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1.  Amyloid Imaging With Carbon 11–Labeled Pittsburgh Compound B for Traumatic Brain Injury 
JAMA neurology  2014;71(1):23-31.
To image amyloid deposition in patients with traumatic brain injury (TBI) using carbon 11–labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) and to validate these findings using tritium-labeled PiB ([3H]PiB) autoradiography and immunocytochemistry in autopsy-acquired tissue.
In vivo PET at tertiary neuroscience referral center and ex vivo immunocytochemistry of autopsy-acquired brain tissue from a neuropathology archive. [11C]PiB PET was used to image amyloid deposition in 11 controls (median [range] age, 35 [24–60] years) and in 15 patients (median [range] age, 33 [21–50] years) between 1 and 361 days after a TBI. [3H]PiB autoradiography and immunocytochemistry for β-amyloid (Aβ) and β-amyloid precursor protein in brain tissue were obtained from separate cohorts of 16 patients (median [range] age, 46 [21–70] years) who died between 3 hours and 56 days after a TBI and 7 controls (median [range] age, 61 [29–71] years) who died of other causes.
We quantified the [11C]PiB distribution volume ratio and standardized uptake value ratio in PET images. The distribution volume ratio and the standardized uptake value ratio were measured in cortical gray matter, white matter, and multiple cortical and white matter regions of interest, as well as in striatal and thalamic regions of interest. We examined [3H]PiB binding and Aβ and β-amyloid precursor protein immunocytochemistry in autopsy-acquired brain tissue.
Compared with the controls, the patients with TBI showed significantly increased [11C]PiB distribution volume ratios in cortical gray matter and the striatum (corrected P < .05 for both), but not in the thalamus or white matter. Increases in [11C]PiB distribution volume ratios in patients with TBI were seen across most cortical subregions, were replicated using comparisons of standardized uptake value ratios, and could not be accounted for by methodological confounders. Autoradiography revealed [3H]PiB binding in neocortical gray matter, in regions where amyloid deposition was demonstrated by immunocytochemistry; white matter showed Aβ and β-amyloid precursor protein by immunocytochemistry, but no [3H]PiB binding. No plaque-associated amyloid immunoreactivity or [3H]PiB binding was seen in cerebellar gray matter in autopsy-acquired tissue from either controls or patients with TBI, although 1 sample of cerebellar tissue from a patient with TBI showed amyloid angiopathy in meningeal vessels.
[11C]PiB shows increased binding following TBI. The specificity of this binding is supported by neocortical [3H]PiB binding in regions of amyloid deposition in the postmortem tissue of patients with TBI. [11C]PiB PET could be valuable in imaging amyloid deposition following TBI.
PMCID: PMC4084932  PMID: 24217171
2.  A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats 
Neuropharmacology  2014;79(100):335-344.
The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.
•We have identified novel targets for the flavonoid actions in the brain.•Flavonoid ingestion facilitates hippocampal-dependent learning in healthy animals.•Flavonoids regulate hippocampal PSA-NCAM in the Dentate Gyrus of the hippocampus.•Flavonoids modulate the levels of hippocampal glutamate receptors (NMDA-NR2B).
PMCID: PMC4062943  PMID: 24333331
Memory; Learning; Flavonoid; Hippocampus; BDNF; PSA-NCAM; NMDR2B
3.  Frictional Resistance of Three Types of Ceramic Brackets 
To investigate the static frictional resistance at the bracket/archwire interface in two recently introduced bracket systems and compare them to conventional ceramic and conventional metal bracket systems. Three variables were considered including the bracket system, archwire type and archwire angulation.
Material and Methods
Four bracket systems were tested in vitro: Self ligating ceramic, ceramic with metal slot and module, conventional ceramic with module and conventional metal with module. A specially constructed jig and an Instron testing machine were used to measure the static frictional resistance for 0.014 inches round and 0.018 x 0.025 inches rectangular stainless steel wires at 0° and 7° angulations. Main outcome measures: static frictional force at the bracket/archwire interface; recorded and measured in units of force (Newtons).
Self ligating ceramic and metal slot ceramic bracket systems generated significantly less static frictional resistance than conventional ceramic bracket systems with the wire at both angulations (P < 0.05). Changing the wire from 0.014 round to 0.018 x 0.025 rectangular wire significantly increased frictional forces for metal slot ceramic and conventional metal bracket systems (P < 0.01). Increasing wire angulation significantly increased frictional resistance at the bracket/archwire interface for all four types of bracket systems tested (P < 0.001).
Compared to conventional ceramic, self ligating ceramic and metal slot ceramic bracket systems should give improved clinical performance, matching that of conventional metal brackets.
PMCID: PMC3904729  PMID: 24478913
friction; ceramics; orthodontic brackets; corrective orthodontics; orthodontic wires.
4.  Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression 
PeerJ  2013;1:e214.
To date, anticonvulsant effects of the plant cannabinoid, cannabidivarin (CBDV), have been reported in several animal models of seizure. However, these behaviourally observed anticonvulsant effects have not been confirmed at the molecular level. To examine changes to epilepsy-related gene expression following chemical convulsant treatment and their subsequent control by phytocannabinoid administration, we behaviourally evaluated effects of CBDV (400 mg/kg, p.o.) on acute, pentylenetetrazole (PTZ: 95 mg/kg, i.p.)-induced seizures, quantified expression levels of several epilepsy-related genes (Fos, Casp 3, Ccl3, Ccl4, Npy, Arc, Penk, Camk2a, Bdnf and Egr1) by qPCR using hippocampal, neocortical and prefrontal cortical tissue samples before examining correlations between expression changes and seizure severity. PTZ treatment alone produced generalised seizures (median: 5.00) and significantly increased expression of Fos, Egr1, Arc, Ccl4 and Bdnf. Consistent with previous findings, CBDV significantly decreased PTZ-induced seizure severity (median: 3.25) and increased latency to the first sign of seizure. Furthermore, there were correlations between reductions of seizure severity and mRNA expression of Fos, Egr1, Arc, Ccl4 and Bdnf in the majority of brain regions in the CBDV+PTZ treated group. When CBDV treated animals were grouped into CBDV responders (criterion: seizure severity ≤3.25) and non-responders (criterion: seizure severity >3.25), PTZ-induced increases of Fos, Egr1, Arc, Ccl4 and Bdnf expression were suppressed in CBDV responders. These results provide the first molecular confirmation of behaviourally observed effects of the non-psychoactive, anticonvulsant cannabinoid, CBDV, upon chemically-induced seizures and serve to underscore its suitability for clinical development.
PMCID: PMC3840466  PMID: 24282673
Cannabinoid; Pentylenetetrazole; Cannabidivarin; qPCR; Seizure; Epilepsy
5.  Dietary Levels of Pure Flavonoids Improve Spatial Memory Performance and Increase Hippocampal Brain-Derived Neurotrophic Factor 
PLoS ONE  2013;8(5):e63535.
Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01), suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.
PMCID: PMC3665790  PMID: 23723987
6.  Dichotomous Organization of the External Globus Pallidus 
Neuron  2012;74(6):1075-1086.
Different striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.
► Identified key elements of fundamentally-important dichotomous organization of GPe ► First correlation of GPe neuron firing in vivo with neurochemistry and structure ► Discovered arkypallidal neurons that massively and specifically innervate striatum ► Defined new factors for widespread and excessive beta oscillations in Parkinson's disease
By rigorously defining the neurochemical and structural properties of individual neurons recorded in vivo, Mallet et al. reveal the foundations of a striking functional dichotomy in the external globus pallidus, including a novel cell type that exclusively targets striatum.
PMCID: PMC3407962  PMID: 22726837
7.  Bilateral Consequences of Chronic Unilateral Deafferentation in the Auditory System of the Cricket Gryllus bimaculatus 
Developmental Neuroscience  2011;33(1):21-37.
The auditory system of the cricket has the unusual ability to respond to deafferentation by compensatory growth and synapse formation. Auditory interneurons such as ascending neuron 2 (AN-2) in the cricket Gryllus bimaculatus possess a dendritic arbor that normally grows up to, but not over, the midline of the prothoracic ganglion. After chronic deafferentation throughout larval development, however, the AN-2 dendritic arbor changes dramatically, and medial dendrites sprout across the midline where they form compensatory synapses with the auditory afferents from the contralateral ear. We quantified the extent of the effects of chronic, unilateral deafferentation by measuring several cellular parameters of 3 different neuronal components of the auditory system: the deafferented AN-2, the contralateral (or nondeafferented) AN-2 and the contralateral auditory afferents. Neuronal tracers and confocal microscopy were used to visualize neurons, and double-label experiments were performed to examine the cellular relationship between pairs of cells. Dendritic complexity was quantified using a modified Sholl analysis, and the length and volume of processes and presynaptic varicosities were assessed under control and deafferented conditions. Chronic deafferentation significantly influenced the morphology of all 3 neuronal components examined. The overall dendritic complexity of the deafferented AN-2 dendritic arbor was reduced, while both the contralateral AN-2 dendritic arbor and the remaining, intact, auditory afferents grew longer. We found no significant changes in the volume or density of varicosities after deafferentation. These complex cellular changes after deafferentation are interpreted in the light of the reported differential regulation of vesicle-associated membrane protein and semaphorin 2a.
PMCID: PMC3080781  PMID: 21346310
Auditory system; Axonal development; Dendrites; Neuronal plasticity; Regeneration; Axon guidance; Chemoattractant; Invertebrate
8.  The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms 
Genes & Nutrition  2009;4(4):251-270.
Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.
PMCID: PMC2775889  PMID: 19727888
Spatial; Memory; Learning; Hippocampus; Flavonoids
9.  Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies 
Genes & Nutrition  2009;4(4):227-242.
Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, with a view to making recommendations for future good practice, we review 15 existing human dietary intervention studies that have examined the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group. However, some domains were overlooked completely (e.g. implicit memory, prospective memory), and for the most part there was little consistency in terms of the particular cognitive tests used making across study comparisons difficult. Furthermore, there was some confusion concerning what aspects of cognitive function particular tests were actually measuring. Overall, while initial results are encouraging, future studies need to pay careful attention when selecting cognitive measures, especially in terms of ensuring that tasks are actually sensitive enough to detect treatment effects.
PMCID: PMC2775887  PMID: 19680703
Flavonoid; Cognition; Cognitive function; Memory; Executive function; Motor function
11.  Contribution of smoking during pregnancy to inequalities in stillbirth and infant death in Scotland 1994-2003: retrospective population based study using hospital maternity records 
Objective To quantify the contribution of smoking during pregnancy to social inequalities in stillbirth and infant death.
Design Population based retrospective cohort study.
Setting Scottish hospitals between 1994 and 2003.
Participants Records of 529 317 singleton live births and 2699 stillbirths delivered at 24-44 weeks’ gestation in Scotland from 1994 to 2003.
Main outcome measures Rates of stillbirth and infant, neonatal, and post-neonatal death for each deprivation category (fifths of postcode sector Carstairs-Morris scores); contribution of smoking during pregnancy (“no,” “yes,” or “not known”) in explaining social inequalities in these outcomes.
Results The stillbirth rate increased from 3.8 per 1000 in the least deprived group to 5.9 per 1000 in the most deprived group. For infant deaths, the rate increased from 3.2 per 1000 in the least deprived group to 5.4 per 1000 in the most deprived group. Stillbirths were 56% more likely (odds ratio 1.56, 95% confidence interval 1.38 to 1.77) and infant deaths were 72% more likely (1.72, 1.50 to 1.97) in the most deprived compared with the least deprived category. Smoking during pregnancy accounted for 38% of the inequality in stillbirths and 31% of the inequality in infant deaths.
Conclusions Both tackling smoking during pregnancy and reducing infants’ exposure to tobacco smoke in the postnatal environment may help to reduce stillbirths and infant deaths overall and to reduce the socioeconomic inequalities in stillbirths and infant deaths perhaps by as much as 30-40%. However, action on smoking on its own is unlikely to be sufficient and other measures to improve the social circumstances, social support, and health of mothers and infants are needed.
PMCID: PMC2755727  PMID: 19797343
12.  Centile charts for birthweight for gestational age for Scottish singleton births 
Centile charts of birthweight for gestational age are used to identify low birthweight babies. The charts currently used in Scotland are based on data from the 1970s and require updating given changes in birthweight and in the measurement of gestational age since then.
Routinely collected data of 100,133 singleton births occurring in Scotland from 1998–2003 were used to construct new centile charts using the LMS method.
Centile charts for birthweight for sex and parity groupings were constructed for singleton birth and compared to existing charts used in Scottish hospitals.
Mean birthweight has been shown to have increased over recent decades. The differences shown between the new and currently used centiles confirm the need for more up-to-date centiles for birthweight for gestational age.
PMCID: PMC2268653  PMID: 18298810

Results 1-12 (12)