bluuebunny/crossref_metadata_2025 huggingface dataset:
LZF1/SALT TOLERANCE HOMOLOG3, anArabidopsisB-Box Protein Involved in Light-Dependent Development and Gene Expression, Undergoes COP1-Mediated Ubiquitination
Authors: Datta Sourav , Johansson Henrik , Hettiarachchi Chamari , Irigoyen María Luisa , Desai Mintu , Rubio Vicente , Holm Magnus
Published: September 2008

B-box containing proteins play an important role in light signaling in plants. Here, we identify LIGHT-REGULATED ZINC FINGER1/SALT TOLERANCE HOMOLOG3 (STH3), a B-box encoding gene that genetically interacts with two key regulators of light signaling, ELONGATED HYPOCOTYL5 (HY5) and CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1). STH3 physically interacts with HY5 in vivo and shows a COP1-dependent localization to nuclear speckles when coexpressed with COP1 in plant cells. A T-DNA insertion mutant, sth3, is hyposensitive to high fluence blue, red, and far-red light and has elongated hypocotyls under short days. Analyses of double mutants between sth3, sth2, and hy5 suggest that they have partially overlapping functions. Interestingly, functional assays in protoplasts suggest that STH3 can activate transcription both independently and together with STH2 through the G-box promoter element. Furthermore, sth3 suppresses the cop1 hypocotyl phenotype in the dark as well as the anthocyanin accumulation in the light. Finally, COP1 ubiquitinates STH3 in vitro, suggesting that STH3 is regulated by COP1. In conclusion, we have identified STH3 as a positive regulator of photomorphogenesis acting in concert with STH2 and HY5, while also being a target of COP1-mediated ubiquitination.
A double‐headed cathepsin B inhibitor devoid of warhead
Authors: Schenker Patricia , Alfarano Pietro , Kolb Peter , Caflisch Amedeo , Baici Antonio
Published: September 2008

Most synthetic inhibitors of peptidases have been targeted to the active site for inhibiting catalysis through reversible competition with the substrate or by covalent modification of catalytic groups. Cathepsin B is unique among the cysteine peptidase for the presence of a flexible segment, known as the occluding loop, which can block the primed subsites of the substrate binding cleft. With the occluding loop in the open conformation cathepsin B acts as an endopeptidase, and it acts as an exopeptidase when the loop is closed. We have targeted the occluding loop of human cathepsin B at its surface, outside the catalytic center, using a high‐throughput docking procedure. The aim was to identify inhibitors that would interact with the occluding loop thereby modulating enzyme activity without the help of chemical warheads against catalytic residues. From a large library of compounds, the in silico approach identified [2‐[2‐(2,4‐dioxo‐1,3‐thiazolidin‐3‐yl)ethylamino]‐2‐oxoethyl] 2‐(furan‐2‐carbonylamino) acetate, which fulfills the working hypothesis. This molecule possesses two distinct binding moieties and behaves as a reversible, double‐headed competitive inhibitor of cathepsin B by excluding synthetic and protein substrates from the active center. The kinetic mechanism of inhibition suggests that the occluding loop is stabilized in its closed conformation, mainly by hydrogen bonds with the inhibitor, thus decreasing endoproteolytic activity of the enzyme. Furthermore, the dioxothiazolidine head of the compound sterically hinders binding of the C‐terminal residue of substrates resulting in inhibition of the exopeptidase activity of cathepsin B in a physiopathologically relevant pH range.
Dynameomics: Large‐scale assessment of native protein flexibility
Authors: Benson Noah C. , Daggett Valerie
Published: September 2008

Structure is only the first step in understanding the interactions and functions of proteins. In this paper, we explore the flexibility of proteins across a broad database of over 250 solvated protein molecular dynamics simulations in water for an aggregate simulation time of ∼6 μs. These simulations are from our Dynameomics project, and these proteins represent approximately 75% of all known protein structures. We employ principal component analysis of the atomic coordinates over time to determine the primary axis and magnitude of the flexibility of each atom in a simulation. This technique gives us both a database of flexibility for many protein fold families and a compact visual representation of a particular protein's native‐state conformational space, neither of which are available using experimental methods alone. These tools allow us to better understand the nature of protein motion and to describe its relationship to other structural and dynamical characteristics. In addition to reporting general properties of protein flexibility and detailing many dynamic motifs, we characterize the relationship between protein native‐state flexibility and early events in thermal unfolding and show that flexibility predicts how a protein will begin to unfold. We provide evidence that fold families have conserved flexibility patterns, and family members who deviate from the conserved patterns have very low sequence identity. Finally, we examine novel aspects of highly inflexible loops that are as important to structural integrity as conventional secondary structure. These loops, which are difficult if not impossible to locate without dynamic data, may constitute new structural motifs.
Mammal community structure in relation to disturbance and resource gradients in southern Africa
Authors: Wallgren Märtha , Skarpe Christina , Bergström Roger , Danell Kjell , Granlund Lilian , Bergström Andreas
Published: September 2008

The arrangements of mammals differ along environmental gradients, such as of disturbance and resources. We examined how mammal community composition in the Kalahari, Botswana, varied in relation to disturbance and resource gradients. We predicted that livestock‐keeping villages are disturbances and pans are resources for wildlife, that the responses of mammals to disturbance and resources depend on their functional types and that increased disturbance over time has reduced the numbers and distributions of wildlife. The methods involved road‐side counts of mammals >0.2 kg and trapping of small mammals, <0.2 kg. The disturbance gradient was more important than the resource gradient for explaining the distribution of mammals >0.2 kg. Communities in low disturbance‐high resource areas were most diverse regarding species and functional types. Small mammal species richness and abundances were unaffected by villages, but increased with distance from pans. Villages were particularly deterring to large wild herbivores, functionally similar to livestock. Most large wild herbivores had decreased since 1975–1983. We conclude that large and medium‐sized mammals are highly affected by large‐scale disturbance gradients, while small mammals are most dependent on small‐scale variation in resources, probably shelter and food. Increased disturbance over time leads to decreasing ranges and numbers of the large wild herbivores.
Factors associated with suni distribution in Tembe Elephant Park, South Africa: implications for management and conservation of a small antelope
Authors: Belton Lydia E. , Dalerum Fredrik , Van Rensburg Berndt J.
Published: September 2008

While small antelopes are becoming increasingly threatened, knowledge of their biology is often limited. Management recommendations are therefore frequently based on insufficient information. One of the declining small antelopes is the suni in South Africa. A reduction in sand forests as well as habitat destruction by increased nyala populations are the suggested causes of suni declines. However, no recent study has quantified the factors that underlie suni distribution in southern Africa. Here we investigate whether the vegetation types, vegetation structures or occurrences of sympatric browsers affect suni distribution within Tembe Elephant Park, South Africa. We found that vegetation type and vegetation structure interacted in their effects on suni distribution, but there were no effects of sympatric browsers. Suni were found most often in the sand forests, but were also present in closed woodland. Vegetation structure was, however, related to the local distribution of suni only in sand forest. This highlights that suni are not exclusively bound to sand forest, and also that the vegetation structure within the sand forest may be as important as the vegetation type. We suggest that the current conservation assessment of this subspecies is based on insufficient data, and that a more detailed assessment of their distribution and the factors that determine the same is critically needed.
Counting elephants in Montane forests: some sources of error
Authors: Vanleeuwe Hilde
Published: September 2008

The dung count method is widely used to estimate elephant numbers in forests. It was developed in the lowland forests of Central Africa but it is also used in Montane forests in eastern Africa. Using data collected on Mount Kenya and computer simulations, this paper explores the following issues associated with dung surveys in Montane forests:

High rainfall at 3000 m altitude on Mount Kenya was expected to accelerate dung pile decay but no significant difference was found between 3000 and 2500 m where less rain falls, possibly because high rainfall at 3000 m is counteracted by lower temperatures;

Physical obstacles make it difficult to walk long, straight transects in Montane forests. Deviating from a straight line pushes the distribution of distance measurements from dung piles to the transect centre line (pdist) towards a negative exponential (NE), which complicates data analysis and may give inaccurate estimates. Using short transects largely alleviate this problem;

Analysis of dung count simulations shows that the expected sightability curve of pdist pushes towards a NE with increasing numbers of obstacles blocking the view, even along perfectly straight transects;

Extrapolating measured dung density to map area on Mount Kenya resulted in an underestimate of c. 13%. An unstratified correction of map area to ground area for Montane areas would be biased because of the strong tendency for elephants to avoid steeply sloping areas.
Clinical trial: a multicentre, randomized, double‐blind, placebo‐controlled, dose‐finding, phase II study of subcutaneous interferon‐β‐1a in moderately active ulcerative colitis
Authors: PENA‐ROSSI C. , SCHREIBER S. , GOLUBOVIC G. , MERTZ‐NIELSEN A. , PANES J. , RACHMILEWITZ D. , SHIEH M. J. , SIMANENKOV V. I. , STANTON D. , GRAFFNER H.
Published: September 2008

Background Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro‐ and anti‐inflammatory cytokines. Interferon (IFN)‐β‐1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment.

Aim To extend pilot data and identify a suitable dose of IFN‐β‐1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety.

Methods In this multicentre, double‐blind, placebo‐controlled trial, adults with moderately active UC were randomized to IFN‐β‐1a 44 or 66 μg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4‐week follow‐up.

Results Endoscopically‐confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8–35.7] of placebo patients, 29.2% (95% CI: 18.6–41.8) of the IFN‐β‐1a 44 μg group and 20.0% (95% CI: 11.1–31.8) of the 66 μg group (P = 0.45). Improvements with IFN‐β‐1a 44 μg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment.

Conclusions Interferon‐β‐1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.
Efficacy and safety of antiviral therapy in patients with Crohn's disease and chronic hepatitis C
Authors: SCHERZER T.‐M. , STAUFER K. , NOVACEK G. , STEINDL‐MUNDA P. , SCHUMACHER S. , HOFER H. , FERENCI P. , VOGELSANG H.
Published: September 2008

Background  Efficacy and safety of antiviral combination therapy in patients with Crohn's disease (CD) and chronic hepatitis C (CHC) is presently not established and consequently CHC is rarely treated in CD patients.

Aim  To analyse the efficacy and tolerability of antiviral interferon/ribavirin therapy in patients with CHC and CD.

Methods  Eleven HCV‐infected CD patients received either 3 × 1.5 μg/kg/week interferon‐α‐2b or 180 μg/week peginterferon‐α‐2a (PEGASYS; Roche, Basel, Switzerland) as monotherapy (n = 1) or in combination with 800–1200 mg/day ribavirin (COPEGUS; Roche) (n = 10) for 24–54 weeks according to HCV‐genotype and initial response respectively. Eight patients were under CD‐specific therapy.

Results  Five (46%) patients (HCV‐1: n = 3; HCV‐2: n = 0; HCV‐3: n = 1; unknown: n = 1) achieved a sustained virological response, three (27%) patients relapsed, three (27%) were nonresponders (all GT 1b). At baseline, the Harvey–Bradshaw Index was 0 (0–8) [median (range)], increased on antiviral therapy to 4 (1–15) (P = 0.005) and decreased to baseline level 0 (0–6) after 6‐month follow‐up.

Conclusions  This preliminary experience demonstrates that treatment of CHC in patients with CD is comparable to the treatment of CHC in those without CD. However, gastrointestinal symptoms may be temporarily exacerbated and haemopoietic growth factors may be required.
Proton pump inhibitors reduce the long‐term risk of recurrent upper gastrointestinal bleeding: an observational study
Authors: MASSÓ GONZÁLEZ E. L. , GARCÍA RODRÍGUEZ L. A.
Published: September 2008

Background  Between 3% and 40% of patients surviving an episode of upper gastrointestinal bleeding (UGIB) experience a recurrence within 1 year.

Aim  To characterize further the recurrence rate of UGIB and to investigate the role of long‐term acid suppressive therapy in its secondary prevention.

Methods  Recurrent cases of UGIB were identified among patients registered in The Health Improvement Network in the UK. A nested case–control analysis provided relative risk (RR) estimates of factors associated with recurrence.

Results  Of 1287 patients included, 67 (5.2%) were identified with a recurrent UGIB episode, corresponding to a recurrence rate of 17.5 per 1000 person‐years during a mean follow‐up of 3 years. The greatest risk of recurrence was in patients prescribed the oral anticoagulant warfarin (RR: 5.38; 95% confidence interval: 2.02–14.36). Use of a single proton pump inhibitor (PPIs) was associated with a reduced risk of recurrence (RR: 0.51; 95% confidence interval: 0.26–0.99), even in patients taking warfarin, while current use of H2‐receptor antagonists was not. After the first episode of UGIB, use of nonsteroidal anti‐inflammatory drugs and aspirin was greatly reduced, preventing estimation of the risk associated with these drugs.

Conclusion  Long‐term PPI therapy reduces the risk of UGIB recurrence.
Clinical trial: randomized, double‐blind, placebo‐controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4
Authors: ROSSIGNOL J. F. , KABIL S. M. , EL‐GOHARY Y. , ELFERT A. , KEEFFE E. B.
Published: September 2008

Background  Nitazoxanide, licensed in the US for treatment of Cryptosporidium parvum and Giardia lamblia, inhibits hepatitis C virus replication in replicon systems.

Aim  To evaluate the safety and efficacy of nitazoxanide monotherapy for the treatment of chronic hepatitis C.

Methods  This multicentre, randomized, double‐blind, placebo‐controlled study randomized 50 adult patients with chronic hepatitis C genotype 4 at three centres in Egypt to nitazoxanide 500 mg tablet or placebo twice daily for 24 weeks. Patients were followed up every 4 weeks during treatment and for 24 weeks after therapy.

Results  Seven of 23 patients (30.4%) in the nitazoxanide group achieved undetectable serum HCV RNA compared to 0 of 24 in the placebo group during therapy (P = 0.004). Each of the seven responders had baseline HCV RNA levels ≤400 000 IU/mL. Six of the seven virological responders were followed up for 24 weeks after the end of treatment, and four patients (17.4% of 23 treated) had a sustained virological response. Adverse events were similar in the nitazoxanide and placebo groups.

Conclusion  Nitazoxanide monotherapy is safe and effective in achieving sustained virological response in a modest number of patients with chronic hepatitis C genotype 4, particularly in patients with low baseline serum HCV RNA levels.
Long‐term outcome of using allopurinol co‐therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease
Authors: ANSARI A. , ELLIOTT T. , BABURAJAN B. , MAYHEAD P. , O’DONOHUE J. , CHOCAIR P. , SANDERSON J. , DULEY J.
Published: September 2008

Background  Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid ‘triple therapy’ improved renal graft survival.

Aim  To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study.

Methods  Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co‐therapy with low‐dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co‐therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests.

Results  Of 11 patients (three Crohn’s disease, eight ulcerative colitis) treated, nine (82%) remain in long‐term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu‐like symptoms. Two stopped: one nausea, one abnormal liver function (steatosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions.

Conclusions  Allopurinol co‐therapy with low‐dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long‐term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses.
Clinical trial: protective effect of a commercial fish protein hydrolysate against indomethacin (NSAID)‐induced small intestinal injury
Authors: MARCHBANK T. , LIMDI J. K. , MAHMOOD A. , ELIA G. , PLAYFORD R. J.
Published: September 2008

Background  A partially hydrolysed and dried product of pacific whiting fish is marketed as a health food supplement supporting ‘intestinal health’.

Aim  To examine whether the partially hydrolysed and dried product of pacific whiting fish influenced the small intestinal damaging side effects of the nonsteroidal anti‐inflammatory drug, indomethacin.

Methods  Eight human volunteers completed a double‐blind, placebo‐controlled, crossover protocol of clinically relevant dose of indomethacin (50 mg t.d.s. p.o. for 5 days) with 7 days of fish hydrolysate or placebo starting 2 days prior to indomethacin. Changes in gut permeability were assessed using 5 h urinary lactulose:rhamnose (L/R) ratios.

Results  Fish hydrolysate given alone did not affect permeability. In the main study (n = 8), baseline values were similar for both arms (0.28 ± 0.05 and 0.35 ± 0.07). Administration of indomethacin (+placebo) caused a fivefold rise in L/R ratios (increasing to 1.54 ± 0.35), whereas L/R ratios in the same subjects ingesting indomethacin + fish hydrolysate was only 0.59 ± 0.14 (P < 0.01 vs. indomethacin alone). Dyspeptic symptoms occurred in four of eight subjects taking indomethacin alone, but zero of eight when hydrolysate was co‐administered.

Conclusion  Natural bioactive products (nutriceuticals), such as fish hydrolysates, may provide a novel approach to the prevention and treatment of NSAID‐induced and other gastrointestinal injurious conditions.
Meta‐analysis: Helicobacter pylori‘test and treat’ compared with empirical acid suppression for managing dyspepsia
Authors: FORD A. C. , MOAYYEDI P. , JARBOL D. E. , LOGAN R. F. A. , DELANEY B. C.
Published: September 2008

Background  Which of Helicobacter pylori‘test and treat’ or empirical acid suppression should be preferred for the initial management of uncomplicated dyspepsia is controversial.

Aim  To conduct an individual patient data meta‐analysis of randomized controlled trials (RCTs) of ‘test and treat’ vs. empirical acid suppression in adults with uncomplicated dyspepsia in primary care.

Methods  Investigators provided original data sets for analysis. Effect of management strategy on symptom status and dyspepsia‐related resource use at 12‐month follow‐up was examined by pooling symptom and cost data to obtain relative risk (RR) of remaining symptomatic at 12 months and weighted mean difference (WMD) in costs between the two strategies with 95% confidence intervals (CI).

Results  We identified three eligible RCTs containing 1547 patients, 791 (51%) of whom were assigned to ‘test and treat’. There was no difference detected in symptom‐cure at 12 months (RR = 0.99; 95% CI: 0.95–1.03). There was a nonsignificant trend towards cost‐savings with ‘test and treat’ (WMD in costs = −£28.91; 95% CI: −£68.48 to £10.65).

Conclusions  There was little difference in symptom‐resolution or costs between the two strategies. A combination of patient and physician preference should determine the initial approach to the management of uncomplicated dyspepsia.
Meta‐analysis: zinc supplementation for acute gastroenteritis in children
Authors: PATRO B. , GOLICKI D. , SZAJEWSKA H.
Published: September 2008

Background  Uncertainty exists regarding the use of zinc in the treatment of acute gastroenteritis in children living in Europe, where zinc deficiency is rare.

Aim  To review evidence for the effectiveness of zinc in treating acute gastroenteritis in children, with special emphasis on data from developed countries.

Methods  MEDLINE, EMBASE, and the Cochrane Library were searched through November 2007 for randomized controlled trials (RCTs) relevant to acute gastroenteritis in children younger than 5 years of age and zinc; additional references were obtained from the reviewed articles.

Results  Eighteen RCTs (11 180 participants, mainly from developing countries) met the inclusion criteria. Use of zinc was associated with a significant reduction in diarrhoea duration (13 RCTs, 5643 infants, weighted mean difference −0.69 day, 95% CI −0.97 to −0.40) and the risk of diarrhoea lasting longer than 7 days [eight RCTs, n = 5769, relative risk (RR) 0.71, 95% CI 0.53–0.96]. No significant reduction in stool volume was observed for those receiving zinc compared with placebo (three RCTs, n = 606, standardized mean difference, −0.38, 95% CI −1.04 to 0.27). Combined data from five RCTs (n = 3156) showed that zinc significantly increased the chance of vomiting compared to the control agent (RR 1.2, 95% CI 1.05–1.4).

Conclusions  These data confirm that zinc supplementation can be useful for treating acute gastroenteritis in children, particularly those from developing countries. However, the role of zinc supplements in treating children with acute gastroenteritis in developed countries needs further evaluation.
Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease
Authors: ANSARI A. , ARENAS M. , GREENFIELD S. M. , MORRIS D. , LINDSAY J. , GILSHENAN K. , SMITH M. , LEWIS C. , MARINAKI A. , DULEY J. , SANDERSON J.
Published: September 2008

Background  One‐third of patients with inflammatory bowel disease (IBD) receiving azathioprine (AZA) withdraw treatment due to side effects or lack of clinical response.

Aim  To investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.

Methods  Patients with IBD were given 2 mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6 months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.

Results  Two hundred and seven patients were analysed. Thirty‐nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild‐type TPMT, P < 0.001). The ITPA 94C>A mutation was associated with withdrawal due to flu‐like symptoms (P = 0.014). A baseline TPMT activity below 35 pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35 pmol/h/mg/Hb (81% vs. 43% respectively, P < 0.001). Patients achieving a mean TGN level above 100 were significantly more likely to respond (P = 0.0017).

Conclusions  TPMT testing predicts adverse effects and reduced chance of clinical response (TPMT >35 pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response.
A comparative study of standard vs. high definition colonoscopy for adenoma and hyperplastic polyp detection with optimized withdrawal technique
Authors: EAST J. E. , STAVRINDIS M. , THOMAS‐GIBSON S. , GUENTHER T. , TEKKIS P. P. , SAUNDERS B. P.
Published: September 2008

Background  Colonoscopy has a known miss rate for polyps and adenomas. High definition (HD) colonoscopes may allow detection of subtle mucosal change, potentially aiding detection of adenomas and hyperplastic polyps.

Aim  To compare detection rates between HD and standard definition (SD) colonoscopy.

Methods  Prospective, cohort study with optimized withdrawal technique (withdrawal time >6 min, antispasmodic, position changes, re‐examining flexures and folds). One hundred and thirty patients attending for routine colonoscopy were examined with either SD (n = 72) or HD (n = 58) colonoscopes.

Results  Groups were well matched. Sixty per cent of patients had at least one adenoma detected with SD vs. 71% with HD, P = 0.20, relative risk (benefit) 1.32 (95% CI 0.85–2.04). Eighty‐eight adenomas (mean ± standard deviation 1.2 ± 1.4) were detected using SD vs. 93 (1.6 ± 1.5) with HD, P = 0.12; however more nonflat, diminutive (<6 mm) adenomas were detected with HD, P = 0.03. Twenty‐three proximal hyperplastic polyps (0.32 ± 0.58) were detected with SD vs. 31 (0.53 ± 0.86) with HD, P = 0.35. Overall prevalence of proximal large (>9 mm) hyperplastic polyps was 7% (0.09 ± 0.36).

Conclusions  High definition did not lead to a significant increase in adenoma or hyperplastic polyp detection, but may help where comprehensive lesion detection is paramount. High detection rates appear possible with either SD or HD, when using an optimized withdrawal technique.
Clinical trial: radiofrequency energy delivery in proton pump inhibitor‐dependent gastro‐oesophageal reflux disease patients
Authors: CORON E. , SEBILLE V. , CADIOT G. , ZERBIB F. , DUCROTTE P. , DUCROT F. , POUDEROUX P. , ARTS J. , LE RHUN M. , PICHE T. , BRULEY DES VARANNES S. , GALMICHE J. P. ,   CONSORTIUM DE RECHERCHE INDÉPENDANT SUR LE TRAITEMENT ET L’EXPLORATION DU REFLUX GASTRO‐OESOPHAGIEN ET DE L’ENDOBRACHYOESOPHAGE (CRITERE)
Published: September 2008

Background  Radiofrequency (RF) energy delivery is an endoscopic procedure developed for the treatment of gastro‐oesophageal reflux disease.

Aim  To compare RF and a proton pump inhibitor strategy (PPI) in PPI‐dependent patients by carrying out a prospective, randomized trial.

Methods  Patients with PPI‐dependent typical reflux symptoms were randomly allocated to either RF or PPI regimen alone. The primary endpoint, evaluated at 6‐month, was defined as the possibility for the patient to stop or to decrease PPI use to <50% of the effective dose required at baseline.

Results  In the RF group, 18/20 patients stopped (n = 3) or decreased (n = 15) PPI use as compared to eight of 16 in the PPI group (P = 0.01). None of the control patients could stop PPI. Health‐related quality of life scores were not different between groups. No significant change in oesophageal acid exposure (OAE) was noted between baseline and 6‐months after RF. No severe complication was reported.

Conclusions  Radiofrequency energy delivery is a safe and effective therapeutic option, allowing reduction in or discontinuation of PPI therapy in patients with PPI‐dependent symptoms, without loss of quality of life. However, in a majority of patients, PPI therapy cannot be completely stopped. The efficacy of RF does not seem to be related to a decrease in OAE.
Barriers to physician adherence to nonsteroidal anti‐inflammatory drug guidelines: a qualitative study
Authors: CAVAZOS J. M. , NAIK A. D. , WOOFTER A. , ABRAHAM N. S.
Published: September 2008

Background  Despite wide availability of physician guidelines for safer use of nonsteroidal anti‐inflammatory drugs (NSAIDs) and widespread use of these drugs in the US, NSAID prescribing guidelines have been only modestly effective.

Aim  To identify and describe comprehensively barriers to provider adherence to NSAID prescribing guidelines.

Methods  We conducted interviews with 25 physicians, seeking to identify the major influences explaining physician non‐adherence to guidelines. Interviews were standardized and structured probes were used for clarification and detail. All interviews were audio‐taped and transcribed. Three independent investigators analysed the transcripts, using the constant‐comparative method of qualitative analysis.

Results  Our analysis identified six dominant physician barriers explaining non‐adherence to established NSAID prescribing guidelines. These included (i) lack of familiarity with guidelines, (ii) perceived limited validity of guidelines, (iii) limited applicability of guidelines among specific patients, (iv) clinical inertia, (v) influences of prior anecdotal experiences and (vi) medical heuristics.

Conclusions  A heterogeneous set of influences are barriers to physician adherence to NSAID prescribing guidelines. Suggested measures for improving guideline‐concordant prescribing should focus on measures to improve physician education and confidence in guidelines, implementation of physician/pharmacist co‐management strategies and expansion of guideline scope.
Low‐dose aspirin reduces the gene expression of gastrokine‐1 in the antral mucosa of healthy subjects
Authors: MARTIN G. , WEX T. , TREIBER G. , MALFERTHEINER P. , NARDONE G.
Published: September 2008

Background  Gastrokine 1 (GKN1), one of the most abundant transcripts in normal stomach, is down‐regulated by Helicobacter pylori infection. Aspirin (ASA), which is often used for secondary prevention of cardiovascular events, can damage gastric‐duodenal mucosa within 1 or 2 h of ingestion.

Aim  To study the gastric mucosal expression of GKN1 during acute low‐dose ASA consumption.

Methods  Ten H. pylori‐negative human volunteers took 100 mg ASA per day for 1 week, and underwent multiple upper GI endoscopies. GKN1 expression was analysed in antral and corpus mucosa by quantitative reverse‐transcriptase polymerase chain reaction, western blot and immunohistochemistry (IHC). Gastric mucosal damage was detected endoscopically and histologically.

Results  Gastrokine 1 was similarly expressed in both antral and corpus mucosa. The use of low‐dose ASA led to a significant decrease (3.07 a.u. vs. 0.23 a.u., P < 0.001) in antrum at day 7, while GKN1 transcript levels in corpus mucosa were slightly elevated (twofold, P < 0.005). Western blot and IHC confirmed these changes at the protein level. Furthermore, IHC revealed a vesicular staining pattern in the cytoplasm for GKN1 that was confirmed by transfected human gastric adenocarcinoma cell line expressing GKN1.

Conclusion  Our data demonstrated that low‐dose ASA downregulates GKN1 expression specifically in antral mucosa.
Lower slope morphology of the Sumatra trench system
Authors: Kopp H. , Weinrebe W. , Ladage S. , Barckhausen U. , Klaeschen D. , Flueh E. R. , Gaedicke C. , Djajadihardja Y. , Grevemeyer I. , Krabbenhoeft A. , Papenberg C. , Zillmer M.
Published: September 2008

At convergent margins, the structure of the subducting oceanic plate is one of the key factors controlling the morphology of the upper plate. We use high‐resolution seafloor mapping and multichannel seismic reflection data along the accretionary Sumatra trench system to investigate the morphotectonic response of the upper plate to the subduction of lower plate fabric. Upper plate segmentation is reflected in varying modes of mass transfer. The deformation front in the southern Enggano segment is characterized by neotectonic formation of a broad and shallow fold‐and‐thrust belt consistent with the resumption of frontal sediment accretion in the wake of oceanic relief subduction. Conversely, surface erosion increasingly shapes the morphology of the lower slope and accretionary prism towards the north where significant oceanic relief is subducted. Subduction of the Investigator Fracture Zone and the fossil Wharton spreading centre in the Siberut segment exemplifies this. Such features also correlate with an irregularly trending deformation front suggesting active frontal erosion of the upper plate. Lower plate fabric extensively modulates upper plate morphology and the large‐scale morphotectonic segmentation of the Sumatra trench system is linked to the subduction of reactivated fracture zones and aseismic ridges of the Wharton Basin. In general, increasing intensity of mass‐wasting processes, from south to north, correlates with the extent of oversteepening of the lower slope (lower slope angle of 3.8° in the south compared with 7.6° in the north), probably in response to alternating phases of frontal accretion and sediment underthrusting. Accretionary mechanics thus pose a second‐order factor in shaping upper plate morphology near the trench.
Selective human endothelial cell activation by chemokines as a guide to cell homing
Authors: Crola Da Silva Claire , Lamerant‐Fayel Nathalie , Paprocka Maria , Mitterrand Michèle , Gosset David , Dus Danuta , Kieda Claudine
Published: September 2008

An original model of organo‐specific, immortalized and stabilized endothelial cell lines was used to delineate the part played by some chemokines (CCL21, CX3CL1, CCL5 and CXCL12) and their receptors in endothelium organo‐specificity. Chemokine receptor expression and chemokine presentation were investigated on organo‐specific human endothelial cell lines. Although the chemokines showed distinct binding patterns for the various endothelial cell lines, these were not correlated with the expression of the corresponding receptors (CX3CR1, CXCR4, CCR5 and CCR7). Experiments with CCL21 on peripheral lymph node endothelial cells demonstrated that the chemokine did not co‐localize with its receptor but was associated with extracellular matrix components. The specific activity of chemokines was clearly shown to be related to the endothelial cell origin. Indeed, CX3CL1 and CCL21 promoted lymphocyte recruitment by endothelial cells from the appendix and peripheral lymph nodes, respectively, while CX3CL1 pro‐angiogenic activity was restricted to endothelial cells from the appendix and skin. The high specificity of the chemokine/endothelium interaction allowed the design of a direct in vitro endothelial cell targeting assay. This unique cellular model demonstrated a fundamental role for chemokines in conferring on the endothelium its organo‐specificity and its potential for tissue targeting through the selective binding, presentation and activation properties of chemokines.
Retracted: Desmoglein 3‐specific T regulatory 1 cells consist of two subpopulations with differential expression of the transcription factor Foxp3
Authors: Veldman Christian , Pahl Andreas , Hertl Michael
Published: September 2008

Pemphigus vulgaris (PV) is an autoimmune bullous skin disorder associated with autoantibodies against desmoglein (Dsg) 3. An imbalance of type 1 regulatory T (Tr1) cells and T helper type 2 (Th2) cells specific for Dsg3 may be critical for the loss of tolerance against Dsg3 in PV. Within the population of Dsg3‐responsive, interleukin (IL)‐10‐secreting Tr1 cell clones, two major subpopulations were identified and sorted by fluorescence‐activated cell sorting (FACS) based on their size and granularity. Upon in vitro culture, the larger subpopulation differentiated back into the two former subpopulations of the Tr1 cell clones, while the smaller subpopulation died within 2 weeks. The smaller subpopulation of the Tr1 cell clones was characterized by the expression of Foxp3, the secretion of IL‐10, transforming growth factor (TGF)‐β and IL‐5 upon stimulation with Dsg3, a proliferative response to IL‐2 but not to Dsg3 or mitogenic stimuli, and an inhibitory effect on the proliferative response of Dsg3‐responsive Th clones in a Dsg3‐specific manner. In contrast, the larger subpopulation showed a Th‐like phenotype, lacking Foxp3, cytotoxic T‐lymphocyte antigen 4 (CTLA4) and glucocorticoid‐induced tumour necrosis factor receptor (GITR) expression and IL‐2 secretion, and did not mount a proliferative response to Dsg3 and mitogenic stimuli. The two Tr1 subpopulations showed expression of identical T‐cell receptor (TCR) Vβ chains which varied among the PV patients studied. Upon inhibition of Foxp3, the smaller Tr1 subpopulation developed a proliferate response to Dsg3 and mitogenic stimuli, no longer suppressed Dsg3‐specific Th cells, lost expression of GITR and CTLA4 and secreted IL‐2. Thus, our observations suggest a distinct relationship between Dsg3‐specific Tr1 and Th‐like cells which may be critical for the continuous generation and survival of Dsg3‐specific Tr1 cells.
Role of 2B4‐mediated signals in the pathogenesis of a murine hepatitis model independent of Fas and Vα14 NKT cells
Authors: Furukawa Hiroshi , Kitazawa Hiroshi , Kaneko Izumi , Matsubara Mitsunobu , Nose Masato , Ono Masao
Published: September 2008

Concanavalin A (Con A)‐induced hepatitis is a T‐cell‐mediated murine experimental model of autoimmune hepatitis. Mice lacking Vα14 NKT cells were found to be less sensitive to this hepatitis and the MRL/Mp‐Faslpr/lpr (MRL/lpr; i.e. Fas deficient) mice were also less sensitive. We report herein that MRL/Mp‐Faslpr/lpr‐Saprpl/− (MRL/lpr/rpl) mice lack Vα14 NKT cells and are deficient in the Fas antigen but sensitive to Con A‐induced hepatitis. The signaling lymphocytic activation molecule (SLAM)‐associated protein (SAP) is an adaptor molecule containing a Src homology 2 (SH2) domain. We previously reported new mutant mice found among MRL/lpr mice and revealed that SAP deficiency led to the regression of autoimmune phenotypes in mutant MRL/lpr/rpl mice. It was also revealed that CD4+ and CD8+ T cells were effector cells and that blockade of 2B4, one of the SLAM family receptors, inhibited the induction of hepatitis in MRL/lpr/rpl mice. These data suggest that signals mediated by molecules other than SAP from 2B4 in T cells played important roles in the induction of hepatitis in MRL/lpr/rpl mice.
Altered homeostasis of CD4+ FoxP3+regulatory T‐cell subpopulations in systemic lupus erythematosus
Authors: Suen Jau‐Ling , Li Hsiao‐Ting , Jong Yuh‐Jyh , Chiang Bor‐Luen , Yen Jeng‐Hsien
Published: September 2008

The role of naturally occurring regulatory T cells (Treg), known to be phenotypically heterogeneous, in controlling the expression of systemic lupus erythematosus (SLE) is incompletely defined. Therefore, different subpopulations of CD4+ FoxP3+Tregs in patients with active or inactive SLE were investigated and compared with those of healthy subjects and patients with ankylosing spondylitis (AS). Characterization of different subsets of circulating CD4+ FoxP3+Tregs was examined using flow cytometry. CD4+ CD25highT cells were sorted and examined for suppressive activityin vitro. The results showed first that a significant decrease in the frequency of CD4+ CD25high FoxP3+T cells was present in patients with active SLE (n = 58), compared with healthy controls (n = 36) and AS patients (n = 23). In contrast, the frequencies of CD25low FoxP3+and CD25− FoxP3+ CD4+T cells were significantly increased in patients with active SLE by comparison with the control subjects. The elevation of these two putative Treg subpopulations was associated with lower plasma levels of complement C3 and C4 in patients with SLE. In addition, the ratios of the three subsets of CD4+ FoxP3+Tregs versus effector T cells (CD4+ CD25+ FoxP3−) were inversely correlated with the titer of anti‐double‐stranded DNA IgG in patients with inactive, but not active, SLE. These results suggest that the pathogenesis of SLE may be associated with a defect in the homeostatic control of different Treg subsets.
Interferon‐γ priming is involved in the activation of arginase by oligodeoxinucleotides containing CpG motifs in murine macrophages
Authors: Liscovsky Miriam V. , Ranocchia Romina P. , Gorlino Carolina V. , Alignani Diego O. , Morón Gabriel , Maletto Belkys A. , Pistoresi‐Palencia María C.
Published: September 2008

Recognition of microbial products by macrophages (Mφ) stimulates an inflammatory response and plays a critical role in directing the host immune response against infection. In the present work, we showed for the first time that synthetic oligodeoxynucleotides containing unmethylated cytosine guanine motifs (CpG) are able to stimulate, in the presence of interferon‐γ (IFN‐γ), both arginase and inducible nitric oxide synthase (iNOS) in murine Mφ. Unexpectedly, IFN‐γ, a cytokine believed to be an inhibitor of arginase activity, intervened in the activation of this enzyme. A significant increase in arginase activity was observed upon a short pre‐incubation (1 hr) with IFN‐γ and subsequent CpG stimulation. Therefore, a very interesting observation of this study was that the CpG‐mediated arginase activity is dependent on IFN‐γ priming. The increase in arginase activity as a result of stimulation with CpG plus IFN‐γwas correlated with augmented expression of the arginase II isoform. The use of pharmacological specific inhibitors revealed that arginase activity was dependent on p38 mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated protein kinase (ERK), but independent of c‐Jun N‐terminal kinase (JNK) activation. This report reveals a singular effect of the combination of CpG and IFN‐γ, one of the mayor cytokines produced in response to CpG administration in vivo.
Uptake and presentation of exogenous antigen and presentation of endogenously produced antigen by skin dendritic cells represent equivalent pathways for the priming of cellular immune responses following biolistic DNA immunization
Authors: Sudowe Stephan , Dominitzki Sabine , Montermann Evelyn , Bros Matthias , Grabbe Stephan , Reske‐Kunz Angelika B.
Published: September 2008

Gene gun‐mediated biolistic DNA vaccination with β‐galactosidase (βGal)‐encoding plasmid vectors efficiently modulated antigen‐induced immune responses in an animal model of type I allergy, including the inhibition of immunoglobulin E (IgE) production. Here we show that CD4+ as well as CD8+ T cells from mice biolistically transfected with a plasmid encoding βGal under the control of the fascin promoter (pFascin‐βGal) are capable of inhibiting βGal‐specific IgE production after adoptive transfer into naïve recipients. Moreover, suppression of IgE production was dependent on interferon (IFN)‐γ. To analyse the modalities of activation of CD4+ and CD8+ T cells regarding the localization of antigen synthesis following gene gun‐mediated DNA immunization, we used the fascin promoter and the keratin 5 promoter (pK5‐βGal) to direct βGal production mainly to dendritic cells (DCs) and to keratinocytes, respectively. Gene gun‐mediated DNA immunization with each vector induced considerable activation of βGal‐specific CD8+ cytotoxic T cells. Cytokine production by re‐stimulated CD4+ T cells in draining lymph nodes and immunoglobulin isotype profiles in sera of immunized mice indicated that immunization with pFascin‐βGal induced a T helper type 1 (Th1)‐biased immune response, whereas immunization with pK5‐βGal generated a mixed Th1/Th2 immune response. Nevertheless, DNA vaccination with pFascin‐βGal and pK5‐βGal, respectively, efficiently inhibited specific IgE production in the mouse model of type I allergy. In conclusion, our data show that uptake of exogenous antigen produced by keratinocytes and its presentation by untransfected DCs as well as the presentation of antigen synthesized endogenously in DCs represent equivalent pathways for efficient priming of cellular immune responses.
The effect of light on the composition of some volatile compounds in wine: an HS‐SPME‐GC‐MS study
Authors: Cellamare Luciana , D’Auria Maurizio , Emanuele Lucia , Racioppi Rocco
Published: September 2008

The HS‐SPME‐GC‐MS analysis of Fiano di Avellino (white wine, Southern Italy) and Aglianico del Vulture (red wine, Southern Italy) showed the presence of ethyl acetate, 2‐methyl‐1‐propanol, 2‐methyl‐1‐butanol (MB), 2‐methylbutyl acetate (MBA), ethyl hexanoate (EH), diethyl butanedioate (DB), ethyl octanoate (EO) and ethyl decanoate (ED). UV irradiation of both the wines in a Pyrex vial with a 15‐W low pressure mercury arc showed an extensive degradation of all the compounds. After 24 h irradiation in the red wine, ethyl acetate decreased from 208 mg L−1 to 58 mg L−1, DB from 16.7 to 4 mg L−1, MBA from 19 to 3 mg L−1, 2‐methyl‐1‐propanol disappeared and MB decreased from 796 to 92.5 mg L−1. Only in the case of DB, MBA, EH, EO and ED in the red wine the degradation occurred after an initial increase of the concentrations of the esters. The irradiation of the esters in the presence of riboflavin showed a clear degradation of the esters (9%–17%). The irradiation of both the wines in the original bottles for 7 days showed an extensive degradation of all the volatile compounds observed in the wines. 2‐Methyl‐1‐propanol disappeared while 90% of MB disappeared. The amount of the esters decreases in the range 65%–91%.
A study on the efficacy of body–mind–spirit group therapy for patients with breast cancer
Authors: Liu Chun‐Ju , Hsiung Ping‐Chuan , Chang King‐Jen , Liu Yu‐Fen , Wang Kuo‐Chang , Hsiao Fei‐Hsiu , Ng Siu‐Man , Chan Cecilia LW
Published: September 2008

Aims and objectives.  This study aims to understand the effects of culturally enriched body–mind–spirit group therapy on anxiety, depression and holistic well‐being among women with breast cancer and to examine patients’ views on what aspects of group therapy worked to enhance their health.

Design.  The study was designed using multiple methods, which consisted of a randomised controlled trial and a focus group interview.

Methods.  A total of 16 subjects in the control group received the standard care of a physician’s treatment at the outpatient department. In addition to standard care, 12 subjects in the experimental group received 10 sessions of weekly body–mind–spirit group therapy for 180 minutes each. This therapy integrates concepts and practices of traditional Chinese medicine and Western medicine (e.g. positive psychology and forgiveness therapy). The subjects in the experimental group were invited to participate in a focus group interview regarding their perceptions of the change mechanisms that occurred in group therapy.

Results.  The results of analysis of covariance indicated that after a two‐month trial, there was a similarity between the experimental and control groups in reducing the scores of Beck depression inventory and increasing the scores of body–mind–spirit well‐being. However, subjects in the experimental group had a better reduction of the scores of state anxiety inventory than subjects in the control group. The qualitative analysis yielded eight domains: (i) imparting of information, (ii) interpersonal learning, (iii) catharsis, (iv) universality, (v) group cohesiveness, (vi) altruism, (vii) instillation of hope and (viii) existential factors. These domains illustrate how the therapeutic effects of group therapy worked to reduce patients’ anxiety.

Conclusion.  The culturally sensitive body–mind–spirit group therapy reduced anxiety among outpatients with breast cancer.

Relevance to clinical practice.  The involvement of mental health nurses in providing group therapy for cancer patients could enhance the quality of care in psycho‐ontological nursing.