bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethics review for international data-intensive research
Authors: Dove Edward S. , Townend David , Meslin Eric M. , Bobrow Martin , Littler Katherine , Nicol Dianne , de Vries Jantina , Junker Anne , Garattini Chiara , Bovenberg Jasper , Shabani Mahsa , Lévesque Emmanuelle , Knoppers Bartha M.
Published: March 2016

Ad hoc approaches mix and match existing components
Thermal trouble in the tropics
Authors: Perez Timothy M. , Stroud James T. , Feeley Kenneth J.
Published: March 2016

Tropical species may be highly vulnerable to climate change

[Also see Report by

Chan
et al.

]
Einstein v. Roberts
Authors: Gates S. J.
Published: March 2016

In the recent U.S. Supreme Court hearing on A. Fisher v. the University of Texas about university admission policies regarding minority students, Chief Justice John Roberts asked, “What unique perspective does a minority student bring to a physics class?” As an African-American physicist researching string theory, and a teacher of university students since 1972, I have a response.
Validation of a Multiplex Real-Time PCR Assay for Detection of Mycobacterium spp., Mycobacterium tuberculosis Complex, and Mycobacterium avium Complex Directly from Clinical Samples by Use of the BD Max Open System
Authors: Rocchetti Talita T. , Silbert Suzane , Gostnell Alicia , Kubasek Carly , Widen Raymond
Published: March 2016

A multiplex real-time PCR was validated on the BD Max open system to detect different
Mycobacterium tuberculosis
complex,
Mycobacterium avium
complex, and
Mycobacterium
spp. directly from clinical samples. The PCR results were compared to those with traditional cultures. The multiplex PCR assay was found to be a specific and sensitive method for the rapid detection of mycobacteria directly from clinical specimens.
Swiftly Decreasing Cerebrospinal Fluid Cathelicidin Concentration Predicts Improved Outcome in Childhood Bacterial Meningitis
Authors: Savonius Okko , Helve Otto , Roine Irmeli , Andersson Sture , Fernández Josefina , Peltola Heikki , Pelkonen Tuula
Published: March 2016

We investigated cerebrospinal fluid (CSF) cathelicidin concentrations in childhood bacterial meningitis on admission and during antimicrobial treatment. CSF cathelicidin concentrations on admission correlated with CSF white cell counts and protein levels but not with bacterial etiology. A greater decrease in the concentration in response to treatment was associated with a better outcome. Since the CSF cathelicidin concentration reflects the degree of central nervous system (CNS) inflammation, it may be used as a novel biomarker in childhood bacterial meningitis. An early decrease during treatment likely signals more rapid mitigation of the disease process and thus a better outcome.
Genetic Modification of Oncolytic Newcastle Disease Virus for Cancer Therapy
Authors: Cheng Xing , Wang Weijia , Xu Qi , Harper James , Carroll Danielle , Galinski Mark S. , Suzich JoAnn , Jin Hong
Published: March 2016

Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has a modification at the fusion protein (F) cleavage site to reduce the efficiency of F protein cleavage and an insertion of a 198-nucleotide sequence into the HN-L intergenic region, resulting in reduced viral gene expression and replication in avian cells but not in mammalian cells. In mammalian cells, except for viral polymerase (L) gene expression, viral gene expression is not negatively impacted or increased by the HN-L intergenic insertion. Furthermore, the virus can be engineered to express a foreign gene while still retaining the ability to grow to high titers in cell culture. The recombinant NDV selectively replicates in and kills tumor cells and is able to drive potent tumor growth inhibition following intratumoral or intravenous administration in a mouse tumor model. The candidate is well positioned for clinical development as an oncolytic virus.

IMPORTANCE
Avian paramyxovirus type 1, NDV, has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step toward moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide without impacting viral production in cell culture. The selective tumor replication of this recombinant NDV, both
in vitro
and
in vivo
, along with efficient tumor cell killing makes it an attractive oncolytic virus candidate that may provide clinical benefit to patients.
Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses
Authors: Palomo Concepción , Mas Vicente , Thom Michelle , Vázquez Mónica , Cano Olga , Terrón María C. , Luque Daniel , Taylor Geraldine , Melero José A.
Published: March 2016

Human respiratory syncytial virus (hRSV) vaccine development has received new impetus from structure-based studies of its main protective antigen, the fusion (F) glycoprotein. Three soluble forms of F have been described: monomeric, trimeric prefusion, and trimeric postfusion. Most human neutralizing antibodies recognize epitopes found exclusively in prefusion F. Although prefusion F induces higher levels of neutralizing antibodies than does postfusion F, postfusion F can also induce protection against virus challenge in animals. However, the immunogenicity and protective efficacy of the three forms of F have not hitherto been directly compared. Hence, BALB/c mice were immunized with a single dose of the three proteins adjuvanted with CpG and challenged 4 weeks later with virus. Serum antibodies, lung virus titers, weight loss, and pulmonary pathology were evaluated after challenge. Whereas small amounts of postfusion F were sufficient to protect mice, larger amounts of monomeric and prefusion F proteins were required for protection. However, postfusion and monomeric F proteins were associated with more pathology after challenge than was prefusion F. Antibodies induced by all doses of prefusion F, in contrast to other F protein forms, reacted predominantly with the prefusion F conformation. At high doses, prefusion F also induced the highest titers of neutralizing antibodies, and all mice were protected, yet at low doses of the immunogen, these antibodies neutralized virus poorly, and mice were not protected. These findings should be considered when developing new hRSV vaccine candidates.

IMPORTANCEProtection against hRSV infection is afforded mainly by neutralizing antibodies, which recognize mostly epitopes found exclusively in the viral fusion (F) glycoprotein trimer, folded in its prefusion conformation, i.e., before activation for membrane fusion. Although prefusion F is able to induce high levels of neutralizing antibodies, highly stable postfusion F (found after membrane fusion) is also able to induce neutralizing antibodies and protect against infection. In addition, a monomeric form of hRSV F that shares epitopes with prefusion F was recently reported. Since each of the indicated forms of hRSV F may have advantages and disadvantages for the development of safe and efficacious subunit vaccines, a direct comparison of the immunogenic properties and protective efficacies of the different forms of hRSV F was made in a mouse model. The results obtained show important differences between the noted immunogens that should be borne in mind when considering the development of hRSV vaccines.
Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression
Authors: MacParland Sonya A. , Ma Xue-Zhong , Chen Limin , Khattar Ramzi , Cherepanov Vera , Selzner Markus , Feld Jordan J. , Selzner Nazia , McGilvray Ian D.
Published: March 2016

Inflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states.

IMPORTANCEInflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of inappropriate innate inflammatory responses is a common characteristic of chronic viral infections. Previous studies have shown that expression of certain interferon-stimulated genes is upregulated in chronic HCV infection, leading to impaired hepatocyte responses. In this study, we show that multiple inflammatory stimuli can modulate interferon stimulated gene expression and thus inhibit hepatocyte interferon signaling via USP18 induction. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with the induction of USP18 representing a potential target for intervention in various inflammatory states.
Kaposi's Sarcoma-Associated Herpesvirus Inhibitor of cGAS (KicGAS), Encoded by ORF52, Is an Abundant Tegument Protein and Is Required for Production of Infectious Progeny Viruses
Authors: Li Wenwei , Avey Denis , Fu Bishi , Wu Jian-jun , Ma Siming , Liu Xia , Zhu Fanxiu
Published: March 2016

Although Kaposi's sarcoma-associated herpesvirus (KSHV) ORF52 (also known as KSHV inhibitor of cGAS [KicGAS]) has been detected in purified virions, the roles of this protein during KSHV replication have not been characterized. Using specific monoclonal antibodies, we revealed that ORF52 displays true late gene expression kinetics and confirmed its cytoplasmic localization in both transfected and KSHV-infected cells. We demonstrated that ORF52 comigrates with other known virion proteins following sucrose gradient centrifugation. We also determined that ORF52 resides inside the viral envelope and remains partially associated with capsid when extracellular virions are treated with various detergents and/or salts. There results indicate that ORF52 is a tegument protein abundantly present in extracellular virions. To characterize the roles of ORF52 in the KSHV life cycle, we engineered a recombinant KSHV ORF52-null mutant virus and found that loss of ORF52 results in reduced virion production and a further defect in infectivity. Upon analysis of the virion composition of ORF52-null viral particles, we observed a decrease in the incorporation of ORF45, as well as other tegument proteins, suggesting that ORF52 is important for the packaging of other virion proteins. In summary, our results indicate that, in addition to its immune evasion function, KSHV ORF52 is required for the optimal production of infectious virions, likely due to its roles in virion assembly as a tegument protein.

IMPORTANCE
The tegument proteins of herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), play key roles in the viral life cycle. Each of the three subfamilies of herpesviruses (alpha, beta, and gamma) encode unique tegument proteins with specialized functions. We recently found that one such gammaherpesvirus-specific protein, ORF52, has an important role in immune evasion during KSHV primary infection, through inhibition of the host cytosolic DNA sensing pathway. In this report, we further characterize ORF52 as a tegument protein with vital roles during KSHV lytic replication. We found that ORF52 is important for the production of infectious viral particles, likely through its role in virus assembly, a critical process for KSHV replication and pathogenesis. More comprehensive investigation of the functions of tegument proteins and their roles in viral replication may reveal novel targets for therapeutic interventions against KSHV-associated diseases.
Perceptions and impact of plain packaging of tobacco products in low and middle income countries, middle to upper income countries and low-income settings in high-income countries: a systematic review of the literature
Authors: Hughes Nicole , Arora Monika , Grills Nathan
Published: March 2016

Objective

To review the current literature around the potential impact, effectiveness and perceptions of plain packaging in low income settings.

Method

A systematic review of the literature.

Data sources

9 databases (PubMed, Global Health, Social Policy and Practice, Applied Social Sciences Index and Abstracts (ASSIA), CINAHL, PsycINFO, British Library for Development Studies (BLDS), Global Health Library and Scopus) were searched. The terms used for searching combined terms for smoking and tobacco use with terms for plain packaging.

Study selection

Studies investigating the impact of plain packaging on the determinants of tobacco use, such as smoking behaviour, appeal, prominence, effectiveness of health warnings, response to plain packs, attitudes towards quitting or likelihood of smoking in low-income settings, were identified. Studies must have been published in English and be original research of any level of rigour.

Data extraction

Two independent reviewers assessed studies for inclusion and extracted data.

Data synthesis

The results were synthesised qualitatively, with themes grouped under four key headings: appeal and attractiveness; salience of health warnings and perceptions of harm; enjoyment and perceived taste ratings; and perceptions of the impact on tobacco usage behaviour.

Results

This review has identified four articles that met the inclusion criteria. Studies identified that tobacco products in plain packaging had less appeal than in branded packaging in low-income settings.

Conclusions

This review indicates that plain packaging appears to be successful in reducing appeal of smoking and packets, and supports the call for plain packaging to be widely implemented in conjunction with other tobacco control policies. However, there are considerable gaps in the amount of research conducted outside high-income countries.
Economic analysis of temperature-controlled laminar airflow (TLA) for the treatment of patients with severe persistent allergic asthma
Authors: Brazier Peter , Schauer Uwe , Hamelmann Eckard , Holmes Steve , Pritchard Clive , Warner John O
Published: March 2016

Introduction

Chronic asthma is a significant burden for individual sufferers, adversely impacting their quality of working and social life, as well as being a major cost to the National Health Service (NHS). Temperature-controlled laminar airflow (TLA) therapy provides asthma patients at BTS/SIGN step 4/5 an add-on treatment option that is non-invasive and has been shown in clinical studies to improve quality of life for patients with poorly controlled allergic asthma. The objective of this study was to quantify the cost-effectiveness of TLA (Airsonett AB) technology as an add-on to standard asthma management drug therapy in the UK.

Methods

The main performance measure of interest is the incremental cost per quality-adjusted life year (QALY) for patients using TLA in addition to usual care versus usual care alone. The incremental cost of TLA use is based on an observational clinical study monitoring the incidence of exacerbations with treatment valued using NHS cost data. The clinical effectiveness, used to derive the incremental QALY data, is based on a randomised double-blind placebo-controlled clinical trial comprising participants with an equivalent asthma condition.

Results

For a clinical cohort of asthma patients as a whole, the incremental cost-effectiveness ratio (ICER) is £8998 per QALY gained, that is, within the £20 000/QALY cost-effectiveness benchmark used by the National Institute for Health and Care Excellence (NICE). Sensitivity analysis indicates that ICER values range from £18 883/QALY for the least severe patients through to TLA being dominant, that is, cost saving as well as improving quality of life, for individuals with the most severe and poorly controlled asthma.

Conclusions

Based on our results, Airsonett TLA is a cost-effective addition to treatment options for stage 4/5 patients. For high-risk individuals with more severe and less well controlled asthma, the use of TLA therapy to reduce incidence of hospitalisation would be a cost saving to the NHS.
Larger size ratio associated with the rupture of very small (≤3 mm) anterior communicating artery aneurysms
Authors: Xu Ting , Lin Boli , Liu Shuailiang , Shao Xiaotong , Xia Nengzhi , Zhang Yue , Xu Haoli , Yang Yunjun , Zhong Ming , Zhuge Qichuan , Zhao Bing , Chen Weijian
Published: March 2016

Background

Anterior communicating artery (AcoA) aneurysms have a high rupture risk, and ruptured AcoA aneurysms tend to be smaller than other intracranial aneurysms. We aimed to determine the incidence and morphologic predictors of aneurysm rupture of very small AcoA aneurysms.

Methods

We conducted a retrospective analysis of 519 consecutive patients with single AcoA aneurysms between December 2007 and February 2015 in our hospital. Aneurysm morphologies were re-measured using CT angiography images. Very small aneurysms were defined as those with a maximum size ≤3 mm, and small aneurysms were defined as those with a maximum size ≤5 mm. Multivariate regression analyses were used to determine the association between aneurysm morphology and aneurysm rupture status.

Results

Of the 474 ruptured AcoA aneurysms, 134 (28.3%) aneurysms were very small and 278 (58.6%) aneurysms were small. In the univariate analysis for very small aneurysms, larger aneurysm size (p=0.037), larger size ratio (p=0.002), higher aneurysm height (p=0.038), smaller vessel size (p=0.012), and dominant A1 segment configuration (p=0.011) were associated with aneurysm rupture. Multivariate analysis revealed that a larger size ratio was independently associated with the rupture status of the very small aneurysms (OR 3.69, 95% CI 1.5 to 9.0; p=0.004), and larger aneurysm size, larger size ratio, and dominant A1 segment configuration were associated with the rupture of small aneurysms.

Conclusions

About one-third of ruptured AcoA aneurysms were very small. A larger size ratio, rather than other aneurysm morphologies, was independently associated with the rupture of very small AcoA aneurysms.
Working in the veterinary marketplace
Authors: Armitage Sara
Published: March 2016

Sara Armitage is director of products and buying for the CVS group of veterinary practices. Neither she, nor this week's 10‐minute chat contributor, Barbara Peel, had planned a career in the veterinary sphere
Bovine TB surveillance in Great Britain in 2014
Authors: Lawes J. R. , Harris K. A. , Brouwer A. , Broughan J. M. , Smith N. H. , Upton P. A.
Published: March 2016

This report, provided by the APHA, summarises the key descriptive epidemiological parameters of bovine TB in cattle in Great Britain from January 1 to December 31, 2014. It summarises some of the temporal trends observed over a longer period and highlights some differences and similarities between Scotland, Wales and the three bovine TB risk areas of England. It updates the previous annual summaries for 2012 and 2013, also published in Veterinary Record (VR, June 14, 2014, vol 174, pp 600‐604; March 28, 2015, vol 176, pp 326‐330).
Effectiveness of soil in vegetated buffers to retain nutrients and sediment transported by concentrated runoff through deep gullies
Authors: Miller J.J. , Curtis T. , Chanasyk D.S. , Reedyk S. , Willms W.D.
Published: March 2016

Little research has evaluated naturally vegetated buffers to retain pollutants in soil from concentrated runoff through deep (2–14 m) gullies. Soil enrichment in the flow path of 11 naturally vegetated gullies in southern Alberta, Canada, was used as a long-term signature of filtering during concentrated flow. Soil was sampled at three depth intervals (0–2.5, 2.5–5, and 5–10 cm) along two 50-m transects inside and outside the flow path of the vegetated gullies in each of 3 yr (2011–2013). The influence of soil type, flow path (inside vs. outside), distance into vegetated flow path, depth, and their interactions on enrichment of nutrients (NH4–N, NO3–N, soil test P (STP), total P) and particle size fractions (clay, silt, and sand) was determined. Significantly (P ≤ 0.05) greater enrichment of nutrients and specific particle size fractions inside than outside the flow path of the vegetated gully suggested that greater deposition occurred inside the concentrated flow path. In contrast, there was little evidence for enrichment of nutrients and sediment at the front or inlet of the buffer (except STP), or for infiltration of more soluble nutrients into the subsoil. Soil enrichment in buffers may reveal long-term filtering processes that may not be shown with short-term runoff experiments.
Genome-wide DNA polymorphisms in Kavuni, a traditional rice cultivar with nutritional and therapeutic properties
Authors: Rathinasabapathi Pasupathi , Purushothaman Natarajan , Parani Madasamy
Published: March 2016

Although rice genome was sequenced in the year 2002, efforts in resequencing the large number of available accessions, landraces, traditional cultivars, and improved varieties of this important food crop are limited. We have initiated resequencing of the traditional cultivars from India. Kavuni is an important traditional rice cultivar from South India that attracts premium price for its nutritional and therapeutic properties. Whole-genome sequencing of Kavuni using Illumina platform and SNPs analysis using Nipponbare reference genome identified 1 150 711 SNPs of which 377 381 SNPs were located in the genic regions. Non-synonymous SNPs (62 708) were distributed in 19 251 genes, and their number varied between 1 and 115 per gene. Large-effect DNA polymorphisms (7769) were present in 3475 genes. Pathway mapping of these polymorphisms revealed the involvement of genes related to carbohydrate metabolism, translation, protein-folding, and cell death. Analysis of the starch biosynthesis related genes revealed that the granule-bound starch synthase I gene had T/G SNPs at the first intron/exon junction and a two-nucleotide combination, which were reported to favour high amylose content and low glycemic index. The present study provided a valuable genomics resource to study the rice varieties with nutritional and medicinal properties.
Casimir energy for perturbed surfaces of revolution
Authors: Morales-Almazan Pedro
Published: March 2016

In this paper, we explore the zeta function arising from a small perturbation on a surface of revolution and the effect of this on the functional determinant and on the change of the Casimir energy associated with the surface.
Novel regulation of equlibrative nucleoside transporter 1 (ENT1) by receptor-stimulated Ca2+-dependent calmodulin binding
Authors: Bicket Alex , Mehrabi Pedram , Naydenova Zlatina , Wong Victoria , Donaldson Logan , Stagljar Igor , Coe Imogen R.
Published: March 2016

Equilibrative nucleoside transporters (ENTs) facilitate the flux of nucleosides, such as adenosine, and nucleoside analog (NA) drugs across cell membranes. A correlation between adenosine flux and calcium-dependent signaling has been previously reported; however, the mechanistic basis of these observations is not known. Here we report the identification of the calcium signaling transducer calmodulin (CaM) as an ENT1-interacting protein, via a conserved classic 1-5-10 motif in ENT1. Calcium-dependent human ENT1-CaM protein interactions were confirmed in human cell lines (HEK293, RT4, U-87 MG) using biochemical assays (HEK293) and the functional assays (HEK293, RT4), which confirmed modified nucleoside uptake that occurred in the presence of pharmacological manipulations of calcium levels and CaM function. Nucleoside and NA drug uptake was significantly decreased (∼12% and ∼39%, respectively) by chelating calcium (EGTA, 50 μM; BAPTA-AM, 25 μM), whereas increasing intracellular calcium (thapsigargin, 1.5 μM) led to increased nucleoside uptake (∼26%). Activation of N-methyl-d-aspartate (NMDA) receptors (in U-87 MG) by glutamate (1 mM) and glycine (100 μM) significantly increased nucleoside uptake (∼38%) except in the presence of the NMDA receptor antagonist, MK-801 (50 μM), or CaM antagonist, W7 (50 μM). These data support the existence of a previously unidentified novel receptor-dependent regulatory mechanism, whereby intracellular calcium modulates nucleoside and NA drug uptake via CaM-dependent interaction of ENT1. These findings suggest that ENT1 is regulated via receptor-dependent calcium-linked pathways resulting in an alteration of purine flux, which may modulate purinergic signaling and influence NA drug efficacy.
L-type calcium channels and MAP kinase contribute to thyrotropin-releasing hormone-induced depolarization in thalamic paraventricular nucleus neurons
Authors: Kolaj Miloslav , Zhang Li , Renaud Leo P.
Published: March 2016

In rat paraventricular thalamic nucleus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances neuronal excitability via concurrent decrease in a G protein-coupled inwardly rectifying K (GIRK)-like conductance and opening of a cannabinoid receptor-sensitive transient receptor potential canonical (TRPC)-like conductance. Here, we investigated the calcium (Ca2+) contribution to the components of this TRH-induced response. TRH-induced membrane depolarization was reduced in the presence of intracellular BAPTA, also in media containing nominally zero [Ca2+]o, suggesting a critical role for both intracellular Ca2+release and Ca2+influx. TRH-induced inward current was unchanged by T-type Ca2+channel blockade, but was decreased by blockade of high-voltage-activated Ca2+channels (HVACCs). Both the pharmacologically isolated GIRK-like and the TRPC-like components of the TRH-induced response were decreased by nifedipine and increased by BayK8644, implying Ca2+influx via L-type Ca2+channels. Only the TRPC-like conductance was reduced by either thapsigargin or dantrolene, suggesting a role for ryanodine receptors and Ca2+-induced Ca2+release in this component of the TRH-induced response. In pituitary and other cell lines, TRH stimulates MAPK. In PVT neurons, only the GIRK-like component of the TRH-induced current was selectively decreased in the presence of PD98059, a MAPK inhibitor. Collectively, the data imply that TRH-induced depolarization and inward current in PVT neurons involve both a dependency on extracellular Ca2+influx via opening of L-type Ca2+channels, a sensitivity of a TRPC-like component to intracellular Ca2+release via ryanodine channels, and a modulation by MAPK of a GIRK-like conductance component.
Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism
Authors: Lee Hyun-Wook , Osis Gunars , Handlogten Mary E. , Lamers Wouter H. , Chaudhry Farrukh A. , Verlander Jill W. , Weiner I. David
Published: March 2016

Glutamine synthetase (GS) catalyzes the recycling of NH4+with glutamate to form glutamine. GS is highly expressed in the renal proximal tubule (PT), suggesting ammonia recycling via GS could decrease net ammoniagenesis and thereby limit ammonia available for net acid excretion. The purpose of the present study was to determine the role of PT GS in ammonia metabolism under basal conditions and during metabolic acidosis. We generated mice with PT-specific GS deletion (PT-GS-KO) using Cre-loxP techniques. Under basal conditions, PT-GS-KO increased urinary ammonia excretion significantly. Increased ammonia excretion occurred despite decreased expression of key proteins involved in renal ammonia generation. After the induction of metabolic acidosis, the ability to increase ammonia excretion was impaired significantly by PT-GS-KO. The blunted increase in ammonia excretion occurred despite greater expression of multiple components of ammonia generation, including SN1 (Slc38a3), phosphate-dependent glutaminase, phospho enolpyruvate carboxykinase, and Na+-coupled electrogenic bicarbonate cotransporter. We conclude that 1) GS-mediated ammonia recycling in the PT contributes to both basal and acidosis-stimulated ammonia metabolism and 2) adaptive changes in other proteins involved in ammonia metabolism occur in response to PT-GS-KO and cause an underestimation of the role of PT GS expression.
Hemodynamic Characterization of Arterialized and Nonarterialized Liver Transplants in the Rat
Authors: Wong John , Zhang Yikun , Lee Samuel S
Published: March 2016

Persistent hyperkinetic circulation after liver transplantation has been described in humans, but similar changes have not been well characterized in the rat model. This study aimed to investigate the hemodynamics of the systemic and splanchnic circulations in both arterialized and nonarterialized hepatic allografts. Orthotopic liver transplantation was performed in four groups of Sprague-Dawley rats. Group A comprised sham-operated rats with hepatic artery ligation that did not receive transplants; group B comprised rats that received transplants without arterialization; group C comprised sham-operated rats with intact hepatic artery that did not receive transplants; and group D comprised rats that received transplants with arterialization. Blood flow measurements were performed three weeks after the surgical procedure, using the radioactive microsphere method. The results showed that rats that received transplants exhibited a significantly higher cardiac index and lower systemic vascular resistance than the control rats. Splanchnic hyperemia was also present with increased mesenteric blood flow. However, there was no difference in hemodynamics between rats that received arterialized transplants and those that received nonarterialized transplants. Arterial collateral vessels from adjacent tissues were observed in the nonarterialized grafts; this was confirmed histologically. It is concluded that rats that undergo orthotopic liver transplantation exhibit hyperdynamic circulation, regardless of the arterial reconstruction procedure, possibly due to extensive collateral formation in the hepatosplanchnic circulation.
Colorectal Cancer Screening: Video-Reviewed Flexible Sigmoidoscopy by Nurse Endoscopists — A Canadian Community-Based Perspective
Authors: Shapero TF , Alexander PE , Hoover J , Burgis E , Schabas R
Published: March 2016

BACKGROUND: Colorectal cancer (CRC) is the third most common incident cancer and the second most fatal cancer in Canada. Flexible sigmoidoscopy (FS) is one of the modalities under consideration for CRC screening. The present series reports on a screening program of FS performed by nonphysician endoscopists in a Canadian community setting, with video review of procedures by physicians and recommendation of follow-up colonoscopy where polyps are identified.

RESULTS: Five hundred twenty-five, average-risk, asymptomatic patients were examined. After exclusion of inappropriate referrals, 488 remained for analysis. The duration and extent of examination were comparable with those of previous studies elsewhere. Compliance with suggested follow-up was 97.3%. Polyps were identified at FS in 15.4% of examinees. In 8.2% of patients, the polyps were neoplastic at subsequent histology. Four malignant lesions were detected, all at an early stage. There were no complications of FS.

INTERPRETATION: This report shows that FS can be carried out safely and effectively by nonphysician personnel in a community setting in Canada. The manpower cost for nonphysician operators is considerably less than that for specialist physician endoscopists. This approach deserves consideration in cost effectiveness analyses of CRC screening.
Cecal Carcinoma: Initially Diagnosed as Crohn's Disease on Small Bowel Follow-Through
Authors: Taves Donald H , Probyn Linda
Published: March 2016

Lesions in the terminal ileum are often difficult to visualize on routine small bowel follow-through (SBFT) and may require further investigation to rule out associated abnormalities in the ileocecal valve or cecum. This may be done by peroral pneumocolon at the same sitting as the SBFT, but may require bowel preparation. Two cases of cecal carcinoma that were initially diagnosed as Crohn's disease on SBFT without further investigation of the cecum are reported.
Update on the Role ofH pyloriInfection in Gastrointestinal Disorders
Authors: Chaun Hugh
Published: March 2016

Infection withHelicobacter pyloriis accepted as the primary cause of peptic ulcer disease, and there is evidence to suggest its role in other gastrointestinal disorders. An estimated 20% to 40% of the Canadian population is infected withH pylori; however, clinically relevant disease is present in only approximately 10% to 20% of these individuals. Therefore, it is crucial to identify the diseases for which eradication ofH pyloriis beneficial to ensure that patients do not receive unnecessary treatment. In patients with ulcers induced by long term treatment with nonsteroidal anti-inflammatory drugs, preliminary results suggest that eradication ofH pylorimay reduce the risk of peptic ulcer bleeding. Furthermore, a benefit has been observed for the eradication ofH pyloribefore patients commence therapy with a nonsteroidal anti-inflammatory drug. An association between the presence ofH pyloriand specific dyspeptic symptoms has yet to be established; however, there may be a subset of patients with functional dyspepsia who benefit from the eradication ofH pylori. The relationship between gastroesophageal reflux disorder andH pyloriinfection remains unclear. In Canada, the recommended therapy for the eradication ofH pyloriis seven days of twice-daily treatment with a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. Although the proton pump inhibitors are treated as a class for use in these regimens, there is suggestion that a faster onset of action may lead to a higher rate of eradication.
Osteonecrosis in a Patient with Crohn's Disease Unrelated to Corticosteroid Use
Authors: Khan Ali , Illiffe Gerald , Houston Donald S , Bernstein Charles N
Published: March 2016

Osteonecrosis is a feared complication of corticosteroid use. However, a direct association between corticosteroid use and osteonecrosis has never been proven. The present report examines the case of a patient with longstanding Crohn's disease who had never been treated with corticosteroids and who developed osteonecrosis of the talus. The association of systemic inflammatory disorders with osteonecrosis and the possible association with vascular thrombosis are discussed.
Studies on the Interleukin‐10 Gene in Animal Models of Colitis
Authors: Freeman Hugh J
Published: March 2016

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin‐10 (IL‐10) has both immunomodulatory and anti‐inflammatory properties. IL‐10‐deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor‐alpha. In patients with inflammatory bowel disease, impaired IL‐10 production by lamina propria T cells occurs and human recombinant IL‐10 improves clinical parameters in inflammatory bowel disease (eg, Crohn′s disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL‐10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL‐10. Interestingly, in IL‐10 gene‐deficient mice raised in germ‐free conditions, the intestinal inflammatory changes normally observed in conventional nongerm‐free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.
Normal Parathyroid Function with Decreased Bone Mineral Density in Treated Celiac Disease
Authors: Lemieux Bernard , Boivin Michel , Brossard Jean-Hugues , Lepage Raymond , Picard Daniel , Rousseau Louise , D’Amour Pierre
Published: March 2016

Decreased bone mineral density (BMD) has been reported in patients with celiac disease in association with secondary hyperparathyroidism. The present study investigated whether basal parathyroid hormone (PTH) remained elevated and whether abnormalities of parathyroid function were still present in celiac disease patients treated with a gluten-free diet. Basal seric measurements of calcium and phosphate homeostasis and BMD were obtained in 17 biopsy-proven patients under treatment for a mean period of 5.7±3.7 years (range 1.1 to 15.9). In addition, parathyroid function was studied with calcium chloride and sodium citrate infusions in seven patients. Basal measurements of patients were compared with those of 26 normal individuals, while parathyroid function results were compared with those of seven sex- and age-matched controls. Basal results were similar in patients and controls except for intact PTH (I-PTH) (3.77±0.88 pmol/L versus 2.28±0.63 pmol/L, P<0.001), which was higher in the former group but still within normal limits. Mean 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D values were normal in patients. Parathyroid function results were also found to be similar in both groups. Compared with a reference population of the same age (Z score), patients had significantly lower BMDs of the hip (-0.60±0.96 SDs, P<0.05) and lumbar spine (-0.76±1.15 SDs, P<0.05). T scores were also decreased for the hip (-1.3±0.9 SDs, P<0.0001) and lumbar spine (-1.4±1.35 SDs, P<0.0001), with two to three patients being osteoporotic (T score less than -2.5 SDs) and seven to eight osteopenic (T score less than -1 SDs but greater than or equal to -2.5 SDs) in at least one site. Height and weight were the only important determinants of BMD values by multivariate or logistical regression analysis in these patients. The results show higher basal I-PTH values with normal parathyroid function in treated celiac disease. Height and weight values are, but I-PTH values are not, an important determinant of the actual bone mass of patients. Normal parathyroid function in treated patients suggests a lack of previous severe secondary hyperparathyroidism and/or complete adaptation to prior changes in parathyroid function.
Familial Occurrence of Lymphocytic Colitis
Authors: Freeman Hugh J
Published: March 2016

The familial occurrence of lymphocytic colitis in a female parent and her two female children is reported. No other genetically based disorder, including celiac disease, was evident. For both children, the age of diagnosis was more than two decades younger than the age of recognition of disease in the parent, and some clinical features, including the requirement for pharmacological agents in both children, suggested that their disease severity was more significant than that of the involved parent. These characteristics of a familial disease have been previously reported and labelled 'genetic anticipation' in some monogenetic forms of neurological disease, as well as in other types of inflammatory bowel diseases, including Crohn's disease. Alternatively, a common cohort effect related to a pathological environmental factor may have played a role in the pathogenesis of this disorder.
Anticipation in an Indo-Canadian Family with Crohn's Disease
Authors: Freeman Hugh J , Hershfield Noel B
Published: March 2016

Genetic anticipation, associated elsewhere with monogenic neurological disorders, has been hypothesized to be present in familial forms of Crohn's disease. Usually, with studies of parent-child pairs, the parent who is initially diagnosed is older at the onset of disease than the child. With each successive generation, an apparent increase in disease severity or behaviour occurs. This phenomenon is believed to have a molecular basis. In the present report, an Indo-Canadian family with Crohn's disease is described. In all members of the family, disease was diagnosed only after prolonged residence in Canada, supporting the view that Crohn's disease arises in individuals with a genetic predisposition following exposure to some, as yet unknown, common environmental factor. Three siblings with Crohn's disease, first diagnosed between ages 15 and 27 years, or six to 11 years after arrival in Canada, had phenotypically concordant disease localized in the ileum and colon, with fistulizing complications, including perianal sepsis. Crohn's disease was only diagnosed in the father at the age of 76 years, almost three decades after his arrival in Canada. His disease was localized to the ileum and had a fibrostenosing behaviour. This is the first reported instance of familial Crohn's disease in an immigrant population, illustrating potential biases in genetically based studies of Crohn's disease that rely solely on phenotypic expression.
Musculoskeletal Manifestations in Inflammatory Bowel Disease
Authors: Fornaciari Giovanni , Salvarani Carlo , Beltrami Marina , Macchioni PierLuigi , Stockbrügger Reinhold W , Russel Maurice G
Published: March 2016

Muscoloskeletal manifestations are the most common extraintestinal complications of inflammatory bowel disease. Wide ranges in prevalence have been reported, depending on the criteria used to define spondylarthropathy. In 1991, the European Spondylarthropathy Study Group developed classification criteria that included previously neglected cases of undifferentiated spondylarthropathies, which had been ignored in most of the oldest epidemiological studies on inflammatory bowel disease. The spectrum of muscoloskeletal manifestations in inflammatory bowel disease patients includes all of the clinical features of spondylarthropathies: peripheral arthritis, inflammatory spinal pain, dactylitis, enthesitis (Achilles tendinitis and plantar fasciitis), buttock pain and anterior chest wall pain. Radiological evidence of sacroiliitis is common but not obligatory. The articular manifestations begin either concomitantly or subsequent to the bowel disease; however, the onset of spinal disease often precedes the diagnosis of inflammatory bowel disease. The prevalence of the different muscoloskeletal manifestations is similar in ulcerative colitis and Crohn's disease. Symptoms usually disappear after proctocolectomy. The pathogenetic mechanisms that produce the muscoloskeletal manifestations in inflammatory bowel disease are unclear. Several arguments favour an important role of the intestinal mucosa in the development of spondylarthropathy. The natural history is characterized by periods of flares and remission; therefore, the efficacy of treatment is difficult to establish. Most patients respond to rest, physical therapy and nonsteroidal anti-inflammatory drugs, but these drugs may activate bowel disease. Sulphasalazine may be recommended in some patients. There is no indication for the systemic use of steroids.
NSAID-Induced Small Bowel Diaphragms and Strictures Diagnosed with Intraoperative Enteroscopy
Authors: Shumaker Douglas A , Bladen Kari , Katon Ronald M
Published: March 2016

Nonsteroidal anti-inflammatory drugs are known to cause mucosal damage in the stomach and duodenum, which may lead to hemorrhage and perforation. However, these medications may also cause damage in the more distal small bowel. Due to the location of these lesions, currently available diagnostic testing may yield false negative results. Two cases of nonsteroidal anti-inflammatory drug-induced small bowel diaphragms presenting as obscure gastrointestinal hemorrhage and recurrent small bowel obstruction, respectively, are discussed. Intraoperative enteroscopy was used to confirm this diagnosis after other diagnostic tests failed to identify the etiology. This procedure may increase the accuracy of exploratory laparotomy in these challenging cases.
A Case of Chronic Pancreatic Insufficiency Due to Valproic Acid in a Child
Authors: Cooper Mary Anne , Groll Aubrey
Published: March 2016

A 14-year-old child treated with valproic acid over several years for a seizure disorder developed abdominal pain with radiological evidence of acute pancreatitis. The association with valproic acid was not recognized, and the child continued to take the drug. The patient eventually developed steatorrhea and weight loss that improved with pancreatic enzyme replacement. Radiological evaluation showed an atrophic pancreas. Without evidence of other etiological factors, valproic acid by itself appeared to be the cause of chronic pancreatitis with exocrine pancreatic insufficiency in this patient.
Elevated Carbohydrate Antigen 19-9 in Patients with True (Epithelial) Splenic Cysts – Rare or Undiscovered?
Authors: Soudack Michal , Ben-Nun Alon , Toledano Chaim
Published: March 2016

Carbohydrate antigen 19-9 is a well known marker for pancreatic adenocarcinoma. However, its limitation is its nonspecificity, because elevated levels may be encountered in other gastrointestinal disorders, both benign and malignant. The following case is a patient with a true (epithelial) splenic cyst with elevated serum levels of carbohydrate antigen 19-9.