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1.  Trkb Signaling in Pericytes Is Required for Cardiac Microvessel Stabilization 
PLoS ONE  2014;9(1):e87406.
Pericyte and vascular smooth muscle cell (SMC) recruitment to the developing vasculature is an important step in blood vessel maturation. Brain-derived neurotrophic factor (BDNF), expressed by endothelial cells, activates the receptor tyrosine kinase TrkB to stabilize the cardiac microvasculature in the perinatal period. However, the effects of the BDNF/TrkB signaling on pericytes/SMCs and the mechanisms downstream of TrkB that promote vessel maturation are unknown. To confirm the involvement of TrkB in vessel maturation, we evaluated TrkB deficient (trkb−/−) embryos and observed severe cardiac vascular abnormalities leading to lethality in late gestation to early prenatal life. Ultrastructural analysis demonstrates that trkb−/− embryos exhibit defects in endothelial cell integrity and perivascular edema. As TrkB is selectively expressed by pericytes and SMCs in the developing cardiac vasculature, we generated mice deficient in TrkB in these cells. Mice with TrkB deficiency in perivascular cells exhibit reduced pericyte/SMC coverage of the cardiac microvasculature, abnormal endothelial cell ultrastructure, and increased vascular permeability. To dissect biological actions and the signaling pathways downstream of TrkB in pericytes/SMCs, human umbilical SMCs were treated with BDNF. This induced membranous protrusions and cell migration, events dependent on myosin light chain phosphorylation. Moreover, inhibition of Rho GTPase and the Rho-associated protein kinase (ROCK) prevented membrane protrusion and myosin light chain phosphorylation in response to BDNF. These results suggest an important role for BDNF in regulating migration of TrkB-expressing pericytes/SMCs to promote cardiac blood vessel ensheathment and functional integrity during development.
PMCID: PMC3909185  PMID: 24498100
2.  Nicotine Increases Cerebellar Activity during Finger Tapping 
PLoS ONE  2013;8(12):e84581.
Nicotine improves performance on several cognitive and sensorimotor tasks. The neuronal mechanisms associated with these changes in performance are, however, largely unknown. Functional magnetic resonance imaging (fMRI) was used to examine the effect of nicotine on neuronal response in nineteen healthy subjects while they performed an auditory-paced finger tapping task. Subjects performed the task, after receiving either a nicotine patch or placebo treatment, in a single blind, crossover design. Compared to placebo, nicotine treatment increased response in the cerebellar vermis. Increased vermal activity, in the absence of changes in other task-related regions suggests specificity in nicotine’s effects.
PMCID: PMC3866129  PMID: 24358367
3.  Safety and Immunomodulatory Effects of Three Probiotic Strains Isolated from the Feces of Breast-Fed Infants in Healthy Adults: SETOPROB Study 
PLoS ONE  2013;8(10):e78111.
We previously described the isolation and characterization of three probiotic strains from the feces of exclusively breast-fed newborn infants: Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036. These strains were shown to adhere to intestinal mucus in vitro, to be sensitive to antibiotics and to resist biliary salts and low pH. In the present study, a multicenter, randomized, double-blind, placebo-controlled trial with 100 healthy volunteers in three Spanish cities was carried out to evaluate the tolerance, safety, gut colonization and immunomodulatory effects of these three probiotics. Volunteers underwent a 15-day washout period, after which they were randomly divided into 5 groups that received daily a placebo, a capsule containing one of the 3 strains or a capsule containing a mixture of two strains for 30 days. The intervention was followed by another 15-day washout period. Patients did not consume fermented milk for the entire duration of the study. Gastrointestinal symptoms, defecation frequency and stool consistency were not altered by probiotic intake. No relevant changes in blood and serum, as well as no adverse events occurred during or after treatment. Probiotic administration slightly modified bacterial populations in the volunteers’ feces. Intestinal persistence occurred in volunteers who received L. rhamnosus CNCM I-4036. Administration of B. breve CNCM I-4035 resulted in a significant increase in fecal secretory IgA content. IL-4 and IL-10 increased, whereas IL-12 decreased in the serum of volunteers treated with any of the three strains. These results demonstrate that the consumption of these three bacterial strains was safe and exerted varying degrees of immunomodulatory effects.
Trial Registration NCT01479543
PMCID: PMC3810271  PMID: 24205115
4.  Nicotine Increases Brain Functional Network Efficiency 
NeuroImage  2012;63(1):73-80.
Despite the use of cholinergic therapies in Alzheimer’s disease and the development of cholinergic strategies for schizophrenia, relatively little is known about how the system modulates the connectivity and structure of large-scale brain networks. To better understand how nicotinic cholinergic systems alter these networks, this study examined the effects of nicotine on measures of whole-brain network communication efficiency. Resting-state fMRI was acquired from fifteen healthy subjects before and after the application of nicotine or placebo transdermal patches in a single blind, crossover design. Data, which were previously examined for default network activity, were analyzed with network topology techniques to measure changes in the communication efficiency of whole-brain networks. Nicotine significantly increased local efficiency, a parameter that estimates the network’s tolerance to local errors in communication. Nicotine also significantly enhanced the regional efficiency of limbic and paralimbic areas of the brain, areas which are especially altered in diseases such as Alzheimer’s disease and schizophrenia. These changes in network topology may be one mechanism by which cholinergic therapies improve brain function.
PMCID: PMC3429645  PMID: 22796985
nicotine; acetylcholine; graph theory; small-world; network; fMRI
5.  Comparative proteomic profiling of dystroglycan-associated proteins in wild type, mdx and Galgt2 transgenic mouse skeletal muscle 
Journal of proteome research  2012;11(9):4413-4424.
Dystroglycan is a major cell surface glycoprotein receptor for the extracellular matrix in skeletal muscle. Defects in dystroglycan glycosylation cause muscular dystrophy and alterations in dystroglycan glycosylation can impact extracellular matrix binding. Here we describe an immunoprecipitation technique that allows isolation of beta dystroglycan with members of the dystrophin-associated protein complex (DAPC) from detergent solubilized skeletal muscle.
Immunoprecipitation, coupled with shotgun proteomics, has allowed us to identify new dystroglycan-associated proteins and define changed associations that occur within the DAPC in dystrophic skeletal muscles. In addition, we describe changes that result from overexpression of Galgt2, a normally synaptic muscle glycosyltransferase that can modify alpha dystroglycan and inhibit the development of muscular dystrophy when it is overexpressed. These studies identify new dystroglycan-associated proteins that may participate in dystroglycan’s roles, both positive and negative, in muscular dystrophy.
PMCID: PMC3436944  PMID: 22775139
6.  Evaluation of the Brief Questionnaire of Smoking Urges in Black Light Smokers 
Nicotine & Tobacco Research  2012;14(9):1110-1114.
This study evaluated the factor structure of the Brief Questionnaire of Smoking Urges (QSU-Brief) within a sample of Black light smokers (1–10 cigarettes per day).
The QSU-Brief was administered to 540 (mean age = 46.5; 66.1% women) urban Black light smokers upon entering a smoking cessation clinical trial. An exploratory factor analysis (EFA) was conducted to evaluate the factor structure of this 10-item measure.
An EFA indicated that as in other samples, the construct of craving in a Black sample is defined by 2 factors; 1 factor emphasizing the positive reinforcement of smoking and the other factor emphasizing the negative reinforcement properties of smoking.
Findings largely replicate a 2-factor structure of craving seen in smokers from other racial/ethnic groups, demonstrating the clinical utility of the QSU-Brief in measuring craving in Black light smokers.
PMCID: PMC3432274  PMID: 22241828
7.  Differential Epidemiology of Salmonella Typhi and Paratyphi A in Kathmandu, Nepal: A Matched Case Control Investigation in a Highly Endemic Enteric Fever Setting 
Enteric fever, a systemic infection caused by the bacteria Salmonella Typhi and Salmonella Paratyphi A, is endemic in Kathmandu, Nepal. Previous work identified proximity to poor quality water sources as a community-level risk for infection. Here, we sought to examine individual-level risk factors related to hygiene and sanitation to improve our understanding of the epidemiology of enteric fever in this setting.
Methodology and principal findings
A matched case-control analysis was performed through enrollment of 103 blood culture positive enteric fever patients and 294 afebrile community-based age and gender-matched controls. A detailed questionnaire was administered to both cases and controls and the association between enteric fever infection and potential exposures were examined through conditional logistic regression. Several behavioral practices were identified as protective against infection with enteric fever, including water storage and hygienic habits. Additionally, we found that exposures related to poor water and socioeconomic status are more influential in the risk of infection with S. Typhi, whereas food consumption habits and migration play more of a role in risk of S. Paratyphi A infection.
Conclusions and significance
Our work suggests that S. Typhi and S. Paratyphi A follow different routes of infection in this highly endemic setting and that sustained exposure to both serovars probably leads to the development of passive immunity. In the absence of a polyvalent vaccine against S. Typhi and S. Paratyphi A, we advocate better systems for water treatment and storage, improvements in the quality of street food, and vaccination with currently available S. Typhi vaccines.
Author Summary
Enteric fever, caused by ingestion of bacteria Salmonella Typhi or Salmonella Paratyphi A, is common in regions with poor water quality and sanitation. We sought to identify individual-level risks for infection in Kathmandu, Nepal, a region endemic for enteric fever. In this study, we enrolled patients presenting to hospital who were blood-culture positive for enteric fever and a series of community controls matched for age, gender and residential ward. Our findings suggest that while some risks for infection with S. Typhi and S. Paratyphi A overlap, these organisms also have distinctive routes of infection in this setting; poor water and socioeconomic status seemed more influential in infection with S. Typhi, whereas food consumption habits and migratory status were shown to play a larger role in infection with S. Paratyphi A. Additionally, serological evaluation of IgG levels against the Vi (Salmonella Typhi) and the O:2 (Salmonella Paratyphi A) antigens demonstrated high titers against both antigens throughout life, suggesting frequent and constant exposure to these organisms in Kathmandu. As major improvements in sanitation infrastructure are unlikely in this setting, we recommend water treatment and storage-based prevention strategies, as well as street food quality regulation, and the promotion of vaccination with existing typhoid vaccines.
PMCID: PMC3749961  PMID: 23991240
8.  Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia 
The American journal of psychiatry  2008;165(8):1040-1047.
Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of α7-nicotinic receptors. Patients’ heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial α7-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.
Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.
There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.
DMXB-A, a nicotinic agonist that activates α7-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.
PMCID: PMC3746983  PMID: 18381905
9.  The capsular polysaccharide Vi from Salmonella Typhi is a B1b antigen 
Vaccination with purified capsular polysaccharide Vi antigen from Salmonella Typhi can protect against typhoid fever, although the mechanism for its efficacy is not clearly established. Here, we have characterised the B cell response to this vaccine in wild-type and T cell-deficient mice. We show that immunization with Typhim Vi rapidly induces proliferation in B1b peritoneal cells, but not in B1a cells or marginal zone (MZ) B cells. This induction of B1b proliferation is concomitant with the detection of splenic Vi-specific antibody secreting cells and protective antibody and Rag1-deficient B1b cell chimeras generated by adoptive transfer induced specific antibody after Vi immunization. Furthermore, antibody derived from peritoneal B cells is sufficient to confer protection against Salmonella that express Vi antigen. Expression of Vi by Salmonella during infection did not inhibit the development of early antibody responses to non-Vi antigens. Despite this, the protection conferred by immunization of mice with porin proteins from Salmonella, which induce antibody-mediated protection, was reduced after infection with Vi-expressing Salmonella, although protection was not totally abrogated. This work therefore suggests that in mice, B1b cells contribute to the protection induced by Vi antigen and targeting non-Vi antigens as sub-unit vaccines may offer an attractive strategy to augment current Vi-based vaccine strategies.
PMCID: PMC3605773  PMID: 23162127
B1b cells; Vi antigen; capsular polysaccharide; antibody; Salmonella Typhi
10.  Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants 
The New England journal of medicine  2012;367(14):1321-1331.
Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.
We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.
Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10−38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02).
Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.)
PMCID: PMC3494411  PMID: 22970919
11.  Dental sealant knowledge, opinion, values and practice of Spanish dentists 
BMC Oral Health  2013;13:12.
Multiple guidelines and systematic reviews recommend sealant use to reduce caries risk. Yet, multiple reports also indicate that sealants are significantly underutilized. This study examined the knowledge, opinions, values, and practice (KOVP) of dentists concerning sealant use in the southwest region of Andalusia, Spain. This is a prelude to the generation of a regional plan for improving children’s oral health in Andalusia.
The survey’s target population was dentists working in western Andalusia, equally distributed in the provinces of Seville, Cadiz, and Huelva (N=2,047). A convenience sample of meeting participants and meeting participant email lists (N=400) were solicited from the annual course on Community and Pediatric Dentistry. This course is required for all public health sector dentists, and is open to all private sector dentists. Information on the dentist’s KOVP of sealants was collected using four-part questionnaire with 31, 5-point Likert-scaled questions.
The survey population demographics included 190 men (48%) and 206 women (52%) with an average clinical experience of 10.6 (± 8.4) years and 9.3 (± 7.5) years, respectively. A significant sex difference was observed in the distribution of place of work (urban/suburb) (p=0.001), but no sex differences between working sector (public/private). The mean ± SD values for each of the four KOVP sections for pit and fissure sealants were: knowledge = 3.57 ± 0.47; opinion = 2.48 ± 0.47; value = 2.74 ± 0.52; and practice = 3.48 ± 0.50. No sex differences were found in KOVP (all p >0.4). Independent of sex: knowledge statistically differed by years of experience and place of work; opinion statistically differed by years of experience and sector; and practice statistically differed by years of experience and sector. Less experienced dentists tended to have slightly higher scores (~0.25 on a Likert 1–5 scale). Statistically significant correlations were found between knowledge and practice (r=0.44, p=0.00) and between opinion and value (r=0.35, p=0.00).
The results suggest that, similar to other countries, Andalusian dentists know that sealants are effective, have neutral to positive attitudes toward sealants; though, based on epidemiological studies, underuse sealants. Therefore, methods other than classical behavior change (eg: financial or legal mechanisms) will be required to change practice patterns aimed at improving children's oral health.
PMCID: PMC3584843  PMID: 23394363
Fissure sealants; Dental; Prevention; Children; Oral health
12.  Efficient extraction of vaccines formulated in aluminum hydroxide gel by including surfactants in the extraction buffer 
Vaccine  2011;30(2):189-194.
Efficient antigen extraction from vaccines formulated on aluminum hydroxide gels is a critical step for the evaluation of the quality of vaccines following formulation. It has been shown in our laboratory that the efficiency of antigen extraction from vaccines formulated on Alhydrogel decreased significantly with increased storage time. To increase antigen extraction efficiency, the present study determined the effect of surfactants on antigen recovery from vaccine formulations. The Plasmodium falciparum apical membrane antigen 1 (AMA1) formulated on Alhydrogel and stored at 2-8 °C for three years was used as a model in this study. The AMA1 on Alhydrogel was extracted in the presence or absence of 30 mM sodium dodecyl sulfate (SDS) or 20 mM cetylpyridinium chloride in the extraction buffer (0.60 M citrate, 0.55 M phosphate, pH 8.5) using our standard antigen extraction protocols. Extracted AMA1 antigen was analyzed by 4-20% Tris-glycine SDS-PAGE followed by silver staining or western blotting. The results showed that inclusion of SDS or cetylpyridinium chloride in extraction buffer increased the antigen recovery dramatically and can be used for efficient characterization of Alhydrogel vaccines.
PMCID: PMC3246088  PMID: 22107848
Alhydrogel; AMA1; extraction; SDS; cetylpyridinium chloride
13.  Propagation of Adult SSCs: From Mouse to Human 
BioMed Research International  2013;2013:384734.
Adult spermatogonial stem cells (SSCs) represent a distinctive source of stem cells in mammals for several reasons. First, by giving rise to spermatogenesis, SSCs are responsible for the propagation of a father's genetic material. As such, autologous SSCs have been considered for treatment of infertility and other purposes, including correction of inherited disorders. Second, adult spermatogonia can spontaneously produce embryonic-like stem cells in vitro, which could be used as an alternative for therapeutic, diagnostic, or drug discovery strategies for humans. Therefore, an increasing urgency is driving efforts to understand the biology of SSCs and improve techniques to manipulate them in vitro as a prerequisite to achieve the aforementioned goals. The characterization of adult SSCs also requires reproducible methods to isolate and maintain them in long-term culture. Herein, we describe recent major advances and challenges in propagation of adult SSCs from mice and humans during the past few years, including the use of unique cell surface markers and defined cultured conditions.
PMCID: PMC3581147  PMID: 23484114
14.  Branding and a child’s brain: an fMRI study of neural responses to logos 
Branding and advertising have a powerful effect on both familiarity and preference for products, yet no neuroimaging studies have examined neural response to logos in children. Food advertising is particularly pervasive and effective in manipulating choices in children. The purpose of this study was to examine how healthy children’s brains respond to common food and other logos. A pilot validation study was first conducted with 32 children to select the most culturally familiar logos, and to match food and non-food logos on valence and intensity. A new sample of 17 healthy weight children were then scanned using functional magnetic resonance imaging. Food logos compared to baseline were associated with increased activation in orbitofrontal cortex and inferior prefrontal cortex. Compared to non-food logos, food logos elicited increased activation in posterior cingulate cortex. Results confirmed that food logos activate some brain regions in children known to be associated with motivation. This marks the first study in children to examine brain responses to culturally familiar logos. Considering the pervasiveness of advertising, research should further investigate how children respond at the neural level to marketing.
PMCID: PMC3871732  PMID: 22997054
children; brands; fMRI; prefrontal cortex; neuromarketing; food logos
15.  O:2-CRM197 Conjugates against Salmonella Paratyphi A 
PLoS ONE  2012;7(11):e47039.
Enteric fevers remain a common and serious disease, affecting mainly children and adolescents in developing countries. Salmonella enterica serovar Typhi was believed to cause most enteric fever episodes, but several recent reports have shown an increasing incidence of S. Paratyphi A, encouraging the development of a bivalent vaccine to protect against both serovars, especially considering that at present there is no vaccine against S. Paratyphi A. The O-specific polysaccharide (O:2) of S. Paratyphi A is a protective antigen and clinical data have previously demonstrated the potential of using O:2 conjugate vaccines. Here we describe a new conjugation chemistry to link O:2 and the carrier protein CRM197, using the terminus 3-deoxy-D-manno-octulosonic acid (KDO), thus leaving the O:2 chain unmodified. The new conjugates were tested in mice and compared with other O:2-antigen conjugates, synthesized adopting previously described methods that use CRM197 as carrier protein. The newly developed conjugation chemistry yielded immunogenic conjugates with strong serum bactericidal activity against S. Paratyphi A.
PMCID: PMC3492368  PMID: 23144798
16.  Importance of Reward and Prefrontal Circuitry in Hunger and Satiety: Prader-Willi Syndrome vs. Simple Obesity 
The majority of research on obesity has focused primarily on clinical features (eating behavior, adiposity measures), or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions which are associated with appetite-regulatory hormones are also involved in the development and maintenance of obesity. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic obesity. Simple (non-PWS) obesity (OB) represents an obesity control state.
This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (i.e., hypothalamus, amygdala) and prefrontal regions associated with cognitive control [i.e., dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC)] after eating.
Design and Participants
Fourteen individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls (HWC) viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC, and DLPFC.
Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in hypothalamus and hippocampus, in response to food (vs. non-food) images pre-meal. Post-meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared to OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control.
In PWS compared with obesity per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple obesity.
PMCID: PMC3270121  PMID: 22024642
obesity; DLPFC; inhibition; motivation; fMRI; Prader-Willi syndrome
17.  Nicotine effects on default mode network during resting state 
Psychopharmacology  2011;216(2):287-295.
The default mode network (DMN), one of several resting-state networks (RSN) in the brain, is thought to be involved in self-referential thought, awareness, and episodic memories. Nicotine improves cognitive performance, in part by improving attention. Nicotinic agonists have been shown to decrease activity in regions within DMN and increase activity in regions involved in visual attention during effortful processing of external stimuli. It is unknown if these pharmacological effects also occur in the absence of effortful processing.
This study aims to determine if nicotine suppresses activity in default mode and enhances activity in extra-striate RSNs in the absence of an external visual task.
Within-subject, single-blinded, counterbalanced study of 19 non-smoking subjects who had resting functional MRI scans after 7 mg nicotine or placebo patch. Group independent component analysis was performed. The DMN component was identified by spatial correlation with a reference DMN mask. A visual attention component was identified by spatial correlation with an extra-striate mask. Analyses were conducted using statistical parametric mapping.
Nicotine was associated with decreased activity in regions within the DMN and increased activity in extra-striate regions.
Suppression of DMN and enhancement of extra-striate resting-state activity in the absence of visual stimuli or effortful processing suggest that nicotine’s cognitive effects may involve a shift in activity from networks that process internal to those that process external information. This is a potential mechanism by which cholinergic agonists may have a beneficial effect in diseases associated with altered resting-state activity.
PMCID: PMC3486925  PMID: 21331518
Resting-state networks; Default mode network; Nicotine; Attention; Posterior cingulate; Extra-striate cortex
18.  Phase 1 Study in Malaria Naïve Adults of BSAM2/Alhydrogel®+CPG 7909, a Blood Stage Vaccine against P. falciparum Malaria 
PLoS ONE  2012;7(10):e46094.
A Phase 1 dose escalating study was conducted in malaria naïve adults to assess the safety, reactogenicity, and immunogenicity of the blood stage malaria vaccine BSAM2/Alhydrogel®+ CPG 7909. BSAM2 is a combination of the FVO and 3D7 alleles of recombinant AMA1 and MSP142, with equal amounts by weight of each of the four proteins mixed, bound to Alhydrogel®, and administered with the adjuvant CPG 7909. Thirty (30) volunteers were enrolled in two dose groups, with 15 volunteers receiving up to three doses of 40 µg total protein at Days 0, 56, and 180, and 15 volunteers receiving up to three doses of 160 µg protein on the same schedule. Most related adverse events were mild or moderate, but 4 volunteers experienced severe systemic reactions and two were withdrawn from vaccinations due to adverse events. Geometric mean antibody levels after two vaccinations with the high dose formulation were 136 µg/ml for AMA1 and 78 µg/ml for MSP142. Antibody responses were not significantly different in the high dose versus low dose groups and did not further increase after third vaccination. In vitro growth inhibition was demonstrated and was closely correlated with anti-AMA1 antibody responses. A Phase 1b trial in malaria-exposed adults is being conducted.
Trial Registration NCT00889616
PMCID: PMC3464250  PMID: 23056238
19.  Medial Frontal Event Related Potentials and Reward Prediction: Do Responses Matter? 
Brain and cognition  2011;77(1):128-134.
Medial frontal event-related potentials (ERPs) following rewarding feedback index outcome evaluation. The majority of studies examining the feedback related medial frontal negativity (MFN) employ active tasks during which participants’ responses impact their feedback, however, the MFN has been elicited during passive tasks. Many of the studies examining the MFN show enhanced effects when an error in reward prediction occurs (i.e. expected rewards are not delivered). To clarify the roles of reward prediction error and active responding in producing the MFN, the current study employed a reward prediction design with active and passive task blocks. Following the presentation of a reward predictor, participants (active task) or the computer (passive task) indicated whether participants would receive the outcome associated with a stimulus presented on the left or right of the reward predictor. The MFN was largest when the trial outcome was worse than predicted and that this effect was enhanced when the participant, rather than the computer, made the choice. These results show that both reward prediction error and active choice impact the neural system of outcome monitoring with the largest MFN when the individual’s decision led to the negative outcome.
PMCID: PMC3159831  PMID: 21621891
20.  Activity of Pyocin S2 against Pseudomonas aeruginosa Biofilms 
In cystic fibrosis patients, chronic lung infection with Pseudomonas aeruginosa and the associated decline in lung function are the major cause of mortality. In this report, we show that pyocin S2 displays potent activity against P. aeruginosa biofilms, thus representing a potentially improved therapeutic option. Using an invertebrate model of P. aeruginosa infection, we also show that pyocin S2 is highly active in vivo.
PMCID: PMC3294903  PMID: 22183174
21.  Functional deficits of the attentional networks in autism 
Brain and Behavior  2012;2(5):647-660.
Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.
PMCID: PMC3489817  PMID: 23139910
Alerting; anterior cingulate cortex; attentional networks; autism; executive control
22.  Characterization of blaCMY-2 Plasmids in Salmonella and Escherichia coli Isolates from Food Animals in Canada 
One hundred thirty-four blaCMY-2 plasmids from Salmonella and Escherichia coli strains from animals and food in Canada were characterized. Five plasmid groups were identified based on replicon type and restriction profiles. Three groups contained E. coli plasmids only. IncA/C plasmids included most multiresistant plasmids and all those of bovine origin.
PMCID: PMC3273016  PMID: 22156427
23.  Perianal Paget's disease—Report of a rare case 
Perianal extra-mammary Paget's disease is a rare skin disorder of unknown aetiology, which is frequently associated with malignancy. This case report draws attention to this rare condition and comments upon its diagnosis and treatment.
A 64-year-old otherwise fit man, presented to us in 2006 with one-year-long history of perianal irritation. On examination there was an erythematous discoid skin lesion in the right perianal area. The lesion was excised with wide margins and the defect closed with a local transposition flap. Histology confirmed extra-mammary Paget's disease (EMPD) with a focus of invasion showing a well-differentiated mucinous adenocarcinoma. Adjuvant therapy was not advised. On follow-up in 2011, a small irregular skin lesion, well away from the previous excision site was noted on the left perianal area. Biopsies from this lesion confirmed EMPD with no focus of invasion. Once again wide local excision with closure using local transposition flap was undertaken. Long term follow up has been advised.
The optimal treatment for Perianal Paget's disease (PPD) remains controversial. Surgery is the commonest modality used with wide local excision being the treatment of choice for resectable disease. We report herein a short review of various therapies reported so far in the management of this rare disorder.
A thorough initial evaluation and long-term follow-up is essential to identify recurrence and the development of other related malignancies.
PMCID: PMC3421141  PMID: 22796514
Extramammary Paget's disease; Perianal Paget's disease
24.  Immunogenicity of Self-Associated Aggregates and Chemically Cross-Linked Conjugates of the 42 kDa Plasmodium falciparum Merozoite Surface Protein-1 
PLoS ONE  2012;7(6):e36996.
Self-associated protein aggregates or cross-linked protein conjugates are, in general, more immunogenic than oligomeric or monomeric forms. In particular, the immunogenicity in mice of a recombinant malaria transmission blocking vaccine candidate, the ookinete specific Plasmodium falciparum 25 kDa protein (Pfs25), was increased more than 1000-fold when evaluated as a chemical cross-linked protein-protein conjugate as compared to a formulated monomer. Whether alternative approaches using protein complexes improve the immunogenicity of other recombinant malaria vaccine candidates is worth assessing. In this work, the immunogenicity of the recombinant 42 kDa processed form of the P. falciparum merozoite surface protein 1 (MSP142) was evaluated as a self-associated, non-covalent aggregate and as a chemical cross-linked protein-protein conjugate to ExoProtein A, which is a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A. MSP142 conjugates were prepared and characterized biochemically and biophysically to determine their molar mass in solution and stoichiometry, when relevant. The immunogenicity of the MSP142 self-associated aggregates, cross-linked chemical conjugates and monomers were compared in BALB/c mice after adsorption to aluminum hydroxide adjuvant, and in one instance in association with the TLR9 agonist CPG7909 with an aluminum hydroxide formulation. Antibody titers were assessed by ELISA. Unlike observations made for Pfs25, no significant enhancement in MSP142 specific antibody titers was observed for any conjugate as compared to the formulated monomer or dimer, except for the addition of the TLR9 agonist CPG7909. Clearly, enhancing the immunogenicity of a recombinant protein vaccine candidate by the formation of protein complexes must be established on an empirical basis.
PMCID: PMC3366955  PMID: 22675476
25.  Long term stability of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Montanide® ISA 720 and stabilized with Glycine 
Vaccine  2011;29(20):3640-3645.
Plasmodium falciparum apical membrane antigen 1 (AMA1) is an asexual blood-stage vaccine candidate against the malaria parasite. AMA1-C1/ISA720 refers to a mixture of recombinant AMA1 proteins representing the FVO and 3D7 alleles in 1:1 mass ratio, formulated with Montanide® ISA 720 as a water-in oil emulsion. In order to develop the AMA1-C1/ISA720 vaccine for human use, it was important to determine the shelf life of this formulation. Previously it was found 267mM glycine stabilized the proteins in Montanide® ISA 720 formulations for a short period of time at 2-8°C[25], we now test the long term stability of AMA1-C1 at 10 and 40 μg/ml formulated with Montanide® ISA 720 with 50 mM glycine as a stabilizer. Stability of AMA1-C1/ISA720 at different time points following formulation (0, 5, 12 or 18 months) was evaluated by determining the mean particle size (diameter of the mean droplet volume), total protein content by a Modified Lowry assay, identity and integrity using western blot and SDS-PAGE. Our results showed that the mean particle size of these emulsions increased over time, whereas protein content, as determined by an ELISA method using a monoclonal antibody against penta-his, decreased over time. For the 10 μg/ml AMA1-C1/ISA720 vaccine, the protein content with was 6.5 ± 2.2 μg/ml, and for the 40 μg/ml AMA1-C1/ISA720 vaccine, the protein content was only 8.2 ± 2.3 μg/ml after 18 months of storage at 2-8°C. These results suggest that the integrity of the protein was affected by long-term storage. The results of the present study indicate that the AMA1-C1/ISA720 emulsion was unstable after 12 months of storage, after which AMA1-C1 proteins were partially degraded.
PMCID: PMC3089892  PMID: 21440641
Montanide® ISA 720; AMA1; Malaria; Vaccine

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