal models but the mechanism is unclear. We have previously demonstrated sex differences in the pro-cognitive effects of ang IV, and that prenatal alcohol exposure (PAE) abolishes these effects. This study aimed to explore a possible mechanism underlying the sex differences and the effects of PAE in male mice. Mouse breeding harems received 5% ethanol in drinking water throughout pregnancy and lactation in a two-bottle schedule. The effects of ang IV were assessed in offspring at 4 months of age using the open field test, novel object recognition test and elevated plus maze. Aminopeptidase activity of brain insulin-regulated aminopeptidase (IRAP), a putative target of ang IV, was determined. As seen in a previous similar study, ang IV administered immediately after the second training trial significantly improved novel object recognition 24 h later in male mice but not female. PAE abolished this pro-cognitive effect in males. PAE also increased anxiety-like behaviour in male but not female offspring. Ang IV decreased the aminopeptidase activity of brain IRAP in control male, but not female, mice; PAE abolished this inhibitory effect. Ang IV improved memory consolidation in male but not female mice and PAE abolished this effect in the males. While the effects of PAE may be related to increased anxiety; ang IV decreased the aminopeptidase activity in male but not female mice and PAE abolished this inhibitory effect. The results therefore suggest that improvements in learning and memory induced by peripheral administration of ang IV correlate with a reduction of the enzyme activity of IRAP. This is the first demonstration that ang IV administered peripherally can induce long-term (24 h) changes in IRAP function which are probably not simple competitive inhibition and the first demonstration that PAE alters IRAP activity.

Changing status in health care: community and hospital pharmacists' perceptions of pharmacy practice.

OBJECTIVES: This study aimed to explore experienced community and hospital pharmacists' perceptions of how their pharmacy practice and status in health care are affected by others' views of them. METHODS: A qualitative collective case study was conducted. The primary data were 20 in-depth semistructured interviews of community and hospital pharmacists in England that were audio-recorded, transcribed and analysed thematically. KEY FINDINGS: Thematic analysis of the data identified four themes: (1) ambiguities about being professionals, (2) internal divisions, (3) medicines experts and (4) shopkeepers as healthcare providers. CONCLUSIONS: Pharmacists want to be recognised as medicines experts in health care. They are aware that their status is assessed by the public based on their practice, which is dispensing of medicines, and that the public's image of all pharmacists is that of 'a typical community pharmacist' working in a retail shop while having little experience of pharmacists in other healthcare settings. Pharmacists consider that the public does not view them as registered healthcare professionals. They mainly associate being registered professionals with being controlled from afar by their professional regulator, instead of utilising this as an enabling strategy to support their reprofessionalisation efforts. Pharmacists remain the hidden healthcare profession and need to act in practice as healthcare professionals, so the public is aware of their place and contributions in health care to maintain or enhance their status. Internal divisions between community and hospital pharmacists appear to be due to differences in practice, knowledge and aspirations having the potential to adversely affect the pharmacy profession's status.

Prenatal alcohol exposure reduces 5-HT concentration in mouse intestinal muscle and mucosa.

The influence of prenatal alcohol exposure on the serotoninergic system in the brain has been well studied, however its influence on the serotoninergic system in the gastrointestinal system remains unknown. The objective of the study was to use a mouse model of prenatal alcohol exposure to investigate the effects on serotonin and its metabolites and precursors in colonic tissue. This study used treatment of mouse breeding harems with 5% ethanol with saccharin via drinking water throughout pregnancy and compared the results with a saccharin control group. Tryptophan, serotonin (5-HT) and 5- hydroxyindoleacetic acid (5-HIAA) concentrations were measured in the longitudinal muscle myenteric plexus (LMMP) and mucosa of intestinal tissue by high-performance liquid chromatography (HPLC). Decreased 5-HT concentrations in mucosa and LMMP (females only) were observed in prenatally exposed mice compared to controls. Increases in mucosal and LMMP tryptophan concentration were only observed in prenatally exposed female mice. In conclusion, prenatal alcohol exposure causes a decrease in conversion of tryptophan to 5-HT in both muscle and mucosa although the effect is more pronounced in females. The observed sex difference may be related to changes associated with the estrous cycle.

The Anatomical Society core anatomy syllabus for pharmacists: outcomes to create a foundation for practice.

The Anatomical Society has developed a series of learning outcomes that 'experts' within the field would recommend as core knowledge outputs for a Master's Degree Programme in Pharmacy (MPharm) within the UK. Using the Anatomical Society core gross anatomy syllabus for medical anatomy as a foundation, a modified Delphi technique was used to develop outcomes specific to pharmacy graduates. A Delphi panel consisting of medical practitioners, pharmacists and anatomists (n = 39) was created and involved 'experts' representing 20 UK Higher Education Institutions. The output from this study was 49 pharmacy-specific learning outcomes that are applicable to all pharmacy programmes. The new MPharm anatomy syllabus offers a basic anatomical framework upon which pharmacy educators can build the necessary clinical practice and knowledge. These learning outcomes could be used to develop anatomy teaching within an integrated curriculum as per requirements of the General Pharmaceutical Council (GPhC).

Pharmacist awareness and views towards counterfeit medicine in Lebanon.

BACKGROUND: Pharmacists, as healthcare professionals, have patients' well-being and safety as their primary concern. However, the safety and efficacy of treatments may be compromised by the availability of counterfeit medicine (CFM) which could have serious consequences for public health. OBJECTIVES: To assess pharmacist awareness and views towards CFM in Lebanon. METHODS: The study used convenience sampling and selected pharmacists based on their willingness to participate and used a questionnaire as a tool to determine their experiences and views towards CFM. The questionnaires were completed in different regions in Lebanon. KEY FINDINGS: A total of 223 pharmacists participated in the study, and all were able to define CFM, however were inconsistent in their definitions. The majority reported identifying CFM by the medicine's effect (67.7%), followed by cost (66.8%). Almost 43% reported knowing of pharmacists who dispensed CFM. Additionally, participants reported that they believed that pharmacists who dealt with CFM were unprofessional (89.2%) and unethical (86.5%), and that they did it for the 'easy money' (87.9%) and large profit (86.5%). CONCLUSION: The study highlighted the need for additional CFM awareness campaigns with an emphasis on the role that pharmacists have in protecting patients from using CFM. In addition, there is a need for an official CFM definition that distinguishes between the different types of counterfeiting. Furthermore, the Lebanese Ministry of Public Health and regulatory authorities should control and secure the supply chain of medicine in the country and enforce the law.

Low-dose chronic prenatal alcohol exposure abolishes the pro-cognitive effects of angiotensin IV.

Prenatal ethanol exposure (PAE) in humans results in a spectrum of disorders including deficits in learning and memory. Animal models to date have typically used high ethanol doses but have not identified the biochemical changes underlying the cognitive deficit. This study used treatment of mouse breeding harems with 5% ethanol via drinking water throughout pregnancy and lactation and explored the behavioural consequences in the progeny at 3-6 months of age using the open field test, novel object recognition test and elevated plus maze to measure anxiety and memory consolidation. The effects of angiotensin IV on behaviour of the progeny were also determined. The results indicated that PAE increased anxiety-like behaviour as determined in the open field test in male but not female progeny. In control animals, angiotensin IV enhanced memory consolidation in males, but this effect was abolished by PAE. The abolition of the pro-cognitive effect of angiotensin IV was not a consequence of increased anxiety, and there was some evidence of a long-lasting anxiolytic effect of angiotensin IV in the male PAE progeny. These results suggest that PAE may act via alteration of the actions of the brain renin-angiotensin system to impair memory consolidation, but these effects may be partially sex-dependent.

Performance monitoring in nicotine dependence: Considering integration of recent reinforcement history.

INTRODUCTION: Impaired monitoring of errors and conflict (performance monitoring; PM) is well documented in substance dependence (SD) including nicotine dependence and may contribute to continued drug use. Contemporary models of PM and complementary behavioural evidence suggest that PM works by integrating recent reinforcement history rather than evaluating individual behaviours. Despite this, studies of PM in SD have typically used indices derived from reaction to task error or conflict on individual trials. Consequently impaired integration of reinforcement history during action selection tasks requiring behavioural control in SD populations has been underexplored. METHODS: A reinforcement learning task assessed the ability of abstinent, satiated, former and never smokers (N=60) to integrate recent reinforcement history alongside a more typical behavioural index of PM reflecting the degree of reaction time slowing following an error (post-punishment slowing; PPS). RESULTS: On both indices there was a consistent pattern in PM data: Former smokers had the greatest and satiated smokers the poorest PM. Specifically satiated smokers had poorer reinforcement integration than former (p=0.005) and never smokers (p=0.041) and had less post-punishment slowing than former (p<0.001), never (p=0.003) and abstinent smokers (p=0.026). CONCLUSIONS: These are the first data examining the effects of smoking status on PM that use an integration of reinforcement history metric. The concordance of the reinforcement integration and PPS data suggest that this could be a promising method to interrogate PM in future studies. PM is influenced by smoking status. As PM is associated with adapting behaviour, poor PM in satiated smokers may contribute towards continued smoking despite negative consequences. Former smokers show elevated PM suggesting this may be a good relapse prevention target for individuals struggling to remain abstinent however prospective and intervention studies are needed. A better understanding of PM deficits in terms of reinforcement integration failure may stimulate development of novel treatment approaches.

Changes of renin-angiotensin system-related aminopeptidases in early stage Alzheimer's disease.

Activities of aminopeptidases A, B, and N (ApA, ApB & ApN) and insulin-regulated aminopeptidase (IRAP) have been seen to be decreased amongst patients with Alzheimer's disease (AD). All of these enzymes are involved with the brain renin-angiotensin system which is believed to be involved with learning and memory. This study aimed to explore the time course and the mechanisms underlying these changes. Serum samples were collected from 45 AD patients at the start of the study, and again 13months later (n=37). The control group was 22 healthy, older, adults. Enzyme activity was determined at two substrate concentrations to allow Michaelis-Menten analysis of the enzyme activity. The results indicated that there was decreased activity of ApA, ApB and ApN amongst AD patients but no difference in serum IRAP activity. There were no associations between enzyme activity and age, gender nor scores on psychomotor tests. Consideration of the data for the two time points for AD patients showed that the changes in ApB occurred at an early stage of the disease and persisted, whilst those of ApA and ApN only became apparent at later stages of the disease. Although differences in Michaelis-Menten parameters were not statistically significant, consideration of the values suggested that the decrease in ApB activity may be a result of changes in enzyme protein conformation, whilst that of ApN may be a consequence of decreased enzyme expression. Importantly, the different time courses of the effects and the differential changes in enzyme affinity and expression indicated that the observed changes with progression of AD were not a 'class effect' for serum aminopeptidases but were idiosyncratic for the individual enzymes.

Acute paraquat exposure impairs colonic motility by selectively attenuating nitrergic signalling in the mouse.

Paraquat, a common herbicide, is responsible for large numbers of deaths worldwide through both deliberate and accidental ingestion. Previous studies have eluded that the bioavailability of paraquat increases substantially with increasing dose and that these changes may in part be due to the effects that these high concentrations have on the gastrointestinal tract (GI tract). To date, the actions of acute, high concentrations (20mM for 60 min) of paraquat on the GI tract, particularly the colon which is a major site of paraquat absorption, are unknown. This study examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse. Acute paraquat exposure decreased colonic motility and the amplitude of colonic migrating motor complexes (CMMCs), which are major motor patterns involved in faecal pellet propulsion. In isolated segments of distal colon, paraquat increased resting tension and markedly attenuated electrical field stimulation-evoked relaxations. Pharmacological dissection of paraquat's mechanism of action on both the CMMCs and field stimulated tissue using the nitric oxide synthase inhibitor NG-nitro-L-arginine and direct measurement of NO release from the myenteric plexus, demonstrated that paraquat selectively attenuates nitrergic signalling pathways. These changes did not appear to be due to alterations in colonic oxidative stress, inflammation or complex 1 activity, but were most likely caused by paraquat's ability to act as a redox couple. In summary, these data demonstrate that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.

The potential role of the sodium iodide symporter gene polymorphism in the development of differentiated thyroid cancer.

The sodium iodide symporter (NIS) (solute carrier family 5; SLC5A), mediates the active transport of iodine anion (I(-)) into thyroid follicular cells to facilitate thyroid hormone biosynthesis. Considering its fundamental role in thyroid function, our objective in this study is to explore its potential involvement in the pathogenesis of differentiated thyroid cancer (DTC). Following a preliminary sequencing of the gene in a representative sample of the general population, five variants, (1) rs45602038, (2) rs4808708, (3) rs4808709, (4) rs7250346 and (5) rs12327843, were selected for a larger population-based association study consisting of 507 cases and 597 controls, of which only the rs45602038_TT [Odds ratio (95% confidence interval)=1.90 (1.26-2.88); p=0.002] was associated with disease following adjustment for other confounders using the multivariate analysis. Furthermore, a 5-mer haplotype CGAGT constructed from the five studied SNPs conferred a significant risk (χ(2)=10.98; p=0.0009) for DTC. This association trickled down through shorter derivatives, with the 4-mer haplotype CGAG (χ(2)=13.25; p=0.0003) displaying the most significant association and the 3-mer GAG (χ(2)=11.80; p=0.0006) being equally strongly linked to the disease. Comparison of the flanking derivatives of the primary 5-mer haplotype also indicated that the 3-mer CGA (χ(2)=4.04; p=0.045) constructed from SNP block 1-3 was a lot weaker than that of the AGT (χ(2)=6.73; p=0.0095) constructed from the blocks 3-5 from the other end of the gene. Put together, these data implicate the three nucleotide changes at the rs4808708, rs4808709 and rs7250346 loci (blocks 2-4) as the core for this relationship.

Hypertension and inflammation in Alzheimer's disease: close partners in disease development and progression!

Alzheimer's disease (AD) is by far the most common sporadic neurodegenerative disorder. Clinically it is associated with cognitive and other neuropsychological impairments, and neuropathologically it is distinguished by presence of amyloid-ß plaques and neurofibrillary tangles. Hypertension has been traditionally associated with the etiology of vascular dementia, however, vascular risk factors including hypertension are increasingly being implicated in AD. Likewise, the importance of neuroinflammation in AD pathogenesis is also widely recognized. Data from animal and non-AD human studies suggest a close reciprocal relationship between hypertension and inflammatory systems. Much less is known on the potential pathological interaction between hypertension and inflammation in AD and its subsequent effects on amyloid and tau misfolding, aggregation, and propagation, events recognized as critical for the development and progression of AD. This review summarizes what is known about the mechanistic interactions between hypertension and inflammatory mediators and assesses their potential synergistic/additive role in AD genesis. Increasing our understanding of the pathological interactions between the recognized risk factors for AD is a worthwhile endeavor in a condition which currently has limited treatment options but an increasing number of potential preventative measures.

Impaired renal function and biomarkers of vascular disease in Alzheimer's disease.

Renal disease is a risk factor for vascular diseases and for dementia, and renal insufficiency can be a feature of Alzheimer's disease (AD). Evidence has suggested that vascular mechanisms mediate the link between renal disease and dementia. Our study sought to test this hypothesis by examining renal and vascular functioning in AD by investigating estimated glomerular filtration rates (eGFR), calculated from serum creatinine concentrations, and established biomarkers of vascular functioning, asymmetrical dimethylarginine (ADMA) and plasma homocysteine (Hcy), in individuals with mild to moderate AD (n = 34) and a group of older adult controls (n = 34). We found significantly reduced eGFR, indicative of impaired renal functioning, in individuals with AD (M = 62.9, SD = 15.2) compared with controls (M = 73.6, SD = 11.8). However, concentrations of ADMA and Hcy did not differ between patient and control groups (ADMA: M = 0.47; M = 0.50; Hcy: M = 17.2; M = 14.9; patients and controls). The criteria for a mediation analysis were not met, as concentrations of ADMA and Hcy did not predict AD, indicating that these biomarkers of vascular functioning did not mediate a relationship between renal functioning and AD. This study indicated that renal insufficiency may independently contribute to AD pathology, and other vascular mechanisms may influence a relationship between renal impairment and AD.

Antihypertensives, angiotensin, glucose and Alzheimer's disease.

Evidence supporting a link between vascular disorders such as hypertension and Alzheimer's disease (AD) is increasing. Population studies have suggested an association between hypertension and an increased risk of developing AD. A potential role for antihypertensive medications in the management of cognitive disorders has also been suggested, although findings are mixed. However, it is of interest that evidence is now leaning towards the possibility that some of these antihypertensive medications may improve cognition independent of their blood pressure lowering effects. Many of these drugs cross the blood-brain barrier and may influence neurotransmitters involved in cognition. Increasing knowledge of the actions of antihypertensives in the brain and the vascular system could lead to better treatment and/or prevention options for AD.

Blood pro-inflammatory cytokines in Alzheimer's disease in relation to the use of acetylcholinesterase inhibitors.

OBJECTIVE: A potential anti-inflammatory role for acetylcholinesterase inhibitors (AChEIs) has been supported by animal studies. As very limited data exist from individuals with Alzheimer's disease (AD), the aim of this study was to assess the potential influence of AChEIs on blood pro-inflammatory cytokines. We hypothesized that pro-inflammatory cytokine concentrations were lower in individuals with AD stabilized on AChEIs. METHODS: Blood interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were assessed using specific enzyme-linked immunosorbent assays in three groups of participants: patients with AD stabilized on a therapeutic dose of an AChEI (n = 42); AChEIs drug naïve patients (n = 24); and a cognitively unimpaired control group (n = 35). Patients in the AChEIs group had received medication for an average of one year. RESULTS: Patients stabilized on an AChEI did not differ significantly from drug naïve patients in relation to the concentrations of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p = 0.874, 0.225, and 0.978, respectively). Within the group taking AChEIs, the levels of cytokines did not differ between those taking donepezil, rivastigmine, or galantamine (p = 0.368, 0.851, and 0.299, respectively). CONCLUSIONS: Results from animal studies suggesting a modulatory anti-inflammatory role for AChEIs was not advanced in this study. In individuals with AD, very limited evidence currently exists to support the hypothesis that AChEIs may influence inflammatory blood markers and function beyond the enhancement of neuronal transmission. However, further studies assessing a wider range of inflammatory markers and processes are still needed before this hypothesis can be ruled out.

Antidepressant-like effects of oxytocin in mice are dependent on the presence of insulin-regulated aminopeptidase.

Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that are different from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletion modifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice were injected subcutaneously with saline, oxytocin or oxytocin combined with angiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded by an open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kg oxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did not influence locomotor behaviour in mice, as shown with the open field. These findings were reproduced in transgenic male (aged 3-6 months) and female (aged 12-18 months) IRAP(+/+) mice. However, the major findings of our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP(+/+) mice and was completely absent in age- and gender-matched IRAP(-/-) mice. The lack of an antidepressant-like effect of oxytocin in young male and middle-aged female IRAP(-/-) mice attributes an important role to IRAP in mediating this effect.

Blockade of pro-cognitive effects of angiotensin IV and physostigmine in mice by oxytocin antagonism.

Low doses of oxytocin enhance learning and memory in animal models. Angiotensin IV inhibits cysteine aminopeptidase, also known as insulin-regulated aminopeptidase and oxytocinase, and enhances memory in animals. The mechanism of this effect of angiotensin IV is unknown. This study explored the role of oxytocin in the cognitive effects of angiotensin IV with physostigmine as a control and used isolated smooth muscle to assess the pharmacological selectivity of the observed antagonism. Using novel object recognition in male mice, the effects of angiotensin IV (4.7 µg/kg), oxytocin (0.1 ng/kg) or physostigmine (200 µg/kg) administered subcutaneously immediately after the second training trial, were assessed in the presence and absence of 10 µg/kg ß-mercapto-ß-ß-cyclopenta-methylenepropionyl; O-Me-Tyr², Orn8-oxytocin, an oxytocin antagonist; n=8 in all cases. The effects of the antagonist on angiotensin IV, oxytocin and acetylcholine-induced contractions of rat isolated uterus were also determined. Oxytocin, angiotensin IV and physostigmine significantly enhanced consolidation of learning (P=0.04, 0.004 and 0.008 respectively), and there were no significant effects on locomotor activity. The oxytocin antagonist similarly not only significantly improved novel object recognition (P=0.03) but also significantly increased locomotor activity (P=0.04). In the learning paradigm the oxytocin antagonist prevented the effects of oxytocin, angiotensin IV and physostigmine but in the uterus, contractions induced by angiotensin IV and acetylcholine were unaffected whilst effects of oxytocin were significantly reduced. These results suggest that the pro-cognitive effects of angiotensin IV may be mediated by accumulation of endogenous oxytocin although the mechanisms underlying the observed interaction between the oxytocin antagonist and physostigmine are unclear.

Healthy children's identification and risk perception of medicines in England.

BACKGROUND: Children's understanding of medicines has an impact on their behavior toward those medicines, and yet there has been a paucity of studies exploring this area. OBJECTIVES: To assess children's ability to identify and to explore their risk perceptions of medicines. METHODS: One hundred eighty-two children aged 4 to 11 years at 2 primary schools in England completed a worksheet containing photos of foods and pharmaceutical products. Children were asked to identify what the picture showed and classify it as "good for them," "bad for them," or "sometimes good/sometimes bad for them." Responses were marked as correct if they identified an item without the need for exact identification. Where an item was correctly identified, risk perception was analyzed. RESULTS: Children correctly identified 5 of the 7 pictures as a form of medicine (mean=5.10, standard deviation=1.51), and identification was positively correlated with age (ρ=0.59, P<.001). A greater percentage of children correctly identified bicolored capsules (86.3% correct, 95% confidence interval [CI]=81.3-91.3) as medicines than either white (71.4% correct, 95% CI=64.9-78) or pink tablets (33.5% correct, 95% CI=26.7-40.4). There was a significant shift with age in the perceptions of the children as they changed from reporting that medicines were good for them to reporting that they were sometimes good and sometimes bad for them. This held for all medicines (χ(2) tests, P<.05) except for the cream and the inhaler. CONCLUSIONS: As children get older, they become better at identifying medicines, and they become more likely to see their potential risks.

Strain differences and the role of AT(1) receptor expression in anxiety.

This study investigated strain specific differences to the anxiolytic response to losartan focusing on genetic variation that may influence such responses. This included: AT(1) receptor sequence variation, angiotensin II receptor associated protein (ATRAP) and receptor expression between strains. Sequencing of exon 3 of AT(1a)R revealed no differences between BKW mice (n=6) and C57 and DBA(2) strains (n=3). Comparisons of AT(1) expression do show significant differences, whereby BKW mice showed the highest levels of expression and DBA(2) mice intermediate levels when compared to the C57 strain. Sequencing of sections of the Angiotensin receptor associated protein (ATRAP) identified a non-synonymous point mutation- (T/C) transversion (position 109-161) (SNP id = rs13467517) resulting in a Valine → Alanine (V157A) amino acid change in the BKW and DBA(2) strains. Our results indicate that the previously reported strain dependent effects are not due to variation in AT(1a) receptor sequence. Differences in AT(1)gene expression levels between strains, which mirror their anxiety phenotype, are observed. This is coupled with a non-synonymous single nucleotide polymorphism in ATRAP, a negative regulator of AT(1) signalling.