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1.  Chiropractic identity, role and future: a survey of North American chiropractic students 
Background
The literature pertaining to chiropractic students’ opinions with respect to the desired future status of the chiropractic physician is limited and is an appropriate topic worthy of study. A previous pilot study was performed at a single chiropractic college. This current study is an expansion of this pilot project to collect data from chiropractic students enrolled in colleges throughout North America.
Objective
The purpose of this study is to investigate North American chiropractic students’ opinions concerning professional identity, role and future.
Methods
A 23-item cross-sectional electronic questionnaire was developed. A total of 7,455 chiropractic students from 12 North American English-speaking chiropractic colleges were invited to complete the survey. Survey items encompassed demographics, evidence-based practice, chiropractic identity and setting, and scope of practice. Data were collected and descriptive statistical analysis was performed.
Results
A total of 1,247 (16.7% response rate) questionnaires were electronically submitted. Most respondents agreed (34.8%) or strongly agreed (52.2%) that it is important for chiropractors to be educated in evidence-based practice. A majority agreed (35.6%) or strongly agreed (25.8%) the emphasis of chiropractic intervention is to eliminate vertebral subluxations/vertebral subluxation complexes. A large number of respondents (55.2%) were not in favor of expanding the scope of the chiropractic profession to include prescribing medications with appropriate advanced training. Most respondents estimated that chiropractors should be considered mainstream health care practitioners (69.1%). Several respondents (46.8%) think that chiropractic research should focus on the physiological mechanisms of chiropractic adjustments.
Conclusion
The chiropractic students in this study showed a preference for participating in mainstream health care, report an exposure to evidence-based practice, and desire to hold to traditional chiropractic theories and practices. The majority of students would like to see an emphasis on correction of vertebral subluxation, while a larger percent found it is important to learn about evidence-based practice. These two key points may seem contradictory, suggesting cognitive dissonance. Or perhaps some students want to hold on to traditional theory (e.g., subluxation-centered practice) while recognizing the need for further research to fully explore these theories. Further research on this topic is needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12998-014-0048-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12998-014-0048-1
PMCID: PMC4313466  PMID: 25646145
Chiropractic; Cross-sectional survey
2.  Protected Areas in Tropical Africa: Assessing Threats and Conservation Activities 
PLoS ONE  2014;9(12):e114154.
Numerous protected areas (PAs) have been created in Africa to safeguard wildlife and other natural resources. However, significant threats from anthropogenic activities and decline of wildlife populations persist, while conservation efforts in most PAs are still minimal. We assessed the impact level of the most common threats to wildlife within PAs in tropical Africa and the relationship of conservation activities with threat impact level. We collated data on 98 PAs with tropical forest cover from 15 countries across West, Central and East Africa. For this, we assembled information about local threats as well as conservation activities from published and unpublished literature, and questionnaires sent to long-term field workers. We constructed general linear models to test the significance of specific conservation activities in relation to the threat impact level. Subsistence and commercial hunting were identified as the most common direct threats to wildlife and found to be most prevalent in West and Central Africa. Agriculture and logging represented the most common indirect threats, and were most prevalent in West Africa. We found that the long-term presence of conservation activities (such as law enforcement, research and tourism) was associated with lower threat impact levels. Our results highlight deficiencies in the management effectiveness of several PAs across tropical Africa, and conclude that PA management should invest more into conservation activities with long-term duration.
doi:10.1371/journal.pone.0114154
PMCID: PMC4254933  PMID: 25469888
3.  Inflammation is an Independent Risk Factor for Colonic Neoplasia in Patients with Ulcerative Colitis: a Case–Control Study 
Background & Aims
An association between inflammatory activity and colorectal neoplasia (CRN) has been documented in patients with ulcerative colitis (UC). However, previous studies did not address the duration of inflammation or the effects of therapy on risk for CRN. We investigated the effects of inflammation, therapies, and characteristics of patients with UC on their risk for CRN.
Methods
We collected data from 141 patients with UC without CRN (controls), and 59 matched patients with UC who developed CRN (cases), comparing disease extent and duration and patients’ ages. We used a new 6-point histologic inflammatory activity (HIA) scale to score biopsy fragments (n=4449). Information on medications, smoking status, primary sclerosing cholangitis (PSC), and family history of CRN were collected from the University of Chicago Inflammatory Bowel Disease Endoscopy Database. Relationships between HIA, clinical features, and CRN were assessed by conditional logistic regression.
Results
Cases and controls were similar in numbers of procedures and biopsies, exposure to steroids or mesalamine, smoking status, and family history of CRN. They differed in proportion of men vs women, exposure to immune modulators, and PSC prevalence. In univariate analysis, HIA was positively associated with CRN (odds ratio [OR], 2.56/ per unit increase; P=.001), whereas immune modulators (including azathioprine, 6-mercaptopurine, and methotrexate) reduced the risk for CRN (OR, 0.35; P<.01). HIA was also associated with CRN in multivariate analysis (OR, 3.68; P=.001).
Conclusion
In a case–control study, we associated increased inflammation with CRN in patients with UC. Use of immune modulators reduced the risk for CRN, indicating that these drugs have chemoprotective effects. Based on these data, we propose new stratified surveillance and treatment strategies to prevent and detect CRN in patients with UC.
doi:10.1016/j.cgh.2013.06.023
PMCID: PMC3840031  PMID: 23872237
IBD; AZA; 6MP; 5-ASA; colorectal cancer; chemoprevention; dysplasia
4.  Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control 
BMC Public Health  2014;14(1):1176.
Background
Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed.
Methods
Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms.
Results
No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms.
Conclusions
Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status.
doi:10.1186/1471-2458-14-1176
PMCID: PMC4251859  PMID: 25407464
Mass drug administration; Azithromycin; Trachoma control; Anthropometry
5.  Brain Activity in Adolescent Major Depressive Disorder Before and After Fluoxetine Treatment 
The American journal of psychiatry  2012;169(4):381-388.
Objective
Major depression in adolescents is a significant public health concern because of its frequency and severity. To examine the neurobiological basis of depression in this population, the authors studied functional activation characteristics of the brain before and after antidepressant treatment in antidepressant-naive depressed adolescents and healthy comparison subjects.
Method
Depressed (N=19) and healthy (N=21) adolescents, ages 11 to 18 years, underwent functional MRI assessment while viewing fearful and neutral facial expressions at baseline and again 8 weeks later. The depressed adolescents received 8 weeks of open-label fluoxetine treatment after their baseline scan.
Results
Voxel-wise whole brain analyses showed that depressed youths have exaggerated brain activation compared with healthy comparison subjects in multiple regions, including the frontal, temporal, and limbic cortices. The 8 weeks of fluoxetine treatment normalized most of these regions of hyperactivity in the depressed group. Region-of-interest analyses of the areas involved in emotion processing indicated that before treatment, depressed youths had significantly greater activations to fearful relative to neutral facial expressions than did healthy comparison subjects in the amygdala, orbitofrontal cortex, and subgenual anterior cingulate cortex bilaterally. Fluoxetine treatment decreased activations in all three regions, as compared with the repeat scans of healthy comparison subjects.
Conclusions
While effective treatments are available, the impact of depression and its treatment on the brain in adolescents is understudied. This study confirms increases in brain activation in untreated depressed adolescents and demonstrates reductions in these aberrant activations with treatment.
doi:10.1176/appi.ajp.2011.11040615
PMCID: PMC4225078  PMID: 22267183
6.  Fabrication and Evaluation of a Micro(Bio)Sensor Array Chip for Multiple Parallel Measurements of Important Cell Biomarkers 
Sensors (Basel, Switzerland)  2014;14(11):20519-20532.
This report describes the design and development of an integrated electrochemical cell culture monitoring system, based on enzyme-biosensors and chemical sensors, for monitoring indicators of mammalian cell metabolic status. MEMS technology was used to fabricate a microwell-format silicon platform including a thermometer, onto which chemical sensors (pH, O2) and screen-printed biosensors (glucose, lactate), were grafted/deposited. Microwells were formed over the fabricated sensors to give 5-well sensor strips which were interfaced with a multipotentiostat via a bespoke connector box interface. The operation of each sensor/biosensor type was examined individually, and examples of operating devices in five microwells in parallel, in either potentiometric (pH sensing) or amperometric (glucose biosensing) mode are shown. The performance characteristics of the sensors/biosensors indicate that the system could readily be applied to cell culture/toxicity studies.
doi:10.3390/s141120519
PMCID: PMC4279497  PMID: 25360580
microbiosensor; screen-printing; MEMS; 96-well plate; metabolism; amperometry; cell monitoring; toxicity testing
7.  Non-Participation during Azithromycin Mass Treatment for Trachoma in The Gambia: Heterogeneity and Risk Factors 
Background
There is concern that untreated individuals in mass drug administration (MDA) programs for neglected tropical diseases can reduce the impact of elimination efforts by maintaining a source of transmission and re-infection.
Methodology/Principal Findings
Treatment receipt was recorded against the community census during three MDAs with azithromycin for trachoma in The Gambia, a hypo-endemic setting. Predictors of non-participation were investigated in 1–9 year olds using random effects logistic regression of cross-sectional data for each MDA. Two types of non-participators were identified: present during MDA but not treated (PNT) and eligible for treatment but absent during MDA (EBA). PNT and EBA children were compared to treated children separately. Multivariable models were developed using baseline data and validated using year one and two data, with a priori adjustment for previous treatment status. Analyses included approximately 10000 children at baseline and 5000 children subsequently. There was strong evidence of spatial heterogeneity, and persistent non-participation within households and individuals. By year two, non-participation increased significantly to 10.4% overall from 6.2% at baseline, with more, smaller geographical clusters of non-participating households. Multivariable models suggested household level predictors of non-participation (increased time to water and household head non-participation for both PNT and EBA; increased household size for PNT status only; non-inclusion in a previous trachoma examination survey and younger age for EBA only). Enhanced coverage efforts did not decrease non-participation. Few infected children were detected at year three and only one infected child was EBA previously. Infected children were in communities close to untreated endemic areas with higher rates of EBA non-participation during MDA.
Conclusions/Significance
In hypo-endemic settings, with good coverage and no association between non-participation and infection, efforts to improve participation during MDA may not be required. Further research could investigate spatial hotspots of infection and non-participation in other low and medium prevalence settings before allocating resources to increase participation.
Author Summary
As the target year for Global Elimination of Trachoma (GET2020) approaches, the scale up of mass drug administration (MDA) with azithromycin will lead to more endemic areas becoming low prevalence settings. In such areas, identification of those at highest risk of Chlamydia trachomatis infection and at highest risk of non-participation during MDA could inform control planning, especially if correlation is present. We investigated non-participation in children aged 1–9 years during three annual MDAs in The Gambia, a low prevalence setting. We found evidence that non-participation is associated with household membership and decision-making, as seen in medium and high prevalence settings in East Africa. In addition, we demonstrate geographical heterogeneity (spatial clustering) of non-participation, persistent non-participation behaviour over time and different non-participator types. Between the first and third MDA, non-participation increased significantly overall from 6.2% to 10.4%, whilst spatial clusters became smaller with non-participation more focused in single households or small groups of households. There was no evidence of association between infection and non-participation. In low prevalence settings with no evidence to suggest non-participation as a risk factor for infection, resources to improve participation may not be required. Spatial hotspot analysis could address this research question in areas with more infection.
doi:10.1371/journal.pntd.0003098
PMCID: PMC4148234  PMID: 25165994
8.  Depressive Symptoms and Concussions in Aging Retired NFL Players 
We examined the relationship between a remote history of concussions with current symptoms of depression in retired professional athletes. Thirty retired National Football League (NFL) athletes with a history of concussion and 29 age- and IQ-matched controls without a history of concussion were recruited. We found a significant correlation between the number of lifetime concussions and depressive symptom severity using the Beck Depression Inventory II. Upon investigating a three-factor model of depressive symptoms (affective, cognitive, and somatic; Buckley et al., 2001) from the BDI-II, the cognitive factor was the only factor that was significantly related to concussions. In general, NFL players endorsed more symptoms of depression on all three Buckley factors compared with matched controls. Findings suggest that the number of self-reported concussions may be related to later depressive symptomology (particularly cognitive symptoms of depression).
doi:10.1093/arclin/act028
PMCID: PMC4007104  PMID: 23644673
Concussion; Depression; Cognition; Aging; Football; NFL
9.  African origin of the malaria parasite Plasmodium vivax 
Nature communications  2014;5:3346.
Plasmodium vivax is the leading cause of human malaria in Asia and Latin America but is absent from most of central Africa due to the near fixation of a mutation that inhibits the expression of its receptor, the Duffy antigen, on human erythrocytes. The emergence of this protective allele is not understood because P. vivax is believed to have originated in Asia. Here we show, using a non-invasive approach, that wild chimpanzees and gorillas throughout central Africa are endemically infected with parasites that are closely related to human P. vivax. Sequence analyses reveal that ape parasites lack host specificity and are much more diverse than human parasites, which form a monophyletic lineage within the ape parasite radiation. These findings indicate that human P. vivax is of African origin and likely selected for the Duffy-negative mutation. All extant human P. vivax parasites are derived from a single ancestor that escaped out of Africa.
doi:10.1038/ncomms4346
PMCID: PMC4089193  PMID: 24557500
10.  Distinct and Diverse: Range-Wide Phylogeography Reveals Ancient Lineages and High Genetic Variation in the Endangered Okapi (Okapia johnstoni) 
PLoS ONE  2014;9(7):e101081.
The okapi is an endangered, evolutionarily distinctive even-toed ungulate classified within the giraffidae family that is endemic to the Democratic Republic of Congo. The okapi is currently under major anthropogenic threat, yet to date nothing is known about its genetic structure and evolutionary history, information important for conservation management given the species' current plight. The distribution of the okapi, being confined to the Congo Basin and yet spanning the Congo River, also makes it an important species for testing general biogeographic hypotheses for Congo Basin fauna, a currently understudied area of research. Here we describe the evolutionary history and genetic structure of okapi, in the context of other African ungulates including the giraffe, and use this information to shed light on the biogeographic history of Congo Basin fauna in general. Using nuclear and mitochondrial DNA sequence analysis of mainly non-invasively collected samples, we show that the okapi is both highly genetically distinct and highly genetically diverse, an unusual combination of genetic traits for an endangered species, and feature a complex evolutionary history. Genetic data are consistent with repeated climatic cycles leading to multiple Plio-Pleistocene refugia in isolated forests in the Congo catchment but also imply historic gene flow across the Congo River.
doi:10.1371/journal.pone.0101081
PMCID: PMC4090074  PMID: 25007188
11.  Depressive symptoms and white matter dysfunction in retired NFL players with concussion history 
Neurology  2013;81(1):25-32.
Objective:
To determine whether correlates of white matter integrity can provide general as well as specific insight into the chronic effects of head injury coupled with depression symptom expression in professional football players.
Method:
We studied 26 retired National Football League (NFL) athletes who underwent diffusion tensor imaging (DTI) scanning. Depressive symptom severity was measured using the Beck Depression Inventory II (BDI-II) including affective, cognitive, and somatic subfactor scores (Buckley 3-factor model). Fractional anisotropy (FA) maps were processed using tract-based spatial statistics from FSL. Correlations between FA and BDI-II scores were assessed using both voxel-wise and region of interest (ROI) techniques, with ROIs that corresponded to white matter tracts. Tracts demonstrating significant correlations were further evaluated using a receiver operating characteristic curve that utilized the mean FA to distinguish depressed from nondepressed subjects.
Results:
Voxel-wise analysis identified widely distributed voxels that negatively correlated with total BDI-II and cognitive and somatic subfactors, with voxels correlating with the affective component (p < 0.05 corrected) localized to frontal regions. Four tract ROIs negatively correlated (p < 0.01) with total BDI-II: forceps minor, right frontal aslant tract, right uncinate fasciculus, and left superior longitudinal fasciculus. FA of the forceps minor differentiated depressed from nondepressed athletes with 100% sensitivity and 95% specificity.
Conclusion:
Depressive symptoms in retired NFL athletes correlate negatively with FA using either an unbiased voxel-wise or an ROI-based, tract-wise approach. DTI is a promising biomarker for depression in this population.
doi:10.1212/WNL.0b013e318299ccf8
PMCID: PMC3770203  PMID: 23709590
12.  Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with MET Gene Amplification in FFPE Tumor Tissue 
PLoS ONE  2014;9(7):e100586.
Background
Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for ‘high Met’ expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue.
Methods
After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH).
Results
Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/µg to 4669.5 amol/µg. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R2 = 0.898). IHC did not correlate well with SRM (n = 44; R2 = 0.537) nor FISH GCN (n = 31; R2 = 0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69–1) and 100% specific (95% CI 0.92–1) for MET amplification.
Conclusions
The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC.
doi:10.1371/journal.pone.0100586
PMCID: PMC4077664  PMID: 24983965
13.  Direct fabrication of graphene on SiO2 enabled by thin film stress engineering 
Scientific Reports  2014;4:5049.
We demonstrate direct production of graphene on SiO2 by CVD growth of graphene at the interface between a Ni film and the SiO2 substrate, followed by dry mechanical delamination of the Ni using adhesive tape. This result is enabled by understanding of the competition between stress evolution and microstructure development upon annealing of the Ni prior to the graphene growth step. When the Ni film remains adherent after graphene growth, the balance between residual stress and adhesion governs the ability to mechanically remove the Ni after the CVD process. In this study the graphene on SiO2 comprises micron-scale domains, ranging from monolayer to multilayer. The graphene has >90% coverage across centimeter-scale dimensions, limited by the size of our CVD chamber. Further engineering of the Ni film microstructure and stress state could enable manufacturing of highly uniform interfacial graphene followed by clean mechanical delamination over practically indefinite dimensions. Moreover, our findings suggest that preferential adhesion can enable production of 2-D materials directly on application-relevant substrates. This is attractive compared to transfer methods, which can cause mechanical damage and leave residues behind.
doi:10.1038/srep05049
PMCID: PMC4031480  PMID: 24854632
14.  Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired NFL Players: A cross-sectional study 
JAMA neurology  2013;70(3):326-335.
Objective
To assess for the presence of cognitive impairment and depression in aging former NFL players, and identify neuroimaging correlates of these dysfunctions.
Design
Comparison of aging NFL players with cognitive impairment and depression to those without these dysfunctions and with matched healthy controls
Setting
Research center in the North Texas region of the United States.
Patients
We performed a cross-sectional study of retired professional football players with and without a history of concussion recruited from the North Texas region, along with age-, education-, and IQ-matched controls. We studied thirty-four retired NFL players (mean age 62) neurologically and neuropsychologically. A subset of 26 also underwent detailed neuroimaging; imaging data in this subset were compared to imaging data acquired in 26 healthy matched controls.
Main Outcome Measures
Neuropsychological measures, clinical diagnoses of depression, neuroimaging measures of white matter pathology, and a measure of cerebral blood flow (CBF).
Results
Of the 34 participants, 20 were cognitively normal, 4 were diagnosed with a fixed cognitive deficit, 8 with Mild Cognitive Impairment, and 2 with dementia; 8 were diagnosed with depression. Of the subgroup in which neuroimaging data were acquired, cognitively impaired (CI) participants showed greatest deficits on tests of naming, word finding, and visual/verbal episodic memory. We found significant differences in white matter abnormalities in CI players and depressed players compared to their respective controls. Regional blood flow differences in the CI group (left temporal pole, inferior parietal lobule, superior temporal gyrus) corresponded to regions associated with impaired neurocognitive performance (problems with memory, naming and word finding).
Conclusions
Cognitive deficits and depression appear to be more common in aging NFL players compared to controls. These deficits are correlated with white matter abnormalities and changes in regional CBF.
doi:10.1001/2013.jamaneurol.340
PMCID: PMC4016798  PMID: 23303193
concussion; memory; depression; cognition; NFL; white matter; DTI; ASL; aging
15.  West Nile virus neuroinvasive disease: neurological manifestations and prospective longitudinal outcomes 
BMC Infectious Diseases  2014;14:248.
Background
West Nile Virus (WNV) is a mosquito-borne flavivirus that has caused ongoing seasonal epidemics in the United States since 1999. It is estimated that ≤1% of WNV-infected patients will develop neuroinvasive disease (West Nile encephalitis and/or myelitis) that can result in debilitating morbidities and long-term sequelae. It is essential to collect longitudinal information about the recovery process and to characterize predicative factors that may assist in therapeutic decision-making in the future.
Methods
We report a longitudinal study of the neurological outcomes (as measured by neurological examination, Glascow Coma Scale, and Modified Mini-Mental State Examination) for 55 subjects with WNV neuroinvasive disease (confirmed by positive CSF IgM) assessed on day 7, at discharge, and on days 14, 30, and 90. The neurological outcome measures were coma (presence and degree), global cognitive status, presence of cranial neuropathy, tremors and/or weakness.
Results
At initial clinical presentation 93% presented with a significant neurological deficit (49% with weakness, 35% with tremor, and 16% with cranial neuropathy). The number of patients with a cognitive deficit fell from 25 at initial evaluation to 9 at their last evaluation. Cranial neuropathy was present in 9 at onset and in only 4 patients at study conclusion. Of the 19 patients who had a tremor at enrollment, 11 continued to exhibit a tremor at follow-up. Seven patients died after initial enrollment in the study, with 5 of those having presented in a coma. The factors that predict either severity or long-term recovery of neurological function include age (older individuals were weaker at follow-up examination), gender (males recovered better from coma), and presentation in a coma with cranial nerve deficits (had a poorer recovery particularly with regard to cognition).
Conclusions
This study represents one of the largest clinical investigations providing prospectively-acquired neurological outcomes data among American patients with WNV central nervous system disease. The findings show that the factors that influence prognosis from the initial presentation include age, gender, and specific neurological deficits at onset.
Trial registration
ClinicalTrials.gov identifier: NCT00138463 and NCT00069316.
doi:10.1186/1471-2334-14-248
PMCID: PMC4020876  PMID: 24884681
West Nile virus; Encephalitis; Neurological deficit; 3MS; Coma
16.  Visual event-related potentials as markers of hyperarousal in Gulf War Illness: evidence against a stress-related etiology 
Psychiatry research  2012;211(3):257-267.
An exaggerated response to emotional stimuli is among the many symptoms widely reported by veterans of the 1991 Persian Gulf War. These symptomologies have been attributed to damage and dysfunction associated with deployment-related exposures. We collected event-related potential data from 22 veterans meeting Haley criteria for Gulf War (GW) Syndromes 1-3 and from 8 matched GW veteran controls, who were deployed but not symptomatic, while they performed a visual three-condition oddball task where images authenticated to be associated with the 1991 Persian Gulf War were the distractor stimuli. Hyperarousal reported by ill veterans was significantly greater than that by control veterans, but this was not paralleled by higher amplitude P3a in their ERP responses to GW-related distractor stimuli. Whereas previous studies of PTSD patients have shown higher amplitude P3b responses to target stimuli that are placed amid trauma-related nontarget stimuli, ill veterans in this study showed P3b amplitudes to target stimuli—placed amid GW-related nontarget stimuli—that were significantly lower than those of the control group. Hyperarousal scores reliably predicted P3b, but not P3a, amplitudes. Although many factors may contribute to P3b amplitude differences—most notably depression and poor sleep quality, symptoms that are prevalent in the GW syndrome groups—our findings in context of previous studies on this population are consistent with the contention that dysfunction in cholinergic and dopaminergic neurotransmitter systems, and in white matter and basal ganglia may be contributing to impairments in GW veterans.
doi:10.1016/j.pscychresns.2012.08.004
PMCID: PMC3578115  PMID: 23149040
ERPs; P3a; P3b; cholinergic; dopaminergic
17.  Gene Signature Distinguishes Patients with Chronic Ulcerative Colitis Harboring Remote Neoplastic Lesions 
Inflammatory bowel diseases  2013;19(3):10.1097/MIB.0b013e3182802bac.
Background
Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer. The standard method of surveillance for neoplasia in UC by colonoscopy is invasive and can miss flat lesions. We sought to identify a gene expression signature in non-dysplastic mucosa without active inflammation that could serve as a marker for remote neoplastic lesions.
Methods
Gene expression was analyzed by cDNA microarray in 5 normal controls, 4 UC patients without dysplasia, and 11 UC patients harboring remote neoplasia. Common gene ontology pathways of significantly differentially expressed genes were identified. Expression of genes which were progressively and significantly up-regulated from controls, to UC without neoplasia, to UC with remote neoplasia were evaluated by real time PCR. Several gene products were also examined by immunohistochemistry.
Results
468 genes were significantly up-regulated and 541 genes were significantly down-regulated in UC patints with neoplasia compared to UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly up-regulated from controls to non-dysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increased expression of S100A9 and REG1α in UC-associated cancer and in non-dysplastic tissue from UC patients harboring remote neoplasia, compared to UC patients without neoplasia and controls.
Conclusions
Gene expression changes occurring as a field effect in the distal colon of patients with chronic UC identify patients harboring remote neoplastic lesions. These markers may lead to a more accurate and less invasive method of detection of neoplasia in patients with inflammatory bowel disease.
doi:10.1097/MIB.0b013e3182802bac
PMCID: PMC3836269  PMID: 23388545
Inflammatory bowel disease; ulcerative colitis; dysplasia; colorectal cancer; gene expression
18.  miR-143 and miR-145 are down-regulated in ulcerative colitis: putative regulators of inflammation and protooncogenes 
Inflammatory bowel diseases  2011;18(1):94-100.
Background
miR-143 and miR-145 are believed to function as colon cancer tumor suppressors as they inhibit colon cancer cell growth and are down-regulated in sporadic colonic tumors. We speculated that miR-143 and miR-145 might also be down-regulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC).
Methods
Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR-143 and miR-145 were quantified by real time PCR and miR-145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K-RAS, API5, MEK-2 (miR-143), and IRS-1 (miR-145) were determined by Western blotting. To assess the effects of miR-143 and miR-145 on these predicted targets, HCT116 and HCA-7 colorectal cancer cells were transfected with miR-143 and miR-145 and expression levels of these proteins were measured.
Results
In UC, miR-143 and miR-145 were significantly down-regulated 8.3-fold (3.4–20.1) (p < 0.0001) and 4.3-fold (2.3–7.8) (p < 0.0001), respectively, compared to normal colon. In contrast, IRS-1, K-RAS, API5, and MEK-2 were up-regulated in ulcerative colitis consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR-143 and miR-145 significantly down-regulated these proteins in HCT116 or HCA7 cells.
Conclusion
Compared to normal colonic mucosa, in chronic ulcerative colitis miR-143 and miR-145 were significantly down-regulated and their predicted targets, IRS-1, K-RAS, API5, and MEK-2 were up-regulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD.
doi:10.1002/ibd.21742
PMCID: PMC3931730  PMID: 21557394
19.  LONG-TERM TREATMENT OF PATIENTS WITH A HISTORY OF ULCERATIVE COLITIS WHO DEVELOP GASTRITIS AND PAN-ENTERITIS AFTER COLECTOMY 
Journal of clinical gastroenterology  2013;47(1):10.1097/MCG.0b013e3182582c1d.
Background
Ulcerative colitis (UC) is generally described as a superficial diffuse inflammation restricted to the colon and rectum. However, several case reports have described a distinct and rare type of UC-related pan-enteritis, typically occurring after colectomy. Corticosteroids are effective for induction of remission of this condition, but it is not clear how these patients should be managed long-term.
Goals
To further describe and define the entity of UC-related pan-enteritis, and to investigate the efficacy of azathioprine for maintenance of remission.
Results
We describe five patients with superficial diffuse ulcerative inflammation of the stomach, small bowel, and pouch if present. Four of the five patients developed enteritis after colectomy for ulcerative pancolitis. Pathology showed severe mucosal inflammation with infiltration of neutrophils and plasma cells from the stomach to the ileum. Video capsule endoscopy in one patient confirmed the presence of mucosal inflammation throughout the small bowel. All patients were started on a standardized treatment with IV corticosteroids for induction of remission and azathioprine for maintenance therapy. They all rapidly improved and subsequently, four patients were in full remission on azathioprine monotherapy, despite failure of this UC therapy prior to surgery, while one patient continues to have steroid-dependent disease.
Conclusions
The outcomes of five cases of UC-related pan-enteritis as described in this report support a role for azathioprine in remission maintenance. Future research is needed to improve our understanding of this rare but distinct intestinal inflammatory disorder.
doi:10.1097/MCG.0b013e3182582c1d
PMCID: PMC3874322  PMID: 22858512
azathioprine; colectomy; duodenitis; enteritis; gastritis; video capsule endoscopy; ulcerative colitis
20.  Estrogen Receptor-β Protects Against Colitis-Associated Neoplasia in Mice 
Estrogen receptor-beta (ERβ) has been suggested to exert anti-inflammatory and anti-tumorigenic effects in the colon, providing a translational potential to prevent and/or treat inflammatory bowel disease (IBD) and its progression to colitis-associated colorectal cancer (CAC). However, the specific direct role of ERβ in CAC has not yet been tested. We assessed the effects of ERβ deficiency in the azoxymethane (AOM)/dextran sodium sulfate(DSS)-induced CAC model using ERβ knockout (βERKO) mice and wild-type (WT) littermates. These mice were injected with AOM followed by one week of DSS treatment, and sacrificed on weeks 9 or 16.βERKO mice developed more severe clinical colitis compared to WT mice, as evidenced by significantly higher disease activity index after DSS treatment, weight to length ratio of the colons, inflammation score, and grade of dysplasia. ERβ-deficient colons presented greater number and size of polyps at weeks 9 and 16, respectively, and were characterized by a significant increase in interleukin (IL)-6, IL-17, tumor necrosis factor alpha, and interferon-gamma mRNA levels. Furthermore, higher protein expression levels of nuclear factor-kappa B, inducible nitric oxide synthase, β-catenin, proliferating cell nuclear antigen, mucin-1, and significantly lower caveolin-1 and mucin-2 protein levels were shown in βERKO mice compared to WT mice. These data suggested a possible anti-inflammatory and anti-neoplastic mechanism of action of ERβ in CAC. These results demonstrate for the first time that ERβ provides protection in the AOM/DSS-induced CAC model in mice, suggesting a preventive and/or therapeutic potential for the use of ERβ-selective agonists in IBD.
doi:10.1002/ijc.27578
PMCID: PMC3404195  PMID: 22488198
Estrogen receptor-beta; azoxymethane; dextran sodium sulfate; inflammatory bowel disease; colon cancer
21.  Blood pressure changes in African American patients receiving chiropractic care in a teaching clinic: a preliminary study 
Objective
The purpose of this preliminary study was to determine if a course of chiropractic care would change blood pressure measurements in African American patients and to determine if a study was feasible in a chiropractic teaching clinic.
Methods
Twenty-four African American patients received chiropractic care in a chiropractic teaching clinic over a study period that spanned 23 visits for each patient. Inclusion criteria consisted of patients having a diagnosis of prehypertension (120-139/80-89) or hypertension stage 1 (140-159/90-99). The mean values of 3 baseline blood pressure readings were compared with the mean values of blood pressure readings taken on visits 21, 22, and 23.
Results
For the entire sample, reductions for both systolic and diastolic blood pressures were not statistically significant (P > .07). When 4 patients having body mass index values that were considered as outliers were excluded, a statistically significant decrease in diastolic blood pressure was observed (P = .004). By group, a statistically significant reduction occurred in the hypertension stage 1 group for systolic and diastolic blood pressures.
Conclusion
This study showed that research of this nature may be feasible in chiropractic teaching clinics. The preliminary findings of this study showed that, for a subgroup of African American patients receiving chiropractic care, blood pressure decreased for (a) hypertension stage 1 patients and (b) the sample when those with excessive body mass index were excluded.
doi:10.1016/j.jcm.2013.06.002
PMCID: PMC3730295  PMID: 24294146
Blood pressure; Chiropractic; Health occupations students
22.  EGFR signals down-regulate tumor suppressors miR-143 and miR-145 in Western diet-promoted murine colon cancer: Role of G1 regulators 
Molecular cancer research : MCR  2011;9(7):10.1158/1541-7786.MCR-10-0531.
Epidermal growth factor receptors (EGFR) contribute to colonic tumorigenesis in experimental models of colon cancer. We previously showed that EGFR was also required for colonic tumor promotion by Western diet. The goal of this study was to identify EGFR-regulated microRNAs that contribute to diet-promoted colonic tumorigenesis.
Methods
Murine colonic tumors from Egfrwt and hypomorphic Egfrwa2 mice were screened using miRNA arrays and miR-143 and miR-145 changes confirmed by Northern, real time PCR and in situ analysis. Rodent and human sporadic and ulcerative colitis-associated colon cancers were examined for miR-143 and miR-145. Effects of EGFR on miR-143 and miR-145 expression were assessed in murine and human colonic cells and their putative targets examined in vitro and in vivo.
Results
miR-143-and miR-145 were readily detected in normal colonocytes and comparable in Egfrwt and Egfrwa2 mice. These miRNAs were down-regulated in azoxymethane and inflammation-associated colonic tumors from Egfrwt mice, but up-regulated in Egfrwa2 tumors. They were also reduced in human sporadic and ulcerative colitis colon cancers. EGFR signals suppressed miR-143 and miR-145 in human and murine colonic cells. Transfected miR-143 and miR-145 inhibited HCT116 cell growth in vitro and in vivo and down-regulated G1 regulators, K-Ras, MYC, CCND2, cdk6 and E2F3, putative or established targets of these miRNAs. miRNA targets, Ras and MYC were increased in colonic tumors from Egfrwt, but not Egfrwa2 mice fed a Western diet.
Conclusions
EGFR suppresses miR-143 and miR-145 in murine models of colon cancer. Furthermore, Western diet unmasks the tumor suppressor roles of these EGFR-regulated miRNAs.
doi:10.1158/1541-7786.MCR-10-0531
PMCID: PMC3819602  PMID: 21653642
epidermal growth factor receptor; microRNA; cell cycle; azoxymethane; ulcerative colitis; Min mouse
23.  Event-Related Potential Patterns Associated with Hyperarousal in Gulf War Illness Syndrome Groups 
Neurotoxicology  2012;33(5):1096-1105.
An exaggerated response to emotional stimuli is one of several symptoms widely reported by veterans of the 1991 Persian Gulf War. Many have attributed these symptoms to post-war stress; others have attributed the symptoms to deployment-related exposures and associated damage to cholinergic, dopaminergic, and white matter systems. We collected event-related potential (ERP) data from 20 veterans meeting Haley criteria for Gulf War Syndromes 1–3 and from 8 matched Gulf War veteran controls, who were deployed but not symptomatic, while they performed an auditory three-condition oddball task with gunshot and lion roar sounds as the distractor stimuli. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans; different ERP profiles emerged to account for their hyperarousability. Syndromes 2 and 3, who have previously shown brainstem abnormalities, show significantly stronger auditory P1 amplitudes, purported to indicate compromised cholinergic inhibitory gating in the reticular activating system. Syndromes 1 and 2, who have previously shown basal ganglia dysfunction, show significantly weaker P3a response to distractor stimuli, purported to indicate dysfunction of the dopaminergic contribution to their ability to inhibit distraction by irrelevant stimuli. All three syndrome groups showed an attenuated P3b to target stimuli, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity.
doi:10.1016/j.neuro.2012.06.001
PMCID: PMC3470732  PMID: 22691951
Gulf War Illness; hyperarousal; ERPs; P1; P3a; P3b; cholinergic; dopaminergic
24.  Both stromal cell and colonocyte epidermal growth factor receptors control HCT116 colon cancer cell growth in tumor xenografts 
Carcinogenesis  2012;33(10):1930-1939.
Colon cancer growth requires growth-promoting interactions between malignant colonocytes and stromal cells. Epidermal growth factor receptors (EGFR) are expressed on colonocytes and many stromal cells. Furthermore, EGFR is required for efficient tumorigenesis in experimental colon cancer models. To dissect the cell-specific role of EGFR, we manipulated receptor function on stromal cells and cancer cells. To assess the role of stromal EGFR, HCT116 human colon cancer cells were implanted into immunodeficient mice expressing dominant negative (DN) EgfrVelvet/+ or Egfr+/+. To assess the role of cancer cell EGFR, HCT116 transfectants expressing inducible DN-Egfr were implanted into immunodeficient mice. To dissect EGFR signals in vitro, we examined colon cancer cells in monoculture or in cocultures with fibroblasts for EGFR transactivation and prostaglandin synthase 2 (PTGS2) induction. EGFR signals were determined by blotting, immunostaining and real-time PCR. Tumor xenografts in EgfrVelvet/+ mice were significantly smaller than tumors in Egfr+/+ mice, with decreased proliferation (Ki67) and increased apoptosis (cleaved caspase-3) in cancer cells and decreased stromal blood vessels. Mouse stromal transforming growth factor alpha (TGFA), amphiregulin (AREG), PTGS2 and Il1b and interleukin-1 receptor 1 (Il1r1) transcripts and cancer cell beta catenin (CTNNB1) and cyclin D1 (CCND1) were significantly lower in tumors obtained from EgfrVelvet/+ mice. DN-EGFR HCT116 transfectants also formed significantly smaller tumors with reduced mouse Areg, Ptgs2, Il1b and Il1r1 transcripts. Coculture increased Caco-2 phospho-active ERBB (pERBB2), whereas DN-EGFR in Caco-2 cells suppressed fibroblast PTGS2 and prostaglandin E2 (PGE2). In monoculture, interleukin 1 beta (IL1B) transactivated EGFR in HCT116 cells. Stromal cell and colonocyte EGFRs are required for robust EGFR signals and efficient tumor growth, which involve EGFR–interleukin-1 crosstalk.
doi:10.1093/carcin/bgs231
PMCID: PMC3529558  PMID: 22791816
25.  AMP-18 Facilitates Assembly and Stabilization of Tight Junctions to Protect the Colonic Mucosal Barrier 
Inflammatory bowel diseases  2012;18(9):1749-1759.
Background
Inflammatory bowel disease (IBD) is characterized by an injured epithelium. Development of agents that could enhance mucosal healing is a major goal in IBD therapeutics. The 18-kDa antrum mucosal protein (AMP-18) and a 21-mer peptide derived from AMP-18, stimulate accumulation of tight junction (TJ) proteins in cultured epithelial cells and mouse colonic mucosa to protect the mucosal barrier, suggesting it might be a useful agent to treat IBD.
Methods
We searched for molecular mechanisms by which AMP peptide or recombinant AMP-18 act on TJs in intact cell monolayers, or those disrupted by low-calcium medium. Roles of the p38 mitogen activated protein kinase (MAPK)/heat shock protein (hsp)25 pathway and PKCζ were investigated by immunoblotting and confocal microscopy.
Results
AMP peptide activated p38 MAPK, which subsequently phosphorylated hsp25. Accumulated phospho-hsp25 was associated with perijunctional actin. AMP-18 also induced rapid phosphorylation of PKCζ and its colocalization with perijunctional actin in Caco2/bbe cells, which was accompanied by translocation and formation of complexes of “polarity proteins” in the TJ-containing detergent-insoluble fraction. Treatment with AMP-18 also stimulated accumulation of ZO-1, ZO-2, and JAM-A in nascent TJs known to associate with the multimeric p-PKCζ/Par6/ Cdc42/ECT2·GTP/Par3 polarity protein complex.
Conclusions
AMP-18 facilitates translocation and assembly of multiple proteins into TJs and their association with and subsequent stabilization of the actin filament network. We speculate that improved barrier function induced by AMP-18 is mediated by enhanced TJ assembly. Thus, AMP-18 may provide a promising lead to develop agents effective in healing injured colonic epithelium in IBD.
doi:10.1002/ibd.22886
PMCID: PMC3337967  PMID: 22271547
Antrum Mucosal Protein (AMP)-18; IBD; Tight Junctions; p38 mitogen activated protein kinase; PKCζ

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