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1.  Computer diagnosis in cardiology 
This article reports upon the emergence of a novel cognitive, computer-based technology which may lead to significantly improved methods of cardiological diagnosis and a rapid and inexpensive method of cardiological screening.
The technology ‘Virtual Scanning’ illustrates how, in blood, the reaction of proteins and their reactive substrates releases light; that the colour and intensity of this bioluminescence is unique to each reaction and it's rate; and that the development of pathologies influence cognition and visual perception. This illustrates that the function of the autonomic nervous system is linked to that of the physiological systems and that the rate of biochemical reactions, and the progression of disease, can be measured by a cognitive test procedure and used as an indication of the disease(s) affecting heart function.
The article discusses the limitations of the conventional biomarker technique, and the potential value of non-invasive cognitive techniques, such as Virtual Scanning, to the medical practitioner. Finally, it discusses how the ability of Virtual Scanning to diagnose disease from its presymptomatic origins may lead to improved diagnostic accuracy and significantly reduced costs.
PMCID: PMC3364659  PMID: 22666689
Computer diagnosis; autonomic nervous system; visual perception; virtual scanning; mathematical modeling; physiological systems
2.  Demonstration 
PMCID: PMC2181748  PMID: 19993313
3.  High-Throughput Assay of Secreted Phospholipases A2 Inhibitors 
Attempts to characterize, quantify, and/or modulate the activity of the secreted phospholipase A2 family of enzymes result from the diversity of physiological roles for which these enzymes have been implicated. The 1-palmitoyl-2-(10-pyrenedecanoyl)-phosphatidylglycerol (pyrenePG)-based fluorometric assay is a sensitive and readily adaptable method for further elucidating phospholipase function under various experimental conditions, as well as a tool for screening chemical libraries for potent inhibitors of this enzymatic activity. This assay is based on the observed difference in fluorescent emission of pyrene aggregated in vesicles compared to sequestered in monomeric form by binding to bovine serum albumin after lipolytic activity, thus allowing direct quantification of hydrolyzed fatty acids by the measurement of the corresponding monomeric emission intensity. The assay can be carried out in multiwell plates for high-throughput screening of compound libraries.
PMCID: PMC4084959  PMID: 22426718
Phospholipase A2; Fluorometric assay; High-throughput screen; Interfacial enzymology; PLA2; Fluorogenic; 1-palmitoyl-2-(10-pyrenedecanoyl)-phosphatidylglycerol; Secreted PLA2 Inhibition Assay
4.  Consequences of Interstitial Cystitis/Bladder Pain Symptoms on Women’s Work Participation and Income: Results from a National Household Sample 
The Journal of urology  2013;191(1):83-88.
To describe differences in work participation and income by bladder symptom impact and comorbidities among women with interstitial cystitis/bladder pain syndrome (IC/BPS).
Materials and Methods
Cross-sectional data from2767 respondents under age 65 identified with IC/BPS symptoms analyzed. The data are from the RAND Interstitial Cystitis Epidemiology (RICE) survey and include retrospective self-reports of IC/BPS impact, severity, years since onset, and related comorbidities (depressive symptomology, number of conditions), work participation and income, and personal characteristics. Multiple regressions predicted five current work outcomes: works now, kept from working by pain, missed work days, days worked when bothered by symptoms, and real income change since symptom onset.
Controlling for work status at symptom onset and personal characteristics, greater bladder symptom impact predicted greater likelihood of not now working, kept more days from working by pain, missed more work days, and working more days with symptoms. More depressive symptomology and greater number of co-morbidities predicted reduced work participation. Women experienced no growth in real income since symptom onset. Measures of symptom severity were not associated with any of the economic outcomes.
Greater IC/BPS symptom impact, depressive symptomology, and count of comorbidities (but not symptom severity) were each associated with less work participation and leveling of women’s long-term earnings. Management of bladder symptom impact on non-work-related activities and depressive symptomology may improve women’s work outcomes.
PMCID: PMC4085039  PMID: 23872030
Interstitial cystitis/bladder pain syndrome; probability sample; employment
5.  Evaluating the Diffusion Coefficient of Dopamine at the Cell Surface During Amperometric Detection: Disk vs. Ring Microelectrodes 
Analytical chemistry  2013;85(13):6421-6428.
During exocytosis, small quantities of neurotransmitters are released by the cell. These neurotransmitters can be detected quantitatively using electrochemical methods, principally with disk carbon fiber microelectrode amperometry. An exocytotic event then results in the recording of a current peak whose characteristic features are directly related to the mechanisms of exocytosis. We have compared two exocytotic peak populations obtained from PC12 cells with a disk carbon fiber microelectrode and with a pyrolyzed carbon ring microelectrode array, with a 500 nm ring thickness. The specific shape of the ring electrode allows for precise analysis of diffusion processes at the vicinity of the cell membrane. Peaks obtained with a ring microelectrode array show a distorted average shape, owing to increased diffusion pathways. This result has been used to evaluate the diffusion coefficient of dopamine at the surface of a cell, which is up to an order of magnitude smaller than that measured in free buffer. The lower rate of diffusion is discussed as resulting from interactions with the glycocalyx.
PMCID: PMC3737586  PMID: 23706095
Exocytosis; microelectrodes; glycocalyx; diffusion coefficient of dopamine; amperometric detection
6.  Large lymphaticovenous malformation resection 
We report a case of a giant cardiac lymphaticovenous malformation arising from the atrioventricular groove in a 38-year old Caucasian female. Cardiac vascular lesions are rare and tend to be poorly described in the literature. Lymphaticovenous malformations are present at birth and develop due to errors in venolymphatic development. As the tumour enlarged, the patient experienced significant shortness of breath on exertion. At resection, the mass measured 6.0 cm anterior–posterior ×10.4 cm craniocaudal. The mass was found to be adhered tightly to the coronary sinus. Histologically, the lesion was composed of dilated vascular and lymphatic channels within a fatty stroma. The mass was resected without complications.
PMCID: PMC3686367  PMID: 23526419
Lymphaticovenous; Vascular; Lymphatic; Malformation; Cardiac; Cardiac tumours; Tumour; Coronary sinus
7.  Family history of cancer associated with breast tumor clinicopathological features 
Journal of Community Genetics  2014;5(3):233-240.
Hereditary breast cancers have unique clinicopathological characteristics. Therefore, the objective of this study was to establish the relationship between self-reported family history of cancer and clinicopathological features in breast cancer patients from Washington, DC. Data on incident breast cancer cases from 2000 to 2010 were obtained from the Washington, DC Cancer Registry. Variables such as estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptor status, as well as stage and grade, were analyzed in those that self-reported with (n = 1,734) and without a family history of cancer (n = 1,712). The breast cancer molecular subtypes were compared when ER, PR, and HER2 statuses were available. Furthermore, tumor characteristics were compared by race/ethnicity. Regression and chi-square analyses were performed. A report of family history was associated with age (OR = 1.27 95 % CI: 1.09–1.48; p < 0.0001), high grade tumors (OR = 1.29 95 % CI: 1.05–1.58; p = 0.02), and having ER and PR negative breast cancer (OR = 1.26 95 % CI: 1.02–1.57; p = 0.029). When tumor characteristics were compared by race/ethnicity, those that self-reported as African American with a family history had a higher frequency of ER negative tumors (OR = 1.51 95 % CI: 1.09–2.08; p = 0.008), PR negative tumors (OR = 1.46 95 % CI: 1.09–1.94; p = 0.028), grade 3 tumors (OR = 1.42 95 % CI: 1.05–1.93; p < 0.0001), and ER/PR negative tumors (OR = 1.5 95 % CI: 1.088–2.064; p = 0.01). These results suggest that a positive family history of cancer in African Americans should increase suspicions of hereditary cancer. Therefore, behavioral risk reduction activities, such as collecting a family history, may reduce late stage diagnosis and cancer mortality.
PMCID: PMC4059846  PMID: 24424917
9.  Spatial Elucidation of Spinal Cord Lipid- and Metabolite- Regulations in Amyotrophic Lateral Sclerosis 
Scientific Reports  2014;4:5266.
Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. We employed time of flight secondary ion mass spectrometry (ToF-SIMS) to profile spatial lipid- and metabolite- regulations in post mortem human spinal cord tissue from ALS patients to investigate chemical markers of ALS pathogenesis. ToF-SIMS scans and multivariate analysis of image and spectral data were performed on thoracic human spinal cord sections. Multivariate statistics of the image data allowed delineation of anatomical regions of interest based on their chemical identity. Spectral data extracted from these regions were compared using two different approaches for multivariate statistics, for investigating ALS related lipid and metabolite changes. The results show a significant decrease for cholesterol, triglycerides, and vitamin E in the ventral horn of ALS samples, which is presumably a consequence of motor neuron degeneration. Conversely, the biogenic mediator lipid lysophosphatidylcholine and its fragments were increased in ALS ventral spinal cord, pointing towards neuroinflammatory mechanisms associated with neuronal cell death. ToF-SIMS imaging is a promising approach for chemical histology and pathology for investigating the subcellular mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis.
PMCID: PMC4053717  PMID: 24919836
10.  A quality control method for detecting and suppressing uncorrected residual motion in fMRI studies 
Magnetic resonance imaging  2013;31(5):707-717.
Motion correction is an important step in the functional magnetic resonance imaging (fMRI) analysis pipeline. While many studies simply exclude subjects who are estimated to have moved beyond an arbitrary threshold, there exists no objective method for determining an appropriate threshold. Furthermore, any criterion based only upon motion estimation ignores the potential for proper realignment. The method proposed here uses unsupervised learning (specifically k-means clustering) on features derived from the mean square derivative (MSD) of the signal before and after realignment to identify problem data. These classifications are refined through analysis of correlation between subject activation maps and the mean activation map, as well as the relationship between tasking and motion as measured through regression of the canonical hemodynamic response functions to fit both estimated motion parameters and MSD. The MSD is further used to identify specific scans containing residual motion, data which is suppressed by adding nuisance regressors to the general linear model; this statistical suppression is performed for identified problem subjects, but has potential for use over all subjects. For problem subjects, our results show increased hemodynamic activity more consistent with group results; that is, the addition of nuisance regressors resulted in a doubling of the correlation between the activation map for the problem subjects and the activation map for all subjects. The proposed method should be useful in helping fMRI researchers make more efficient use of their data by reducing the need to exclude entire subjects from studies and thus collect new data to replace excluded subjects.
PMCID: PMC3648631  PMID: 23290482
motion correction; motion detection; realignment; regression; quality control; functional magnetic resonance imaging
11.  Nutrition Knowledge of Low Income Parents of Obese Children 
Minority and low-income children are overrepresented among obese U.S. children. Lack of basic nutrition knowledge among parents may contribute to this disparity.
To measure nutrition knowledge of parents of Medicaid-insured obese children using a simple low-literacy tool.
Parents, recruited from pediatric clinics, demonstrated their nutrition knowledge by placing food stickers into cells on a printed grid with food groups displayed in columns and three nutrition categories displayed in rows.
In general, parents (n=135; 74.8% black; 79.2% income≤$25K/year) correctly identified food groups (median=90.5% correct). Nutritional categories were more commonly misidentified (median=67% correct), with parents mostly believing foods were healthier than they were. Multivariable linear regression revealed black race (p=.02), no college education (p=.02) and income <$15,000 (p=.03) independently predicted misidentification of nutritional categories.
Parents’ understanding of food’s nutritional value is variable. Black race, less education and very low income are associated with poorer nutrition knowledge.
PMCID: PMC3717981  PMID: 24039639
pediatric obesity; nutrition knowledge; assessment; health disparity
12.  Neuroimaging mechanisms of change in psychotherapy for addictive behaviors: Emerging translational approaches that bridge biology and behavior 
Research on mechanisms of behavior change provides an innovative method to improve treatment for addictive behaviors. An important extension of mechanisms of change research involves the use of translational approaches, which examine how basic biological (i.e., brain-based mechanisms) and behavioral factors interact in initiating and sustaining positive behavior change as a result of psychotherapy. Articles in this special issue include integrative conceptual reviews and innovative empirical research on brain-based mechanisms that may underlie risk for addictive behaviors and response to psychotherapy from adolescence through adulthood. Review articles discuss hypothesized mechanisms of change for cognitive and behavioral therapies, mindfulness-based interventions, and neuroeconomic approaches. Empirical articles cover a range of addictive behaviors, including use of alcohol, cigarettes, marijuana, cocaine, and pathological gambling and represent a variety of imaging approaches including fMRI, magneto-encephalography, real time fMRI, and diffusion tensor imaging. Additionally, a few empirical studies directly examined brain-based mechanisms of change, whereas others examined brain-based indicators as predictors of treatment outcome. Finally, two commentaries discuss craving as a core feature of addiction, and the importance of a developmental approach to examining mechanisms of change. Ultimately, translational research on mechanisms of behavior change holds promise for increasing understanding of how psychotherapy may modify brain structure and functioning and facilitate the initiation and maintenance of positive treatment outcomes for addictive behaviors.
PMCID: PMC3864922  PMID: 23815447
translational; psychotherapy; neuroimaging; fMRI; MEG; real time fMRI; DTI; adolescence; addictive behaviors
13.  Facial Trustworthiness Judgments in Children with ASD Are Modulated by Happy and Angry Emotional Cues 
PLoS ONE  2014;9(5):e97644.
Appearance-based trustworthiness inferences may reflect the misinterpretation of emotional expression cues. Children and adults typically perceive faces that look happy to be relatively trustworthy and those that look angry to be relatively untrustworthy. Given reports of atypical expression perception in children with Autism Spectrum Disorder (ASD), the current study aimed to determine whether the modulation of trustworthiness judgments by emotional expression cues in children with ASD is also atypical. Cognitively-able children with and without ASD, aged 6–12 years, rated the trustworthiness of faces showing happy, angry and neutral expressions. Trust judgments in children with ASD were significantly modulated by overt happy and angry expressions, like those of typically-developing children. Furthermore, subtle emotion cues in neutral faces also influenced trust ratings of the children in both groups. These findings support a powerful influence of emotion cues on perceived trustworthiness, which even extends to children with social cognitive impairments.
PMCID: PMC4039438  PMID: 24878763
15.  Covariance among Multiple Health Risk Behaviors in Adolescents 
PLoS ONE  2014;9(5):e98141.
In a diverse group of early adolescents, this study explores the co-occurrence of a broad range of health risk behaviors: alcohol, cigarette, and marijuana use; physical inactivity; sedentary computing/gaming; and the consumption of low-nutrient energy-dense food. We tested differences in the associations of unhealthy behaviors over time, and by gender, race/ethnicity, and socioeconomic status.
Participants were 8360 students from 16 middle schools in California (50% female; 52% Hispanic, 17% Asian, 16% White, and 15% Black/multiethnic/other). Behaviors were measured with surveys in Spring 2010 and Spring 2011. Confirmatory factor analysis was used to assess if an underlying factor accounted for the covariance of multiple behaviors, and composite reliability methods were used to determine the degree to which behaviors were related.
The measured behaviors were explained by two moderately correlated factors: a ‘substance use risk factor’ and an ‘unhealthy eating and sedentary factor’. Physical inactivity did not reflect the latent factors as expected. There were few differences in the associations among these behaviors over time or by demographic characteristics.
Two distinct, yet related groups of health compromising behaviors were identified that could be jointly targeted in multiple health behavior change interventions among early adolescents of diverse backgrounds.
PMCID: PMC4032285  PMID: 24858838
16.  Imaging Mass Spectrometry in Neuroscience 
ACS Chemical Neuroscience  2013;4(5):666-679.
Imaging mass spectrometry is an emerging technique of great potential for investigating the chemical architecture in biological matrices. Although the potential for studying neurobiological systems is evident, the relevance of the technique for application in neuroscience is still in its infancy. In the present Review, a principal overview of the different approaches, including matrix assisted laser desorption ionization and secondary ion mass spectrometry, is provided with particular focus on their strengths and limitations for studying different neurochemical species in situ and in vitro. The potential of the various approaches is discussed based on both fundamental and biomedical neuroscience research. This Review aims to serve as a general guide to familiarize the neuroscience community and other biomedical researchers with the technique, highlighting its great potential and suitability for comprehensive and specific chemical imaging.
PMCID: PMC3656743  PMID: 23530951
Imaging mass spectrometry; SIMS; MALDI; neurotransmitters
17.  Gain of interaction with IRS1 by p110α helical domain mutants is crucial for their oncogenic functions 
Cancer cell  2013;23(5):583-593.
PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers. Most of these mutations occur at two hot-spots E545K and H1047R located in the helical domain and the kinase domain, respectively. Here, we report that p110α E545K, but not p110α H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110α E545K interaction destabilizes the p110α protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110α E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110α E545K.
PMCID: PMC3671608  PMID: 23643389
18.  Detection of Mixed Populations of Clostridium difficile from Symptomatic Patients Using Capillary-Based Polymerase Chain Reaction Ribotyping 
To investigate the simultaneous occurrence of more than 1 Clostridium difficile ribotype in patients' stool samples at the time of diagnostic testing.
Stool samples submitted for diagnostic testing for the presence of toxigenic C. difficile were obtained for 102 unique patients. A total of 95 single colonies of C. difficile per stool sample were isolated on selective media, subcultured alongside negative (uninoculated) controls, and polymerase chain reaction (PCR) ribotyped using capillary gel electrophoresis.
Capillary-based PCR ribotyping was successful for 9,335 C. difficile isolates, yielding a median of 93 characterized isolates per stool sample (range, 69–95). More than 1 C. difficile ribotype was present in 16 of 102 (16%) C. difficile infection (CDI) cases; 2 of the 16 mixtures were composed of at least 3 ribotypes, while the remaining 14 were composed of at least 2.
Deep sampling of patient stool samples coupled with capillary-based PCR ribotyping identified a high rate of mixed CDI cases compared with previous estimates. Studies seeking to quantify the clinical significance of particular C. difficile ribotypes should account for mixed cases of disease.
PMCID: PMC4016961  PMID: 23917911
19.  Single Cell Amperometry Reveals that the Glycocalyx Hinders the Release of Neurotransmitters During Exocytosis 
Analytical chemistry  2013;85(9):4822-4828.
The diffusional hindrance of the glycocalyx along the cell surface on exocytotic peaks, observed with single cell amperometry, was investigated. Partial digestion of the glycocalyx with neuraminidase led to the observation of faster peaks, as shown by varied peak parameters. This result indicates that diffusion of small molecules in the partially digested glycocalyx is 2.2 faster than in the intact glycocalyx. Similarly, neutralization of the negative charges present in the cell microenvironment led to faster peak kinetics. The analysis of the vesicular efflux indicates that the diffusion coefficient of dopamine at the cell surface is at most 45 % of the diffusion coefficient in free solution. This study shows that the glycocalyx plays an important role in the diffusion kinetics of processes along the cell surface, including exocytotic events.
PMCID: PMC3696406  PMID: 23544960
20.  Long-term high frequency deep brain stimulation of the nucleus accumbens drives time-dependent changes in functional connectivity in the rodent limbic system 
Brain stimulation  2012;6(3):274-285.
Deep brain stimulation of the ventral striatum is an effective treatment for a variety of treatment refractory psychiatric disorders yet the mechanism of action remains elusive. We examined how five days of stimulation affected rhythmic brain activity in freely moving rats in terms of oscillatory power within, and coherence between, selected limbic regions bilaterally. Custom made bipolar stimulating/recording electrodes were implanted, bilaterally, in the nucleus accumbens core. Local field potential (LFP) recording electrodes were implanted, bilaterally in the prelimbic and orbitofrontal cortices and mediodorsal thalamic nucleus. Stimulation was delivered bilaterally with 100μs duration constant current pulses at a frequency of 130Hz delivered at an amplitude of 100μA using a custom-made stimulation device. Synchronized video and LFP data were collected from animals in their home cages before, during and after stimulation. Signals were processed to remove movement and stimulation artifacts, and analyzed to determine changes in spectral power within, and coherence between regions. Five days stimulation of the nucleus accumbens core yielded temporally dynamic modulation of LFP power in multiple bandwidths across multiple brain regions. Coherence was seen to decrease in the alpha band between the mediodorsal thalamic nucleus and core of the nucleus accumbens. Coherence between each core of the nucleus accumbens bilaterally showed rich temporal dynamics throughout the five day stimulation period. Stimulation cessation revealed significant “rebound” effects in both power and coherence in multiple brain regions. Overall, the initial changes in power observed with short-term stimulation are replaced by altered coherence, which may reflect the functional action of DBS.
PMCID: PMC3536888  PMID: 22981894
deep brain stimulation; local field potential; ventral striatum; obsessive-compulsive disorder; nucleus accumbens
21.  Four-Year Analysis of Cardiovascular Disease Risk Factors, Depression Symptoms, and Antidepressant Medicine Use in the Look AHEAD (Action for Health in Diabetes) Clinical Trial of Weight Loss in Diabetes 
Diabetes Care  2013;36(5):1088-1094.
To study the association of depressive symptoms or antidepressant medicine (ADM) use with subsequent cardiovascular disease (CVD) risk factor status in the Look AHEAD (Action for Health in Diabetes) trial of weight loss in type 2 diabetes.
Participants (n = 5,145; age [mean ± SD] 58.7 ± 6.8 years; BMI 35.8 ± 5.8 kg/m2) in two study arms (intensive lifestyle [ILI], diabetes support and education [DSE]) completed the Beck Depression Inventory (BDI), reported ADM use, and were assessed for CVD risk factors at baseline and annually for 4 years. Risk factor–positive status was defined as current smoking, obesity, HbA1c >7.0% or insulin use, and blood pressure or cholesterol not at levels recommended by expert consensus panel or medicine to achieve recommended levels. Generalized estimating equations assessed within-study arm relationships of elevated BDI score (≥11) or ADM use with subsequent year CVD risk status, controlled for demographic variables, CVD history, diabetes duration, and prior CVD risk status.
Prior year elevated BDI was associated with subsequent CVD risk factor–positive status for the DSE arm (A1C [odds ratio 1.30 (95% CI 1.09–1.56)]; total cholesterol [0.80 (0.65–1.00)]; i.e., protective from high total cholesterol) and the ILI arm (HDL [1.40 (1.12–1.75)], triglyceride [1.28 (1.00–1.64)]). Prior year ADM use predicted subsequent elevated CVD risk status for the DSE arm (HDL [1.24 (1.03–1.50)], total cholesterol [1.28 (1.05–1.57)], current smoking [1.73 (1.04–2.88)]) and for the ILI arm (A1C [1.25 (1.08–1.46)], HDL [1.32 (1.11–1.58)], triglycerides [1.75 (1.43–2.14)], systolic blood pressure [1.39 (1.11–1.74)], and obesity [1.46 (1.22–2.18)]).
Aggressive monitoring of CVD risk in diabetic patients with depressive symptoms or who are treated with ADM may be warranted.
PMCID: PMC3631821  PMID: 23359362
22.  A Pilot Trial of a Stress Management Intervention for Primary Caregivers of Children Newly Diagnosed With Cancer: Preliminary Evidence That Perceived Social Support Moderates the Psychosocial Benefit of Intervention 
Journal of Pediatric Psychology  2013;38(4):449-461.
Objectives (1) To examine the acceptability and feasibility of a stress management intervention for caregivers of children recently diagnosed with cancer. (2) To explore whether caregivers with lower baseline perceived social support derive greater benefit from the intervention than those with higher perceived support. Methods 45 primary caregivers were randomly assigned to intervention or standard care. Of these, 37 completed measures of social support, depression, anxiety, and perceived stress at both pre-intervention (T1; mean = 24 days post-diagnosis) and post-intervention time points (T2; mean = 165 days post-diagnosis). Results Enrollment, retention, and satisfaction data support feasibility and acceptability of the intervention. There was no overall significant impact of participation in the intervention on levels of distress at T2. However, T1 social support moderated intervention response, with caregivers who perceived lower T1 support showing greater psychological benefit from the intervention. Conclusions Primary caregivers with lower levels of perceived social support may benefit from preemptive stress management intervention.
PMCID: PMC3633253  PMID: 23341547
caregivers; childhood cancer; social support; stress management intervention
23.  Oral Administration of Methylphenidate Blocks the Effect of Cocaine on Uptake at the Drosophila Dopamine Transporter 
ACS Chemical Neuroscience  2013;4(4):566-574.
Although our understanding of the actions of cocaine in the brain has improved, an effective drug treatment for cocaine addiction has yet to be found. Methylphenidate binds the dopamine transporter and increases extracellular dopamine levels in mammalian central nervous systems similar to cocaine, but it is thought to elicit fewer addictive and reinforcing effects owing to slower pharmacokinetics for different routes of administration between the drugs. This study utilizes the fruit fly model system to quantify the effects of oral methylphenidate on dopamine uptake during direct cocaine exposure to the fly CNS. The effect of methylphenidate on the dopamine transporter has been explored by measuring the uptake of exogenously applied dopamine. The data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter and the inhibition is concentration dependent. The peak height increased to 150% of control when cocaine was used to block the dopamine transporter for untreated flies but only to 110% for methylphenidate-treated flies. Thus, the dopamine transporter is mostly inhibited for the methylphenidate-fed flies before the addition of cocaine. The same is true for the rate of the clearance of dopamine measured by amperometry. For untreated flies the rate of clearance changes 40% when the dopamine transporter is inhibited with cocaine, and for treated flies the rate changes only 10%. The results were correlated to the in vivo concentration of methylphenidate determined by CE-MS. Our data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter for cocaine uptake, and the inhibition is concentration dependent.
PMCID: PMC3629741  PMID: 23402315
In vivo; methylphenidate; voltammetry; mass spectrometry; dopamine; Drosophila
24.  Pathology Slide Review in Vulvar Cancer Does Not Change Patient Management 
ISRN Surgery  2014;2014:385386.
Hypothesis. Pathology slide review in vulvar cancer is only necessary in a restricted number of cases. Methods. A retrospective chart review of all cases of vulvar cancer treated in a tertiary centre between January 1, 2000, and April 1, 2006. Histopathology reports from the referring and tertiary centre were compared. Results. 121 pathology reports from 112 patients were reviewed. Of the original reports, 56% were deemed adequate, commenting on tumor type and depth of infiltration; of the reviews, 83% were adequate. Conclusion. There were no discrepancies that influenced patient management. We suggest that vulvar cancer biopsies need to be reviewed only when the tumor is less than 10 mm in linear extension, when the infiltration is 1 mm or less, when there is no residual tumor on inspection, and in any nonsquamous cancer.
PMCID: PMC4005029
25.  Average structure and local configuration of excess oxygen in UO2+x 
Scientific Reports  2014;4:4216.
Determination of the local configuration of interacting defects in a crystalline, periodic solid is problematic because defects typically do not have a long-range periodicity. Uranium dioxide, the primary fuel for fission reactors, exists in hyperstoichiometric form, UO2+x. Those excess oxygen atoms occur as interstitial defects, and these defects are not random but rather partially ordered. The widely-accepted model to date, the Willis cluster based on neutron diffraction, cannot be reconciled with the first-principles molecular dynamics simulations present here. We demonstrate that the Willis cluster is a fair representation of the numerical ratio of different interstitial O atoms; however, the model does not represent the actual local configuration. The simulations show that the average structure of UO2+x involves a combination of defect structures including split di-interstitial, di-interstitial, mono-interstitial, and the Willis cluster, and the latter is a transition state that provides for the fast diffusion of the defect cluster. The results provide new insights in differentiating the average structure from the local configuration of defects in a solid and the transport properties of UO2+x.
PMCID: PMC3958918  PMID: 24642875

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