bluuebunny/crossref_metadata_2025 huggingface dataset:
A new cation‐modified Al‐polyacrylamide flocculant for solid–liquid separation in waste drilling fluid
Authors: Zhang Yongming , Miao Zongcheng , Zou Jing
Published: November 2014

A new cation‐modified Al‐polyacrylamide (CAPAM) flocculant was prepared by the in situ polymerization of acrylamide (AM) and (2‐methacryloyloxyethyl) trimethyl ammonium chloride (DMC) with Al(OH)3 sol. The optimum preparation conditions were obtained by a one‐factor experimental design: as the amount of AlCl3 was fixed at 0.025 mol, the polymerization time, polymerization temperature, n(AM) : n(AlCl3), n(DMC) : n(AlCl3), and n(K2S2O8) : n(AM) were 4 h, 70°C, 8, 0.9, and 1.82 × 10−3, respectively. The CAPAM was characterized by thermogravimetric analysis, Fourier transform infrared spectroscopy, scanning electron microscopy, and transmission electron microscopy. The solid–liquid separation performance of the CAPAM was evaluated in terms of water content. The CAPAM showed better flocculation performance than cationic polyacrylamide and polyaluminum sulfate at a fixed concentration of 0.3% in waste drilling fluid and tended to perform well in alkaline solution. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41641.
Sulphurous additives for polystyrene: Influencing decomposition behavior in the condensed phase
Authors: Braun Ulrike , Eisentraut Paul , Fuchs Sabine , Deglmann Peter
Published: November 2014

The thermal decomposition behaviour of polystyrene (PS) containing sulphur and phosphorus additives was investigated, using thermogravimetry coupled with Fourier transform infrared spectroscopy (TGA‐FTIR). It was found that the additives influence the decomposition process of the polymer in the condensed phase, resulting in a decrease in styrene monomer formation and an increase in styrene oligmer derivatives. Via reference measurements with binary mixtures it was found that the presence of sulphur additives influences the radicalic decomposition process of PS. In combination with quantum chemical calculations it was concluded that this is due to the formation of radicals that abstract hydrogen from the polymer matrix at lower temperatures, disfavouring the radicalic decomposition pathway leading to styrene. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2015,132, 41665.
Effect of the composition of methanol−water mixtures on tacticity of poly(N‐ethylacrylamide) gel
Authors: Biswas Chandra Sekhar , Sulu Elvan , Hazer Baki
Published: November 2014

Two series of macroporous poly(N‐ethylacrylamide) (PNEAM) gels are synthesized in different composition of methanol–water mixtures (xm = 0, 0.06, 0.13, 0.21, 0.31, and 0.43; where xm = mole fraction of methanol) in presence as well as in the absence of 0.1M Y(OTf)3 Lewis acid as additive. The gels synthesized in the absence of Lewis acid are atactic and in the presence of the same are isotactic. Synthesis of the corresponding linear PNEAM homopolymers shows that, the isotacticity (meso dyad, %) of the resulted polymers increases for the gels prepared in the presence of Lewis acid (LA) and remains constant for the gel prepared in the absence of LA, respectively, with the increase in the concentration of the synthesis solvent methanol. SEM micrographs reveal that, the hydrogels synthesized in the presence of LA are more porous than the gels prepared in the absence of LA. Swelling ratio of all the hydrogels decreases with the increase in the temperature and LA gels show higher swelling ratio values than non LA gels (NLA). Deswelling rate of the hydrogels prepared in methanol–water mixture in presence of LA is faster than the hydrogels prepared in absence of LA. Moreover, reswelling rate increases with increase in the isotacticity of the PNEAM segment in the gel. All these results have been explained on the basis of the formation of highly porous hydrogels with higher isotactic PNEAM chain segment in the presence of LA in methanol–water mixtures. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41668.
Concentration effect on aggregation and dissolution behavior of poly(N‐isopropylacrylamide) in water
Authors: Yan Yongbin , Huang Lianghui , Zhang Quan , Zhou Hu
Published: November 2014

The concentration effect on aggregation and dissolution behavior of poly(N‐isopropylacrylamide) (PNIPAM) in water was studied. Three concentration regimes with different phase behavior were identified by differential scanning calorimetry (DSC). Further optical, light‐scattering, and rheological studies indicated that the appearance of different regimes arose from their corresponding solution structures below lower critical solution temperature (LCST): free chains and small clusters in regime I, large clusters in regime II, and a gel‐like network in regime III. Different solution structures below LCST led to different phase‐separated patterns formed above LCST: colloidal particles in regime I, large precipitate in regime II, and the sponge‐like solid in regime III, which was well understood based on the overlapping parameter P. Different phase‐separated patterns therefore resulted in different remixing behavior as observed by DSC. This work suggests that the swelling and collapse behavior of PNIPAM based hydrogels was controlled through the design of their phase‐separated patterns, and therefore provided a way to develop high performance thermo‐sensitive materials. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2015,132, 41669.
Morphological Features of Herbst Corpuscles in the Oropharynx of the Ostrich (Struthio camelus) and Emu (Dromaius novaehollandiae)
Authors: Crole Martina R. , du Plessis Lizette , Soley John T.
Published: November 2014

The distribution of Herbst corpuscles in the oropharynx of the ostrich and emu has recently been documented. However, although the morphology of these mechanoreceptors is well known in neognathous birds, little structural information is available on the Herbst corpuscles of ratites. Tissue sections from those regions of the oropharynx known to possess a high concentration of Herbst corpuscles were sampled from ostrich and emu heads collected after slaughter and prepared for light and transmission electron microscopy. Intra‐oral Herbst corpuscles in the ostrich and emu displayed the same basic components (capsule, outer zone, inner core and axon) described in neognathous birds. However, some important differences were observed, notably, the presence of myofibroblasts in the capsule, sensory cilia in cells of the outer layers, a relatively larger, less organized outer zone and narrower inner core, and variations in the shape of the axon. The previously unreported presence of myofibroblasts in the capsule possibly indicates its ability to contract, thus altering the tension of the capsule, which in turn has implications for the conduction of vibrational stimuli. The sensory cilia in the myofibroblasts of the capsule bordering the outer zone, and in the fibroblasts of the outer zone itself, may play a regulatory role in controlling the contraction of the capsule. Such a function has not previously been reported for Herbst corpuscles in any species of bird. Anat Rec, 298:783–796, 2015. © 2014 Wiley Periodicals, Inc.
Transcription Factor CREB is Involved in CaSR‐mediated Cytoskeleton Gene Expression
Authors: Huang Shuaishuai , Ren Yu , Wang Ping , Li Yanyuan , Wang Xue , Zhuang Haihui , Fang Rong , Wang Yuduo , Liu Ningsheng , Hehir Michael , Zhou Jeff X.
Published: November 2014

Our previous studies illustrated that a steady increase of intracellular calcium concentration ([Ca2+]i) was important for maintaining microtubules (MTs) rearrangement in apoptotic cells. However, little is known about the effect of calcium sensing receptor (CaSR)‐mediated increase in [Ca2+]i on cytoskeleton gene expression. We examined the impact of taxol or CaSR agonist/antagonist on the regulation of [Ca2+]i concentration, cytoskeleton arrangement, phosphorylated CREB and cytoskeleton gene expressions in HeLa cells with dominant negative plasmid of CREB (PM). This study demonstrated that Gdcl3 (a specific CaSR agonist) evoked a rapid increase of [Ca2+]i, formed a rigid bundle of MTs which surrounded the nucleus and decreased the cytoskeleton gene expressions in HeLa cells. These effects were rescued by addition of NPS2390 (a specific CaSR antagonist). Moreover, CaSR activity affected cytoskeleton gene expression through transcription factor CREB. Histoscores of pCREB immunoreactivity in tissues of cervical adenocarcinoma, renal clear cell carcinoma, and diffuse large B‐cell lymphoma were markedly increased compared with non malignant tissue. These data demonstrate, for the first time, that CaSR‐mediated increase in [Ca2+]i probably modulate cytoskeleton organization and gene expression via transcription factor CREB. Anat Rec, 298:501–512, 2015. © 2014 Wiley Periodicals, Inc.
Teat Morphology Characterization With 3D Imaging
Authors: Vesterinen Heidi M. , Corfe Ian J. , Sinkkonen Ville , Iivanainen Antti , Jernvall Jukka , Laakkonen Juha
Published: November 2014

The objective of this study was to visualize, in a novel way, the morphological characteristics of bovine teats to gain a better understanding of the detailed teat morphology. We applied silicone casting and 3D digital imaging in order to obtain a more detailed image of the teat structures than that seen in previous studies. Teat samples from 65 dairy cows over 12 months of age were obtained from cows slaughtered at an abattoir. The teats were classified according to the teat condition scoring used in Finland and the lengths of the teat canals were measured. Silicone molds were made from the external teat surface surrounding the teat orifice and from the internal surface of the teat consisting of the papillary duct, Fürstenberg's rosette, and distal part of the teat cistern. The external and internal surface molds of 35 cows were scanned with a 3D laser scanner. The molds and the digital 3D models were used to evaluate internal and external teat surface morphology. A number of measurements were taken from the silicone molds. The 3D models reproduced the morphology of the teats accurately with high repeatability. Breed didn't correlate with the teat classification score. The rosette was found to have significant variation in its size and number of mucosal folds. The internal surface morphology of the rosette did not correlate with the external surface morphology of the teat implying that it is relatively independent of milking parameters that may impact the teat canal and the external surface of the teat. Anat Rec, 298:1359–1366, 2015. © 2014 Wiley Periodicals, Inc.
Carbohydrate‐binding module tribes
Authors: Carvalho Caio C. , Phan Ngoc N. , Chen Yingfei , Reilly Peter J.
Published: November 2014

At present, 69 families of carbohydrate‐binding modules (CBMs) have been isolated by statistically significant differences in the amino acid sequences (primary structures) of their members, with most members of different families showing little if any homology. On the other hand, members of the same family have primary and tertiary (three‐dimensional) structures that can be computationally aligned, suggesting that they are descended from common protein ancestors. Members of the large majority of CBM families are β‐sandwiches. This raises the question of whether members of different families are descended from distant common ancestors, and therefore are members of the same tribe. We have attacked this problem by attempting to computationally superimpose tertiary structure representatives of each of the 53 CBM families that have members with known tertiary structures. When successful, we have aligned locations of secondary structure elements and determined root mean square deviations and percentages of similarity between adjacent amino acid residues in structures from similar families. Further criteria leading to tribal membership are amino acid chain lengths and bound ligands. These considerations have led us to assign 27 families to nine tribes. Eight of the tribes have members with β‐sandwich structures, while the ninth is composed of structures with β‐trefoils. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 203–214, 2015.
The response of DNA length and twist to changes in ionic strength
Authors: Manning Gerald S.
Published: November 2014

We examine twist‐stretch coupling of unconstrained DNA using polyelectrolyte theory as applied to a line‐charge model along with published data on the ionic‐strength dependence of the twist angle. We conclude that twist‐stretch coupling is negative: environmental changes that stretch free DNA, unconstrained by externally applied pulling or twisting forces, are accompanied by unwinding of the double helix. We also analyze a helical model and conclude that the observed unwinding of the DNA helix when ionic strength is decreased is driven by radial swelling of the helix. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 223–226, 2015.
Influence of a cis,syn‐cyclobutane pyrimidine dimer damage on DNA conformation studied by molecular dynamics simulations
Authors: Knips Alexander , Zacharias Martin
Published: November 2014

The photo‐induced formation of cis‐syn‐cyclobutane pyrimidine dimers (CPD) is a highly mutagenic and cancerogenic DNA lesion. In bacteria photolyases can efficiently reverse the dimer formation employing a light‐driven reaction after looping out the CPD damaged bases into the enzyme active site. The exact mechanism how the repair enzyme identifies a damaged site within a large surplus of undamaged DNA is not fully understood. The CPD damage may alter the DNA structure and dynamics already in the absence of the repair enzyme which can facilitate the initial binding of a photolyase repair enzyme. To characterize the effect of a CPD damage, extensive comparative molecular dynamics (MD) simulations on duplex DNA with central regular or CPD damaged nucleotides were performed supplemented with simulations of the DNA‐photolyase complex. Although no spontaneous flipping out transitions of the damaged bases were observed, the simulations showed significant differences in the conformational states of regular and CPD damage DNA. The isolated damaged DNA adopted transient conformations which resembled the global shape of the repair enzyme bound conformation more closely compared to regular B‐DNA. In particular, these conformational changes were observed in most of helical and structural parameters where the protein bound DNA differs drastically from regular B‐DNA. It is likely that the transient overlap of isolated DNA with the enzyme bound DNA conformation plays a decisive role for the specific and rapid initial recognition by the repair enzyme prior to the looping out process of the damaged DNA. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 215–222, 2015.
Self‐repositioning of an embolized patent ductus arteriosus device—a nightmare turned into sweet dreams
Authors: Subramanian Venkateshwaran , Kavassery Mahadevan Krishnamoorthy , Sivasubramonian Sivasankaran
Published: November 2014

A 7‐month‐old boy was admitted for the device closure of symptomatic patent ductus arteriosus (PDA) with moderate pulmonary hypertension. The PDA measured 4.2 mm with adequate ampulla. It was closed with an 8–6 mm Heart R device from pulmonary artery (PA) end. Post extubation, the device embolized to proximal descending thoracic aorta just distal to PDA ampulla. While attempting to snare from the venous side, the device self‐repositioned to PDA. It was stable thereafter and patient was discharged after 2 days. We report a complication, which got self‐corrected. © 2014 Wiley Periodicals, Inc.
Effective radiation doses associated with non‐invasive versus invasive assessment of coronary anatomy and physiology
Authors: Toth G.G. , Ntalianis A. , Ntarladimas Y. , de Booij M. , De Winter O. , Barbato E. , Pilet B. , Van Mieghem C. , Wijns W. , De Bruyne B.
Published: November 2014

Objectives

To compare the effective radiation dose (ERD) needed to obtain information on coronary anatomy and physiology by a non‐invasive versus an invasive diagnostic strategy.

Background

Knowledge of anatomy and physiology is needed for management of patients with coronary artery disease (CAD). There is, however, a growing concern about detrimental long‐term effects of radiation associated with diagnostic procedures.

Methods

In a total of 671 patients with suspected CAD, we compared the ERD needed to obtain anatomical and physiological information through a non‐invasive strategy or an invasive strategy. The non‐invasive strategy consisted of coronary computed tomography angiography (CCTA) and single photon emission computed tomography (SPECT). The invasive strategy included coronary angiography (CA) and fractional flow reserve (FFR) measurement. In 464 patients, the data were acquired in Period 2009 and in 207 the data were acquired in Period 2011 (after each period, the CCTA‐ and the CA‐equipment had been upgraded).

Results

For the Period 2009 total ERD of the non‐invasive approach was significantly larger compared to the invasive approach (28.45 ± 5.37 mSv versus 15.79 ± 7.95 mSv, respectively; P < 0.0001). For Period 2011, despite the significant decrease in ERD for both groups (P < 0.0001 for both), the ERD remained higher for the non‐invasive approach compared to the invasive approach (16.67 ± 10.45 mSv vs. 10.36 ± 5.87 mSv, respectively; P < 0.0001). Simulation of various diagnostic scenarios showed cumulative radiation dose is the lowest when a first positive test is followed by an invasive strategy.

Conclusion

To obtain anatomic and physiologic information in patients with suspected CAD, the combination of CA and FFR is associated with lower ERD than the combination of CCTA and SPECT. © 2014 Wiley Periodicals, Inc.
Abciximab‐induced alveolar hemorrhage treated with rescue extracorporeal membranous oxygenation
Authors: Choi Andrew W. , Blair John E.A. , Flaherty James D.
Published: November 2014

We describe a case of a 75‐year‐old woman presenting emergently with an anterior S‐T elevation myocardial infarction that deteriorated into ventricular fibrillation requiring prompt resuscitation, resulting in cardiogenic shock. Emergency primary percutaneous coronary intervention of the left anterior descending coronary artery with adjunctive abciximab and heparin resulted in adequate coronary flow, and intra‐aortic balloon pump was used to support hemodynamics. Within one hour of intervention, she developed acute respiratory distress with four‐quadrant opacification of lung fields, difficulty with oxygenation, and hypotension. Emergency bronchoscopy revealed diffuse erythematous proximal airways with bloody secretions bilaterally confirming diffuse alveolar hemorrhage. An emergency veno‐arterial extracorporeal membranous oxygenation (ECMO) circuit was placed at the bedside, acutely improving oxygenation and hemodynamics. She survived the hospitalization with multiple complications related to access site and prolonged intensive care unit stay, was discharged to acute rehabilitation. She is currently thriving 18 months post‐procedure. This case highlights the use of ECMO in the often‐fatal condition of diffuse alveolar hemorrhage related to glycoprotein inhibitor use. © 2014 Wiley Periodicals, Inc.
Potential risk factors of re‐intervention after endovascular repair for type B aortic dissections
Authors: Zhang Lei , Zhou Jian , Lu Qingsheng , Zhao Zhiqing , Bao Junmin , Jing Zaiping
Published: November 2014

Objectives

To assess the potential risk factors of re‐intervention after thoracic endovascular aortic repair (TEVAR).

Background

TEVAR has been chosen as a less invasive alternative for Type B aortic dissections (TBADs); however, the potential risk factors of re‐intervention remain unclear. Methods: A total of 252 TBADs patients initially treated with TEVAR between September 1998 and July 2012 were retrospectively reviewed. The indications for the initial TEVAR were 32 aorta enlargement (24 chronic), 71 malperfusion, 46 rupture (32 chronic), 67 refractory pain (54 chronic), and 44 refractory hypertension (38 chronic). The patients were stratified into single‐intervention group and multi‐intervention group.

Results

The mean age was 54.1 years with 81.7% of male. We found the time from symptom onset to TEVAR was longer in multi‐intervention group (17 vs. 112.5 days, P = 0.006). Higher proportions of chronic dissection and smoking occurred in multi‐intervention group (53.9% vs. 79.2% and 43.9% vs. 70.8%, P = 0.018 and 0.012, respectively). The differences of oversizing, operation time, contrast medium dose, and blood loss between the groups were significant (13.8 ± 2.4% vs. 16.4 ± 2.9%, 92.5 vs. 196 minutes, 110 vs. 210 ml, 100 vs. 300 ml; P < 0.001, <0.001, =0.002, and =0.003, respectively). The mortality within 30 days was 2.4% and the rates of stoke, paraplegia and retrograde dissection were 3.6%, 5.6% and 0.8%, respectively. The most common reasons of re‐intervention were endoleaks, new dissections and incomplete thrombosis of the false lumen.

Conclusions

we concluded that chronic phase, smoking and too big oversizing were potential risk factors of re‐intervention. © 2014 Wiley Periodicals, Inc.
PFO closure with only fluoroscopic guidance: 7 years real‐world single centre experience
Authors: Mangieri Antonio , Godino Cosmo , Montorfano Matteo , Arioli Francesco , Rosa Isabella , Ajello Silvia , Piraino Daniela , Monello Alberto , Pavon Anna Giulia , Viani Giacomo , Magni Valeria , Cappelletti Alberto , Margonato Alberto , Colombo Antonio
Published: November 2014

Aims

To evaluate the safety and the efficacy of fluoroscopy‐guided only (Fluo‐G) and of echocardiography‐guided (Echo‐G; trans‐esophageal echocardiography—TEE—or intracardiac echocardiography‐ICE) percutaneous closure of patent foramen ovale (PFO).

Methods and Results

Single center retrospective registry enrolling 368 consecutive patients (mean age 50.5 years) who underwent PFO closure between June 2004 and December 2011. Most patients had prior cryptogenic stroke (n = 126; 34.2%), TIA (n = 218; 51.1%); some of these had recurrent neurological events [multiple strokes n = 28 (7.8%); multiple TIAs n = 72 (18.6%)]. All the patients underwent a preprocedure TEE. PFO closure was performed with Echo‐G in 187 patients (50.8%) (TEE n = 69, 36.8% and ICE n = 124, 66.3%). In Fluo‐G cases, PFO with atrial septal aneurysm (ASA) was significantly less present (P < 0.005) and smaller devices (<25 mm) were implanted more frequently (P < 0.001). Both fluoroscopy and total procedural time were lower in the Fluo‐G group (P < 0.0001). No differences were found in terms of successful device deployment (98.3% Fluo‐G vs. 98.3% Echo‐G) and RtL‐shunt at follow‐up (11.7% Fluo‐G vs. 7.6% Echo‐G). The rate of conversion from Fluoro‐G to Echo‐G procedure was 4.4% (n = 8). At a median follow‐up of 4 years, freedom from recurrent embolic events rate was similar between the two groups (Echo‐G 94.5 vs. Fluo‐G 95.7%).

Conclusions

In our experience Fluoro‐G PFO closure was performed mainly in cases of simple anatomy, with similar results in terms of safety and efficacy compared to Echo‐G cases. Both fluoroscopy and total procedural times were lower in the Fluo‐G cases. © 2015 Wiley Periodicals, Inc.
A smoothed finite element method for analysis of anisotropic large deformation of passive rabbit ventricles in diastole
Authors: Jiang Chen , Liu Gui‐Rong , Han Xu , Zhang Zhi‐Qian , Zeng Wei
Published: November 2014

The smoothed FEM (S‐FEM) is firstly extended to explore the behavior of 3D anisotropic large deformation of rabbit ventricles during the passive filling process in diastole. Because of the incompressibility of myocardium, a special method called selective face‐based/node‐based S‐FEM using four‐node tetrahedral elements (FS/NS‐FEM‐TET4) is adopted in order to avoid volumetric locking. To validate the proposed algorithms of FS/NS‐FEM‐TET4, the 3D Lame problem is implemented. The performance contest results show that our FS/NS‐FEM‐TET4 is accurate, volumetric locking‐free and insensitive to mesh distortion than standard linear FEM because of absence of isoparametric mapping. Actually, the efficiency of FS/NS‐FEM‐TET4 is comparable with higher‐order FEM, such as 10‐node tetrahedral elements. The proposed method for Holzapfel myocardium hyperelastic strain energy is also validated by simple shear tests through the comparison outcomes reported in available references. Finally, the FS/NS‐FEM‐TET4 is applied in the example of the passive filling of MRI‐based rabbit ventricles with fiber architecture derived from rule‐based algorithm to demonstrate its efficiency. Hence, we conclude that FS/NS‐FEM‐TET4 is a promising alternative other than FEM in passive cardiac mechanics. Copyright © 2015 John Wiley & Sons, Ltd.
Assays and Strategies for Immunogenicity Assessment of Biological Agents
Authors: Nencini Francesca , Pratesi Sara , Petroni Giulia , Matucci Andrea , Maggi Enrico , Vultaggio Alessandra
Published: November 2014

Enabling Technology, Genomics, Proteomics
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics

Some patients with chronic inflammatory diseases either do not respond to or lose their initial responsiveness to Tumor Necrosis Factor (TNF) inhibitor therapy. In these patients, the clinical response after switching to another anti‐TNF drug suggests that lack of response is not related to the therapeutic target itself but immunogenicity. All biologics are potentially immunogenic and can induce the development of antidrug antibodies (ADAs). ADA formation is associated with lower serum drug levels, infusion reactions, and loss of response. Analytical methods for ADA detection include enzyme‐linked immunosorbent assay (ELISA), radioimmunoassay (RIA), surface plasmon resonance, and electrochemiluminescence. Currently, RIA and ELISA are the preferred methods due to a combination of reproducibility, sensitivity, and cost but have some limitations. There is no single available assay that has all pros and no cons, and therefore the use of more methods for the assessment of samples is a high priority.
Pharmacogenetics and Future Therapeutic Scenarios: What Affects the Prediction of Response to Treatment with Etanercept?
Authors: Murdaca Giuseppe , Gulli Rossella , Spanò Francesca , Mandich Paola , Puppo Francesco
Published: November 2014

Enabling Technology, Genomics, Proteomics
Clinical Development Phases I‐III Regulatory, Quality, Manufacturing

There are five tumor necrosis factor alpha (TNF‐α) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti‐inflammatory or disease‐modifying anti‐rheumatic drugs (DMARDs) in the treatment of immune‐mediated diseases. These include the anti‐TNF‐α monoclonal antibodies infliximab, adalimumab, golimumab, and certolizumab pegol, and the fusion protein, etanercept. The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to, or toxicities from, TNF‐α inhibitors, and could be used to individualize therapy. Several studies have reported associations between genetic polymorphisms and the response to etanercept, but most are small and insufficiently powered to detect effect, and markers tend to be more prognostic than predictive of therapeutic response. Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms (SNPs), genes in linkage with other loci, interaction of environmental factors, and cohort heterogeneity, all of which can complicate the relationship between genetic polymorphisms and treatment response. Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice.
Detection of Adalimumab and Anti‐Adalimumab Levels by ELISA: Clinical Considerations
Authors: Marinari Barbara , Botti Elisabetta , Bavetta Mauro , Spallone Giulia , Zangrilli Arianna , Talamonti Marina , Richetta Antonio , Chimenti Sergio , Costanzo Antonio
Published: November 2014

Enabling Technology, Genomics, Proteomics
Clinical Development Phases I‐III Regulatory, Quality, Manufacturing

Psoriasis (Ps) is a common and stigmatizing chronic inflammatory skin disease that may cause other chronic inflammatory conditions with overlapping pathology, such as rheumatoid arthritis (RA). Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a pivotal role in chronic inflammatory and autoimmune diseases such as uveitis, multiple sclerosis, systemic lupus, arthritis, Ps, and Crohn's disease. The TNF superfamily and receptors represent active targets for drug development. Anti‐TNF biological therapies, such as infliximab, adalimumab (ADL), and etanercept, are effective in treating RA, spondyloarthritis, Ps, and inflammatory bowel diseases, but long‐term treatment can induce anti‐drug antibody (ADA) formation associated with lower drug levels and clinical nonresponse. An investigation of the relationship between serum ADL/anti‐adalimumab antibody (AAA) concentration, and clinical response in moderate to severe Ps, confirmed an association between ADL and AAA levels and response. Although the detection of ADAs can be used to determine the cause of nonresponse and aid therapy decisions, the contrary observation of long‐term responders with low drug levels and detectable ADA suggests that another mechanism is also involved.
Killer‐Cell Immunoglobulin‐Like Receptors (KIR) and HLA‐Class I Heavy Chains in Ankylosing Spondylitis
Authors: Cauli Alberto , Piga Matteo , Dessole Grazia , Porru Giovanni , Floris Alberto , Vacca Alessandra , Desogus Elisabetta , La Nasa Giorgio , Mathieu Alessandro
Published: November 2014

Postmarketing Phase IV

HLA‐B27 (B27) interactions with the killer‐cell immunoglobulin‐like receptors (KIR) have been implicated in the pathogenesis of ankylosing spondylitis (AS), with consistent differences among populations. KIR3DL1 and possibly KIR3DS1 interact with classical B27, whereas KIR3DL2 binds B27 heavy chain dimers. The aim of this review is to summarize data from recent studies performed in our laboratory and from the literature, which provide support for a possible role of KIR3DL2/B27 dimer interactions in the pathogenesis of AS. Recent studies in cells from AS patients and from health controls carrying the predisposing B*2705 and the nonpredisposing B*2709 haplotypes, have shown a higher percentage of positive cells and a higher surface expression of KIR3DL2 receptors on natural killer (NK) and CD4+ T cells in B*2705 AS patients compared with B*2705, B*2709 and B27‐negative healthy controls. Increased expression of HC10‐reactive molecules on AS monocytes was seen, supporting the possible role of the KIR3DL2/B272 pair in the pathogenesis of AS. These results underline the importance of NK cells and innate immunity, and of CD4+ T cells in the inflammatory pathogenesis of AS.
Thalassemic Trait Prevalence in Patients Affected by Psoriatic Arthritis in Anti‐TNF Treatment
Authors: Atteno Mariangela , Costa Luisa , Vitiello Maria , Caso Francesco , Sarnelli Giovanni , Del Puente Antonio , Scarpa Raffaele
Published: November 2014

Clinical Development Phases I‐III Regulatory, Quality, Manufacturing
Postmarketing Phase IV

Thalassemic trait (Thal) is associated with rheumatic disease, particularly a mild form of seronegative polyarthritis resembling rheumatoid arthritis (RA), but not with other rheumatic diseases. The aim of this study was to estimate the frequency of Thal in patients with psoriatic arthritis (PsA) and to evaluate the efficacy of anti‐tumor necrosis factor alpha (TNF‐α) therapy in patients with PsA and Thal. We performed a retrospective study in 321 patients with PsA who started therapy with TNF‐α blockers. For all patients included in the study, at baseline and every 3 months for the 1 year of follow up, data concerning PsA activity and ferritin levels were registered. In our group of PsA patients, a total of 27 (8%) with concomitant Thal were identified and included in the study. In patients without Thal, all variables improved significantly after 6 months of therapy, while in patients with Thal, the same variables showed a significant decrease after 12 months.: Our study shows that PsA is significantly associated with Thal, but further studies are needed to address this issue. The presence of Thal could be a negative predictor of achieving remission during treatment with TNF‐α‐blockers.
Treatment Adherence to Different Etanercept Regimens, Continuous vs. Intermittent, in Patients Affected by Plaque‐Type Psoriasis
Authors: Esposito Maria , Gisondi Paolo , Cassano Nicoletta , Babino Graziella , Cannizzaro Maria Vittoria , Ferrucci Giuliano , Chimenti Sergio , Giunta Alessandro
Published: November 2014

Postmarketing Phase IV

Treatment adherence to anti‐tumor necrosis factor alpha (anti‐TNF‐α) agents is marker of treatment success, but overall efficacy of anti‐TNF‐α therapy decreases over time leading to a progressive loss of adherence. The present observational study was conducted in order to estimate the long‐term adherence to etanercept in patients affected by plaque‐type psoriasis, evaluating differences among intermittent and continuous treatment regimen. Our findings reflect routine clinical practice in three academic referral centers and show high treatment adherence with etanercept in psoriatic patients. Treatment survival was consistently high in the short/medium term. The univariate analysis showed longer treatment duration in patients undergoing intermittent treatment regimen (mean 1,706 days) compared with continuous regimen (mean 1,249 days). Results showed that a flexible pulsed treatment with etanercept can be optimal in terms of clinical success and adherence.
Monoclonal Gammopathy of Undetermined Significance in Patients with Psoriasis: Is it Really a Side Effect of Biological Therapy?
Authors: Conti Andrea , Esposito Ilaria , Lasagni Claudia , Miglietta Roberta , Padalino Claudia , Fabiano Antonella , Pellacani Giovanni
Published: November 2014

Postmarketing Phase IV

Moderate‐to‐severe psoriasis is treated using biological drugs targeting cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor alpha (TNF‐α) (adalimumab, infliximab, etanercept) and interleukin 12/23 (IL 12/23) (ustekinumab). There is a slight risk of developing hematological malignancies, such as monoclonal gammopathy of undetermined significance (MGUS) with anti TNF‐α agents. There are no data available on anti‐IL12/23 drugs. This retrospective study of data from 191 patients describes the appearance and follow‐up of MGUS in three patients with psoriasis receiving long‐term biological therapy. Since the appearance of MGUS occurred after about 6 years of anti‐TNFα treatment in only three subjects, it was deemed unlikely to be due to the biological treatment. The decision not to suspend biological therapy after the appearance of MGUS was taken after careful assessment of the possible risks and benefits.
Use of Anti‐Tumor Necrosis Factor Alpha Therapy in Patients with Concurrent Rheumatoid Arthritis and Hepatitis B or Hepatitis C: A Retrospective Analysis of 32 Patients
Authors: Ballanti Eleonora , Conigliaro Paola , Chimenti Maria Sole , Kroegler Barbara , Di Muzio Gioia , Guarino Maria Domenica , Triggianese Paola , Gigliucci Gianfranco , Novelli Lucia , Barbato Carmen , Perricone Roberto
Published: November 2014

Postmarketing Phase IV

The safety of tumor necrosis factor‐alpha (TNF‐α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti‐TNF‐α in rheumatoid arthritis (RA) is associated with an increased risk of hepatitis re‐activation. This paper reports experience of using etanercept and adalimumab in 32 patients with RA and previous HBV or HCV infection. No cases of HBV or HCV reactivation were seen. In just over a fifth of patients, increased transaminases levels were seen, which were associated with concomitant use of disease‐modifying antirheumatic drugs, isoniazid prophylaxis, or alcohol abuse. In our experience, anti‐TNF‐α therapy appears to be safe in RA patients with previous HBV or HCV infection, but monitoring remains necessary in these patients.
Periodontal Disease: An Oral Manifestation of Psoriasis or an Occasional Finding?
Authors: Ganzetti Giulia , Campanati Anna , Santarelli Andrea , Pozzi Valentina , Molinelli Elisa , Minnetti Ilaria , Brisigotti Valerio , Procaccini Maurizio , Emanuelli Monica , Offidani Annamaria
Published: November 2014

Postmarketing Phase IV

Even if the existence of oral psoriasis has been suggested, it is still a debated issue. Indeed, oral inflammatory diseases may histologically resemble psoriasis‐related oral lesions. However, an increased prevalence of fissured tongue and geographic tongue has been associated with psoriatic patients, being a transitory and permanent lesion, respectively. Recently, it was hypothesized that gingivitis and periodontitis share the same underlying inflammatory pathogenetic process of psoriasis. Thus, in the present study, psoriatic patients were investigated for oral mucosa lesions prevalence as well as gum disease. Results displayed an increased association between gingivitis/periodontitis and psoriasis, which may suggest common underlying pathogenic risk factors. However, large‐scale studies are needed to evaluate the real prevalence of gingivitis and periodontitis in these patients, to consider them a comorbidity of psoriasis.
The Use of an Interferon‐Gamma Release Assay as a Biomarker of Response to Anti‐TNF‐Alpha Treatment
Authors: Cacciapaglia Fabio , Buzzulini Francesca , Arcarese Luisa , Ferraro Elisabetta , Afeltra Antonella
Published: November 2014

Postmarketing Phase IV

Tumor necrosis factor alpha (TNF‐α) is a pleiotropic cytokine that plays a central role in the immune system functioning and in the pathogenesis of rheumatoid arthritis (RA). TNF‐α inhibition has been demonstrated effective to treat RA; however, response to anti‐TNF‐α therapies is heterogeneous, with roughly one‐third of patients not achieving disease control. Identification of a biological marker to assess the effectiveness of TNF‐α inhibition may help to discriminate patients with a reduced response to anti‐TNF‐α agents. The aim of this study was to assess whether anti‐TNF‐α treatment was able to modify the cytokine network interfering with interferon gamma (INFγ) release after phytohemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMCs) from RA patients, according to disease activity. We found that RA patients with active disease had low release of INFγ after PHA stimulation, but anti‐TNF‐α agents were able to modify INFγ production. In anti‐TNF‐α responders, we observed a higher release of INFγ, achieving levels comparable with those seen in healthy subjects. The ability of PBMCs from RA patients to release INFγ may serve as a biomarker of disease activity and response to anti‐TNF‐α. Larger studies are needed to validate these data.
Insights on the Role of Physical Activity in Patients with Rheumatoid Arthritis
Authors: Conigliaro Paola , Triggianese Paola , Ippolito Francesco , Lucchetti Ramona , Chimenti Maria Sole , Perricone Roberto
Published: November 2014

Postmarketing Phase IV

Patients with rheumatoid arthritis (RA) are physically inactive, and trials have been undertaken to examine the effect of physical activity on pain, disease activity, functional ability and quality of life (QoL) in RA. The aim of this study was to explore the relationship between physical activity and disease‐activity in RA and in healthy controls. Our findings showed that fewer RA patients had a professional occupation compared with controls, but patients and controls were similar with respect to the sedentary extent of their job. Physical exercise was inversely associated with disease activity (DAS‐28), stiffness visual analog scale (VAS), patient global VAS and SF‐36, but not associated with Health Assessment Questionnaire (HAQ), pain VAS, fatigue VAS, global health and the Arthritis Ipact Measurement Scale (AIMS), suggesting that pain and fatigue are important barriers to physical activity. Our findings suggest that this is more pronounced in RA patients who do not participate in regular physical activity, and so physical exercise should be recommended as part of comprehensive RA care.
Self‐Reported Adherence to a Home‐Based Exercise Program Among Patients Affected by Psoriatic Arthritis with Minimal Disease Activity
Authors: Chimenti Maria Sole , Triggianese Paola , Conigliaro Paola , Santoro Matteo , Lucchetti Ramona , Perricone Roberto
Published: November 2014

Postmarketing Phase IV

More than half of all patients with psoriatic arthritis (PsA) exhibit progressive erosive arthritis, associated with severe functional impairment and psychosocial disability. Biologics have been suggested to be more effective in inducing minimal disease activity” (MDA) than disease‐modifying antirheumatic drugs (DMARDs). Behavioral patient education appears to be more effective in encouraging patients to increase their physical activity (PA) levels. The aim of the study was to evaluate the benefits of home‐based exercises program on disease activity and quality of life in MDA‐PsA patients treated with an anti‐tumor necrosis factor (TNF) and DMARD therapy. We observed a self‐reported adherence rate to home‐based exercise of 76.6% and data showed the impact of the exercise program on self‐reported health and mental assessment. A positive relationship between patient and therapist is crucial, influencing the quality of the performance, the emotional support, and increasing motivation in PsA patients.
Emergence of Antinuclear Antibodies in Psoriatic Patients Treated with Infliximab: Personal Experience and Literature Review
Authors: Chimenti Maria Sole , Spinelli Francesca Romana , Giunta Alessandro , Martinelli Francesco , Saraceno Rosita , Conti Fabrizio , Perricone Roberto , Valesini Guido
Published: November 2014

Postmarketing Phase IV

Psoriasis is a chronic inflammatory skin disease affecting up to 2.5% of the population, with joint involvement in approximately 30% of patients. Given the role of tumor necrosis factor (TNF) in the pathogenesis of psoriasis, anti‐TNF therapies have been developed; several studies have demonstrated the efficacy of infliximab (IFX) as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis. The development of antinuclear antibodies (ANA) in anti‐TNF‐treated patients has been frequently reported. The aim of this study was to investigate the incidence of ANA and anti‐double stranded DNA (anti‐dsDNA) antibodies in psoriatic patients receiving IFX. Incidence of new ANA and anti‐ds‐DNA was 16.2% and 8.1% respectively. No case of anti‐TNF induced Lupus was observed during the follow‐up.
A Possible Role of Polycystic Ovary Syndrome for Pregnancy Complications in Women with Psoriasis
Authors: De Simone Clara , Caldarola Giacomo , Corbeddu Marialuisa , Moro Francesca , Tropea Anna , Moretta Gaia , Apa Rosanna
Published: November 2014

Postmarketing Phase IV

Psoriasis is a common, chronic, relapsing immune‐mediated inflammatory disease (IMID) of the skin. IMIDs are multifactorial diseases characterized by common molecular pathways leading to a systemic inflammation. Patients with an IMID are also at higher risk of developing co‐morbidities, such as adverse pregnancy outcomes, than the general population. A higher rate of pregnancy complications have been seen in inflammatory bowel disease and rheumatoid arthritis. The data for psoriasis are inconsistent but it appears that women with moderate‐to‐severe psoriasis may also have an increased risk of poor pregnancy outcomes. The cause of this association is unknown, although it may be related to elevated proinflammatory cytokines such as IL‐6 and TNF‐α, the high prevalence of comorbidities and other unhealthy behaviours, or the high prevalence of polycystic ovary syndrome (PCOS). In a recent study, PCOS prevalence in a psoriatic cohort (n = 51) was higher than in non‐psoriatic women (n = 102) (47% versus 11%), and women with PCOS and psoriasis had a greater probability of insulin resistance, hyperinsulinaemia, and dyslipidaemia as well as a more severe skin condition, than those with psoriasis alone. Further studies are necessary to clarify the impact of psoriasis on pregnancy and in particular if these effects are mediated by concomitant PCOS.
Decrease of Asymmetric Dimethyl Arginine After Anti‐TNF Therapy in Patients with Rheumatoid Arthritis
Authors: Spinelli Francesca Romana , Di Franco Manuela , Metere Alessio , Conti Fabrizio , Iannuccelli Cristina , Agati Luciano , Valesini Guido
Published: November 2014

Postmarketing Phase IV

Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti‐TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti‐TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA.
Hyperuricemia in Patients with Chronic Plaque Psoriasis
Authors: Gisondi Paolo
Published: November 2014

Postmarketing Phase IV

Psoriasis is frequently associated with obesity, which may favor the development of hyperuricemia. Hyperuricemia predisposes patients to gout arthritis and is an emerging cardiovascular risk factor. In this study, we investigated the prevalence of hyperuricemia and serum uric acid (SUA) levels in psoriatic patients. SUA was measured in consecutive psoriatic patients (n = 338) and prevalence of hyperuricemia was estimated. Hyperuricemia was defined as SUA ≥7 mg/dL in men and ≥6 mg/dL in women. Hyperuricemia affected 20% (67 out 338) of patients with psoriasis. SUA levels were 5.8 ± 1.6 (mean ± SD) in patients with psoriasis. Levels of SUA were significantly higher in obese patients compared to non‐obese patients (6.1 ± 1.5 vs 5.2 ± 1.4, P < 0.05). Levels of SUA showed a significant, positive correlation with body mass index (r = 0.30; P < 0.01) and serum triglycerides (r = 0.31; P < 0.01) but they were not significantly associated with age, sex, psoriasis duration or Psoriasis Area Severity Index score. Hyperuricemia is a common finding in psoriatic patients. Dosing levels of SUA could be appropriate in the global management of patients with psoriasis, particularly in those who are obese and with serum triglycerides upper the normal range.