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1.  Plasma 25-hydroxyvitamin D concentrations and periodontal disease in postmenopausal women 
Journal of periodontology  2012;84(9):1243-1256.
Vitamin D has anti-inflammatory and anti-microbial properties that, together with its influence on bone health, may confer periodontal benefit.
We investigated cross-sectional associations (1997–2000) between plasma 25-hydroxyvitamin D concentrations [25(OH)D] and periodontal measure among 920 postmenopausal women. Chronic measures of disease were defined based on: 1) alveolar crestal height (ACH) measures from intraoral radiographs and tooth loss, and the 2) Center for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) criteria using measures of clinical attachment level (CAL) and probing pocket depth (PD). Acute oral inflammation was assessed by the % of gingival sites that bled upon assessment with a probe. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for periodontal disease among participants with adequate ([25(OH)D]≥50 nmol/L) compared to deficient/inadequate ([25(OH)D]<50 nmol/L) vitamin D status adjusted for age, dental visit frequency, and body mass index.
No association was observed between vitamin D status and periodontal disease defined by ACH and tooth loss (adjusted OR=0.96, 95% CI: 0.68–1.35). In contrast, women with adequate compared to deficient/inadequate vitamin D status had a 33% lower odds (95% CI: 5%–53%) of periodontal disease defined using the CDC/AAP definition and a 42% lower odds (95% CI: 21%-58%) of having ≥50% of gingival sites that bled.
Vitamin D status was inversely associated with gingival bleeding, an acute measure of oral health and inflammation and inversely associated with clinical categories of chronic periodontal disease that incorporated PD, an indicator of oral inflammation. However, vitamin D was not associated with chronic periodontal disease based on measures of ACH in combination with tooth loss.
PMCID: PMC3745794  PMID: 23259413
vitamin D; 25-hydroxyvitamin D; periodontal diseases; postmenopausal period; epidemiology; women
2.  Evaluation of endoscopist and pathologist factors affecting the incidence of microscopic colitis 
Microscopic colitis (MC) is an umbrella term for collagenous colitis (CC) and lymphocytic colitis (LC). The incidence of these diseases is increasing for unclear reasons.
To identify factors that may impact diagnosis rates of MC in a North American population.
Population-based pathology and endoscopy databases were searched to identify all cases of MC and the number of lower endoscopy (LE) procedures performed over a five-year period (January 2004 to December 2008) in a catchment area of 1.2 million people. Endoscopist characteristics were compared with diagnostic rates.
MC incidence increased from 1.68 per 10,000 in 2004, to 2.68 per 10,000 in 2008, with an average annual increase of 12% per year (95% CI 7% to 16%; P<0.0001). The incidence rate of LC increased but the rate of CC remained stable over the study period. Approximately one-half of the cases were probable and one-half were definite based on pathologists’ reports – a proportion that remained stable over time. The number of LEs per population increased by 4.6% annually over the study period (95% CI 2.8% to 6.4%; P<0.0001), and biopsy rates in LE for MC indications (eg, unexplained diarrhea, altered bowel habits) increased over time (3.4% annual increase [95% CI 1.8% to 6.0%]; P<0.001). Endoscopists with an academic practice, gastroenterologists and those with lower annual endoscopy volumes were more likely to make a diagnosis of MC.
The incidence of MC is rising due to increased diagnosis of LC, while CC incidence remains stable. Patients with MC symptoms have stable endoscopy rates but are being biopsied more often. Physician training, practice type and endoscopy volume impact the diagnostic rates of MC.
PMCID: PMC3414472  PMID: 22891175
Biopsy; Clinical practice; Collagenous colitis; Colonoscopy; Diagnosis; Diarrhea; Incidence; Lymphocytic colitis
3.  Repolarization Changes Underlying Long-Term Cardiac Memory Due to Right Ventricular Pacing: Noninvasive Mapping with ECGI 
Cardiac memory refers to the observation that altered cardiac electrical activation results in repolarization changes that persist after the restoration of a normal activation pattern. Animal studies, however, have yielded disparate conclusions both regarding the spatial pattern of repolarization changes in cardiac memory and the underlying mechanisms. This study was undertaken to produce three dimensional images of the repolarization changes underlying long-term cardiac memory in humans.
Methods and Results
Nine adult subjects with structurally normal hearts and dual-chamber pacemakers were enrolled in the study. Non-invasive electrocardiographic imaging (ECGI) was used before and after one month of ventricular pacing to reconstruct epicardial activation and repolarization patterns. Eight subjects exhibited cardiac memory in response to ventricular pacing. In all subjects, ventricular pacing resulted in a prolongation of the activation recovery interval (a surrogate for action potential duration) in the region close to the site of pacemaker-induced activation from 228.4±7.6 ms during sinus rhythm to 328.3±6.2 ms during cardiac memory. As a consequence, increases are observed in both apical-basal and right-left ventricular gradients of repolarization resulting in a significant increase in the dispersion of repolarization.
These results demonstrate that electrical remodeling in response to ventricular pacing in human subjects results in action potential prolongation near the site of abnormal activation and a marked dispersion of repolarization. This dispersion of repolarization is potentially arrhythmogenic and, intriguingly, was less evident during continuous RV pacing, suggesting the novel possibility that continuous RV pacing at least partially suppresses pacemaker-induced cardiac memory.
PMCID: PMC3445629  PMID: 22772896
action potentials; pacemakers; remodeling; T wave memory; cardiac memory
4.  Lichen Planus Is an Uncommon Cause of Nonspecific Proximal Esophageal Inflammation 
Gut and Liver  2013;7(4):401-405.
Esophageal lichen planus (LP) has been described as a cause of nonspecific esophagitis that may cause dysphagia, but its incidence is unknown. We aimed to estimate the incidence of esophageal LP in a defined geographic region and describe the clinical characteristics of affected patients.
A histopathology database for a population of 1 million people was searched for all esophageal mucosal biopsy results over an 8-year period. Cases showing inflammation or abnormalities without a diagnosis after three or more biopsies were reviewed for findings of LP.
Of 13,589 esophageal biopsies, only one received a diagnosis of LP. Seven patients (four male; mean age, 59 years; range, 39 to 76 years) were identified as having chronic dysphagia and nonspecific proximal esophagitis for which no diagnosis could be made. All patients had proximal inflammation, and six of seven had full-thickness lymphocytic infiltration. Elongation of the lamina propria papillae was noted in all patients, whereas six patients had parakeratosis and ballooning. Only one patient had findings potentially consistent with, but not sufficient for, a diagnosis of esophageal LP.
Esophageal LP appears to be extremely uncommon in this North American population, and esophageal biopsy alone is likely not sufficient to establish a diagnosis of LP.
PMCID: PMC3724026  PMID: 23898378
Esophagus; Inflammation; Esophagitis; Gastroesophageal reflux disease; Lichen planus
5.  Intraindividual variation in plasma 25-hydroxyvitamin D measures 5 years apart among postmenopausal women 
Current literature examining associations between vitamin D and chronic disease generally use a single assessment of 25-hydroxyvitamin D (25(OH)D), assuming an individual’s 25(OH)D concentration is consistent over time.
We investigated the intraindividual variability between two measures of plasma 25(OH)D concentrations collected ~5 years apart (1997-2000 to 2002-2005) in 672 postmenopausal women participating in the Women’s Health Initiative. Plasma 25(OH)D was assessed using the DiaSorin LIAISON® chemiluminescence immunoassay. The within-pair coefficient of variation (CV) was 4.9% using blinded quality control samples. Mean and standard deviations (SD) of 25(OH)D at the two time points were compared using a paired t-test. An intraindividual CV and intra-class correlation coefficient (ICC) were used to assess intraindividual variability. A Spearman correlation coefficient (r) assessed the strength of the association between the two measures and concordance in vitamin D status at two time points
Mean 25(OH)D concentrations (nmol/L) significantly increased over time from 60.0 (SD=22.2) to 67.8 (SD=22.2) (p<0.05). The CV was 24.6%, the ICC (95% Confidence Interval (CI)) was 0.59 (0.54-0.64), and the Spearman r was 0.61 (95% CI=0.56-0.66). Greater concordance over 5 years was observed in participants with sufficient compared to deficient or inadequate baseline 25(OH)D concentrations (weighted kappa=0.39). Reliability measures were moderately influenced by season of blood draw and vitamin D supplement use.
There is moderate intraindividual variation in 25(OH)D concentrations over approximately 5 years.
These data support the use of a one-time measure of blood 25(OH)D in prospective studies with ≤ 5 years of follow-up.
PMCID: PMC3372646  PMID: 22523182
25-hydroxyvitamin D; intraindividual variation; vitamin D; biomarkers; postmenopausal women
6.  Performance of Multiplex Cytokine Assays in Serum and Saliva among Community-Dwelling Postmenopausal Women 
PLoS ONE  2013;8(4):e59498.
Multiplexing arrays increase the throughput and decrease sample requirements for studies employing multiple biomarkers. The goal of this project was to examine the performance of Multiplex arrays for measuring multiple protein biomarkers in saliva and serum. Specimens from the OsteoPerio ancillary study of the Women’s Health Initiative Observational Study were used. Participants required the presence of at least 6 teeth and were excluded based on active cancer and certain bone issues but were not selected on any specific condition. Quality control (QC) samples were created from pooled serum and saliva. Twenty protein markers were measured on five multiplexing array panels. Sample pretreatment conditions were optimized for each panel. Recovery, lower limit of quantification (LLOQ) and imprecision were determined for each analyte. Statistical adjustment at the plate level was used to reduce imprecision estimates and increase the number of usable observations. Sample pre-treatment improved recovery estimates for many analytes. The LLOQ for each analyte agreed with manufacturer specifications except for MMP-1 and MMP-2 which were significantly higher than reported. Following batch adjustment, 17 of 20 biomarkers in serum and 9 of 20 biomarkers in saliva demonstrated acceptable precision, defined as <20% coefficient of variation (<25% at LLOQ). The percentage of cohort samples having levels within the reportable range for each analyte varied from 10% to 100%. The ratio of levels in saliva to serum varied from 1∶100 to 28∶1. Correlations between saliva and serum were of moderate positive magnitude and significant for CRP, MMP-2, insulin, adiponectin, GM-CSF and IL-5. Multiplex arrays exhibit high levels of analytical imprecision, particularly at the batch level. Careful sample pre-treatment can enhance recovery and reduce imprecision. Following statistical adjustments to reduce batch effects, we identified biomarkers that are of acceptable quality in serum and to a lesser degree in saliva using Multiplex arrays.
PMCID: PMC3618114  PMID: 23577067
7.  Towards solving enigmas in electrical injury 
Critical Care  2012;16(2):117.
The paper by Park and colleagues in the previous issue of Critical Care highlights vascular changes in electrical injury and finds them to be relatively long-lasting and significant. This finding is consistent with long-lasting disability seen clinically in electrically injured patients. Furthermore, the authors report that the changes seen in the shocked part of the body are accompanied by similar changes that are measurable in other parts of the body but that are not involved with electric current. This latter finding is of significant importance. A psychological syndrome - consistent and predictable - exists following an electrical injury. The causation is enigmatic. Recent psychiatric research indicates the importance of circulating cortisol and brain-derived neurotrophic factor (BDNF), which causes loss of hippocampal volume, in the genesis of depression. This psychiatric research has stimulated a speculative theory of the genesis of the psychological effects of electric shock. The paper by Park and colleagues is circumstantial support for the possibility that such a process is real and available.
PMCID: PMC3681344  PMID: 22385987
8.  Elevated Expression of the Serine-Arginine Protein Kinase 1 Gene in Ovarian Cancer and Its Role in Cisplatin Cytotoxicity In Vitro 
PLoS ONE  2012;7(12):e51030.
Alternatively spliced variants of several oncogenes and tumor suppressors have been shown to be important for their tumorigenicity. In the present study we have tested whether serine-arginine protein kinase 1 (SRPK1), a major regulator of splicing factors, is involved in ovarian cancer progression and plays a role in chemo-sensitivity. By Western blot analyses, SRPK1 protein was found to be overexpressed in 4 out of 6 ovarian cancer cell lines as compared with an immortalized ovarian surface epithelial cell line; and in 55% of ovarian tumor samples as compared with non-neoplastic ovarian tissue samples. Reduction of SRPK1 expression using small interfering RNA (siRNA) encoding small hairpin RNA in ovarian cancer cells led to (i) reduced cell proliferation rate, slower cell cycle progression and compromised anchorage-independent growth and migration ability in vitro, (ii) decreased level of phosphorylation of multiple serine-arginine proteins, and P44/42MAPK and AKT proteins, and (iii) enhanced sensitivity to cisplatin. Together, these results suggest that elevated SRPK1 expression may play a role in ovarian tumorigenesis and SRPK1 may be a potential target for ovarian cancer therapy.
PMCID: PMC3517604  PMID: 23236423
9.  The pathophysiology of chronic constipation 
Canadian Journal of Gastroenterology  2011;25(Suppl B):16B-21B.
Constipation is broadly defined as an unsatisfactory defecation characterized by infrequent stools, difficult stool passage or both. The common approach to the pathophysiology of constipation groups the disorder into primary and secondary causes. Primary causes are intrinsic problems of colonic or anorectal function, whereas secondary causes are related to organic disease, systemic disease or medications. The normal process of colonic transit and defecation is discussed, and the etiology of constipation is reviewed.
PMCID: PMC3206564  PMID: 22114753
Colonic transit; Constipation; Defecation disorders; Dyssynergia
10.  Assessment of Biological and Environmental Phenology at a Landscape Level from 30 Years of Fixed-Date Repeat Photography in Northern Sweden 
Ambio  2011;40(6):600-609.
A 30-year series (1978–2007) of photographic records were analysed to determine changes in lake ice cover, local (low elevation) and montane (high elevation) snow cover and phenological stages of mountain birch (Betula pubescens ssp. czerepanovii) at the Abisko Scientific Research Station, Sweden. In most cases, the photographic-derived data showed no significant difference in phenophase score from manually observed field records from the same period, demonstrating the accuracy and potential of using weekly repeat photography as a quicker, cheaper and more adaptable tool to remotely study phenology in both biological and physical systems. Overall, increases in ambient temperatures coupled with decreases in winter ice and snow cover, and earlier occurrence of birch foliage, signal a reduction in the length of winter, a shift towards earlier springs and an increase in the length of available growing season in the Swedish sub-arctic.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-011-0167-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3357859  PMID: 21954723
Lake ice; Phenophase; Mountain birch; Snow cover; Swedish sub-arctic
11.  Multi-Decadal Changes in Tundra Environments and Ecosystems: Synthesis of the International Polar Year-Back to the Future Project (IPY-BTF) 
Ambio  2011;40(6):705-716.
Understanding the responses of tundra systems to global change has global implications. Most tundra regions lack sustained environmental monitoring and one of the only ways to document multi-decadal change is to resample historic research sites. The International Polar Year (IPY) provided a unique opportunity for such research through the Back to the Future (BTF) project (IPY project #512). This article synthesizes the results from 13 papers within this Ambio Special Issue. Abiotic changes include glacial recession in the Altai Mountains, Russia; increased snow depth and hardness, permafrost warming, and increased growing season length in sub-arctic Sweden; drying of ponds in Greenland; increased nutrient availability in Alaskan tundra ponds, and warming at most locations studied. Biotic changes ranged from relatively minor plant community change at two sites in Greenland to moderate change in the Yukon, and to dramatic increases in shrub and tree density on Herschel Island, and in sub-arctic Sweden. The population of geese tripled at one site in northeast Greenland where biomass in non-grazed plots doubled. A model parameterized using results from a BTF study forecasts substantial declines in all snowbeds and increases in shrub tundra on Niwot Ridge, Colorado over the next century. In general, results support and provide improved capacities for validating experimental manipulation, remote sensing, and modeling studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-011-0179-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3357861  PMID: 21954732
IPY; Glaciers; Permafrost; Snow stratigraphy; Tundra vegetation; Limnology; Shrubs; Treeline
12.  Colometer: A real-time quality feedback system for screening colonoscopy 
AIM: To investigate the performance of a new software-based colonoscopy quality assessment system.
METHODS: The software-based system employs a novel image processing algorithm which detects the levels of image clarity, withdrawal velocity, and level of the bowel preparation in a real-time fashion from live video signal. Threshold levels of image blurriness and the withdrawal velocity below which the visualization could be considered adequate have initially been determined arbitrarily by review of sample colonoscopy videos by two experienced endoscopists. Subsequently, an overall colonoscopy quality rating was computed based on the percentage of the withdrawal time with adequate visualization (scored 1-5; 1, when the percentage was 1%-20%; 2, when the percentage was 21%-40%, etc.). In order to test the proposed velocity and blurriness thresholds, screening colonoscopy withdrawal videos from a specialized ambulatory colon cancer screening center were collected, automatically processed and rated. Quality ratings on the withdrawal were compared to the insertion in the same patients. Then, 3 experienced endoscopists reviewed the collected videos in a blinded fashion and rated the overall quality of each withdrawal (scored 1-5; 1, poor; 3, average; 5, excellent) based on 3 major aspects: image quality, colon preparation, and withdrawal velocity. The automated quality ratings were compared to the averaged endoscopist quality ratings using Spearman correlation coefficient.
RESULTS: Fourteen screening colonoscopies were assessed. Adenomatous polyps were detected in 4/14 (29%) of the collected colonoscopy video samples. As a proof of concept, the Colometer software rated colonoscope withdrawal as having better visualization than the insertion in the 10 videos which did not have any polyps (average percent time with adequate visualization: 79% ± 5% for withdrawal and 50% ± 14% for insertion, P < 0.01). Withdrawal times during which no polyps were removed ranged from 4-12 min. The median quality rating from the automated system and the reviewers was 3.45 [interquartile range (IQR), 3.1-3.68] and 3.00 (IQR, 2.33-3.67) respectively for all colonoscopy video samples. The automated rating revealed a strong correlation with the reviewer’s rating (ρ coefficient= 0.65, P = 0.01). There was good correlation of the automated overall quality rating and the mean endoscopist withdrawal speed rating (Spearman r coefficient= 0.59, P = 0.03). There was no correlation of automated overall quality rating with mean endoscopists image quality rating (Spearman r coefficient= 0.41, P = 0.15).
CONCLUSION: The results from a novel automated real-time colonoscopy quality feedback system strongly agreed with the endoscopists’ quality assessments. Further study is required to validate this approach.
PMCID: PMC3436041  PMID: 22969189
Colonoscopy; Quality assurance; Quality improvement; Withdrawal time; Colon cancer; Bowel preparation
13.  Duration of Physical Activity and Serum 25-hydroxyvitamin D Status of Postmenopausal Women 
Annals of epidemiology  2011;21(6):440-449.
To investigate whether the association between physical activity and serum 25-hydroxyvitamin D (25(OH)D) concentrations is independent of sun exposure, body size, and other potential explanatory variables.
Using data from a sample of 1,343 postmenopausal women, from the Women’s Health Initiative, linear regression was used to examine the associations of duration (minutes/week) of recreational activity and of yard work with 25(OH)D concentrations (nmol/L).
In age-adjusted analyses, positive associations were observed between 25(OH)D concentrations and both duration of recreational physical activity (β=0.71, SE(0.09), P<0.001) and yard work (β=0.36, SE(0.10), P=0.004). After further adjustment for vitamin D intake, self-reported sunlight exposure, waist circumference, and season of blood draw, 25(OH)D was significantly associated with recreational activity (β=0.21, SE(0.09), P=0.014) but not with yard work (β=0.18, SE(0.09), P=0.061). Interactions were observed between season and both recreational activity (Pinteraction=0.082) and yard work (Pinteraction=0.038) such that these activity-25(OH)D associations were greater during summer/fall compared to winter/spring. Self-reported sunlight exposure and measures of body size did not modify the associations.
The observed age-adjusted activity-25(OH)D associations were attenuated after adjusting for explanatory variables and were modified by season of blood draw. Adopting a lifestyle that incorporates outdoor physical activity during summer/fall, consuming recommended amounts of vitamin D, and maintaining a healthy weight may improve or maintain vitamin D status in postmenopausal women.
PMCID: PMC3090482  PMID: 21414803
25-hydroxyvitamin D; vitamin D; serum; sunlight exposure; physical activity; epidemiology; women
14.  Unsedated peroral wireless pH capsule placement vs. standard pH testing: A randomized study and cost analysis 
BMC Gastroenterology  2012;12:58.
Wireless capsule pH-metry (WC) is better tolerated than standard nasal pH catheter (SC), but endoscopic placement is expensive. Aims: to confirm that non-endoscopic peroral manometric placement of WC is as effective and better tolerated than SC and to perform a cost analysis of the available esophageal pH-metry methods.
Randomized trial at 2 centers. Patients referred for esophageal pH testing were randomly assigned to WC with unsedated peroral placement or SC after esophageal manometry (ESM). Primary outcome was overall discomfort with pH-metry. Costs of 3 different pH-metry strategies were analyzed: 1) ESM + SC, 2) ESM + WC and 3) endoscopically placed WC (EGD + WC) using publicly funded health care system perspective.
86 patients (mean age 51 ± 2 years, 71% female) were enrolled. Overall discomfort score was less in WC than in SC patients (26 ± 4 mm vs 39 ± 4 mm VAS, respectively, p = 0.012) but there were no significant group differences in throat, chest, or overall discomfort during placement. Overall failure rate was 7% in the SC group vs 12% in the WC group (p = 0.71). Per patient costs ($Canadian) were $1475 for EGD + WC, $1014 for ESM + WC, and $906 for ESM + SC. Decreasing the failure rate of ESM + WC from 12% to 5% decreased the cost of ESM + WC to $991. The ESM + SC and ESM + WC strategies became equivalent when the cost of the WC device was dropped from $292 to $193.
Unsedated peroral WC insertion is better tolerated than SC pH-metry both overall and during placement. Although WC is more costly, the extra expense is partially offset when the higher patient and caregiver time costs of SC are considered.
Trial registration Identifier NCT01364610
PMCID: PMC3413593  PMID: 22650250
Esophagus; Gastroesophageal reflux disease; pH-metry; Clinical trial
16.  Expression Profiling of the Ovarian Surface Kinome Reveals Candidate Genes for Early Neoplastic Changes12 
Translational Oncology  2009;2(4):341-349.
OBJECTIVES: We tested the hypothesis that co-coordinated up-regulation or down-regulation of several ovarian cell surface kinases may provide clues for better understanding of the disease and help in rational design of therapeutic targets. STUDY DESIGN: We compared the expression signature of 69 surface kinases in normal ovarian surface epithelial cells (OSE), with OSE from patients at high risk and with ovarian cancer. RESULTS: Seven surface kinases, ALK, EPHA5, EPHB1, ERBB4, INSRR, PTK, and TGFβR1 displayed a distinctive linear trend in expression from normal, highrisk, and malignant epithelium. We confirmed these results using semiquantitative reverse transcription-polymerase chain reaction and tissue array of 202 ovarian cancer samples. A strong correlate was shown between disease-free survival and the expression of ERBB4. DNA sequencing revealed two novel mutations in ERBB4 in two cancer samples. CONCLUSIONS: A distinct subset of the ovarian surface kinome is altered in the transition from high risk to invasive cancer and genetic mutation is not a dominant mechanism for these modifications. These results have significant implications for early detection and targeted therapeutic approaches for women at high risk of developing ovarian cancer.
PMCID: PMC2781076  PMID: 19956396
17.  Microscopic colitis: a review for the surgical endoscopist 
Canadian Journal of Surgery  2009;52(5):E167-E172.
Microscopic colitis (MC) is an inflammatory condition of the colon distinct from Crohn disease or ulcerative colitis that can cause chronic diarrhea as well as cramping and bloating. Although it was first described 30 years ago, awareness of this entity as a cause of diarrhea has only become more widespread recently. Up to 20% of adults with chronic diarrhea who have an endoscopically normal colonoscopy may have MC. Endoscopic and radiological examinations are usually normal, but histology reveals increased lymphocytes in the colonic mucosa, which typically cause watery nonbloody diarrhea. Treatment is initially supportive but can include corticosteroids and immunomodulatory therapy for resistant cases. Since surgeons perform a large number of colonoscopies and sigmoidoscopies to assess diarrhea, it is important to be aware of this disease and to look for it with mucosal biopsy in appropriate patients.
PMCID: PMC2769103  PMID: 19865548
18.  Expression and serum immunoreactivity of developmentally restricted differentiation antigens in epithelial ovarian cancer 
Cancer-embryo antigens or developmentally restricted differentiation antigens (DRDAGs), such as PLAC1 (CT92) and developmental pluripotency associated-2 (DPPA2/CT100), are expressed in pluripotent embryonic cells. They are also recognized as cancer-testis antigens (CT) which are proteins normally expressed only in the human germ line but that are also present in a significant subset of malignant tumors. These antigens may prove to be markers of 'repopulating' cells with stem cell-like characteristics and could be critical targets for immunotherapy in epithelial ovarian cancer (EOC). Our objective was to define the frequency of expression and immunogenicity of PLAC1 and DPPA2 in EOC and correlate expression with clinical outcome. One-step reverse transcriptase PCR was performed on 101 EOC samples and a panel of normal tissues. Expression of PLAC1 and DPPA2 in the EOC specimens was 21/101 (21%) and 31/101 (31%) respectively. In normal tissues, PLAC1 expression was restricted to the placenta while DPPA2 expression was restricted to the placenta and testis. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were also performed on a subset of specimens. Humoral immunity was demonstrable in 2/12 serum samples from patients whose tumors expressed DPPA2. There was no demonstrable antibody response to PLAC1 in patients with PLAC1 positive tumors. The presence of PLAC1 and DPPA2 did not have a statistically significant effect on recurrence-free and overall survival. The tissue-restricted expression of PLAC1 and DPPA2, their expression in a significant proportion of EOC patients, and their potential to represent markers of stem cells make DRDAGs attractive targets for antigen-specific immunotherapy in EOC.
PMCID: PMC2935768  PMID: 19705800
human; ovarian cancer; PLAC1; DPPA2; RT-PCR; immunohistochemistry; humoral immunity
Irritable bowel syndrome (IBS) has been associated with mucosal dysfunction,, mild inflammation, and altered colonic bacteria. We used microarray expression profiling of sigmoid colon mucosa to assess whether there are stably expressed sets of genes that suggest there are objective molecular biomarkers associated with IBS.
Gene expression profiling was performed using Affymetrix GeneChips with RNA from sigmoid colon mucosal biopsies from 36 IBS patients and 25 healthy control subjects. RTQ-PCR was used to confirm the data in 12 genes of interest. Statistical methods for microarray data were applied to search for differentially expressed genes, and to assess the stability of molecular signatures in IBS patients.
Mucosal gene expression profiles were consistent across different sites within the sigmoid colon and were stable on repeat biopsy over ~3 months. Differentially expressed genes suggest functional alterations of several components of the host mucosal immune response to microbial pathogens. The most strikingly increased expression involved a yet uncharacterized gene, DKFZP564O0823. Identified specific genes suggest the hypothesis that molecular signatures may enable distinction of a subset of IBS patients from healthy controls. Using 75% of the biopsies as a validation set to develop a gene profile, the test set (25%) was correctly predicted with ~70% accuracy.
Mucosal gene expression analysis shows there are relatively stable alterations in colonic mucosal immunity in IBS. These molecular alterations provide the basis to test the hypothesis that objective biomarkers may be identified in IBS and enhance understanding of the disease.
PMCID: PMC2453689  PMID: 18237869
22.  Synergism of CPT-11 and Apo2L/TRAIL against Two Differentially Sensitive Human Colon Tumor Xenografts 
Oncology  2008;74(3-4):188-197.
The ability to sustain and grow portions of human tumors as xenografts in SCID mice provides a valuable preclinical opportunity to test the response of human tumors to treatments, both individually and in combination. Using this model, our laboratory has previously demonstrated that the growth of several human adenocarcinomas can be inhibited by Apo2L/TRAIL. Apo2L/TRAIL triggers apoptosis in many types of tumor cells, and when combined with various chemotherapeutic agents results in enhanced inhibition of tumor growth in many xenograft models.
To gain further insight into the antitumor potential of Apo2L/TRAIL in combination with chemotherapy, we compared the responses of 2 human colon adenocarcinomas, both of which were sensitive to CPT-11 while one was sensitive and the other comparatively resistant to Apo2L/TRAIL.
In both cases, a greater degree of growth inhibition was achieved when these agents were used in combination. Western blot analysis demonstrated that in the Apo2L/TRAIL-sensitive tumor total cellular expression of Apo2L/TRAIL death receptors (DR4 and DR5) as well as protein expression of the pro-apoptotic molecule BAX were higher and the anti-apoptotic molecule Bcl-2 was lower in comparison to the Apo2L/TRAIL-resistant tumor.
These results indicate that both Apo2L/TRAIL-sensitive and -resistant colon tumors will respond to a combination of CPT-11 and Apo2L/TRAIL and predict that this will be useful in the treatment of human colon cancers in a clinical setting.
PMCID: PMC2826876  PMID: 18714167
Apo2L/TRAIL; Apoptosis; Colon cancer; CPT-11; Xenograft
Gastroenterology  2006;132(1):17-25.
The pathophysiology of irritable bowel syndrome (IBS) remains enigmatic; abnormalities in serotonin metabolism have been implicated. Two proteins that influence the function of serotonin and serotonergic receptors are serotonin transporter protein (SERT or soluble carrier protein SLC6A4) and p11 (S-100A10, or calpactin I light chain). Both proteins are reported to be associated with depression-like states, a frequent co-morbid condition in IBS. We explored the hypothesis that expression of these two proteins in colonic and rectal mucosa is abnormal in patients with IBS as compared to healthy controls.
mRNA expression of SLC6A4 and p11 was measured in sigmoid and rectal mucosal biopsies. Genotype of the promoter for SLC6A4 was also assessed in all participants. Validation studies explored reproducibility of two biopsies taken from the same region, and biopsies taken an average of ~3 months apart.
We found normal colonic mucosal expression of SLC6A4 in diarrhea (IBS-D) or constipation predominant IBS (IBS-C). On the other hand, p11 expression was increased in IBS. No significant effect on p11 mRNA expression in sigmoid colon or rectum was noted from antidepressant treatment in any of the analyzed subgroups.
Colonic mucosal expression of SLC6A4 in IBS is normal. Given that overexpression of p11 can increase serotonergic receptor functions (e.g. 5-HT1B receptors), these data support the need for further study of the interaction between p11 expression in health and disease and its role in the therapeutic response to serotonergic agents, including antidepressants.
PMCID: PMC2474784  PMID: 17241856
Genotype; mucosal gene expression; IBS phenotype; SERT; SLC6A4; p11
24.  Role for protease activity in visceral pain in irritable bowel syndrome 
Journal of Clinical Investigation  2007;117(3):636-647.
Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-κB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor–2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.
PMCID: PMC1794118  PMID: 17304351
25.  Celiac disease. CME update for family physicians. 
Canadian Family Physician  2004;50:719-725.
OBJECTIVE: To review current understanding of the epidemiology, pathophysiology, diagnosis, and management of celiac disease. QUALITY OF EVIDENCE: Few recent randomized controlled trials (level I evidence) have studied treatments for celiac disease. There are recent comparative studies (level II evidence) and there is well established consensus (level III evidence) on diagnosis and treatment of celiac disease. MAIN MESSAGE: Celiac disease is an immune-mediated small bowel enteropathy caused by exposure to wheat gluten protein. The disease can be insidious and often presents with only subtle extraintestinal manifestations in a variety of organ systems. Recent epidemiologic surveys suggest celiac disease is much more common in North America than previously thought. Advances in immunology and screening have made diagnosis more reliable than in the past. Removing gluten from the diet is effective in most cases. CONCLUSION: Celiac disease manifests subtly and is an easy diagnosis to miss. Good laboratory screening tests and effective treatment are available. Family practitioners should consider celiac disease in patients who present with confounding symptoms.
PMCID: PMC2214607  PMID: 15171674

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