bluuebunny/crossref_metadata_2025 huggingface dataset:
New Poly(arylene ether sulfone)s Containing Phenolphthalein and Fluorene Moieties in the Main Chain
Authors: Ciobanu Manuela , Cozan Vasile , Bruma Maria , Begunov Roman S. , Rusanov Alexander L. , Belomoina Nataliya M.
Published: March 2010

New poly(arylene ether sulfone)s have been synthesized by solution polycondensation reaction of 2,4-bis[(4-chlorophenyl)sulfonyl]-1-(phenylthio)benzene)] with 4,4'-(9-fluorenylidene) bisphenol (FBP) and phenolphthalein (PP). The chemical structure of the polymers was confirmed by using both spectroscopical (FTIR, 1H-NMR) and elemental analysis methods. All the polymers were soluble in aprotic dipolar solvents. The thermal properties were investigated by differential scanning calorimetry and thermogravimetric analysis, and they, were discussed in connection with the chemical structure of the polymers. The investigation of optical properties by photoluminescence spectroscopy revealed that all the polymers displayed one emission peak in the blue domain beetwen 449 and 460 nm.
The Structure, Properties and Application of NR/BR/OMMT Nanocomposites
Authors: Yang Xiaoyu , Song Guojun , Li Peiyao , Gu Zheng , Wang Li , Liangdong Sun  , Gao Li
Published: March 2010

Almost completely exfoliated natural rubber/butadiene rubber/organophilic montmorillonite (NR/BR/OMMT) nanocomposites were successfully prepared by mechanical blending. The optimal type of OMMT was carefully selected, using characterization by X-ray diffraction (XRD) and the mechanical properties of composites, from three NR/BR/OMMT composites with different kinds of OMMT. The almost completely exfoliated NR/BR/OMMT nanocomposites were confirmed by transmission electron microscopy (TEM) and XRD. Then a series of NR/BR/OMMT (the optimal organoclay) nanocomposites with various amounts of OMMT were prepared and characterized. The results showed the tensile strength and tear strength of nanocomposite with only 3 parts per hundreds of rubber (phr) of clay were improved by about 90.8 and 54.0% in comparison with the pure NR/BR, respectively; and the stress relaxation behavior showed the equilibrium stress was higher than that of the pure sample. The increase of the cure rate index (VC) and reduction of the optimum time ( T90) indicated the efficiency of vulcanization was improved. The addition of OMMT also improved the oil resistance of the NR/BR composite; however, the thermal stability was not changed significantly. The outstanding performance of these tire sidewall materials with OMMT reinforcement means that they are good prospects for application in the tire industry.
Update on anti-phospholipid antibodies in SLE: the Hopkins’ Lupus Cohort
Authors: Petri M.
Published: March 2010

Anti-phospholipid antibodies are common in patients in the Hopkins’ Lupus Cohort: 47% have anti-cardiolipin, 32.5% anti-β2-glycoprotein I and 26% lupus anticoagulant (by dRVVT confirmatory testing). Systemic lupus erythematosus patients with the lupus anticoagulant at baseline have a 50% chance of a deep venous thrombosis/pulmonary embolus in the next 20 years. Anti-phospholipid antibodies differ in their association with thrombosis: the lupus anticoagulant is most strongly associated with arterial and venous thrombosis and is the only anti-phospholipid antibody associated with myocardial infarction. Anti-phospholipid antibodies are not associated with atherosclerosis. Lupus (2010) 19, 419—423.
Antiphospholipid syndrome: critical analysis of the diagnostic path
Authors: Pengo V. , Banzato A. , Bison E. , Denas G. , Padayattil Jose S. , Ruffatti A.
Published: March 2010

Antiphospholipid syndrome (APS) is diagnosed in the presence of vascular thrombosis or pregnancy morbidity occurring in patients with circulating antiphospholipid antibodies (lupus anticoagulant [LA] and/or IgG/IgM anticardiolipin [aCL] and/or IgG/IgM anti-β2glycoprotein I [aβ2GPI] antibodies). Each test may identify different autoantibodies; a single test makes the diagnosis possible when positive on two or more occasions at least 12 weeks apart. However, single test positivity may be unrelated to pathogenic antibodies, which are now considered to be a subclass of aβ2GPI antibodies directed against the domain I of this protein. Conversely, all three positive tests identify a single class of aβ2GPI antibodies, thus identifying high-risk patients with APS.
Non-criteria manifestations of antiphospholipid syndrome
Authors: Erkan D. , Lockshin MD
Published: March 2010

Only few studies have addressed the pathogenesis and treatment of the non-criteria manifestations of antiphospholipid antibodies (aPL) such as thrombocytopenia, nephropathy, cardiac valve disease, cognitive dysfunction, skin ulcers, or diffuse pulmonary hemorrhage. There is no consensus on the management of these manifestations; they may occur despite full-dose anticoagulation or may not improve if anticoagulation is initiated after their discovery. This brief review may help physicians in the management of the non-criteria manifestations of aPL.
Role of tissue factor in thrombosis in antiphospholipid antibody syndrome
Authors: Boles J. , Mackman N.
Published: March 2010

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of an antiphospholipid antibody (aPL) and the occurrence of at least one associated clinical condition that includes venous thrombosis, arterial thrombosis or pregnancy morbidity. The aPL detected in APS have long been thought to have a direct prothrombotic effect in vivo. However, the pathophysiology underlying their coagulopathic effect has not been defined. Emerging data suggest a role for the procoagulant protein tissue factor (TF). In this review we provide an overview of TF, describe mouse models used in the evaluation of the role of TF in thrombosis, as well as summarize recent work on TF and APS. Lupus (2010) 19, 370—378.
Antiphospholipid antibodies and the protein C pathway
Authors: Urbanus RT , de Laat B.
Published: March 2010

Haemostasis is a delicate balance between procoagulant and anticoagulant processes. In the human body usually anticoagulant mechanisms prevail over procoagulant mechanisms, thereby preventing a prothrombotic state. The antiphospholipid syndrome is an example in which this balance is shifted to a more prothrombotic state due to the presence of antiphospholipid antibodies. One of the most extensively proposed pathogenic mechanisms within the antiphospholipid syndrome is the inhibition of protein C by antiphospholipid antibodies. Antiphospholipid antibodies have been described to have different actions on the protein C pathway, for example decreasing protein C and/or S plasma levels, inducing increased resistance against activated protein C and lowering thrombin levels (resulting in an impaired protein C activation). This review briefly discusses the actions of protein C in human body but mainly focuses on the effects of antiphospholipid antibodies on the protein C pathway that have been described in literature.
Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view
Authors: Meroni PL , Tedesco F. , Locati M. , Vecchi A. , Di Simone N. , Acaia B. , Pierangeli SS , Borghi MO
Published: March 2010

Antiphospholipid antibodies (aPL) are associated with recurrent miscarriages and pregnancy complications, however their pathogenic mechanisms are still matter of research. Thrombotic events at the placental level cannot explain all of the clinical manifestations. It has been suggested that aPL may be responsible for a local acute inflammatory response mediated by complement activation and neutrophil infiltration eventually leading to fetal loss. However histological and immunohistological studies on human placental samples do support such a mechanism only in part and with no any clear relationship with the pregnancy outcome. A direct effect of aPL on both maternal and fetal placental tissues has been reported through the reactivity of the antibodies with beta2 glycoprotein I (β2GPI) expressed on the cell membranes. These events do not require an inflammatory response and can be in part related to the inhibition of growth factors favouring a physiological placentation. Understanding the different pathogenic mechanisms of aPL-associated miscarriages may help in improving our therapeutic approach particularly in recurrent cases not responsive to the usual treatment. Lupus (2010) 19, 453—456.
Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?
Authors: Cohen H. , Machin SJ
Published: March 2010

Anticoagulation with oral vitamin K antagonists (VKA) is the mainstay of the treatment of venous and/or arterial thromboembolism in patients with antiphospholipid syndrome (APS), although the optimal intensity of anticoagulation remains controversial. The limitations of existing anticoagulants have driven a search for novel agents. Dabigatran etexilate (Pradaxa®), a direct thrombin inhibitor (DTI), and rivaroxaban (Xarelto®), the first in a new class of drugs, the oral direct factor Xa (FXa) inhibitors, are both fixed-dose orally administered agents. They are now licensed in the UK and Europe for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective total hip replacement (THR) or total knee replacement (TKR). Prospective randomized clinical trials suggest that these agents, and also apixaban, a further oral direct anti-Xa inhibitor, may have potential in other areas including the treatment of acute VTE, prevention of stroke or systemic embolism in patients with atrial fibrillation (AF) and acute coronary syndromes. Here, we summarize current indications for these agents and address the potential for their use in patients with thrombotic APS.
Risky business: the interpretation, use, and abuse of antiphospholipid antibody tests in clinical practice
Authors: Roubey RAS
Published: March 2010

Antiphospholipid antibodies (aPL) are best considered as risk factors. aPL are not diagnostic tests and considering them as such can be misleading and may direct attention away from the more important clinical issue of risk modification and management. When considering aPL as risk factors, quantitative aPL tests such enzyme-linked immunosorbent assay (ELISA) for anticardiolipin (aCL) and anti-β 2-glycoprotein I (anti-β2GPI) antibodies, should be interpreted carefully. Risk for clinical manifestations appears to be associated with moderate to high levels of these autoantibodies. Lower levels may be statistically abnormal compared with a control population, but may not be associated with the risk of thrombosis or pregnancy loss. Lupus anticoagulants (LA) are generally thought to be more strongly associated with the risk of clinical manifestation of antiphospholipid syndrome (APS) than aCL and anti-β2GPI antibodies. One reason for the stronger association may be related to patients’ antibody titers. LA assays are not very analytically sensitive, i.e. a relatively high concentration of antibodies is required to prolong the clotting time in these tests. Thus, the presence of LA indicates a high titer of aPL and this, rather than the intrinsic functional characteristics of LA antibodies, may explain the high risk of clinical manifestations associated with LA.
The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis
Authors: Rand JH , Wu X-X. , Quinn AS , Taatjes DJ
Published: March 2010

Annexin A5 (AnxA5) binds to phospholipid bilayers, forming two-dimensional crystals that block the phospholipids from availability for coagulation enzyme reactions. Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of AnxA5 which expose phospholipids and thereby accelerate blood coagulation reactions. The aPL antibody-mediated disruption of AnxA5 crystallization has been confirmed on artificial phospholipid bilayers and on cell membranes including endothelial cells, placental trophoblasts and platelets. Recently, we reported that hydroxychloroquine, a synthetic antimalarial drug, can reverse this antibody-mediated process through two mechanisms: (1) by inhibiting the formation of aPL IgG-β2glycoprotein I complexes; and (2) by promoting the formation of a second layer of AnxA5 crystal ‘patches’ over areas where the immune complexes had disrupted AnxA5 crystallization. In another translational application, we have developed a mechanistic assay that reports resistance to AnxA5 anticoagulant activity in plasmas of patients with aPL antibodies. AnxA5 resistance may identify a subset of aPL syndrome patients for whom this is a mechanism for pregnancy losses and thrombosis. The elucidation of aPL-mediated mechanisms for thrombosis and pregnancy complications may open new paths towards addressing this disorder with targeted treatments and mechanistic assays.
Some antiphospholipid antibodies bind to various serine proteases in hemostasis and tip the balance toward hypercoagulant states
Authors: Chen PP , Wu M. , Hahn BH
Published: March 2010

The body has an elaborate system that maintains blood circulation and rapidly stops bleeding when vessels are damaged. Abnormalities that disrupt this balance may lead to thrombosis. While β2-glycoprotein I is generally accepted as the major antigen for antiphospholipid antibodies in the antiphospholipid syndrome, our accumulated studies show that some antiphospholipid antibodies bind homologous enzymatic domains of several serine proteases involved in hemostasis and fibrinolysis. Functionally, some of the protease-reactive antiphospholipid antibodies hinder anticoagulant regulation and resolution of clots, thus tip the balance toward thrombosis. Intriguingly, several serine protease-reactive antiphospholipid antibodies also react with β2-glycoprotein I, and interactions between antiphospholipid antibodies and antigens are cross-inhibited, indicating that these antiphospholipid antibodies recognize conformational epitope(s) on β2-glycoprotein I and target serine proteases. Viewed as a whole, these results extend previous reports that antiphospholipid antibodies bind to various hemostasis factors, and provide a new perspective about some antiphospholipid antibodies in terms of their binding specificities and related functional properties in promoting thrombosis.
Obstetric antiphospholipid syndrome: current uncertainties should guide our way
Authors: Branch DW , Silver RM , Porter TF
Published: March 2010

The subject of obstetric antiphospholipid syndrome (APS) has been reviewed dozens of times, and there is little doubt that the international APS community has done well in bringing APS to the attention of clinicians around the world. However, the evolution of clinical practice, at least in the US, also has convinced us that our field would benefit from further clinical study. For example, the number of women diagnosed with ‘APS’, but who do not meet the revised Sapporo criteria, seems to have increased. It is now common practice for women with recurrent miscarriage or prior fetal death to be treated with heparin, even in the presence of indeterminate or low titer antiphospholipid antibody (aPL) levels and even after only one positive test. In part, this common practice derives from confusion on the part of many clinicians and patients regarding the diagnosis of APS as well as the clinical and laboratory criteria for the syndrome. In part, this derives from the common practice of so-called ‘empiric treatment’ in US reproductive medicine, often driven as much by patients as by clinicians. This brief commentary focuses on areas of uncertainty that we see as deserving of new or renewed study for the sake of improving our understanding of APS and best patient care.
Antiphospholipid antibody profile: implications for the evaluation and management of patients
Authors: Tincani A. , Andreoli L. , Casu C. , Cattaneo R. , Meroni P.
Published: March 2010

According to the classification criteria of antiphospholipid syndrome, lupus anticoagulant, anticardiolipin and anti-β2 glycoprotein I antibody assays are independent risk factors for the occurrence of vascular thrombosis and pregnancy loss. However, it is generally accepted that patients carrying multiple positivity have more a severe disease and higher recurrence rate despite treatment. On the other hand, the diagnostic value of a positive result in one only assay is more controversial, particularly in the presence of clinical manifestations such as deep vein thrombosis or early miscarriages, which are rather common in the general population. In this review we speculate on current and future strategies to interpret different antiphospholipid antibody profiles in the clinical practice. Lupus (2010) 19, 432—435.
The dual role of innate immunity in the antiphospholipid syndrome
Authors: Rauch J. , Dieudé M. , Subang R. , Levine JS
Published: March 2010

The antiphospholipid syndrome (APS), as both a primary syndrome and a syndrome in association with systemic lupus erythematosus (SLE), can be a devastating disease. It is unclear what factors (genetic and/or environmental) lead to the generation of antiphospholipid antibodies (aPL). It is equally unclear why only certain individuals with aPL develop clinical events. We hypothesize that innate immune activation plays a critical role at two distinct stages of APS, namely, the initiation phase, in which aPL first appear, and the effector phase, in which aPL precipitate a thrombotic event. According to the model we propose, aPL alone are insufficient to cause thrombosis and a concomitant trigger of innate immunity, e.g. a toll-like receptor (TLR) ligand, must be present for thrombosis to occur. Here, we discuss our findings that mice immunized with β2-glycoprotein I (β2GPI) and lipopolysaccharide (LPS), a TLR ligand, produce high levels of aPL and other SLE-associated autoantibodies, and develop lupus-like glomerulonephritis. We also discuss our data showing that autoantibodies to heat shock protein 60 (HSP60), an ‘endogenous TLR ligand’, promote thrombus generation in a murine model of arterial injury. Thus, both pathogen-derived TLR ligands (e.g. LPS) and endogenous TLR ligands (e.g. HSP60) may contribute to the pathogenesis of APS. This putative dual role of innate immunity provides new insight into the generation of aPL as well as the enigma of why some individuals with aPL develop APS, while others do not.
Validation of the Iranian version of the Uncertainty In Illness Scale - Family form
Authors: Vagharseyyedin Seyyed Abolfazl , Vanaki Zohreh
Published: March 2010

This study aimed to evaluate the reliability and validity of the Iranian version of the Uncertainty In Illness Scale — Family form. For this purpose, the Uncertainty In Illness Scale — Family form was translated from English into Persian and tested for psychometric properties. The analyses were carried out with data from a sample of 310 patients’ family members at one general hospital in Birjand city, the center of the Southern Khorasan province. The Iranian version of the Uncertainty In Illness Scale — Family form demonstrated an acceptable level of content validity with a content validity index of 0.91. The Cronbach’s alpha of 0.83 showed that the scale had reasonable internal consistency. This preliminary validation study of the Iranian version of the Uncertainty In Illness Scale — Family form showed that it is an acceptable measure to be used with Iranian patients’ family members. Additional research is recommended for further evaluation of the psychometric properties of the scale.
The Attachment Paradox
Authors: Ein-Dor Tsachi , Mikulincer Mario , Doron Guy , Shaver Phillip R.
Published: March 2010

Bowlby’s (1969/1982) attachment theory has generated an enormous body of research and conceptual elaborations. Although attachment theory and research propose that attachment security provides a person with many adaptive advantages during all phases of the life cycle, numerous studies indicate that almost half of the human species can be classified as insecurely attached or insecure with respect to attachment. It seems odd that evolution left humans in this vulnerable position unless there are some advantages, under at least some conditions, to anxious and avoidant attachment styles. We argue that a social group containing members with different attachment patterns may be more conducive to survival than a homogeneous group of securely attached individuals. In making this argument, we extend the scope of attachment theory and research by considering a broader range of adaptive functions of insecure attachment strategies. We also present preliminary data to support our argument.
The Costs and Benefits of Calculation and Moral Rules
Authors: Bennis Will M. , Medin Douglas L. , Bartels Daniel M.
Published: March 2010

There has been a recent upsurge of research on moral judgment and decision making. One important issue with this body of work concerns the relative advantages of calculating costs and benefits versus adherence to moral rules. The general tenor of recent research suggests that adherence to moral rules is associated with systematic biases and that systematic cost-benefit analysis is a normatively superior decision strategy. This article queries both the merits of cost-benefit analyses and the shortcomings of moral rules. We argue that outside the very narrow domain in which consequences can be unambiguously anticipated, it is not at all clear that calculation processes optimize outcomes. In addition, there are good reasons to believe that following moral rules can lead to superior consequences in certain contexts. More generally, different modes of decision making can be seen as adaptations to particular environments.
Review: Hepatocellular carcinoma: the place of new medical therapies
Authors: Peck-Radosavljevic Markus
Published: March 2010

Medical therapies have entered center stage in the treatment of hepatocellular carcinoma (HCC) little more than a year after the positive results of a large phase III trial of sorafenib showed a clear survival benefit with sorafenib, a targeted agent, in this setting. Even though this marks a breakthrough in the treatment of HCC, the narrow patient profile necessary for the study to be successful has generated a number of questions regarding the efficacy of this approach in other clinical settings. New studies aiming to define the role of sorafenib from in the adjuvant setting, through patients with more advanced liver disease, all the way to combination treatments of HCC have been initiated. The success of one targeted drug has stimulated enormously the efforts of competitors to develop additional and better drugs, either in a first-line or a second-line setting. These are exciting times for the treatment of HCC, both for physicians and patients. In the years to come we will see an extension of treatment options in different clinical situations in patients with HCC, and survival will be improved in many stages of the disease, except for the most advanced. The rapid increase in knowledge about the molecular mechanisms underlying the development and progression of HCC will lead to a more tailored approach to treatment depending on the molecular characteristics of the tumor and the disease stage.
Synergism between platelet collagen receptors defined using receptor-specific collagen-mimetic peptide substrata in flowing blood
Authors: Pugh Nicholas , Simpson Anna M. C. , Smethurst Peter A. , de Groot Philip G. , Raynal Nicolas , Farndale Richard W.
Published: March 2010

Exposed subendothelial collagen acts as a substrate for platelet adhesion and thrombus formation after vascular injury. Synthetic collagen-derived triple-helical peptides, designated collagen-related peptide (CRP), GFOGER, and VWF-III, can specifically engage the platelet collagen receptors, glycoprotein VI and integrin α2β1, and plasma von Willebrand factor (VWF), respectively. Hitherto, the role of these 3 collagen-binding axes has been studied indirectly. Use of these uniform peptide substrates, rather than collagen fibers, provides independent control of each axis. Here, we use confocal imaging and novel image analysis techniques to investigate the effects of receptor-ligand engagement on platelet binding and activation during thrombus formation under flow conditions. At low shear (100s−1 and 300s−1), both GFOGER and CRP are required for thrombus formation. At 1000s−1, a combination of either CRP or GFOGER with VWF-III induces comparable thrombus formation, and VWF-III increases thrombus deposition at all shear rates, being indispensable at 3000s−1. A combination of CRP and VWF-III is sufficient to support extensive platelet deposition at 3000s−1, with slight additional effect of GFOGER. Measurement of thrombus height after specific receptor blockade or use of altered proportions of peptides indicates a signaling rather than adhesive role for glycoprotein VI, and primarily adhesive roles for both α2β1 and the VWF axis.
17-DMAG targets the nuclear factor-κB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition
Authors: Hertlein Erin , Wagner Amy J. , Jones Jeffrey , Lin Thomas S. , Maddocks Kami J. , Towns William H. , Goettl Virginia M. , Zhang Xiaoli , Jarjoura David , Raymond Chelsey A. , West Derek A. , Croce Carlo M. , Byrd John C. , Johnson Amy J.
Published: March 2010

The HSP90 client chaperone interaction stabilizes several important enzymes and antiapoptotic proteins, and pharmacologic inhibition of HSP90 results in rapid client protein degradation. Therefore, HSP90 inhibition is an attractive therapeutic approach when this protein is active, a phenotype commonly observed in transformed but not normal cells. However, preclinical studies with HSP90 inhibitors such as 17-AAG demonstrated depletion of only a subset of client proteins and very modest tumor cytotoxicity in chronic lymphocytic leukemia (CLL) cells. Herein, we describe another HSP90 inhibitor, 17-DMAG, which is cytotoxic to CLL but not normal lymphocytes. Treatment with 17-DMAG leads to depletion of the HSP90 client protein IKK, resulting in diminished NF-κB p50/p65 DNA binding, decreased NF-κB target gene transcription, and caspase-dependent apoptosis. Furthermore, treatment with 17-DMAG significantly decreased the white blood cell count and prolonged the survival in a TCL1-SCID transplant mouse model. The ability of 17-DMAG to function as an NF-κB inhibitor is of great interest clinically, as few currently available CLL drugs target this transcription factor. Therefore, the effect of 17-DMAG on NF-κB signaling pathways represents a novel therapy warranting further clinical pursuit in this and other B-cell lymphoproliferative disorders.
Overexpression of transforming growth factor-β1 in fetal monkey lung results in prenatal pulmonary fibrosis
Authors: Tarantal A.F. , Chen H. , Shi T.T. , Lu C-H. , Fang A.B. , Buckley S. , Kolb M. , Gauldie J. , Warburton D. , Shi W.
Published: March 2010

Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates.

Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry.

Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident.

Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.
Phosphoinositide 3-kinase δ inhibitor suppresses interleukin-17 expression in a murine asthma model
Authors: Park S.J. , Lee K.S. , Kim S.R. , Min K.H. , Moon H. , Lee M.H. , Chung C.R. , Han H.J. , Puri K.D. , Lee Y.C.
Published: March 2010

Phosphoinositide 3-kinases (PI3Ks) contribute to the pathogenesis of asthma by regulating the activation of inflammatory mediators, inflammatory cell recruitment and immune cell function. Recent findings have indicated that PI3Ks also regulate the expression of interleukin (IL)-17, which has been recognised as an important cytokine involved in airway inflammation.

In the present study, we investigated a role of PI3Kδ in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma.

After ovalbumin inhalation, administration of a selective p110δ inhibitor, IC87114, significantly attenuated airway infiltration of total cells, lymphocytes, neutrophils and eosinophils, as well as airway hyperresponsiveness, and attenuated the increase in IL-17 protein and mRNA expression. Moreover, IC87114 reduced levels of IL-4, -5 and -13, expression of keratinocyte chemoattractant protein and mRNA, and nuclear factor (NF)-κB activity. In addition, a NF-κB inhibitor, BAY 11-7085 substantially reduced the increase in IL-17 protein levels. Our results also showed that inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness.

These findings suggest that inhibition of the p110δ signalling pathway suppresses IL-17 expression through regulation of NF-κB activity and, thus, has therapeutic potential in asthma.
Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil
Authors: Mouchaers K.T.B. , Schalij I. , de Boer M.A. , Postmus P.E. , van Hinsbergh V.W.M. , van Nieuw Amerongen G.P. , Vonk Noordegraaf A. , van der Laarse W.J.
Published: March 2010

Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments.

Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied.

MCT (40 mg·kg body weight−1) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect.

Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.
Systemic sclerosis and bilateral lung transplantation: a single centre experience
Authors: Saggar R. , Khanna D. , Furst D.E. , Belperio J.A. , Park G.S. , Weigt S.S. , Kubak B. , Ardehali A. , Derhovanessian A. , Clements P.J. , Shapiro S. , Hunter C. , Gregson A. , Fishbein M.C. , Lynch III J.P. , Ross D.J. , Saggar R.
Published: March 2010

Lung involvement is the leading cause of death in systemic sclerosis (SSc), but lung transplantation (LT) for systemic disease remains controversial. Our objective was to comprehensively evaluate post-LT outcomes for SSc compared to idiopathic pulmonary fibrosis (IPF).

We retrospectively evaluated bilateral LT recipients (LTRs) with SSc or IPF at our centre between January 1, 2003 and December 31, 2007. The primary end-point was all-cause mortality at 1 yr post-LT. Secondary end-points included assessments of acute rejection (AR), pulmonary function, infection and chronic rejection.

14 patients with SSc and 38 patients with IPF underwent LT. Apart from a younger SSc cohort (53.2versus58.8 yrs; p = 0.02), the two groups were well matched. 1-yr all-cause mortality was no different between SSc (6.6%) and IPF (13.1%) groups, after adjusting for age (p = 0.62). Rates of (AR) ≥2 were significantly increased for the SSc compared with the IPF group (hazard ratio (HR) 2.91; p = 0.007). Other end-points, including chronic rejection, infection and pulmonary function, showed no differences.

SSc LTRs experience similar survival 1 yr post-LT when compared to IPF. AR rates may be significantly higher in the SSc group. Longer follow-up is necessary to determine the effects of gastrointestinal dysfunction and AR on late allograft function in SSc LTR.
Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD
Authors: Van Pottelberge G.R. , Bracke K.R. , Van den Broeck S. , Reinartz S.M. , van Drunen C.M. , Wouters E.F. , Verleden G.M. , Vermassen F.E. , Joos G.F. , Brusselle G.G.
Published: March 2010

Plasmacytoid dendritic cells (pDCs) are professional antigen-presenting cells with antiviral and tolerogenic capabilities. Viral infections and autoimmunity are proposed to be important mechanisms in the pathogenesis of chronic obstructive pulmonary disease (COPD).

The study aimed to quantify blood dendritic cell antigen 2-positive pDCs in lungs of subjects with or without COPD by immunohistochemistry and flow cytometry, combined with the investigation of the influence of cigarette smoke extract (CSE) on the function of pDCsin vitro.

pDCs were mainly located in lymphoid follicles, a finding compatible with their expression of lymphoid homing chemokine receptors CXCR3 and CXCR4. pDC accumulated in the lymphoid follicles and in lung digests of patients with mild to moderate COPD, compared with smokers without airflow limitation and patients with COPD Global Initiative for Chronic Obstructive Lung disease (GOLD) stage III–IV. Exposing maturing pDC of healthy subjects to CSEin vitrorevealed an attenuation of the expression of co-stimulatory molecules and impaired interferon-α production. Maturing pDC from patients with COPD produced higher levels of tumour necrosis factor (TNF)-α and interleukin (IL)-8 compared to pDC from healthy subjects.

CSE significantly impairs the antiviral function of pDCs. In COPD, a GOLD stage dependent accumulation of pDC in lymphoid follicles is present, combined with an enhanced production of TNF-α and IL-8 by maturing pDCs.
Repaired oesophageal atresia: respiratory morbidity and pulmonary function in adults
Authors: Sistonen S. , Malmberg P. , Malmström K. , Haahtela T. , Sarna S. , Rintala R.J. , Pakarinen M.P.
Published: March 2010

Although after oesophageal atresia (OA) repair in infancy, respiratory problems are common, their natural history remains unclear. We assessed morbidity, pulmonary function (PF), and bronchial hyperresponsiveness (BHR) in adults with repaired OA respiratory.

588 patients who underwent surgery for OA during 1947–1985 were identified and those 262 who were alive and had their native oesophagus were included. Respiratory symptoms and respiratory symptom-related quality of life (RSRQoL) were assessed by questionnaire and interview, and the patients underwent spirometry, a histamine challenge test, and an exhaled nitric oxide test. For the questionnaires, we added 287 carefully matched general population-derived controls.

Among the 101 (58 male) patients, median age 36 yrs (range 22–56 yrs), respiratory morbidity was significantly increased compared to controls. Patients had more respiratory symptoms and infections, as well as asthma and allergies, and more often impaired RSRQoL (p<0.001 for all). PF tests revealed restrictive ventilatory defect in 21 (21%) patients, obstructive ventilatroy defect in 21 (21%) patients, and both in 36 (36%) patients. A total of 41 (41%) had BHR, and in 15 (15%), it was consistent with asthma. The most significant risk factors for restrictive ventilatory defect were thoracotomy-induced rib fusions (OR 3.4, 95% CI 1.3–8.7; p = 0.01) and oesophageal epithelial metaplasia (OR 3.0, 95% CI 1.0–8.9; p = 0.05).

After repair of OA, respiratory-related morbidity, restrictive ventilatory defect and BHR extended into adulthood. Nearly half the patients had BHR and over half had a restrictive ventilatory defect. Thoracotomy-induced rib fusions and gastro-oesophageal reflux-associated oesophageal epithelial metaplasia were the strongest risk factors for restrictive ventilatory defect.
An experimental model of pneumonia induced by methicillin-resistantStaphylococcus aureusin ventilated piglets
Authors: Martínez-Olondris P. , Sibila O. , Agustí C. , Rigol M. , Soy D. , Esquinas C. , Piñer R. , Luque N. , Guerrero L. , Quera M.Á. , Marco F. , de la Bellacasa J.P. , Ramirez J. , Torres A.
Published: March 2010

The objectives of the study were to validate a model of methicillin-resistantStaphylococcus aureus(MRSA) pneumonia in ventilated piglets and to study the time-course of biological markers and histopathological changes.

12 piglets were intubated and inoculated with 15 mL of a suspension of 106colony forming units of MRSA in every lobe through the bronchoscope channel. The piglets were ventilated for 12 h (n = 6) and 24 h (n = 6). Clinical parameters were assessed every 6 h and pro-inflammatory cytokines were measured in serum and in bronchoalveolar lavage (BAL) at baseline and sacrifice. Histopathology of each lobe and cultures from blood, lungs and BAL were performed.

Animals developed histopathological evidence of pneumonia at necropsy. At 12 h, pneumonia was present in all animals and was severe pneumonia at 24 h. Microbiological studies confirmed the presence of MRSA. A significant increase in interleukin (IL)-6, IL-8 and tumour necrosis factor-α values was seen in BAL at 24 h and IL-6 at 12 h. In serum, only IL-6 levels had increased significantly at 24 h.

In ventilated piglets, bronchoscopic inoculation of MRSA induces pneumonia at 12 h and severe pneumonia at 24 h. This severity was associated with a corresponding increase in systemic and local inflammatory response.
CDK-Taverna: an open workflow environment for cheminformatics
Authors: Kuhn Thomas , Willighagen Egon L , Zielesny Achim , Steinbeck Christoph
Published: March 2010

Background

Small molecules are of increasing interest for bioinformatics in areas such as metabolomics and drug discovery. The recent release of large open access chemistry databases generates a demand for flexible tools to process them and discover new knowledge. To freely support open science based on these data resources, it is desirable for the processing tools to be open source and available for everyone.

Results

Here we describe a novel combination of the workflow engine Taverna and the cheminformatics library Chemistry Development Kit (CDK) resulting in a open source workflow solution for cheminformatics. We have implemented more than 160 different workers to handle specific cheminformatics tasks. We describe the applications of CDK-Taverna in various usage scenarios.

Conclusions

The combination of the workflow engine Taverna and the Chemistry Development Kit provides the first open source cheminformatics workflow solution for the biosciences. With the Taverna-community working towards a more powerful workflow engine and a more user-friendly user interface, CDK-Taverna has the potential to become a free alternative to existing proprietary workflow tools.
Comprehensive analysis of MHC class I genes from the U-, S-, and Z-lineages in Atlantic salmon
Authors: Lukacs Morten F , Harstad Håvard , Bakke Hege G , Beetz-Sargent Marianne , McKinnel Linda , Lubieniecki Krzysztof P , Koop Ben F , Grimholt Unni
Published: March 2010

Background

We have previously sequenced more than 500 kb of the duplicated MHC class I regions in Atlantic salmon. In the IA region we identified the loci for the MHC class I geneSasa-UBAin addition to a soluble MHC class I molecule,Sasa-ULA. A pseudolocus forSasa-UCAwas identified in the nonclassical IB region. Both regions contained genes for antigen presentation, as wells as orthologues to other genes residing in the human MHC region.

Results

The genomic localisation of two MHC class I lineages (Z and S) has been resolved. 7 BACs were sequenced using a combination of standard Sanger and 454 sequencing. The new sequence data extended the IA region with 150 kb identifying the location of one Z-lineage locus,ZAA. The IB region was extended with 350 kb including three new Z-lineage loci,ZBA,ZCAandZDAin addition to aUGAlocus. An allelic version of the IB region contained a functionalUDAlocus in addition to theUCApseudolocus. Additionally a BAC harbouring two MHC class I genes (UHA) was placed on linkage group 14, while a BAC containing the S-lineage locusSAA(previously known asUAA) was placed on LG10. Gene expression studies showed limited expression range for all class I genes with exception ofUBAbeing dominantly expressed in gut, spleen and gills, andZAAwith high expression in blood.

Conclusion

Here we describe the genomic organization of MHC class I loci from the U-, Z-, and S-lineages in Atlantic salmon. Nine of the described class I genes are located in the extension of the duplicated IA and IB regions, while three class I genes are found on two separate linkage groups. The gene organization of the two regions indicates that the IB region is evolving at a different pace than the IA region. Expression profiling, polymorphic content, peptide binding properties and phylogenetic relationship show that Atlantic salmon has only one MHC class Ia gene (UBA), in addition to a multitude of nonclassical MHC class I genes from the U-, S- and Z-lineages.
Mercury-induced hepatotoxicity in zebrafish: in vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation
Authors: Ung Choong Yong , Lam Siew Hong , Hlaing Mya Myintzu , Winata Cecilia Lanny , Korzh Svetlana , Mathavan Sinnakaruppan , Gong Zhiyuan
Published: March 2010

Background

Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information onin vivomolecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in thein vitrohuman cell line studies.

Results

Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations.

Conclusion

Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling pathway, gluconeogenesis, and adipogenesis, leading to mitochondrial dysfunction, endocrine disruption and metabolic disorders. This study provides important mechanistic insights into mercury-induced liver toxicity in a whole-animal physiology context, which will help in understanding the syndromes caused by mercury poisoning. The molecular conservation of mercury-induced hepatotoxicity between zebrafish and human cell line reveals the feasibility of using zebrafish to model molecular toxicity in human for toxicant risk assessments.
An insight into the sialome of Glossina morsitans morsitans
Authors: Alves-Silva Juliana , Ribeiro José MC , Abbeele Jan Van Den , Attardo Geoffrey , Hao Zhengrong , Haines Lee R , Soares Marcelo B , Berriman Matthew , Aksoy Serap , Lehane Michael J
Published: March 2010

Background

Blood feeding evolved independently in worms, arthropods and mammals. Among the adaptations to this peculiar diet, these animals developed an armament of salivary molecules that disarm their host's anti-bleeding defenses (hemostasis), inflammatory and immune reactions. Recent sialotranscriptome analyses (from the Greek sialo = saliva) of blood feeding insects and ticks have revealed that the saliva contains hundreds of polypeptides, many unique to their genus or family. Adult tsetse flies feed exclusively on vertebrate blood and are important vectors of human and animal diseases. Thus far, only limited information exists regarding the Glossina sialome, or any other fly belonging to the Hippoboscidae.

Results

As part of the effort to sequence the genome of Glossina morsitans morsitans, several organ specific, high quality normalized cDNA libraries have been constructed, from which over 20,000 ESTs from an adult salivary gland library were sequenced. These ESTs have been assembled using previously described ESTs from the fat body and midgut libraries of the same fly, thus totaling 62,251 ESTs, which have been assembled into 16,743 clusters (8,506 of which had one or more EST from the salivary gland library). Coding sequences were obtained for 2,509 novel proteins, 1,792 of which had at least one EST expressed in the salivary glands. Despite library normalization, 59 transcripts were overrepresented in the salivary library indicating high levels of expression. This work presents a detailed analysis of the salivary protein families identified. Protein expression was confirmed by 2D gel electrophoresis, enzymatic digestion and mass spectrometry. Concurrently, an initial attempt to determine the immunogenic properties of selected salivary proteins was undertaken.

Conclusions

The sialome of G. m. morsitans contains over 250 proteins that are possibly associated with blood feeding. This set includes alleles of previously described gene products, reveals new evidence that several salivary proteins are multigenic and identifies at least seven new polypeptide families unique to Glossina. Most of these proteins have no known function and thus, provide a discovery platform for the identification of novel pharmacologically active compounds, innovative vector-based vaccine targets, and immunological markers of vector exposure.