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N-acetylaspartylglutamate (NAAG) is a common neurotransmitter in the mammalian nervous system; however, it has never been reported in the nervous system of the fruit fly, Drosophila melanogaster. Using antiserum against NAAG, we localized NAAG-like immunoreactivity to neurons in the ventral nerve cord and to type Is glutamatergic nerve terminals in larval neuromuscular junctions. Using liquid chromatography tandem mass spectrometry (LC-MS), we failed to find NAAG but found the related peptide N-acetylaspartylglutamylglutamate (NAAG(2)) in Drosophila CNS and body wall tissue. This is the first report of any NAAG-family peptide in the nervous system of Drosophila and is also the first report of NAAG(2) being present in a much higher concentration than NAAG in the nervous system of any species. Thus, the larval fruit fly presents an interesting model for the study of the functional role of NAAG(2) of which very little is known – especially in the absence of an abundance of NAAG.

Introduction Hepatic resection is the only potentially curative treatment for patients with colorectal liver metastases (CLM). Patient selection is key, but there is wide variation in practice. Pre-operative chemotherapy can improve oncological outcomes, however chemotherapy-associated liver injury (CALI) may hinder liver regenerative capacity. Standard pre-operative assessments fail to accurately capture factors such as CALI and future liver remnant (FLR) function. The CLiFF and CoNoR studies utilise two novel assessment techniques, aiming to improve patient outcomes. Method The CLiFF study prospectively assesses two primary outcomes in 35 patients undergoing pre-operative chemotherapy for CLM: 1) change in liver function (via LiMAx test: direct assessment of hepatic functional capacity), and 2) change in liver fat (via advanced MR imaging (in-house spectroscopy and modified Dixon technique, scaled up via Perspectum LiverMultiScan)). The CoNoR study assesses potential added benefit of these novel tools in CLM resectability decision-making via sequential workstreams: a systematic review and international hepatobiliary expert interviews inform the online survey, assessing added benefit via online MDT scenarios. Result Preliminary CLiFF analysis suggests that CALI changes in liver fat and function are unrelated. Liver fat analysis techniques are compared and correlated with digital histological analysis. The CoNoR systematic review identifies key factors influencing CLM resectability decision-making and informs the international expert interviews, scheduled to occur during a February 2020 international hepatobiliary conference. Conclusion These studies are the first to assess where these novel tools might be utilised to maximal patient benefit within the Hepatobiliary MDT, and the first systematic review in CLM resectability decision-making. Take-home message These two linked studies evaluate the use of two novel assessment tools in the treatment of colorectal liver metastases, with the potential to improve patient selection for curative resection and patient outcomes. PATEY PRIZE SESSION

IntroductionPreoperative chemotherapy in patients undergoing resection for colorectal liver metastases (CLM) improves oncological outcomes. However, chemotherapy-associated liver injury (occurring in two patterns: vascular and fat deposition) is a real clinical concern prior to hepatic resection. After major liver resection, regeneration of the residual liver is a prerequisite for recovery and avoidance of liver failure, but this regenerative capacity may be hindered by chemotherapy. Thus, there is a need to predict for this serious complication. Over the past two decades, several tests and derived indices have been developed, which have failed to achieve clinical utility, mainly as they were indirect measurements of liver function. Here, we will use a novel test of liver function (the liver maximum capacity (LiMAx) test), and measure liver fat using MRI.Methods and analysisThis prospective study will assess changes in liver function longitudinally, measured by the LiMAx test, and liver fat, measured by advanced MRI using both MR spectroscopy and the modified Dixon method, in up to 35 patients undergoing preoperative chemotherapy for CLM. The primary outcomes will be the changes in liver function and fat compared with baseline prechemotherapy measurements. Secondary outcome measures include: routinely measured liver function blood tests, anthropometric measurements, postoperative histology and digital quantification of fat, postoperative complications and mortality and quality of life.Ethics and disseminationThe study was approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences and the National Institute for Health Research network. Manuscripts will be published.Trial registration numberThis study is registered online atwww.clinicaltrials.gov(registration numberNCT03562234).

Functional magnetic resonance imaging (fMRI) has increasingly been employed to establish whether there is a specific brain neural network dedicated to maternal responsiveness. We undertook systematic review and meta-analysis of all studies in which healthy new mothers were exposed to visual stimuli of own versus other infants to determine the quality of evidence for a dedicated maternal neural network. Systematic literature review revealed a pattern of specific neural responses commonly induced by visual infant paradigms. Brain areas consistently reported as activated in mothers in response to own versus unknown infant included the left thalamus, bilateral pre-central gyrus, left limbic lobe, uncus, amygdala and left caudate. These regions are implicated in reward, attention, emotion processing and other core social cognitive skills. Meta-analysis, however, revealed a more limited subset of brain areas activated in mothers specifically in response to their own versus unknown infant and suggested considerable inter-study variability. Further work is needed if functional imaging is to become an objective tool for the assessment of neural pathways associated with distinct patterns of maternal care behaviour. Such a tool would be invaluable in developing biomarkers of neural activity associated with healthy maternal care and for monitoring treatment/intervention effects of costly parenting interventions. Electronic supplementary material The online version of this article (10.1007/s00737-018-0878-2) contains supplementary material, which is available to authorized users.

Background Excess body adiposity is associated with increased risk of pancreatic cancer, and in animal models excess intra-pancreatic fat is a driver of pancreatic carcinogenesis. Within a programme to evaluate pancreatic fat and PC risk in humans, we assessed whether MR-quantified pancreatic fat fraction (PFF) was ‘fit for purpose’ as an imaging biomarker. Methods We determined PFF using MR spectroscopy (MRS) and MR chemical shift imaging (CS-MR), in two groups. In Group I, we determined accuracy of MR-derived PFF with histological digital fat quantification in 12 patients undergoing pancreatic resection. In a second study, we assessed reproducibility in 15 volunteers (Group IIa), and extended to 43 volunteers (Group IIa & IIb) to relate PFF with MR-derived hepatic fat fraction (HFF), body mass index (BMI), and waist circumference (WC) using linear regression models. We assessed intra- and inter-observer, and between imaging modality levels of agreement using Bland-Altman plots. Results In Group I patients, we found strong levels of agreement between MRS and CS-MR derived PFF and digitally quantified fat on histology (rho: 0.781 and 0.672 respectively). In Group IIa, there was poor reproducibility in initial assessments. We refined our protocols to account for 3D dimensionality of the pancreas, and found substantially improved intra-observer agreements. In Group II, HFF and WC were significantly correlated with PFF (p values Interpretation Both CS-MR and MRS (after accounting for pancreatic 3D dimensionality) were ‘fit for purpose’ to determine PFF and might add information on cancer prediction independent from measures of general body adiposity.

There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD), however its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, a need exists to find new ways of investigating neuroinflammation in both health and disease. Here we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APPswe ×PS1Δe9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [18 F]DPA-714 positron emission tomography and myo-inositol levels using 1 H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N-acetylaspartate (NAA), choline containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12m-old in the TG mice as assessed by working memory tests. A significant increase in [18 F]DPA-714 uptake was seen in the hippocampus and cortex of 18m-old TG mice when compared to age matched WT mice and 6m-old TG mice. No overall effect of gene was seen on metabolite levels; however a significant reduction in NAA was observed in 18m-old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in aging.

It has become increasingly evident that neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased glial cell activation is consistently reported in both rodent models of AD and in AD patients. Moreover, recent genome wide association studies have revealed multiple genes associated with inflammation and immunity are significantly associated with an increased risk of AD development (e.g. TREM2). Non‐invasive in vivo detection and tracking of neuroinflammation is necessary to enhance our understanding of the contribution of neuroinflammation to the initiation and progression of AD. Importantly, accurate methods of quantifying neuroinflammation may aid early diagnosis and serve as an output for therapeutic monitoring and disease management. This review details current in vivo imaging biomarkers of neuroinflammation being explored and summarizes both pre‐clinical and clinical results from molecular imaging studies investigating the role of neuroinflammation in AD, with a focus on positron emission tomography and magnetic resonance spectroscopy (MRS).

Paired associative stimulation (PAS), is a novel non-invasive technique where two neural substrates are employed in a temporally coordinated manner in order to modulate cortico-motor excitability within the motor cortex (M1). In swallowing, combined pharyngeal electrical and transcranial-magnetic-stimulation induced beneficial neurophysiological and behavioural effects in healthy subjects and dysphagic stroke patients. Here, we aimed to investigate the whole-brain changes in neural activation during swallowing using functional magnetic resonance imaging (fMRI) following PAS application and in parallel assess associated GABA changes with magnetic resonance spectroscopy (MRS).Healthy adults (n=11, 38±9years old) were randomised to receive real and sham PAS to the 'stronger' motor cortex pharyngeal representation, on 2 separate visits. Following PAS, event-related fMRI was performed to assess changes in brain activation in response to water and saliva swallowing and during rest. Data were analysed (SPM8) at P.001. MRS data were acquired using MEGA-PRESS before and after the fMRI acquisitions on both visits and GABA concentrations were measured (AMARES, jMRUI).Following real PAS, BOLD signal changes (group analyses) increased at the site of stimulation during water and saliva swallowing, compared to sham PAS. It is also evident that PAS induced significant increases in BOLD signal to contralateral (to stimulation) hemispheric areas that are of importance to the swallowing neural network. Following real PAS, GABA:creatine ratio showed a trend to increase contralateral to PAS.Targeted PAS applied to the human pharyngeal motor cortex induces local and remote changes in both primary and non-primary areas for water and saliva tasks. There is a possibility that changes of the inhibitory neurotransmitter, GABA, may play a role in the changes in BOLD signal. These findings provide evidence for the mechanisms underlying the beneficial effects of PAS on the brain swallowing network.

Tracking stem cells in vivo using non-invasive techniques is critical to evaluate the efficacy and safety of stem cell therapies. Superparamagnetic iron oxide nanoparticles (SPIONs) enable cells to be tracked using magnetic resonance imaging (MRI), but to obtain detectable signal cells need to be labelled with a sufficient amount of iron oxide. For the majority of SPIONs, this can only be obtained with the use of transfection agents, which can adversely affect cell health. Here, we have synthesised a library of dextran-based polymer coated SPIONs with varying surface charge from -1.5 mV to +18.2 mV via a co-precipitation approach and investigated their ability to be directly internalised by stem cells without the need for transfection agents. The SPIONs were colloidally stable in physiological solutions. The crystalline phase of the particles was confirmed with powder X-ray diffraction and their magnetic properties were characterised using SQUID magnetometry and magnetic resonance. Increased surface charge led to six-fold increase in uptake of particles into stem cells and higher MRI contrast, with negligible change in cell viability. Cell tracking velocimetry was shown to be a more accurate method for predicting MRI contrast of stem cells compared to measuring iron oxide uptake through conventional bulk iron quantification.

Schizophrenia is a severe mental illness that may significantly affect maternal sensitive behaviour. Neural correlates of maternal behaviour represent a potentially valuable means of differentiating objectively between healthy mothers expressing variations in maternal sensitivity. As mothers with schizophrenia (MWS) show deficits in behavioural responses to infants compared to healthy mothers, we explored whether maternal brain responses to infant stimuli would be significantly reduced in MWS. We also examined whether differences in maternal behaviour between healthy and ill mothers (during play interactions with own infant) were associated with differences in brain activation to infant stimuli. We found no evidence of differential ‘maternal brain’ responses or ‘maternal behavioural’ responses in 11 new MWS compared to 20 healthy new mums; neither were neural responses to infants linked to behavioural or cognitive aspects of the mother's relationship with her infant in MWS. These preliminary findings suggest maternal sensitivity differences between MWS and healthy mothers, suggested in previous studies, may be reversible in stable treated MWS.

Calibration experiments precede multicenter trials to identify potential sources of variance and bias. In support of future imaging studies of mental health disorders and their treatment, the Neuro/PsyGRID consortium commissioned a calibration experiment to acquire functional and structural MRI from twelve healthy volunteers attending five centers on two occasions. Measures were derived of task activation from a working memory paradigm, fractal scaling (Hurst exponent) from resting fMRI, and grey matter distributions from T(1)‐weighted sequences. At each intracerebral voxel a fixed‐effects analysis of variance estimated components of variance corresponding to factors of center, subject, occasion, and within‐occasion order, and interactions of center‐by‐occasion, subject‐by‐occasion, and center‐by‐subject, the latter (since there is no intervention) a surrogate of the expected variance of the treatment effect standard error across centers. A rank order test of between‐center differences was indicative of crossover or noncrossover subject‐by‐center interactions. In general, factors of center, subject and error variance constituted >90% of the total variance, whereas occasion, order, and all interactions were generally

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630).

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Due to ongoing advances in our understanding of the underlying pathology of AD, many potential new targets for therapeutics are becoming available. Transgenic mouse models of AD have helped in furthering our understanding of AD and also provide a vehicle for preclinical testing of new, putative disease-modifying therapeutics, which may have potential for translation to use in clinical trials. To identify possible translational biomarkers, we have studied the longitudinal cerebral metabolic pattern of the TASTPM transgenic AD mouse, a double transgenic mouse overexpressing human mutant amyloid precursor protein (hAPP695swe) and presenilin-1 (M146V) by (1) H magnetic resonance spectroscopy, along with concurrent brain T(1) /T(2) mapping and behavioral testing. We found significant differences in creatine, glutamate, N-acetylaspartate, choline-containing compounds, and myo-inositol between TASTPM and wild-type mice. In the case of N-acetylaspartate and myo-inositol, there were similarities to differences detected in human AD. T(1) /T(2) values were shorter overall in TASTPM mice, indicating possible differences in water content between TASTPM and wild-type mice. In older TASTPM mice, exploratory behavior became more random, indicating a possible memory deficiency. The decrease in behavioral performance correlated in the transgenic group with higher expression of myo-inositol. Magn Reson Med, 2012. (c) 2012 Wiley Periodicals, Inc.

The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression.A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design.In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206.Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.

BackgroundProblematic polypharmacy is at the heart of medicines usage in patients with multimorbidity, and review by medicines experts in primary care is essential.AimTo assess the impact of medication reviews by a clinical pharmacist on ambulatory patients with hyper polypharmacyMethodThe study took place within a large urban practice in Dorset. Patients over ≥75 years old with ≥10 regular medicines were identified using the NHS Business Service Authority Polypharmacy database. Patients who were housebound, lived in a care home or with dementia were excluded and GP partners were asked to confirm the validity of these exclusions. Patients were sent a letter from their personalised GP inviting them to attend a 30-minute consultation with a clinical pharmacist prescriber employed by the practice. The age and frailty status of patients, number of medicines pre- and post-consultation, and the nature of medicines optimisation decisions were recorded. Patient satisfaction with the consultations was assessed using a 7-point Likert scale questionnaire.Results91 out of 17000 (0.5%) patients were receiving ≥ 10 medicines. 25 patients were excluded and to date 20/26 (77 %) patients invited had a consultation booked or been seen. Medicines optimisation changes varied in number and complexity and controversial changes discussed with patients’ individual GP. To date all patients rated the consultation as very good to outstanding (median score 6.5)ConclusionAmbulatory patients with hyper polypharmacy highly rated medication reviews with a clinical pharmacist and medication regimens in most were optimised through shared decision making.

Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT(2C)-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic.

Having a clinical pharmacist in the primary healthcare team is a ‘no brainer’. Prof. Avery1 suggests that any GP, and indeed patients, who have benefited from a clinical pharmacist working in their practice would never choose to be without their medicines expert. Take a look at the numbers. A practice serving a patient population of around 30 000 patients can expect to issue half a million prescriptions a year. They will have 1000 patients on more than eight medicines,2 there is a potential prescription error rate of 5%,3 and they might reasonably expect around 300 medication-related non-elective hospital admissions.4 However, as Prof. Avery alludes to, the payment model in general practice does not currently place any value on the quality and safety aspects of medicines usage. He also throws down …

Some strains of Pseudomonas aeruginosa produce R-type pyocins, which are high-molecular-weight phage tail-like protein complexes that have bactericidal activity against other Pseudomonas strains. These particles recognize and bind to bacterial surface structures via tail fibers, their primary spectrum determinant. R-type pyocins kill the cell by contracting a sheath-like structure and inserting their hollow core through the cell envelope, resulting in dissipation of the cellular membrane potential. We have retargeted an R-type pyocin to Escherichia coli O157:H7 by fusing a tail spike protein from an O157-specific phage, φV10, to the pyocin tail fiber. The φV10 tail spike protein recognizes and degrades the O157 lipopolysaccharide. This engineered pyocin, termed AVR2-V10, is sensitive and specific, killing 100% of diverse E. coli O157:H7 isolates but no other serotypes tested. AVR2-V10 can kill E. coli O157:H7 on beef surfaces, making it a candidate agent for the elimination of this pathogen from food products. All rare AVR2-V10-resistant mutants isolated and examined have lost the ability to produce the O157 antigen and are expected to have compromised virulence. In addition, E. coli O157:H7 exposed to and killed by AVR2-V10 do not release Shiga toxin, as is often the case with many antibiotics, suggesting potential therapeutic applications. The demonstration that a novel R-type pyocin can be created in the laboratory by fusing a catalytic tail spike from the family Podoviridae to a tail fiber of a member of the family Myoviridae is evidence that the plasticity observed among bacteriophage tail genes can, with modern molecular techniques, be exploited to produce nonnatural, targeted antimicrobial agents.

This study assessed the effects of a session of eye movement desensitization and reprocessing (EMDR) with auditory alternating bilateral stimulation (ABS) using functional magnetic resonance imaging (fMRI) of brain activations. A case study was conducted with a female participant who was suffering from posttraumatic stress disorder following a severe assault. The fMRI scan began with safe-place imagery, for purposes of comparison, and then attention to the trauma memory without ABS. After this, ABS was provided as she began using EMDR procedures to process the traumatic memory. At postsession, the traumatic memory showed robust and significant changes on self-report measures. The initiation of the EMDR protocol with provision of ABS was associated with a marked change in brain activation within the prefrontal cortex demonstrating a ventromedial shift. The authors argue that the structure of the EMDR protocol encourages such a ventromedial activation, which is then intensified by ABS to overcome the block to information processing that has been preventing natural healing from occurring spontaneously.

OBJECTIVE: There is increasing evidence for subtle changes in brain morphology and function in patients with borderline personality disorder (BPD). Structural brain imaging studies show lower volume in frontal, temporal and parietal brain regions than in healthy controls. The aim of our preliminary study of men with BPD was to investigate structural brain changes and their relationship with a measure of impulsivity. METHODS: We examined seven male patients with BPD and six control men using voxel-based morphometry. Analysis of covariance was carried out to assess regionally specific differences in grey and white matter (WM) volumes. Correlations between trait impulsivity as measured using the Impulsiveness-Venturesomeness-Empathy scale and brain volumes were studied. RESULTS: Compared with healthy men, men with BPD had similar WM volumes but smaller grey matter (GM) volumes in frontal, temporal and parietal cortices. The latter were negatively correlated with trait impulsivity. CONCLUSIONS: Our findings fit with previous reports of smaller regional GM volumes reported in women with BPD, and suggest that in men there may be an association between smaller GM volumes and impulsivity.

In this study, pharmacological-challenge magnetic resonance imaging was used to further characterize the central action of serotonin on feeding. In both feeding and pharmacological-challenge magnetic resonance imaging experiments, we combined 5-HT(1B/2C) agonist m-chlorophenylpiperazine (mCPP) challenge with pre-treatment with the selective 5-HT(1B) and 5-HT(2C) receptor antagonists, SB 224289 (2.5 mg/kg) and SB 242084 (2 mg/kg), respectively. Subcutaneous injection of mCPP (3 mg/kg) completely blocked fast-induced refeeding in freely behaving, non-anaesthetized male rats, an effect that was not modified by the 5-HT(1B) receptor antagonist but was partially reversed by the 5-HT(2C) receptor antagonist. mCPP alone induced both positive and negative blood oxygen level-dependent (BOLD) responses in the brains of anaesthetized rats, including in the limbic system and basal ganglia. Overall, the 5-HT(2C) antagonist SB 242084 reversed the effects elicited by mCPP, whereas the 5-HT(1B) antagonist SB 224289 had virtually no impact. SB 242084 eliminated BOLD signal in nuclei associated with the limbic system and diminished activation in basal ganglia. In addition, BOLD signal was returned to baseline levels in the cortical regions and cerebellum. These results suggest that mCPP may reduce food intake by acting specifically on brain circuits that are modulated by 5-HT(2C) receptors in the rat.

We have used blood-oxygenation-level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) to characterise brain regions responsive to a regulator of appetite. An anorectic dose of the 5-HT 1B/2C receptor agonist m -chlorophenylpiperazine (mCPP; 3 mg/kg s.c.) was used to compare BOLD contrast fMRI with expression of the c-Fos protein. mCPP was administered to rats, which were then anaesthetised and perfused with fixative 90 min later to allow immunohistochemistry. In a separate experiment, rats were imaged using a T 2 *-weighted gradient echo in a 7 T magnet for 70 min under α-chloralose anaesthesia. Both methods detected positive activation in areas of the limbic system: cingulate and orbitofrontal cortices, nucleus accumbens, paraventricular and dorsomedial regions of the hypothalamus. fMRI detected increased signal in the pontine nuclei, the hippocampal formation and olfactory cortex, areas that did not display c-Fos. In addition, BOLD signal was diminished in the ventral tegmental area, preoptic area and the cerebellum—presumably due to decreased neuronal signalling and, therefore, unlikely to display c-Fos. Activity in the limbic system may reflect the appetitive agonist activity of mCPP at the 5-HT 2C receptor. We conclude that c-Fos provides excellent spatial information but is less useful for detecting inhibited regions, whereas fMRI provides greater temporal resolution. Thus, the two methodologies provide complementary details of brain activity following pharmacological challenge.

Our objective was to develop a diffusion tensor MR imaging pulse sequence that allows whole brain coverage with isotropic resolution within a clinically acceptable time. A single‐shot, cardiac‐gated MR pulse sequence, optimized for measuring the diffusion tensor in human brain, was developed to provide whole‐brain coverage with isotropic (2.5 × 2.5 × 2.5 mm) spatial resolution, within a total imaging time of approximately 15 min. The diffusion tensor was computed for each voxel in the whole volume and the data processed for visualization in three orthogonal planes. Anisotropy data were further visualized using a maximum‐intensity projection algorithm. Finally, reconstruction of fiber‐tract trajectories i.e., ‘tractography’ was performed. Images obtained with this pulse sequence provide clear delineation of individual white matter tracts, from the most superior cortical regions down to the cerebellum and brain stem. Because the data are acquired with isotropic resolution, they can be reformatted in any plane and the sequence can therefore be used, in general, for macroscopic neurological or psychiatric neuroimaging investigations. The 3D visualization afforded by maximum intensity projection imaging and tractography provided easy visualization of individual white matter fasciculi, which may be important sites of neuropathological degeneration or abnormal brain development. This study has shown that it is possible to obtain robust, high quality diffusion tensor MR data at 1.5 Tesla with isotropic resolution (2.5 × 2.5 × 2.5 mm) from the whole brain within a sufficiently short imaging time that it may be incorporated into clinical imaging protocols. Hum. Brain Mapping 15:216–230, 2002. © 2002 Wiley‐Liss, Inc.

With only a few exceptions, the precursor cells representing the normal counterparts of human tumours are unknown. The comparative lack of information about the lineages involved in tissue development, and difficulties in growing many human tumors in a manner suitable for cellular biological analysis, together often make it difficult to study the differences between normal and tumor cells and to develop many of the model systems that would be useful in the study of human cancer. By applying techniques previously utilized to study glial progenitor cells, we have isolated a human glioblastoma multiforme (GBM)-derived population that expresses many properties otherwise uniquely expressed by oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. Hu-O-2A/Gb1 (for Human O-2A lineage Glioblastoma number 1) cells responded to similar mitogens and differentiation modulators as rodent O-2A progenitors, and generated cells with features of precursor cells, oligodendrocytes and astrocytes. Moreover, 1H-NMR analysis of amino acid composition demonstrated a striking conversation of types and quantities of free amino acids between the human tumour cells and the rodent primary cells. Hu-O-2A/Gb1 cells represent the first human glioma-derived population for which unambiguous lineage assignment has been possible, and our results indicate that the human O-2A lineage can contribute to one of the most malignant of glial tumours. In addition, the highly diagnostic 1H-NMR spectrum expressed by Hu-O-2A/Gb1 cells raises the possibility of eventual non-invasive identification of tumors of this lineage.

Poly[2-(methacryloyloxy)ethylphosphorylcholine]-coated SPIONs were prepared through ATRP and amidation coupling reactions. The coated SPIONs exhibited high stability and re-dispersability in phosphate buffered saline and uptake in a stem cell line, with high T(2) relaxivity.

OBJECTIVE: Increased amygdala response to negative emotions seen in functional MRI (fMRI) has been proposed as a biomarker for negative emotion processing bias underlying depressive symptoms and vulnerability to depressive relapse that are normalized by antidepressant drug treatment. The purpose of this study was to determine whether abnormal amygdala responses to face emotions in depression are related to specific emotions or change in response to antidepressant treatment and whether they are present as a stable trait in medication-free patients in remission. METHOD: Sixty-two medication-free unipolar depressed patients (38 were currently depressed, and 24 were in remission) and 54 healthy comparison subjects underwent an indirect face-emotion processing task during fMRI. Thirty-two currently depressed patients were treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring citalopram plasma concentrations. RESULTS: Patients with current depression had increased bilateral amygdala responses specific to sad faces relative to healthy comparison subjects and nonmedicated patients in stable remission. Treatment with citalopram abolished the abnormal amygdala responses to sad faces in currently depressed patients but did not alter responses to fearful faces. CONCLUSIONS: Aberrant amygdala activation in response to sad facial emotions is specific to the depressed state and is a potential biomarker for a negative affective bias during a depressive episode.

Aims: Pharmacological-challenge magnetic resonance imaging (phMRI) is powerful new tool enabling researchers to map the central effects of neuroactive drugs in vivo. To employ this technique pre-clinically, head movements and the stress of restraint are usually reduced by maintaining animals under general anaesthesia. However, interactions between the drug of interest and the anaesthetic employed may potentially confound data interpretation. NMDA receptor (NMDAR) antagonists used widely to mimic schizophrenia have recently been shown to interact with the anaesthetic halothane. It may be the case that neural and cerebrovascular responses to NMDAR antagonists are dependent on the types of anaesthetic used. Methodology: We compared the phMRI response to NMDAR antagonist ketamine in rats maintained under α -chloralose to those under isoflurane anaesthesia. A randomized placebo/vehicle controlled design was used in each of the anaesthetic groups. Results: Changes in the anaesthetic agent resulted in two very different profiles of activity. In the case of α -chloralose, positive activations in cortical and sub-cortical structures reflected a response which was similar to patterns seen in healthy human volunteers and metabolic maps of conscious rats. However, the use of isoflurane completely reversed such effects, causing widespread deactivations in the cortex and hippocampus. Conclusion: This study provides initial evidence for a drug-anesthetic interaction between ketamine and isoflurane that is very different from responses toα -chloraloseketamine. Research Article

Hemopressin is the first peptide ligand to be described for the CB₁ cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB₁ inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB₁ inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB₁ receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways.

Objective Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. Design phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. Results A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. Conclusion Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.

Background Brain morphometry is extensively used in cross-sectional studies. However, the difference in the estimated values of the morphometric measures between patients and healthy subjects may be small and hence overshadowed by the scanner-related variability, especially with multicentre and longitudinal studies. It is important therefore to investigate the variability and reliability of morphometric measurements between different scanners and different sessions of the same scanner. Methods We assessed the variability and reliability for the grey matter, white matter, cerebrospinal fluid and cerebral hemisphere volumes as well as the global sulcal index, sulcal surface and mean geodesic depth using Brainvisa. We used datasets obtained across multiple MR scanners at 1.5 T and 3 T from the same groups of 13 and 11 healthy volunteers, respectively. For each morphometric measure, we conducted ANOVA analysis and verified whether the estimated values were significantly different across different scanners or different sessions of the same scanner. The between-centre and between-visit reliabilities were estimated from their contribution to the total variance, using a random-effects ANOVA model. To estimate the main processes responsible for low reliability, the results of brain segmentation were compared to those obtained using FAST within FSL. Results In a considerable number of cases, the main effects of both centre and visit factors were found to be significant. Moreover, both between-centre and between-visit reliabilities ranged from poor to excellent for most morphometric measures. A comparison between segmentation using Brainvisa and FAST revealed that FAST improved the reliabilities for most cases, suggesting that morphometry could benefit from improving the bias correction. However, the results were still significantly different across different scanners or different visits. Conclusions Our results confirm that for morphometry analysis with the current version of Brainvisa using data from multicentre or longitudinal studies, the scanner-related variability must be taken into account and where possible should be corrected for. We also suggest providing some flexibility to Brainvisa for a step-by-step analysis of the robustness of this package in terms of reproducibility of the results by allowing the bias corrected images to be imported from other packages and bias correction step be skipped, for example.

Aberrant signalling through central 5-HT(2C) receptor pathways has been implicated in various psychiatric disorders but this has not been amenable to experimental investigation in the absence of a valid in-vivo biomarker of functional 5-HT(2C) neurotransmission. One approach is drug-challenge pharmaco-magnetic resonance imaging (phMRI). We have previously shown that intravenous administration of the 5-HT(2C) agonist m-chlorophenylpiperazine (mCPP) elicits increases in blood oxygenation dependent signal (BOLD) in regions consistent with the distribution of 5-HT(2C) receptors. In the current study we determined whether BOLD signal responses to mCPP could be blocked by pre-treatment with a 5-HT(2C) antagonist. Healthy male volunteers received oral mirtazapine, 5-HT(2)/5-HT(3) receptor antagonist, or placebo 90min prior to intravenous mCPP challenge phMRI. BOLD signal increases following mCPP infusion occurred in areas known to be rich in 5-HT(2C) receptors such as the substantia nigra, hypothalamus, pallidum and amygdala. These responses were attenuated by mirtazapine pre-treatment. The results suggest that mCPP-challenge phMRI produces reliable patterns of response that are mediated by 5-HT(2C) receptors; these responses may therefore be useful in-vivo measures of 5-HT(2C) function in psychiatric disorders.

The glucose analogue, 2-deoxy-D-glucose (2-DG) is an inhibitor of glycolysis and, when administered systemically or centrally, induces glucoprivation leading to counter-regulatory responses, including increased feeding behaviour. Investigations into how the brain responds to glucoprivation could have important therapeutic potential, as disruptions or defects in the defence of the brain's 'glucostatic' circuitry may be partly responsible for pathological conditions resulting from diabetes and obesity. To define the 'glucostat' brain circuitry further we have combined blood-oxygen-level-dependent pharmacological-challenge magnetic resonance imaging (phMRI) with whole-brain c-Fos functional activity mapping to characterise brain regions responsive to an orexigenic dose of 2-DG [200 mg/kg; subcutaneous (s.c.)]. For phMRI, rats were imaged using a T(2)*-weighted gradient echo in a 7T magnet for 60 min under alpha-chloralose anaesthesia, whereas animals for immunohistochemistry were unanaesthetised and freely behaving. These complementary methods demonstrated functional brain activity in a number of previously characterised glucose-sensing brain regions such as those in the hypothalamus and brainstem following administration of 2-DG compared with vehicle. As the study mapped whole-brain functional responses, it also identified the orbitofrontal cortex and striatum (nucleus accumbens and ventral pallidum) as novel 2-DG-responsive brain regions. These regions make up a corticostriatal connection with the hypothalamus, by which aspects of motivation, salience and reward can impinge on the hypothalamic control of feeding behaviour. This study, therefore, provides further evidence for a common integrated circuit involved in the induction of feeding behaviour, and illustrates the valuable potential of phMRI in investigating central pharmacological actions.

Magnetic resonance imaging (MRI) is widely used in brain imaging research (neuroimaging) to explore structural and functional changes across dispersed neural networks visible only via multisubject experiments. Multicenter investigations are an effective way to increase recruitment rates. This article describes image‐based power calculations for a two‐group, cross‐sectional design specified by the mean effect size and its standard error, sample size, false discovery rate (FDR), and size of the network (i.e., proportion of image locations) that truly demonstrates an effect. Minimum sample size (for fixed effect size) and the minimum effect size (for fixed sample size) are calculated by specifying the acceptable power threshold. Within‐center variance was estimated in five participating centers by repeat MRI scanning of 12 healthy participants from whom distributions of gray matter were estimated. The effect on outcome measures when varying FDR and the proportion of true positives is presented. Their spatial patterns reflect within‐center variance, which is consistent across centers. Sample sizes 3–6 times larger are needed when detecting effects in subcortical regions compared to the neocortex. Hypothesized multicenter studies of patients with first episode psychosis and control participants were simulated with varying proportions of the cohort recruited at each center. There is little penalty to sample size for recruitment at five centers compared to the center with the lowest variance alone. At 80% power 80 participants per group are required to observe differences in gray matter in high variance regions. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

The 6 year review of voluntary medication incident reporting by Cousins et al. [1] is very interesting, and I agree wholeheartedly with its conclusions that the new National Health Service (NHS) must continue to interrogate the National Reporting and Learning System (NRLS) to mandate NHS organizations to make changes to reduce harms from, in particular, high-risk medication/practices. It is, however, impractical to expect health professionals voluntarily to report all medication incidents, because prescribing errors alone have been shown to occur in 8.9% of all medication orders written in UK hospitals [2]. This equates to approximately 40 000/year, of which 700 are potentially fatal, for an average 900-bedded hospital. The sheer ‘size’ of the medication error problem thus adds to the already accepted barriers to the reporting of any adverse events by health professionals [3], namely knowledge (what and when to report), outcomes (perceived lack of feedback and positive change), effort (simplicity of reporting form) and fears (personal). Recently, I have explored the attitudes of hospital pharmacists to reporting medication errors, involving both focus groups [4] and a Theory of Planned Behaviour [5] questionnaire, and this has led me to conclude that the key to improved reporting of medication errors by pharmacists, and possibly by all health professionals, is potentially threefold, and in this order: (i) confidence, i.e. increasing personal confidence of health professionals to report their clinical colleagues' errors and increasing overall confidence by positively ‘selling’ system changes after reporting; (ii) clarity, i.e. greater clarity about which medication errors should be reported, including locally targeted reporting or a nationally implemented reporting hierarchy; and (iii) simplicity, i.e. simpler drug-specific reporting forms. Whilst increasing confidence is not a short-term fix, the introduction of a national simpler reporting form and introduction of targeted reporting could be done more easily and swiftly. With regard to greater clarity about reporting, I think it could be extremely helpful if NHS organizations uniformly adopted a ‘yellow card'-like approach to which medication incident reports we really want health professionals to report, such as the following: all serious medication errors for any drugs which are fatal, life-threatening, disabling or incapacitating, which result in or prolong hospitalization or are medically significant; all medication errors (including near misses) for high-risk medicines or medicines under intensive surveillance by the NRLS (identified by a new symbol in the British National Formulary, like the black triangle for adverse drug reactions); any medication errors due to a witnessed repetitive failure by an individual practitioner or because of a system; and all malicious or reckless violation-type medication errors. Exactly as for our national voluntary adverse drug reaction reporting scheme, we need to be able to ‘see the wood for the trees’ and reliably detect the important signals in all the noise that is generated about medication incidents. I believe this measure, in particular, could allow local organizations, and the NHS as a whole, better to focus their efforts in protecting our patients from preventable and repetitive harms due to medication.

CONTEXT: Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. OBJECTIVES: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. DESIGN: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level-dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. SETTING: Wellcome Trust Clinical Research Facility, Manchester, England. PARTICIPANTS: Thirty-three healthy, right-handed men were recruited by advertisements. INTERVENTIONS: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. MAIN OUTCOME MEASURES: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores. RESULTS: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. CONCLUSIONS: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

In this study, pharmacological-challenge magnetic resonance imaging was used to further characterize the central action of serotonin on feeding. In both feeding and pharmacological-challenge magnetic resonance imaging experiments, we combined 5-HT(1B/2C) agonist m-chlorophenylpiperazine (mCPP) challenge with pre-treatment with the selective 5-HT(1B) and 5-HT(2C) receptor antagonists, SB 224289 (2.5 mg/kg) and SB 242084 (2 mg/kg), respectively. Subcutaneous injection of mCPP (3 mg/kg) completely blocked fast-induced refeeding in freely behaving, non-anaesthetized male rats, an effect that was not modified by the 5-HT(1B) receptor antagonist but was partially reversed by the 5-HT(2C) receptor antagonist. mCPP alone induced both positive and negative blood oxygen level-dependent (BOLD) responses in the brains of anaesthetized rats, including in the limbic system and basal ganglia. Overall, the 5-HT(2C) antagonist SB 242084 reversed the effects elicited by mCPP, whereas the 5-HT(1B) antagonist SB 224289 had virtually no impact. SB 242084 eliminated BOLD signal in nuclei associated with the limbic system and diminished activation in basal ganglia. In addition, BOLD signal was returned to baseline levels in the cortical regions and cerebellum. These results suggest that mCPP may reduce food intake by acting specifically on brain circuits that are modulated by 5-HT(2C) receptors in the rat.

Background There is a need for effective and early functional rehabilitation of patients with gait and balance problems including those with spinal cord injury, neurological diseases and recovering from hip fractures, a common consequence of falls especially in the elderly population. Gait training in these patients using partial body weight support (BWS) on a treadmill, a technique that involves unloading the subject through a harness, improves walking better than training with full weight bearing. One problem with this technique not commonly acknowledged is that the harness provides external support that essentially eliminates associated postural adjustments (APAs) required for independent gait. We have developed a device to address this issue and conducted a training study for proof of concept of efficacy. Methods We present a tool that can enhance the concept of BWS training by allowing natural APAs to occur mediolaterally. While in a supine position in a 90 deg tilted environment built around a modified hospital bed, subjects wear a backpack frame that is freely moving on air-bearings (cf. puck on an air hockey table) and attached through a cable to a pneumatic cylinder that provides a load that can be set to emulate various G-like loads. Veridical visual input is provided through two 3-D automultiscopic displays that allow glasses free 3-D vision representing a virtual surrounding environment that may be acquired from sites chosen by the patient. Two groups of 12 healthy subjects were exposed to either strength training alone or a combination of strength and balance training in such a tilted environment over a period of four weeks. Results Isokinetic strength measured during upright squat extension improved similarly in both groups. Measures of balance assessed in upright showed statistically significant improvements only when balance was part of the training in the tilted environment. Postural measures indicated less reliance on visual and/or increased use of somatosensory cues after training. Conclusion Upright balance function can be improved following balance specific training performed in a supine position in an environment providing the perception of an upright position with respect to gravity. Future studies will implement this concept in patients.

The tarsier skull has been of particular interest in studies of primate taxonomy and functional morphology for several decades. Despite this, there remains no comprehensive data on how the tarsier skull develops, especially in relation to the soft-tissues of the head. Here we have documented for the first time fetal development of the skull and brain as well as the nasal septum and eyes in T. bancanus. We have also tested for the possible influence of these tissues in shaping skull architecture. Nineteen post-mortem specimens were imaged using high-resolution magnetic resonance imaging and magnetic resonance microscopy. Landmarks and volume data were collected and analysed. Findings demonstrated massive increases of brain size and eye size as well as flattening of the midline cranial base, facial projection and orbital margin frontation. Little evidence was found to support the notion that growth of the brain or nasal septum physically drives the observed changes of the skull. However, increases in the size of the eyes relative to skull size were associated with orbital margin frontation. With the possible exception of the results for eye size, the findings indicate that rather than forcing change the soft-tissues form a framework that physically constrains the morphogenetic template of the skeletal elements. This suggests, for example, that the degree of cranial base angulation seen in adulthood is not directly determined by brain expansion bending the basicranium, but by brain enlargement limiting the extent of cranial base flattening (retroflexion) in the fetus.

Prevention of neuron death after peripheral nerve injury is vital to regaining adequate cutaneous innervation density and quality of sensation, and while experimentally proven neuroprotective therapies exist, there lacks suitable clinical outcome measures for translational research. Axotomized dorsal root ganglia (DRG) histologically exhibit volume reduction in proportion to the amount of neuronal death within them. Hence, this study evaluated the validity of using magnetic resonance imaging (MRI) to quantify DRG volume as a proxy measure of cell death. A high-resolution 3D MRI sequence was developed for volumetric quantification of the L4 DRG in the rat sciatic nerve model. An unoperated "control" group (n=4), and a "nerve transection" group (n=6), 4 weeks after axotomy, were scanned. Accuracy and validity of the technique were evaluated by comparison with morphological quantification of DRG volume and stereological counts of surviving neurons (optical fractionator). The technique was precise (coefficient of variation=4.3%), highly repeatable (9% variability), and sensitive (mean 15.0% volume reduction in axotomized ganglia detected with statistical significance: p

Stimulation of mature T cells activates a downstream signaling cascade involving temporally and spatially regulated phosphorylation and dephosphorylation events mediated by protein-tyrosine kinases and phosphatases, respectively. PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin, notably in T cells where it represses signaling through the T cell receptor. We used substrate trapping coupled with mass spectrometry-based peptide identification in an unbiased approach to identify physiological substrates of PTPN22. Several potential substrates were identified in lysates from pervanadate-stimulated Jurkat cells using PTPN22-D195A/C227S, an optimized substrate trap mutant of PTPN22. These included three novel PTPN22 substrates (Vav, CD3epsilon, and valosin containing protein) and two known substrates of PEP, the mouse homolog of PTPN22 (Lck and Zap70). T cell antigen receptor (TCR) zeta was also identified as a potential substrate in Jurkat lysates by direct immunoblotting. In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.

Changes in serotonin neurotransmission have also been implicated in the etiology and treatment of impulse control disorders, depression, and anxiety. We have investigated the effect of enhancing serotonin function on fundamental brain processes that we have proposed are abnormal in these disorders. In all, 12 male volunteers received citalopram (7.5?mg intravenously) and placebo pretreatment in a single-blind crossover design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces. Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss (ie relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric disorders but argue for a process-specific, rather than general effect. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human psychiatric disorders.

BACKGROUND: Accumulating evidence suggests that mothers show a different pattern of brain responses when viewing their own compared to other infants. However, there is inconsistency across functional imaging studies regarding the key areas involved, and none have examined relationships between brain and behavioural responses to infants. We examined the brain regions activated when mothers viewed videos of their own infant contrasted with an unknown infant, and whether these are associated with behavioural and self-reported measures of mother-infant relations. METHOD: Twenty right-handed mothers viewed alternating 30-sec blocks of video of own 4-9 month infant and an unfamiliar matched infant, interspersed with neutral video. Whole brain functional magnetic resonance images (fMRI) were acquired on a 1.5T Philips Intera scanner using a TR of 2.55 s. Videotaped mother-infant interactions were systematically evaluated blind to family information to generate behavioural measures for correlational analysis. RESULTS: Enhanced blood oxygenation functional imaging responses were found in the own versus unknown infant contrast in the bilateral precuneus, right superior temporal gyrus, right medial and left middle frontal gyri and left amygdala. Positive mother-infant interaction (less directive parent behaviour; more positive/attentive infant behaviour) was significantly associated with greater activation in several regions on viewing own versus unknown infant, particularly the middle frontal gyrus. Mothers' perceived warmth of her infant was correlated with activations in the same contrast, particularly in sensory and visual areas. CONCLUSION: This study partially replicates previous reports of the brain regions activated in mothers in response to the visual presentation of their own infant. It is the first to report associations between mothers' unique neural responses to viewing their own infant with the quality of her concurrent behaviour when interacting with her infant and with her perceptions of infant warmth. These findings provide support for developing fMRI as a potential biomarker of parenting risk and change.

Cell culture techniques, high-resolution in vitro H-1 nuclear magnetic resonance (NMR) spectroscopy, and chromatographic analyses were used to compare the properties of purified cell populations derived from the PNS and cortical neurones, Cell cultures were immunocytochemically characterised with specific antibodies to ensure purity of the individual cultures, Spectra of perchloric acid extracts of cultured Schwann cells, perineural fibroblasts, dorsal root ganglion neurones, and cortical neurones displayed several common features. However, statistically significant differences were found by H-1 NMR spectroscopy in most metabolites among the cell types studied. In addition, cells could be distinguished by the presence or absence of certain amino acids, For example, N-acetylaspartate was present in dorsal root ganglion neurones and cortical neurones, gamma-aminobutyric acid was present in large amounts in cortical neurones, and Schwann cell spectra displayed a large signal from glycine, These results extend our earlier findings that different cell types of the CNS exhibit highly characteristic metabolite profiles to now include the major cell types of the PNS, These latter cell types also exhibit characteristic metabolite compositions, such that even Schwann cells and oligodendrocyte type 2 astrocyte (O-2A) progenitor cells-precursors of the myelinating cells of the CNS and PNS, respectively-can be readily distinguished from each other.

The effect of novel anti-cancer agents on the vascular properties of radiation-induced fibrosarcomas in C3H-strain mice was evaluated in vivo using dynamic contrast-enhanced (DCE) MRI. A T1-weighted volume acquisition was used to obtain DCE-MRI data. Pre-contrast T1 measurements and the contrast agent arterial input function were used to estimate the volume transfer constant (Ktrans) and extravascular extracellular volume fraction (ve). Five novel combretastatin analogues, combretastatin A-4 (CA-4) and hazelnut oil (vehicle) were tested for their effect 24 hours after administration on the tumours. Three of the five agents and the positive control (CA-4), significantly decreased tumour Ktrans and ve: Ktrans for CA-4 by 72%; fluorocombretastatin by 75%; methylcombretastatin by 68%; and ve by 40% for methylcombretastatin and 75% for the combretastatin quinone. These agents were recommended for further consideration. These results suggest that DCE-MRI may be a useful tool for pre-clinical evaluation of anti-cancer drugs.