bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double‐headed cathepsin B inhibitor devoid of warhead
Authors: Schenker Patricia , Alfarano Pietro , Kolb Peter , Caflisch Amedeo , Baici Antonio 
Published: September 2008

AbstractMost 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

AbstractStructure 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

AbstractThe 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

AbstractWhile 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

AbstractThe 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

SummaryBackground 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

SummaryBackground  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

SummaryBackground  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

SummaryBackground  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

SummaryBackground  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

SummaryBackground  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

SummaryBackground  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

SummaryBackground  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

SummaryBackground  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.