bluuebunny/crossref_metadata_2025 huggingface dataset:
Caribbean precipitation: review, model and prospect
Authors: Gamble Douglas W. , Curtis Scott
Published: September 2008

The study of Caribbean climate pre-1990 focused almost exclusively on attempts to link spatial patterns in climatic variables to physical processes. Much of this research assumed a `simple' regional climate, warm year round with a wet season dominated by tropical cyclones, but researchers soon found that a precipitation regionalization of the Caribbean was not as straightforward and simple. Consequently, a satisfactory understanding of the regional precipitation climate has eluded researchers for much of the second half of the twentieth century. Recently, with the increased availability and quality of satellite and precipitation data, researchers have begun to use gridded data sets to identify the spatial boundaries of the bimodal precipitation region and the atmospheric processes associated with the two maxima and minimum in precipitation. The findings of these most recent studies can be combined to construct a five part (North Atlantic high pressure, low level Caribbean jet, subsidence caused by Central America convection, basin wide increased wind shear, and divergence around Jamaica) conceptual Caribbean precipitation model that begins to address spatial variability in the bimodal structure of annual rainfall and the development of the midsummer minimum in precipitation. Such a regional precipitation climate model provides hypotheses to be tested and investigated in future research. Further, researchers must work towards a more effective and clear communication of the bimodal nature of Caribbean precipitation and the associated summer decrease in precipitation, integrate upper air analysis into the current working hypotheses, and further examine the interannual to interdecadal variability of the Caribbean midsummer drought for prediction purposes.
`It really was rather disgraceful. Still, that is politics'
Authors: Dorey Peter
Published: September 2008

The 1964—70 Labour Governments were formally committed to a major expansion and reorganization of education in Britain, at both secondary and higher levels. Alongside the commitment to `comprehensivisation' of secondary schools and the expansion of universities, Labour was also committed to raising the school leaving age from 15 to 16. However, the increasingly severe economic problems that affected Britain from 1966 onwards, culminating in devaluation in November 1967, prompted an urgent search for significant cutbacks in public expenditure, with one of the casualties being the raising of the school leaving age. A case study of this decision reveals several aspects of interest to students of public policy and administration, including the extent to which short-term economic exigencies were privileged over long-term social objectives. This enabled the Treasury to exercise dominance over spending Departments, with its senior officials presenting the options for financial savings in a manner that led almost ineluctably to the raising of the school leaving age being sacrificed. The decision also revealed the existence of tensions within the Cabinet, not merely on traditional ideological and inter-Departmental grounds, important though these were, but also, to some extent, in terms of the socio-educational backgrounds of Ministers. Consequently, the Treasury and its officials were able to pursue a subtle process of `divide and rule' among Ministers and their Departments.
Benchmarking Innovation in the Valencian Community
Authors: Mikel Zabala-Iturriagagoitia Jon , Gutiérrez-Gracia Antonio , Jiménez-Sáez Fernando
Published: September 2008

Benchmarking on innovation policies allows less developed territories to adjust their learning processes along with the experiences of others. There are successful territories in Europe where innovation policies have become key to their development, but there are others where this is not the case, as in most Spanish regions. The purpose of this article is to benchmark the Valencian Innovation System, at three levels of analysis: (a) Spanish; (b) Mediterranean; and (c) European regions. Our results highlight its main strengths and weaknesses, which are indicative of the deficiencies in the Valencian industrial structure and the difficulties involved in absorbing newly qualified, highly educated people. The Valencian Community shows relative strengths in those aspects related to public funding while its weaknesses are related to private activities. This structural imbalance drives us to categorize the Valencian Innovation System as weak, unarticulated and unbalanced, which makes us question the real existence of a regional innovation system in the Valencian Community.We consider that support from the regional government should be oriented first towards the definition of some common consensus-based targets in which the main actors are involved. Then second, entrepreneurial activities should be fostered, which may link the existing industrial structure to the public research system in the region. Third, a structural change should be promoted in Valencian universities, with greater emphasis on cooperation with regional firms, and knowledge transfer to small and medium-sized enterprises (SMEs) so as to increase their competitiveness.
Urban—Rural Health Differences and the Availability of Green Space
Authors: Verheij R.A. , Maas J. , Groenewegen P.P.
Published: September 2008

It is argued that urban—rural health differences, which are found in many studies, may be at least partially associated with the availability of green space. Until recently there was only limited evidence from experimental research for this relationship, but recent large-scale epidemiological work found new evidence for the association between urban—rural health differences and availability of green space. It is argued that this would fit in with the theories of the classic urban sociologists Wirth and Milgram and the theories of environmental psychologists like Kaplan and Kaplan. The availability of new evidence and the fit into the classic theories would also justify renewed attention for green space in urban planning.
An Institutionalist Approach to Spatial Variations in Public Service Failure
Authors: Andrews Rhys
Published: September 2008

Institutionalist approaches to regional development suggest that a host of regulative structures, normative expectations and cognitive identities constrain the behaviour of organizations operating in local areas. However, policymakers in England currently pay little attention to the influence of such institutions when assessing performance in the public sector. In particular, they do not consider their potential effects on poorly performing public organizations. This assumption is challenged here by analysing spatial variations in the rate of failure in English public services between 2002 and 2004. The interdependence between failure and institutional variables is modelled and explored using local authority area level data.The statistical analysis suggests that regulative, normative and cognitive institutions have a strong statistically significant impact on the prospect of public service failure, even when controlling for the effects of other important environmental constraints. These findings provide support for institutionalist approaches to understanding spatial dimensions of public policy.
New Evidence for the Theory of Groups
Authors: Drope Jeffrey M. , Hansen Wendy L.
Published: September 2008

Group theorists led by Olson have observed that common interests do not produce collective action, except under conditions that overcome the free-rider incentive. While collective action theories have captured the imagination of the discipline, there has been surprisingly little examination of the relationship between business collective action and patterns of market structures. Research has instead focused more on firm-level political activity. Accordingly, this research addresses the original theoretical propositions by examining industry associations' political activity nationally. Some forty years after the formulation of the theoretical argument, we find evidence supporting the logic of collective action. More concentrated industries are likelier to have politically active associations than more competitive industries.
Religious Stereotyping and Voter Support for Evangelical Candidates
Authors: McDermott Monika L.
Published: September 2008

While much important research exists on the topic of religion and politics, very little exists on candidate religious affiliation and its potential effect on voters' behavior. This article addresses the issue of candidate religion from the point of view that it acts as an information cue for voters in elections through trait and belief stereotypes. Using a case study of hypothetical evangelical Christian candidates and an original experimental data set, this analysis demonstrates that voters stereotype evangelicals as more conservative than other candidates, as well as more competent and trustworthy, all else equal. These stereotypes subsequently play a significant role in voters' choices of whom to support.
On Saint-Venant’s Principle for Elasto-Plastic Bodies
Authors: Knops R.J. , Villaggio Piero
Published: September 2008

This paper concerns Zanaboni’s version of Saint-Venant’s principle, which states that an elongated body in equilibrium subject to a self-equilibrated load on a small part of its smooth but otherwise arbitrary surface, possesses a stored energy that in regions of the body remote from the load surface decreases with increasing distance from the load surface. We here prove this formulation of Saint-Venant’s principle for elastic-plastic bodies. The present proof, which for linear elasticity considerably simplifies that developed by Zanaboni, depends crucially upon the principle of minimum strain energy to obtain a fundamental inequality that leads to the required result. Differential inequalities are not involved. The conclusion is not restricted to cylinders but is valid for plastic bodies of general geometries. Although no conditions are imposed on the plastic theories discussed here, counter-examples indicate that in certain circumstances the fundamental inequality, and hence the result, may be valid only for restricted data that includes the body’s minimum length.
A Galerkin Method for Biot Consolidation Model
Authors: Owczarek Sebastian
Published: September 2008

The main aim of this paper is to prove the existence and uniqueness of solutions to an initial-boundary value problem corresponding to the Biot model. The existence theorem is proved by Galerkin method and the passage to the limit in the approximation process is shown in a standard way. Assuming that the given data satisfy some natural regularity requirements a better regularity of solutions is obtained than it could be found in the literature.
Existence, Uniqueness and Stability in Linear Cosserat Elasticity for Weakest Curvature Conditions
Authors: Jeong Jena , Neff Patrizio
Published: September 2008

We investigate the weakest possible constitutive assumptions on the curvature energy in linear Cosserat models still providing for existence, uniqueness and stability. The assumed curvature energy is μL2 c ∥dev sym ∇axl A∥2 where axl A is the axial vector of the skewsymmetric microrotation A ∈ so (3 ) and dev is the orthogonal projection on the Lie-algebra sl (3 ) of trace free matrices. The proposed Cosserat parameter values coincide with values adopted in the experimental literature by R. S. Lakes. It is observed that unphysical stiffening for small samples is avoided in torsion and bending while size effects are still present. The number of Cosserat parameters is reduced from six to four. One Cosserat coupling parameter µc > 0 and only one length scale parameter L c > 0. Use is made of a new coercive inequality for conformal Killing vectorfields. An interesting point is that no (controversial) essential boundary conditions on the microrotations need to be specified; thus avoiding boundary layer effects. Since the curvature energy is the weakest possible consistent with non-negativity of the energy, it seems that the Cosserat couple modulus µc > 0 remains a material parameter independent of the sample size which is impossible for stronger curvature expressions.
Yield Criteria for Shape Memory Materials: Convexity Conditions and Surface Transport
Authors: Laydi Mohamed Rachid , Lexcellent Christian
Published: September 2008

We study the yield conditions of phase transformation initiation for shape memory alloys exhibiting asymmetry between tension and compression. An extension of the choice of the classical invariant parameters such as those of Lode is proposed. A necessary and sufficient condition of convexity of these surfaces representing the elastic domain of austenite in the stress space, is established. Moreover the transport of these surfaces in the space of effective transformations strains of martensite is done. Hence, the duality between these two spaces is built. Some applications involving Cu—Al—Be and NiTi shape memory alloys end the purpose.
Basic Science Review: Current Insights on the Biology and Clinical Aspects of VEGF Regulation
Authors: Birk Daniel M. , Barbato Joel , Mureebe Leila , Chaer Rabih A.
Published: September 2008

Vascular endothelial growth factor (VEGF) is a key molecule that orchestrates the formation and function of vascular networks. Impaired regulation of angiogenesis is implicated in a number of pathologic states. For instance, neoplasias exhibit uncontrolled angiogenesis, whereas ischemia and states of vascular insufficiency involve reduced VEGF activity. As the role of VEGF has been elucidated in these disease processes, its therapeutic role has been developed. The Food and Drug Administration has approved several anti-VEGF agents for treating colorectal, lung, and kidney cancer. VEGF-inducing agents have also been used experimentally to induce angiogenesis in patients with critical limb ischemia. As more knowledge is gathered about the biology of VEGF and its receptors, there is greater promise for therapeutic modulation of VEGF expression. The purpose of this review is to describe the various therapeutic and biologic factors that regulate the expression of VEGF.
Effect of process parameters on deformation and temperature rise during forging of TC6 alloy disc
Authors: Li M.-Q. , Xiong A.-M. , Lin H.
Published: September 2008

Effect of the deformation temperature, hammer velocity, height reduction and shear factor on the equivalent stress, strain and temperature rise has been studied in forging process of a TC6 titanium alloy disc with deformation temperatures of 1153–1213 K, hammer velocities of 1·2–12 000 mm min−1 and shear factors of 0·1–0·4. The calculated results show that the deformation temperature, hammer velocity and height reduction have a significant effect on the equivalent stress and temperature rise, but have a slight effect on the equivalent strain. The predicted load–displacement curves are found to be in a good agreement with the experimental results.
Effect of solid solution treatment on semisolid microstructure of dendritic zinc alloy ZA27
Authors: Chen T.-J. , Hao Y. , Li Y.-D. , Ma Y.
Published: September 2008

The effect of solid solution treatment on semisolid microstructure of a Zn alloy ZA27 with developed dendrites was investigated and a new approach to produce non-dendritic semisolid microstructure available for thixoforming was developed. The results indicated that a semisolid microstructure with small and spherical primary particles could be obtained when the alloy with developed dendrites was solution treated for 3 h at 370°C and then partially remelted at a semisolid temperature of 460°C. This method could not only overcome some inevitable shortcomings resulting from using some present popular approaches, but also simplify the procedure of thixoforming. Too short or too long solution treatment duration could increase the shape factor, size and inhomogeneity of the primary particles. All of these microstructural changes were attributed to the dendrite coalescence and phase transformation which occurred during solid solution treatment.
TEM investigation of intermediate phase transformation and micromodulation in Ni–Mn–Ga ferromagnetic shape memory alloys
Authors: Tsuchiya K. , Todaka Y. , Umemoto M.
Published: September 2008

Intermediate phase transformation, martensitic transformations and modulated structures in Ni–Mn–Ga ferromagnetic shape memory alloys were investigated by TEM. The transformation from high temperature L21 phase to intermediate phase was characterised by the appearance of diffuse satellite spots at 0˙167 q220 positions in electron diffraction patterns and intense fine striations in bright field images. These results are consistent with the reported results of neutron diffraction measurements related to the phonon anomaly. Also, high resolution TEM observations and fast Fourier transformation analysis on the near intermediate phase state in Ni–Mn–Ga–Gd were conducted. It was revealed that the coarse tweed contrast was associated with a long wavelength strain field while the fine striations are associated with the satellite spots and domains of micromodulation aligned parallel to {110}.
Domain switching in rhombohedral PZT ceramics under electrical and mechanical loading
Authors: Hall D. A. , Mori T. , Withers P. J. , Kungl H. , Hoffmann M. J. , Wright J.
Published: September 2008

Ferroelectric domain switching in rhombohedral lead zirconate titanate (PZT) ceramics has been studied using high energy synchrotron X-ray diffraction. The diffraction data for a range of different grain orientations were obtained rapidly, with a data acquisition time of 20 s, using a Frelon CCD camera. Changes in the lattice strain and ferroelectric domain fractions under an applied electric field or compressive stress were determined by measuring the positions and relative intensities of the diffraction peaks. It was observed that domain switching under an electric field occurred over a narrow range of field strength, whereas that due to a compressive stress occurred more gradually, over a wider range of applied stress. This effect is due to a combination of factors, including the influence of residual stress, the presence of the electrical depolarisation field, and the nature of the electric field and stress tensors. It was confirmed that the work required for domain switching is the same under electrical or mechanical loading, and approximately equal to 0˙34 MJ m−3.
Interfacial characterisation in Al–20 vol.-%SiCp explosively compacted composite
Authors: Ghasemi H. M. , Emamy M. , Eskandari H. , Hokamoto K. , Nishida M. , Matsuda M.
Published: September 2008

Al–20 vol.-%SiCp composite was prepared using direct explosive compaction. Interfacial characterisation of the composite was preformed using scanning electron microscopy, X-ray diffraction and transmission electron microscopy. The results showed that the interface seemed to be clean and no interfacial Al4C3 reaction product was generated along the interface between SiC particles and Al matrix. The results also showed a better bonding between SiC particles and Al matrix in the central region of the compact sample.
Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling
Authors: Epling-Burnette P. K. , Sokol Lubomir , Chen Xianhong , Bai Fanqi , Zhou Junmin , Blaskovich Michelle A. , Zou JianXiang , Painter Jeffrey S. , Edwards Todd D. , Moscinski Lynn , Yoder Jeffrey A. , Djeu Julie Y. , Sebti Said , Loughran Thomas P. , Wei Sheng
Published: September 2008

Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.
In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein
Authors: Fukumoto Risaku , Andresen Vibeke , Bialuk Izabela , Cecchinato Valentina , Walser Jean-Claude , Valeri Valerio W. , Nauroth Julie M. , Gessain Antoine , Nicot Christophe , Franchini Genoveffa
Published: September 2008

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99–amino acid hydrophobic membrane protein, p12I, that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12I. The removal of a noncanonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12I is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8-kDa protein. The 8-kDa protein in turn traffics to the cell surface, is recruited to the immunologic synapse following T-cell receptor (TCR) ligation, and down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12I resides in the ER and interacts with the β and γc chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1–infected patients reveals predominant amino acid substitutions within ORF-I that affect proteolytic cleavage, suggesting that ER-associated functions of p12I may contribute to the survival and proliferation of the infected T cells in the host.
Suppression of LPS-induced Interferon-γ and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation
Authors: Dai Rujuan , Phillips Rebecca A. , Zhang Yan , Khan Deena , Crasta Oswald , Ahmed S. Ansar
Published: September 2008

MicroRNAs (miRNAs), recently identified noncoding small RNAs, are emerging as key regulators in homeostasis of the immune system. Therefore, aberrant expression of miRNAs may be linked to immune dysfunction, such as in chronic inflammation and autoimmunity. In this study, we investigated the potential role of miRNAs in estrogen-mediated regulation of innate immune responses, as indicated by up-regulation of lipopolysaccharide (LPS)–induced interferon-gamma (IFNγ), inducible nitric oxide synthase (iNOS), and nitric oxide in splenic lymphocytes from estrogen-treated mice. We found that miR-146a, a negative regulator of Toll-like receptor (TLR) signaling, was decreased in freshly isolated splenic lymphocytes from estrogen-treated mice compared with placebo controls. Increasing the activity of miR-146a significantly inhibited LPS-induced IFNγ and iNOS expression in mouse splenic lymphocytes. Further, miRNA microarray and real-time reverse transcriptase–polymerase chain reaction (RT-PCR) analysis revealed that estrogen selectively up-regulates/down-regulates the expression of miRNAs in mouse splenic lymphocytes. miR-223, which is markedly enhanced by estrogen, regulates LPS-induced IFNγ, but not iNOS or nitric oxide in splenic lymphocytes. Inhibition of miR-223 activity decreased LPS-induced IFNγ in splenic lymphocytes from estrogen-treated mice. Our data are the first to demonstrate the selective regulation of miRNA expression in immune cells by estrogen and are indicative of an important role of miRNAs in estrogen-mediated immune regulation.
Winter mortality modifies the heat-mortality association the following summer
Authors: Rocklöv J. , Forsberg B. , Meister K.
Published: September 2008

The present study aimed to investigate how the heat-related increase in deaths in summer and the extent of mortality displacement depend on influenza and other categories of mortality in the previous winter, which when low leaves a greater pool of susceptible individuals.

Mortality data from Stockholm, Sweden, from 1990–2002 were stratified into a summer period and a winter period. A Poisson regression model was established for the daily mortality in the summer, with temperature and confounders as explanatory variables. In addition, indicators of total, respiratory, cardiovascular and influenza mortality of the winter period were incorporated as effect modifiers in the summer model, and lagged effects in strata defined by indicators were studied.

A high rate of respiratory as well as cardiovascular mortality in winter reduced the heat effect the following summer, and influenza mortality tended to do so as well. The cumulative effect per °C increase was 0.95% below and 0.89% above a threshold (21.3°C) after a winter with low cardiovascular and respiratory mortality, but -0.23% below and 0.21% above the threshold after a winter with high cardiovascular and respiratory mortality.

The current study shows that high respiratory, cardiovascular and influenza mortality in winter leads to lower temperature effects in the following summer. It also suggests that persons for whom influenza may be fatal are often also susceptible to heat and this subgroup might, therefore, not benefit as much as expected from influenza vaccinations.
Screening for pulmonary arteriovenous malformations using transthoracic contrast echocardiography: a prospective study
Authors: van Gent M. W. F. , Post M. C. , Luermans J. G. L. M. , Snijder R. J. , Westermann C. J. J. , Plokker H. W. M. , Overtoom T. T. , Mager J. J.
Published: September 2008

Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in patients with hereditary haemorrhagic telangiectasia (HHT). The objective of the present study was to prospectively establish the diagnostic value of transthoracic contrast echocardiography (TTCE) as a screening technique for PAVM using chest high-resolution computed tomography (HRCT) as the gold standard for PAVMs.

All consecutive adult patients referred for HHT screening underwent a chest HRCT (n = 299), TTCE (n = 281), arterial blood gas analysis (n = 291), shunt fraction measurement (n = 111) and chest radiography (n = 296).

TTCE was positive in 87 (58.8%), 12 (16.7%) and four (6.7%) patients, and chest HRCT was positive in 54 (36.5%), three (4.2%) and zero (0%) patients with a definite, possible and negative clinical diagnosis of HHT, respectively. Two patients with a negative TTCE were diagnosed with PAVMs after computed tomography; in both cases the PAVMs were too small to be treated by embolotherapy. The sensitivity of TTCE was 97% (95% confidence interval (CI) 93.6–98.3) and negative predictive value 99% (95% CI 96.9–99.8). The other diagnostic tests showed a considerable lower diagnostic value.

The present prospective study shows that transthoracic contrast echocardiography has an excellent diagnostic value and can be used as an initial screening procedure for pulmonary arteriovenous malformations. The high false-positive rate of transthoracic contrast echocardiography possibly represents microscopic pulmonary arteriovenous malformations.
Risk factors for chronic thromboembolic pulmonary hypertension
Authors: Bonderman D. , Wilkens H. , Wakounig S. , Schäfers H-J. , Jansa P. , Lindner J. , Simkova I. , Martischnig A. M. , Dudczak J. , Sadushi R. , Skoro-Sajer N. , Klepetko W. , Lang I. M.
Published: September 2008

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by nonresolving pulmonary thromboemboli that can be treated by surgical pulmonary endarterectomy (PEA). The authors of the present study sought to confirm known and to identify novel CTEPH risk factors in a controlled retrospective cohort study of prevalent CTEPH cases collected in three European centres offering PEA.

Data from CTEPH patients were compared with nonthromboembolic pre-capillary pulmonary arterial hypertension cohorts at the participating institutions.

The study population comprised 687 patients assessed at the time of diagnosis between 1996 and 2007. Ventriculo-atrial shunts and infected pacemakers (odds ratio (OR) 76.40, 95% confidence interval (CI) 7.67–10,351), splenectomy (OR 17.87, 95% CI 1.56–2,438), previous venous thromboembolism (VTE; OR 4.52, 95% CI 2.35–9.12), recurrent VTE (OR 14.49, 95% CI 5.40–43.08), blood groups other than 0 (2.09, 95% CI 1.12–3.94), and lupus anticoagulant/antiphospholipid antibodies (OR 4.20, 95% CI 1.56–12.21) were more often associated with CTEPH. Thyroid replacement therapy (OR 6.10, 95% CI 2.73–15.05) and a history of malignancy (OR 3.76, 95% CI 1.47–10.43) emerged as novel CTEPH risk factors.

In conclusion, the European database study confirmed previous knowledge of chronic thromboembolic pulmonary hypertension risk factors, and identified thyroid replacement therapy and a history of malignancy as new medical conditions associated with chronic thromboembolic pulmonary hypertension.
Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD?
Authors: Man S. F. P. , Xing L. , Connett J. E. , Anthonisen N. R. , Wise R. A. , Tashkin D. P. , Zhang X. , Vessey R. , Walker T. G. , Celli B. R. , Sin D. D.
Published: September 2008

The balance between inflammatory and repair processes is important in maintaining lung homeostasis in chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine whether or not an integrated index of a biomarker involved in inflammation, C-reactive protein (CRP), and another involved in wound repair, fibronectin, may be a good measure to predict clinical outcomes in COPD.

Circulating blood levels of CRP and fibronectin were measured in 4,787 individuals with mild-to-moderate COPD who were prospectively followed for >7 yrs after blood collection as part of the Lung Health Study. To assess the balance between repair and inflammation, a simple ratio was calculated by dividing fibronectin levels by CRP levels and a Cox proportional hazards model was used to determine the relationship between this ratio and all-cause and disease-specific causes of mortality.

The relationship between the fibronectin to CRP ratio and all-cause mortality was L-shaped. There was an exponential decay in the adjusted hazard function (i.e.the risk of mortality) as the ratio decreased until a value of 148 was reached, beyond which point the hazard function did not change significantly. Similar results were observed for the risk of coronary and cardiovascular mortality.

Circulating fibronectin to CRP ratio is significantly associated with all-cause mortality of COPD patients. However, in contrast to other biomarkers, the relationship appears to be L-shaped (and not linear), suggesting a threshold at ∼150. While promising, future studies are needed to validate this simple index as a biomarker in COPD.
Association of mast cells with lung function in chronic obstructive pulmonary disease
Authors: Gosman Margot ME , Postma Dirkje S , Vonk Judith M , Rutgers Bea , Lodewijk Monique , Smith Mieke , Luinge Marjan A , ten Hacken Nick HT , Timens Wim
Published: September 2008

Background

In asthma, higher chymase positive mast cell (MC-C) numbers are associated with less airway obstruction. In COPD, the distribution of MC-C and tryptase positive mast cells (MC-T) in central and peripheral airways, and their relation with lung function, is unknown. We compared MC-T and MC-C distributions in COPD and controls without airflow limitation, and determined their relation with lung function.

Methods

Lung tissue sections from 19 COPD patients (median [interquartile range] FEV1% predicted 56 [23–75]) and 10 controls were stained for tryptase and chymase. Numbers of MC-T and MC-C were determined in different regions of central and peripheral airways and percentage of degranulation was determined.

Results

COPD patients had lower MC-T numbers in the subepithelial area of central airways than controls. In COPD, MC-T numbers in the airway wall and more specifically in the epithelium and subepithelial area of peripheral airways correlated positively with FEV1/VC (Spearman's rho (rs) 0.47, p = 0.05 and rs0.48, p = 0.05, respectively); MC-C numbers in airway smooth muscle of peripheral airways correlated positively with FEV1% predicted (rs0.57, p = 0.02). Both in COPD patients and controls the percentage of degranulated MC-T and MC-C mast cells was higher in peripheral than in central airways (all p < 0.05), but this was not different between the groups.

Conclusion

More MC-T and MC-C in peripheral airways correlate with better lung function in COPD patients. It is yet to determine whether this reflects a protective association of mast cells with COPD pathogenesis, or that other explanations are to be considered.
Establishment and characterization of immortalized Gli-null mouse embryonic fibroblast cell lines
Authors: Lipinski Robert J , Bijlsma Maarten F , Gipp Jerry J , Podhaizer David J , Bushman Wade
Published: September 2008

Background

Hedgehog (Hh) signaling is a conserved morphogenetic pathway which plays critical roles in embryonic development, with emerging evidence also supporting a role in healing and repair processes and tumorigenesis. The Gli family of transcription factors (Gli1, 2 and 3) mediate the Hedgehog morphogenetic signal by regulating the expression of downstream target genes. We previously characterized the individual and cooperative roles of the Gli proteins in Hh target gene regulation using a battery of primary embryonic fibroblasts from Gli null mice.

Results

Here, we describe the establishment of spontaneously immortalized mouse embryonic fibroblast (iMEF) cell lines lacking single and multiple Gli genes. These non-clonal cell lines recapitulate the unique ligand mediated transcriptional response of primary MEFs. While loss of Gli1 had no effect on target gene induction, Gli2 null cells demonstrated reduced target gene induction while Gli3 null cells exhibited elevated basal and ligand-induced expression. Target gene response in Gli1
-/-
2
-/- iMEFs was severely reduced while Gli2
-/-
3
-/- iMEFs were incapable of ligand-induced transcriptional response. However, we found that both Gli1
-/-
2
-/- and Gli2
-/-
3
-/- iMEFs exhibited robust leukotriene synthesis-dependent migration responses to Hh ligand, demonstrating that this response is not transcriptionally-dependent.

Conclusion

This study provides fundamental characterizations of the transcriptional and non-transcriptional Hh responsiveness of a battery of Gli-null iMEFs. Moving forward, these cell lines should prove a valuable tool set to study the unique functional regulation of the Gli proteins in a Hh-responsive cell-type.
Inhibition of cell growth and invasion by epidermal growth factor-targeted phagemid particles carrying siRNA against focal adhesion kinase in the presence of hydroxycamptothecin
Authors: Cai Xiu-Mei , Xie Hai-Long , Liu Ming-Zhu , Zha Xi-Liang
Published: September 2008

Background

Previous studies demonstrated the EGF-targeted phagemid particles carrying siRNA against Akt could be expressed efficiently in the presence of hydroxycamptothecin (HCPT). However, no significant cell growth inhibition was obtained. This study was to further investigate whether the EGF-targeted phagemid particles carrying siRNA would be a promising tool for anti-cancer siRNA delivery.

Results

We found that pSi4.1-siFAK phagemid particles could significantly inhibit the expression of focal adhesion kinase in the HCPT-treated cells. Moreover, we also observed that the particles could potently suppress cell growth and cell invasion.

Conclusion

These results indicated that EGF-targeted phagemid particles might be a promising tool for anti-cancer siRNA delivery in the presence of HCPT.
Recessive genetic mode of an ADH4 variant in substance dependence in African-Americans: A model of utility of the HWD test
Authors: Luo Xingguang , Zuo Lingjun , Kranzler Henry R , Wang Shuang , Anton Raymond F , Gelernter Joel
Published: September 2008

Background

In our previous studies, we reported positive associations between sevenADH4polymorphisms and substance dependence [i.e., alcohol dependence (AD) and/or drug dependence (DD)] in European-Americans (EAs). In the present study, we address the relationship betweenADH4variation and substance dependence in an African-American (AA) population, and report evidence that supports an association between a differentADH4polymorphism (rs2226896) and these phenotypes in AAs.

Methods

Two family-based association study methods, i.e., TDT and FBAT, were applied to test the relationship betweenADH4variation and substance dependence in Sample 3 (112 small nuclear families) and in Sample 4 (632 pedigrees), respectively. A population-based case-control association study method was also applied to test this relationship in 1303 unrelated subjects, with and without controlling for admixture effects. Finally, a Hardy-Weinberg Disequilibrium (HWD) test was applied to examine the association in the case-only sample, infer the genetic disease models, and distinguish the disease and non-disease factors contributing to HWD.

Results

The marker examined was found to be in significant HWD in AA alcoholics (p = 0.0071) and drug dependent subjects (p = 0.0341), but in Hardy-Weinberg Equilibrium (HWE) in all other subgroups. Other association methods failed to detect any association between this variation and phenotypes. The best-fit genetic disease model for this marker is a recessive genetic model.

Conclusion

ADH4variation might play a role in risk for substance dependence in AAs, potentially via a recessive mechanism. Under certain conditions, the HWD test could be a more powerful association method than conventional family-based and population-based case-control association analyses, for which, the present study provides an extreme example.
Intensive care for the adult population in Ireland: a multicentre study of intensive care population demographics
Authors:   The Irish Critical Care Trials Group
Published: September 2008

Introduction

This prospective observational study was conducted to describe the nature of the intensive care population across Ireland, identify adherence to international benchmarks of practice, and describe patient outcomes in critically ill patients.

Methods

A prospective observational multicentre study of demographics and organ failure incidence was carried out over a 10-week period in 2006 across the intensive care units (ICUs) of 14 hospitals in both the Republic and Northern Ireland.

Results

In total, there were 1,029 patient episodes entered across 14 ICUs. Emergency admissions accounted for 70% of episodes. Admissions after major elective surgery accounted for 20.5% of admissions. The mean length of ICU stay was 5.7 days, with a median of 2 days. Severe sepsis was identified in 35% of patients during their ICU admission. Mechanical ventilation was used in 70.7% of all patients admitted, of whom 26.9% had acute lung injury. Acute kidney injury occurred in 28% of all patients. Interhospital transfers were undertaken in 85 (8.3%) patients. The overall intensive care mortality of the study population was 19%.

Conclusions

Intensive care medicine in Ireland serves a patient population with high requirement for mechanical ventilation and support of the function of multiple organs. The overall mortality compares favourably with international benchmarks.
Effects of targeted deletion of cannabinoid receptors CB1 and CB2 on immune competence and sensitivity to immune modulation by Δ9-tetrahydrocannabinol
Authors: Springs Alison E B , Karmaus Peer W F , Crawford Robert B , Kaplan Barbara L F , Kaminski Norbert E
Published: September 2008

The role of cannabinoid receptors, CB1 and CB2, in immune competence and modulation by Δ9-tetrahydrocannabinol (Δ9-THC) was investigated in CB1−/−/CB2−/− mice. Immunofluorescence analysis of splenic leukocytes showed no significant differences in the percentage of T cell subsets, B cells, or macrophages between wild-type and CB1−/−/CB2−/− mice. Lymphoproliferative control responses to PHA, phorbol ester plus ionomycin, or LPS and sensitivity to suppression by Δ9-THC showed no profound differences between the two genotypes, although some differences were observed in control baseline responses. Likewise, similar control responses and sensitivity to Δ9-THC were observed in mixed lymphocyte responses (MLR) and in IL-2 and IFN-γ production in both genotypes. Conversely, humoral immune responses showed a markedly different profile of activity. Δ9-THC suppressed the in vivo T cell-dependent, anti-sheep RBC (anti-sRBC) IgM antibody-forming cell (AFC) response in wild-type but not in CB1−/−/CB2−/− mice, and the in vitro anti-sRBC IgM response in CB1−/−/CB2−/− splenocytes was too low to rigorously assess CB1/CB2 involvement in modulation by Δ9-THC. Conversely, comparable in vitro IgM AFC control responses to LPS and CD40 ligand (CD40L) activation were observed in the two genotypes. Interestingly, LPS-induced IgM responses were refractory to suppression by Δ9-THC, regardless of genotype, and CD40L-induced IgM responses were only suppressed by Δ9-THC in wild-type but not in CB1−/−/CB2−/− B cells. Collectively, we demonstrate differential involvement of CB1 and/or CB2 in immune modulation by Δ9-THC and in some control responses. Moreover, CB1/CB2 involvement was observed in humoral responses requiring CD40-initiated signaling for suppression by Δ9-THC.
Induction of iNOS byChlamydophila pneumoniaerequires MyD88-dependent activation of JNK
Authors: Rodriguez Nuria , Lang Roland , Wantia Nina , Cirl Christine , Ertl Tanja , Dürr Susanne , Wagner Hermann , Miethke Thomas
Published: September 2008

Innate immune cells produce NO via inducible NO synthase (iNOS) in response to certain infections or upon stimulation with cytokines such as IFN-γ and TNF. NO plays an important role in host defense against intracellular bacteria including Chlamydophila pneumoniae as a result of its microbicidal activity. In MyD88-deficient mice, which succumb to C. pneumoniae infection, iNOS induction is impaired 6 days postinfection, although pulmonary levels of IFN-γ and TNF are elevated as in wild-type mice at this time-point. Here, we demonstrate that induction of iNOS in macrophages upon C. pneumoniae infection is controlled by MyD88 via two pathways: NF-κB activation and phosphorylation of the MAPK JNK, which leads to the nuclear translocation of c-Jun, one of the two components of the AP-1 complex. In addition, phosphorylation of STAT1 and expression of IFN regulatory factor 1 (IRF-1) were delayed in the absence of MyD88 after C. pneumoniae infection but not after IFN-γ stimulation. Taken together, our data show that for optimal induction of iNOS during C. pneumoniae infection, the concerted action of the MyD88-dependent transcription factors NF-κB and AP-1 and of the MyD88-independent transcription factors phosphorylated STAT1 and IRF-1 is required.
MIP-3α and MIP-1α rapidly mobilize dendritic cell precursors into the peripheral blood
Authors: He Shan , Cao Qi , Yoneyama Hiroyuki , Ge Hailiang , Zhang Yi , Zhang Yanyun
Published: September 2008

Acquisition of dendritic cells (DCs) or DC precursors in vitro is critical for DC-based immunotherapy. We reported previously that administration of MIP-1α mobilized a population of F4/80−B220−CD11c+ DC precursors into peripheral blood by the expression of CCR1 and CCR5. In this study, we identified a new subset of CCR6+CCR1−CCR5−B220−CD11c+ cells in MIP-1α-administered mice. When cultured with GM-CSF, IL-4, and TNF-α, these cells differentiated into mature DCs, possessing the typical morphologic characteristics, phenotypes, and antigen-presenting function (termed CCR6+ DC precursors). Although it did not directly drive the CCR6+ DC precursors, MIP-1α could recruit a population of F4/80+CD11c− monocyte/macrophage-producing MIP-3α in the peripheral blood to mobilize a CCR6+ DC precursor subset of B220−CD11c+ DC precursors. Importantly, exogenous administration of MIP-3α significantly enhanced MIP-1α-induced mobilization of DC precursors. Moreover, these MIP-3α- and MIP-1α-mobilized DC precursors could be prepared for a DC vaccine capable of eliciting CTL responses to tumor cells, leading to tumor rejection in vitro and in vivo. Taken together, this study further demonstrates the mechanism of DC precursor mobilization induced by MIP-1α; that is, besides mobilizing DC precursors with CCR1 and CCR5 expressions, MIP-1α recruited F4/80+CD11c− monocyte/macrophage-producing MIP-3α, which finally mobilized the CCR6+ DC precursor subset to amplify the B220−CD11c+ DC precursor population. Furthermore, combined administration of MIP-3α and MIP-1α may be an efficient strategy for collecting a large number of DCs appropriate for immunotherapy.
Skeletal Health After Continuation, Withdrawal, or Delay of Alendronate in Men With Prostate Cancer Undergoing Androgen-Deprivation Therapy
Authors: Greenspan Susan L. , Nelson Joel B. , Trump Donald L. , Wagner Julie M. , Miller Megan E. , Perera Subashan , Resnick Neil M.
Published: September 2008

Purpose

Androgen-deprivation therapy (ADT) for prostate cancer is associated with bone loss and osteoporotic fractures. Our objective was to examine changes in bone density and turnover with sustained, discontinued, or delayed oral bisphosphonate therapy in men receiving ADT.

Patients and Methods

A total of 112 men with nonmetastatic prostate cancer receiving ADT were randomly assigned to alendronate 70 mg once weekly or placebo in a double-blind, partial-crossover trial with a second random assignment at year 2 for those who initially received active therapy. Outcomes included bone mineral density and bone turnover markers.

Results

Men initially randomly assigned to alendronate and randomly reassigned at year 2 to continue had additional bone density gains at the spine (mean, 2.3% ± 0.7) and hip (mean, 1.3% ± 0.5%; both P < .01); those randomly assigned to placebo in year 2 maintained density at the spine and hip but lost (mean, −1.9% ± 0.6%; P < .01) at the forearm. Patients randomly assigned to begin alendronate in year 2 experienced improvements in bone mass at the spine and hip, but experienced less of an increase compared with those who initiated alendronate at baseline. Men receiving alendronate for 2 years experienced a mean 6.7% (± 1.2%) increase at the spine and a 3.2% (± 1.5%) at the hip (both P < .05). Bone turnover remained suppressed.

Conclusion

Among men with nonmetastatic prostate cancer receiving ADT, once-weekly alendronate improves bone density and decreases turnover. A second year of alendronate provides additional skeletal benefit, whereas discontinuation results in bone loss and increased bone turnover. Delay in bisphosphonate therapy appears detrimental to bone health.