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26.  Evaluation and management of skeletal health in celiac disease: Position statement 
OBJECTIVE:
To review the evaluation and management of skeletal health in patients with celiac disease (CD), and to make recommendations on screening, diagnosis, treatment and follow-up of low bone mineral density (BMD) in CD patients.
METHODS:
A multidisciplinary team developed clinically relevant questions for review. An electronic search of the literature was conducted using the MEDLINE and EMBASE databases from 1996 to 2010. All original studies, reviews and guidelines, both pediatric and adult, were included. A document summarizing the results of the review and proposed recommendations was prepared and underwent multiple revisions until consensus was reached.
RESULTS:
At diagnosis, approximately one-third of adult CD patients have osteoporosis, one-third have osteopenia and one-third have normal BMD. Children with CD have low bone mass at diagnosis. Adult and pediatric CD patients are at increased risk of fractures.
DISCUSSION:
For adults, serum calcium, albumin, 25(OH) vitamin D3, parathyroid hormone and 24 h urine calcium testing should be performed at diagnosis; patients with ‘classic’ CD and those at risk for osteoporosis should undergo a dual x-ray absorptiometry scan. An abnormal baseline dual x-ray absorptiometry scan should be repeated one to two years after initiation of a gluten-free diet (GFD). For children, BMD should be assessed one year after diagnosis if GFD adherence is not strict. A GFD is the most important treatment for bone loss. Supplemental antiresorptives may be justified in those who remain at high fracture risk (eg, postmenopausal women, older men) after implementation of a GFD.
CONCLUSION:
Current evidence does not support the screening of all CD patients for low BMD at diagnosis. Follow-up BMD assessment should be performed one to two years after initiation of a GFD.
PMCID: PMC3495700  PMID: 23166906
Bone; Celiac disease; Osteoporosis
27.  The system of care for the diabetic foot: objectives, outcomes, and opportunities 
Diabetic Foot & Ankle  2013;4:10.3402/dfa.v4i0.21847.
Most cases of lower extremity limb loss in the United States occur among people with diabetes who have a diabetic foot ulcer (DFU). These DFUs and the associated limb loss that may occur lead to excess healthcare costs and have a large negative impact on mobility, psychosocial well-being, and quality of life. The strategies for DFU prevention and management are evolving, but the implementation of these prevention and management strategies remains challenging. Barriers to implementation include poor access to primary medical care; patient beliefs and lack of adherence to medical advice; delays in DFU recognition; limited healthcare resources and practice heterogeneity of specialists. Herein, we review the contemporary outcomes of DFU prevention and management to provide a framework for prioritizing quality improvement efforts within a resource-limited healthcare environment.
doi:10.3402/dfa.v4i0.21847
PMCID: PMC3796020  PMID: 24130936
foot ulcer; diabetes; peripheral vascular disease; diabetic neuropathy; delivery of healthcare; physician's practice patterns
28.  Long-Term Prognosis of Diabetic Foot Patients and Their Limbs 
Diabetes Care  2012;35(10):2021-2027.
OBJECTIVE
There is a dearth of long-term data regarding patient and limb survival in patients with diabetic foot ulcers (DFUs). The purpose of our study was therefore to prospectively investigate the limb and person survival of DFU patients during a follow-up period of more than 10 years.
RESEARCH DESIGN AND METHODS
Two hundred forty-seven patients with DFUs and without previous major amputation consecutively presenting to a single diabetes center between June 1998 and December 1999 were included in this study and followed up until May 2011. Mean patient age was 68.8 ± 10.9 years, 58.7% were male, and 55.5% had peripheral arterial disease (PAD). Times to first major amputation and to death were analyzed with Kaplan-Meier curves and Cox multiple regression.
RESULTS
A first major amputation occurred in 38 patients (15.4%) during follow-up. All but one of these patients had evidence of PAD at inclusion in the study, and 51.4% had severe PAD [ankle-brachial pressure index ≤0.4]). Age (hazard ratio [HR] per year, 1.05 [95% CI, 1.01–1.10]), being on dialysis (3.51 [1.02–12.07]), and PAD (35.34 [4.81–259.79]) were significant predictors for first major amputation. Cumulative mortalities at years 1, 3, 5, and 10 were 15.4, 33.1, 45.8, and 70.4%, respectively. Significant predictors for death were age (HR per year, 1.08 [95% CI, 1.06–1.10]), male sex ([1.18–2.32]), chronic renal insufficiency (1.83 [1.25–2.66]), dialysis (6.43 [3.14–13.16]), and PAD (1.44 [1.05–1.98]).
CONCLUSIONS
Although long-term limb salvage in this modern series of diabetic foot patients is favorable, long-term survival remains poor, especially among patients with PAD or renal insufficiency.
doi:10.2337/dc12-0200
PMCID: PMC3447849  PMID: 22815299
29.  Approach to diagnosing celiac disease in patients with low bone mineral density or fragility fractures 
Canadian Family Physician  2013;59(10):1055-1061.
Abstract
Objective
To provide clinicians with an update on the diagnosis of celiac disease (CD) and to make recommendations on the indications to screen for CD in patients presenting with low bone mineral density (BMD) or fragility fractures.
Quality of evidence
A multidisciplinary task force developed clinically relevant questions related to the diagnosis of CD as the basis for a literature search of the MEDLINE, EMBASE, and CENTRAL databases (January 2000 to January 2009) using the key words celiac disease, osteoporosis, osteopenia, low bone mass, and fracture. The existing literature consists of level I and II studies.
Main message
The estimated prevalence of asymptomatic CD is 2% to 3% in individuals with low BMD. Routine screening for CD is not justified in patients with low BMD. However, targeted screening for CD is recommended for patients who have T-scores of −1.0 or less at the spine or hip, or a history of fragility fractures in association with any CD-related symptoms or conditions; family history of CD; or low urinary calcium levels, vitamin D insufficiency, and raised parathyroid hormone levels despite adequate intake of calcium and vitamin D. Celiac disease testing should be performed while the subject is consuming a gluten-containing diet; initial screening should be performed with human recombinant immunoglobulin (Ig) A tissue transglutaminase or other IgA tissue transglutaminase assays, in association with IgA endomysial antibody immunofluorescence. Duodenal biopsy is necessary to confirm the diagnosis of CD. Human leukocyte antigen typing might assist in confirming or ruling out the diagnosis of CD in cases where serology and histology are discordant. Definitive diagnosis is based on clinical, serologic, and histologic features, combined with a positive response to a gluten-free diet.
Conclusion
Current evidence does not support routine screening for CD in all patients with low BMD. A targeted case-finding approach is appropriate for patients who are at higher risk of CD.
PMCID: PMC3796969  PMID: 24130278
30.  Approche au diagnostic de la maladie cœliaque chez les patients ayant une faible densité minérale osseuse ou des fractures de fragilité 
Canadian Family Physician  2013;59(10):e441-e448.
Résumé
Objectif
Présenter aux cliniciens une mise à jour sur le diagnostic de la maladie cœliaque (MC), ainsi que des recommandations sur les indications de procéder au dépistage de la MC chez les patients présentant une faible densité minérale osseuse (DMO) ou des fractures de fragilité.
Qualité des données
Un groupe de travail multidisciplinaire a élaboré des questions cliniquement pertinentes relativement au diagnostic de la MC servant de fondement à une recherche documentaire dans les bases de données MEDLINE, EMBASE et CENTRAL (de janvier 2000 à janvier 2009) à l’aide des mots clés en anglais celiac disease, osteoporosis, osteopenia, low bone mass et fracture. Les ouvrages scientifiques existants comportent des études de niveaux I et II.
Message principal
La prévalence estimée de la MC asymptomatique est de 2 % à 3 % chez les personnes qui ont une faible DMO. Par ailleurs, un dépistage ciblé est recommandé pour les patients qui ont des T-scores de −1,0 ou moins à la colonne vertébrale ou aux hanches ou des antécédents de fractures de fragilité associées à des symptômes ou à des problèmes reliés à la MC, des antécédents familiaux de MC ou de bas niveaux de calcium urinaire, une insuffisance en vitamine D et des niveaux à la hausse d’hormones parathyroïdiennes en dépit d’un apport suffisant en calcium et en vitamine D. Le dépistage de la MC devrait se faire pendant que le sujet consomme un régime alimentaire contenant du gluten. On procède au dépistage initial par le dosage d’immunoglobuline (Ig) A antitransglutaminase en utilisant la transglutaminase tissulaire humaine recombinante ou une autre transglutaminase tissulaire, en association avec l’immunofluorescence des IgA anti-endomysium. Une biopsie du duodénum est nécessaire pour confirmer le diagnostic de la MC. Le typage des antigènes des leucocytes humains peut aider à confirmer ou à exclure le diagnostic de la MC dans les cas où la sérologie et l’histologie ne concordent pas. Le diagnostic définitif se fonde sur les caractéristiques cliniques, sérologiques et histologiques combinées à une réponse positive à une alimentation sans gluten.
PMCID: PMC3796989
31.  Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity 
PLoS ONE  2013;8(9):e74691.
Background
Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation.
Methods and Findings
We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p<0.05).
Conclusions
Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus’s response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment.
doi:10.1371/journal.pone.0074691
PMCID: PMC3764127  PMID: 24040322
32.  Developing a Hetero-Alkali-Metal Chemistry of 2,2,6,6-Tetramethyl-piperidide (TMP): Stoichiometric and Structural Diversity within a Series of Lithium/Sodium, Lithium/Potassium and Sodium/Potassium TMP Compounds 
Studied extensively in solution and in the solid state, Li(TMP) (TMP=2,2,6,6-tetramethylpiperidide) is an important utility reagent popular as a strongly basic, weakly nucleophilic tool for C–H metallation. Recently, there has been a surge in interest in mixed metal derivatives containing the bulky TMP anion. Herein, we start to develop hetero (alkali metal) TMP chemistry by reporting the N,N,N′,N′-tetramethylethylenediamine (TMEDA)-hemisolvated sodium–lithium cycloheterodimer [(tmeda)Na(μ-tmp)2Li], and its TMEDA-free variant [{Na(μ-tmp)Li(μ-tmp)}∞], which provides a rare example of a crystallographically authenticated polymeric alkali metal amide. Experimental observations suggest that the former is a kinetic intermediate en route to the latter thermodynamic product. Furthermore, a third modification, the mixed potassium–lithium-rich cycloheterotrimer [(tmeda)K(μ-tmp)Li(μ-tmp)Li(μ-tmp)], has also been synthesised and crystallographically characterised. On moving to the bulkier tridentate donor N,N,N′,N′′,N′′-pentamethyldiethylenediamine (PMDETA), the additional ligation forces the sodium–lithium and potassium–dilithium ring species to open giving the acyclic arc-shaped complexes [(pmdeta)Na(μ-tmp)Li(tmp)] and [(pmdeta)K(μ-tmp)Li(μ-tmp)Li(tmp)], respectively. Completing the series, the potassium–lithium and potassium–sodium derivatives [(pmdeta)K(μ-tmp)2M] (M=Li, Na) have also been isolated as closed structures with a distinctly asymmetric central MN2K ring. Collectively, these seven new bimetallic compounds display five distinct structural motifs, four of which have never hitherto been witnessed in TMP chemistry and three of which are unprecedented in the vast structural library of alkali metal amide chemistry.
doi:10.1002/chem.201101167
PMCID: PMC3761191  PMID: 21766365
aggregation; alkali metals; amides; heterometallic complexes; X-ray diffraction
33.  Safety of esophagogastroduodenoscopy within 30 days of myocardial infarction: A retrospective cohort study from a Canadian tertiary centre 
Patients who experience gastrointestinal bleeding after myocardial infarction (MI) often have comorbidities that could place them at increased risk of complications if evaluative endoscopy were to be performed. Although esophagogastroduodenoscopy is considered to be generally safe in high-risk individuals, some post-MI patients may be more susceptible to a variety of cardiopulmonary complications. This cohort study examined cardiopulmonary safety in post-MI patients and evaluated specific predictors of complications of post-MI endoscopy.
BACKGROUND:
Patients who experience myocardial infarction (MI) are at risk of gastrointestinal (GI) bleeding complications. Endoscopic evaluation may lead to cardiopulmonary complications. Guidelines and studies regarding the safety of endoscopy in this population are limited.
OBJECTIVE:
To evaluate the safety of endoscopy in a retrospective cohort of post-MI patients at a Canadian tertiary centre.
METHODS:
Using hospital diagnostic/procedure codes, the charts of patients meeting the inclusion criteria of having ST elevation MI or non-ST elevation MI, and GI bleeding detected at endoscopy were reviewed. The information retrieved included demographics, medical history, medications, endoscopy details and cardiopulmonary/GI events.
RESULTS:
A total of 121 patients experienced an MI and underwent endoscopy within 30 days. However, only 44 met the inclusion criteria and were reviewed. The mean age of the patients was 75 years, and 55% were female. The mean hemoglobin level was 86 g/L, and 38 of 44 patients required a transfusion. Comorbidities included hypertension (82%), diabetes (46%), heart failure (55%), stroke (21%), lung disease (27%), previous MI (46%), cardiac bypass surgery (30%), history of GI bleed (25%), history of ulcer (18%) and ejection fraction <50% (48%). The median number of days to endoscopy after MI was three. Complications included seven patients with acute coronary syndrome, one with arrhythmia, one with respiratory failure, one with aspiration pneumonia and two with perforation. Age, hemoglobin level or timing of endoscopy did not significantly predict a complication.
CONCLUSIONS:
Patients with GI bleeding after MI often have comorbidities and are on antiplatelet agents. Endoscopy is a valuable tool in the diagnosis and management of bleeding complications, but must be weighed against the potential risk of other complications, which in the present study occurred in more than 25% of procedures.
PMCID: PMC3299238  PMID: 22408766
Acute myocardial infarction; Complication; Gastrointestinal endoscopy; Safety
34.  Effectiveness of disseminating consensus management recommendations for ulcer bleeding: a cluster randomized trial 
Background:
International guidelines for the management of nonvariceal upper gastrointestinal bleeding have not been widely adopted in clinical practice. We sought to determine whether a national, multifaceted intervention could improve adherence to guidelines, especially for patients at high risk of nonvariceal upper gastrointestinal bleeding.
Methods:
In this randomized trial, we stratified hospitals by region and size and allocated sites to either the control or experimental group. Health care workers in the experimental group were given published guidelines, generic algorithms, stratification scoring systems and written reminders and attended multidisciplinary guideline education groups and case-based workshops. These interventions were implemented over a 12-month period after randomization, with performance feedback and benchmarking. The primary outcome of adherence rates to key guidelines in endoscopic and pharmacologic management, determined by chart review, was adjusted according to site characteristics and possible within-site dependencies. We also report the rates of adherence to other recommendations.
Results:
Forty-three sites were randomized to the experimental (n = 21) or control (n = 22) groups. In our primary analysis, we compared patients before (experimental group: n = 402 patients; control group: n = 424 patients) and after (experimental group: n = 361 patients; control group: n = 389 patients) intervention. Patient-level analysis revealed no significant difference in adherence rates to the guidelines after the intervention (experimental group: 9.8%; control group: 4.8%; p = 0.99) after adjustment for the rate of adherence before the intervention (experimental group: 13.2%; control group: 7.1%). The adherence rates to other guidelines were similar and decreased over time, varying between 5% and 93%.
Interpretation:
This national knowledge translation–based trial suggests poor adherence to guidelines on nonvariceal upper gastrointestinal bleeding. Adherence was not improved by an educational intervention, which highlights both the complexity and poor predictability of attempting to alter the behaviour of health care providers (Trial registration: ClinicalTrials.gov, no. MCT-88113).
doi:10.1503/cmaj.120095
PMCID: PMC3576461  PMID: 23318399
35.  Indicators of safety compromise in gastrointestinal endoscopy 
The growth in the use of endoscopy to diagnose and treat many gastointestinal disorders, and its central role in cancer screening programs, has led to a significant increase in the number of procedures performed. This growth, however, has also led to many variations in, among others, the provision of services, the choice of sedative medications and the training of providers. The recognition of the significance of quality in endoscopy has prompted several countries, including Canada, to initiate efforts to adopt nationwide quality improvement programs. The Canadian Association of Gastroenterology formed a committee to review endoscopy and quality with the aim of stimulating improvement. This article focuses specifically on patient safety indicators that were developed at a consensus conference aimed at generating a broad range of recommendations for selected endoscopic procedures, which if adopted, could lead to significant changes in how endoscopy services are provided.
INTRODUCTION:
The importance of quality indicators has become increasingly recognized in gastrointestinal endoscopy. Patient safety requires the identification and monitoring of occurrences associated with harm or the potential for harm. The identification of relevant indicators of safety compromise is, therefore, a critical element that is key to the effective implementation of endoscopy quality improvement programs.
OBJECTIVE:
To identify key indicators of safety compromise in gastrointestinal endoscopy.
METHODS:
The Canadian Association of Gastroenterology Safety and Quality Indicators in Endoscopy Consensus Group was formed to address issues of quality in endoscopy. A subcommittee was formed to identify key safety indicators. A systematic literature review was undertaken, and articles pertinent to safety in endoscopy were identified and reviewed. All complications and measures used to document safety were recorded. From this, a preliminary list of 16 indicators was compiled and presented to the 35-person consensus group during a three-day meeting. A revised list of 20 items was subsequently put to the consensus group for vote for inclusion on the final list of safety indicators. Items were retained only if the consensus group highly agreed on their importance.
RESULTS:
A total of 19 indicators of safety compromise were retained and grouped into the three following categories: medication-related – the need for CPR, use of reversal agents, hypoxia, hypotension, hypertension, sedation doses in patients older than 70 years of age, allergic reactions and laryngospasm/bronchospasm; procedure-related early – perforation, immediate postpolypectomy bleeding, need for hospital admission or transfer to emergency department from the gastroenterology unit, instrument impaction, severe persistent abdominal pain requiring evaluation proven to not be perforation; and procedure-related delayed – death within 30 days of procedure, 14-day unplanned hospitalization, 14-day unplanned contact with a health provider, gastrointestinal bleeding within 14 days of procedure, infection or symptomatic metabolic complications.
CONCLUSIONS:
The 19 indicators of safety compromise in endoscopy, identified by a rigorous, evidence-based consensus process, provide clear outcomes to be recorded by all facilities as part of their continuing quality improvement programs.
PMCID: PMC3275408  PMID: 22312605
Digestive system; Endoscopy; Health care; Quality assurance; Surgical complications; Safety
36.  Canadian Association of Gastroenterology consensus guidelines on safety and quality indicators in endoscopy 
Several organizations worldwide have developed procedure-based guidelines and/or position statements regarding various aspects of quality and safety indicators, and credentialing for endoscopy. Although important, they do not specifically address patient needs or provide a framework for their adoption in the context of endoscopy services. The consensus guidelines reported in this article, however, aimed to identify processes and indicators relevant to the provision of high-quality endoscopy services that will support ongoing quality improvement across many jurisdictions, specifically in the areas of ethics, facility standards and policies, quality assurance, training and education, reporting standards and patient perceptions.
BACKGROUND:
Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality, highlight the need for clearly defined, evidence-based processes to support quality improvement in endoscopy.
OBJECTIVE:
To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery.
METHODS:
A multidisciplinary group of 35 voting participants developed recommendation statements and performance indicators. Systematic literature searches generated 50 initial statements that were revised iteratively following a modified Delphi approach using a web-based evaluation and voting tool. Statement development and evidence evaluation followed the AGREE (Appraisal of Guidelines, REsearch and Evaluation) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidelines. At the consensus conference, participants voted anonymously on all statements using a 6-point scale. Subsequent web-based voting evaluated recommendations for specific, individual quality indicators, safety indicators and mandatory endoscopy reporting fields. Consensus was defined a priori as agreement by 80% of participants.
RESULTS:
Consensus was reached on 23 recommendation statements addressing the following: ethics (statement 1: agreement 100%), facility standards and policies (statements 2 to 9: 90% to 100%), quality assurance (statements 10 to 13: 94% to 100%), training, education, competency and privileges (statements 14 to 19: 97% to 100%), endoscopy reporting standards (statements 20 and 21: 97% to 100%) and patient perceptions (statements 22 and 23: 100%). Additionally, 18 quality indicators (agreement 83% to 100%), 20 safety indicators (agreement 77% to 100%) and 23 recommended endoscopy-reporting elements (agreement 91% to 100%) were identified.
DISCUSSION:
The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services.
CONCLUSIONS:
The guidelines support quality improvement in endoscopy by providing explicit recommendations on systematic monitoring, assessment and modification of endoscopy service delivery to yield benefits for all patients affected by the practice of gastrointestinal endoscopy.
PMCID: PMC3275402  PMID: 22308578
Digestive system; Endoscopy; Guideline; Health care; Quality assurance
37.  Intraoperative Fluorescence Vascular Angiography: During Tibial Bypass 
Preventing amputations in persons with lower extremity complications of diabetes is a complex endeavor, particularly in those with concomitant ischemia and tissue loss. Fluorescence angiography (Novadaq SPY system) may provide a tool for objective evaluations of tissue viability in the diabetic foot, which is an important indicator of the ability of the diabetic ulcer to heal adequately. The SPY system uses a low-power laser coupled with a charge-coupled device camera and indocyanine green (ICG) to sequence perfusion at the surface of the skin. We present an illustrated example of the potential utility of ICG fluorescence angiography (ICGFA) before and after vascular intervention in a high-risk limb. ICGFA appeared to reveal demarcation between viable and nonviable tissue and real-time perfusion, specifically capillary fill. ICGFA clarified the extent of necessary debridement and provided an immediate indication of improvement in regional perfusion status following revascularization. Future studies involving ICGFA may include pre- and postdebridement and closure perfusion, comparison of tissue perfusion pre- and post-endovascular therapy, and lower extremity flap viability. Future works will also address the consistency of results with ICGFA by analyzing a larger cohort of patients being treated by our unit.
PMCID: PMC3320839  PMID: 22401340
diabetic foot ulcers; noninvasive imaging; peripheral vascular disease; tissue health; wound healing
38.  Methodology for Use of a Neuroprosthetic to Reduce Plantar Pressure: Applications in Patients with Diabetic Foot Disease 
PMCID: PMC3320844  PMID: 22401344
diabetic foot ulcers; functional electrical stimulation; neuroprosthetics; plantar pressure; wound healing
39.  Acute Hypersensitivity of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma to Low-Dose 5-Aza Deoxycytidine Is Associated with Global DNA Damage-Associated p53 Activation, Anti-Pluripotency and DNA Demethylation 
PLoS ONE  2012;7(12):e53003.
Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low-dose 5-aza induces a p53 transcriptional signature distinct from that induced with cisplatin in NT2/D1 cells and also uniquely downregulates genes associated with pluripotency including NANOG, SOX2, GDF3 and Myc target genes. Changes in the p53 and pluripotency signatures with 5-aza were to a large extent dependent on high levels of DNMT3B. In contrast to the majority of p53 target genes upregulated by 5-aza that did not show DNA hypomethylation, several other genes induced with 5-aza had corresponding decreases in promoter methylation. These genes include RIN1, SOX15, GPER, and TLR4 and are novel candidate tumors suppressors in TGCTs. Our studies suggest that the hypersensitivity of NT2/D1 cells to low-dose 5-aza is multifactorial and involves the combined activation of p53 targets, repression of pluripotency genes, and activation of genes repressed by DNA methylation. Low-dose 5-aza therapy may be a general strategy to treat those tumors that are sustained by cells with embryonic stem-like properties.
GEO number for the microarray data: GSE42647.
doi:10.1371/journal.pone.0053003
PMCID: PMC3531428  PMID: 23300844
40.  A literature review of quality in lower gastrointestinal endoscopy from the patient perspective 
Colorectal cancer (CRC) is the third most frequently diagnosed cancer, and the second leading cause of cancer death among men and women in Canada. Prompted by nationally accepted CRC guidelines, the use of colonoscopy – widely regarded to be the optimal method of CRC screening – has increased dramatically in recent years. However, when evaluating colonoscopy performance and the delivery of high-quality care, it is important to also consider factors relevant to the patients who require colonoscopy services. Understanding the patient perspective on what comprises quality in colonoscopy/endoscopy is essential to tailoring improvements in the standards of practice and quality of care. Accordingly, this study systematically reviewed the literature pertaining to aspects of colonoscopy and endoscopy that may be considered to be important to patients.
BACKGROUND:
Given the limited state of health care resources, increased demand for colorectal cancer (CRC) screening raises concerns about the quality of endoscopy services. Little is known about quality in colonoscopy and endoscopy from the patient perspective.
OBJECTIVE:
To systematically review the literature on quality that is relevant to patients who require colonoscopy or endoscopy services.
METHODS:
A systematic PubMed search was performed on articles that were published between January 2000 and February 2011. Keywords included “colonoscopy” or “sigmoidoscopy” or “endoscopy” AND “quality”; “colonoscopy” or “sigmoidoscopy” or “endoscopy” AND “patient satisfaction” or “willingness to return”. The included articles were qualitative and quantitative English language studies regarding aspects of colonoscopy and/or endoscopy services that were evaluated by patients in which data were collected within one year of the colonoscopy/endoscopy procedure.
RESULTS:
In total, 28 quantitative studies were identified, of which eight (28.6%) met the inclusion criteria (four cross-sectional, three prospective cohort and one single-blinded controlled study). Aspects of quality included comfort, management of pain and anxiety, endoscopy unit staff manner, skills and specialty, procedure and results discussion with the doctor, physical environment, wait times for the appointment and procedure, and discharge. Qualitative studies eliciting the patient perspective on what constituted quality in colonoscopy/endoscopy were not found.
CONCLUSIONS:
Factors related to comfort, staff, communication and the service environment were evaluated from the patient perspective using closed-ended questions that were designed by clinicians and researchers. Future research using qualitative methodology to elicit the patient perspective on quality in colonoscopy and/or endoscopy services is needed.
PMCID: PMC3266160  PMID: 22175059
Colonoscopy; Endoscopy; Patient perspective; Quality; Review
41.  Diabetic Foot Ulcers and Vascular Insufficiency: Our Population Has Changed, but Our Methods Have Not 
Diabetic foot complications are increasing in prevalence worldwide. Care and attention to these complications have improved greatly. Many advanced therapies are now being investigated or taken through final stages of clinical studies worldwide. However, the data upon which assumptions regarding morbidity, healing, and mortality have been based are grossly outdated. The purpose of this brief article is to report on current data regarding neuropathic and neuroischemic wounds and to propose that the latter category of advanced-stage diabetic foot wound may now be emerging as the most commonly encountered lesion in the developed world. Unfortunately, it is still systematically excluded from most clinical study criteria. Additionally, just as in the care of cancer, we call for therapy of these advanced-stage diabetic foot ulcers to be managed in similarly interdisciplinary centers where patients may have access to potentially beneficial clinical trials.
PMCID: PMC3262731  PMID: 22226282
amputation; diabetic foot ulcers; infection; ischemia; wound healing
42.  Between Celiac Disease and Irritable Bowel Syndrome: The “No Man’s Land” of Gluten Sensitivity 
The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.
doi:10.1038/ajg.2009.188
PMCID: PMC3480312  PMID: 19455131
43.  A tale of two soles: sociomechanical and biomechanical considerations in diabetic limb salvage and amputation decision-making in the worst of times 
Diabetic Foot & Ankle  2012;3:10.3402/dfa.v3i0.18633.
Foot ulcerations complicated by infection are the major cause of limb loss in people with diabetes. This is especially true in those patients with severe sepsis. Determining whether to amputate or attempt to salvage a limb often requires in depth evaluation of each individual patient's physical, mental, and socioeconomic status. The current report presents and juxtaposes two similar patients, admitted to the same service at the same time with severe diabetic foot infections complicated by sepsis. We describe in detail the similarities and differences in the clinical presentation, extent of infection, etiology, and socioeconomic concerns that ultimately led to divergent clinical decisions regarding the choices of attempting diabetic limb salvage versus primary amputation and prompt rehabilitation.
doi:10.3402/dfa.v3i0.18633
PMCID: PMC3464045  PMID: 23050063
diabetic foot; Charcot arthropathy; diabetic limb salvage; diabetic foot infection; amputation
44.  Patient accounts of diagnostic testing for familial hypercholesterolaemia: comparing responses to genetic and non-genetic testing methods 
BMC Medical Genetics  2012;13:87.
Background
Continuing developments in genetic testing technology together with research revealing gene-disease associations have brought closer the potential for genetic screening of populations. A major concern, as with any screening programme, is the response of the patient to the findings of screening, whether the outcome is positive or negative. Such concern is heightened for genetic testing, which it is feared may elicit stronger reactions than non-genetic testing.
Methods
This paper draws on thematic analysis of 113 semi-structured interviews with 39 patients being tested for familial hypercholesterolaemia (FH), an inherited predisposition to early-onset heart disease. It examines the impact of disease risk assessments based on both genetic and non-genetic information, or solely non-genetic information.
Results
The impact of diagnostic testing did not seem to vary according to whether or not genetic information was used. More generally, being given a positive or negative diagnosis of FH had minimal discernible impact on people's lives as they maintained the continuity of their beliefs and behaviour.
Conclusions
The results suggest that concerns about the use of genetic testing in this context are unfounded, a conclusion that echoes findings from studies in this and other health contexts.
doi:10.1186/1471-2350-13-87
PMCID: PMC3495051  PMID: 22994377
Behaviour change; Genetics; Genetic testing; Health behaviour; Risk; Qualitative
45.  The Charcot Foot in Diabetes 
Diabetes Care  2011;34(9):2123-2129.
The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity.
doi:10.2337/dc11-0844
PMCID: PMC3161273  PMID: 21868781
46.  Plasmalemmal vesicle associated protein (PV1) modulates SV40 virus infectivity in CV-1 cells 
Plasmalemmal vesicle associated protein (Plvap/PV1) is a structural protein required for the formation of the stomatal diaphragms of caveolae. Caveolae are plasma membrane invaginations that were implicated in SV40 virus entry in primate cells. Here we show that de novo Plvap/PV1 expression in CV-1 green monkey epithelial cells significantly reduces the ability of SV40 virus to establish productive infection, when cells are incubated with low concentrations of the virus. However, in presence of high viral titers PV1 has no effect on SV40 virus infectivity. Mechanistically, PV1 expression does not reduce the cell surface expression of known SV40 receptors such as GM1 ganglioside and MHC class I proteins. Furthermore, PV1 does not reduce the binding of virus-like particles made by SV40 VP1 protein to the CV-1 cell surface and does not impact their internalization when cells are incubated with either high or low VLP concentrations. These results suggest that PV1 protein is able to block SV40 infectivity at low but not at high viral concentration either by interfering with the infective internalization pathway at the cell surface or at a post internalization step.
doi:10.1016/j.bbrc.2011.07.063
PMCID: PMC3171970  PMID: 21827737
47.  Plantar Temperature Response to Walking in Diabetes with and without Acute Charcot: The Charcot Activity Response Test 
Journal of Aging Research  2012;2012:140968.
Objective. Asymmetric plantar temperature differences secondary to inflammation is a hallmark for the diagnosis and treatment response of Charcot foot syndrome. However, little attention has been given to temperature response to activity. We examined dynamic changes in plantar temperature (PT) as a function of graduated walking activity to quantify thermal responses during the first 200 steps. Methods. Fifteen individuals with Acute Charcot neuroarthropathy (CN) and 17 non-CN participants with type 2 diabetes and peripheral neuropathy were recruited. All participants walked for two predefined paths of 50 and 150 steps. A thermal image was acquired at baseline after acclimatization and immediately after each walking trial. The PT response as a function of number of steps was examined using a validated wearable sensor technology. The hot spot temperature was identified by the 95th percentile of measured temperature at each anatomical region (hind/mid/forefoot). Results. During initial activity, the PT was reduced in all participants, but the temperature drop for the nonaffected foot was 1.9 times greater than the affected side in CN group (P = 0.04). Interestingly, the PT in CN was sharply increased after 50 steps for both feet, while no difference was observed in non-CN between 50 and 200 steps. Conclusions. The variability in thermal response to the graduated walking activity between Charcot and non-Charcot feet warrants future investigation to provide further insight into the correlation between thermal response and ulcer/Charcot development. This stress test may be helpful to differentiate CN and its response to treatment earlier in its course.
doi:10.1155/2012/140968
PMCID: PMC3413979  PMID: 22900177
48.  Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial 
PLoS ONE  2012;7(4):e35249.
Background
The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA.
Methods and Findings
We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference  =  5.0%, 95% CI −0.9,10.8, p  =  0.098). Motivation to make another quit attempt among those (n  =  331) not abstinent at six months was not significantly different between groups (p  =  0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference  =  5.8%, 95% CI 1.0,10.7, p  =  0.018).
Conclusions
Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation.
Trial registration
Controlled-Trials.com ISRCTN14352545.
doi:10.1371/journal.pone.0035249
PMCID: PMC3324463  PMID: 22509402
49.  Testing for gluten-related disorders in clinical practice: The role of serology in managing the spectrum of gluten sensitivity 
Immunoglobulin A tissue transglutaminase is the single most efficient serological test for the diagnosis of celiac disease. It is well known that immunoglobulin A tissue transglutaminase levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with celiac disease. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Antigliadin tests are no longer recommended for the diagnosis of classical celiac disease. However, our understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. Studies are needed to determine the clinical utility of antigliadin serology in the diagnosis of gluten sensitivity.
PMCID: PMC3088693  PMID: 21523259
Antigliadin antibodies; Antitissue transglutaminase; Celiac disease; Diagnosis; Gluten intolerance; Serology
50.  Adventitious Bursae Underlying Chronic Wounds: Another Possible Deterrent to Healing 
Eplasty  2012;12:e14.
Adventitious bursae typically develop in areas of chronic frictional irritation, usually under bony prominences. Although adventitious bursae are generally well understood, there is a paucity of data on effects of bursae underlying chronic wounds in neuropathic patients. This manuscripts reviews 4 clinical cases, each with a neuropathic patient with adventitious bursae underlying chronic nonhealing wound and strategies for treatment.
PMCID: PMC3286309  PMID: 22389747

Results 26-50 (131)