bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-chain Fv phage display propensity exhibits strong positive correlation with overall expression levels
Authors: Scott Nathan , Reynolds Catherine B , Wright Michael J , Qazi Omar , Fairweather Neil , Deonarain Mahendra P
Published: January 2009

Background

Single chain Fvs (scFvs) are widely applied in research, diagnostics and therapeutic settings. Display and selection from combinatorial libraries is the main route to their discovery and many factors influence the success of this process. They exhibit low thermodynamic stability, resulting in low levels of premature cytosolic folding or aggregation which facilitates sec YEG-mediated translocation and phage in E. coli. However, there is little data analysing how this is related to and influenced by scFv protein expression.

Results

We characterised the relationship between overall scFv expression and display propensity for a panel of 15 anti-tetanus toxin scFvs and found a strong positive correlation (Rho = 0.88, p < 0.005) between the two parameters. Display propensity, overall expression and soluble localisation to the periplasm and extracellular fractions were clone specific characteristics which varied despite high levels of sequence homology. There was no correlation between display of scFv or its expression in non-fused (free) form with soluble scFv localisation to the periplasm or culture supernatant. This suggests that divergence in the fate of scFv-pIII and non-fused scFv after translocation to the periplasm accounts for the observed disparity. Differential degrees of periplasmic aggregation of non-fused scFv between clones may affect the partitioning of scFv in the periplasm and culture supernatant abrogating any correlation. We suggest that these factors do not apply to the scFv-pIII fusion since it remains anchored to the bacterial inner membrane as part of the innate phage packaging and budding process.

Conclusion

We conclude that in the absence of premature cytosolic aggregation or folding, the propensity of a scFv to be displayed on phage is directly related to its overall expression level and is thus indirectly influenced by factors such as codon bias, mRNA abundance or putative DNA motifs affecting expression. This suggests that scFvs capable of high overall expression and display levels may not produce high yields of non phage-fused soluble protein in either the periplasmic or extracellular fractions of E. coli. This should be considered when screening clones selected from combinatorial libraries for further study.

The nucleotide and amino acid sequences of the anti-tetanus toxin scFvs have been deposited in the EMBL data base: accession numbers-C1: AM749134, C2: AM749135, C3: AM749136, C4: AM749137, C5: AM749138, N1: AM749139, N2: AM749140, N3: AM749141, N4: AM749142, N5: AM749143 J1; AM749144, J2: AM749145, J3: AM749146, J4: AM749147, J5: AM749148.
Accuracy of drug advertisements in medical journals under new law regulating the marketing of pharmaceutical products in Switzerland
Authors: Santiago Macarena Gonzalez , Bucher Heiner C , Nordmann Alain J
Published: January 2009

Background

New legal regulations for the marketing of pharmaceutical products were introduced in 2002 in Switzerland. We investigated whether claims in drug advertisements citing published scientific studies were justified by these studies after the introduction of these new regulations.

Methods

In this cross-sectional study, two independent reviewers screened all issues of six major Swiss medical journals published in the year 2005 to identify all drug advertisements for analgesic, gastrointestinal and psychopharmacologic drugs and evaluated all drug advertisements referring to at least one publication. The pharmaceutical claim was rated as being supported, being based on a potentially biased study or not to be supported by the cited study according to pre-specified criteria. We also explored factors likely to be associated with supported advertisement claims.

Results

Of 2068 advertisements 577 (28%) promoted analgesic, psychopharmacologic or gastrointestinal drugs. Among them were 323 (56%) advertisements citing at least one reference. After excluding multiple publications of the same drug advertisement and advertisements with non-informative references, there remained 29 unique advertisements with at least one reference to a scientific study. These 29 advertisements contained 78 distinct pairs of claims of analgesic, gastrointestinal and psychopharmacologic drugs and referenced studies. Thirty-seven (47%) claims were supported, 16 (21%) claims were not supported by the corresponding reference, and 25 (32%) claims were based on potentially biased evidence, with no relevant differences between drug groups. Studies with conflict of interest and studies stating industry funding were more likely to support the corresponding claim (RR 1.52, 95% CI 1.07–2.17 and RR 1.50, 95% CI 0.98–2.28) than studies without identified conflict of interest and studies without information on type of funding.

Conclusion

Following the introduction of new regulations for drug advertisement in Switzerland, 53% of all assessed pharmaceutical claims published in major medical journals are not supported by the cited referenced studies or based on potentially biased study information. In light of the discrepancy between the new legislation and the endorsement of these regulations, physicians should not trust drug advertisement claims even when they seem to refer to scientific studies.
Highly efficient transduction of human plasmacytoid dendritic cells without phenotypic and functional maturation
Authors: Veron Philippe , Boutin Sylvie , Martin Samia , Chaperot Laurence , Plumas Joel , Davoust Jean , Masurier Carole
Published: January 2009

Background

Gene modified dendritic cells (DC) are able to modulate DC functions and induce therapeutic immunity or tolerance in an antigen-specific manner. Among the different DC subsets, plasmacytoid DC (pDC) are well known for their ability to recognize and respond to a variety of viruses by secreting high levels of type I interferon.

Methods

We analyzed here, the transduction efficiency of a pDC cell line, GEN2.2, and of pDC derived from CD34+ progenitors, using lentiviral vectors (LV) pseudotyped with different envelope glycoproteins such as the vesicular stomatitis virus envelope (VSVG), the gibbon ape leukaemia virus envelope (GaLV) or the feline endogenous virus envelope (RD114). At the same time, we evaluated transgene expression (E-GFP reporter gene) under the control of different promoters.

Results

We found that efficient gene transfer into pDC can be achieved with VSVG-pseudotyped lentiviral vectors (LV) under the control of phoshoglycerate kinase (PGK) and elongation factor-1 (EF1α) promoters (28% to 90% of E-GFP+ cells, respectively) in the absence of phenotypic and functional maturation. Surprisingly, promoters (desmin or synthetic C5–12) described as muscle-specific and which drive gene expression in single strand AAV vectors in gene therapy protocols were very highly active in pDC using VSVG-LV.

Conclusion

Taken together, our results indicate that LV vectors can serve to design pDC-based vaccines in humans, and they are also useful in vitro to evaluate the immunogenicity of the vector preparations, and the specificity and safety of given promoters used in gene therapy protocols.
Assigning strains to bacterial species via the internet
Authors: Bishop Cynthia J , Aanensen David M , Jordan Gregory E , Kilian Mogens , Hanage William P , Spratt Brian G
Published: January 2009

Background

Methods for assigning strains to bacterial species are cumbersome and no longer fit for purpose. The concatenated sequences of multiple house-keeping genes have been shown to be able to define and circumscribe bacterial species as sequence clusters. The advantage of this approach (multilocus sequence analysis; MLSA) is that, for any group of related species, a strain database can be produced and combined with software that allows query strains to be assigned to species via the internet. As an exemplar of this approach, we have studied a group of species, the viridans streptococci, which are very difficult to assign to species using standard taxonomic procedures, and have developed a website that allows species assignment via the internet.

Results

Seven house-keeping gene sequences were obtained from 420 streptococcal strains to produce a viridans group database. The reference tree produced using the concatenated sequences identified sequence clusters which, by examining the position on the tree of the type strain of each viridans group species, could be equated with species clusters. MLSA also identified clusters that may correspond to new species, and previously described species whose status needs to be re-examined. A generic website and software for electronic taxonomy was developed. This site http://www.eMLSA.net allows the sequences of the seven gene fragments of a query strain to be entered and for the species assignment to be returned, according to its position within an assigned species cluster on the reference tree.

Conclusion

The MLSA approach resulted in the identification of well-resolved species clusters within this taxonomically challenging group and, using the software we have developed, allows unknown strains to be assigned to viridans species via the internet. Submission of new strains will provide a growing resource for the taxonomy of viridans group streptococci, allowing the recognition of potential new species and taxonomic anomalies. More generally, as the software at the MLSA website is generic, MLSA schemes and strain databases for other groups of related species can be hosted at this website, providing a portal for microbial electronic taxonomy.
Determinants in HIV-1 Nef for enhancement of virus replication and depletion of CD4+ T lymphocytes in human lymphoid tissue ex vivo
Authors: Homann Stefanie , Tibroni Nadine , Baumann Ingo , Sertel Serkan , Keppler Oliver T , Fackler Oliver T
Published: January 2009

Background

HIV-1 Nef critically contributes to AIDS in part by augmenting virus titers in infected individuals. Analyzing which of Nef's activities contribute to HIV pathogenesis has been hampered by the lack of a cell culture model in which Nef exerts pronounced effects on HIV replication. The human lymphoid aggregate culture (HLAC) from tonsil maintains the cell populations and cytokine milieu found in vivo, supports a productive infection without exogenous stimulation, and Nef contributes to efficient HIV-1 replication as well as CD4+ T cell depletion in this experimental ex vivo-model.

Results

To identify determinants in Nef that mediate these activities, we infected HLAC with a panel of isogenic HIV-1NL4-3 strains that encode for well-characterized mutants of HIV-1SF2 Nef. Determination of HIV-1 replication revealed that enhancement of the virus spread by Nef is governed by a complex set of protein interaction surfaces. In contrast, increased CD4+ T lymphocyte depletion depended on only two protein interaction surfaces in Nef that mediate either downregulation of cell surface CD4 or interaction with the NAKC signalosome. Consistently, in HLAC from 9 out of 14 donors, Nef enhanced CD4+ T cell depletion in the absence of a significant effect on virus replication. Moreover, our results suggest that this Nef-dependent enhancement in depletion occurred predominately in uninfected bystander CD4+ T cells.

Conclusion

Our findings suggest that Nef facilitates depletion of CD4+ T lymphocytes in HIV-1-infected lymphoid tissue ex vivo by increasing the pool of productively infected cells and by sensitizing bystander cells for killing. This ability might contribute to Nef's pathogenic potential in vivo.
Molecular characterization of Mycobacterium bovisstrains isolated from cattle slaughtered at two abattoirs in Algeria
Authors: Sahraoui Naima , Müller Borna , Guetarni Djamel , Boulahbal Fadéla , Yala Djamel , Ouzrout Rachid , Berg Stefan , Smith Noel H , Zinsstag Jakob
Published: January 2009

Background

Bovine Tuberculosis is prevalent in Algeria despite governmental attempts to control the disease. The objective of this study was to conduct, for the first time, molecular characterization of a population sample of Mycobacterium bovis strains isolated from slaughter cattle in Algeria. Between August and November 2007, 7250 animals were consecutively screened at the abattoirs of Algiers and Blida. In 260 animals, gross visible granulomatous lesions were detected and put into culture. Bacterial isolates were subsequently analysed by molecular methods.

Results

Altogether, 101 bacterial strains from 100 animals were subjected to molecular characterization. M. bovis was isolated from 88 animals. Other bacteria isolated included one strain of M. caprae, four Rhodococcus equi strains, three Non-tuberculous Mycobacteria (NTM) and five strains of other bacterial species. The M. bovis strains isolated showed 22 different spoligotype patterns; four of them had not been previously reported. The majority of M. bovis strains (89%) showed spoligotype patterns that were previously observed in strains from European cattle. Variable Number of Tandem Repeat (VNTR) typing supported a link between M. bovis strains from Algeria and France. One spoligotype pattern has also been shown to be frequent in M. bovis strains from Mali although the VNTR pattern of the Algerian strains differed from the Malian strains.

Conclusion

M. bovis infections account for a high amount of granulomatous lesions detected in Algerian slaughter cattle during standard meat inspection at Algiers and Blida abattoir. Molecular typing results suggested a link between Algerian and European strains of M. bovis.
GRIP: A web-based system for constructing Gold Standard datasets for protein-protein interaction prediction
Authors: Browne Fiona , Wang Haiying , Zheng Huiru , Azuaje Francisco
Published: January 2009

Background

Information about protein interaction networks is fundamental to understanding protein function and cellular processes. Interaction patterns among proteins can suggest new drug targets and aid in the design of new therapeutic interventions. Efforts have been made to map interactions on a proteomic-wide scale using both experimental and computational techniques. Reference datasets that contain known interacting proteins (positive cases) and non-interacting proteins (negative cases) are essential to support computational prediction and validation of protein-protein interactions. Information on known interacting and non interacting proteins are usually stored within databases. Extraction of these data can be both complex and time consuming. Although, the automatic construction of reference datasets for classification is a useful resource for researchers no public resource currently exists to perform this task.

Results

GRIP (Gold Reference dataset constructor from Information on Protein complexes) is a web-based system that provides researchers with the functionality to create reference datasets for protein-protein interaction prediction in Saccharomyces cerevisiae. Both positive and negative cases for a reference dataset can be extracted, organised and downloaded by the user. GRIP also provides an upload facility whereby users can submit proteins to determine protein complex membership. A search facility is provided where a user can search for protein complex information in Saccharomyces cerevisiae.

Conclusion

GRIP is developed to retrieve information on protein complex, cellular localisation, and physical and genetic interactions in Saccharomyces cerevisiae. Manual construction of reference datasets can be a time consuming process requiring programming knowledge. GRIP simplifies and speeds up this process by allowing users to automatically construct reference datasets. GRIP is free to access at http://rosalind.infj.ulst.ac.uk/GRIP/.
The hierarchically organized splitting of chromosomal bands for all human chromosomes
Authors: Kosyakova Nadezda , Weise Anja , Mrasek Kristin , Claussen Uwe , Liehr Thomas , Nelle Heike
Published: January 2009

Background

Chromosome banding is widely used in cytogenetics. However, the biological nature of hierarchically organized splitting of chromosomal bands of human chromosomes is an enigma and has not been, as yet, studied.

Results

Here we present for the first time the hierarchically organized splitting of chromosomal bands in their sub-bands for all human chromosomes. To do this, array-proved multicolor banding (aMCB) probe-sets for all human chromosomes were applied to normal metaphase spreads of three different G-band levels. We confirmed for all chromosomes to be a general principle that only Giemsa-dark bands split into dark and light sub-bands, as we demonstrated previously by chromosome stretching. Thus, the biological band splitting is in > 50% of the sub-bands different than implemented by the ISCN nomenclature suggesting also a splitting of G-light bands. Locus-specific probes exemplary confirmed the results of MCB.

Conclusion

Overall, the present study enables a better understanding of chromosome architecture. The observed difference of biological and ISCN band-splitting may be an explanation why mapping data from human genome project do not always fit the cytogenetic mapping.
Acute right iliac fossa pain: not always appendicitis or a caecal tumour: two case reports
Authors: Kumar Susim , Fitzmaurice Gerard J , O'Donnell Mark E , Brown Robin
Published: January 2009

Background

A solitary diverticulum of the caecum is a rare benign condition which was first described by Potier in 1912 [1]. Clinical symptoms are usually a manifestation of complications arising from inflammation, perforation or haemorrhage. Despite radiological imaging, a pre-operative diagnosis is infrequent.

Case presentation

We report two cases of right iliac fossa pain associated with a solitary caecal diverticulum. We discuss the clinical presentation, investigative modalities, and current therapeutic guidelines associated with this rare condition and highlight the difference from the more common conditions of appendicitis in the young and caecal neoplasms in the older patient.

Conclusion

Complications of a solitary caecal diverticulum should be considered in the differential diagnosis of acute right lower quadrant pain. Mild caecal diverticulitis verified pre-operatively by radiological imaging or laparoscopically can be ameliorated by antibiotics alone. However, severe inflammation, perforation, haemorrhage or torsion necessitates a localised or radical resection. The presence of multiple diverticula, caecal phlegmon, or the inability to rule out an underlying caecal neoplasm warrants a right hemicolectomy.
Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing
Authors: Sokolenko Anna P , Voskresenskiy Dmitry A , Iyevleva Aglaya G , Bit-Sava Elena M , Gutkina Nadezhda I , Anisimenko Maxim S , Yu Sherina Nathalia , Mitiushkina Nathalia V , Ulibina Yulia M , Yatsuk Olga S , Zaitseva Olga A , Suspitsin Evgeny N , Togo Alexandr V , Pospelov Valery A , Kovalenko Sergey P , Semiglazov Vladimir F , Imyanitov Evgeny N
Published: January 2009

Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.
Genetic variants in MUTYH are not associated with endometrial cancer risk
Authors: Ashton Katie A , Proietto Anthony , Otton Geoffrey , Symonds Ian , Scott Rodney J
Published: January 2009

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant inherited predisposition to a number of epithelial cancers, most notably colorectal and endometrial cancer. Outside of the context of Lynch syndrome there is little evidence for an autosomal dominant or recessive condition that predisposes to endometrial cancer. Recently, genetic variants in MUTYH have been associated with a recessive form of colorectal cancer, known as MUTYH associated polyposis or MAP. MUTYH is involved in base excision repair of DNA lesions and as such a breakdown in the fidelity of this process would necessarily not be predicted to result in a specific disease. At present there is little information about the role of MUTYH in other types of cancer and only one report indicating a possible relationship with endometrial cancer.

Similar to a previous study, we investigated a series of endometrial cancer patients to determine if MUTYH variants were over-represented compared to a series of healthy control subjects and to assess whether or not endometrial cancer risk could be explained by an autosomal recessive model of inheritance.

Two MUTYH mutations, Y165C and G382D, and three common MUTYH polymorphisms, V22M, Q324H and S501F, were genotyped in 213 endometrial cancer patients and 226 controls from Australia using real time PCR. Differences in genotype frequencies were compared using Chi-squared analysis and by calculating odds ratios and 95% confidence intervals.

Three endometrial cancer patients were identified with heterozygous MUTYH mutations (two G382D and one Y165C). No bi-allelic mutation carriers were identified. Two of the three patients' clinical characteristics were similar to those commonly identified in HNPCC and lend support to the notion that MUTYH mutations increase the risk of developing HNPCC related diseases. There was no difference in the five genotype frequencies of the endometrial cancer patients compared to the controls. The results of our study suggest that MUTYH is unlikely to be involved in the genetic basis of endometrial cancer but a possible association of MUTYH variants with HNPCC related diseases cannot be excluded.
Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug
Authors: Zimmermann Grant R , Avery William , Finelli Alyce L , Farwell Melissa , Fraser Christopher C , Borisy Alexis A
Published: January 2009

Introduction

Glucocorticoids are a mainstay of anti-inflammatory therapy, but significant adverse effects ultimately limit their utility. Previous efforts to design glucocorticoid structures with an increased therapeutic window have focused on dissociating anti-inflammatory transcriptional repression from adverse effects primarily driven by transcriptional activation. An alternative to this medicinal chemistry approach is a systems biology based strategy that seeks to amplify selectively the anti-inflammatory activity of very low dose glucocorticoid in immune cells without modulating alternative cellular networks that mediate glucocorticoid toxicity.

Methods

The combination of prednisolone and the antithrombotic drug dipyridamole was profiled using in vitro and in vivo models of anti-inflammatory activity and glucocorticoid-induced adverse effects to demonstrate a dissociated activity profile.

Results

The combination synergistically suppresses release of proinflammatory mediators, including tumour necrosis factor-α, IL-6, chemokine (C-C motif) ligand 5 (RANTES), matrix metalloproteinase-9, and others, from human peripheral blood mononuclear cells and mouse macrophages. In rat models of acute lipopolysaccharide-induced endotoxemia and delayed-type hypersensitivity, and in chronic models of collagen-induced and adjuvant-induced arthritis, the combination produced anti-inflammatory activity that required only a subtherapeutic dose of prednisolone. The immune-specific amplification of prednisolone anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects, including corticosterone suppression or increased expression of tyrosine aminotransferase, in vivo after repeat dosing in rats. After 8 weeks of oral dosing in mice, treatment with the combination did not alter prednisolone-induced reduction in osteocalcin and mid-femur bone density, which are markers of steroid-induced osteoporosis. Additionally, amplification was not observed in the cellular network of corticotroph AtT-20/D16v-F2 cells in vitro, as measured by pro-opiomelanocortin expression and adrenocorticotropic hormone secretion.

Conclusions

These data suggest that the multi-target mechanism of low-dose prednisolone and dipyridamole creates a dissociated activity profile with an increased therapeutic window through cellular network selective amplification of glucocorticoid-mediated anti-inflammatory signaling.
Automatic versus manual pressure support reduction in the weaning of post-operative patients: a randomised controlled trial
Authors: Taniguchi Corinne , Eid Raquel C , Saghabi Cilene , Souza Rogério , Silva Eliezer , Knobel Elias , Paes Ângela T , Barbas Carmen S
Published: January 2009

Introduction

Reduction of automatic pressure support based on a target respiratory frequency or mandatory rate ventilation (MRV) is available in the Taema-Horus ventilator for the weaning process in the intensive care unit (ICU) setting. We hypothesised that MRV is as effective as manual weaning in post-operative ICU patients.

Methods

There were 106 patients selected in the post-operative period in a prospective, randomised, controlled protocol. When the patients arrived at the ICU after surgery, they were randomly assigned to either: traditional weaning, consisting of the manual reduction of pressure support every 30 minutes, keeping the respiratory rate/tidal volume (RR/TV) below 80 L until 5 to 7 cmH2O of pressure support ventilation (PSV); or automatic weaning, referring to MRV set with a respiratory frequency target of 15 breaths per minute (the ventilator automatically decreased the PSV level by 1 cmH2O every four respiratory cycles, if the patient's RR was less than 15 per minute). The primary endpoint of the study was the duration of the weaning process. Secondary endpoints were levels of pressure support, RR, TV (mL), RR/TV, positive end expiratory pressure levels, FiO2 and SpO2 required during the weaning process, the need for reintubation and the need for non-invasive ventilation in the 48 hours after extubation.

Results

In the intention to treat analysis there were no statistically significant differences between the 53 patients selected for each group regarding gender (p = 0.541), age (p = 0.585) and type of surgery (p = 0.172). Nineteen patients presented complications during the trial (4 in the PSV manual group and 15 in the MRV automatic group, p < 0.05). Nine patients in the automatic group did not adapt to the MRV mode. The mean ± sd (standard deviation) duration of the weaning process was 221 ± 192 for the manual group, and 271 ± 369 minutes for the automatic group (p = 0.375). PSV levels were significantly higher in MRV compared with that of the PSV manual reduction (p < 0.05). Reintubation was not required in either group. Non-invasive ventilation was necessary for two patients, in the manual group after cardiac surgery (p = 0.51).

Conclusions

The duration of the automatic reduction of pressure support was similar to the manual one in the post-operative period in the ICU, but presented more complications, especially no adaptation to the MRV algorithm.

Trial Registration

Trial registration number: ISRCTN37456640
The effect of glutamine infusion on the inflammatory response and HSP70 during human experimental endotoxaemia
Authors: Andreasen Anne Sofie , Pedersen-Skovsgaard Theis , Mortensen Ole Hartvig , van Hall Gerrit , Moseley Pope Lloyd , Pedersen Bente Klarlund
Published: January 2009

Introduction

Glutamine supplementation has beneficial effects on morbidity and mortality in critically ill patients, possibly in part through an attenuation of the proinflammatory cytokine response and a stimulation of heat shock protein (HSP)70. We infused either alanine-glutamine or saline during endotoxin challenge and measured plasma cytokines and HSP70 protein expression.

Methods

This crossover study, conducted in eight healthy young men, was double-blind, randomized and placebo-controlled. It was performed on 2 trial days, separated by a 4-week washout period. The volunteers received an infusion of alanine-glutamine at a rate of 0.025 g/(kg body weight × hour) or saline for 10 hours. After 2 hours, an intravenous bolus of Escherichia coli endotoxin (0.3 ng/kg) was administered. Blood samples were collected hourly for the following 8 hours. HSP70 protein content in isolated blood mononuclear cells (BMNCs) was measured by Western blotting.

Results

Plasma glutamine increased during alanine-glutamine infusion. Endotoxin reduced plasma glutamine during both trials, but plasma glutamine levels remained above baseline with alanine-glutamine supplementation. Endotoxin injection was associated with alterations in white blood cell and differential counts, tumour necrosis factor-α, IL-6, temperature and heart rate, but glutamine affected neither the endotoxin-induced change in these variables nor the expression of HSP70 in BMNCs.

Conclusions

Endotoxin reduced plasma glutamine independently of alanine-glutamine infusion, but supplementation allows plasma levels to be maintained above baseline. Glutamine alters neither endotoxin-induced systemic inflammation nor early expression of HSP70 in BMNCs.

Trial Registration

ClinicalTrials.gov ID: NCT 00780520.
Excellent Outcome With Reduced Treatment for Infants With Disseminated Neuroblastoma Without MYCN Gene Amplification
Authors: De Bernardi Bruno , Gerrard Mary , Boni Luca , Rubie Hervé , Cañete Adela , Di Cataldo Andrea , Castel Victoria , Forjaz de Lacerda Ana , Ladenstein Ruth , Ruud Ellen , Brichard Benédicte , Couturier Jerome , Ellershaw Caroline , Munzer Caroline , Bruzzi Paolo , Michon Jean , Pearson Andrew D.J.
Published: January 2009

Purpose

On the assumption that most infants with disseminated neuroblastoma without MYCN amplification (MYCNA) have a favorable prognosis, two concomitant prospective trials were started in which chemotherapy was limited to patients presenting life- or organ-threatening symptoms or overt metastases to skeleton, lung, or CNS. Surgery was to be performed only in the absence of surgical risk factors.

Patients and Methods

One hundred seventy infants with disseminated neuroblastoma without MYCNA, diagnosed between June 1999 and June 2004 in nine European countries were eligible for either of the two studies. Trial 99.2 included all stage 4S infants and those with stage 4 with a primary tumor infiltrating across the midline or positive skeletal scintigraphy who were to be observed in absence of symptoms. Trial 99.3 included infants with overt metastases to the skeleton, lung, and CNS to be treated with a minimum of four chemotherapy courses.

Results

The 125 infants treated on trial 99.2 had a 2-year overall survival (OS) of 97.6% with no difference between asymptomatic and symptomatic patients (97.7% v 97.3%), patients without or with unresectable primary tumors (96.8% v 100%), and patients without or with positive skeletal scintigraphy without radiologic abnormalities (97.2% v 100%). The 45 infants treated on trial 99.3 had a 2-year OS of 95.6%. No patients died of surgery- or chemotherapy-related complications.

Conclusion

Infants with disseminated disease without MYCNA have excellent survival with minimal or no treatment. Asymptomatic infants with an unresectable primary tumor or positive skeletal scintigraphy without radiologic abnormalities may undergo observation alone.
Sensitivity of Surveillance Studies for Detecting Asymptomatic and Unsuspected Relapse of High-Risk Neuroblastoma
Authors: Kushner Brian H. , Kramer Kim , Modak Shakeel , Cheung Nai-KongV.
Published: January 2009

Purpose

Relapse-free survival (RFS) is a powerful measure of treatment efficacy. We describe the sensitivity of standard surveillance studies for detecting relapse of neuroblastoma (NB).

Patients and Methods

The patients were in complete/very good partial remission of high-risk NB; routine monitoring revealed asymptomatic and, therefore, unsuspected relapses in 113 patients, whereas 41 patients had symptoms prompting urgent evaluations. Assessments every 2 to 4 months included computed tomography, iodine-131–metaiodobenzylguanidine 131I-MIBG; through November 1999) or iodine-123–metaiodobenzylguanidine (123I-MIBG) scan, urine catecholamines, and bone marrow (BM) histology. Bone scan was routine through 2002.

Results

123I-MIBG scan was the most reliable study for revealing unsuspected relapse; it had an 82% detection rate, which was superior to the rates with 131I-MIBG scan (64%; P = .1), bone scan (36%; P < .001), and BM histology (34%; P < .001). Among asymptomatic patients, 123I-MIBG scan was the sole positive study indicating relapse in 25 (27%) of 91 patients compared with one (4.5%) of 22 patients for 131I-MIBG scan (P = .04) and 0% to 6% of patients for each of the other studies (P < .001). Patients whose monitoring included 123I-MIBG scan were significantly less likely than patients monitored by 131I-MIBG scan to have an extensive osteomedullary relapse and had a significantly longer survival from relapse (P < .001) and from diagnosis (P = .002). They also had significantly longer survival than patients with symptomatic relapses (P = .002).

Conclusion

123I-MIBG scan is essential for valid estimation of the duration of RFS of patients with high-risk NB. Without monitoring that includes 123I-MIBG scan, caution should be used when comparing RFS between institutions and protocols.
Randomized Phase II Trial of First-Line Treatment With Sorafenib Versus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma
Authors: Escudier Bernard , Szczylik Cezary , Hutson Thomas E. , Demkow Tomasz , Staehler Michael , Rolland Frédéric , Negrier Sylvie , Laferriere Nicole , Scheuring Urban J. , Cella David , Shah Sonalee , Bukowski Ronald M.
Published: January 2009

Purpose

An open-label, phase II study to evaluate progression-free survival (PFS), overall best response, adverse events (AEs), and patient-reported outcomes with sorafenib versus interferon alfa-2a (IFN-α-2a) in patients with untreated, advanced renal cancer.

Patients and Methods

A total of 189 patients were randomly assigned to oral sorafenib 400 mg twice daily or to subcutaneous IFN-α-2a 9 million U three times weekly (period 1). Sorafenib patients who progressed were dose-escalated to 600 mg twice daily; IFN-α-2a patients who progressed were switched to sorafenib 400 mg twice daily (period 2).

Results

In period 1 PFS was similar for sorafenib-treated (n = 97; 5.7 months) and IFN-α-2a–treated patients (n = 92; 5.6 months); more sorafenib-treated patients had tumor shrinkage (68.2% v 39.0%). Common drug-related AEs (Grades ≥ 3) for sorafenib were hand-foot skin reaction (11.3%), diarrhea (6.2%), and rash/desquamation (6.2%); for IFN-α-2a, these were fatigue (10.0%), nausea (3.3%), flu-like syndrome (2.2%), and anorexia (2.2%). Sorafenib-treated patients reported fewer symptoms, better quality of life (QOL), and greater treatment satisfaction. In period 2, 41.9% of patients who received sorafenib 600 mg twice daily (n = 43) experienced tumor reduction (median PFS, 3.6 months). After the switch to sorafenib 400 mg twice daily, tumors were reduced in 76.2% of 50 patients (median PFS, 5.3 months). AEs were mostly grade 1 to 2; no increase in AEs of grades ≥ 3 occurred after sorafenib dose escalation.

Conclusion

In this study, sorafenib resulted in similar PFS as IFN-α-2a in patients with untreated RCC. However, sorafenib-treated patients experienced greater rates of tumor size reduction, better QOL, and improved tolerability. Both dose escalation of sorafenib after progression and a switch to sorafenib after progression on IFN-α-2a resulted in clinical benefit.
Peripheral Administration of Nesfatin-1 Reduces Food Intake in Mice: The Leptin-Independent Mechanism
Authors: Shimizu H. , Oh-I S. , Hashimoto K. , Nakata M. , Yamamoto S. , Yoshida N. , Eguchi H. , Kato I. , Inoue K. , Satoh T. , Okada S. , Yamada M. , Yada T. , Mori M.
Published: January 2009

Nesfatin-1 is a novel satiety molecule in the hypothalamus and is also present in peripheral tissues. Here we sought to identify the active segment of nesfatin-1 and to determine the mechanisms of its action after peripheral administration in mice. Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner. Nesfatin-1 has three distinct segments; we tested the effect of each segment on food intake. Injection of the midsegment decreased food intake under leptin-resistant conditions such as db/db mice and mice fed a high-fat diet. After injection of the midsegment, expression of c-Fos was significantly activated in the brainstem nucleus tractus solitarius (NTS) but not in the hypothalamic arcuate nucleus; the nicotinic cholinergic pathway to the NTS contributed to midsegment-induced anorexia. Midsegment injection significantly increased expression of proopiomelanocortin and cocaine- and amphetamine-regulated transcript genes in the NTS but not in the arcuate nucleus. Investigation of mutant midsegments demonstrated that a region with amino acid sequence similarity to the active site of agouti-related peptide was indispensable for anorexigenic induction. Our findings indicate that the midsegment of nesfatin-1 causes anorexia, possibly by activating POMC and CART neurons in the NTS via a leptin-independent mechanism after peripheral stimulation.

Peripherally administered nesfatin-1 and its mid-segment suppress food intake in mice. The nicotinic cholinergic pathway to the nucleus tractus solitarius contributes to the anorexigenic action of the mid-segment.
A unified manufacturing resource model for representation of computerized numerically controlled machine tools
Authors: Vichare P , Nassehi A , Newman S
Published: January 2009

The capability of any manufacturing system primarily depends on its available machine tools. Thus machine tool representation is a vital part of modelling any manufacturing system. With the rapid advances in computerized numerically controlled (CNC) machines, machine tool representation has become a more challenging task than ever before. Today's CNC machine tools are more than just automated manufacturing machines, as they can be considered multi-purpose, multi-tasking, and hybrid machining centres. This paper presents a versatile methodology for representing such state-of-the-art CNC machining system resources.

A machine tool model is a conceptual representation of the real machine tool and provides a logical framework for representing its functionality in the manufacturing system. There are several commercial modelling tools available in the market for modelling machine tools. However, there is no common methodology among them to represent the wide diversity of machine tool configurations. These modelling tools are either machine vendor specific or limited in their scope to represent machine tool capability. In addition, the current information models of STEP-NC, namely ISO 14649, can only describe machining operations, technologies, cutting tools, and product geometries. However, they do not support the representation of machine tools. The proposed unified manufacturing resource model (UMRM) has a data model which can fill this gap by providing machine specific data in the form of an EXPRESS schema and act as a complementary part to the STEP-NC standard to represent various machine tools in a standardized form. UMRM is flexible enough to represent any type of CNC machining centre. This machine tool representation can be utilized to represent machine tool functionality and consequential process capabilities for allocating resources for process planning and machining.
Vibration control of an electrorheological fluid-based suspension system with an energy regenerative mechanism
Authors: Choi S-B , Seong M-S , Kim K-S
Published: January 2009

This work presents vibration control of a vehicle suspension system using a controllable electrorheological (ER) shock absorber activated by an energy generator without external power sources. The ER shock absorber has a rack and pinion mechanism which converts a linear motion of the piston to a rotary motion. This rotary motion is amplified by gears and subsequently activates a generator to produce electrical energy. The generated voltage is experimentally evaluated with respect to excitation magnitude and frequency of the ER shock absorber. After evaluating the damping force using the regenerated voltage, a quarter-car ER suspension model is established. A skyhook controller is then formulated and experimentally implemented to attenuate vibration using the regenerated energy. It has been demonstrated via experiment that suspension vibration under bumpy and sinusoidal road conditions is significantly controlled by activating the ER shock absorber operated by the proposed regenerative energy mechanism.
Development of control laws for the simulation of a new transport aircraft
Authors: Holzapfel F , Heller M , Weingartner M , Sachs G , da Costa O
Published: January 2009

This article presents the development of fly-by-wire control laws used for the high-fidelity simulation of a new transport category aircraft. Beyond structural and gain design aspects for normal operations, envelope protections and limitations as well as mode transition issues are also addressed. As the control system is to be adjusted to changing aircraft datasets at different levels of fidelity, particular emphasis has been put on a high level of automation in gain design and system assessment routines. For lateral dynamics, eigenstructure assignment is used as the design methodology whereas pole placement is used for the pitch axis.
Elastic analysis of short orthotropic composite columns subjected to uniform load over a part of the tip
Authors: Deb Nath S K , Reaz Ahmed S
Published: January 2009

A stiffened edge column of orthotropic composite material is considered to analyse the elastic field due to a uniform load over a part of the tip. By the approach of a displacement potential, the present mixed-boundary-value elastic problem is solved. Results of different stress and displacement components at different sections of the column are presented in the form of graphs. Effects of aspect ratio, loading area of the tip, and fibre orientation on the elastic field are also investigated. Finally, the present analytical solutions are compared with those of two different numerical methods, namely finite element and finite difference method.
Experimental results and numerical simulations on strongly non-linear rolling of multihulls in moderate beam seas
Authors: Bulian G , Francescutto A
Published: January 2009

A trimaran and a pentamaran ship have been investigated to study the effect of transversal hull separation on roll motion in waves. Four different configurations for the trimaran have been tested in beam waves and two for the pentamaran, all using the same main hull. Typical outriggers with small beam and draught have been used. The experiments in regular waves revealed the extreme sensitivity of these hull typologies to roll motion in beam waves, even in mild sea conditions (wave steepness=1/60). Two configurations of the trimaran and one of the pentamaran exhibited a multivalued roll response curve in the low frequency range. This is, to the best of the authors knowledge, the first experimental evidence of bifurcations in roll motion of multihull ships, which are usually designed and selected for their superior stability characteristics and low rolling. Three mathematical models have been used with the aim of reproducing the experimental roll response curve. Two models are based on a partially semi-empirical extension of the standard linear seakeeping equations in the non-linear range, while one model is based on a non-linear one-degree-of-freedom modelling of roll motion. Two models are based on a relative angle approach for the non-linear restoring, while one model is based on an absolute angle approach for the computation of the non-linear restoring.
The protection motivation theory within the stages of the transtheoretical model – Stage‐specific interplay of variables and prediction of exercise stage transitions
Authors: Lippke Sonia , Plotnikoff Ronald C.
Published: January 2009

Objective Two different theories of health behaviour have been chosen with the aim of theory integration: a continuous theory (protection motivation theory, PMT) and a stage model (transtheoretical model, TTM). This is the first study to test whether the stages of the TTM moderate the interrelation of PMT‐variables and the mediation of motivation, as well as PMT‐variables' interactions in predicting stage transitions.

Design Hypotheses were tested regarding (1) mean patterns, stage pair‐comparisons and nonlinear trends using ANOVAs; (2) prediction‐patterns for the different stage groups employing multi‐group structural equation modelling (MSEM) and nested model analyses; and (3) stage transitions using binary logistic regression analyses.

Method Adults (N=1,602) were assessed over a 6 month period on their physical activity stages, PMT‐variables and subsequent behaviour.

Results (1) Particular mean differences and nonlinear trends in all test variables were found. (2) The PMT adequately fitted the five stage groups. The MSEM revealed that covariances within threat appraisal and coping appraisal were invariant and all other constrains were stage‐specific, i.e. stage was a moderator. Except for self‐efficacy, motivation fully mediated the relationship between the social‐cognitive variables and behaviour. (3) Predicting stage transitions with the PMT‐variables underscored the importance of self‐efficacy. Only when threat appraisal and coping appraisal were high, stage movement was more likely in the preparation stage.

Conclusions Results emphasize stage‐specific differences of the PMT mechanisms, and hence, support the stage construct. The findings may guide further theory building and research integrating different theoretical approaches.
Trait anxiety as an independent predictor of poor health‐related quality of life and post‐traumatic stress symptoms in rectal cancer
Authors: Ristvedt Stephen L. , Trinkaus Kathryn M.
Published: January 2009

Objectives To determine the influence of trait anxiety on patient reports of health‐related quality of life (HRQoL) and post‐traumatic stress symptoms (PTSS) in a sample of rectal cancer survivors.

Design Eighty patients who had been diagnosed with rectal cancer were assessed at two points in time in a longitudinal study.

Methods At Time 1, soon after initial treatment, participants completed the State‐Trait Anxiety Inventory and the Temperament and Character Inventory Harm Avoidance scale, which were combined into a composite measure of trait anxiety. At Time 2, 2–5 years following Time 1, participants were assessed for HRQoL using the Functional Assessment of Cancer Therapy‐Colorectal scale (FACT‐C) and for PTSS using the Impact of Event Scale‐Revised (IES‐R).

Results HRQoL and PTSS were generally favourable on average, although many of the patients reported faring poorly. Higher levels of trait anxiety were predictive of poorer scores on all of the FACT‐C and the IES‐R total and subscale measures. More severe faecal incontinence was associated with poorer scores on the FACT Emotional well‐being subscale, the FACT‐Colorectal Cancer Scale, and all of the IES‐R scales. Males were more likely than females to have poorer scores on the FACT Social well‐being subscale, and those patients who were further out from active treatment had more favourable scores on the FACT‐Colorectal Cancer Scale. The presence of a colostomy did not impact HRQoL or PTSS.

Conclusion Trait anxiety had a significant influence on HRQoL and PTSS several years following diagnosis and treatment of rectal cancer.