bluuebunny/crossref_metadata_2025 huggingface dataset:
Microstructure based creep constitutive model for precipitation strengthened alloys: Theory and application
Authors: Dyson B. F.
Published: February 2009

A kinetic creep equation for precipitation strengthened alloys has been derived using the climb/glide particle bypass micromechanism. It is applicable only when stresses lie within the range delineated by the dislocation network strength and the athermal yield strength — the lower of particle shear strength or Orowan strength. In this ‘dispersion controlled’ creep regime, strain rate is a hyperbolic sinh function of stress and interparticle spacing, making the state of dispersion an important microstructural feature. Existing equations have been used to quantify the evolution of dislocation and particulate microstructures and also stress redistribution between the two phases. The resulting constitutive equation set has been used to predict proof stresses, minimum creep rates and lifetimes for Nimonic 90. Comparison to industry data over a 600–900°C temperature range concludes that proof stresses are creep controlled once temperatures are above 700–725°C. Minimum creep rates and lifetimes over a similar temperature range are well predicted between 600 and 700°C but become progressively less accurate at higher temperatures/lower stresses, particularly lifetimes.
Formation of secondary reaction zone in ruthenium bearing nickel based single crystal superalloys with diffusion aluminide coatings
Authors: Das D. K. , Gleeson B. , Murphy K. S. , Ma S. , Pollock T. M.
Published: February 2009

Several Ru bearing experimental single crystal superalloys were coated with β-NiAl and Pt–Hf modified γ– γ′ coatings and subjected to elevated temperature exposure. The microstructure, oxidation resistance and the propensity for the formation of secondary reaction zones (SRZ) were investigated for these coatings. The presence of significant amounts of Ru in the superalloys did not prevent the cellular transformation leading to the formation of SRZ beneath the β-NiAl coating. Cyclic oxidation exposure of the β-NiAl coated alloys at 1100°C led to a significant further growth of the SRZ. In contrast, the γ– γ′ coating did not induce the undesirable cellular transformation, even after prolonged high temperature exposure. The γ– γ′ coating also provided good oxidation resistance to the superalloys. The driving forces for SRZ formation in case of the β-NiAl coating as compared to the γ– γ′ coating are discussed.
Influence of process parameters during secondary melting of nickel based superalloys
Authors: Mitchell A.
Published: February 2009

The superalloys are characterised by a strong tendency to form segregation defects during solidification and consequently have been the subject of much attention in the development of suitable melting and casting techniques. Processes such as vacuum arc remelting and electroslag remelting are now mature technologies and have well developed strategies for minimising segregation defects in the ingots produced. However, as the process control systems have gradually become more complex and automated, the need for control logic and a good understanding of it has become pronounced. Here, the underlying technical reasons for adopting particular process control methodologies are considered. The role of process parameters in controlling slag temperature and flow patterns in the electroslag remelting process and the metal pool thermal regime in the vacuum arc remelting process is reviewed in the context of ingot solidification, with particular attention being paid to electrode position, dimensions and the need for parameter stability. It is concluded that the equipment designs presently available for these processes are fundamentally correct, but that the control systems must be instructed carefully in order to produce the desired results.
Exegeting the Passio of St Agatha: patriarch Methodios (†847) on sexual differentiation and the perfect ‘man’
Authors: Krausmüller Dirk
Published: February 2009

This article challenges the widespread belief that Byzantine authors of the Dark Ages showed no interest in anthropological speculation. It focuses on patriarch Methodios of Constantinople († 847) who developed a highly original exegesis of Late Antique hagiographical texts, which he presented in the form of authorial comments in his paraphrases of these texts. His Encomium of St Agatha, which is based on the Passio of the saint, reveals a keen interest in the significance of gender and gender-related roles within the Christian belief system. Analysis of select passages shows that Methodios no longer subscribed to the widely held Late Antique belief that human perfection necessitated the dissociation from gender and gender-related roles, and that he therefore radically redefined such dissociation as an intermediary stage leading towards the sanctification of such urges through a redirection towards Christ.
The dialectics of expansion and retraction: recent scholarship on the Palaiologan aristocracy
Authors: Stathakopoulos Dionysios
Published: February 2009

In the first half of the fifteenth century a man donated an icon to the monastery of Mega Spelaion at Kalavryta; his name was less an instrument of identification than a manifesto of social association: John Tornikes Doukas Angelos Palaiologos Raoul Laskaris Philanthropenos Asanes. To judge from the chain of such resounding names of the leading late Byzantine families he clearly belonged to the dominant class of his time, and since nothing else is known of him, for lack of more precise social coordinates, we surely must count him among the aristocracy. Can we take an educated guess at what constituted a person of such social standing? He must have owned land; he probably held some office, while the accumulation of all his names points to marriage alliances between families of similar social standing. None of these assumptions suggests anything new about the aristocracy of the Palaiologan period, and yet, the overview that will follow aims to disclose exactly that: the points in which this era brought forth new developments that challenge the (thankfully dwindling) misconception of Byzantium as a state in which hardly anything changed. In 1973 Angeliki Laiou published her important article on the Palaiologan aristocracy. In twenty dense pages she made a number of remarks and reached several important conclusions that have influenced the direction of scholarship on the topic. As such it is worth summarizing these conclusions briefly.
International prognostic scoring system for Waldenström macroglobulinemia
Authors: Morel Pierre , Duhamel Alain , Gobbi Paolo , Dimopoulos Meletios A. , Dhodapkar Madhav V. , McCoy Jason , Crowley John , Ocio Enrique M. , Garcia-Sanz Ramon , Treon Steven P. , Leblond Veronique , Kyle Robert A. , Barlogie Bart , Merlini Giampaolo
Published: February 2009

Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 109/L, β2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.
A critical role of TAK1 in B-cell receptor–mediated nuclear factor κB activation
Authors: Schuman James , Chen Yuhong , Podd Andrew , Yu Mei , Liu Hong-Hsing , Wen Renren , Chen Zhijian J. , Wang Demin
Published: February 2009

The kinase TAK1 is essential for T-cell receptor (TCR)–mediated nuclear factor κB (NF-κB) activation and T-cell development. However, the role of TAK1 in B-cell receptor (BCR)–mediated NF-κB activation and B-cell development is not clear. Here we show that B-cell–specific deletion of TAK1 impaired the transition from transitional type 2 to mature follicular (FO) B cells and caused a marked decrease of marginal zone (MZ) B cells. TAK1-deficient B cells exhibited an increase of BCR-induced apoptosis and impaired proliferation in response to BCR ligation. Importantly, TAK1-deficient B cells failed to activate NF-κB after BCR stimulation. Thus, TAK1 is critical for B-cell maturation and BCR-induced NF-κB activation.
Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells
Authors: Lundqvist Andreas , Yokoyama Hisayuki , Smith Aleah , Berg Maria , Childs Richard
Published: February 2009

Ligation of inhibitory receptors renders natural killer (NK) cells inactive against autologous tumors. Recently, the proteasome inhibitor bortezomib was shown to sensitize tumors to autologous NK-cell cytotoxicity in vitro. Here, we show bortezomib augments the antitumor effects of syngeneic NK-cell infusions in tumor-bearing animals; this effect is further enhanced in regulatory T cell (Treg cell)–depleted hosts. In vitro, bortezomib-treated tumors had higher tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and perforin/granzyme-mediated caspase-8 activity, which enhanced their susceptibility to NK-cell lysis. Bioluminescence imaging of mice with established tumors showed treatment with bortezomib and syngeneic NK cells reduced tumor growth and prolonged survival compared with controls receiving bortezomib or NK cells alone. In contrast, tumor progression was not delayed when animals received bortezomib and perforin-deficient NK cells, showing drug-induced augmentation in NK-cell cytotoxicity was mediated through perforin/granzyme. Furthermore, tumor growth was slower in bortezomib-treated recipients when host Treg cells were eradicated with anti-CD25 antibody before infusing NK cells compared with mice without Treg-cell ablation (tumor doubling time, 16.7 vs 4.9 days, respectively; P = .02). These findings suggest that depletion of Treg cells followed by bortezomib-induced tumor sensitization to autologous NK cells could be used as a novel strategy to treat cancer.
Joint effect of obesity andTNFAvariability on asthma: two international cohort studies
Authors: Castro-Giner F. , Kogevinas M. , Imboden M. , de Cid R. , Jarvis D. , Mächler M. , Berger W. , Burney P. , Franklin K. A. , Gonzalez J. R. , Heinrich J. , Janson C. , Omenaas E. , Pin I. , Rochat T. , Sunyer J. , Wjst M. , Antó J-M. , Estivill X. , Probst-Hensch N. M.
Published: February 2009

Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-α (TNFA) gene. The current authors examined the joint effect of obesity andTNFAvariability on asthma in adults by combining two population-based studies.

The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped forTNFA -308and lymphotoxin-α (LTA)+252gene variants.

Obesity andTNFAwere associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (CI) 1.7–3.2; OR forTNFA -308polymorphism 1.3, 95% CI 1.1–1.6). The association of obesity with asthma was stronger for subjects carrying theG/AandA/ATNFA -308genotypes compared with the more commonG/Ggenotype, particularly among nonatopics (OR forG/AandA/Agenotypes 6.1, 95% CI 2.5–14.4; OR forG/Ggenotype 1.7, 95% CI 0.8–3.3).

The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.
COPD prevalence is increased in lung cancer, independent of age, sex and smoking history
Authors: Young R. P. , Hopkins R. J. , Christmas T. , Black P. N. , Metcalf P. , Gamble G. D.
Published: February 2009

Chronic obstructive pulmonary disease (COPD) is a common comorbid disease in lung cancer, estimated to affect 40–70% of lung cancer patients, depending on diagnostic criteria. As smoking exposure is found in 85–90% of those diagnosed with either COPD or lung cancer, coexisting disease could merely reflect a shared smoking exposure. Potential confounding by age, sex and pack-yr smoking history, and/or by the possible effects of lung cancer on spirometry, may result in over-diagnosis of COPD prevalence.

In the present study, the prevalence of COPD (pre-bronchodilator Global Initiative for Chronic Obstructive Lung Disease 2+ criteria) in patients diagnosed with lung cancer was 50% compared with 8% in a randomly recruited community control group, matched for age, sex and pack-yr smoking exposure (n = 602, odds ratio 11.6; p<0.0001).

In a subgroup analysis of those with lung cancer and lung function measured prior to the diagnosis of lung cancer (n = 127), we found a nonsignificant increase in COPD prevalence following diagnosis (56–61%; p = 0.45). After controlling for important variables, the prevalence of COPD in newly diagnosed lung cancer cases was six-fold greater than in matched smokers; this is much greater than previously reported.

We conclude that COPD is both a common and important independent risk factor for lung cancer.
Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study
Authors: Spears M. , Donnelly I. , Jolly L. , Brannigan M. , Ito K. , McSharry C. , Lafferty J. , Chaudhuri R. , Braganza G. , Adcock I. M. , Barnes P. J. , Wood S. , Thomson N. C.
Published: February 2009

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms.

In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 μg·day−1), theophylline (400 mg·day−1) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores.

At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L·min−1, 95% confidence intervals (CI) 10.9–68.8) and ACQ score (-0.47, 95% CI -0.91– -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13–342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99– -0.11), but not lung function.

In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.
Exploring the role of CT densitometry: a randomised study of augmentation therapy in α1-antitrypsin deficiency
Authors: Dirksen A. , Piitulainen E. , Parr D. G. , Deng C. , Wencker M. , Shaker S. B. , Stockley R. A.
Published: February 2009

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with α1-antitrypsin (α1-AT) deficiency.

In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg·kg−1human α1-AT (Prolastin®) or placebo for 2–2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices.

CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin®versusplacebo ranged 0.049–0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed.

In patients with α1-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from α1-AT augmentation.
Outcome prediction based on microarray analysis: a critical perspective on methods
Authors: Zervakis Michalis , Blazadonakis Michalis E , Tsiliki Georgia , Danilatou Vasiliki , Tsiknakis Manolis , Kafetzopoulos Dimitris
Published: February 2009

Background

Information extraction from microarrays has not yet been widely used in diagnostic or prognostic decision-support systems, due to the diversity of results produced by the available techniques, their instability on different data sets and the inability to relate statistical significance with biological relevance. Thus, there is an urgent need to address the statistical framework of microarray analysis and identify its drawbacks and limitations, which will enable us to thoroughly compare methodologies under the same experimental set-up and associate results with confidence intervals meaningful to clinicians. In this study we consider gene-selection algorithms with the aim to reveal inefficiencies in performance evaluation and address aspects that can reduce uncertainty in algorithmic validation.

Results

A computational study is performed related to the performance of several gene selection methodologies on publicly available microarray data. Three basic types of experimental scenarios are evaluated, i.e. the independent test-set and the 10-fold cross-validation (CV) using maximum and average performance measures. Feature selection methods behave differently under different validation strategies. The performance results from CV do not mach well those from the independent test-set, except for the support vector machines (SVM) and the least squares SVM methods. However, these wrapper methods achieve variable (often low) performance, whereas the hybrid methods attain consistently higher accuracies. The use of an independent test-set within CV is important for the evaluation of the predictive power of algorithms. The optimal size of the selected gene-set also appears to be dependent on the evaluation scheme. The consistency of selected genes over variation of the training-set is another aspect important in reducing uncertainty in the evaluation of the derived gene signature. In all cases the presence of outlier samples can seriously affect algorithmic performance.

Conclusion

Multiple parameters can influence the selection of a gene-signature and its predictive power, thus possible biases in validation methods must always be accounted for. This paper illustrates that independent test-set evaluation reduces the bias of CV, and case-specific measures reveal stability characteristics of the gene-signature over changes of the training set. Moreover, frequency measures on gene selection address the algorithmic consistency in selecting the same gene signature under different training conditions. These issues contribute to the development of an objective evaluation framework and aid the derivation of statistically consistent gene signatures that could eventually be correlated with biological relevance. The benefits of the proposed framework are supported by the evaluation results and methodological comparisons performed for several gene-selection algorithms on three publicly available datasets.
Analysis of small nucleolar RNAs reveals unique genetic features in malaria parasites
Authors: Mishra Prakash Chandra , Kumar Anuj , Sharma Amit
Published: February 2009

Background

Ribosome biogenesis is an energy consuming and stringently controlled process that involves hundreds of trans-acting factors. Small nucleolar RNAs (snoRNAs), important components of ribosome biogenesis are non-coding guide RNAs involved in rRNA processing, nucleotide modifications like 2'-O-ribose methylation, pseudouridylation and possibly gene regulation. snoRNAs are ubiquitous and are diverse in their genomic organization, mechanism of transcription and process of maturation. In vertebrates, most snoRNAs are present in introns of protein coding genes and are processed by exonucleolytic cleavage, while in plants they are transcribed as polycistronic transcripts.

Results

This is a comprehensive analysis of malaria parasite snoRNA genes and proteins that have a role in ribosomal biogenesis. Computational and experimental approaches have been used to identify several box C/D snoRNAs from different species ofPlasmodiumand confirm their expression. Our analyses reveal that the gene for endoribonuclease Rnt1 is absent fromPlasmodium falciparumgenome, which indicates the existence of alternative pre-rRNA processing pathways. The structural features of box C/D snoRNAs are highly conserved inPlasmodiumgenus; however, unlike other organisms most parasite snoRNAs are present in single copy. The genomic localization of parasite snoRNAs shows mixed patterns of those observed in plants, yeast and vertebrates. We have localized parasite snoRNAs in untranslated regions (UTR) of mRNAs, and this is an unprecedented and novel genetic feature. Akin to mammalian snoRNAs, those inPlasmodiummay also behave as mobile genetic elements.

Conclusion

This study provides a comprehensive overview on trans-acting genes involved in ribosome biogenesis and also a genetic insight into malaria parasite snoRNA genes.
PGC-1alphaas modifier of onset age in Huntington disease
Authors: Taherzadeh-Fard Elahe , Saft Carsten , Andrich Jürgen , Wieczorek Stefan , Arning Larissa
Published: February 2009

Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD.
Dysregulation of CXCL9 and reduced tumor growth in Egr-1 deficient mice
Authors: Caso Giuseppe , Barry Catherine , Patejunas Gerald
Published: February 2009

Background

Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli. Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization. Previous studies have shown that manipulating Egr-1 expression can have either positive or negative effects on tumor growth. We hypothesized that Egr-1 knockout mice might exhibit reduced tumor growth, possibly due to a reduced capacity to respond to angiogenic signals from a growing tumor.

Results

We injected 106 Lewis lung carcinoma (LLC1) cells subcutaneously in the flank of wild type and Egr-1 knockout mice. The average mass of tumors from wild type mice at 12 days after implantation was 413 +/- 128 mg, while those from Egr-1-/- mice was 219 +/- 81 mg (p = 0.001, mean +/- SD). However, sectioning the tumors and staining with anti-CD31 antibodies revealed no difference in the vascularity of the tumors and there was no difference in angiogenic growth factor expression. Expression of the chemokine Mig (CXCL9) was increased 2.8-fold in tumors from knockout mice, but no increase was found in serum levels of Mig. Natural killer cells have a 1.7-fold greater prevalence in the CD45+ cells found in tumors from Egr-1-/- mice compared to those from wild type mice. Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages.

Conclusion

Mice deficient in Egr-1 exhibit reduced growth of LLC1 tumors, and this phenomenon is associated with overexpression of Mig locally within the tumor. There are no obvious differences in tumor vascularity in the knockout mice. Natural killer cells accumulate in the tumors grown in Egr-1-/- mice, providing a potential mechanism for the reduction in growth.
Distinct synovial immunopathology in Behçet disease and psoriatic arthritis
Authors: Cañete Juan D , Celis Raquel , Noordenbos Troy , Moll Conchita , Gómez-Puerta Jose A , Pizcueta Pilar , Palacin Antonio , Tak Paul P , Sanmartí Raimon , Baeten Dominique
Published: February 2009

Introduction

The aim of the study was to investigate synovial immunopathology differences between early Behçet disease (BD) and psoriatic arthritis (PsA).

Methods

Needle arthroscopy of an inflamed knee joint was performed in patients with early untreated BD (n = 8) and PsA (n = 9). Synovial fluid (SF) was collected for cytokines, perforin, and granzyme analysis. Eight synovial biopsies per patient were obtained for immunohistochemical analysis of the cellular infiltrate (T cells, natural killer cells, macrophages, B cells, plasma cells, mast cells, and neutrophils), blood vessels as well as expression of perforin and granzyme. The stained slides were evaluated by digital image analysis.

Results

The global degree of synovial inflammation was similar in the two types of arthritis. In the analysis of the innate immune cell infiltration, there was a striking neutrophilic inflammation in BD synovitis whereas PsA displayed significantly higher numbers of cells positive for c-kit, a marker of mast cells. As for lymphocytes, CD3+ T cells, but neither CD20+ B cells nor CD138+ plasma cells, were significantly increased in BD versus PsA. Further analysis of the T-lymphocyte population showed no clear shift in CD4/CD8 ratio or Th1/Th2/Th17 profile. The SF levels of perforin, an effector molecule of cytotoxic cells, displayed a significant four- to fivefold increase in BD.

Conclusions

This systematic comparative analysis of early untreated synovitis identifies neutrophils and T lymphocytes as important infiltrating cell populations in BD. Increased levels of perforin in BD suggest the relevance of cytotoxicity in this disease.
Impaired vascular responses to parasympathetic nerve stimulation and muscarinic receptor activation in the submandibular gland in nonobese diabetic mice
Authors: Berggreen Ellen , Nyløkken Krister , Delaleu Nicolas , Hajdaragic-Ibricevic Hamijeta , Jonsson Malin V
Published: February 2009

Introduction

Decreased vascular responses to salivary gland stimulation are observed in Sjögren's syndrome patients. We investigate whether impaired vascular responses to parasympathetic stimulation and muscarinic receptor activation in salivary glands parallels hyposalivation in an experimental model for Sjögren's syndrome.

Methods

Blood flow responses in the salivary glands were measured by laser Doppler flowmeter. Muscarinic receptor activation was followed by saliva secretion measurements. Nitric oxide synthesis-mediated blood flow responses were studied after administration of a nitric oxide synthase inhibitor. Glandular autonomic nerves and muscarinic 3 receptor distributions were also investigated.

Results

Maximal blood flow responses to parasympathetic stimulation and muscarinic receptor activation were significantly lower in nonobese diabetic (NOD) mice compared with BALB/c mice, coinciding with impaired saliva secretion in nonobese diabetic mice (P < 0.005). Nitric oxide synthase inhibitor had less effect on blood flow responses after parasympathetic nerve stimulation in nonobese diabetic mice compared with BALB/c mice (P < 0.02). In nonobese diabetic mice, salivary gland parasympathetic nerve fibres were absent in areas of focal infiltrates. Muscarinic 3 receptor might be localized in the blood vessel walls of salivary glands.

Conclusions

Impaired vasodilatation in response to parasympathetic nerve stimulation and muscarinic receptor activation may contribute to hyposalivation observed in nonobese diabetic mice. Reduced nitric oxide signalling after parasympathetic nerve stimulation may contribute in part to the impaired blood flow responses. The possibility of muscarinic 3 receptor in the vasculature supports the notion that muscarinic 3 receptor autoantibodies present in nonobese diabetic mice might impair the fluid transport required for salivation. Parasympathetic nerves were absent in areas of focal infiltrates, whereas a normal distribution was found within glandular epithelium.

Trial registration

The trial registration number for the present study is 79-04/BBB, given by the Norwegian State Commission for Laboratory Animals.
Characteristics and outcomes of cancer patients in European ICUs
Authors: Taccone Fabio Silvio , Artigas Antonio A , Sprung Charles L , Moreno Rui , Sakr Yasser , Vincent Jean-Louis
Published: February 2009

Introduction

Increasing numbers of cancer patients are being admitted to the intensive care unit (ICU), either for cancer-related complications or treatment-associated side effects, yet there are relatively few data concerning the epidemiology and prognosis of cancer patients admitted to general ICUs. The aim of this study was to assess the characteristics of critically ill cancer patients, and to evaluate their prognosis.

Methods

This was a substudy of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a cohort, multicentre, observational study that included data from all adult patients admitted to one of 198 participating ICUs from 24 European countries during the study period. Patients were followed up until death, hospital discharge or for 60 days.

Results

Of the 3147 patients enrolled in the SOAP study, 473 (15%) had a malignancy, 404 (85%) had solid tumours and 69 (15%) had haematological cancer. Patients with solid cancers had the same severity of illness as the non-cancer population, but were older, more likely to be a surgical admission and had a higher frequency of sepsis. Patients with haematological cancer were more severely ill and more commonly had sepsis, acute lung injury/acute respiratory distress syndrome, and renal failure than patients with other malignancies; these patients also had the highest hospital mortality rate (58%). The outcome of all cancer patients was comparable with that in the non-cancer population, with a 27% hospital mortality rate. However, in the subset of patients with more than three failing organs, more than 75% of patients with cancer died compared with about 50% of patients without cancer (p = 0.01).

Conclusions

In this large European study, patients with cancer were more often admitted to the ICU for sepsis and respiratory complications than other ICU patients. Overall, the outcome of patients with solid cancer was similar to that of ICU patients without cancer, whereas patients with haematological cancer had a worse outcome.
α-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood
Authors: Pott Gregory B , Chan Edward D , Dinarello Charles A , Shapiro Leland
Published: February 2009

Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. α-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-α, IL-1β, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-α, IL-1β, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-α, and IL-1β significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis.
Pivotal Advance: Up-regulation of acetylcholine synthesis and paracrine cholinergic signaling in intravascular transplant leukocytes during rejection of rat renal allografts
Authors: Hecker Andreas , Mikulski Zbigniew , Lips Katrin S , Pfeil Uwe , Zakrzewicz Anna , Wilker Sigrid , Hartmann Petra , Padberg Winfried , Wessler Ignaz , Kummer Wolfgang , Grau Veronika
Published: February 2009

A new role and source of the old mediator acetylcholine is described, which is produced by graft monocytes and attenuates monocytic ATP-signaling.

During acute rejection, large numbers of leukocytes accumulate in the blood vessels of experimental renal allografts. About 70% of them are activated, cytotoxic monocytes that appear to be involved in allograft destruction. ACh exerts anti-inflammatory effects upon monocytes/macrophages and has been proposed to be a key player in neuroimmunological interactions. Its short half-life, however, makes it unlikely that neuronal ACh affects blood leukocytes. Renal transplantation was performed in the allogeneic DA to LEW and in the isogeneic LEW to LEW rat strain combination. Intravascular leukocytes were harvested after 4 days, and the expression of CHT1, cChAT, pChAT, and nAChR subunits was investigated by RT-PCR, immunoblotting, and immunohistochemistry. Monocytes were identified by double-labeling with ED1-antibody, directed to a CD68-like antigen. ACh content was measured by HPLC. [Ca2+]i was monitored by Fura-2. Intravascular graft leukocytes express CHT1 and cChAT mRNA and protein and pChAT protein. Their expression is strongly up-regulated in vivo during acute allograft rejection. Immunohistochemistry revealed CHT1, cChAT, and pChAT protein in ED1-positive monocytes. The ACh content of allograft intravascular leukocytes was sixfold higher than that of isografts. Intravascular leukocytes express nAChR subunits, and an ATP-induced increase in [Ca2+]i was augmented in vitro by a nAChR inhibitor in allograft but not isograft leukocytes. Intravascular graft leukocytes, among them monocytes, up-regulate non-neuronal ACh synthesis and develop auto-/paracrine cholinergic attenuation of ATP signaling during acute allograft rejection.
Role of Parathyroid Hormone-Related Protein in the Decreased Osteoblast Function in Diabetes-Related Osteopenia
Authors: Lozano Daniel , de Castro Luis F. , Dapía Sonia , Andrade-Zapata Irene , Manzarbeitia Félix , Alvarez-Arroyo M. Victoria , Gómez-Barrena Enrique , Esbrit Pedro
Published: February 2009

A deficit in bone formation is a major factor in diabetes-related osteopenia. We examined here whether diabetes-associated changes in osteoblast phenotype might in part result from a decrease in PTH-related protein (PTHrP). We used a bone marrow ablation model in diabetic mice by multiple streptozotocin injections. PTHrP (1–36) (100 μg/kg, every other day) or vehicle was administered to mice for 13 d starting 1 wk before marrow ablation. Diabetic mice showed bone loss in both the intact femur and the regenerating tibia on d 6 after ablation; in the latter, this was related to decreased bone-forming cells, osteoid surface, and blood vessels, and increased marrow adiposity. Moreover, a decrease in matrix mineralization occurred in ex vivo bone marrow cultures from the unablated tibia from diabetic mice. These skeletal alterations were associated with decreased gene expression (by real-time PCR) of Runx2, osterix, osteocalcin, PTHrP, the PTH type 1 receptor, vascular endothelial growth factor and its receptors, and osteoprotegerin to receptor activator of nuclear factor-κB ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-γ2 mRNA levels. Similar changes were induced by hyperosmotic (high glucose or mannitol) medium in osteoblastic MC3T3-E1 cells, which were mimicked by adding a neutralizing anti-PTHrP antibody or PTH type 1 receptor antagonists to these cells in normal glucose medium. PTHrP (1–36) administration reversed these changes in both intact and regenerating bones from diabetic mice in vivo, and in MC3T3-E1 cells exposed to high glucose. These findings strongly suggest that PTHrP has an important role in the altered osteoblastic function related to diabetes.
Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling
Authors: Ikeda Yasumasa , Aihara Ken-ichi , Yoshida Sumiko , Sato Takashi , Yagi Shusuke , Iwase Takashi , Sumitomo Yuka , Ise Takayuki , Ishikawa Kazue , Azuma Hiroyuki , Akaike Masashi , Kato Shigeaki , Matsumoto Toshio
Published: February 2009

Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system’s involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg · d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-β1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-β-phosphorylated Smad pathway.
Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions
Authors: Kleinberg David L. , Wood Teresa L. , Furth Priscilla A. , Lee Adrian V.
Published: February 2009

Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.
Minireview: GPCR and G Proteins: Drug Efficacy and Activation in Live Cells
Authors: Vilardaga Jean-Pierre , Bünemann Moritz , Feinstein Timothy N. , Lambert Nevin , Nikolaev Viacheslav O. , Engelhardt Stefan , Lohse Martin J. , Hoffmann Carsten
Published: February 2009

Many biochemical pathways are driven by G protein-coupled receptors, cell surface proteins that convert the binding of extracellular chemical, sensory, and mechanical stimuli into cellular signals. Their interaction with various ligands triggers receptor activation that typically couples to and activates heterotrimeric G proteins, which in turn control the propagation of secondary messenger molecules (e.g. cAMP) involved in critically important physiological processes (e.g. heart beat). Successful transfer of information from ligand binding events to intracellular signaling cascades involves a dynamic interplay between ligands, receptors, and G proteins. The development of Förster resonance energy transfer and bioluminescence resonance energy transfer-based methods has now permitted the kinetic analysis of initial steps involved in G protein-coupled receptor-mediated signaling in live cells and in systems as diverse as neurotransmitter and hormone signaling. The direct measurement of ligand efficacy at the level of the receptor by Förster resonance energy transfer is also now possible and allows intrinsic efficacies of clinical drugs to be linked with the effect of receptor polymorphisms.
Negative Regulation of TSHα Target Gene by Thyroid Hormone Involves Histone Acetylation and Corepressor Complex Dissociation
Authors: Wang Dongqing , Xia Xianmin , Liu Ying , Oetting Alexis , Walker Robert L. , Zhu Yuelin , Meltzer Paul , Cole Philip A. , Shi Yun-Bo , Yen Paul M.
Published: February 2009

Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T3) decreased transcription, and surprisingly increased histone acetylation, of TSHα promoter. This increase was mediated directly by thyroid hormone receptor. Histone acetylation of H3K9 and H3K18 sites, two modifications usually associated with transcriptional activation, occur in negative regulation of TSHα promoter. T3 also caused release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin β-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSHα promoter in chromatin immunoprecipitation assays. NCoR and HDAC3 overexpression selectively increased ligand-independent basal transcription. Two histone acetyltransferase inhibitors increased overall transcription but did not abrogate negative regulation or NCoR/HDAC3 complex release by T3. Chromatin immunoprecipitation analyses of an endogenous positively regulated target gene showed increased histone acetylation and corepressor complex release with T3 treatment. Finally, microarray analyses suggested there is a subset of negatively regulated genes with increased histone acetylation. These findings demonstrate the critical role of NCoR/HDAC3 complex in negative regulation of TSHα gene expression and show that similar complexes and overlapping epigenetic modifications can participate in both negative and positive transcriptional regulation.
TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase
Authors: Matthews Randolph P. , Lorent Kristin , Mañoral-Mobias Rafael , Huang Yuehua , Gong Weilong , Murray Ian V. J. , Blair Ian A. , Pack Michael
Published: February 2009

Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtpmutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFα. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wild-type adult fish treated with an Ahcy inhibitor. These data argue that AHCYpolymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis,particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.