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Objective: Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer., Design: Hypomorphic Apc mice ( Apcfl/fl ) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation., Results: Overexpression of the T-UCR uc.158- could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158- was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158- expression in human malignant hepatocytes. uc.158- expression was increased in CTNNB1 -mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158- was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158- expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158- reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158- sequence. Modulation of uc.158- changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158- inhibitor and anti-miR-193b rescued the effect of uc.158- inhibition on cell viability., Conclusions: We showed that uc.158- is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Chronic Kidney Disease (CKD) is a pressing global health concern that is placing increased strain on health care resources. CKD patients regularly receive peritoneal dialysis as a common CKD treatment. An emerging technological solution is telehomecare as way to support patients receiving PD in their homes. This study protocol outlines a mixed methods evaluation exploring a telehomecare developed to enhance CKD patients' outcomes and experiences. The study aims to assess the usability, acceptability and scalability of this virtual care application., Methods: A realist evaluation using an embedded case study design will be used to understand the usability, acceptability and scalability of a telehomecare application for patients with CKD undergoing PD. The realist evaluation that is further described in this paper is part of a larger evaluation of the eQ Connect™ intervention that includes a randomized, parallel-arm control trial aimed at determining if utilizing eQ Connect improves selected clinical outcomes for PD patients (CONNECT Trial)., Discussion: Potential implications of this study include elucidating which components of the intervention are most effective and under what conditions with a focus on the contextual influences. Collectively, our multi-method design will yield knowledge around how best to implement, sustain and spread the telehomecare application that will be useful to guide the development, implementation and evaluation of future virtual care applications aimed at improving the quality of care outcomes and experiences of patients., Trial Registration: NCT02670512 . Registered: January 18, 2016.

Objective: There are concerns that structured electronic documentation systems can limit expressivity and encourage long and unreadable notes. We assessed the impact of an electronic clinical documentation system on the quality of admission notes for patients admitted to a general medical unit., Methods: This was a prospective randomized crossover study comparing handwritten paper notes to electronic notes on different patients by the same author, generated using a semistructured electronic admission documentation system over a 2-month period in 2014. The setting was a 4-team, 80-bed general internal medicine clinical teaching unit at a large urban academic hospital. The quality of clinical documentation was assessed using the QNOTE instrument (best possible score = 100), and word counts were assessed for free-text sections of notes., Results: Twenty-one electronic-paper note pairs (42 notes) written by 21 authors were randomly drawn from a pool of 303 eligible notes. Overall note quality was significantly higher in electronic vs paper notes (mean 90 vs 69, P < .0001). The quality of free-text subsections (History of Present Illness and Impression and Plan) was significantly higher in the electronic vs paper notes (mean 93 vs 78, P < .0001; and 89 vs 77, P = .001, respectively). The History of Present Illness subsection was significantly longer in electronic vs paper notes (mean 172.4 vs 92.4 words, P = .0001)., Conclusions: An electronic admission documentation system improved both the quality of free-text content and the overall quality of admission notes. Authors wrote more in the free-text sections of electronic documents as compared to paper versions., (© The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Management of diabetes through improved glycemic control and risk factor modification can help prevent long-term complications. Much diabetes management is self-management, in which healthcare providers play a supporting role. Well-designed e-Health solutions targeting behavior change can improve a range of measures, including glycemic control, perceived health, and a reduction in hospitalizations., Methods: The primary objective of this study is to evaluate if a mobile application designed to improve self-management among patients with type 2 diabetes (T2DM) improves glycemic control compared to usual care. The secondary objectives are to determine the effects on patient experience and health system costs; evaluate how and why the intervention worked as observed; and gain insight into considerations for system-wide scale-up. This pragmatic, randomized, wait-list-control trial will recruit adult participants from three Diabetes Education Programs in Ontario, Canada. The primary outcome is glycemic control (measured by HbA1c). Secondary outcomes include patient-reported outcomes and patient-reported experience measures, health system utilization, and intervention usability. The primary outcome will be analyzed using an ANCOVA, with continuous secondary outcomes analyzed using Poisson regression. Direct observations will be conducted of the implementation and application-specific training sessions provided to each site. Semi-structured interviews will be conducted with participants, healthcare providers, organizational leaders, and system stakeholders as part of the embedded process evaluation. Thematic analysis will be applied to the qualitative data in order to describe the relationships between (a) key contextual factors, (b) the mechanisms by which they effect the implementation of the intervention, and (c) the impact on the outcomes of the intervention, according to the principles of Realist Evaluation., Discussion: The use of mobile health and virtual tools is on the rise in health care, but the evidence of their effectiveness is mixed and their evaluation is often lacking key contextual data. Results from this study will provide much needed information about the clinical and cost-effectiveness of a mobile application to improve diabetes self-management. The process evaluation will provide valuable insight into the contextual factors that influence the application effectiveness, which will inform the potential for adoption and scale., Trial Registration: Clinicaltrials.gov NCT02813343 . Registered on 24 June 2016 (retrospectively registered). Trial Sponsor: Ontario Telemedicine Network.

Background: Mental illness is a substantial and rising contributor to the global burden of disease. Access to and utilization of mental health care, however, is limited by structural barriers such as specialist availability, time, out-of-pocket costs, and attitudinal barriers including stigma. Innovative solutions like virtual care are rapidly entering the health care domain. The advancement and adoption of virtual care for mental health, however, often occurs in the absence of rigorous evaluation and adequate planning for sustainability and spread., Methods: A pragmatic randomized controlled trial with a nested comparative effectiveness arm, and concurrent realist process evaluation to examine acceptability, effectiveness, and cost-effectiveness of the Big White Wall (BWW) online platform for mental health self-management and peer support among individuals aged 16 and older who are accessing mental health services in Ontario, Canada. Participants will be randomized to 3 months of BWW or treatment as usual. At the end of the 3 months, participants in the intervention group will have the opportunity to opt-in to an intervention extension arm. Those who opt-in will be randomized to receive an additional 3 months of BWW or no additional intervention. The primary outcome is recovery at 3 months as measured by the Recovery Assessment Scale-revised (RAS-r). Secondary outcomes include symptoms of depression and anxiety measured with the Personal Health Questionnaire-9 item (PHQ-9) and the Generalized Anxiety Disorder Questionnaire-7 item (GAD-7) respectively, quality of life measured with the EQ-5D-5L, and community integration assessed with the Community Integration Questionnaire. Cost-effectiveness evaluations will account for the cost of the intervention and direct health care costs. Qualitative interviews with participants and stakeholders will be conducted throughout., Discussion: Understanding the impact of virtual strategies, such as BWW, on patient outcomes and experience, and health system costs is essential for informing whether and how health system decision-makers can support these strategies system-wide. This requires clear evidence of effectiveness and an understanding of how the intervention works, for whom, and under what circumstances. This study will produce such effectiveness data for BWW, while simultaneously exploring the characteristics and experiences of users for whom this and similar online interventions could be helpful., Trial Registration: Clinicaltrials.gov NCT02896894 . Registered on 31 August 2016 (retrospectively registered).

Background: We describe the development and evaluation of a secure Web-based system for the purpose of collaborative care called Loop. Loop assembles the team of care with the patient as an integral member of the team in a secure space., Objective: The objectives of this paper are to present the iterative design of the separate views for health care providers (HCPs) within each patient's secure space and examine patients', caregivers', and HCPs' perspectives on this separate view for HCP-only communication., Methods: The overall research program includes cycles of ethnography, prototyping, usability testing, and pilot testing. This paper describes the usability testing phase that directly informed development. A descriptive qualitative approach was used to analyze participant perspectives that emerged during usability testing., Results: During usability testing, we sampled 89 participants from three user groups: 23 patients, 19 caregivers, and 47 HCPs. Almost all perspectives from the three user groups supported the need for an HCP-only communication view. In an earlier prototype, the visual presentation caused confusion among HCPs when reading and composing messages about whether a message was visible to the patient. Usability testing guided us to design a more deliberate distinction between posting in the Patient and Team view and the Health Care Provider Only view at the time of composing a message, which once posted is distinguished by an icon., Conclusions: The team made a decision to incorporate an HCP-only communication view based on findings during earlier phases of work. During usability testing we tested the separate communication views, and all groups supported this partition. We spent considerable effort designing the partition; however, preliminary findings from the next phase of evaluation, pilot testing, show that the Patient and Team communication is predominantly being used. This demonstrates the importance of a subsequent phase of the clinical trial of Loop to validate the concept and design.

Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.

Unlabelled: Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5'-untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors., Significance: Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small-molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo., Competing Interests: The authors declare no conflict of interest., (©2015 American Association for Cancer Research.)

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

In recent years, biochar has become of considerable interest for a variety of environmental applications. However, the feasibility of its application is entirely dependent on its physical and chemical properties, including the characteristics of biochar-derived dissolved organic matter (DOM). The goal of this study was to assess the use of optical analysis for the purpose of characterizing biochar-derived DOM. Three different biochars (slow pyrolysis birch and maple; fast pyrolysis maple) were produced and leached in distilled water over 17d. Samples were taken on days 3, 10, 13 and 17, filtered, and analyzed for DOC content. Samples were also subjected to optical analysis using UV-visible absorption and excitation-emission matrix (EEM) fluorescence spectroscopies. EEM fluorescence data were further analyzed using parallel factor analysis (PARAFAC). Absorbance and fluorescence results were combined and examined using principal component analysis (PCA). Significant differences in the water soluble organic carbon content were observed for all biochar types. The estimated aromaticity (SUVA254) and mean molecular weight (S275-295) of biochar-derived DOM were also found to differ based on biochar type. PARAFAC analysis identified three humic-like components and one protein-like component. Distinct DOM signatures were observed for each biochar type. Transformations in biochar DOM characteristics over time were also observed. The PCA showed a clear delineation in biochar types based on their optical properties. The results of this study indicate that optical analysis may provide valuable information regarding the characteristics of biochar-derived DOM., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The inflammatory response is normally limited by mechanisms regulating its resolution. In the absence of resolution, inflammatory pathologies can emerge, resulting in substantial morbidity and mortality. We have been studying the D6 chemokine scavenging receptor, which played an indispensable role in the resolution phase of inflammatory responses and does so by facilitating removal of inflammatory CC chemokines. In D6-deficient mice, otherwise innocuous cutaneous inflammatory stimuli induce a grossly exaggerated inflammatory response that bears many similarities to human psoriasis. In the present study, we have used transcriptomic approaches to define the molecular make up of this response. The data presented highlight potential roles for a number of cytokines in initiating and maintaining the psoriasis-like pathology. Most compellingly, we provide data indicating a key role for the type I interferon pathway in the emergence of this pathology. Neutralizing antibodies to type I interferons are able to ameliorate the psoriasis-like pathology, confirming a role in its development. Comparison of transcriptional data generated from this mouse model with equivalent data obtained from human psoriasis further demonstrates the strong similarities between the experimental and clinical systems. As such, the transcriptional data obtained in this preclinical model provide insights into the cytokine network active in exaggerated inflammatory responses and offer an excellent tool to evaluate the efficacy of compounds designed to therapeutically interfere with inflammatory processes.

Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology. Such misplacement of neutrophils is also seen with D6-deficient mice in other inflammatory models, suggesting a role for D6 in the spatial positioning of neutrophils within inflamed sites. We further show that D6 functions cell autonomously in this context and that D6, expressed by neutrophils, limits their migrational responses to CCR1 ligands such as CCL3. Our data therefore indicate that D6 is able to play a cell-autonomous role as a migratory rheostat restricting migration of D6-expressing cells such as neutrophils toward ligands for coexpressed inflammatory chemokine receptors. These data have important implications for our understanding of the roles for D6 in regulating inflammation and for our understanding of the control of spatial positioning of leukocytes at inflamed sites.

D6 is a scavenging-receptor for inflammatory CC chemokines that are essential for resolution of inflammatory responses in mice. Here, we demonstrate that D6 plays a central role in controlling cutaneous inflammation, and that D6 deficiency is associated with development of a psoriasis-like pathology in response to varied inflammatory stimuli in mice. Examination of D6 expression in human psoriatic skin revealed markedly elevated expression in both the epidermis and lymphatic endothelium in "uninvolved" psoriatic skin (ie, skin that was more than 8 cm distant from psoriatic plaques). Notably, this increased D6 expression is associated with elevated inflammatory chemokine expression, but an absence of plaque development, in uninvolved skin. Along with our previous observations of the ability of epidermally expressed transgenic D6 to impair cutaneous inflammatory responses, our data support a role for elevated D6 levels in suppressing inflammatory chemokine action and lesion development in uninvolved psoriatic skin. D6 expression consistently dropped in perilesional and lesional skin, coincident with development of psoriatic plaques. D6 expression in uninvolved skin also was reduced after trauma, indicative of a role for trauma-mediated reduction in D6 expression in triggering lesion development. Importantly, D6 is also elevated in peripheral blood leukocytes in psoriatic patients, indicating that upregulation may be a general protective response to inflammation. Together our data demonstrate a novel role for D6 as a regulator of the transition from uninvolved to lesional skin in psoriasis., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.

Objective: To report a case of refractory tachycardia after an excessive dose of inhaled tiotropium., Case Summary: A 74-year-old male with atrial fibrillation was admitted for increased heart rate and shortness of breath. The patient's heart rate was initially stabilized between 80 and 90 beats/min with metoprolol succinate 50 mg daily. During hospitalization, he accidentally received 5 capsules of tiotropium 18 microg inhaled as a single dose (total 90 microg) and, approximately 15 minutes later, his heart rate increased from 80 to 160 beats/min. Over 5 days of hospitalization, the patient's tachycardia was difficult to control and he required multiple atrioventricular (AV) nodal blocking agents (physostigmine, metoprolol tartrate, diltiazem) for effective stabilization prior to discharge. On outpatient follow-up 11 days after the ingestion the patient's heart rate was in the 40s and the AV nodal blocking agents were proportionately decreased., Discussion: Tiotropium is a long-acting anticholinergic medication used to treat chronic obstructive pulmonary disease. Little has been reported as to the potential systemic toxicities of tiotropium. Tachycardia is listed as a potential adverse effect, but based on a MEDLINE search (1966-July 2009) using tiotropium, tachycardia, and overdose as search terms, there have been no case reports published. Renal impairment may increase plasma concentrations of tiotropium; our patient's creatinine clearance was estimated to be below 50 mL/min. According to the Naranjo probability scale, our patient's development of tachycardia was probably associated with tiotropium inhalation., Conclusions: Tiotropium can be temporally implicated in a rapid heart rate following excessive ingestion. Health care professionals should be aware of tachycardic effects of tiotropium, particularly in patients with underlying structural heart disease, atrial fibrillation, and renal impairment.

Postpolypectomy bleeding and perforation are the most common complications of colonoscopy. A case of acute pancreatitis and ileus after colonoscopy is described. A 60-year-old woman underwent a gastroscopy and colonoscopy for investigation of iron deficiency anemia. Gastroscopy was normal; however, the colonoscope could not be advanced beyond the splenic flexure due to a tight angulation. Two polypectomies were performed in the descending colon. After the procedure, the patient developed a distended, tender abdomen. Bloodwork was remarkable for an elevated amylase level. An abdominal x-ray and computed tomography scan showed pancreatitis (particularly of the tail), a dilated cecum and a few air-fluid levels. The patient improved within 24 h of a repeat colonoscopy and decompression tube placement. The patient had no risk factors for pancreatitis. The causal mechanism of pancreatitis was uncertain but likely involved trauma to the tail of the pancreas during the procedure. Our patient developed ileus, likely secondary to pancreatitis. The present case is the first report of clinical pancreatitis and ileus associated with colonoscopy.

Toll-like receptors orchestrate rapid local protective innate-immune responses to invading pathogens and optimize leukocyte priming of subsequent adaptive responses. Paradoxically, systemic excess of the TLR2 ligand, bacterial lipoprotein (BLP), suppresses peripheral inflammatory responses. Here, we demonstrate that this phenomenon is regulated via the TLR2-dependent, cell-autonomous down-regulation of inflammatory chemokine receptor expression on a variety of leukocyte subsets. Remarkably, BLP mediated no effect on constitutive chemokine receptor expression. By tracking adoptively transferred wild-type and TLR2(-/-) leukocytes in vivo, we observed that BLP mediated chemokine receptor switching directed leukocytes away from inflamed sites toward secondary lymphoid organs. These data highlight a novel role for TLR ligands, such as BLP, in regulating leukocyte retention and migration away from innate immune lesions via discrete constitutive and inflammatory chemokine receptor regulation.

Museums in Canada have been found to possess radioactive items. The origin of the radiation can be broadly categorized as either natural (generally, radioactive ores) or anthropogenic (generally, luminous gauges). Radioluminescent gauges, especially bearing radium (226Ra), can also generate significant radiation fields. This is especially true if many gauges are located in close proximity. In addition, the radon may out-gas from these gauges, and generate a loose contamination problem in enclosed spaces (such as display cases). Radioactive ores, bearing naturally occurring uranium and thorium, can generate radiation fields many times greater than the ambient background levels. In addition, they will increase the ambient radon level and potentially generate loose contamination. In this paper, we discuss the specific results of radiological decommissioning at three museums: the National Air Force Museum of Canada (Trenton, Ontario); the Quebec Air and Space Museum (Montreal, PQ); and the Canadian Museum of Nature (Aylmer, PQ). In addition, a radiological survey performed at Canadian Forces Detachment Mountain View (Mountain View, Ontario) of surplus aircraft is included. The primary conclusion is that museums holding radioactive materials may have detectable levels of loose Ra and progeny contamination. They, therefore, have a requirement to be surveyed for loose contamination periodically with the potential for periodic decontamination caused by radon out-gassing. In addition, public access to displays bearing radioactive material should generally be restricted, and comprehensive radiation safety and security programs at museum facilities should be developed and enacted.

Various pieces of equipment in use by the Canadian Department of National Defence (DND) contain radiation-emitting components. One such piece is a sight knob used on light artillery. At the request of the DND's Director General Nuclear Safety (DGNS-DND's internal nuclear regulatory agency), the authors were contacted to remove the luminous tritium-impregnated paint strip from over 300 sight knobs. This paper discusses the physical description of the sight knobs, the protocol developed for decontaminating the sight knobs, the rationale for the release limits used, and experience gained in using and modifying the decontamination protocol.

Quantum dots (QDs) are a novel class of inorganic fluorophore which are gaining widespread recognition as a result of their exceptional photophysical properties. They are rapidly being applied to existing and emerging technologies, and could have an important role in many areas. Significant challenges remain, however, which must be understood and more fully defined before they can be widely validated. This review provides on overview of QD technology, covering QD characteristics, synthesis methods, and the applications in which they have been put to use. The influence of synthesis methods on QD characteristics and their subsequent suitability to different applications is discussed, and a broad outline of the technologies into which they have been incorporated is presented, and the relative merits and weaknesses of their incorporation are evaluated. The potential for further development, and inclusion in other technologies is also discussed, and barriers restricting further progress specified, particularly with regard to the poorly understood surface chemistry of QDs, the potential for alteration of function of biological molecules when complexed with QDs, and on a larger scale the significant potential for cytotoxicity both in vitro and in vivo.

How the inflammatory response is initiated has been well defined but relatively little is known about how such responses are resolved. Here we show that the D6 chemokine receptor is involved in the post-inflammatory clearance of beta-chemokines from cutaneous sites. After induction of inflammation by phorbol esters, wild-type mice showed a transient inflammatory response. However, in D6-deficient mice, an excess concentration of residual chemokines caused a notable inflammatory pathology with similarities to human psoriasis. These results suggest that D6 is involved in the resolution of the cutaneous inflammatory response.

Sacrococcygeal teratomas are rare tumours, occurring in approximately 1 in 40,000 live births. The sacrococcygeal area is, however, the commonest site for teratomas that are present at birth. There are many conflicting theories as to the origin of sacrococcygeal teratomas. Recent studies have begun to shed light on some of the dilemmas posed by these enigmatic tumours and have revealed factors that impact on therapy and outcome. Advances contributing to the understanding of sacrococcygeal teratomas and their impact on prognosis and therapy are reviewed in this article.

Purpose: To evaluate the incidence, severity, and clinical/dosimetric predictors of acute and chronic esophageal toxicities in patients with non-small cell lung cancer (NSCLC) treated with high-dose conformal thoracic radiation., Methods and Materials: Ninety-one patients with localized NSCLC treated definitively with high-dose conformal radiation therapy (RT) at Duke University Medical Center (DUMC) were reviewed. Patient characteristics were as follows: 53 males and 38 females; median age 64 yr (range 46-82); stage I--16, II--3, IIIa--40, IIIb--30, X--2; dysphagia pre-RT--6 (7%). Treatment parameters included: median corrected dose-78.8 Gy (range 64.2-85.6); BID fractionation-58 (64%); chemotherapy-43 (47%). Acute and late esophageal toxicities were graded by RTOG criteria. Using 3D treatment planning tools, the esophagus was contoured in a uniform fashion, the 3D dose distribution calculated (with lung density correction), and the dose-volume (DVH) and dose-surface histograms (DSH) generated. At each axial level, the percentage of the esophageal circumference at each dose level was calculated. The length of circumferential esophagus and the maximum circumference treated to doses >50 Gy were assessed. Patient and treatment factors were correlated with acute and chronic esophageal dysfunction using univariate and multivariate logistic regression analyses., Results: There were no acute or late grade 4 or 5 esophageal toxicities. Ten of 91 patients (11%) developed grade 3 acute toxicity. On univariate analysis of clinical parameters, both dysphagia pre-RT (p = 0.10) and BID fractionation (p = 0.11) tended toward significantly predicting grade 3 acute esophagitis. None of the dosimetric parameters analyzed significantly predicted for grade 3 acute esophagitis. Twelve of 66 assessable patients (18%) developed late esophageal toxicity. Of the clinical parameters analyzed, only dysphagia pre-RT (p = 0.06) tended toward significantly predicting late esophageal toxicity. On univariate analyses, the effects of percent organ volume treated >50 Gy (p = 0.05), percent surface area treated >50 Gy (p = 0.05), length of 100% circumference treated >50 Gy (p = 0.04), and maximum percent of circumference treated >80 Gy (p = 0.01) significantly predicted for late toxicity of all grades. On multivariate analysis, percent organ volume treated >50 Gy (p = 0.02) and maximum percent of circumference treated >80 Gy (p = 0.02) predicted for late toxicity., Conclusions: Late esophageal toxicity following aggressive, high-dose conformal radiotherapy is common but rarely severe. Dosimetric variables addressing the longitudinal and circumferential character of the esophagus have biologic rationale and are predictive of late toxicity. Further studies are needed to assess whether these parameters are better predictors than those derived from traditional DVHs.

The c-sea proto-oncogene is a member of the Met/hepatocyte growth factor/scatter factor family of receptor protein tyrosine kinases. A distinguishing feature of this family, whose other member is the Ron/Stk receptor, is a novel heterodimeric structure. We have previously described cDNA clones encoding the avian Sea receptor. In this report we show that a full length c-sea cDNA directed the synthesis of a single 155 kDa polypeptide chain in vitro, while in vivo two polypeptides of 160 and 180 kDa were observed. We analysed the structure of the Sea receptor using a soluble chimeric protein consisting of the Sea extracellular domain linked to the hinge and constant regions of human IgG gamma 1. These studies indicated that the receptor undergoes proteolytic processing in the extracellular domain yielding an approximate 35 kDa alpha and a 160 kDa beta chain, and thus the Sea receptor appears to display a structure similar to that of the Met and Ron proteins. An examination of embryonic avian tissues using Sea extracellular domain-specific monoclonal antibodies revealed low levels of Sea receptor in a variety of tissues including kidney, intestine, liver, stomach, white blood cells and allantochorion. Elevated levels of expression were observed upon transformation of chicken embyro cells by the Src oncoprotein.

Cognitive function was investigated in a random sample of subjects on the general practitioners' registry of hypertensive patients in an inner city area and matched with normotensive controls. The response rate was 66% giving 90 matched pairs, average age 63 yrs, with 47% men. There was no difference in educational background or measures of reading ability between the two groups. Cognitive function tests showed a consistent trend of poorer performance in hypertensives, with significant differences in Verbal Learning (immediate recall and retention). Age was inversely related to cognitive function, but no additional deterioration with increasing age was shown in hypertensives.

Transcription of the c-myc gene is initiated mainly from two promoters, P1 and P2. By S1 nuclease analysis we found that there is 8 times more P2- than P1-initiated RNA in total RNA from HL60 cells. The half-lives of P1- and P2-initiated transcripts are 26 and 18 min, respectively, so the difference in the relative abundance of the mRNAs is not due to differences in their stabilities. The relative rates of transcription from the P1 and P2 promoters, estimated by in vitro nuclear run-on analysis, were found to differ by about 10-fold, sufficient to account for the difference in the steady-state levels of the two mRNAs. The abundance of c-myc mRNA changes dramatically during differentiation of HL60 cells. Dimethyl sulphoxide causes a very rapid reduction in total c-myc mRNA, while with phorbol ester a transient increase occurs followed by a more gradual decline. At no time during these dramatic alterations were significant changes detected in the relative abundance of P1- and P2-initiated mRNAs, or in their stabilities.

The wrist is an unusual anatomic location for pigmented villonodular synovitis (PVNS). PVNS is generally a benign or minimally destructive process, but in our patient it resulted in progressive erosive changes in a bilateral wrist distribution. This is the first histologically documented case of bilateral PVNS in this anatomic distribution, to our knowledge. Although uncommon, PVNS should be considered a possible cause of unexplained upper extremity inflammatory arthritis.

Of the corticosteroid preparations available, the intermediate-acting agents are the preparations most commonly used in the rheumatic diseases. Careful tailoring of dosage is important to avoid adrenal atrophy and signs of adrenocortical hypofunction. The best regimen in a given patient depends on the amount of antiinflammatory and immunosuppressive activity required. The therapeutic strategies in use include pulse therapy, daily high-dose therapy, daily low-dose therapy, and alternate-day dosing. The latter two methods are preferable because of the decreased likelihood of adverse reactions, yet are not sufficient in cases of fulminant systemic inflammatory processes.

In some optical applications, such as thermal imagery, chromatic aberration, correction may not be necessary. The various forms of aplantic doublet are compared with respect to high order aberrations. A set of equations is described, which generates aplanatic anastigmatic two-element single aspheric systems with any specified lens separation and back focus and, as a corollary, three-element systems with two elements in contact. The method is applied to germanium Petzval, telephoto, and inverse telephoto systems.

Thick meniscus lenses with almost equal curvatures are routinely used for the correction of spherical aberration in optical systems. The use of such quasi-concentric menisci (QCM) for correction of field curvature and astigmatism is less well known. Three limiting forms of QCM can be identified, namely, equal curvatures, true concentric, and zero deviation, and each exhibits radically different field aberrations. A doublet lens has field curvature and astigmatism; the former can be removed by adding a strong negative lens at the image plane, but the latter is uncorrected. Use of a QCM, however, corrects both aberrations, moreover, without causing the chief rays to diverge as the conventional field flattener does. Indeed the chief rays may be made to converge so that the QCM can be used as a field-correcting field lens, and we illustrate its use in a periscopic vehicle sight comprising an objective lens, relay stage, and eyepiece. Even in cases in which a measure of field curvature and astigmatism correction is possible, for example, when a double Gauss-type relay lens is used, the QCM results in smaller high-order aberrations and lower ray heights through the system.

Collagen induced arthritis was elicited in rats and monitored with serial magnification radiographs and serologic studies. Total lymphoid irradiation (TLI), 1050 rad in 3 fractions, was given at 1 of 2 days after primary immunization. Erosive arthritis and periostitis evolved more slowly in rats irradiated on Day 9 compared to nonirradiated control animals; in contrast, rats irradiated on Day 21 showed no significant differences. At Day 114 neither group receiving TLI differed from nonirradiated controls. Additional groups of rats were irradiated at varying times relative to collagen immunization. On Day 18 the mean IgM and IgG anticollagen antibody responses were transiently decreased in animals receiving TLI by Day 9, with no differences by Day 36.

Serial whole body and lateral hindpaw magnification radiographs were obtained on 15 rats with collagen-induced arthritis. The radiographs were evaluated for findings of inflammatory arthritis. Soft tissue swelling and juxta-articular osteopenia usually developed two weeks after immunization. The swelling remained stable for the remaining seven weeks of the study, but the osteopenia apparently improved. Three weeks after immunization, erosions and periostitis began to develop in ten of the rats. These latter radiographic changes rapidly worsened over the next three weeks and then stabilized. The most frequent and severe changes were seen in the intertarsal, tibiotalar, and metatarsophalangeal joints. The toes, forepaws, and knees were infrequently involved. Other peripheral joints and the axial skeleton were spared. Five rats developed soft tissue swelling but had no articular erosions or periostitis. Serial radiography has potential usefulness for monitoring the effects of treatment in this experimental model for inflammatory arthritis.