bluuebunny/crossref_metadata_2025 huggingface dataset:
GarlicESTdb: an online database and mining tool for garlic EST sequences
Authors: Kim Dae-Won , Jung Tae-Sung , Nam Seong-Hyeuk , Kwon Hyuk-Ryul , Kim Aeri , Chae Sung-Hwa , Choi Sang-Haeng , Kim Dong-Wook , Kim Ryong Nam , Park Hong-Seog
Published: May 2009

Background

Allium sativum., commonly known as garlic, is a species in the onion genus (Allium), which is a large and diverse one containing over 1,250 species. Its close relatives include chives, onion, leek and shallot. Garlic has been used throughout recorded history for culinary, medicinal use and health benefits. Currently, the interest in garlic is highly increasing due to nutritional and pharmaceutical value including high blood pressure and cholesterol, atherosclerosis and cancer. For all that, there are no comprehensive databases available for Expressed Sequence Tags(EST) of garlic for gene discovery and future efforts of genome annotation. That is why we developed a new garlic database and applications to enable comprehensive analysis of garlic gene expression.

Description

GarlicESTdb is an integrated database and mining tool for large-scale garlic (Allium sativum) EST sequencing. A total of 21,595 ESTs collected from an in-house cDNA library were used to construct the database. The analysis pipeline is an automated system written in JAVA and consists of the following components: automatic preprocessing of EST reads, assembly of raw sequences, annotation of the assembled sequences, storage of the analyzed information into MySQL databases, and graphic display of all processed data. A web application was implemented with the latest J2EE (Java 2 Platform Enterprise Edition) software technology (JSP/EJB/JavaServlet) for browsing and querying the database, for creation of dynamic web pages on the client side, and for mapping annotated enzymes to KEGG pathways, the AJAX framework was also used partially. The online resources, such as putative annotation, single nucleotide polymorphisms (SNP) and tandem repeat data sets, can be searched by text, explored on the website, searched using BLAST, and downloaded. To archive more significant BLAST results, a curation system was introduced with which biologists can easily edit best-hit annotation information for others to view. The GarlicESTdb web application is freely available at http://garlicdb.kribb.re.kr.

Conclusion

GarlicESTdb is the first incorporated online information database of EST sequences isolated from garlic that can be freely accessed and downloaded. It has many useful features for interactive mining of EST contigs and datasets from each library, including curation of annotated information, expression profiling, information retrieval, and summary of statistics of functional annotation. Consequently, the development of GarlicESTdb will provide a crucial contribution to biologists for data-mining and more efficient experimental studies.
Molecular characterisation and genetic mapping of candidate genes for qualitative disease resistance in perennial ryegrass (Lolium perenne L.)
Authors: Dracatos Peter M , Cogan Noel OI , Sawbridge Timothy I , Gendall Anthony R , Smith Kevin F , Spangenberg German C , Forster John W
Published: May 2009

Background

Qualitative pathogen resistance in both dicotyledenous and monocotyledonous plants has been attributed to the action of resistance (R) genes, including those encoding nucleotide binding site – leucine rich repeat (NBS-LRR) proteins and receptor-like kinase enzymes. This study describes the large-scale isolation and characterisation of candidate R genes from perennial ryegrass. The analysis was based on the availability of an expressed sequence tag (EST) resource and a functionally-integrated bioinformatics database.

Results

Amplification of R gene sequences was performed using template EST data and information from orthologous candidate using a degenerate consensus PCR approach. A total of 102 unique partial R genes were cloned, sequenced and functionally annotated. Analysis of motif structure and R gene phylogeny demonstrated thatLoliumR genes cluster with putative ortholoci, and evolved from common ancestral origins. Single nucleotide polymorphisms (SNPs) predicted through resequencing of amplicons from the parental genotypes of a genetic mapping family were validated, and 26 distinct R gene loci were assigned to multiple genetic maps. Clusters of largely non-related NBS-LRR genes were located at multiple distinct genomic locations and were commonly found in close proximity to previously mapped defence response (DR) genes. A comparative genomics analysis revealed the co-location of several candidate R genes with disease resistance quantitative trait loci (QTLs).

Conclusion

This study is the most comprehensive analysis to date of qualitative disease resistance candidate genes in perennial ryegrass. SNPs identified within candidate genes provide a valuable resource for mapping in various ryegrass pair cross-derived populations and further germplasm analysis using association genetics. In parallel with the use of specific pathogen virulence races, such resources provide the means to identify gene-for-gene mechanisms for multiple host pathogen-interactions and ultimately to obtain durable field-based resistance.
Inflammatory (B) symptoms are independent predictors of myelosuppression from chemotherapy in Non-Hodgkin Lymphoma (NHL) patients – analysis of data from a British National Lymphoma Investigation phase III trial comparing CHOP to PMitCEBO
Authors: Sharma Rohini , Cunningham David , Smith Paul , Robertson Graham , Dent Owen , Clarke Stephen J
Published: May 2009

Background

Toxicity from chemotherapy is highly variable, unpredictable and results in substantial morbidity and increased healthcare costs. New predictors of toxicity are required to improve the safety and efficacy of chemotherapy. Inflammatory or B symptoms in lymphoma are associated with elevated plasma inflammatory markers and predict worse treatment response and survival. Recent data suggest that systemic inflammation results in reduced hepatic drug metabolism and increased toxicity from chemotherapy. We investigated whether B symptoms were associated with greater toxicity in patients treated for non-Hodgkin lymphoma (NHL).

Methods

The British National Lymphoma Investigation compared two chemotherapy regimens in older patients with aggressive NHL. Approximately 50% of patients had B symptoms. Demographic and toxicity data on 664 patients were analysed to identify predictors of toxicity by multivariate analysis, with particular reference to B symptoms.

Results

Using univariate analyses, severe (grades 3–4) leucopenia, anaemia, thrombocytopenia, nausea and vomiting and diarrhoea occurred more frequently in patients with B symptoms. The associations between B symptoms and severe leucopenia (OR 1.7, p = 0.005) and anaemia (OR 2.3, p = 0.025) persisted after adjustment for other prognostic factors in multivariate analyses. The use of granulocyte colony stimulating factor reduced neutropenia in patients with both A and B symptoms.

Conclusion

For the first time and in a large NHL cohort we have shown that inflammatory symptoms are independent predictors for myelosuppression from chemotherapy. These data will enable improved prognostication for toxicity and provide individualisation of therapy in NHL and other tumours. These findings also create the potential for strategies used prior to chemotherapy aimed at reducing systemic inflammation in order to improve drug metabolism and reduce treatment-related toxicity.

Trial registration number

ISRCTN98741793
Occurrence of HSV-1-induced pneumonitis in patients under standard immunosuppressive therapy for rheumatic, vasculitic, and connective tissue disease
Authors: Witt Matthias N , Braun Gerald S , Ihrler Stephan , Schmid Holger
Published: May 2009

Background

Herpes simplex virus type-1 (HSV-1) has been described to cause respiratory tract infections in critically ill patients or in individuals that are immunocompromised. It is a continuing matter of debate under which circumstances HSV-1 is a relevant pathogen for pneumonitis. While its role during critical illness has been investigated by prospective interventional studies, comparatively little systematic data is available on the role of HSV-1 for pneumonitis in outpatients with autoimmune disease under a maintenance regimen of immunosuppression.

Methods

We retrospectively reviewed the charts of ~1400 patients with rheumatoid arthritis, vasculitis, and systemic lupus erythematosus (SLE) that were followed at the outpatient clinic of a German University hospital during the years 2000–2007. Episodes of admission to a ward resulting in the diagnosis of pneumonia/pneumonitis were identified, and the type of pneumonia and clinical features retrospectively studied.

Results

63 patients with rheumatoid arthritis, vasculitis, or SLE were admitted to a ward and diagnosed to have pneumonia/pneumonitis. Using bronchoscopy a total of 6 cases of pulmonary infection associated with HSV-1 in the lower respiratory tract were identified. Among those, 2 cases suggested a causative role of HSV-1 as the sole agent causing pneumonitis that proved clinically responsive to antiviral treatment. In the remaining 4 cases HSV-1 appeared as a bystander of bacterial infection. Maintenance therapy with leflunomide, which inhibits HSV-1 assembly in vitro, was associated with a milder course of pneumonitis in one patient. Detection of HSV-1 was associated with stronger immunosuppressive regimens and vasculitic disease.

Conclusion

The present study analyzed the frequency and hallmarks of cases of HSV-1 associated pneumonitis that occurred in a comparatively large cohort of patients with rheumatologic autoimmune diseases. In an area of controversy, this study provides further evidence that HSV-1 causes isolated pneumonitis in the immunocompromised. The study may provide an estimate on the frequency of relevant HSV-1 infection and bacterial agents in outpatients with autoimmune disease.
An investigation of theory-practice gap in undergraduate paramedic education
Authors: Michau Rebecca , Roberts Samantha , Williams Brett , Boyle Malcolm
Published: May 2009

Background

Bachelor of Emergency Health (Paramedic) (BEH) students at Monash University undertake clinical placements to assist with the transition from student to novice paramedic. Anecdotally, students report a lack of opportunity to practise their clinical skills whilst on placements. The barriers to participation and the theory-practice gap have not been previously documented in Australian paramedic literature. The purpose of this study was to investigate the theory-practice gap for paramedic students by linking education and skill level to case exposure and skills praxis during clinical placements.

Methods

A cross-sectional retrospective study using a convenience sample of second and third year BEH undergraduate students. Ethics approval was granted.

Results

Eighty four second and third year BEH students participated. 59.5% were female (n = 50), 40.5% were male (n = 34). Overall, students most commonly reported exposure to cardiac and respiratory cases and were satisfied with the number of cases encountered during placement. However, over half (n = 46) reported being exposed to < 50% of cases that allowed skills praxis. The most common barrier to participation (34.5%) was the opportunity to participate in patient care and 68% of student's were unsure if paramedics understood their role during clinical placements.

Conclusion

This study demonstrates that the majority of students were satisfied with their clinical placement experience; even though they were exposed to < 50% of cases that allowed skills practice. Identifying these educational barriers will assist in improving the quality and theory-practice gap of paramedic clinical education.
Chloroquine resistance before and after its withdrawal in Kenya
Authors: Mwai Leah , Ochong Edwin , Abdirahman Abdi , Kiara Steven M , Ward Steve , Kokwaro Gilbert , Sasi Philip , Marsh Kevin , Borrmann Steffen , Mackinnon Margaret , Nzila Alexis
Published: May 2009

Background

The spread of resistance to chloroquine (CQ) led to its withdrawal from use in most countries in sub-Saharan Africa in the 1990s. In Malawi, this withdrawal was followed by a rapid reduction in the frequency of resistance to the point where the drug is now considered to be effective once again, just nine years after its withdrawal. In this report, the polymorphisms of markers associated with CQ-resistance against Plasmodium falciparum isolates from coastal Kenya (Kilifi) were investigated, from 1993, prior to the withdrawal of CQ, to 2006, seven years after its withdrawal. Changes to those that occurred in the dihydrofolate reductase gene (dhfr) that confers resistance to the replacement drug, pyrimethamine/sulphadoxine were also compared.

Methods

Mutations associated with CQ resistance, at codons 76 of pfcrt, at 86 of pfmdr1, and at codons 51, 59 and 164 of dhfr were analysed using PCR-restriction enzyme methods. In total, 406, 240 and 323 isolates were genotyped for pfcrt-76, pfmdr1-86 and dhfr, respectively.

Results

From 1993 to 2006, the frequency of the pfcrt-76 mutant significantly decreased from around 95% to 60%, while the frequency of pfmdr1-86 did not decline, remaining around 75%. Though the frequency of dhfr mutants was already high (around 80%) at the start of the study, this frequency increased to above 95% during the study period. Mutation at codon 164 of dhf r was analysed in 2006 samples, and none of them had this mutation.

Conclusion

In accord with the study in Malawi, a reduction in resistance to CQ following official withdrawal in 1999 was found, but unlike Malawi, the decline of resistance to CQ in Kilifi was much slower. It is estimated that, at current rates of decline, it will take 13 more years for the clinical efficacy of CQ to be restored in Kilifi. In addition, CQ resistance was declining before the drug's official withdrawal, suggesting that, prior to the official ban, the use of CQ had decreased, probably due to its poor clinical effectiveness.
Psychometric properties of the Brazilian version of the Child Perceptions Questionnaire (CPQ11–14) – short forms
Authors: Torres Cíntia S , Paiva Saul M , Vale Miriam P , Pordeus Isabela A , Ramos-Jorge Maria L , Oliveira Ana C , Allison Paul J
Published: May 2009

Background

The need to evaluate the impact of oral health has led to the development of instruments for measuring oral health-related quality of life (OHQoL). One such instrument is the Child Perceptions Questionnaire (CPQ11–14), developed specifically for 11-to-14-year-old children. As this questionnaire was considered long (37 items), shorter forms were developed with 8 (Impact Short Form: 8 – ISF:8) and 16 items (Impact Short Form: 16 – ISF:16) to facilitate use in the clinical setting and population-based health surveys. The aim of the present study was to translate and cross-culturally adapt these CPQ11–14short forms for Brazilian Portuguese and evaluate the measurement properties of these versions for use on Brazilian children.

Methods

Following translation and cross-cultural adaptation, the ISF:8 and ISF:16 were tested on 136 children from 11 to 14 years of age in the city of Belo Horizonte, Brazil. The instrument was administered by a trained researcher who also performed clinical examinations. The measurement properties (i.e. criterion validity, construct validity, internal consistency reliability, test-retest reliability) were determined. Discriminant validity was tested between groups, which were divided into children with no cavities and no malocclusion; children with cavities and without malocclusion; and children with malocclusion and without cavities.

Results

The mean total score was 6.8 [standard deviation (SD) 4.2] for the ISF:8 and 11.9 (SD 7.6) for the ISF:16 (p < 0.001). Statistically significant associations were found between oral abnormalities and the subscales of the ISF:8 and ISF:16 (p< 0.05). Both test-retest stability and internal consistency, as measured by the intra-class correlation coefficient (ICC) (ISF:8 = 0.98 and ISF:16 = 0.97) and Cronbach's alpha (ISF:8 = 0.70 and ISF:16 = 0.84) proved to be adequate. Construct validity was confirmed from the correlation between the short form scores and oral health and overall well-being ratings. The score on the short forms of the CPQ11–14was able to discriminate between different oral conditions. Criterion validity was satisfactory (p < 0.05).

Conclusion

The Brazilian versions of CPQ11–14ISF:8 and ISF:16 have satisfactory psychometric properties, similar to those of the original instrument.
Management of appendiceal pseudomyxoma peritonei diagnosed during pregnancy
Authors: Haase Erika , Yoo Dal , Sugarbaker Paul H
Published: May 2009

Background

The incidence of cancer during pregnancy is approximately 1 in 1000. The most common types encountered during pregnancy are cervical, breast and ovarian. Epithelial tumors of the appendix on the other hand are rare and account for only approximately 1% of all colorectal neoplasms; the occurrence of this neoplasm during pregnancy is extremely rare.

Case Presentation

The medical history of a 30 year old woman diagnosed at 17 weeks gestation with an appendiceal mucinous tumor with large volume pseudomyxoma peritonei was presented. Her pregnancy was preserved and she had an early vaginal delivery of a healthy baby at 35 weeks. At 2 1/2 weeks postpartum the patient underwent extensive cytoreductive surgery and intraperitoneal chemotherapy. She remains disease-free 5 years after her initial diagnosis. A literature review of this clinical situation and a discussion of treatment plans were presented.

Conclusion

The management of an appendiceal tumor with pseudomyxoma peritonei diagnosed during pregnancy requires full knowledge of the natural history of this disease to achieve a balance of concern for maternal survival and fetal health.
Antiphospholipid (Hughes) syndrome: beyond pregnancy morbidity and thrombosis
Authors: Mialdea Maria , Sangle Shirish R , D'Cruz David P
Published: May 2009

The antiphospholipid syndrome is an autoimmune disease characterised by recurrent arterial or venous thrombosis, pregnancy morbidity and the persistence of positive antiphospholipid antibodies. Many other clinical manifestations may occur including heart valve disease, livedo reticularis, thrombocytopenia and neurological manifestations such as migraine and seizures. We review a number of other manfestations including stenotic lesions, coronary artery disease and accelerated atherosclerosis, skeletal disorders and the concept of seronegative antiphospholipid syndrome.
Soluble aggregates of the amyloid-β peptide are trapped by serum albumin to enhance amyloid-β activation of endothelial cells
Authors: Reyes Barcelo Adriana A , Gonzalez-Velasquez Francisco J , Moss Melissa A
Published: May 2009

Background

Self-assembly of the amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). As a result, synthetic molecules capable of inhibiting Aβ self-assembly could serve as therapeutic agents and endogenous molecules that modulate Aβ self-assembly may influence disease progression. However, increasing evidence implicating a principal pathogenic role for small soluble Aβ aggregates warns that inhibition at intermediate stages of Aβ self-assembly may prove detrimental. Here, we explore the inhibition of Aβ1–40self-assembly by serum albumin, the most abundant plasma protein, and the influence of this inhibition on Aβ1–40activation of endothelial cells for monocyte adhesion.

Results

It is demonstrated that serum albumin is capable of inhibiting in a dose-dependent manner both the formation of Aβ1–40aggregates from monomeric peptide and the ongoing growth of Aβ1–40fibrils. Inhibition of fibrillar Aβ1–40aggregate growth is observed at substoichiometric concentrations, suggesting that serum albumin recognizes aggregated forms of the peptide to prevent monomer addition. Inhibition of Aβ1–40monomer aggregation is observed down to stoichiometric ratios with partial inhibition leading to an increase in the population of small soluble aggregates. Such partial inhibition of Aβ1–40aggregation leads to an increase in the ability of resulting aggregates to activate endothelial cells for adhesion of monocytes. In contrast, Aβ1–40activation of endothelial cells for monocyte adhesion is reduced when more complete inhibition is observed.

Conclusion

These results demonstrate that inhibitors of Aβ self-assembly have the potential to trap small soluble aggregates resulting in an elevation rather than a reduction of cellular responses. These findings provide further support that small soluble aggregates possess high levels of physiological activity and underscore the importance of resolving the effect of Aβ aggregation inhibitors on aggregate size.
Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs
Authors: Evans Perry , Dampier William , Ungar Lyle , Tozeren Aydin
Published: May 2009

Background

Host protein-protein interaction networks are altered by invading virus proteins, which create new interactions, and modify or destroy others. The resulting network topology favors excessive amounts of virus production in a stressed host cell network. Short linear peptide motifs common to both virus and host provide the basis for host network modification.

Methods

We focused our host-pathogen study on the binding and competing interactions of HIV-1 and human proteins. We showed that peptide motifs conserved across 70% of HIV-1 subtype B and C samples occurred in similar positions on HIV-1 proteins, and we documented protein domains that interact with these conserved motifs. We predicted which human proteins may be targeted by HIV-1 by taking pairs of human proteins that may interact via a motif conserved in HIV-1 and the corresponding interacting protein domain.

Results

Our predictions were enriched with host proteins known to interact with HIV-1 proteins ENV, NEF, and TAT (p-value < 4.26E-21). Cellular pathways statistically enriched for our predictions include the T cell receptor signaling, natural killer cell mediated cytotoxicity, cell cycle, and apoptosis pathways. Gene Ontology molecular function level 5 categories enriched with both predicted and confirmed HIV-1 targeted proteins included categories associated with phosphorylation events and adenyl ribonucleotide binding.

Conclusion

A list of host proteins highly enriched with those targeted by HIV-1 proteins can be obtained by searching for host protein motifs along virus protein sequences. The resulting set of host proteins predicted to be targeted by virus proteins will become more accurate with better annotations of motifs and domains. Nevertheless, our study validates the role of linear binding motifs shared by virus and host proteins as an important part of the crosstalk between virus and host.
Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice
Authors: Butoescu Nicoleta , Seemayer Christian A , Palmer Gaby , Guerne Pierre-André , Gabay Cem , Doelker Eric , Jordan Olivier
Published: May 2009

Introduction

Conventional corticosteroid suspensions for the intra-articular treatment of arthritis suffer from limitations such as crystal formation or rapid clearance from the joint. The purpose of this study was to investigate an innovative alternative consisting of corticosteroid encapsulation into magnetically retainable microparticles.

Methods

Microparticles (1 or 10 μm) containing both superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were prepared. In a preliminary study, we compared the persistence of microparticles of both sizes in the joint. A second study evaluated the influence of a subcutaneously implanted magnet near the knee on the retention of magnetic microparticles in the joint by in vivo imaging. Finally, the efficacy of 10-μm microparticles was investigated using a model of antigen-induced arthritis (AIA) in mice. Phosphate-buffered saline, DXM suspension, SPION suspension, blank microparticles and microparticles containing only SPIONs were used as controls. Arthritis severity was assessed using 99mTc accumulation and histological scoring.

Results

Due to their capacity of encapsulating more corticosteroid and their increased joint retention, the 10-μm microparticles were more suitable vectors than the 1-μm microparticles for corticosteroid delivery to the joint. The presence of a magnet resulted in higher magnetic retention in the joint, as demonstrated by a higher fluorescence signal. The therapeutic efficacy in AIA of 10-μm microparticles containing DXM and SPIONs was similar to that of the DXM suspension, proving that the bioactive agent is released. Moreover, the anti-inflammatory effect of DXM-containing microparticles was more important than that of blank microparticles or microparticles containing only SPIONs. The presence of a magnet did not induce a greater inflammatory reaction.

Conclusions

This study confirms the effectiveness of an innovative approach of using magnetically retainable microparticles as intra-articular drug delivery systems. A major advantage comes from a versatile polymer matrix, which allows the encapsulation of many classes of therapeutic agents (for example, p38 mitogen-activated protein kinase inhibitors), which may reduce systemic side effects.
Model for predicting short-term mortality of severe sepsis
Authors: Adrie Christophe , Francais Adrien , Alvarez-Gonzalez Antonio , Mounier Roman , Azoulay Elie , Zahar Jean-Ralph , Clec'h Christophe , Goldgran-Toledano Dany , Hammer Laure , Descorps-Declere Adrien , Jamali Samir , Timsit Jean-Francois ,   the Outcomerea Study Group
Published: May 2009

Introduction

To establish a prognostic model for predicting 14-day mortality in ICU patients with severe sepsis overall and according to place of infection acquisition and to sepsis episode number.

Methods

In this prospective multicentre observational study on a multicentre database (OUTCOMEREA) including data from 12 ICUs, 2268 patients with 2737 episodes of severe sepsis were randomly divided into a training cohort (n = 1458) and a validation cohort (n = 810). Up to four consecutive severe sepsis episodes per patient occurring within the first 28 ICU days were included. We developed a prognostic model for predicting death within 14 days after each episode, based on patient data available at sepsis onset.

Results

Independent predictors of death were logistic organ dysfunction (odds ratio (OR), 1.22 per point, P < 10-4), septic shock (OR, 1.40; P = 0.01), rank of severe sepsis episode (1 reference, 2: OR, 1.26; P = 0.10 ≥ 3: OR, 2.64; P < 10-3), multiple sources of infection (OR; 1.45, P = 0.03), simplified acute physiology score II (OR, 1.02 per point; P < 10-4), McCabe score ([greater than or equal to]2) (OR, 1.96; P < 10-4), and number of chronic co-morbidities (1: OR, 1.75; P < 10-3, ≥ 2: OR, 2.24, P < 10-3). Validity of the model was good in whole cohorts (AUC-ROC, 0.76; 95%CI, 0.74 to 0.79; and HL Chi-square: 15.3 (P = 0.06) for all episodes pooled).

Conclusions

In ICU patients, a prognostic model based on a few easily obtained variables is effective in predicting death within 14 days after the first to fourth episode of severe sepsis complicating community-, hospital-, or ICU-acquired infection.
Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis
Authors: Oliveira Gisele P , Oliveira Mariana BG , Santos Raquel S , Lima Letícia D , Dias Cristina M , AB' Saber Alexandre M , Teodoro Walcy R , Capelozzi Vera L , Gomes Rachel N , Bozza Patricia T , Pelosi Paolo , Rocco Patricia RM
Published: May 2009

Introduction

The protective effect of glutamine, as a pharmacological agent against lung injury, has been reported in experimental sepsis; however, its efficacy at improving oxygenation and lung mechanics, attenuating diaphragm and distal organ injury has to be better elucidated. In the present study, we tested the hypothesis that a single early intravenous dose of glutamine was associated not only with the improvement of lung morpho-function, but also the reduction of the inflammatory process and epithelial cell apoptosis in kidney, liver, and intestine villi.

Methods

Seventy-two Wistar rats were randomly assigned into four groups. Sepsis was induced by cecal ligation and puncture surgery (CLP), while a sham operated group was used as control (C). One hour after surgery, C and CLP groups were further randomized into subgroups receiving intravenous saline (1 ml, SAL) or glutamine (0.75 g/kg, Gln). At 48 hours, animals were anesthetized, and the following parameters were measured: arterial oxygenation, pulmonary mechanics, and diaphragm, lung, kidney, liver, and small intestine villi histology. At 18 and 48 hours, Cytokine-Induced Neutrophil Chemoattractant (CINC)-1, interleukin (IL)-6 and 10 were quantified in bronchoalveolar and peritoneal lavage fluids (BALF and PLF, respectively).

Results

CLP induced: a) deterioration of lung mechanics and gas exchange; b) ultrastructural changes of lung parenchyma and diaphragm; and c) lung and distal organ epithelial cell apoptosis. Glutamine improved survival rate, oxygenation and lung mechanics, minimized pulmonary and diaphragmatic changes, attenuating lung and distal organ epithelial cell apoptosis. Glutamine increased IL-10 in peritoneal lavage fluid at 18 hours and bronchoalveolar lavage fluid at 48 hours, but decreased CINC-1 and IL-6 in BALF and PLF only at 18 hours.

Conclusions

In an experimental model of abdominal sepsis, a single intravenous dose of glutamine administered after sepsis induction may modulate the inflammatory process reducing not only the risk of lung injury, but also distal organ impairment. These results suggest that intravenous glutamine may be a potentially beneficial therapy for abdominal sepsis.
Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial
Authors: Reade Michael C , O'Sullivan Kim , Bates Samantha , Goldsmith Donna , Ainslie William RSTJ , Bellomo Rinaldo
Published: May 2009

Introduction

Agitated delirium is common in patients undergoing mechanical ventilation, and is often treated with haloperidol despite concerns about safety and efficacy. Use of conventional sedatives to control agitation can preclude extubation. Dexmedetomidine, a novel sedative and anxiolytic agent, may have particular utility in these patients. We sought to compare the efficacy of haloperidol and dexmedetomidine in facilitating extubation.

Methods

We conducted a randomised, open-label, parallel-groups pilot trial in the medical and surgical intensive care unit of a university hospital. Twenty patients undergoing mechanical ventilation in whom extubation was not possible solely because of agitated delirium were randomised to receive an infusion of either haloperidol 0.5 to 2 mg/hour or dexmedetomidine 0.2 to 0.7 μg/kg/hr, with or without loading doses of 2.5 mg haloperidol or 1 μg/kg dexmedetomidine, according to clinician preference.

Results

Dexmedetomidine significantly shortened median time to extubation from 42.5 (IQR 23.2 to 117.8) to 19.9 (IQR 7.3 to 24) hours (P = 0.016). Dexmedetomidine significantly decreased ICU length of stay, from 6.5 (IQR 4 to 9) to 1.5 (IQR 1 to 3) days (P = 0.004) after study drug commencement. Of patients who required ongoing propofol sedation, the proportion of time propofol was required was halved in those who received dexmedetomidine (79.5% (95% CI 61.8 to 97.2%) vs. 41.2% (95% CI 0 to 88.1%) of the time intubated; P = 0.05). No patients were reintubated; three receiving haloperidol could not be successfully extubated and underwent tracheostomy. One patient prematurely discontinued haloperidol due to QTc interval prolongation.

Conclusions

In this preliminary pilot study, we found dexmedetomidine a promising agent for the treatment of ICU-associated delirious agitation, and we suggest this warrants further testing in a definitive double-blind multi-centre trial.

Trial registration

Clinicaltrials.gov NCT00505804
Conserved features of cohesin binding along fission yeast chromosomes
Authors: Schmidt Christine K , Brookes Neil , Uhlmann Frank
Published: May 2009

Background

Cohesin holds sister chromatids together to enable their accurate segregation in mitosis. How, and where, cohesin binds to chromosomes are still poorly understood, and recent genome-wide surveys have revealed an apparent disparity between its chromosomal association patterns in different organisms.

Results

Here, we present the high-resolution analysis of cohesin localization along fission yeast chromosomes. This reveals that several determinants, thought specific for different organisms, come together to shape the overall distribution. Cohesin is detected at chromosomal loading sites, characterized by the cohesin loader Mis4/Ssl3, in regions of strong transcriptional activity. Cohesin also responds to transcription by downstream translocation and accumulation at convergent transcriptional terminators surrounding the loading sites. As cells enter mitosis, a fraction of cohesin leaves chromosomes in a cleavage-independent reaction, while a substantial pool of cohesin dissociates when it is cleaved at anaphase onset. We furthermore observe that centromeric cohesin spreads out onto chromosome arms during mitosis, dependent on Aurora B kinase activity, emphasizing the plasticity of cohesin behavior.

Conclusions

Our findings suggest that features that were thought to differentiate cohesin between organisms collectively define the overall behavior of fission yeast cohesin. Apparent differences between organisms might reflect an emphasis on different aspects, rather than different principles, of cohesin action.
CC chemokine ligand-2 synergizes with the nonchemokine G protein-coupled receptor ligand fMLP in monocyte chemotaxis, and it cooperates with the TLR ligand LPS via induction of CXCL8
Authors: Gouwy Mieke , Struyf Sofie , Verbeke Hannelien , Put Willy , Proost Paul , Opdenakker Ghislain , Van Damme Jo
Published: May 2009

Novel mechanism of enhancing monocyte chemotaxis during bacterial infections with gram-negative bacteria demonstrates the importance of local contexts in inflammatory and infectious insults.

During inflammatory reactions, endogenously produced cytokines and chemokines act in a network and interact with hormones and neurotransmitters to regulate host immune responses. These signaling circuitries are even more interfaced during infections, when microbial agonists activate TLR, RLR, and NLR receptors. On the basis of the discovery of synergy between chemokines for neutrophil attraction, we extend here this phenomenon between the chemokine MCP-1/CCL2 and the GPCR ligand fMLP or the TLR4 agonist LPS on monocytes. In fact, the bacterial tripeptide fMLP, but not the cytokines IL-1β or IFN-γ, significantly and dose-dependently synergized with CCL2 in monocyte chemotaxis. Furthermore, LPS rapidly induced the expression of IL-8/CXCL8 but not of the CCL2 receptor CCR2 in monocytic cells. In turn, the induced CXCL8 synergized with CCL2 for mononuclear cell chemotaxis, and the chemotactic effect was mediated by CXCR1/CXCR2, because CXCL8 receptor antagonists or antibodies were capable of blocking the synergy, while keeping the responsiveness to CCL2 intact. These data recapitulate in vitro the complexity of innate immune regulation, provide a novel mechanism of enhancing monocyte chemotaxis during bacterial infections with gram-negative bacteria and demonstrate the importance of local contexts in inflammatory and infectious insults.
The endogenous Toll–like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer
Authors: Ehrchen Jan M , Sunderkötter Cord , Foell Dirk , Vogl Thomas , Roth Johannes
Published: May 2009

S100A8 and S100A9 are novel members of the group of damage–associated molecular pattern molecules (DAMP) which are early amplifiers of innate immune responses to tissue damage or danger signals.

The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin–induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.
Fast acquisition aperture correction in prestack depth migration using beamlet decomposition
Authors: Cao Jun , Wu Ru-Shan
Published: May 2009

Wave-equation-based acquisition aperture correction in the local angle domain can improve image amplitude significantly in prestack depth migration. However, its original implementation is inefficient because the wavefield decomposition uses the local slant stack (LSS), which is demanding computationally. We propose a faster method to obtain the image and amplitude correction factor in the local angle domain using beamlet decomposition in the local wavenumber domain. For a given frequency, the image matrix in the local wavenumber domain for all shots can be calculated efficiently. We then transform the shot-summed image matrix from the local wavenumber domain to the local angle domain (LAD). The LAD amplitude correction factor can be obtained with a similar strategy. Having a calculated image and correction factor, one can apply similar acquisition aperture corrections to the original LSS-based method. For the new implementation, we compare the accuracy and efficiency of two beamlet decompositions: Gabor-Daubechies frame (GDF) and local exponential frame (LEF). With both decompositions, our method produces results similar to the original LSS-based method. However, our method can be more than twice as fast as LSS and cost only twice the computation time of traditional one-way wave-equation-based migrations. The results from GDF decomposition are superior to those from LEF decomposition in terms of artifacts, although GDF requires a little more computing time.
One-step extrapolation method for reverse time migration
Authors: Zhang Yu , Zhang Guanquan
Published: May 2009

We have proposed a new method, a one-step extrapolation algorithm, to solve the acoustic wave equation. By introducing a square-root operator, the two-way wave equation can be formulated as a first-order partial differential equation in time, which is similar to the one-way wave equation. To solve the new wave equation, we used a stable explicit extrapolation method in the time direction and handled lateral velocity variations in the space and wavenumber domains. Unlike the conventional explicit finite-difference schemes, the new method does not suffer from numerical instability or numerical dispersion problems. It can be used to design cost-effective and high-quality reverse time migration or modeling code.
This issue of GEOPHYSICS
Authors: Wapenaar Kees
Published: May 2009

In this article, the Editor of Geophysics provides an overview of all technical articles in this issue of the journal.
Improved Survival for Stage IV Melanoma From an Unknown Primary Site
Authors: Lee Chris C. , Faries Mark B. , Wanek Leslie A. , Morton Donald L.
Published: May 2009

Purpose

We previously demonstrated a survival advantage for nodal metastasis of melanoma from an unknown primary (MUP) versus melanoma from a known primary (MKP). We hypothesized that this survival benefit would extend to MUP patients with distant (stage IV) metastasis.

Patients and Methods

We reviewed prospectively acquired data for 2,247 patients diagnosed with American Joint Committee on Cancer stage IV melanoma at our cancer center between 1971 and 2005. Cox regression analysis in a multivariate model identified prognostic factors significant for survival. MUP and MKP patients were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis.

Results

There were 1,849 MKP and 398 MUP patients. Multivariate analysis of patients with complete data sets identified known/unknown primary (hazard ratio [HR], 1.141; P = .032) and five other significant covariates: age (HR, 1.148; P = .007), sex (HR, 1.17; P = .001), site of metastasis (HR, 1.336; P < .001), number of different metastatic sites (HR, 1.303; P < .001), and decade of diagnosis (HR, 0.713; P < .001). Prognostic matching yielded 392 MUP-MKP pairs. Median OS and 5-year OS rate were significantly greater (P < .001) for MUP patients than for all matched MKP patients or for MKP patients matched by M1 category (for M1b and M1c) or number of metastatic sites.

Conclusion

The survival advantage previously reported for patients with stage III MUP also applies to patients with stage IV MUP. The mechanism responsible for this improved survival may provide clues for more effective treatment of stage IV melanoma and therefore warrants further investigation. The improved results for MUP suggest that these patients deserve aggressive therapy.
Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience
Authors: Angelov Lilyana , Doolittle Nancy D. , Kraemer Dale F. , Siegal Tali , Barnett Gene H. , Peereboom David M. , Stevens Glen , McGregor John , Jahnke Kristoph , Lacy Cynthia A. , Hedrick Nancy A. , Shalom Edna , Ference Sandra , Bell Susan , Sorenson Lisa , Tyson Rose Marie , Haluska Marianne , Neuwelt Edward A.
Published: May 2009

Purpose

Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved.

Patients and Methods

This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age ≥ 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis.

Results

The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS ≥ 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae.

Conclusion

This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.
Circulating Tumor Cells and [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Outcome Prediction in Metastatic Breast Cancer
Authors: De Giorgi Ugo , Valero Vicente , Rohren Eric , Dawood Shaheenah , Ueno Naoto T. , Miller M. Craig , Doyle Gerald V. , Jackson Summer , Andreopoulou Eleni , Handy Beverly C. , Reuben James M. , Fritsche Herbert A. , Macapinlac Homer A. , Hortobagyi Gabriel N. , Cristofanilli Massimo
Published: May 2009

Purpose

Circulating tumor cells (CTCs) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC).

Patients and Methods

A retrospective analyses of 115 MBC patients who started a new line of therapy and who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks during therapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts as favorable (ie, < five CTCs/7.5 mL blood) or unfavorable (≥ five CTCs/7.5 mL blood) outcomes. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival.

Results

In 102 evaluable patients, the median overall survival time was 14 months (range, 1 to > 41 months). Midtherapy CTC levels correlated with FDG-PET/CT response in 68 (67%) of 102 evaluable patients. In univariate analysis, midtherapy CTC counts and FDG-PET/CT response predicted overall survival (P < .001 and P = .001, respectively). FDG-PET/CT predicted overall survival (P = .0086) in 31 (91%) of 34 discordant patients who had fewer than five CTCs at midtherapy. Only midtherapy CTC levels remained significant in a multivariate analysis (P = .004).

Conclusion

Detection of five or more CTCs during therapeutic monitoring can accurately predict prognosis in MBC beyond metabolic response. FDG-PET/CT deserves a role in patients who have fewer than five CTCs at midtherapy. Prospective trials should evaluate the most sensitive and cost-effective modality for therapeutic monitoring in MBC.
Prognostic Effects of 25-Hydroxyvitamin D Levels in Early Breast Cancer
Authors: Goodwin Pamela J. , Ennis Marguerite , Pritchard Kathleen I. , Koo Jarley , Hood Nicky
Published: May 2009

Purpose

Vitamin D has been linked to breast cancer risk, but prognostic effects are unknown. Such effects are biologically plausible given the presence of vitamin D receptors in breast cancer cells, which act as nuclear transcription factors to regulate gene activity.

Patients and Methods

The study was conducted in a prospective inception cohort of 512 women with early breast cancer diagnosed 1989 to 1996. Vitamin D levels were measured in stored blood. Clinical, pathologic, and dietary data were accessed to examine prognostic effects of vitamin D.

Results

Mean age was 50.4 years, mean vitamin D was 58.1 ± 23.4 nmol/L. Vitamin D levels were deficient (< 50 nmol/L) in 37.5% of patients, insufficient (50 to 72 nmol/L) in 38.5% of patients, and sufficient (> 72 nmol/L) in 24.0% of patients. There was little variation in mean vitamin D levels between summer and winter months. Mean follow-up was 11.6 years; 116 women had distant recurrences, and 106 women died. Women with deficient vitamin D levels had an increased risk of distant recurrence (hazard ratio [HR] = 1.94; 95% CI, 1.16 to 3.25) and death (HR = 1.73; 95% CI, 1.05 to 2.86) compared with those with sufficient levels. The association remained after individual adjustment for key tumor and treatment related factors but was attenuated in multivariate analyses (HR = 1.71; 95% CI, 1.02 to 2.86 for distant recurrence; HR = 1.60; 95% CI, 0.96 to 2.64 for death).

Conclusion

Vitamin D deficiency may be associated with poor outcomes in breast cancer.