bluuebunny/crossref_metadata_2025 huggingface dataset:
Just a guy in pajamas? Framing the blogs in mainstream US newspaper coverage (1999—2005)
Authors: Jones Julie , Himelboim Itai
Published: January 2010

When new technologies are introduced to the public, their widespread adoption is dependent, in part, on news coverage (Rogers, 1995).Yet, as weblogs began to play major role in the public spheres of politics and journalism, journalists faced a paradox: how to cover a social phenomenon that was too large to ignore and posed a significant threat to their profession. This article examines how blogs were framed by US newspapers as the public became more aware of the blogging world. A content analysis of blog-related stories in major US newspapers from 1999 to 2005 was conducted. Findings suggest that newspaper coverage framed blogs as more beneficial to individuals and small cohorts than to larger social entities such as politics, business and journalism. Moreover, only in the realm of journalism were blogs framed as more of a threat than a benefit, and rarely were blogs considered an actual form of journalism.
‘Don’t talk to me’: effects of ideologically homogeneous online groups and politically dissimilar offline ties on extremism
Authors: Wojcieszak Magdalena
Published: January 2010

This study analyzes cross-sectional data obtained from respondents in neo-Nazi online discussion forums and textual data from postings to these forums. It assesses the impact of participation in radical and homogeneous online groups on opinion extremism and probes whether this impact depends on political dissimilarity of strong and weak offline ties. Specifically, does dissimilarity attenuate (as deliberative theorists hope) or rather exacerbate (as research on biased processing predicts) extreme opinions? As expected, extremism increases with increased online participation, likely due to the informational and normative influences operating within online groups. Supporting the deliberative and biased processing models, both like-minded and dissimilar social ties offline exacerbate extremism. Consistent with the biased processing model, dissimilar offline ties exacerbate the effects of online groups. The theoretical and practical implications are discussed.
Co-creating games: a co-evolutionary analysis
Authors: Banks John , Potts Jason
Published: January 2010

The phenomenon of consumer co-creation is often framed in terms of whether either economic market forces or socio-cultural non-market forces ultimately dominate. We propose an alternate model of consumer co-creation in terms of co-evolution between markets and non-markets. Our model is based on a recent ethnographic study of a massively multiplayer online game through its development, release and ultimate failure, and is cast in terms of two explanatory models: multiple games and social network markets.We conclude that consumer co-creation is indeed complex, but in ways that relate to both emergent market expectations and the evolution of markets, not to the transcendence of markets.
How to become a sophisticated user: a two-dimensional approach to e-literacy
Authors: Brandtweiner Roman , Donat Elisabeth , Kerschbaum Johann
Published: January 2010

The internet media require the development of new user skills not required by the traditional media. Current European initiatives focus on providing access to a PC with internet and ensuring basic usage skills to address the digital divide, while media competence is of less importance. Although access rates in European countries are quite high, this study finds persistent rates of non-users, because access and basic skills alone do not guarantee usage. The article presents a representative survey carried out in Austria in 2007 ( N = 529) which illustrates the full spectrum of internet usage and its determinants, employing a typology developed by the authors. In addition to the continuing influence of sociodemographics on usage behaviour, location of access is shown to be an important influence on skills development. Furthermore, deficits in digital literacy can often be compensated by social support, given either in the form of emotional support during learning, or in the form of technical support. The authors conclude that to become a sophisticated user, however, requires guidance beyond merely attending computer classes or the assistance of relatives, colleagues, or friends, but is also a societal issue, if the goal of universal participation and integration is to be achieved.
Higher Education Leadership Competencies: Quantitatively Refining a Qualitative Model
Authors: Smith Zachary A. , Wolverton Mimi
Published: January 2010

This article highlights exploratory research in which a qualitative higher education leadership competencies model is refined through quantitative methods. Three groups of higher education leaders identify important competencies necessary for effective leadership. A survey was administered and analyzed. Five competency categories emerged: analytical, communication, student affairs, behavioral, and external relations.
Emotional Intelligence and Transformational and Transactional Leadership: A Meta-Analysis
Authors: Harms P.D. , Credé Marcus
Published: January 2010

The purpose of this study is to evaluate claims that emotional intelligence is significantly related to transformational and other leadership behaviors. Results (based on 62 independent samples) indicated a validity estimate of .59 when ratings of both emotional intelligence and leadership behaviors were provided by the same source (self, subordinates, peers, or superiors). However, when ratings of the constructs were derived from different sources, the validity estimate was .12. Lower validity estimates were found for transactional and laissez-faire leadership behaviors. Separate analyses were performed for each measure of emotional intelligence. Trait measures of emotional intelligence tended to show higher validities than ability-based measures of emotional intelligence. Agreement across ratings sources for the same construct was low for both transformational leadership (.14) and emotional intelligence (.16).
An in vivo model to study and manipulate the hematopoietic stem cell niche
Authors: Song Junhui , Kiel Mark J. , Wang Zhou , Wang Jingcheng , Taichman Russell S. , Morrison Sean J. , Krebsbach Paul H.
Published: January 2010

Because the microenvironment that supports hematopoietic stem cell (HSC) proliferation and differentiation is not fully understood, we adapted a heterotopic bone formation model as a new approach for studying the HSC microenvironment in vivo. Endogenous HSCs homed to tissue-engineered ossicles and individually sorted HSCs from ossicles were able to reconstitute lethally irradiated mice. To further explore this model as a system to study the stem cell niche, ossicles were established with or without anabolic parathyroid hormone (PTH) treatment during the 4-week course of bone development. Histology and micro–computed tomography showed higher bone area-to-total area ratios, thicker cortical bone and trabecular bone, significantly higher bone mineral density and bone volume fraction in PTH-treated groups than in controls. By an in vivo competitive long-term reconstitution assay, HSC frequency in the ossicle marrow was 3 times greater in PTH groups than in controls. When whole bone marrow cells were directly injected into the ossicles after lethal irradiation, the PTH-treated groups showed an enhanced reconstitution rate compared with controls. These findings suggest the residence of HSCs in heterotopic bone marrow and support the future use of this ossicle model in elucidating the composition and regulation of the HSC niche.
Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation
Authors: Micklethwaite Kenneth P. , Savoldo Barbara , Hanley Patrick J. , Leen Ann M. , Demmler-Harrison Gail J. , Cooper Laurence J. N. , Liu Hao , Gee Adrian P. , Shpall Elizabeth J. , Rooney Cliona M. , Heslop Helen E. , Brenner Malcolm K. , Bollard Catherine M. , Dotti Gianpietro
Published: January 2010

Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR+ CTLs produced interferon-γ (IFNγ) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 ± 104 to 1034 ± 304 spot-forming cells [SFCs]/105 T cells) and lysed primary B-ALL blasts in 51Cr-release assays (mean, 66% ± 5% specific lysis; effector-target [E/T] ratio, 40:1) and the CD19+ Raji cell line (mean, 78% ± 17%) in contrast to nontransduced controls (8% ± 8% and 3% ± 2%). CB-derived CAR+ CTLs showed similar antiviral and antitumor function and both PB and CB CAR+ CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.
Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenström macroglobulinemia
Authors: Roccaro Aldo M. , Sacco Antonio , Aujay Monette , Ngo Hai T. , Azab Abdel Kareem , Azab Feda , Quang Phong , Maiso Patricia , Runnels Judith , Anderson Kenneth C. , Demo Susan , Ghobrial Irene M.
Published: January 2010

Proteasome inhibition represents a valid antitumor approach and its use has been validated in Waldenström macroglobulinemia (WM), where bortezomib has been successfully tested in clinical trials. Nevertheless, a significant fraction of patients relapses, and many present toxicity due to its off-target effects. Selective inhibition of the chymotrypsin-like (CT-L) activity of constitutive proteasome 20S (c20S) and immunoproteasome 20S (i20S) represents a sufficient and successful strategy to induce antineoplastic effect in hematologic tumors. We therefore studied ONX0912, a novel selective, irreversible inhibitor of the CT-L activity of i20S and c20S. Primary WM cells express higher level of i20S compared with c20S, and that ONX0912 inhibited the CT-L activity of both i20S and c20S, leading to induction of toxicity in primary WM cells, as well as of apoptosis through c-Jun N-terminal kinase activation, nuclear factor κB (NF-κB) inhibition, caspase cleavage, and initiation of the unfolded protein response. Importantly, ONX0912 exerted toxicity in WM cells, by reducing bone marrow (BM)–derived interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1) secretion, thus inhibiting BM-induced p-Akt and phosphorylated extracellular signal-related kinase (p-ERK) activation in WM cells. These findings suggest that targeting i20S and c20S CT-L activity by ONX0912 represents a valid antitumor therapy in WM.
COPD prevalence and its association with occupational exposures in a general population
Authors: Melville A.M. , Pless-Mulloli T. , Afolabi O.A. , Stenton S.C.
Published: January 2010

The aim of this study was to ascertain the population prevalence of chronic obstructive pulmonary disease (COPD) in an area with past heavy industry and to establish the relative contributions of occupational and other risk factors.

We investigated respiratory symptoms and the prevalence of spirometrically-defined COPD in a population-based study in North-East England (UK) between 2002 and 2004. Questionnaires were posted to 6,000 males and 6,000 females, 45–69 yrs of age, who were randomly selected from a primary care database (response rate 64%, n = 7,566). Spirometric measurements were performed on 845 randomly selected responders. We defined COPD by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) II criteria.

The prevalence of respiratory symptoms was 55%. Symptoms were strongly associated with smoking, occupational exposures and hay fever. COPD was present in 10% of subjects. Its presence was significantly associated with occupational exposures, smoking and hay fever.

COPD is common in North-East England. Respiratory effects of occupational exposures can be detected within the general population: there were clear associations between occupational exposures and respiratory symptoms. The association with COPD was more marked in females.
Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD
Authors: Vogiatzis I. , Simoes D.C.M. , Stratakos G. , Kourepini E. , Terzis G. , Manta P. , Athanasopoulos D. , Roussos C. , Wagner P.D. , Zakynthinos S.
Published: January 2010

It is known that non-cachectic patients with chronic obstructive pulmonary disease (COPD) respond well to pulmonary rehabilitation, but whether cachectic COPD patients are capable of adaptive responses is both important and unknown.

10 cachectic and 19 non-cachectic COPD patients undertook high-intensity cycling training, at the same relative intensity, for 45 min·day−1, 3 days·week−1for 10 weeks. Before and after rehabilitation vastus lateralis muscle biopsies were analysed morphologically and for the expression of muscle remodelling factors (insulin-like growth factor (IGF)-I, myogenic differentiation factor D (MyoD), tumour necrosis factor (TNF)-α, nuclear factor (NF)-κB and myostatin) and key components of ubiquitin-mediated proteolytic systems (muscle ring finger protein (MURF)-1 and Atrogin-1).

Rehabilitation improved peak work-rate and the 6-min walk distance similarly in non-cachectic (18±3% and 42±13 m, respectively) and cachectic (16±2% and 53±16 m, respectively) patients, but quality of life only improved in non-cachectic COPD. Mean muscle fibre cross-sectional area increased in both groups, but significantly less in cachectic (7±2%) than in non-cachectic (11±2%) patients. Both groups equally decreased the proportion of type IIb fibres and increased muscle capillary/fibre ratio. IGF-I mRNA expression increased in both groups, but IGF-I protein levels increased more in non-cachectic COPD. MyoD was upregulated, whereas myostatin was downregulated at the mRNA and protein level only in non-cachectic patients. Whilst rehabilitation had no effect on TNF-α expression, it decreased the activation of the transcription factor NF-κB in both groups by the same amount. Atrogin-1 and MURF-1 expression were increased in cachectic COPD, but it was decreased in non-cachectic patients.

Cachectic COPD patients partially retain the capacity for peripheral muscle remodelling in response to rehabilitation and are able to increase exercise capacity as much as those without cachexia, even if they exhibit both quantitative and qualitative differences in the type of muscle fibre remodelling in response to exercise training.
Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a
Authors: Bertrand J. , Boucherle B. , Billet A. , Melin-Heschel P. , Dannhoffer L. , Vandebrouck C. , Jayle C. , Routaboul C. , Molina M-C. , Décout J-L. , Becq F. , Norez C.
Published: January 2010

One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal α-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure–activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR.

Here, we present the effect of GPact-11a on CFTR activity usingin vitro(iodide efflux, fluorescence imaging and patch-clamp recordings),ex vivo(short-circuit current measurements) andin vivo(salivary secretion) experiments.

We report that GPact-11a: 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulatesex vivothe colonic chloride secretion and increasesin vivothe salivary secretion incftr+/+but notcftr−/−mice; and 4) is selective for CFTR because its effect is inhibited by CFTRinh-172, GlyH-101, glibenclamide and GPinh-5a.

To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis.
Measuring asthma control: a comparison of three classification systems
Authors: O’Byrne P.M. , Reddel H.K. , Eriksson G. , Östlund O. , Peterson S. , Sears M.R. , Jenkins C. , Humbert M. , Buhl R. , Harrison T.W. , Quirce S. , Bateman E.D.
Published: January 2010

There are various ways to classify asthma control; however, no classification is universally accepted. This retrospective analysis compared asthma control as assessed by the Asthma Control Questionnaire (5-item version; ACQ-5), Global Initiative for Asthma (GINA) or Gaining Optimal Asthma Control (GOAL) study criteria.

Pooled data at the final study week (n = 8,188) from three budesonide/formoterol maintenance and reliever therapy studies which measured ACQ-5 were stratified according to GINA or GOAL criteria and ACQ-5 score distribution. The percentages of patients with a controlled/partly controlled week (GINA), totally/well-controlled week (GOAL) and range of ACQ-5 cut-off points were compared.

Patients with GINA controlled, partly controlled and uncontrolled asthma had mean ACQ-5 scores of 0.43, 0.75 and 1.62, respectively. Patients with GOAL totally controlled, well-controlled and uncontrolled asthma had ACQ-5 scores of 0.39, 0.78 and 1.63. The kappa measure of agreement was 0.80 for GINA and GOAL criteria, and 0.63 for GINA controlled/partly controlled and ACQ-5 <1.00. ACQ-5 detected clinically important improvements in 49% of patients who, according to GINA criteria, remained uncontrolled at the end of the study.

Asthma control measured by GINA or GOAL criteria provides similar results. GINA Controlled/Partly Controlled and GOAL Totally Controlled/Well-Controlled correspond to ACQ-5 <1.00. The ACQ-5 is more responsive to change in a clinical trial setting than a categorical scale.
MEK modulates force-fluctuation-induced relengthening of canine tracheal smooth muscle
Authors: Dowell M.L. , Lavoie T.L. , Lakser O.J. , Dulin N.O. , Fredberg J.J. , Gerthoffer W.T. , Seow C.Y. , Mitchell R.W. , Solway J.
Published: January 2010

Tidal breathing, and especially deep breathing, is known to antagonise bronchoconstriction caused by airway smooth muscle (ASM) contraction; however, this bronchoprotective effect of breathing is impaired in asthma. Force fluctuations applied to contracted ASMin vitrocause it to relengthen, force-fluctuation-induced relengthening (FFIR). Given that breathing generates similar force fluctuations in ASM, FFIR represents a likely mechanism by which breathing antagonises bronchoconstriction. Thus it is of considerable interest to understand what modulates FFIR, and how ASM might be manipulated to exploit this phenomenon. It was demonstrated previously that p38 mitogen-activated protein kinase (MAPK) signalling regulates FFIR in ASM strips. Here, it was hypothesised that the MAPK kinase (MEK) signalling pathway also modulates FFIR.

In order to test this hypothesis, changes in FFIR were measured in ASM treated with the MEK inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene).

Increasing concentrations of U0126 caused greater FFIR. U0126 reduced extracellular signal-regulated kinase 1/2 phosphorylation without affecting isotonic shortening or 20-kDa myosin light chain and p38 MAPK phosphorylation. However, increasing concentrations of U0126 progressively blunted phosphorylation of high-molecular-weight caldesmon (h-caldesmon), a downstream target of MEK. Thus changes in FFIR exhibited significant negative correlation with h-caldesmon phosphorylation.

The present data demonstrate that FFIR is regulated through MEK signalling, and suggest that the role of MEK is mediated, in part, through caldesmon.
Ventilatory chemoresponsiveness, narcolepsy–cataplexy and human leukocyte antigen DQB1*0602 status
Authors: Han F. , Mignot E. , Wei Y.C. , Dong S.X. , Li J. , Lin L. , An P. , Wang L.H. , Wang J.S. , He M.Z. , Gao H.Y. , Li M. , Gao Z.C. , Strohl K.P.
Published: January 2010

We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy–cataplexy (mean±sdage 20±10 yrs, 69% male) and 117 controls (22±6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (δV′E)/carbon dioxide tension (δPCO2) L·min−1·mmHg−1) and hypoxic (δV′E/change in arterial oxygen saturation measured by probe oximetry (δSp,O2) L·min−1per %Sp,O2) responsiveness, and by spirometry. Hypocretin deficiency was determined either by measures of cerebrospinal fluid hypocretin-1 (37 patients) or by positive HLA-DQB1*0602 status. All patients and 49% of controls underwent polysomnography and multiple sleep latency testing. Despite similar spirometric values, patients had a higher apnoea/hypopnoea index (AHI) (2.8±5.4versus0.8±1.6 h−1; p = 0.03) and lower minimal oxygen saturation during sleep (87%±7versus91±4%; p = 0.0002), independent of age, sex and body mass index. Patients had depressed hypoxic responsiveness (0.13±0.09versus0.19±0.13 L·min−1per %Sp,O2; p<0.0001), independent of AHI, but hypercapnic responsiveness did not differ. Examined by HLA status, positive (26 out of 117) controls had lower hypoxic but similar hypercapnic responsiveness than those marker-negative (0.13±0.08versus0.20±0.14 L·min−1per %Sp,O2; p<0.0001). Thus, a lower hypoxic responsiveness in the narcolepsy–cataplexy group is a result of DQB1*0602 status rather than the clinical features of disease.
Th2-associated immunity to bacteria in teenagers and susceptibility to asthma
Authors: Hollams E.M. , Hales B.J. , Bachert C. , Huvenne W. , Parsons F. , de Klerk N.H. , Serralha M. , Holt B.J. , Ahlstedt S. , Thomas W.R. , Sly P.D. , Holt P.G.
Published: January 2010

Bacterial colonisation of the airways is associated with increased risk of childhood asthma. Immunoglobulin (Ig)E against bacterial antigens has been reported in some asthmatics, suggesting a role for bacterial-specific type-2 immunity in disease pathogenesis. We aimed to investigate relationships between bacterial-specific IgE amongst teenagers and asthma susceptibility.

We measured titres of IgE againstHaemophilus influenzae,Streptococcus pneumoniaeandStaphylococcus aureusin 1,380 teenagers, and related these to asthma symptomatology and immunophenotypes.

IgE titres againstS. aureus-derived enterotoxins were highest amongst atopics and were associated with asthma risk. Surprisingly, IgE titres againstH. influenzaeandS. pneumoniaesurface antigens were higher, not stratified by atopy and independently associated with decreased asthma risk.

The positive association between type-2 immunity toS. aureusand asthma phenotypes probably reflects IgE-mediated effector cell activationviaenterotoxin super antigens which are secreted in soluble form. The contrasting benign nature of type-2 immunity toH. influenzaeandS. pneumoniaeantigens may reflect their lower availability in soluble forms that can crosslink IgE receptors. We theorise that instead they may be processed by antigen presenting cells and presented to type-2 memory cells leading to mucosal secretion of interleukin (IL)-4/IL-13, a mechanism widely recognised in other tissues to attenuate T-helper-1 associated bacterial-induced inflammation.
Adrenal function is related to prognosis in moderate community-acquired pneumonia
Authors: Kolditz M. , Halank M. , Schulte-Hubbert B. , Höffken G.
Published: January 2010

The aim of our study was to prospectively examine adrenal function, including cosyntropin stimulation, and its prognostic value in patients with moderate community-acquired pneumonia (CAP).

59 consecutive adult patients hospitalised on normal wards because of CAP were enrolled. A cosyntropin stimulation test was performed and serum concentrations of C-reactive protein, procalcitonin, interleukin-6, tumour necrosis factor-α, ACTH, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) were measured. Predefined outcome parameters were clinical instability after 72 h, mortality and combined intensive care unit (ICU) admission or mortality.

Critical illness-related corticosteroid insufficiency (CIRCI) occurred in six patients (10.3%). Cortisol, age-corrected DHEA, ACTH and the DHEA/DHEAS ratio were elevated in patients remaining unstable after 72 h. In multivariate analysis, cortisol (p = 0.03), ACTH (p = 0.04) and the pneumonia severity index (PSI) score (p = 0.005) independently predicted clinical instability after 72 h, and only cortisol predicted mortality (p = 0.04) and combined ICU-admission or mortality (p = 0.006). The predictive value of serum cortisol after receiver operating characteristic curve analysis equalled that of the PSI score. Patients with serum cortisol >734 nmol·L−1had a high probability for mortality (OR 38.3; p = 0.002).

CIRCI is rare in patients with moderate CAP. Adrenal function is related to the prognosis of CAP. The diagnostic accuracy of serum cortisol equals that of the PSI score. Serum cortisol should be evaluated within clinical prediction scores on larger studies.
Haplotype allelic classes for detecting ongoing positive selection
Authors: Hussin Julie , Nadeau Philippe , Lefebvre Jean-François , Labuda Damian
Published: January 2010

Background

Natural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in underlying genomic segments that can be recognized through deviations in allelic or haplotypic frequency spectra. To provide an identifiable signature of recent positive selection that can be detected by comparison with the background distribution, we introduced a new way of looking at genomic polymorphisms: haplotype allelic classes.

Results

The model combines segregating sites and haplotypic information in order to reveal useful data characteristics. We developed a summary statistic, Svd, to compare the distribution of the haplotypes carrying the selected allele with the distribution of the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, haplotype allelic class performance and the derived statistic in capturing deviation from neutrality due to positive selection, we analyzed haplotypic variation in detail in the locus of lactase persistence in the three HapMap Phase II populations.

Conclusions

We showed that the Svd statistic is less sensitive than other tests to confounding factors such as demography or recombination. Our approach succeeds in identifying candidate loci, such as the lactase-persistence locus, as targets of strong positive selection and provides a new tool complementary to other tests to study natural selection in genomic data.
Identification of tomato plant as a novel host model for Burkholderia pseudomallei
Authors: Lee Yian Hoon , Chen Yahua , Ouyang Xuezhi , Gan Yunn-Hwen
Published: January 2010

Background

Burkholderia pseudomallei is the causative agent for melioidosis, a disease with significant mortality and morbidity in endemic regions. Its versatility as a pathogen is reflected in its relatively huge 7.24 Mb genome and the presence of many virulence factors including three Type Three Secretion Systems known as T3SS1, T3SS2 and T3SS3. Besides being a human pathogen, it is able to infect and cause disease in many different animals and alternative hosts such as C. elegans.

Results

Its host range is further extended to include plants as we demonstrated the ability of B. pseudomallei and the closely related species B. thailandensis to infect susceptible tomato but not rice plants. Bacteria were found to multiply intercellularly and were found in the xylem vessels of the vascular bundle. Disease is substantially attenuated upon infection with bacterial mutants deficient in T3SS1 or T3SS2 and slightly attenuated upon infection with the T3SS3 mutant. This shows the importance of both T3SS1 and T3SS2 in bacterial pathogenesis in susceptible plants.

Conclusions

The potential of B. pseudomallei as a plant pathogen raises new possibilities of exploiting plant as an alternative host for novel anti-infectives or virulence factor discovery. It also raises issues of biosecurity due to its classification as a potential bioterrorism agent.
Uptake of purines in Plasmodium falciparum-infected human erythrocytes is mostly mediated by the human Equilibrative Nucleoside Transporter and the human Facilitative Nucleobase Transporter
Authors: Quashie Neils B , Ranford-Cartwright Lisa C , de Koning Harry P
Published: January 2010

Background

Plasmodium parasites are unable to synthesize purines de novo and have to salvage them from the host. Due to this limitation in the parasite, purine transporters have been an area of focus in the search for anti-malarial drugs. Although the uptake of purines through the human equilibrative nucleoside transporter (hENT1), the human facilitative nucleobase transporter (hFNT1) and the parasite-induced new permeation pathway (NPP) has been studied, no information appears to exist on the relative contribution of these three transporters to the uptake of adenosine and hypoxanthine. Using the appropriate transporter inhibitors, the role of each of these salvage pathways to the overall purine transport in intraerythrocytic Plasmodium falciparum was systematically investigated.

Methods

The transport of adenosine, hypoxanthine and adenine into uninfected and P. falciparum-infected human erythrocytes was investigated in the presence or absence of classical inhibitors of the hFNT1, hENT1 and NPP. The effective inhibition of the various transporters by the classical inhibitors was verified using appropriate known substrates. The ability of high concentration of unlabelled substrates to saturate these transporters was also studied.

Results

Transport of exogenous purine into infected or uninfected erythrocytes occurred primarily through saturable transporters rather than through the NPP. Hypoxanthine and adenine appeared to enter erythrocytes mainly through the hFNT1 nucleobase transporter whereas adenosine entered predominantly through the hENT1 nucleoside transporter. The rate of purine uptake was approximately doubled in infected cells compared to uninfected erythrocytes. In addition, it was found that the rate of adenosine uptake was considerably higher than the rate of hypoxanthine uptake in infected human red blood cells (RBC). It was also demonstrated that furosemide inhibited the transport of purine bases through hFNT1.

Conclusion

Collectively, the data obtained in this study clearly show that the endogenous host erythrocyte transporters hENT1 and hFNT1, rather than the NPP, are the major route of entry of purine into parasitized RBC. Inhibitors of hENT1 and hFNT1, as well as the NPP, should be considered in the development of anti-malarials targeted to purine transport.
Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury
Authors: Doroszko Adrian , Hurst Thomas S , Polewicz Dorota , Sawicka Jolanta , Fert-Bober Justyna , Johnson David H , Sawicki Grzegorz
Published: January 2010

Background

Although mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses.

Results

Mechanical function and gas exchange parameters improved following treatment with doxycycline in the high volume ventilated group as compared to the placebo group. Nine pulmonary proteins have shown significant changes between the two biochemically analysed (high volume ventilated) groups. Treatment with doxycycline resulted in a decrease of pulmonary MMP-9 activity as well as in an increase in the levels of soluble receptor for advanced glycation endproduct, apoliporotein A-I, peroxiredoxin II, four molecular forms of albumin and two unnamed proteins. Using the pharmacoproteomic approach we have shown that treatment with doxycycline leads to an increase in levels of several proteins, which could potentially be part of a defense mechanism.

Conclusion

Administration of doxycycline might be a significant supportive therapeutic strategy in prevention of VILI.
A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic Renal Cell Carcinoma
Authors: Rahma Osama E , Ashtar Ed , Ibrahim Ramy , Toubaji Antoun , Gause Barry , Herrin Vincent E , Linehan W Marston , Steinberg Seth M , Grollman Frank , Grimes George , Bernstein Sarah A , Berzofsky Jay A , Khleif Samir N
Published: January 2010

Background

Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau (VHL) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides.

Methods

Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock.

Results

Four out of five evaluable patients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively.

Conclusions

The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. Trial registration: 98C0139
Progressive changes in microglia and macrophages in spinal cord and peripheral nerve in the transgenic rat model of amyotrophic lateral sclerosis
Authors: Graber David J , Hickey William F , Harris Brent T
Published: January 2010

Background

The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS.

Methods

Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were pre-clinical, at clinical onset, and near disease end-stage. Changes in CD11b expression were compared to the detection of MHC class II and CD68 microglial activation markers in the ventral horn of the spinal cord, as well as to the changes in astrocytic GFAP expression.

Results

Our study reveals an accumulation of microglia/macrophages both in the spinal cord and peripheral nerve prior to clinical onset based on CD11b tissue expression. The microglia formed focal aggregates in the ventral horn and became more widespread as the disease progressed. Hypertrophic astrocytes were not prominent in the ventral horn until after clinical onset, and the enhancement of GFAP did not have a strong correlation to increased CD11b expression. Detection of MHC class II and CD68 expression was found in the ventral horn only after clinical onset. The macrophages in the ventral nerve root and sciatic nerve of hmSOD1 rats were observed encircling axons.

Conclusions

These findings describe for the first time in the hmSOD1 rat transgenic model of ALS that enhancement of microglia/macrophage activity occurs pre-clinically both in the peripheral nerve and in the spinal cord. CD11b expression is shown to be a superior indicator for early immunological changes compared to other microglia activation markers and astrogliosis. Furthermore, we suggest that the early activity of microglia/macrophages is involved in the early phase of motor neuron degeneration and propose that studies involving immunomodulation in hmSOD1transgenic models need to consider effects on macrophages in peripheral nerves as well as to microglia in the spinal cord.
Interleukin 18 in the CNS
Authors: Alboni Silvia , Cervia Davide , Sugama Shuei , Conti Bruno
Published: January 2010

Interleukin (IL)-18 is a cytokine isolated as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, the localization of the IL-18 receptor complex in neurons and the neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease.
Proposal for field sampling of plants and processing in the lab for environmental metabolic fingerprinting
Authors: Maier Tanja S , Kuhn Jürgen , Müller Caroline
Published: January 2010

Background

Samples for plant metabolic fingerprinting are prepared generally by metabolism quenching, grinding of plant material and extraction of metabolites in solvents. Further concentration and derivatisation steps follow in dependence of the sample nature and the available analytical platform. For plant material sampled in the field, several methods are not applicable, such as, e.g., collection in liquid nitrogen. Therefore, a protocol was established for sample pre-treatment, grinding, extraction and storage, which can be used for analysis of field-collected plant material, which is further processed in the laboratory. Ribwort plantain (Plantago lanceolata L., Plantaginaceae) was used as model plant. The quality criteria for method suitability were high reproducibility, extraction efficiency and handling comfort of each subsequent processing step.

Results

Highest reproducibility of results was achieved by sampling fresh plant material in a solvent mixture of methanol:dichloromethane (2:1), crushing the tissue with a hand-held disperser and storing the material until further processing. In the laboratory the material was extracted threefold at different pH. The gained extracts were separated with water (2:1:1 methanol:dichloromethane:water) and the aqueous phases used for analysis by LC-MS, because the polar metabolites were in focus. Chromatograms were compared by calculating a value Ξ for similarities. Advantages and disadvantages of different sample pre-treatment methods, use of solvents and solvent mixtures, influence of pH, extraction frequency and duration, and storing temperature are discussed with regard to the quality criteria.

Conclusions

The proposed extraction protocol leads to highly reproducible metabolic fingerprints and allows optimal handling of field-collected plant material and further processing in the laboratory, which is demonstrated for an exemplary field data-set. Calculation of Ξ values is a useful tool to judge similarities between chromatograms.
Ultrasound imaging in an experimental model of fatty liver disease and cirrhosis in rats
Authors: Lessa Andréia S , Paredes Bruno D , Dias Juliana V , Carvalho Adriana B , Quintanilha Luiz Fernando , Takiya Christina M , Tura Bernardo R , Rezende Guilherme FM , Campos de Carvalho Antonio C , Resende Célia MC , Goldenberg Regina CS
Published: January 2010

Background

Domestic dogs and cats are very well known to develop chronic hepatic diseases, including hepatic lipidosis and cirrhosis. Ultrasonographic examination is extensively used to detect them. However, there are still few reports on the use of the ultrasound B-mode scan in correlation with histological findings to evaluate diffuse hepatic changes in rodents, which represent the most important animal group used in experimental models of liver diseases. The purpose of this study was to determine the reliability of ultrasound findings in the assessment of fatty liver disease and cirrhosis when compared to histological results in Wistar rats by following up a murine model of chronic hepatic disease.

Results

Forty Wistar rats (30 treated, 10 controls) were included. Liver injury was induced by dual exposure to CCl4and ethanol for 4, 8 and 15 weeks. Liver echogenicity, its correlation to the right renal cortex echogenicity, measurement of portal vein diameter (PVD) and the presence of ascites were evaluated and compared to histological findings of hepatic steatosis and cirrhosis. Liver echogenicity correlated to hepatic steatosis when it was greater or equal to the right renal cortex echogenicity, with a sensitivity of 90%, specificity of 100%, positive and negative predictive values of 100% and 76.9% respectively, and accuracy of 92.5%. Findings of heterogeneous liver echogenicity and irregular surface correlated to liver cirrhosis with a sensitivity of 70.6%, specificity of 100%, positive and negative predictive values of 100% and 82.1% respectively, and accuracy of 87.5%. PVD was significantly increased in both steatotic and cirrhotic rats; however, the later had greater diameters. PVD cut-off point separating steatosis from cirrhosis was 2.1 mm (sensitivity of 100% and specificity of 90.5%). One third of cirrhotic rats presented with ascites.

Conclusion

The use of ultrasound imaging in the follow-up of murine diffuse liver disease models is feasible and efficient, especially when the studied parameters are used in combination. The potential implication of this study is to provide a non-invasive method that allows follow-up studies of fatty liver disease and cirrhosis of individual rats for pre-clinical drug or cell based therapies.
Intraparenchymal metastases to the spleen from ovarian cancer: a case report
Authors: Ghani Abdul A , Hashmi Zubair A , Chase Daniel M , Patel Shonak B , Jones Daniel F
Published: January 2010

Introduction

Splenic tumors are rare and present a diagnostic dilemma. Metastatic carcinoma to the spleen is unusual. Visceral metastases in patients with ovarian cancer represent hematogenous spread of the disease; capsular involvement resulting from serosal and peritoneal seeding is more common. We present a patient with intraparenchymal splenic metastasis from ovarian carcinoma. This case demonstrates a rare etiology of an intraparenchymal solid splenic mass.

Case presentation

An 85-year-old woman presented with left upper quadrant pain. During her evaluation, a computed tomography scan revealed intraparenchymal splenic masses. An elective splenectomy was performed, during which ovarian cancer, which had not been revealed by the pre-operative computed tomography, was detected. There was no involvement of the splenic capsule by direct extension of the tumor, as is usually the case for ovarian cancer, but only intraparenchymal metastases. This mode of metastasis to the spleen has been described but is quite rare, and ovarian cancer presenting as a splenic mass is even more so.

Conclusion

Splenic metastasis is a relatively rare event. It is often asymptomatic and is usually detected as part of multiorgan metastases. Symptomatic cases, though rare, do occur, and as in our patient, a thorough clinical evaluation is important to help direct the treatment plan. This case is a reminder to be cognizant of one of the less likely differential diagnoses of an intraparenchymal solid splenic mass.
A peptidyl-glucosamine derivative affects IKKα kinase activity in human chondrocytes
Authors: Scotto d'Abusco Anna , Politi Laura , Giordano Cesare , Scandurra Roberto
Published: January 2010

Introduction

Nuclear factor-κB (NF-κB) transcription factor regulates several cell signaling pathways, such as differentiation and inflammation, which are both altered in osteoarthritis. Inhibitor κB kinase (IKK)α and IKKβ are kinases involved in the activation of the NF-κB transcription factor. The aim of the present study was to determine the effects of glucosamine (GlcN), which is administered in the treatment of osteoarthritis, and of its 2-(N-Acetyl)-L-phenylalanylamido-2-deoxy-β-D-glucose (NAPA) derivative on IKK kinases and, consequently, on NF-κB activation in human chondrocytes.

Methods

The human chondrosarcoma cell line HTB-94 and human primary chondrocytes were stimulated with tumor necrosis factor (TNF)α after pre-treatment with GlcN or NAPA. Gene mRNA expression level was evaluated by real-time PCR. Inhibitor κB protein (IκB)α phosphorylation and p65 nuclear re-localization were analyzed by Western blotting; IKKα nuclear re-localization was also investigated by immunocytochemistry and Western blotting. IKK kinase activity was studied by in vitro kinase assay.

Results

After TNFα stimulation, the mRNA expression level of some of the genes under NF-κB control, such as interleukin (IL)-6 and IL-8, increased, while treatment with GlcN and NAPA reverted the effect. We investigated the possibility that GlcN and NAPA inhibit IKK kinase activity and found that NAPA inhibits the IKKα kinase activity, whereas GlcN does not. Interestingly, both GlcN and NAPA inhibit IKKα nuclear re-localization.

Conclusions

Our results demonstrate that glucosamine and its peptidyl derivative can interfere with NF-κB signaling pathway by inhibiting IKKα activity in human chondrocytes. However, the mechanism of action of the two molecules is not completely overlapping. While NAPA can both specifically inhibit the IKKα kinase activity and IKKα nuclear re-localization, GlcN only acts on IKKα nuclear re-localization.