bluuebunny/crossref_metadata_2025 huggingface dataset:
Steady state thermomechanical modelling of friction stir welding
Authors: Bastier A. , Maitournam M. H. , Dang Van K. , Roger F.
Published: July 2006

This paper presents a computational method for the simulation of a welding process called friction stir welding. This simulation is divided into two main steps. The first one uses an Eulerian description of the thermomechanical problem; a 3D mixed finite element model based on a computational fluid dynamics package is used to establish the material flow, the temperature and the pressure fields during the process. These results are compared with experimental data. The second step of the simulation is more original. A part of the initial geometry is extracted in order to evaluate the material flow in a local domain around the tool. A steady state algorithm is then used to calculate the residual state induced by the process. This calculation takes into account the whole mechanical history of the material because the algorithm is based on an integration along the trajectories of the particles. Finally, the residual stresses of a friction stir welded assembling are evaluated. It should be noted that only the steady state phase of the process is simulated, which leads to a substantial reduction of computational time.
Transient thermal stress analysis on rapid post-weld heat treatments applied to flash butt welded rails
Authors: Tawfik D. , Mutton P. J. , Chiu W. K.
Published: July 2006

A finite element (FE) model has been established to estimate the transient thermal stresses developed during rapid post-weld heat treatments (RPWHT) and post-weld quenching (PWQ) of rail flash butt welds. Rapid post-weld heat treatment parameters, such as heat flux intensity, location and heating duration, were varied. Altering the PWQ initiation times was also studied. The sequentially coupled thermomechanical FE model incorporated rate independent plasticity with a constitutive linear kinematic hardening rule. This described the inelastic behaviour of the rail material caused by post-weld thermal cyclic loadings. Representative temperature dependent thermal and mechanical properties including the pearlitic transformation behaviour of rail steel were also used in the FE model. Significant reduction of local tensile residual stresses in the web region of the weld was obtained by RPWHT applied to the entire foot region. RPWHT applied to both the web and the foot regions of the weld resulted in further reductions in vertical tensile residual stresses but a lesser effect on the longitudinal tensile residual stresses. A series of PWQ conditions, which were initiated after completion of the austenite–pearlite phase transformation, had significantly affected residual stresses. Numerical predictions revealed that PWQ initiated after transformation induced higher tensile residual stresses in the web region of the weld with respect to normal cooled welds, without affecting the microstructure.
Two modes of metal flow phenomenon in friction stir welding process
Authors: Muthukumaran S. , Mukherjee S. K.
Published: July 2006

It has been widely recognised that the fundamental mechanism of weld formation in friction stir welding (FSW) is too complex, a phenomenon to be understood completely. In the present study two modes of metal transfer phenomenon in FSW have been discussed with the help of three FSW techniques. In the first technique a strip is welded to the plate by the process, in the second one the brass sheet is inserted perpendicular to the welding direction and in the third one the process is performed with tools having different pin lengths. The results suggest a strategy to model the process particularly for predicting welding tool performance.
Observation of hybrid (cw Nd:YAG laser + MIG) welding phenomenon in AA 5083 butt joints with different gap condition
Authors: Kim Y.-P. , Alam N. , Bang H.-S. , Bang H.-S.
Published: July 2006

In recent time there has been vigorous development of laser hybrid welding technology for applications in numerous industrial fields. Many of those research achievements have already been reported to relevant technology users. However, there are many issues still requiring further research and development, including more comprehensive understanding of the various welding phenomena in laser hybrid welding. In the present study, therefore, the laser hybrid welding process was examined using high speed video in order to understand the relationships between bead formation and the relative locations of the laser beam, arc and molten wire droplet during aluminium butt joint welds. It is apparent from the results of experiments and observations of high speed images that the heat input delivered to the plate is dependent on the nature of the leading heat source and also the joint condition used in hybrid set-up. In particular the presence of a gap in the joint changes the heat transfer efficiency and electrical circuit conditions. These aspects affect the stability of the welding process; therefore, a joint stabilisation mechanism is needed before laser irradiation if the process instabilities are to be overcome. From this perspective a metal inert gas (MIG) leading hybrid (MIG + laser) process is more suitable for butt joints with gaps larger than the beam diameter, even though the laser leading hybrid (laser + MIG) configuration makes better use of heat input in bead on plate (BOP) welding. Synergistic effects of the two heat sources are maximised when the laser beam is located between the arc centre and the impact point of the molten droplet within the weld puddle. It is understood that the final bead shape in hybrid welding is influenced by the volume of the molten pool before the impingement of the laser beam. That is, a critical depth of molten material needs to form before being irradiated by the laser beam in order to maximise the coupling effects of the respective heat inputs. The bead shape was also found to be dependant on other features of the welding process such as gap condition, leading heat source, motion of molten wire in the gap and preheating effects.
Fracture toughness of structural aluminium alloy thick plate joints by friction stir welding
Authors: Mochizuki M. , Inuzuka M. , Nishida H. , Nakata K. , Toyoda M.
Published: July 2006

The fracture toughness in a friction stir welded joint of thick plates of structural aluminium alloy type A5083-O is investigated. A joint between two 25 mm thick plates is fabricated by one sided, one pass friction stir welding. The Charpy impact energy and critical crack tip opening displacement (CTOD) in the friction stir weld are much higher than those in the base metal or heat affected zone, whereas mechanical properties such as stress–strain curve and Vickers hardness are not conspicuously different. The effects of the microstructure on crack initiation and propagation are studied in order to clarify the difference in fracture toughness between the stir zone and base metal. The analyses of the fracture resistance curves and the diameters of dimples in the fracture surface after both tensile and bending tests show that the fine grained microstructure in the stir zone helps to increase ductile crack initiation and propagation resistance. It is found that the high fracture toughness value in the stir zone is affected by the fine grained microstructure in friction stir welds.
Investigation of cracks in original material of Cleuson-Dixence shaft
Authors: Enzinger N. , Cerjak H.
Published: July 2006

After the big accident in the Cleuson-Dixence Hydropower Plant in December, 2000, several investigations were performed. This contribution summarises the efforts undertaken to clarify the mechanism of the catastrophic failure by the investigation of original material taken from the shaft near the zone of the accident. By extensive non-destructive testing, four plates were removed by flame cutting and tested in the laboratory again. From these results some specimens were taken for further investigations using light microscope and scanning electron microscope. It was found that the investigated cracks are caused by the hydrogen induced cold cracking mechanism after welding, which is also called delayed cracking. By applying a proper pre- and post-weld heat treatment, these cracks can be avoided and by a diligent use of non-destructive testing methods, the required quality of the welding can be assured.
Welding current prediction in GMAW and UGMAW processes using response surface methodology
Authors: Shahi A. S. , Pandey S.
Published: July 2006

Among all process variables in gas metal arc welding (GMAW) process, welding current is the most influential variable affecting heat input and weld quality. Its dependence on other process variables in GMAW and universal gas metal arc welding (UGMAW) processes (which makes use of a specially designed torch to preheat the filler wire independently, before its emergence from the torch) has been investigated using four factor five level central composite rotatable design to develop relationship for predicting welding current, which enables to quantify the direct and interactive effects of four numeric factors, namely wire feedrate, open circuit voltage, welding speed and electrode stickout and one categorical factor preheat current. Mathematical models developed show that welding current increased linearly with increaseing wire feedrate and open circuit voltage, whereas it decreased with increasing electrode stickout and preheat current. Numerical optimisation was carried out, and the optimal solutions generated indicate that under the same input conditions higher deposition rates are achievable in UGMAW process.
Numerical simulation on temperature and stress fields of welding with weaving
Authors: Hu J.-F. , Yang J.-G. , Fang H.-Y. , Li G.-M. , Zhang Y.
Published: July 2006

Although welding with weaving had been widely adopted to improve welding efficiency, the effects of weaving arc on temperature and stress fields were not clearly understood. In the present paper, a conversion of coordinates was implanted in a finite element model to improve the calculation precision and comprehend the characteristic of welding with weaving. Comparing with the results of the welding without weaving, a characteristic with lower peak temperature and wider weld bead was presented during the welding with weaving, and the temperature gradients near the weld pool was steeper. The results also indicated that the transverse residual stress of welding with weaving was greater than that of welding without weaving, while the longitudinal residual stress was similar. Both temperatures and residual stresses were compared with those of the experiments.
Weld metal hydrogen assisted cracking in 50 mm TMCP steel plate with SAW process
Authors: Lee H. W. , Choe W. H. , Park J. U. , Kang C. Y. , Park W. J.
Published: July 2006

The transverse crack, a type of cold crack, occurs perpendicular to the welding direction. From experience, preheating and interpass temperature are important factors in cold crack occurrence. Transverse cracks were detected in the specimen welded with 70°C preheat and an interpass temperature below 30°C; cracks were detected 9·5–14 mm away from the weld surface. Hardness values of preheating 70°C and interpass temperatures below 30°C were higher than those of preheating 70°C and interpass temperatures 100–120°C in the deposited weld metal. The residual stress values for the specimen welded with 70°C preheat and an interpass temperature below 30°C were higher than those of the specimen welded at preheating 70°C and interpass temperatures 100–120°C. The weld cracks were detected in the area of the maximum residual stresses.
Antiadhesive effect of fibrinogen: a safeguard for thrombus stability
Authors: Lishko Valeryi K. , Burke Timothy , Ugarova Tatiana
Published: July 2006

The recruitment of phagocytic leukocytes to sites of vessel wall injury plays an important role in thrombus dissolution by proteases elaborated on their adhesion. However, leukocyte adhesion to the fibrin clot can be detrimental at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss. Adhesion of circulating leukocytes to the insoluble fibrin(ogen) matrix is mediated by integrins and occurs in the presence of a high concentration of plasma fibrinogen. In this study, the possibility that soluble fibrinogen could protect fibrin from excessive adhesion of leukocytes was examined. Fibrinogen was a potent inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which soluble fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated with the fibrin(ogen) substrate. Consequently, leukocytes that engage fibrinogen molecules loosely bound to the surface of fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various cells and performed under static and flow conditions. These findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion and suggest that this mechanism may protect the thrombus from premature dissolution.
The Hlx homeobox transcription factor is required early in enteric nervous system development
Authors: Bates Michael D , Dunagan Dana T , Welch Lynn C , Kaul Ajay , Harvey Richard P
Published: July 2006

Background

Development of the enteric nervous system (ENS) requires interactions between migrating neural crest cells and the nascent gastrointestinal tract that are dependent upon genes expressed by both cell compartments. Hlx, a homeobox transcription factor gene that is expressed in mouse intestinal and hepatic mesenchyme, is required for normal embryonic growth of intestine and liver, and the Hlx-/- genotype is embryonic lethal. We hypothesized that Hlx is required for ENS development.

Results

Enteric neurons were identified in Hlx+/+ and Hlx-/- mouse embryos by immunostaining of embryo sections for the neural markers PGP9.5 and Phox2b, or by staining for β-galactosidase in whole-mount embryos containing the dopamine β-hydroxylase-nLacZ transgene. In Hlx+/+ embryos, neural crest cells/enteric neurons have moved from the stomach into the intestine by E10.5. By contrast, neural crest cells/enteric neurons remain largely restricted to the lateral stomach mesenchyme of Hlx-/- embryos, with only a few scattered neural crest cells/enteric neurons in the intestine between E10.5–16.5.

Conclusion

The Hlx homeobox transcription factor is required for early aspects of ENS development.
Extra-osseous osteochondroma-like soft tissue mass of the patello-femoral space
Authors: Oliva Francesco , Marconi Alessandro , Fratoni Stefano , Maffulli Nicola
Published: July 2006

Background

Extraskeletal cartilaginous tumors are uncommon. Osteochondromas usually arise from the metaphyseal region of the growing skeleton.

Case presentation

A 53 year old man presented with a three years history of anterior knee pain and inability to flex his knee more than 90°. Clinical examination and imaging studies revealed a nodular calcific mass in the anterior portion of the knee, displacing the medial portion of the patellar tendon. Following excision, histopathology confirmed the diagnosis of extra-osseous osteochondroma-like soft tissue mass, with no recurrence 24 months after surgery.

Conclusion

An integrated clinical-pathologic diagnosis helps to clarify the nature of extraskeletal cartilaginous tumors that can arise at unusual anatomic site. Complete local surgical excision is the management of choice.
The contribution of qualitative research in designing a complex intervention for secondary prevention of coronary heart disease in two different healthcare systems
Authors: Corrrigan Mairead , Cupples Margaret E , Smith Susan M , Byrne Molly , Leathem Claire S , Clerkin Pauline , Murphy Andrew W
Published: July 2006

Background

Developing complex interventions for testing in randomised controlled trials is of increasing importance in healthcare planning. There is a need for careful design of interventions for secondary prevention of coronary heart disease (CHD). It has been suggested that integrating qualitative research in the development of a complex intervention may contribute to optimising its design but there is limited evidence of this in practice. This study aims to examine the contribution of qualitative research in developing a complex intervention to improve the provision and uptake of secondary prevention of CHD within primary care in two different healthcare systems.

Methods

In four general practices, one rural and one urban, in Northern Ireland and the Republic of Ireland, patients with CHD were purposively selected. Four focus groups with patients (N = 23) and four with staff (N = 29) informed the development of the intervention by exploring how it could be tailored and integrated with current secondary prevention activities for CHD in the two healthcare settings. Following an exploratory trial the acceptability and feasibility of the intervention were discussed in four focus groups (17 patients) and 10 interviews (staff). The data were analysed using thematic analysis.

Results

Integrating qualitative research into the development of the intervention provided depth of information about the varying impact, between the two healthcare systems, of different funding and administrative arrangements, on their provision of secondary prevention and identified similar barriers of time constraints, training needs and poor patient motivation. The findings also highlighted the importance to patients of stress management, the need for which had been underestimated by the researchers. The qualitative evaluation provided depth of detail not found in evaluation questionnaires. It highlighted how the intervention needed to be more practical by minimising administration, integrating role plays into behaviour change training, providing more practical information about stress management and removing self-monitoring of lifestyle change.

Conclusion

Qualitative research is integral to developing the design detail of a complex intervention and tailoring its components to address individuals' needs in different healthcare systems. The findings highlight how qualitative research may be a valuable component of the preparation for complex interventions and their evaluation.
Inhibition of HIV-1 replication by RNA interference of p53 expression
Authors: Pauls Eduardo , Senserrich Jordi , Clotet Bonaventura , Esté Jose A
Published: July 2006

p53 expression and activation have been associated to faster human immunodeficiency virus (HIV) disease progression, most probably by inducing CD4+ T cell death but also through its cooperative effect in the control of viral gene transcription by viral regulatory proteins. Here, we show that RNA interference of p53 in HIV-1 reporter (HeLa P4-R5 MAGI) and lymphoid (SupT1) cell lines blocked HIV-1 and Tat-induced transcription from the HIV-1 promoter and HIV-1 replication in acutely infected cells, suggesting a cooperative role of p53 in HIV-1 transcription. Contrary to SupT1 cells, which encoe several mutations on the p53 DNA binding domain, death of HIV-1-induced syncytia was reduced in cocultures of HeLa P4-R5 MAGI with persistently infected HIV-1 cells. To our knowledge, this is the first demonstration of the effect of the loss of function of p53 in HIV-1 replication, which is independent on its classical DNA binding activity. Our results suggest two independent roles for p53 in HIV-1 infection: cooperation in HIV long-terminal repeat transcription and virus-induced cell death.
The dermal microenvironment induces the expression of the alternative activation marker CD301/mMGL in mononuclear phagocytes, independent of IL-4/IL-13 signaling
Authors: Dupasquier Marcel , Stoitzner Patrizia , Wan Hui , Cerqueira Denise , Van Oudenaren Adri , Voerman Jane S A , Denda-Nagai Kaori , Irimura Tatsuro , Raes Geert , Romani Nikolaus , Leenen Pieter J M
Published: July 2006

Recently, we have shown that mononuclear phagocytes comprise the majority of interstitial cells in the mouse dermis, as indicated by their phenotypic and functional characteristics. In particular, these cells express the mouse macrophage galactose-/N-acetylgalactosamine-specificlectin (mMGL)/CD301, identified by the monoclonal antibody ER-MP23, as well as other macrophage markers. As expression of mMGL is induced by IL-4 or IL-13 and is therefore a marker of alternatively activated macrophages, we asked whether dermal mononuclear phagocytes are genuinely alternatively activated. We observed that these cells expressed, next to mMGL, two other alternative activation markers, namely, the mannose receptor/CD206 and Dectin-1. Yet, as this expression profile was similar in IL-4 receptor α knockout mice, neither IL-4 nor IL-13 signaling appeared to be required for this phenotype. We also found that Langerhans cells (LC), which showed only a low level of mMGL in the epidermis, up-regulated mMGL expression upon migration through the dermis, allowing these cells to internalize limited amounts of mMGL ligands. LC isolated from epidermal preparations did not show this up-regulation when cultured in standard medium, but whole skin-conditioned medium did stimulate mMGL expression by LC. The vast majority of mMGL molecules was present in the cytoplasm, however. LC, which arrived in skin-draining lymph nodes, quickly down-regulated mMGL expression, and dermally derived cells retained significant mMGL levels. Taken together, these data suggest that the dermal microenvironment induces mononuclear phagocyte subpopulations to express mMGL and possibly other markers of alternatively activated macrophages, independent of IL-4/IL-13 signaling.
The C-terminal flavin domain of gp91phox bound to plasma membranes of granulocyte-like X-CGD PLB-985 cells is sufficient to anchor cytosolic oxidase components and support NADPH oxidase-associated diaphorase activity independent of cytosolic phospholipase A2 regulation
Authors: Pessach Itai , Shmelzer Zeev , Leto Thomas L , Dinauer Mary C , Levy Rachel
Published: July 2006

We have previously established a model of cytosolic phospholipase A2 (cPLA2)-deficient PLB-985 cells and demonstrated that cPLA2-generated arachidonic acid (AA) is essential for reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and NADPH-dependent diaphorase activity. The present study focuses on the C-terminal cytoplasmic domain of gp91phox (residues 283–570), which contains the NADPH binding and flavin adenine dinucleotide-reducing center, to determine if this portion is regulated by AA. The gp91phox C-terminal reductase domain was expressed in X-CGD PLB-985 cells lacking normal gp91phox (X-CGD PLB 91CT cells) and was detected in the plasma membrane. It appears to be bound electrostatically to the plasma membrane, as it is eluted by high salt. Permeabilized, granulocyte-like X-CGD PLB 91CT cells lacking cPLA2 protein and activity, as well as AA release after stimulation, supported NADPH-dependent diaphorase activity after stimulation, similar to granulocyte-like X-CGD PLB 91CT cells. Normal translocation of p47phox and p67phox to the membrane fractions of both stimulated cell types indicated that the gp91phox C-terminal region is sufficient to anchor the cytosolic oxidase components to the membranes. cPLA2 translocated to membranes and bound the assembled oxidase in granulocyte-like X-CGD PLB 91CT cells after stimulation. Therefore, the assembled membrane-bound oxidase complex encompassing the flavin domain of gp91phox provides a docking site for cPLA2 but is not the site of AA-based regulation of oxidase activity.
IP3Rs are sufficient for dendritic cell Ca2+ signaling in the absence of RyR1
Authors: Stolk Meaghan , Leon-Ponte Matilde , Merrill Mia , Ahern Gerard P , O’Connell Peta J
Published: July 2006

Calcium (Ca2+) signaling plays a pivotal role in the function of dendritic cells (DC). The Type 1 ryanodine receptor (RyR), a major intracellular Ca2+ channel, is highly expressed in immature DC. We therefore investigated whether RyR1 plays a role in DC development and function by studying properties of DC derived from wild-type (WT) and RyR1 null [knockout (KO)] mice. Fetal liver cells from WT and RyR1 KO mice retained full hematopoietic competence. Adoptive transfer of these cells into congenic hosts resulted in the generation of functionally equivalent DC populations. WT and RyR1 KO DC exhibited a similar capacity to mature in response to inflammatory and/or activation stimuli, to endocytose antigen, and to stimulate T cell proliferation. Moreover, the absence of RyR1 did not lead to de novo expression of RyR2 or RyR3. WT and RyR KO DC express all three isoforms of inositol 1,4,5-trisphosphate receptor (IP3R), although Type 3 IP3R gene transcripts are predominant. Further, IP3-mediated Ca2+ transients proceed normally after inhibition of RyRs with dantrolene. Signaling via IP3R may therefore be sufficient to drive essential DC Ca2+ signaling processes in the absence of RyR expression or function.
Terminal B cell differentiation is skewed by deregulated interleukin-6 secretion in β2 integrin-deficient mice
Authors: Peters Thorsten , Bloch Wilhelm , Wickenhauser Claudia , Tawadros Samir , Oreshkova Tsvetelina , Kess Daniel , Krieg Thomas , Müller Werner , Scharffetter-Kochanek Karin
Published: July 2006

Absence of the common β chain (CD18) of β2 integrins leads to leukocyte-adhesion deficiency type-1 (LAD1) in humans. Mice with a CD18 null mutation suffer from recurrent bacterial infections, impaired wound healing, and skin ulcers, closely resembling human LAD1. Previous findings in CD18−/− mice demonstrated a skewed terminal B cell differentiation with plasmacytosis and elevated serum immunoglobulin G (IgG). As interleukin-6 (IL-6) is a potent enhancer of plasma cell formation and Ig secretion, we assessed IL-6 serum levels of CD18−/− and wild-type (WT) mice kept under a conventional or barrier facility or specific pathogen-free (SPF) conditions. We detected an up to 20-fold increase in IL-6 in serum of CD18−/− mice compared with WT controls when kept under conventional or barrier facility conditions, respectively. Under SPF conditions, no significant differences in terms of IL-6 serum levels were found between CD18−/− and WT mice. However, histological alterations of secondary lymphoid tissues, plasmacytosis, abnormal plasmacytoid cells (Mott cells), and hypergammaglobulinemia persisted. To further analyze the role of IL-6 in these pathological alterations, we established a CD18−/− IL-6−/− double-deficient mouse mutant. In these mice, serum IgG levels were normal, and the altered plasma cell phenotype, including Mott cells, was no longer detectable. The CD18−/− IL-6−/− double-deficient mouse model thus demonstrated that IL-6 is responsible for parts of the phenotype seen in the CD18−/− mouse mutants. It may be of interest to examine human leukocyte-adhesion deficiency type-1 patients closer and search for pathological changes possibly induced via overproduction of IL-6.
Sequence Variants of the CRH 5′‐Flanking Region
Authors: WAGNER UTA , WAHLE MATTHIAS , MALYSHEVA OLGA , WAGNER ULF , HÄNTZSCHEL HOLM , BAERWALD CHRISTOPH
Published: July 2006

Abstract:  Recently, studies in adult rheumatoid arthritis patients have shown an association with four single‐nucleotide polymorphisms (SNPs) in the 3.7‐kb regulatory region of human corticotropin‐releasing hormone (hCRH) gene located at positions −3531, −3371, −2353, and −684 bp. Three of these novel polymorphisms are in absolute linkage disequilibrium, resulting in three combined alleles, named A1B1, A2B1, and A2B2. To study whether the described polymorphic nucleotide sequences in the 5′ region of the hCRH gene interfere with binding of nuclear proteins, an electric mobility shift assay (EMSA) was performed. At position −2353 bp, a specific DNA protein complex was detected for the wild‐type sequence only, possibly interfering with a binding site for the activating transcription factor 6 (ATF6). In contrast, no difference could be detected for the other SNPs. However, at position −684, a quantitative difference in protein binding due to cAMP incubation could be observed. To further investigate whether these SNPs in the CRH promoter are associated with an altered regulation of the CRH gene, we performed a luciferase reporter gene assay with transiently transfected rat pheochromocytoma cells PC12. Incubation with 8‐Br‐cAMP alone or in combination with cytokines enhanced significantly the promoter activity in PC12 cells. The promoter haplotypes studied exhibited a differential capacity to modulate CRH gene expression. In all our experiments, haplotype A1B1 showed the most pronounced influence on promoter activity. Taken together, our results demonstrate a differential binding capacity of nuclear proteins of the promoter polymorphisms resulting in a different gene regulation. Most probably the SNP at position −2,353 plays a major role in mediating these differences.
Neuroendocrine‐Immune Interactions
Authors: FERONE DIEGO , BOSCHETTI MARA , RESMINI EUGENIA , GIUSTI MASSIMO , ALBANESE VALERIA , GOGLIA UMBERTO , ALBERTELLI MANUELA , VERA LARA , BIANCHI FEDERICO , MINUTO FRANCESCO
Published: July 2006

Abstract:  Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst1–5). Neuronal and accessory cells, so‐called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti‐inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system.
Microsomal Prostaglandin E Synthase‐1, Ephrins, and Ephrin Kinases as Suspected Therapeutic Targets in Arthritis
Authors: ROMANOVSKY ANDREJ A. , IVANOV ANDREI I. , PETERSEN SCOTT R.
Published: July 2006

Abstract:  Feeding information obtained in one criminal case into the profile of another crime often helps to solve the latter. The literature on two different “crimes,” namely, acute systemic inflammation and arthritis (including osteoarthritis [OA] and rheumatoid arthritis [RA] deals largely with the same “gang” of inflammatory mediators, such as prostaglandin (PG) E2. Early investigations suggested that microsomal PGE synthase‐1 (mPGES‐1; a terminal PGE2‐synthesizing enzyme) plays a pivotal role in bacterial lipopolysaccharide (LPS)‐induced systemic inflammation, but overlooked the possibility that the same enzyme could be involved in OA or RA. Later studies showed that mPGES‐1 is indeed a key perpetrator in arthritic diseases, a fact that could have been predicted earlier by pooling the new knowledge about mPGES‐1 into the profile of arthritic diseases. In this review, we analyze our recent study on the expression of erythropoietin‐producing hepatocellular (Eph) receptor kinases and their ligands, ephrins, in LPS‐induced systemic inflammation. By pooling these results together with literature data into the profile of RA, we conclude that Eph kinases and ephrins are prime suspects for being involved in the pathogenesis of RA. We further conjecture that the involvement of Eph kinases and ephrins may be realized via the induction of angiogenesis in the inflamed joint, promotion of leukocyte infiltration, and activation of the infiltrated cells. Studies to test this new hypothesis seem warranted, and our prediction is that the “smoking gun” will be found.
Role of Estrogens in Inflammatory Response
Authors: CAPELLINO SILVIA , MONTAGNA PAOLA , VILLAGGIO BARBARA , SULLI ALBERTO , SOLDANO STEFANO , FERRERO SIMONE , REMORGIDA VALENTINO , CUTOLO MAURIZIO
Published: July 2006

Abstract:  Estrogens are involved in the immune response, and macrophages express estrogen receptors (ER). Moreover, macrophages are the predominant cell type in the peritoneal fluid from endometriosis patients. On this basis, the aim of our study was to evaluate the expression of ER on peritoneal macrophages from endometriosis patients and to compare these results with what is already known about ER and macrophages in RA. After macrophage extraction from peritoneal fluids we performed the immunohistochemical localization of ERα and ERβ and then the image analysis. We found that both ERs were significantly overexpressed in macrophages of women with endometriosis compared with controls. These results suggest that estrogens, through their functional receptors, might modulate the immune response at least on macrophages. Therefore, estrogens seem to play an important role in the immune response, independently from the pathology.
Are Glucocorticoids DMARDs?
Authors: BIJLSMA JOHANNES W.J. , HOES JOS N. , VAN EVERDINGEN AMALIA A. , VERSTAPPEN SUZAN M.M. , JACOBS JOHANNES W.G.
Published: July 2006

Abstract:  Disease modifying antirheumatic drugs (DMARDs) are drugs used in rheumatoid arthritis (RA) to control the disease and to limit joint damage and improve long‐term outcome. The last decade evidence has accumulated that suggests that low dosages of glucocorticoids are indeed able to control the disease and limit the destruction. This role is especially present in early disease and in combination with other drugs. The evidence is carefully evaluated and discussed. The ultimate conclusion is that indeed glucocorticoids are DMARDs and are especially useful in early RA.
Glucocorticoid Effects on Adrenal Steroids and Cytokine Responsiveness in Polymyalgia Rheumatica and Elderly Onset Rheumatoid Arthritis
Authors: SULLI ALBERTO , MONTECUCCO CARLO MAURIZIO , CAPORALI ROBERTO , CAVAGNA LORENZO , MONTAGNA PAOLA , CAPELLINO SILVIA , FAZZUOLI LAURA , SERIOLO BRUNO , ALESSANDRO CALVIA , SECCHI MARIA ELENA , CUTOLO MAURIZIO
Published: July 2006

Abstract:  Polymyalgia rheumatica (PMR) usually exhibits a good clinical response to glucocorticoid (GC) treatment, but early clinical symptoms may create some difficulties in the differential diagnosis with elderly onset rheumatoid arthritis (EORA), particularly in patients complaining of shoulder and pelvic girdle involvement at onset (PMR‐like clinical onset) (EORA/PMR). Since neuroendocrine mechanisms seem to play a pathogenetic role in these clinical conditions, the aim of this study was to evaluate hormone and cytokine responsiveness to GC treatment in these patients. Cortisol (CO), dehydroepiandrosterone sulphate (DHEAS), 17‐OH‐progesterone (PRG), interleukin‐1 receptor antagonist (IL‐1Ra), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) were evaluated at base line, and 1 month after GC treatment (prednisone 10 mg/day), in 14 PMR, 11 EORA/PMR, and 13 EORA patients (mean age 73 ± 5 years, ± SD, mean disease duration 3 ± 2 months, ± SD). No patient was taking GCs or immunosuppressive agents at base line. Following GC treatment, CO, DHEAS, and PRG decreased significantly in both PMR and EORA/PMR patients (P < 0.05), but not in EORA patients. On the contrary, IL‐1Ra was significantly increased in both PMR and EORA/PMR patients (P < 0.05). IL‐6 and TNF‐α serum levels were significantly decreased in all groups of patients (P < 0.05). In conclusion, PMR and EORA/PMR seem to exhibit similar hormonal variations after GC administration, when compared to EORA patients. These differences suggest a deficient function of the hypothalamic‐pituitary‐adrenal (HPA) axis in PMR and EORA/PMR patients, with a related higher responsiveness to GC treatment. Interestingly, in PMR and EORA/PMR patients, GC treatment was found to downregulate PRG serum levels.
Nerve Growth Factor and Brain‐Derived Neurotrophic Factor Levels in Patients with Rheumatoid Arthritis Treated with TNF‐α Blockers
Authors: PORTO FLAVIA DEL , ALOE LUIGI , LAGANÀ BRUNO , TRIACA VIVIANA , NOFRONI ITALO , D'AMELIO RAFFAELE
Published: July 2006

Abstract:  Twenty consecutive rheumatoid arthritis (RA) patients (mean age 50.4 ± 10.5 years; 17 females; mean disease duration 5.78 ± 3.75 years) enrolled for tumor necrosis factor‐α (TNF‐α) blockers therapy (10 infliximab and 10 etanercept) were selected. Before starting therapy, 3 and 6 months thereafter all patients were evaluated for disease activity score (DAS), erythrocyte sedimentation rate (ESR), serum levels of C‐reactive protein (CRP), interleukin‐6 (IL‐6), nerve growth factor (NGF), and brain‐derived neurotrophic factor (BDNF). After 3 and 6 months a significant reduction in DAS, ESR, CRP, and IL‐6 was observed, whereas no significant differences of NGF and BDNF serum levels were found. These preliminary results confirm that TNF‐α blockers significantly improve disease activity and inflammation in RA; nevertheless further studies are needed to explain the mechanisms regulating NGF and BDNF release in RA patients treated with TNF‐α blockers.
Leptin Is a Link between Adipose Tissue and Inflammation
Authors: HÄRLE PETER , STRAUB RAINER H.
Published: July 2006

Abstract:  Leptin is a hormone of the pluripotent white adipose tissue and confers a multitude of regulatory functions within the organism. It controls the energy storage, lipoprotein metabolism, acute phase reactants, sex hormones and glucocorticoid metabolism, and immune function. In this review, we describe these multiple functions of leptin, the regulation of leptin expression, and how leptin can modulate the immune system via direct and indirect mechanisms. We show how leptin can be a link between the adipose tissue and inflammation.
Impact of Thiopurine Methyltransferase Activity and 6‐Thioguanine Nucleotide Concentrations in Patients with Chronic Inflammatory Diseases
Authors: SCHEDEL JÖRG , GÖDDE ANDREA , SCHÜTZ EKKEHARD , BONGARTZ TIM A. , LANG BERNHARD , SCHÖLMERICH JÜRGEN , MÜLLER‐LADNER ULF
Published: July 2006

Abstract:  As azathioprine is one of the standard immunosuppressive drugs used for treatment of patients with different chronic inflammatory diseases, the effect of the azathioprine metabolizing enzyme thiopurine methyltransferase (TPMT) activity on incidence of adverse events (AE) was examined. In addition, potential correlations between the concentration of the azathioprine metabolite 6‐thioguanine nucleotide (6‐TGN) in erythrocytes (RBC) and inflammatory disease activity as well as hematological AE were investigated. TPMT activities were investigated prospectively in 139 patients (35 male, 104 female) with chronic inflammatory diseases [systemic lupus erythematosus (SLE, 38), progressive systemic sclerosis (PSS, 13), Wegener's granulomatosis (4), rheumatoid arthritis (RA, 5), and other chronic inflammatory diseases (79)]. In addition, 6‐TGN concentrations were investigated in a second cohort of 58 patients (17 patients with SLE, 5 with PSS, 5 with vasculitides, 4 with undifferentiated connective tissue diseases, 1 with dermatomyositis, 1 with Sjögren's syndrome, 1 with RA, 20 with Crohn's disease, and 4 with ulcerative colitis) prior to and during therapy with azathioprine. The distribution of activities of TPMT in 139 patients showed a normal Gaussian distribution in the Caucasian population. Within the group of 96 patients taking azathioprine, known azathioprine‐related AE could be observed: minor AE (sickness, rash, and increase in cholestasis parameters) in 11 patients (11.4%), and severe AE (bone marrow toxicity) in 7 patients (7.3%). Below a “cutoff” value of 11.9 nmol/mL RBC × h of TPMT activity, AE were significantly more frequent. In the second cohort of patients, no significant correlations could be observed between 6‐TGN concentrations and parameters of disease activity. Reduced activity of TPMT in patients with chronic inflammatory diseases requiring immunosuppressive therapy with azathioprine, especially below a distinct cutoff, appears to inherit a substantial risk for development of AE.
An Orally Administered Multitarget Tyrosine Kinase Inhibitor, SU11248, Is a Novel Potent Inhibitor of Thyroid Oncogenic RET/Papillary Thyroid Cancer Kinases
Authors: Kim Dong Wook , Jo Young Suk , Jung Hye Sook , Chung Hyo Kyun , Song Jung Hun , Park Ki Cheol , Park Su Hyeon , Hwang Jung Hwan , Rha So Young , Kweon Gi Ryang , Lee Su-Jae , Jo Ki-Won , Shong Minho
Published: July 2006

Context: The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC.

Objective: The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC.

Design: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells.

Results: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC50 of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1.

Conclusion: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.
STUDIES ON THE PROPERTIES OF DIASPORE AND BAUXITE
Authors: Yamaguchi Yohei , Takebe Toshimasa
Published: July 2006

(1) It was found that the vapour pressures of decomposition of diaspore could be calculated by the following equation in the range from 400° to 500°. Logπ=14.820–9255.1/T.

(2) In the case of bauxite, the curve of decomposition pressure was found to be consisted of two parts. The first part can be expressed by the equation logπ=6.5277–2206.5/T, in the range from 200° to 340°, and the second roughly by logπ=5.2566–1780/T in the range from 350° to 450°.

(3) The heats of decomposition of diaspore and bauxite were calculated by the integrated equation of Clapeyron and Clausius.

(4) The specific heat of diaspore was determined by the calorimetric investigation and found to be c=0.2085+0.000127 t.
THE HEATS OF FUSION OF SOME ORGANIC SOLVENTS WHOSE MELTING POINTS ARE RELATIVELY LOW
Authors: Mitsukuri Shinroku
Published: July 2006

An apparatus which is suited to determine the lowering of freezing point of organic solvent was describd.

The lowerings of the freezing points of the solutions of chloroform, acetone, carbon-bisulphide, ethyl-ether, methyl-alcohol and ethyl-alcohol were determined, and their heats of fusion were calculated.

This paper is a brief abstract of the following papers:

The heats of fusion of chloroform, acetone and carbon-bisulphide. by S. Mitsukuri and S. Aoki.

The heats of fusion of ethyl-ether, methyl-alcohol and ethyl-alcohol. by S. Mitsukuri and K. Hara.

which are going to be published in the science reports of the Tohoku Imperial University. The full description of the experiments and some discussions on the results are to be found in the above papers.
ON THE ACTION OF PHOSPHATE UPON HEXOSES. I. THE FORMATION OF ACETOL FROM GLUCOSE IN ACIDIC SOLUTION OF POTASSIUM PHOSPHATE
Authors: Nodzu Ryuzaburo
Published: July 2006

On steam distillation of a mixture of glucose and about 40% potassium phosphate solution of pH from 7.0 to 5.0, an appreciable quantity (4–5% of glucose used) of acetol and a little quantity of diacetyl- and methylglyoxal are found in the distillate. The more concentrated and the nearer to neutrality the phosphate solution is, the more favourable for the formation of acetol.
ON A NEW HYDROCARBON IN BASKING SHARK LIVER OIL
Authors: Tsujimoto Mitsumaru
Published: July 2006

Although small in proportion, a new octadecylene, C18H36, has been found to occur, together with pristane, in basking shark liver oil. In far smaller proportions, it probably occurs in many other, squalene-containing shark liver oils in association with pristane. The author has proposed the name “Zamene” for this new hydrocarbon.
ON THE FATTY ACIDS OF JAPAN WAX.
Authors: Tsujimoto Mitsumaru
Published: July 2006

The component fatty acids of a specimen of unbleached Japan wax, which contains no kernel oil, have been examined.

In agreement with the description in fat literature, palmitic acid is, of course, the main component. Myristic acid and the lower homologues appear not to be present; volatile lower acids stated to occur in Japan wax by old investigators are undoubtedly decomposition products formed by bleaching process. On the other hand, stearic and arachidic acids occur in appreciable proportions. The unsaturated acids consist mostly of oleic acid. A small proportion of linolic acid is present. Hexadecenoic and linolenic acids are probably not present.

It is difficult to mention the quantitative proportion of the individual acids, but rough approximation would be as follows: Palmitic acid 77%, stearic and arachidic acids 5%, oleic acid 12%, linolic acid small amount (less than 1%), dibasic acids 6%.

The above proportion of stearic and arachidic acids would be rather high; in their relative amounts the former seems to predominate.

It is interesting to observe that whereas myristic acid can not be detected in Japan wax obtained from Rhus succedanea, it occurs abundantly in the wax of “Tsutaurushi”, Rhus toxicodendron, var. vulgaris, a viny shrub belonging to the same genus Rhus.

The free acids in Japan wax have nearly the same composition as the mixed acids of the wax, but oleic acid is present in a far larger proportion.