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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.  Enthesitis in association with inflammatory bowel disease 
BMJ Case Reports  2013;2013:bcr2012008418.
PMCID: PMC3604248  PMID: 23413295
4.  Evaluation and costs of volunteer telephone cessation follow-up counseling for Veteran smokers discharged from inpatient units: a quasi-experimental, mixed methods study 
Tobacco Induced Diseases  2015;13(1):4.
The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to evaluate the volunteer telephone smoking cessation counseling follow-up program implemented as part of the inpatient Tobacco Tactics intervention in a Veterans Affairs (VA) hospital.
This was a quasi-experimental, mixed methods design that collected data through electronic medical records (EMR), observations of telephone smoking cessation counseling calls, interviews with staff and Veterans involved in the program, and intervention costs.
Reach: Of the 131 Veterans referred to the smoking cessation telephone follow-up program, 19% were reached 0–1 times, while 81% were reached 2–4 times. Effectiveness: Seven-day point-prevalence 60-day quit rates (abstracted from the EMR) for those who were reached 2–4 times were 26%, compared to 8% among those who were reached 0–1 times (p = 0.06). Sixty-day 24-hour point-prevalence quit rates were 33% for those reached 2–4 times, compared to 4% of those reached 0–1 times (p < 0.01). Adoption and Implementation: The volunteers correctly followed protocol and were enthusiastic about performing the calls. Veterans who were interviewed reported positive comments about the calls. The cost to the hospital was $21 per participating Veteran, and the cost per quit was $92. Maintenance: There was short-term maintenance (about 1 year), but the program was not sustainable long term.
Quit rates were higher among those Veterans that had greater participation in the calls. Joint Commission standards for inpatient smoking with follow-up calls are voluntary, but should these standards become mandatory, there may be more motivation for VA administration to institute a hospital-based, volunteer telephone smoking cessation follow-up program.
Trial registration
ClinicalTrials.Gov NCT01359371.
PMCID: PMC4324430
Tobacco cessation; Smoking cessation; Peer support; Telephone calls; Veterans
5.  Longitudinal family effects on substance use among an at-risk adolescent sample 
Addictive behaviors  2014;41:185-191.
Adult and peer factors may influence whether adolescents use alcohol and other drugs (AOD). This longitudinal study examined the direct effects of adult monitoring, perceived adult AOD use, and cultural values on adolescent AOD use.
Participants were 193 at-risk adolescents referred to a California diversion program called Teen Court for a first-time AOD offense. We assessed youth reports of past 30 day AOD use (any alcohol use, heavy drinking, marijuana use), demographics, changes in parental monitoring and family values (from baseline to follow-up 180 days later), as well as family structure and perceived adult substance use at follow-up.
Adolescents who reported that a significant adult in their life used marijuana were more likely to have increased days of drinking, heavy drinking, and marijuana use at follow-up. Higher levels of familism (importance the teen places on their family’s needs over their own needs) and being in a nuclear family served as protective factors for future alcohol use. Additionally, poor family management was associated with increased alcohol use and heavy drinking.
Findings highlight how family management and perceptions of adult marijuana use influence subsequent adolescent AOD use, and how an increase in familism over time is associated with a decrease in adolescent drinking. Tailoring interventions, by including the teen’s family and/or providing support to adults who use AOD may be crucial for improving interventions for adolescent AOD use.
PMCID: PMC4314308  PMID: 25452064
Parental Monitoring; Adolescents; Substance Use
6.  Local Recurrence Rates are Low in High-Risk Neoadjuvant Breast Cancer in the I-SPY 1 Trial (CALGB 150007/150012; ACRIN 6657) 
Annals of surgical oncology  2014;21(9):2889-2896.
Increasingly, women with stage 2 and 3 breast cancers receive neoadjuvant therapy, after which many are eligible for breast-conserving surgery (BCS). The question often arises as to whether BCS, if achievable, provides adequate local control. We report the results of local recurrence (LR) from the I-SPY 1 Trial in the setting of maximal multidisciplinary treatment where approximately 50 % of patients were treated with BCS.
We analyzed data from the I-SPY 1 Trial. Women with tumors ≥3 cm from nine clinical breast centers received neoadjuvant doxorubicin, cyclophosphamide and paclitaxel followed by definitive surgical therapy, and radiation at physician discretion. LR following mastectomy and BCS were analyzed in relation to clinical characteristics and response to therapy as measured by residual cancer burden.
Of the 237 patients enrolled in the I-SPY 1 Trial, 206 were available for analysis. Median tumor size was 6.0 cm, and median follow-up was 3.9 years. Fourteen patients (7 %) had LR and 45 (22 %) had distant recurrence (DR). Of the 14 patients with LR, nine had synchronous DR; one had DR > 2 years later. Only four (2 % of evaluable patients) had LR alone. The rate of LR was low after mastectomy and after BCS, even in the setting of significant residual disease.
Overall, these patients at high risk for early recurrence, treated with maximal multidisciplinary treatment, had low LR. Recurrence was associated with aggressive biological features such as more advanced stage at presentation, where LR occurs most frequently in the setting of DR.
PMCID: PMC4303244  PMID: 24788555
7.  Perceptions and utilization of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine in young children in the Chikhwawa District of Malawi: a mixed methods study 
Malaria Journal  2015;14:13.
Adherence to anti-malarial dosing schedules is essential to ensure effective treatment. Measuring adherence is challenging due to recall issues and the participants’ awareness of the desired behaviour influencing their actions or responses. This study used qualitative methods, which allow for rapport building, to explore issues around anti-malarial utilization in young children, and used the results to guide the development of a context specific questionnaire on perceptions and adherence to artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ).
Qualitative data collection included 12 focus group discussions which explored community perceptions of anti-malarials and experiences of administering medications to children. Critical incidence interviews were conducted with 22 caregivers to explore experiences of administering the dispersible or original formulation of AL to young children during recent febrile episodes. A structured questionnaire was used to gather data on experience of recent treatment and adherence to anti-malarials during follow-up visits with 218 caregivers whose child was recently treated with either dispersible AL or DHA-PPQ.
Caregivers experience great difficulty in administering medication to children. While the sweet taste of dispersible AL may have reduced conflict between the child and caregiver, sub-optimal dosing due to medication loss remained a problem and overall adherence was greater among those receiving DHA-PPQ, which requires fewer doses. Some caregivers were found to deliberately alter the dosing schedule according to whether they perceived the medication to be too weak or strong. They also developed theories for poor treatment outcomes, such as attributing this to lack of compatibility between the medication and the child. Health education messages should be strengthened to ensure a combination of clear pictorial and verbal instructions are used during dispensing, and consequences of under and over-dosing are explained alongside appropriate responses to possible adverse events. Further optimizing of anti-malarial adherence among children requires the development of anti-malarials with pharmacological properties that allow user-friendly administration and simplified dosing schedules.
PMCID: PMC4311415  PMID: 25605477
Malaria; Antimalarials; ACT; Adherence; Utilization; Perceptions; Malawi; Sub-Saharan Africa; Paediatric
8.  Actin Controls the Vesicular Fraction of Dopamine Released During Extended Kiss and Run Exocytosis 
ACS Chemical Biology  2014;9(3):812-820.
The effect of latrunculin A, an inhibitor of actin cross-linking, on exocytosis in PC12 cells was investigated with single cell amperometry. This analysis strongly suggests that the actin cytoskeleton might be involved in regulating exocytosis, especially by mediating the constriction of the pore. In an extended kiss-and-run release mode, actin could actually control the fraction of neurotransmitters released by the vesicle. This scaffold appears to contribute, with the lipid membrane and the protein machinery, to the closing dynamics of the pore, in competition with other forces mediating the opening of the exocytotic channel.
PMCID: PMC3985473  PMID: 24400601
9.  Acculturation and Subclinical Atherosclerosis among U.S. South Asians: Findings from the MASALA study 
Longer duration of residence among immigrants to the United States, a proxy measure of acculturation, has been associated with higher subclinical atherosclerosis. South Asian immigrants are the second fastest growing immigrant group in the U.S. but little is known about the effects of acculturation with atherosclerosis in this high cardiovascular risk population.
We conducted a cross-sectional analysis using data from a community-based cohort called the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. Participants (n=900) were between ages of 40–84 years and had no existing cardiovascular disease. We developed a multi-dimensional measure of acculturation in South Asians, called traditional cultural beliefs, and measured other proxy measures of acculturation to determine whether they were associated with higher levels of subclinical atherosclerosis after controlling for socioeconomic, behavior/lifestyle, and cardiovascular risk factors.
Mean duration of residence in the U.S. was 27±11 years and tertiles of strength of traditional cultural beliefs were examined. Longer duration of U.S. residence was associated with higher levels of coronary artery calcium even after adjustment for covariates and lifestyle mediators. The novel measure of strength of traditional cultural beliefs was associated with lower common carotid intima media thickness among those with moderate traditional beliefs only.
These findings support the need for better conceptualization and measurement of how migration influences cultural beliefs and practices, and their subsequent influence on health behaviors and cardiovascular disease risk.
PMCID: PMC4283837  PMID: 25568891
Atherosclerosis; Acculturation; Athnicity
10.  Integrated analysis of the Wnt responsive proteome in human cells reveals diverse and cell-type specific networks 
Molecular bioSystems  2014;10(1):45-53.
Wnt signalling is a fundamentally important signalling pathway that regulates many aspects of metazoan development and is frequently dysregulated in cancer. Although many of the core components of the Wnt signalling pathway, such as β-catenin, have been extensively studied, the broad systems level responses of the mammalian cell to Wnt signalling are less well understood. In addition, the cell- or tissue-specific protein networks that modulate Wnt signalling in the diverse tissues or developmental stages in which it functions remain to be defined. To address these questions, we undertook a broad survey of the Wnt response in different human cell lines using both interaction and expression proteomics approaches. Our data reveal both similar and divergent responses of pathways and processes in the three cell-lines analyzed as well as a marked attenuation of the response to exogenous Wnt treatment in cells harbouring a stabilizing (activating) mutation of β-catenin. We also identify cell-type specific components of the Wnt signalling network and find that by integrating expression and interaction proteomics data a more complete description of the Wnt interaction network can be achieved. Finally, our results attest to the power of LCMS/MS to reveal novel cellular responses in even relatively well studied biological pathways such as Wnt signalling.
PMCID: PMC3909504  PMID: 24201312
11.  Carbon Nanotube Fiber Microelectrodes Show a Higher Resistance to Dopamine Fouling 
Analytical chemistry  2013;85(15):7447-7453.
We have compared the properties and resistance to DA fouling of a carbon nanotube fiber (CNTF) microelectrode to a traditional carbon fiber (CF) microelectrode. These two materials show comparable electrochemical activities for outer-sphere and inner-sphere redox reactions. Although the CNTF might have a higher intrinsic RC constant, thus limiting its high-frequency behavior, the CNTF show a significantly higher durability than the CF in terms of electrode stability. During constant oxidation of 100 μM DA, the signal measured by the CNTF microelectrode shows a 2-hour window over which no decrease in current is observed. Under the same conditions, the current obtained at the CF microelectrode decreases by almost 50 %. A model of the fouling process, assuming the formation of growing patches of insulator on the surface, has been compared to the data. This model is found to be in good agreement with our results, and indicates a growth rate of the patches in the 0.1 - 2 nm s−1 range.
PMCID: PMC4276597  PMID: 23789970
12.  Preliminary Evidence for Associations of CHRM2 with Substance Use and Disinhibition in Adolescence 
Evidence for shared heritable influences across domains of substance use suggests that some genetic variants influence broad risk for externalizing behaviors. Theories of externalizing psychopathology also suggest that genetic liability for substance use manifests as temperamental risk factors, particularly those related to behavioral disinhibition, during adolescence. The cholinergic muscarinic receptor 2 gene (CHRM2) is a promising candidate for studying genetic influences on broad-based risk for externalizing traits. This study examined a candidate CHRM2 polymorphism (rs1455858) in relation to substance use and personality measures of disinhibition in a sample of high-risk adolescents (n = 124). Bivariate analyses and structural equation modeling (SEM) evaluated associations of rs1455858 with measures of drug involvement (alcohol, tobacco and marijuana) and disinhibition (indexed by impulsivity and sensation seeking scores). Bivariate analyses showed significant associations of CHRM2 with several behavioral phenotypes. In SEM analyses CHRM2 related significantly to latent measures of substance use and disinhibition; additionally, disinhibition mediated the association of CHRM2 with substance use. These results suggest that CHRM2 variants are potentially relevant for adolescent substance use and that temperamental risk factors could contribute to these associations.
PMCID: PMC4254849  PMID: 21494862
Disinhibitory psychopathology; drug dependence; response inhibition; risk-taking; SNP
13.  Alcohol and Marijuana Use in Middle School: Comparing Solitary and Social-Only Users 
Middle school students with a history of solitary substance use are at elevated risk for substance problems by young adulthood. Understanding how these students differ from social-only users on substance use behaviors and consequences, normative beliefs, social influences and attitudes can inform efforts to reduce solitary use and its related negative consequences.
6th–7th grade students completed an in-school survey. We compared those with a history of solitary vs. social-only alcohol use (n=202 and n=616, respectively) and marijuana use (n=92 and n=208, respectively) on a range of substance use-related characteristics.
Any solitary use was reported by 25% of lifetime alcohol users and 31% of lifetime marijuana users. Those with a history of solitary use of either substance were more likely to hold positive expectancies about their use, but also reported more negative consequences during the past year. Solitary users tended to have greater exposure to substance using peers and more difficulty resisting offers to use. Compared to social-only drinkers, those with a history of solitary drinking perceived that more of their peers were alcohol users. Significant group differences were not found on negative outcome expectancies or attempts to cut down on substance use.
Solitary use is an important, yet overlooked problem among middle school students who have just begun drinking or using marijuana. Results suggest that positive expectancies, peer influences, resistance self-efficacy, and normative beliefs may be important areas to target in reducing solitary use and the risk it poses for problematic use in young adulthood.
PMCID: PMC4252711  PMID: 25223477
14.  Self-Monitoring as a Mediator of Weight Loss in the SMART Randomized Clinical Trial 
International journal of behavioral medicine  2013;20(4):10.1007/s12529-012-9259-9.
Integral components of behavioral weight-loss treatment include self-monitoring of diet and physical activity along with feedback to participants regarding their behaviors. While providing feedback has been associated with weight loss, no studies have examined the impact of feedback frequency on weight loss, or the mediating role of self-monitoring adherence in this relationship.
This study examined the effect of participant feedback frequency on weight loss and determined if this effect was mediated by adherence to self-monitoring in a behavioral weight-loss trial conducted in the United States.
Participants (N=210) were randomly assigned to one of three self-monitoring methods with either no daily feedback messages or daily feedback messages: 1) paper diary (PD)- no daily feedback, 2) personal digital assistant (PDA)- no daily feedback, and 3) PDA- daily, tailored feedback messages (PDA+FB). The Sobel test via bootstrapping examined the direct effect of feedback frequency on weight loss and the indirect effect through self-monitoring adherence.
Receiving daily feedback messages significantly increased participants’ self-monitoring adherence. A significant effect of feedback frequency on weight loss was noted; however, after adjusting for self-monitoring adherence, the effect of feedback frequency on weight loss was no longer significant. Feedback frequency had a significant indirect effect on weight loss through self-monitoring adherence.
Self-monitoring adherence mediated the effect of feedback frequency on weight loss. Increasing the frequency with which participants receive feedback could enhance self-monitoring adherence, a critical component of behavioral weight-loss treatment.
PMCID: PMC3529986  PMID: 22936524
self-monitoring; mediation; adherence; feedback; weight loss; obesity
15.  A longitudinal examination of alcohol, marijuana, and cigarette perceived norms among middle school adolescents 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.08.008.
Adolescents tend to overestimate the prevalence of substance use among their peers and these perceived norms are associated with their current and future use. However, little is known about how perceived norms change over time during middle school, a developmental period when adolescents are at-risk for initiating substance use.
We examined changes in perceived norms of alcohol, marijuana, and cigarettes over a two year period among a large and diverse sample of 6th and 7th grade youth (N = 6,097; 50.1% female; 54% Hispanic). Participants completed a baseline survey and two subsequent annual surveys. Participants estimated the percentage of their peers they believed used each substance, as well as indicated levels of personal use, offers to use from peers, and exposure to peers who were using each substance.
Perceived norms of all three substances increased over time. Increases were somewhat attenuated when controlling for demographic factors, personal use, and peer factors, but remained significant. Female adolescents and those reporting non-Hispanic White ethnicity experienced the greatest increase in perceived norms over time.
Normative perceptions of substance use increase greatly during the middle school years, an effect which cannot be fully explained by demographics, personal use, or peer factors. Given that perceived norms are often associated with personal use, early interventions with middle school youth are warranted to prevent the growth of these influential factors during this developmental period.
PMCID: PMC3836211  PMID: 24012070
alcohol; marijuana; cigarettes; adolescents; perceived norms
16.  Psychometric Evaluation of the Social Problem-Solving Inventory- Revised among Overweight or Obese Adults 
Problem solving is a key component of weight loss programs. The Social Problem Solving Inventory-Revised (SPSI-R) has not been evaluated in weight loss studies. The purpose of this study was to evaluate the psychometrics of the SPSI-R. Cronbach’s alpha (.95 for total score; .67 – .92 for subscales) confirmed internal consistency reliability. The SPSI-R score was significantly associated (ps<.05) with decreased eating barriers and binge eating, increased self-efficacy in following a cholesterol-lowering diet, consumption of fewer calories and fat grams, more frequent exercise, lower psychological distress, and higher mental quality of life; all suggesting concurrent validity with other instruments used in weight loss studies. However, confirmatory factor analysis of the hypothesized 5-factor structure did not fit the data well (χ2=350, p<.001).
PMCID: PMC4130479  PMID: 25132720
Problem Solving; Behavior therapy; Weight loss; Psychometrics
17.  RADIA: RNA and DNA Integrated Analysis for Somatic Mutation Detection 
PLoS ONE  2014;9(11):e111516.
The detection of somatic single nucleotide variants is a crucial component to the characterization of the cancer genome. Mutation calling algorithms thus far have focused on comparing the normal and tumor genomes from the same individual. In recent years, it has become routine for projects like The Cancer Genome Atlas (TCGA) to also sequence the tumor RNA. Here we present RADIA (RNA and DNA Integrated Analysis), a novel computational method combining the patient-matched normal and tumor DNA with the tumor RNA to detect somatic mutations. The inclusion of the RNA increases the power to detect somatic mutations, especially at low DNA allelic frequencies. By integrating an individual’s DNA and RNA, we are able to detect mutations that would otherwise be missed by traditional algorithms that examine only the DNA. We demonstrate high sensitivity (84%) and very high precision (98% and 99%) for RADIA in patient data from endometrial carcinoma and lung adenocarcinoma from TCGA. Mutations with both high DNA and RNA read support have the highest validation rate of over 99%. We also introduce a simulation package that spikes in artificial mutations to patient data, rather than simulating sequencing data from a reference genome. We evaluate sensitivity on the simulation data and demonstrate our ability to rescue back mutations at low DNA allelic frequencies by including the RNA. Finally, we highlight mutations in important cancer genes that were rescued due to the incorporation of the RNA.
PMCID: PMC4236012  PMID: 25405470
18.  Gridless Overtone Mobility Spectrometry 
Analytical chemistry  2013;85(21):10174-10179.
A novel overtone mobility spectrometry (OMS) instrument utilizing a gridless elimination mechanism and cooperative radio frequency confinement is described. The gridless elimination region uses a set of mobility-discriminating radial electric fields that are designed so that the frequency of field application results in selective transmission and elimination of ions. To neutralize ions with mobilities that do not match the field application frequency, active elimination regions radially defocus ions towards the lens walls. Concomitantly, a lens-dependent radio frequency waveform is applied to the transmission regions of the drift tube resulting in radial confinement for mobility-matched ions. Compared with prior techniques, which use many grids for ion elimination, the new gridless configuration substantially reduces indiscriminate ion losses. A description of the apparatus and elimination process, including detailed simulations showing how ions are transmitted and eliminated is presented. A prototype 28 cm long OMS instrument is shown to have a resolving power of 20 and is capable of attomole detection limits of a model peptide (angiotensin I) spiked into a complex mixture (in this case peptides generated from digestion of β-casein with trypsin).
PMCID: PMC3994891  PMID: 24125033
19.  Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia 
Journal of psychiatric research  2013;47(11):1630-1635.
A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced “noise” in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbtiofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the “signal-to-noise” ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input.
PMCID: PMC3786048  PMID: 23932574
MAM; schizophrenia; prepulse inhibition; auditory evoked potentials; intensity processing
20.  Dietary inequalities of mother-child pairs in the rural Amazon: Evidence of maternal-child buffering? 
This paper explores the expected outcome of maternal nutritional “buffering,” namely that children’s diets will be more adequate than mothers’ diets under conditions of food scarcity. Data on Amazonian mothers and their children, household demography and economics and direct, weighed measures of household food availability and dietary intakes of mother-child pairs were collected from 51 households to address the following research questions: (1) is there evidence of food scarcity in this setting?; (2) are there differences in energy and protein adequacy between children and their mothers?; and, (3) which individual and household-level factors are associated with these mother-child differences in energy and protein adequacy? In this context of food scarcity, we found that the majority of children had more adequate energy (p<0.001) and protein (p<0.001) intakes than their mothers. Multivariate OLS regression models showed that of the individual-level factors, child age and height-for-age were negatively associated with maternal-child energy and protein inequalities while maternal reproductive status (lactation) was positively associated with energy inequality. While there were no gender differences in dietary adequacy among children, boys had a larger advantage over their mothers in terms of protein adequacy than girls. Household food availability was related to maternal-child energy and protein inequalities in a curvilinear fashion with the lowest inequalities found in households with extremely low food availability and those with adequate food resources. This is the first study to quantify maternal-child dietary inequalities in a setting of food scarcity and demonstrates the importance of the household context and individual characteristics in understanding the degree to which mothers protect their children from resource scarcity.
PMCID: PMC3796132  PMID: 24034966
Brazil; Amazon; food security; intra-household resource distribution; parental investment; nutrition; food provisioning
21.  Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[14C]DTPA 
An intravenous step-down infusion procedure that maintained a constant gadolinium-diethylene-triaminepentaacetic acid (Gd-DTPA) blood concentration and magnetic resonance imaging (MRI) were used to localize and quantify the blood–brain barrier (BBB) opening in a rat model of transient cerebral ischemia (n = 7). Blood-to-brain influx rate constant (Ki) values of Gd-DTPA from such regions were estimated using MRI–Patlak plots and compared with the Ki values of Gd-[14C]DTPA, determined minutes later in the same rats with an identical step-down infusion, quantitative autoradiography (QAR), and single-time equation. The normalized plasma concentration–time integrals were identical for Gd-DTPA and Gd-[14C]DTPA, indicating that the MRI protocol yielded reliable estimates of plasma Gd-DTPA levels. In six rats with a BBB opening, 14 spatially similar regions of extravascular Gd-DTPA enhancement and Gd-[14C]DTPA leakage, including one very small area, were observed. The terminal tissue–plasma ratios of Gd-[14C]DTPA tended to be slightly higher than those of Gd-DTPA in these regions, but the differences were not significant. The MRI-derived Ki values for Gd-DTPA closely agreed and correlated well with those obtained for Gd-[14C]DTPA. In summary, MRI estimates of Gd-DTPA concentration in the plasma and brain and the influx rate are quantitatively and spatially accurate with step-down infusions.
PMCID: PMC4205544  PMID: 19319145
arterial input function; blood–brain barrier; magnetic resonance contrast agents; Patlak plot; rat; stroke
22.  An inexpensive, charge-balanced rodent deep brain stimulation device: a step-by-step guide to its procurement and construction 
Journal of neuroscience methods  2013;219(2):10.1016/j.jneumeth.2013.08.003.
Despite there being a relatively large number of methods papers which detail specifically the development of stimulation devices, only a small number of reports involve the application of these devices in freely moving animals. To date multiple preclinical neural stimulators have been designed and described but have failed to make an impact on the methods employed by the majority of laboratories studying DBS. Thus, the overwhelming majority of DBS studies are still performed by tethering the subject to an external stimulator. We believe that the low adoption rate of previously described methods is a result of the complexity of replicating and implementing these methods.
New Method
Here were describe both the design and procurement of a simple and inexpensive stimulator designed to be compatible with commonly used, commercially available electrodes (Plastics 1).
This system is initially programmable in frequency, pulsewidth and current amplitude, and delivers biphasic, charge-balanced output to two independent electrodes.
Comparison with Existing Method(s)
It is easy to implement requiring neither subcutaneous implantation or custom-made electrodes and has been optimized for either direct mounting to the head or for use with rodent jackets.
This device is inexpensive and universally accessible, facilitating high throughput, low cost, long-term rodent deep brain stimulation experiments.
PMCID: PMC3809915  PMID: 23954265
deep brain stimulation; rodent; programmable; chronic; bilateral; charge-balanced
23.  Single-Cell Imaging Mass Spectrometry 
Current opinion in chemical biology  2013;17(5):10.1016/j.cbpa.2013.07.017.
Single-cell imaging mass spectrometry (IMS) is a powerful technique used to map the distributions of endogenous biomolecules with sub-cellular resolution. Currently, secondary ion mass spectrometry is the predominant technique for single-cell IMS, thanks to its sub-micron lateral resolution and surface sensitivity. However, recent methodological and technological developments aimed at improving the spatial resolution of matrix assisted laser desorption ionization (MALDI) have made this technique a potential platform of single-cell IMS. MALDI opens the field of single-cell IMS to new possibilities, including single cell proteomic imaging and atmospheric pressure analyses; however, sensitivity is a challenge. In this report, we estimate the availability of proteins and lipids in a single cell and discuss strategies employed to improve sensitivity at the single-cell level.
PMCID: PMC3823831  PMID: 23948695
SIMS; MALDI; nanoSIMS; Single-cell; Imaging Mass Spectrometry
24.  Working Memory and Corpus Callosum Microstructural Integrity after Pediatric Traumatic Brain Injury: A Diffusion Tensor Tractography Study 
Journal of Neurotrauma  2013;30(19):1609-1619.
Deficits in working memory (WM) are a common consequence of pediatric traumatic brain injury (TBI) and are believed to contribute to difficulties in a range of cognitive and academic domains. Reduced integrity of the corpus callosum (CC) after TBI may disrupt the connectivity between bilateral frontoparietal neural networks underlying WM. In the present investigation, diffusion tensor imaging (DTI) tractography of eight callosal subregions (CC1–CC8) was examined in relation to measures of verbal and visuospatial WM in 74 children sustaining TBI and 49 typically developing comparison children. Relative to the comparison group, children with TBI demonstrated poorer visuospatial WM, but comparable verbal WM. Microstructure of the CC was significantly compromised in brain-injured children, with lower fractional anisotropy (FA) and higher axial and radial diffusivity metrics in all callosal subregions. In both groups of children, lower FA and/or higher radial diffusivity in callosal subregions connecting anterior and posterior parietal cortical regions predicted poorer verbal WM, whereas higher radial diffusivity in callosal subregions connecting anterior and posterior parietal, as well as temporal, cortical regions predicted poorer visuospatial WM. DTI metrics, especially radial diffusivity, in predictive callosal subregions accounted for significant variance in WM over and above remaining callosal subregions. Reduced microstructural integrity of the CC, particularly in subregions connecting parietal and temporal cortices, may act as a neuropathological mechanism contributing to long-term WM deficits. The future clinical use of neuroanatomical biomarkers may allow for the early identification of children at highest risk for WM deficits and earlier provision of interventions for these children.
PMCID: PMC3787334  PMID: 23627735
axonal injury; cognitive function; diffusion tensor imaging; pediatric brain injury
25.  Magnetic Resonance Imaging Estimation of Longitudinal Relaxation Rate Change (ΔR1) in Dual Gradient Echo Sequences Using an Adaptive Model 
Magnetic Resonance Imaging (MRI) estimation of contrast agent concentration in fast pulse sequences such as Dual Gradient Echo (DGE) imaging is challenging. An Adaptive Neural Network (ANN) was trained with a map of contrast agent concentration estimated by Look-Locker (LL) technique (modified version of inversion recovery imaging) as a gold standard. Using a set of features extracted from DGE MRI data, an ANN was trained to create a voxel based estimator of the time trace of CA concentration. The ANN was trained and tested with the DGE and LL information of six Fisher rats using a K-Fold Cross-Validation (KFCV) method with 60 folds and 10500 samples. The Area Under the Receiver Operator Characteristic Curve (AUROC) for 60 folds was used for training, testing and optimization of the ANN. After training and optimization, the optimal ANN (4:7:5:1) produced maps of CA concentration which were highly correlated (r =0.89, P < 0.0001) with the CA concentration estimated by the LL technique. The estimation made by the ANN had an excellent overall performance (AUROC = 0.870).
PMCID: PMC4181328  PMID: 25285243

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