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1.  Neuroimaging Studies of Factors Related to Exercise: Rationale and design of a 9 month trial 
Contemporary clinical trials  2013;37(1):58-68.
The prevalence of obesity is high resulting from chronic imbalances between energy intake and expenditure. On the expenditure side, regular exercise is associated with health benefits, including enhanced brain function. The benefits of exercise are not immediate and require persistence to be realized. Brain regions associated with health-related decisions, such as whether or not to exercise or controlling the impulse to engage in immediately rewarding activities (e.g., sedentary behavior), include reward processing and cognitive control regions. A 9 month aerobic exercise study will be conducted in 180 sedentary adults (n = 90 healthy weight [BMI= 18.5 to 26.0 kg/m2]; n = 90 obese [BMI=29.0 to 41.0 kg/m2) to examine the brain processes underlying reward processing and impulse control that may affect adherence in a new exercise regimen. The primary aim is to use functional magnetic resonance imaging (fMRI) to examine reward processing and impulse control among participants that adhere (exercise >80% of sessions) and those that do not adhere to a nine-month exercise intervention with secondary analyses comparing sedentary obese and sedentary healthy weight participants. Our results will provide valuable information characterizing brain activation underlying reward processing and impulse control in sedentary obese and healthy weight individuals. In addition, our results may identify brain activation predictors of adherence and success in the exercise program along with measuring the effects of exercise and improved fitness on brain activation.
doi:10.1016/j.cct.2013.11.007
PMCID: PMC3946871  PMID: 24291150
Exercise Adherence; Functional Magnetic Resonance Imaging; Obesity
2.  Tonic Hyper-Connectivity of Reward Neurocircuitry in Obese Children 
Obesity (Silver Spring, Md.)  2014;22(7):1590-1593.
Objective
Obese children demonstrate less activation in prefrontal regions associated with self-control and inhibition when presented with food cues and advertisements. The current study evaluates the differences between obese and healthy weight children in resting-state functional connectivity to these brain regions.
Design and Methods
Seed regions in bilateral middle frontal gyri were chosen based on previous task-based analysis showing differences between obese and healthy weight children’s responses to food-associated stimuli. Functional connectivity to these seed regions was measured in resting-state scans collected in obese and lean children undergoing fMRI.
Results
Obese children exhibited greater resting-state functional connectivity than healthy weight children between the left middle frontal gyrus and reward-related regions in the left ventromedial prefrontal cortex, as well as the left lateral OFC.
Conclusion
Previously published results demonstrate that obese children exhibit less activity in brain regions associated with self-control when viewing motivationally salient food advertisements. Here we show that obese children also have tonically greater input to these self-control regions from reward neurocircuitry. The greater functional connectivity between reward and self-control regions, in conjunction with weaker activation of self-control neurocircuitry, may render these children more susceptible to food advertisements, placing them at elevated risk for over-feeding and obesity.
doi:10.1002/oby.20741
PMCID: PMC4077951  PMID: 24634397
children; functional magnetic resonance imaging (fMRI); resting-state; impulsivity; orbitofrontal cortex; ventromedial prefrontal cortex
3.  Evening Hyperphagia and Food Motivation: A Preliminary Study of Neural Mechanisms 
Eating behaviors  2013;14(4):10.1016/j.eatbeh.2013.08.006.
Evening hyperphagia (EH; consumption of ≥ 25% of total daily calories after the evening meal) is a circadian delay in the pattern of daily food intake and is a core criterion of night eating syndrome (Allison et al., 2010). This preliminary study examined the brain response to food cues using functional magnetic resonance imaging (fMRI) in seven obese adults with EH compared to seven obese adults without EH. When contrasting food to non-food and blurry baseline images pre-meal, groups differed in brain activation in the inferior frontal gyrus, precentral gyrus, cingulate gyrus, superior temporal gyrus and cerebellum. At post meal, groups differed in brain activation in the fusiform gyrus, inferior frontal gyrus, inferior parietal lobule and the cerebellum. Significant interactions between time (pre-meal, post-meal) and group (EH, control) when contrasting food to non-food images were also noted in the inferior frontal gyrus and the superior temporal gyrus. Further research is necessary to replicate these findings and determine if they have a mechanistic role in the development of circadian delayed eating behavior in obese adults with EH.
doi:10.1016/j.eatbeh.2013.08.006
PMCID: PMC3817498  PMID: 24183133
evening hyperphagia; food motivation; disinhibition; inferior frontal gyrus; neural mechanisms; functional magnetic resonance imaging
4.  Winning and losing: differences in reward and punishment sensitivity between smokers and nonsmokers 
Brain and Behavior  2014;4(6):915-924.
Background
Smokers show increased brain activation in reward processing regions in response to smoking-related cues, yet few studies have examined secondary rewards not associated with smoking (i.e., money). Inconsistencies exist in the studies that do examine secondary rewards with some studies showing increased brain activation in reward processing brain regions, while others show decreased activation or no difference in activation between smokers and nonsmokers.
Aims
The goal of the current study is to see if smokers process the evaluation and delivery of equally salient real world rewards similarly or differently than nonsmokers.
Methods
The current study employed functional magnetic resonance imaging (fMRI) to examine brain responses in smokers and nonsmokers during the evaluation and delivery of monetary gains and losses.
Results
In comparison to nonsmokers, smokers showed increased activation in the ventromedial prefrontal cortex to the evaluation of anticipated monetary losses and the brain response. Moreover, smokers compared to nonsmokers showed decreased activation in the inferior frontal gyrus to the delivery of expected monetary gains. Brain activations to both the evaluation of anticipated monetary losses and the delivery of expected monetary gains correlated with increased self-reported smoking craving to relieve negative withdrawal symptoms and craving related to positive aspects of smoking, respectively.
Discussion
Together these results indicate that smokers are hyperresponsive to the evaluation of anticipated punishment and hyporesponsive to the delivery of expected rewards. Although further research is needed, this hypersensitivity to punishments coupled with increased craving may negatively impact quit attempts as smokers anticipate the negative withdrawal symptoms associated with quitting.
doi:10.1002/brb3.285
PMCID: PMC4178298  PMID: 25365800
fMRI; punishment sensitivity; reward sensitivity; smoking
5.  Winning and losing: differences in reward and punishment sensitivity between smokers and nonsmokers 
Brain and Behavior  2014;10.1002/brb3.285.
Abstract
Background
Smokers show increased brain activation in reward processing regions in response to smoking‐related cues, yet few studies have examined secondary rewards not associated with smoking (i.e., money). Inconsistencies exist in the studies that do examine secondary rewards with some studies showing increased brain activation in reward processing brain regions, while others show decreased activation or no difference in activation between smokers and nonsmokers.
Aims
The goal of the current study is to see if smokers process the evaluation and delivery of equally salient real world rewards similarly or differently than nonsmokers.
Methods
The current study employed functional magnetic resonance imaging (fMRI) to examine brain responses in smokers and nonsmokers during the evaluation and delivery of monetary gains and losses.
Results
In comparison to nonsmokers, smokers showed increased activation in the ventromedial prefrontal cortex to the evaluation of anticipated monetary losses and the brain response. Moreover, smokers compared to nonsmokers showed decreased activation in the inferior frontal gyrus to the delivery of expected monetary gains. Brain activations to both the evaluation of anticipated monetary losses and the delivery of expected monetary gains correlated with increased self‐reported smoking craving to relieve negative withdrawal symptoms and craving related to positive aspects of smoking, respectively.
Discussion
Together these results indicate that smokers are hyperresponsive to the evaluation of anticipated punishment and hyporesponsive to the delivery of expected rewards. Although further research is needed, this hypersensitivity to punishments coupled with increased craving may negatively impact quit attempts as smokers anticipate the negative withdrawal symptoms associated with quitting.
doi:10.1002/brb3.285
PMCID: PMC4178298  PMID: 25365800
fMRI; punishment sensitivity; reward sensitivity; smoking
6.  A Field Evaluation of the Hardy TB MODS Kit™ for the Rapid Phenotypic Diagnosis of Tuberculosis and Multi-Drug Resistant Tuberculosis 
PLoS ONE  2014;9(9):e107258.
Background
Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory.
Methods & Findings
2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3–99.8%), 98.3% (97.5–98.8%), 95.8% (94.0–97.1%), and 99.7% (99.3–99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9–13) days for conventional MODS and 8.5 (7–11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples).
Conclusions
MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.
doi:10.1371/journal.pone.0107258
PMCID: PMC4167337  PMID: 25225802
7.  MiR-592 Regulates the Induction and Cell Death-Promoting Activity of p75NTR in Neuronal Ischemic Injury 
The Journal of Neuroscience  2014;34(9):3419-3428.
The neurotrophin receptor p75NTR has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction in pathologic states, there is limited understanding of the mechanisms that regulate p75NTR expression after injury. Here, we show that after focal cerebral ischemia in vivo or oxygen–glucose deprivation in organotypic hippocampal slices or neurons, p75NTR is rapidly induced. A concomitant induction of proNGF, a ligand for p75NTR, is also observed. Induction of this ligand/receptor system is pathologically relevant, as a decrease in apoptosis, after oxygen–glucose deprivation, is observed in hippocampal neurons or slices after delivery of function-blocking antibodies to p75NTR or proNGF and in p75NTR and ngf haploinsufficient slices. Furthermore, a significant decrease in infarct volume was noted in p75NTR−/− mice compared with the wild type. We also investigated the regulatory mechanisms that lead to post-ischemic induction of p75NTR. We demonstrate that induction of p75NTR after ischemic injury is independent of transcription but requires active translation. Basal levels of p75NTR in neurons are maintained in part by the expression of microRNA miR-592, and an inverse correlation is seen between miR-592 and p75NTR levels in the adult brain. After cerebral ischemia, miR-592 levels fall, with a corresponding increase in p75NTR levels. Importantly, overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p75NTR and attenuates activation of pro-apoptotic signaling and cell death. These results identify miR-592 as a key regulator of p75NTR expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury.
doi:10.1523/JNEUROSCI.1982-13.2014
PMCID: PMC3935094  PMID: 24573298
ischemia; microRNA; neurotrophin; NGF; p75NTR; stroke
8.  A comparison of functional brain changes associated with surgical versus behavioral weight loss 
Obesity (Silver Spring, Md.)  2013;22(2):337-343.
Objective
Few studies have examined brain changes in response to effective weight loss; none have compared different methods of weight-loss intervention. We compared functional brain changes associated with a behavioral weight loss intervention to those associated with bariatric surgery.
Methods
15 obese participants were recruited prior to adjustable gastric banding surgery and 16 obese participants were recruited prior to a behavioral diet intervention. Groups were matched for demographics and amount of weight lost. fMRI scans (visual food motivation paradigm while hungry and following a meal) were conducted before, and 12 weeks after surgery/behavioral intervention.
Results
When compared to bariatric patients in the pre-meal analyses, behavioral dieters showed increased activation to food images in right medial PFC and left precuneus following weight loss. When compared to behavioral dieters, bariatric patients showed increased activation in in bilateral temporal cortex following the weight loss.
Conclusions
Behavioral dieters showed increased responses to food cues in medial PFC – a region associated with valuation and processing of self-referent information – when compared to bariatric patients. Bariatric patients showed increased responses to food cues in brain regions associated with higher level perception—when compared to behavioral dieters. The method of weight loss determines unique changes in brain function.
doi:10.1002/oby.20630
PMCID: PMC3946492  PMID: 24115765
functional MRI; bariatric surgery; neuroscience; weight loss; neuroimaging
9.  Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation 
Stem Cell Reports  2014;3(2):219-226.
Summary
Pathogenic de novo mutations increase with fathers’ age and could be amplified through competition between genetically distinct subpopulations of spermatogonial stem cells (SSCs). Here, we tested the fitness of SSCs bearing wild-type human FGFR2 or an Apert syndrome mutant, FGFR2 (S252W), to provide experimental evidence for SSC competition. The S252W allele conferred enhanced FGFR2-mediated signaling, particularly at very low concentrations of ligand, and also subtle changes in gene expression. Mutant SSCs exhibited improved competitiveness in vitro and increased stem cell activity in vivo upon transplantation. The fitness advantage in vitro only occurred in low concentrations of fibroblast growth factor (FGF), was independent of FGF-driven proliferation, and was accompanied by increased response to glial cell line-derived neurotrophic factor (GDNF). Our studies provide experimental evidence of enhanced stem cell fitness in SSCs bearing a paternal age-associated mutation. Our model will be useful for interrogating other candidate mutations in the future to reveal mechanisms of disease risk.
Graphical Abstract
Highlights
•FGFR2-mediated signaling regulates SSC self-renewal•Age-associated Apert syndrome FGFR2 mutation confers a fitness advantage to SSCs•Mutant FGFR2 enables SSCs to withstand limiting GDNF•Excessive growth factor exposure impairs SSC self-renewal signals
Seandel and colleagues address whether competition among stem cells in the testis mediates the increased frequency of mutations as the father ages. Using a paternal age-associated human FGFR2 mutation in Apert syndrome delivered to mouse spermatogonial stem cells as a model, their study demonstrates enhanced self-renewal activity of mutant cells versus wild-type populations. Furthermore, mutant cells exhibit higher sensitivity to limited growth factors, suggesting a selection mechanism mediated by the aged niche.
doi:10.1016/j.stemcr.2014.06.007
PMCID: PMC4176532  PMID: 25254335
10.  Electrophysiological and Hemodynamic Responses to Reward Prediction Violation 
Neuroreport  2009;20(13):1140-1143.
Anterior cingulate cortex has been functionally linked to the detection of outcomes that are worse than expected using both scalp electrophysiological (ERP) and hemodynamic (fMRI) responses. The current study used a reward prediction violation design acquired both ERP and fMRI data from the same participants in different sessions. Both the medial frontal negativity (MFN) ERP response and anterior cingulate cortex hemodynamic activity differentiated between reward delivery and expectation with the largest MFN and anterior cingulate cortex response when predicted rewards were not delivered. Inverse modeling placed the MFN source near the anterior cingulate cortex hemodynamic activation. The fMRI study also showed increased striatal response to rewards regardless of prediction indicating dissociation of neural processing of reward and reward expectation.
doi:10.1097/WNR.0b013e32832f0dca
PMCID: PMC4095766  PMID: 19690501
Reward; Event Related Potentials; fMRI; anterior cingulate cortex
11.  Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor 
ACS Medicinal Chemistry Letters  2013;4(6):560-564.
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug–drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
doi:10.1021/ml400049p
PMCID: PMC4027471  PMID: 24900709
SERT; NET; dual; reuptake inhibitor; SNRI; SERT RO; α-MMT; pain
12.  Effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 on Hepatic Steatosis in Zucker Rats 
PLoS ONE  2014;9(5):e98401.
We have previously described the safety and immunomodulatory effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 in healthy volunteers. The scope of this work was to evaluate the effects of these probiotic strains on the hepatic steatosis of obese rats. We used the Zucker rat as a genetic model of obesity. Zucker-Leprfa/fa rats received one of three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo for 30 days. An additional group of Zucker-lean+/fa rats received a placebo for 30 days. No alterations in intestinal histology, in the epithelial, lamina propria, muscular layers of the ileal or colonic mucosa, or the submucosae, were observed in any of the experimental groups. Triacylglycerol content decreased in the liver of Zucker-Leprfa/fa rats that were fed L. rhamnosus, B. breve, or the mixture of B. breve and L. paracasei. Likewise, the area corresponding to neutral lipids was significantly smaller in the liver of all four groups of Zucker-Leprfa/fa rats that received probiotics than in rats fed the placebo. Zucker-Leprfa/fa rats exhibited significantly greater serum LPS levels than Zucker-lean+/fa rats upon administration of placebo for 30 days. In contrast, all four groups of obese Zucker-Leprfa/fa rats that received LAB strains exhibited serum LPS concentrations similar to those of Zucker-lean+/fa rats. Serum TNF-α levels decreased in the Zucker-Leprfa/fa rats that received B. breve, L. rhamnosus, or the mixture, whereas L. paracasei feeding decreased IL-6 levels in the serum of Zucker-Leprfa/fa rats. In conclusion, the probiotic strains reduced hepatic steatosis in part by lowering serum LPS, and had an anti-inflammatory effect in obese Zucker rats.
doi:10.1371/journal.pone.0098401
PMCID: PMC4031175  PMID: 24852284
13.  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.
doi:10.1371/journal.pone.0087406
PMCID: PMC3909185  PMID: 24498100
14.  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.
doi:10.1371/journal.pone.0084581
PMCID: PMC3866129  PMID: 24358367
15.  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
ClinicalTrials.gov NCT01479543
doi:10.1371/journal.pone.0078111
PMCID: PMC3810271  PMID: 24205115
16.  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.
doi:10.1016/j.neuroimage.2012.06.079
PMCID: PMC3429645  PMID: 22796985
nicotine; acetylcholine; graph theory; small-world; network; fMRI
17.  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.
doi:10.1021/pr300328r
PMCID: PMC3436944  PMID: 22775139
18.  Evaluation of the Brief Questionnaire of Smoking Urges in Black Light Smokers 
Nicotine & Tobacco Research  2012;14(9):1110-1114.
Introduction:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1093/ntr/ntr267
PMCID: PMC3432274  PMID: 22241828
19.  Differential Epidemiology of Salmonella Typhi and Paratyphi A in Kathmandu, Nepal: A Matched Case Control Investigation in a Highly Endemic Enteric Fever Setting 
Background
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.
doi:10.1371/journal.pntd.0002391
PMCID: PMC3749961  PMID: 23991240
20.  Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia 
The American journal of psychiatry  2008;165(8):1040-1047.
Objective
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.
Method
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.
Results
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.
Conclusion
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.
doi:10.1176/appi.ajp.2008.07071135
PMCID: PMC3746983  PMID: 18381905
21.  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.
doi:10.4049/jimmunol.1103166
PMCID: PMC3605773  PMID: 23162127
B1b cells; Vi antigen; capsular polysaccharide; antibody; Salmonella Typhi
22.  Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants 
The New England journal of medicine  2012;367(14):1321-1331.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.)
doi:10.1056/NEJMoa1200395
PMCID: PMC3494411  PMID: 22970919
23.  Dental sealant knowledge, opinion, values and practice of Spanish dentists 
BMC Oral Health  2013;13:12.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1472-6831-13-12
PMCID: PMC3584843  PMID: 23394363
Fissure sealants; Dental; Prevention; Children; Oral health
24.  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.
doi:10.1016/j.vaccine.2011.11.025
PMCID: PMC3246088  PMID: 22107848
Alhydrogel; AMA1; extraction; SDS; cetylpyridinium chloride
25.  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.
doi:10.1155/2013/384734
PMCID: PMC3581147  PMID: 23484114

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