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Refractory reflux-like symptoms have a substantial impact on patients and healthcare providers. The aim of the survey was to qualitatively assess the needs and attitudes of practicing clinicians around the management of refractory reflux symptoms and refractory gastroesophageal reflux disease (rGERD).An International Working Group for the Classification of Oesophagitis (IWGCO) steering committee invited clinicians to complete an online survey including 17 questions.Of the 113 clinicians who completed the survey, 70% were GIs, 20% were primary care physicians, and 10% were other specialties. Functional heartburn was considered the most common reason for an incomplete response to proton pump inhibitor (PPI) therapy (82%), followed by stress/anxiety (69%). More GIs identified esophageal hypersensitivity as a cause, while more non-GIs identified esophageal dysmotility and non-reflux-related esophageal conditions. As the first step, most clinicians would order investigations (70-88%). Overall, 72% would add supplemental therapy for patients with partial response, but only 58% for those with non-response. Antacid/alginate was the most common choice overall, while non-GIs were more likely to add a prokinetic than were GIs (47.8 vs. 24.1%). Approximately 40% of clinicians would switch PPIs in patients with partial response, but only 29% would do so in non-responders. Preferences for long-term therapy were highly variable. The most common initial investigation was upper endoscopy. Choice of esophageal manometry and pH monitoring was more variable, with no clear preference for whether pH monitoring should be conducted on, or off, PPI therapy.The survey identified a number of challenges for clinicians, especially non-GI physicians, treating patients with refractory reflux-like symptoms or rGERD on a daily basis.

Delays in triage processes in the emergency department (ED) can compromise patient safety. The aim of this study was to provide proof-of-concept that a self-check-in kiosk could decrease the time needed to identify ambulatory patients arriving in the ED. We compared the use of a novel automated self-check-in kiosk to identify patients on ED arrival to routine nurse-initiated patient identification.We performed a prospective trail with random weekly allocation to intervention or control processes during a 10-week study period. During intervention weeks, patients used a self-check-in kiosk to self-identify on arrival. This electronically alerted triage nurses to patient arrival times and primary complaint before triage. During control weeks, kiosks were unavailable and patients were identified using routine nurse-initiated triage. The primary outcome was time-to-first-identification, defined as the interval between ED arrival and identification in the hospital system.Median (interquartile range) time-to-first-identification was 1.4 minutes (1.0-2.08) for intervention patients and 9 minutes (5-18) for control patients. Regression analysis revealed that the adjusted time-to-first-identification was 13.6 minutes (95% confidence interval 12.8-14.5) faster for the intervention group.A self-check-in kiosk significantly reduced the time-to-first-identification for ambulatory patients arriving in the ED.Les délais d'attente inhérents au processus de triage des malades au service des urgences (SU) peuvent mettre en péril leur sécurité. L’étude visait donc à valider le principe selon lequel l'utilisation d'un guichet d'auto-inscription diminuerait le temps nécessaire pour signaler l'arrivée des malades ambulatoires au SU. A été comparé le processus d'utilisation d'un guichet d'auto-inscription d'un nouveau type pour signaler l'arrivée des malades au SU avec le processus habituel d'inscription des malades par le personnel infirmier.L’étude consistait en un essai prospectif, à répartition aléatoire et hebdomadaire, d'inscription, réalisé selon le processus expérimental ou le processus témoin, sur une période de 10 semaines. Durant les semaines d'expérimentation, les malades se dirigeaient vers le guichet d'auto-inscription à leur arrivée; un signal électronique informait le personnel infirmier affecté au triage de l'heure d'arrivée des malades et des motifs de consultation avant le triage lui-même. Durant les semaines témoins, les guichets étaient fermés et les malades étaient inscrits selon le processus habituel de triage effectué par le personnel infirmier. Le principal critère d’évaluation était le temps écoulé avant le signal d'arrivée, défini comme l'intervalle entre l'arrivée des malades au SU et leur inscription dans le système de l'hôpital.Le temps médian (écart interquartile) écoulé avant le signal d'arrivée était de 1,4 minute (1,0–2,08) durant les semaines d'expérimentation contre 9 minutes (5 –18) durant les semaines témoins. D'après les résultats de l'analyse de régression, le temps rajusté écoulé avant le signal d'arrivée était de 13,6 minutes (IC à 95% : 12,8–14,5) plus court dans le groupe d'expérimentation que dans le groupe témoin.L'utilisation d'un guichet d'auto-inscription a permis de réduire considérablement le temps écoulé avant le signal d'arrivée des malades ambulatoires au SU.

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by in-vivo and ex-vivo luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia-initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumor suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-cell acute lymphoblastic leukemia. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-cell acute lymphoblastic leukemia and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms1. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21)2, 3. We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

The CAG is a professional organization that seeks to promote the discipline of gastroenterology in Canada and internationally through a series of activities aligned with a Strategic Plan (renewed and updated every five years) in order to advance our mandate of (i) supporting and engaging in the study of the organs of the digestive tract in health and disease, (ii) promoting the advancement of the science and art of gastroenterology by providing leadership in patient care, research, education, and continuing professional development (CPD), and (iii) promoting and maintaining the highest ethical standards (https://www.cag-acg.org/about/what-is-the-cag/).

BACKGROUND: Funders of health research in Canada seek to determine how their funding programs impact research capacity and knowledge creation.OBJECTIVE: To evaluate the impact of a focused grants and award program that was cofunded by the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes, and the Canadian Association of Gastroenterology; and to measure the impact of the Program on the career paths of funded researchers and assess the outcomes of research supported through the Program.METHODS: A survey of the recipients of grants and awards from 2000 to 2008 was conducted in 2012. The CIHR Funding Decisions database was searched to determine subsequent funding; a bibliometric citation analysis of publications arising from the Program was performed.RESULTS: Of 160 grant and award recipients, 147 (92%) completed the survey. With >$17.4 million in research funding, support was provided for 131 fellowship awards, seven career transition awards, and 22 operating grants. More than three-quarters of grant and award recipients continue to work or train in a research-related position. Combined research outputs included 545 research articles, 130 review articles, 33 book chapters and 11 patents. Comparative analyses indicate that publications supported by the funding program had a greater impact than other Canadian and international comparators.CONCLUSIONS: Continuity in support of a long-term health research funding partnership strengthened the career development of gastroenterology researchers in Canada, and enhanced the creation and dissemination of new knowledge in the discipline.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome.

Significant gains have been achieved by the CAG during the past five years. The CAG remains dedicated to professional education, research and patient care in all areas of digestive health and disease in support of the economic and social health of all Canadians. All of the goals and targets associated with the five principal initiatives of the 2004 strategic plan have been addressed, and most have been fully or partially achieved. The organization is active on many fronts by engaging partners, strengthening existing programs, addressing areas where goals and targets have not been achieved and creating new initiatives. The focus of these activities is to provide value to you, the member, by improving digestive health and disease programs. We believe the CAG is well positioned to meet the opportunities and challenges in the years to come. To this end, a new five-year strategic plan is in development and will be presented to the membership in the near future. The CAG leadership welcomes your comments and suggestions to enhance the ongoing development and operation of the organization.

BACKGROUND: The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinal symptoms remains controversial.OBJECTIVE: To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting.METHODS: The present study analyzed data from four randomized trials assessing homogeneous and complementary populations of Canadian patients with uninvestigated upper gastrointestinal symptoms with comparable outcomes. Symptom-free months, quality-adjusted life-years (QALYs) and direct costs in Canadian dollars of two management approaches based on the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool, and four additional strategies (two empirical antisecretory agents, and two prompt endoscopy) were examined and compared. Prevalence data, probabilities, utilities and costs were included in a Markov model, while sensitivity analysis used Monte Carlo simulations. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were determined.RESULTS: Empirical omeprazole cost $226 per QALY ($49 per symptom-free month) per patient. CanDys omeprazole and endoscopy approaches were more effective than empirical omeprazole, but more costly. Alternatives using H2-receptor antagonists were less effective than those using a proton pump inhibitor. No significant differences were found for most incremental cost-effectiveness ratios. As willingness to pay (WTP) thresholds rose from $226 to $24,000 per QALY, empirical antisecretory approaches were less likely to be the most cost-effective choice, with CanDys omeprazole progressively becoming a more likely option. For WTP values ranging from $24,000 to $70,000 per QALY, the most clinically relevant range, CanDys omeprazole was the most cost-effective strategy (32% to 46% of the time), with prompt endoscopy-proton pump inhibitor favoured at higher WTP values.CONCLUSIONS: Although no strategy was the indisputable cost-effective option, CanDys omeprazole may be the strategy of choice over a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.

The management of Helicobacter pylori negative patients with dyspepsia in primary care has not been studied in placebo-controlled studies.H. pylori negative patients with dyspepsia symptoms of at least moderate severity (or =4 on a seven-point Likert scale) were recruited from 35 centers. Patients were randomized to a 4-wk treatment of omeprazole 20 mg od, ranitidine 150 mg bid, cisapride 20 mg bid, or placebo, followed by on-demand therapy for an additional 5 months. Treatment success was defined as no or minimal symptoms (scoreor = 2 out of 7), and was assessed after 4 wk and at 6 months.Five hundred and twelve patients were randomized and included in the intention-to-treat (ITT) analysis. At 4 wk, success rates (95% CI) were: omeprazole 51% (69/135; 43-60%), ranitidine 36% (50/139, 28-44%), cisapride 31% (32/105, 22-39%), and placebo 23% (31/133, 16-31%). Omeprazole was significantly better than all other treatments (p0.05). The proportion of patients who were responders at 4 wk and at 6 months was significantly greater for those receiving omeprazole 31% (42/135, 23-39%) compared with cisapride 13% (14/105, 7-20%), and placebo 14% (18/133, 8-20%) (p= 0.001), but not ranitidine 21% (29/139, 14-27%) (p= 0.053). The mean number of on-demand study tablets consumed and rescue antacid used was comparable across groups. Economic analysis showed a trade-off between superior efficacy and increased cost between omeprazole and ranitidine.Treatment with omeprazole provides superior symptom relief compared to ranitidine, cisapride, and placebo in the treatment of H. pylori negative primary care dyspepsia patients.

Background & Aims. The acid inhibitory effect of proton pump inhibitors is reported to be greater in the presence than in the absence of an H. pylori infection. This study was undertaken to test the hypothesis that the acid inhibitory effect of omeprazole given twice a day is greater in H. pylori infected healthy volunteers than in the same individuals following eradication because of differences in the pharmacodynamics of omeprazole, greater duodenogastric reflux, the effects of ammonia produced by the H. pylori, or lower gastric juice concentrations of selected cytokines, which may inhibit gastric acid secretion. Materials and Methods. We undertook 24-hour pH-metry in 12 H. pylori-positive healthy volunteers: (1) when on no omeprazole; (2) when on omeprazole 20 mg bid for 8 days; (3) 2 months after eradication of H. pylori and when on no omeprazole; and (4) after eradication of H. pylori and when on omeprazole 20 mg twice a day. Results. In subjects given omeprazole, eradication of H. pylori reduced pH and percentage pH ≥ 3, as well as increasing the area under the H+ concentration-time curve. These differences were not due to alterations in (1) gastric juice concentrations of IL-1α, IL-8, IL-13, epidermal growth factor, or bile acids; (2) serum gastrin concentrations; or (3) the pharmacokinetics of omeprazole. There was no change in the difference in the H+ concentration-time curve ‘without omeprazole’ minus ‘with omeprazole’, when comparing ‘after’ versus ‘before’ eradication of H. pylori. Conclusions. Eradication of H. pylori was not associated with an alteration in the acid inhibitory potency when comparing the difference in gastric acidity ‘with’ versus ‘without’ omeprazole. When the results were expressed by simply taking into account the acid measurements while on omeprazole before versus after eradication of H. pylori, the acid inhibition with omeprazole was greater in the presence than in the absence of a H. pylori infection. The clinical significance of the small difference is not clear.

The annual survey of Canadian Association of Gastroenterology (CAG) members’ educational needs was conducted online this past April. One hundred eightyseven individuals (one fifth of the membership) completed the needs assessment. The topic most in demand for future educational events was inflammatory bowel disease, both from the clinical and basic science perspectives. Other highly rated topics were endoscopy, pharmacological therapeutics, celiac disease and pancreatitis/pancreatic disease. Educational materials were judged to be the most valuable component of exhibit areas. Results of the needs assessment were used to shape the 2004 Canadian Digestive Diseases Week (CDDW) program.

The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.

An important mandate of the Canadian Association of Gastroenterology (CAG), as documented in the Association’s governance policies, is to optimize the care of patients with digestive disorders. Clinical practice guidelines are one means of achieving this goal. The benefits of timely, high-quality and evidenced-based recommendations include:Enhancing the professional development of clinical members through education and dissemination of synthesized clinical research;Improving patient care provided by members by providing focus on quality and evidence;Creating legislative environments that favour effective clinical practice;Enhancing the clinical care provided to patients with digestive disease by nongastroenterologists; andIdentifying areas that require further information or research to improve clinical care.The present document provides the foundation required to ensure that clinical practice guidelines produced by the CAG are necessary, appropriate, credible and applicable. These recommendations should be adhered to as closely as possible to obtain CAG endorsement.

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.

In-depth meetings of the XIth International Workshop on Gastroduodenal Pathology andHelicobacter pyloriled to the presentation and discussion of extensive new data onH pyloriand its diseases. The mode of transmission ofH pyloriremains unclear, and it remains unknown why only a small proportion of infected individuals develop duodenal or gastric ulcer disease and even fewer develop gastric cancer. The role ofH pylorieradication in persons with uninvestigated dyspepsia remains controversial. New clinical trials ofH pyloritreatment show symptom relief and improvement in the quality of life of persons with functional dyspepsia, especially in those with ulcer-like or reflux-like dyspepsia. Clearly the move is toward symptom-based management of persons with dyspepsia, with fewer endoscopies being needed in the otherwise healthy young dyspeptic patients. It remains controversial whether eradicatingH pyloriin duodenal ulcer or functional dyspepsia increases the risk of subsequent development of gastroesophageal reflux disease. The one-week proton pump inhibitor-based triple regimens remain the gold standard ofH pyloritherapy, but some of the ranitidine bismuth citrate plus two antibiotic regimens also achieve an 80%H pylorieradication rate on an intention-to-treat basis. While the urea breath test remains the noninvasive test of choice, interesting new data are available on the use of stool antigen testing to diagnoseH pyloriinfection. The number ofH pylori-associated gastroduodenal diseases grows to include possible liver, vascular, immune and skin conditions.

This study compared the 24 h intragastric pH profile and bioavailability at repeated dosing conditions of the omeprazole 20 mg enteric-coated tablet versus the 20 mg capsule. Forty duodenal ulcer patients in asymptomatic remission completed this randomized open two-way crossover study. Omeprazole 20 mg tablets or capsules were administered for seven days in each period. A 24 h pH recording was performed before the start of treatment and on day 7 of each treatment period. Plasma concentrations of omeprazole were determined 24 h after the dose. The treatment periods were separated by two to four weeks. The difference in percentage of time with pH of at least 3 was less than 16% in favour of the tablet (not significant). The estimated mean area under the plasma concentration-time curve as well as the maximum plasma concentration (Cmax) for omeprazole were 18% and 41% higher, respectively, for the tablet versus the capsule, with the latter percentage being statistically significant. The time to reach Cmax (tmax) with the tablet was, on average, about 0.5 h longer than to reach the tmax of the capsule. This study indicates that the enteric-coated tablet formulation of omeprazole is biodynamically equivalent to the capsule regarding their effects on intragastric pH during repeated dosing.

This paper presents the results of a consensus-driven process identifying 50 priority research questions for historical ecology obtained through crowdsourcing, literature reviews, and in-person workshopping. A deliberative approach was designed to maximize discussion and debate with defined outcomes. Two in-person workshops (in Sweden and Canada) over the course of two years and online discussions were peer facilitated to define specific key questions for historical ecology from anthropological and archaeological perspectives. The aim of this research is to showcase the variety of questions that reflect the broad scope for historical-ecological research trajectories across scientific disciplines. Historical ecology encompasses research concerned with decadal, centennial, and millennial human-environmental interactions, and the consequences that those relationships have in the formation of contemporary landscapes. Six interrelated themes arose from our consensus-building workshop model: (1) climate and environmental change and variability; (2) multi-scalar, multi-disciplinary; (3) biodiversity and community ecology; (4) resource and environmental management and governance; (5) methods and applications; and (6) communication and policy. The 50 questions represented by these themes highlight meaningful trends in historical ecology that distill the field down to three explicit findings. First, historical ecology is fundamentally an applied research program. Second, this program seeks to understand long-term human-environment interactions with a focus on avoiding, mitigating, and reversing adverse ecological effects. Third, historical ecology is part of convergent trends toward transdisciplinary research science, which erodes scientific boundaries between the cultural and natural.

BACKGROUND: Periodically surveying wait times for specialist health services in Canada captures current data and enables comparisons with previous surveys to identify changes over time.METHODS: During one week in April 2012, Canadian gastroenterologists were asked to complete a questionnaire (online or by fax) recording demographics, reason for referral, and dates of referral and specialist visits for at least 10 consecutive new patients (five consultations and five procedures) who had not been seen previously for the same indication. Wait times were determined for 18 indications and compared with those from similar surveys conducted in 2008 and 2005.RESULTS: Data regarding adult patients were provided by 173 gastroenterologists for 1374 consultations, 540 procedures and 293 same-day consultations and procedures. Nationally, the median wait times were 92 days (95% CI 85 days to 100 days) from referral to consultation, 55 days (95% CI 50 days to 61 days) from consultation to procedure and 155 days (95% CI 142 days to 175 days) (total) from referral to procedure. Overall, wait times were longer in 2012 than in 2005 (PDISCUSSION: Wait times for gastroenterology services continue to exceed recommended targets, remain unchanged since 2008 and exceed wait times reported in 2005.

Description: A multidisciplinary group of 34 experts from 15 countries developed this update and expansion of the recommendations on the management of acute nonvariceal upper gastrointestinal bleeding (UGIB) from 2003. Methods: The Appraisal of Guidelines for Research and Evaluation (AGREE) process and independent ethics protocols were used. Sources of data included original and published systematic reviews; randomized, controlled trials; and abstracts up to October 2008. Quality of evidence and strength of recommendations have been rated by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Recommendations: Recommendations emphasize early risk stratification, by using validated prognostic scales, and early endoscopy (within 24 hours). Endoscopic hemostasis remains indicated for high-risk lesions, whereas data support attempts to dislodge clots with hemostatic, pharmacologic, or combination treatment of the underlying stigmata. Clips or thermocoagulation, alone or with epinephrine injection, are effective methods; epinephrine injection alone is not recommended. Second-look endoscopy may be useful in selected high-risk patients but is not routinely recommended. Preendoscopy proton-pump inhibitor (PPI) therapy may downstage the lesion; intravenous high-dose PPI therapy after successful endoscopic hemostasis decreases both rebleeding and mortality in patients with high-risk stigmata. Although selected patients can be discharged promptly after endoscopy, high-risk patients should be hospitalized for at least 72 hours after endoscopic hemostasis. For patients with UGIB who require a nonsteroidal anti-inflammatory drug, a PPI with a cyclooxygenase-2 inhibitor is preferred to reduce rebleeding. Patients with UGIB who require secondary cardiovascular prophylaxis should start receiving acetylsalicylic acid (ASA) again as soon as cardiovascular risks outweigh gastrointestinal risks (usually within 7 days); ASA plus PPI therapy is preferred over clopidogrel alone to reduce rebleeding.

The mammalian inactive X chromosome (Xi) is a model for facultative heterochromatin. Increased DNA compaction for the Xi, and for facultative heterochromatin in general, has long been assumed based on recognition of a distinct Barr body using nucleic-acid staining. This conclusion has been challenged by a report revealing equal volumes occupied by the inactive and active X chromosomes. Here, we use light and electron microscopy to demonstrate in mouse and human fibroblasts a unique Xi ultrastructure, distinct from euchromatin and constitutive heterochromatin, containing tightly packed, heterochromatic fibers/domains with diameters in some cases approaching that of prophase chromatids. Significant space between these packed structures is observed even within condensed regions of the Xi. Serial-section analysis also reveals extensive contacts of the Xi with the nuclear envelope and/or nucleolus, with nuclear envelope association being observed in all cells. Implications of our results for models of Xi gene silencing and chromosome territory organization are discussed.

Many clinically important oncogenes and tumor suppressor genes have been identified through analysis of recurrent chromosomal rearrangements in acute leukemia. The contribution of sporadic rearrangements to malignancy is less clear and few have been mapped in detail. In this study we investigated the significance of novel translocations and inversions of 6q in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).Breakpoints of balanced 6q rearrangements were mapped in sequential fluorescent in situ hybridization (FISH) experiments with BAC and PAC clones in 11 patients.Six of seven breakpoints in ALL and two in a single case of AML were localized to within a 10.5 Mb hotspot at 6q22-q23 with five analyzed to the level of a single probe. In two cases of childhood T-ALL, both carrying a t(6;7)(q23;q32 through 36), split FISH signals were produced by adjacent PAC, mapping the breakpoints to within an approximately 150 Kb region containing the genes c-MYB and AHI1. Five similar rearrangements, four also in pediatric T ALL were identified in the literature. Other 6q22-q23 translocations mapped in detail interrupted regions containing no recognized genes. 6q breakpoints outside the q22-q23 region were widely dispersed and in two were mapped to positions overlapping the cloned fragile sites FRA6E and FRA6F. The involvement of MLL was demonstrated in one case with t(6;11)(q15;q23).We identified a new primary recurrent translocation t(6;7) (q22;q23 through q26) in pediatric T-ALL. Other translocations interrupting the 6q22-q23 breakpoint cluster region did not appear to be recurrent and may contribute to leukemogenesis through a novel mechanism. Key words; chromosome 6, translocation, c-Myb, AHI1.

Expression of BCR/ABL, a constitutively active tyrosine kinase, is a primary event in the pathogenesis of chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph+ALL). Inhibition of the BCR/ABL kinase activity in the BV173 CML cell line with STI571 resulted in a significant overexpression of a 10-kb novel mRNA, found to be the human ortholog of the murine Bach2, a B-cell-specific transcription factor. The human BACH2 cDNA is >9,120 bp long and includes an open reading frame of 2,526 bp encoding a protein with a basic leucine zipper (bZip) and a BTB/POZ domain, mediating DNA-binding and heterodimerization. BACH2 was consistently upregulated (2-10-fold) in all 10 Ph+ lymphoid lines tested following BCR/ABL inhibition. In CML myeloid cell lines (n = 8) and BCR/ABL-negative lines (n = 6), BACH2 was either undetectable by Northern blotting or did not change in response to STI571, suggesting that BACH2 repression by BCR/ABL may be specifically relevant to lymphoid transformation. Quantitative RT/PCR revealed a significantly lower level of BACH2 expression in leukocytes from patients with CML (n = 24) as compared to normal individuals (n = 23) (P < 0.0005). Moreover, CD34+ cells treated in vitro with STI571 exhibited a consistent upregulation of BACH2 in 8 of 10 CMLs but in none of the 9 normal individuals tested. Transcription regulation of BACH2 in BCR/ABL-positive cells was exerted via the MEK pathways, as shown by their responses to the U0126-specific inhibitor. Radiation hybrid mapping and FISH revealed that BACH2 is located on chromosome 6, band q15, a region frequently associated with deletions in ALL and non-Hodgkin's lymphoma, suggesting its possible role as a tumor suppressor gene. However, no rearrangement or loss of signal was observed by Southern blotting in 34 lymphomas, 10 B-cell ALLs, or seven reactive lymph nodes. The pattern of BACH2 expression in BCR/ABL-positive cells suggests that transcriptional repression by this regulator is impaired in CML and may contribute to the emergence of lymphoid blast crisis.

The molecular basis for blast transformation of chronic myeloid leukemia (CML) remains poorly understood. Cytogenetic alterations associated with CML blast crisis have previously been extensively studied by conventional G-banding analysis. However the complexity of some chromosome abnormalities or poor chromosome morphology or both has exceeded the resolution of G-banding analysis in a significant proportion of CML cases, and complex chromosome rearrangements have remained unidentified. In this study, comparative genomic hybridization (CGH) was used to elucidate genome imbalances in chronic phase or blast crisis samples or both from 12 CML patients. CGH and G-banding results were compared, and discrepancies were further clarified by using multipaint chromosome analysis and locus-specific DNA probes. No imbalances were detected in the 4 early disease phase samples studied. Eleven blast crisis samples were analyzed by G-banding and CGH, and the commonest genomic abnormality detected was overrepresentation of the long arm of chromosome 8, which was detected in 5 patients. This overrepresentation was attributable to trisomy 8 in 4 patients, whereas amplification of the entire long arm of chromosome 8 was detected in 1 patient. The formation of isochromosomes of the long arm of chromosome 8 was observed as a mechanism for gene amplification in this patient. Additional material originating from chromosome 8 was also observed intercalated into three marker chromosomes in peripheral blood metaphase spreads from this patient. These markers may further define areas on chromosome 8 that harbor oncogenes implicated in transformation of chronic myeloid leukemia.

OBJECTIVE: To study whether an intravenous infusion dose of omeprazole (80 mg + 8 mg/h) during 24 h can be subsequently reduced with maintained effect. Second, to study the effect of oral omeprazole 20 mg given once or twice daily up to day 10, after cessation of a 3-day intravenous infusion (80 mg + 8 mg/h). DESIGN: Prospective, randomized, partly blinded study. METHODS: Twelve Helicobacter pylori(+) patients and 12 H. pylori(-) subjects were included. In part I the patients received omeprazole, 80 mg + 8 mg/h, during 24 h followed by 8, 4 or 2 mg/h. In part II the subjects received 80 mg + 8 mg/h during 3 days followed by 20 mg omeprazole orally, once or twice daily until day 10. Intragastric pH was measured. RESULTS: All H. pylori(+) patients showed a rapid increase of intragastric pH with a mean intragastric pH of 6.7 during the second half of the first day. After the subsequent dose reduction, the mean pH decreased to 6.1-6.2. Patients continuing on 8 mg/h showed the best results. Likewise, all H. pylori(-) subjects showed a rapid and sustained reduction of intragastric acidity during the infusion. Subsequent dose reduction to 20 mg once daily led to a stable fraction of time with pH > 3 of 72%. CONCLUSIONS: Omeprazole given as a continuous infusion of 80 mg + 8 mg/h for 72 h followed by omeprazole 20 mg once daily raised the intragastric pH to and above levels alleged to allow haemostasis in patients with peptic ulcer bleeding and subsequent healing of the ulcer.

With the exponential increase in research in the field of Helicobacter pylori a paradigm shift has occurred. It is now recognized that H pylori is a chronic infection of the stomach causing inflammation. Some patients remain asymptomatic, while others may develop dyspepsia, duodenal or gastric ulcer, gastric cancer or a mucosa-associated lymphoid tissue lymphoma. However, the role of H pylori in contributing to nonulcer dyspepsia or nonsteroidal anti-inflammatory drug gastropathy remains controversial. An effective vaccine against H pylori is years away. Major interest has focused on the questions "who should be investigated and therefore treated" and "what is the latest gold standard for eradication of H pylori"? In Europe, guidelines have been developed to help the practitioner answer these important questions. Canadian guidelines will soon be available. For persons with known peptic ulcer disease there should be unequivocal acceptance that the good clinical practice of eradicating H pylori will result in substantial savings in health care expenses. The original 'classical triple therapy' (bismuth, metronidazole and tetracycline [BMT]) has now been surpassed by the combination of a proton pump inhibitor (PPI) plus two antibiotics (metronidazole plus clarithromycin; amoxicillin plus clarithromycin; or amoxicillin plus metronidazole), each given twice a day for one week. In Canada, the regimen of omeprazole plus one antibiotic (amoxicillin or clarithromycin) was approved recently but gives an eradication rate that is lower than the current target of 90%. According to the European (Mäastricht) recommendations, if a single treatment attempt with PPI plus two antibiotics fails, PPI plus BMT is recommended.

We report the case of a 55-year-old female who despite having developed extensive chronic graft-versus-host disease (GVHD), relapsed 35 months after a T cell-replete sibling donor bone marrow transplant for Philadelphia-positive chronic myeloid leukaemia (Ph CML). She achieved complete cytogenetic remission after discontinuation of cyclosporin A and administration of two low-dose donor leucocyte infusions (DLI 1 x 10(6) and 5 x 10(6) CD3+ cells/kg). Eighteen months after the first infusion she remains well and in complete cytogenetic remission with a normocellular marrow and no exacerbation of GVHD.

A 42-year-old male patient with a history of occupational exposure to benzene presented with pancytopenia. His bone marrow showed evidence of trilineage dysplasia and cytogenetic analysis revealed a unique t(9;13)(q34;q12) translocation. Five months after diagnosis he developed secondary AML. He was treated with four courses of chemotherapy and an autologous bone marrow transplantation (BMT). Four years post-transplantation he remains in haematological and morphological remission though the cytogenetic abnormality is still present in all metaphases examined.

How chromatin folds into mitotic and interphase chromosomes has remained a difficult question for many years. We have used three generations of engineered chromosome regions as a means of visualizing specific chromosome regions in live cells and cells fixed under conditions that preserve large-scale chromatin structure. Our results confirm the existence of large-scale chromatin domains and fibers formed by the folding of 10-nm and 30-nm chromatin fibers into larger, spatially distinct domains. Transcription at levels within severalfold of the levels measured for endogenous loci occur within these large-scale chromatin structures on a condensed template linearly compacted several hundred fold to 1000-fold relative to B-form DNA. However, transcriptional induction is accompanied by a severalfold decondensation of this large-scale chromatin structure that propagates hundreds of kilobases beyond the induced gene. Examination of engineered chromosome regions in mouse embryonic stem cells (ESCs) and differentiated cells suggests a surprising degree of plasticity in this large-scale chromatin structure, allowing long-range DNA interactions within the context of large-scale chromatin fibers. Recapitulation of gene-specific differences in large-scale chromatin conformation and nuclear positioning using these engineered chromosome regions will facilitate identification of cis and trans determinants of interphase chromosome architecture.