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The 2008 presidential and parliamentary elections in Zimbabwe and their attendant violence and disorder fitted the image some governments and groups have had about that country as one whose politics has resisted change. There was another side to the elections that observers failed to recognize, however, and it was about the important issues for which voters were seeking answers. As flawed as the electoral process in Zimbabwe seemed, it was not different from elections which governments in other parts of Africa have organized. It was also perplexing that observers of Zimbabwe's politics barely acknowledged that the equitable allotment of land between blacks and whites was at the core of the electoral debate. This study shows that elections in Zimbabwe are more nuanced than the graphic images of violence that television cameras portrayed. Zimbabwe's political history is unique among African countries because of the biracial makeup of its society and repressive laws have helped to create a horrendous gap in wealth between whites and blacks. It is also a country where blacks won independence through war. It has been customary for observers and aid donors to blame President Mugabe for the missteps in his decisions, but have had little sympathy trying to understand the protracted issues of wealth, power, and privilege. [ABSTRACT FROM AUTHOR]

The expression of chemokines is critical in leukocyte recruitment and inflammation, but the regulatory mechanisms involved remain incompletely defined. While endocrine disrupter chemicals (EDCs) are known to be ubiquitous in the environment and often associated with altered inflammatory response, their potential impact on chemokine expression in monocytes is at present unknown. To this end, the effects of EDCs on the expression of Th1- and Th2-related chemokines in a human monocytic cell line, THP-1, were investigated. THP-1 cells were pre-treated with varying concentrations of EDCs (nonylphenol and 4-octylphenol) with or without the addition of an estrogen receptor (ER) antagonist, ICI 182,780 and then stimulated by lipopolysaccharide (LPS). The levels of chemokines, CXCL10/ IFN-α-inducible protein 10 (IP-10, a Th1 chemokine) and monocyte-derived chemokine (MDC)/CCL22, a Th2 chemokine) were measured by ELISA. EDC-mediated signaling events and histone modifications were examined by the use of Western blotting and chromatin immunoprecipitation (ChIP) assay. Nonylphenol and 4-octylphenol were able to suppress LPS-induced MDC and IP-10 expression. This suppressive effect was not reversed by the addition of ICI 182,780. Nonylphenol and 4-octylphenol reduced LPS-induced activation of MAPK signaling pathway, MKK1/2 and ERK, concomitant with decreased levels of LPS-induced acetylated histone 4 (H4) at the IP-10 and MDC gene loci. Nonylphenol and 4-octylphenol suppressed LPS-induced MDC expression in monocytes via, at least in part, the MKK1/2-ERK MAPK pathway and histone H4 acetylation, but not the estrogen receptor. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) involves an abnormal chemokine regulation. The chemokine receptor CCR4 is necessary for T cell migration to the skin. We, therefore, studied if CCR4 and its ligand macrophage-derived chemokine (MDC/CCL22) could participate in spreading the disease between skin and joints by examining RA, PsA and osteoarthritis (OA) patients. In synovial fluid from RA and PsA patients we observed a significantly higher MDC/CCL22 level compared to OA patients. Additionally, the MDC/CCL22 protein was found to be elevated in RA and PsA plasma compared to OA and healthy volunteers. Flow cytometry revealed that most CD4+CCR4+ lymphocytes also co-expressed CD45RO. Neither the MDC/CCL22 level nor the expression of CCR4 correlated to CRP. Immunohistochemistry of the RA and OA synovial membrane demonstrated CCR4 to be expressed by mononuclear cells and endothelial cells. Our results show that MDC/CCL22 is present within the synovial membrane of RA and OA patients and in high amount in the synovial fluid of patients with RA and PsA. This will enable migration of CCR4 expressing memory cells supporting that MDC/CCR4 could play a role in attracting skin specific memory T cells to the joints. [Copyright &y& Elsevier]

Abstract: Background: Dendritic cells (DCs) play a pivotal role in linking the innate and adaptive immune response and have been implicated in a variety of pulmonary diseases. Currently, studies on the role of DCs are limited by difficulties in isolating DCs from the lung. Surgical lung specimens are not readily available and purification of DCs from digested lung tissue is likely to induce phenotypical and functional changes. DCs obtained from the alveolar spaces are thought to represent the local microenvironment and can be obtained using minimally invasive techniques. We developed a novel method of isolating DCs from bronchoalveolar lavage (BAL) fluid. Methods: After removal of macrophages, the remaining BAL cells were stained with a lineage mix (CD3-, CD14-, CD16-, CD19-, CD56-FITC), CD11c and HLA-DR and sorted with a FACS ARIA. DAPI was used as a dead-live marker. mDCs were low autofluorescent, lineage mix negative, CD11c+ and HLA-DR+ cells. pDCs were CD11c− but CD123+. Morphological assessment of sorted mDCs and pDCs was performed. Sorted mDCs were tested in a mixed leukocyte reaction (MLR) with naive CD4+ T cells and evaluated for T cell differentiation and cytokine production. With confocal microscopy DC–T cell interaction was assessed. Results: Using our sorting strategy, mDCs and pDCs, with a high purity upon FACS analysis of the sorted fraction, were obtained. These cells showed the morphological characteristics of DCs. Most importantly, mDCs were able to induce T cell proliferation and differentiation in a MLR, and interact with T cells as assessed by confocal microscopy. These results indicate the presence of functional DCs. Freezing and thawing of the BAL cells did not affect phenotype or T cell stimulatory capacity of the isolated DCs. Conclusion: Using a novel sorting strategy, functional mDCs can be isolated from BAL fluid, enabling a detailed study in pulmonary disease. [Copyright &y& Elsevier]

Background: Dendritic cells (DC) represent an important and integral part of the immune system and are potent initiators of inflammation. Two distinct subsets of DC have been identified: myeloid DC (MDC) and plasmacytoid DC (PDC), which differ widely in many respects. Despite the importance of the DC in the inflammatory response that occurs after severe multiple injury, there is a profound lack of information regarding the distribution and regulation of DC subtypes following multiple trauma. The main goal of this study was to assess whether the normal distribution of circulating DC subpopulations is altered during the first 5 d after multiple trauma. Patients and methods: Sixty-three patients with multiple trauma (ISS 31 ± 15 points) and 11 healthy volunteers (control group) were enrolled. Blood samples were taken on admission (D0) and daily for the following 5 d. The percentages of MDC and PDC were determined by flow cytometry. Results: A significant decline of the MDC concentration was observable on days 3 to 5 after admission in comparison to the values obtained on the day of admission. The ratio of MDC to PDC decreased significantly (3-fold, P < 0.05). This reduction correlated significantly with changes observed in the plasma concentrations of IL-10 (r = 0.5; P < 0.05). Discussion: Our data demonstrate that multiple trauma is followed by a marked change in the subpopulation composition of the DC compartment, and that these changes are inversely associated with enhanced IL-10 plasma concentrations. This imbalance in the DC compartment favoring PDC concentrations may contribute to the immunological alterations that are observed following multiple trauma. [Copyright &y& Elsevier]

Abstract: Patients with atopic dermatitis (AD) have significantly reduced plasma cAMP levels, and the cAMP level is correlated with the immunopathogenesis of AD. The production of thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) in keratinocytes is significantly enhanced in patients with AD. In the present study, we investigated the in vitro effects of the adenylyl cyclase-cAMP system on IFN-γ and TNF-α-stimulated production of TARC and MDC in human HaCaT keratinocytes. Both forskolin (a direct activator of adenylyl cyclase) and dibutyryl-cAMP (DBcAMP, a permeable analog of cAMP) suppressed production of TARC and MDC in parallel with the activation of NF-κB in IFN-γ and TNF-α-stimulated HaCaT cells. Moreover, inhibition of NF-κB suppressed TARC and MDC production induced by IFN-γ plus TNF-α. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the secretion of these chemokines. An inhibitor of p38 MAPK suppressed the production of TARC and MDC in parallel to the activation of NF-κB in HaCaT cells. Of note, the IFN-γ plus TNF-α-stimulated activation of p38 MAPK was suppressed following incubation with forskolin or DBcAMP alone. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in IFN-γ plus TNF-α-stimulated production of TARC and MDC in HaCaT keratinocytes by inhibiting NF-κB activation through p38 MAPK pathway, implying that the adenylyl cyclase-cAMP system could be a candidate therapeutic target of Th2-skewed skin inflammation such as AD. [Copyright &y& Elsevier]

In human trials, Bifidobacterium longum BB536 alleviates subjective symptoms of Japanese cedar pollinosis, an IgE-mediated type I allergy caused by exposure to Japanese cedar, and significantly suppresses the increase of plasma thymus- and activation-regulated chemokine (TARC) associated with pollen dispersion. In the present study, we investigated the suppressive effects of BB536 on the production of T helper type 2 (Th2)-attracting chemokines, such as TARC and macrophage-derived chemokine (MDC), together with the mechanisms of their production. Murine splenocytes were cultured with heat-killed BB536, and the levels of Th2-attracting chemokines in the supernatants were measured. TARC and MDC were produced in cultures without stimulation, and the production was significantly suppressed by BB536. These chemokines were produced by antigen-presenting cells (APCs) of splenocytes stimulated with an anti-CD40 antibody. Furthermore, TARC production was induced with granulocyte macrophage colony-stimulating factor that was produced by T cells and dendritic cells. BB536 suppressed MDC production induced with the anti-CD40 antibody by APCs from the spleen, mesenteric lymph nodes (MLNs) and Peyer's patches, and it suppressed TARC production by APCs from the spleen and MLNs. These results indicate that BB536 suppresses the production of Th2-attracting chemokines induced by the T cell–APC interaction, suggesting a novel mechanism for alleviating symptoms of allergic disorders by probiotics. [ABSTRACT FROM AUTHOR]

Abstract: A next generation real time trigger method to improve the enrichment of lepton events in the High Acceptance DiElectron Spectrometer (HADES) trigger system has been developed. In addition, a flexible Hardware Platform (Gigabit Ethernet-Multi-Node, GE-MN) was developed to implement and test the trigger method. The trigger method correlates the ring information of the HADES Ring Imaging Cherenkov (RICH) detector with the fired wires (drift cells) of the HADES Mini Drift Chamber (MDC) detector. It is demonstrated that this Level 3 trigger method can enhance the number of events which contain leptons by a factor of up to 50 at efficiencies above 80%. The performance of the correlation method in terms of the events analyzed per second has been studied with the GE-MN prototype in a lab test setup by streaming previously recorded experiment data to the module. This paper is a compilation from Kirschner [Level 3 trigger algorithm and Hardware Platform for the HADES experiment, Ph.D. Thesis, II. Physikalisches Institut der Justus-Liebig-Universität Gießen, urn:nbn:de:hebis:26-opus-50784, October 2007 ]. [Copyright &y& Elsevier]

In order to shorten the time of through-the-canopy-ejection, and to ensure pilot safely escape and survive. The application of linear cutting technique using miniature detonation cord( MDC) in through-the-canopy-ejection-system is proposed. A series of different kinds of MDC are designed. Firstly experimental study on the cutting process of the PMMA plate wiht MDC is carried out. Material of metal cover explosive types and the range of charge quantities are determined. Consequently the phenomena of spallation is observed, and the relationship between the cutting depth and charge quantities is obtained. For the comparison, the process of explosion cutting PMMA plate is simulated by means of nonlinear dynamic analysis code LS-DYNA. Spallation phenomena which occurs in the experiment, is also observed in the simulation. Simulation results present the relationship of cutting depth of PMMA plate versus charge linear density, which well agree with experimental ones. [ABSTRACT FROM AUTHOR]

Abstract: Probing and modeling of surface polarization phenomena originating from dipoles and electrons in organic materials are studied. We use an electrical measurement that can directly probe orientational dipolar motion in monolayers by Maxwell Displacement Current, and show that a two-dimensional domain shape is dependent on electrostatic energy stored in the domain owing to the polar orientational alignment of permanent dipoles. Also, we demonstrate a novel optical second harmonic generation technique that allows carrier motion in active layers of organic field-effect transistors to be directly probed as the migration of electric field. We conclude that probing of electric field generated from moving charged particles, e.g., dipoles and electrons, at the interface is a common concept for studying dielectric polarization and its related two-dimensional interfacial phenomena in organic materials. [Copyright &y& Elsevier]

Multiple description coding (MDC) is an effective error resilience (ER) technique for video coding. In case of frame loss, error concealment (EC) techniques can be used in MDC to reconstruct the lost frame, with error, from which subsequent frames can be decoded directly. With such direct decoding, the subsequent decoded frames will gradually recover from the frame loss, though slowly. In this paper we propose a novel algorithm using multihypothesis error concealment (MHC) to improve the error recovery rate of any EC in the temporal subsampling MDC. In MHC, the simultaneous temporal-interpolated frame is used as an additional hypothesis to improve the reconstructed video quality after the lost frame. Both subjective and objective results show that MHC can achieve significantly better video quality than direct decoding. [ABSTRACT FROM PUBLISHER]

Summary: Background: Antihistamines are widely used for the treatment of allergic diseases, such as urticaria and allergic rhinitis. They are also effective for the treatment of diseases in which T cells are mainly involved in the pathogenesis, such as atopic dermatitis (AD) and contact dermatitis. Dendritic cells (DCs) drive polarization of naive T cells into Th1 or Th2 subsets, and are also likely to be involved in AD pathogenesis. Objectives: The aim of this study was to determine the effects of antihistamines on DCs and CD4+ T cells. Methods: Human monocyte-derived DCs (MoDCs) and autologous CD4+ T cells were obtained from healthy subjects, and cultured together or independently in the presence of antihistamines. As a stimulant, we used staphylococcal enterotoxin B or the combination of anti-CD3 monoclonal antibody (mAb) and anti-CD28 mAb. The concentrations of cytokines and chemokines in culture supernatants were measured by ELISA. The expression of surface molecules on MoDCs was measured by flow cytometry. Cell proliferation in the cocultures of MoDCs and CD4+ T cells (DC-T cocultures) was measured by a [3H] thymidine incorporation assay. Results: Antihistamines inhibited the production of IFN-γ, and enhanced the production of IL-4 in DC-T cocultures. Antihistamines inhibited the production of TNF-α, TARC, MDC, IP-10, and Mig from MoDCs. Epinastine, one of antihistamines, suppressed the expression of ICAM-1 (CD54) on MoDCs. Epinastine also inhibited the proliferation of CD4+ T cells cocultured with MoDCs. Conclusions: Our findings show that antihistamines regulate immune responses by affecting the interaction between DCs and CD4+ T cells, and further DCs and CD4+ T cells independently, which may partially contribute to the control of allergic diseases such as AD and contact dermatitis. [Copyright &y& Elsevier]

On Sunday 13 March 2005 prominent Zimbabwean musician, Oliver Mtukudzi performed at the function to celebrate the appointment of Joyce Mujuru of ZANU PF party to the office of Vice President of the Republic of Zimbabwe. There were many conflicting reactions to this action of Tuku, particularly in the context of political polarization in Zimbabwe. This article explores the validity of reactions and concerns of various readers and letter writers to a website called newzimbabwe.com. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease with over 200 million individuals infected worldwide. The vast majority of acutely infected humans develop chronic infection, which is characterized by attenuated antiviral T-cell responses. The mechanisms leading to such attenuation/suppression are poorly understood. It has been proposed that dysfunction of antigen-presenting cells (APC) may underlie the downregulation of antiviral immune responses. However, studies using bulk or in vitro-derived APC populations have resulted in conflicting reports. In this study, we evaluated the functional and immunophenotypic features of ex vivo-purified dendritic cell (DC) subsets during chronic HCV infection. We found that plasmacytoid DC (PDC) from HCV-infected patients (HCV-PDC) showed a striking deficit in IFN-α production in response to CpG stimulation. In addition, we found that myeloid DC (MDC) from these patients showed a diminished capacity to induce a mixed lymphocyte response (MLR), correlating with lower levels of HLA-DR and CD86 expression and higher IL-10 production in response to poly-IC stimulation. In contrast, HCV-PDC showed increased ability to stimulate an MLR. Of note, within the HCV-PDC preparation, we noted a distinctly expanded DC subset that expressed some markers of MDC, but showed significantly lower HLA-DR and CD86 expression, suggesting an expansion of DC at an immature/intermediate stage of differentiation. Our studies demonstrate distinct and contrasting dysfunctional features in DC subsets and underscore the importance of evaluating APC subpopulations separately. [Copyright &y& Elsevier]

Abstract: The design, synthesis, and SAR studies of ‘core’ variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 ∼10mg/kg). [Copyright &y& Elsevier]

This cross-cultural study of international tourists' main destination choices (MDCs) within China's three major gateway cities – Beijing, Shanghai and Guangzhou – adds to the literature in two respects. First, a cognitive ‘cultural distance’ variable, formed from cultural constructs perceived by the respondents was used to underpin the comparative framework in addition to usually applied cultural proxies, such as nationality, in cross-cultural studies. A discreet choice modelling approach is used to address the operational challenges of incorporating behavioural elements in choice analysis. The research findings support the international gateway positions of Beijing and Shanghai, but that of Guangzhou is questioned. The research also revealed that, although both of the two types of cultural variables are related to the MDCs of the tourists, the level of significance of ‘cultural distance’ and ‘cultural proxies’ at expressing the differences of tourists' MDCs within a destination country are not parallel. The former appeared to be a more sensitive element in determining the behavioural patterns of international tourists than the latter. Geographical distance and demographic characteristics show no significant interrelationship with the MDCs of international tourists within a destination country. [ABSTRACT FROM AUTHOR]

ADAMs (a disintegrin and metalloproteinase) are sheddases possessing extracellular metalloproteinase/disintegrin/cysteine-rich (MDC) domains. ADAMs uniquely display both proteolytic and adhesive activities on the cell surface, however, most of their physiological targets and adhesion mechanisms remain unclear. Here for the first time, we reveal the ADAMs' MDC architecture and a potential target-binding site by solving crystal structures of VAP1, a snake venom homolog of mammalian ADAMs. The D-domain protrudes from the M-domain opposing the catalytic site and constituting a C-shaped arm with cores of Ca2+ ions. The disintegrin-loop, supposed to interact with integrins, is packed by the C-domain and inaccessible for protein binding. Instead, the hyper-variable region (HVR) in the C-domain, which has a novel fold stabilized by the strictly conserved disulfide bridges, constitutes a potential protein–protein adhesive interface. The HVR is located at the distal end of the arm and faces toward the catalytic site. The C-shaped structure implies interplay between the ADAMs' proteolytic and adhesive domains and suggests a molecular mechanism for ADAMs' target recognition for shedding. [ABSTRACT FROM AUTHOR]

Abstract: Electrostatic phenomena occurring at the interface between metal/organic and organic/organic materials are discussed from the viewpoint of dielectrics physics. Focusing on two important origins of surface polarization phenomena, orientational ordering of polar molecules and displacement of excess charges at the interface, surface polarization phenomena of organic thin films are discussed. To define the orientational order of polar molecules, orientational order parameters are introduced, and surface polarization due to the alignment of dipoles is expressed. The generation of Maxwell displacement current (MDC) and optical second harmonic generation (SHG) that are specific for surface organic monomolecular films are discussed, and some experimental evidence are shown. As an extension of the concept of surface Fermi level introduced to discuss the electrostatic phenomena due to electron transfer at the interface between metal–organic insulators, the surface Fermi level is extended to the discussion on the electrostatic phenomena of organic semiconductor materials on metals. In this paper, some experimental evidence of surface polarization originating from polar molecules and displacement of excess charges are shown. After that, with consideration of these surface phenomena, single electron tunneling of organic films are briefly discussed in association with surface polarization phenomena. [Copyright &y& Elsevier]

Abstract: A series of 2-aminothiazole-derived antagonists of the CCR4 receptor has been synthesized and their affinity for the receptor evaluated using a [125I]TARC (CCL17) displacement assay. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent, orally bioavailable antagonists. [Copyright &y& Elsevier]

Abstract: Human immunodeficiency virus (HIV)-wasting syndrome might be facilitated by the HIVgp120 affecting the immunological system. We studied the effect (subchronic administration: 5 days) of HIVgp120, and a few immune-response mediators: regulated upon activation normal T-cell expressed and presumably secreted (RANTES), stromal derived factor-1α (SDF-1α), macrophage-derived chemokine (MDC), and their combination, on food and water intake in rats, motor control and pain perception. Eighty male adult Wistar rats received an intracerebroventricular (icv) administration of: vehicle 5μl/day or 0.92nmol daily of HIVgp120IIIB, RANTES, SDF-1α, or MDC, and the combination of RANTES+HIVgp120IIIB, SDF-1α+HIVgp120IIIB, or MDC+HIVgp120IIIB. Food and water intake was measured every day during administration, and 24 and 48h after the last administration. Rats were also weighed the first and the last day of experiment in order to detect the impact of these treatments in the body weight. HIVgp120IIIB significantly decreased food and water intake. These rats gain less weight than the control (vehicle) and chemokines-treated subjects with exception of those treated with SDF-1α that also gain less weight. In addition, HIVgp120 deteriorated motor control. HIVgp120IIIB effects on food and water intake, and motor control were prevented by these chemokines. HIVgp120+RANTES, HIVgp120+SDF-1α, and SDF-1α alone induced hyperalgesia. Results suggest an interaction between HIVgp120 and the chemokine system to generate the HIV-wasting syndrome, the motor abnormalities and changes in pain perception. [Copyright &y& Elsevier]

Abstract: The design, synthesis, and activity of novel and selective small molecule antagonists of the CC chemokine receptor-4 (CCR4) are presented. Compound 8c was efficacious in a murine allergic inflammation model (ED50 30mg/kg). [Copyright &y& Elsevier]

Background: Pseudomonas aeruginosa infection determines the course of cystic fibrosis (CF) lung disease. Studies in human peripheral blood indicate that P aeruginosa infection is associated with a predominant TH2 immune response, whereas TH1 responses are accompanied by a better pulmonary outcome. Objective: Analyses of peripheral blood may not correspond directly with the local pulmonary immune response. Therefore, we asked whether the TH1/TH2 response is altered in bronchoalveolar lavage fluid from P aeruginosa–infected patients with CF. Methods: Bronchoalveolar lavage fluid was obtained from 12 patients with CF chronically infected with P aeruginosa, 11 noninfected patients with CF, and 8 healthy controls. Pulmonary CXCR3+ (TH1) and CCR4+ (TH2) expressing CD4+ and CD8+ lymphocytes were quantified by flow cytometry. Levels of TH1-associated (IL-2, IFN-γ, IFN-γ inducible T cell-α chemoattractant, Monokine induced by IFN-γ, IFN-γ inducible protein of 10 kd) and TH2-associated (IL-4, IL-5, IL-10, thymus and activation-regulated chemokine [TARC], macrophage-derived chemokine) cytokines and chemokines and a panel of proinflammatory molecules were quantified at the protein level. Chemokines mRNA levels were assessed by real time RT-PCR. Results: P aeruginosa–infected patients with CF had significantly higher levels of pulmonary CCR4+CD4+ (TH2) cells, IL-4, IL-13, and TARC and lower levels of IFN-γ compared with noninfected patients with CF and healthy controls. Bronchoalveolar lavage fluid levels of IL-4, IL-13, and TARC correlated inversely with FEV1 in P aeruginosa–infected patients with CF. Conclusion: These results reveal the prevalence of a pulmonary TH2 immune response in P aeruginosa–infected patients with CF. The modulation of the pulmonary TH2 response in P aeruginosa infection may be an option for the treatment of P aeruginosa lung disease in patients with CF. [Copyright &y& Elsevier]

Abstract: TARC (CCL17) and MDC (CCL22) are well-known chemoattractants for Th2 cells. Here, we evaluated the role of both chemokines for cigarette smoke-induced airway inflammation. The expression profiles of MDC, TARC, and their receptor CCR4 were analyzed in models of acute and chronic cigarette smoke-induced airway inflammation that is characterized by a Th1 immune response. The results were compared to the expression of both chemokines in models of idiopathic pulmonary fibrosis and acute asthma, which are associated with a Th2 immune response. The expression of MDC and TARC was found to be elevated in all lung inflammation models. In contrast to the findings in the asthma and lung fibrosis models, the increased expression of MDC and TARC in the cigarette-smoke model was not associated with an increased infiltration of Th2 cells into smoke-treated lungs. Our data indicate that instead of Th2 cells, airway epithelial cells expressing CCR4 might be the principal targets for MDC and TARC released from alveolar macrophages during cigarette smoke-induced airway inflammation. [Copyright &y& Elsevier]

Background: Cough is a frequent symptom in children, but the differentiation of asthmatic cough from cough of other origins can be difficult. Chemokines recruit T lymphocytes to inflamed tissues, and the corresponding chemokine receptors are differentially expressed on TH1 and TH2 cells. Objective: We sought to determine whether levels of TH1/TH2-related chemokines and their receptors differ in bronchoalveolar lavage fluid (BALF) from 12 children with allergic asthma, 15 nonatopic children with chronic cough, and 10 children without airway disease. Methods: The TH1-related (IFN-γ–inducible protein of 10 kd [IP-10], IFN-γ–inducible T cell α chemoattractant [ITAC], monokine induced by IFN-γ [Mig], and IFN-γ) and TH2-related (thymus- and activation-regulated chemokine [TARC], macrophage-derived chemokine [MDC], IL-5, and IL-4) chemokines and cytokines were quantified in BALF by ELISA and a particle-based multiplex array. Percentages of pulmonary lymphocytes expressing CXCR3+ and CCR5+ (TH1) and CCR4+ and CCR3+ (TH2) chemokine receptors were determined in BALF by flow cytometry. Results: Pulmonary CCR4+CD4+ cells and levels of TARC and MDC were significantly increased in asthmatic children versus children with chronic cough or without airway disease. In asthmatic children CCR4+CD4+ cells correlated positively with levels of TARC, MDC, and serum IgE levels and negatively with FEV1. In contrast, CXCR3+CD8+ cells and levels of ITAC were significantly increased in children with non-atopic chronic cough compared with the other groups. In children with chronic cough, CXCR3+CD8+ cells correlated with levels of ITAC and IFN-γ. Conclusion: Pulmonary CCR4+CD4+ and CXCR3+CD8+ cells and their ligands TARC, MDC, and ITAC clearly differentiate asthmatic children from nonatopic children with chronic cough. The analysis of these markers could facilitate the diagnostic discrimination of asthma versus other reasons for chronic cough in children. [Copyright &y& Elsevier]

Dendritic cells (DCs) are professional antigen-presenting cells that enhance and regulate both innate and acquired immune reactions. It has been reported that several viruses actively down regulate DC function to escape from host immune system. To clarify the involvement of DC in anti-hepatitis C virus (HCV) immune reactions, we compared DC function between chronic hepatitis C patients and healthy donors. Monocyte-derived DCs generated from patients were relatively immature and were impaired in allostimulatory capacity and IL-12 p70 production when compared to that from donors. In addition, MDC and PDC in HCV-infected patients were reduced in number and impaired in their ability to promote Th1 polarization. These results demonstrate that DCs are numerically and functionally impaired in HCV-infected patients, which is critically involved in the pathogenesis and persistence of HCV infection. [ABSTRACT FROM AUTHOR]

Autophagy is an intracellular bulk degradation system that is found ubiquitously in eukaryotes. Autophagy is responsible for the degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membraned autophagosomes, which subsequently fuse with lysosomes where their contents are degraded. This system has been implicated in various physiological processes including protein and organelle turnover, the starvation response, cellular differentiation, cell death, and pathogenesis. However, methods for monitoring autophagy have been very limited and unsatisfactory. The most standard method is conventional electron microscopy. In addition, some biochemical methods have been utilized to measure autophagic activity. Recently, the molecular basis of autophagosome formation has been extensively studied using yeast cells; these studies have provided useful marker proteins for autophagosomes. Importantly, most of these proteins are conserved in mammals. Using these probes, we can now specifically monitor autophagic activity. [Copyright &y& Elsevier]

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive collagen deposition in the skin and internal organs. Several cytokines and chemokines have been implicated in the induction of fibrosis, but a definitive relationship between specific cytokines and organ involvement has not been established yet. Serum samples, PBMC and T cell lines (TCL) obtained from 54 patients affected by SSc and 20 healthy donors (HD) were examined by ELISA for Interferon-y (IFN-γ), interleukin (IL)-4, IL-6, IL-b, IL-18, Transforming growth factor (TGF)-Β1, Tumour necrosis factor (TNF)-α, sCD30, Macrophage derived chemokine (MDC), Monocyte chemo attractant protein (MCP) -1, Macrophage inflammatory protein (MIP)-1α and Regulated on activation normal T-cell expressed and secreted (RANTES). In all the SSc serum samples, we found significantly increased levels of IL6, TNFα and MCP-1 but reduced amounts of γ-IFN and MDC. IL6, IL10, IL18, MIP-1α and TNFα measured in supernatants from PHA-stimulated PBMC and 1L6, MCP- 1 and RANTES in supernatants from stimulated TCL were also increased in patients. MDC was decreased in all the biological SSc sources studied. TGF-Β1, IL10, and sCD30 were produced at a significantly lower level by SSc TCL. Serum IL6 and sCD30 levels were significantly increased in dc-SSc patients compared to lc-SSc as were levels of MCP-1 produced by PBMC and IL10 from TCL. We observed a strict relationship between pulmonary fibrosis and IL10, MCP-1 (both from TCL) and serum 1L6. Kidney involvement was related to serum MCP-i levels and IL18 production from PBMC. Oesophageal involvement correlated with MDC production from PBMC and IL10 synthesis by TCL. We showed that IL-6, IL-10, MDC and MCP-1 are variably associated with internal organ involvement and allow the discrimination between limited and diffuse forms of the disease. [ABSTRACT FROM AUTHOR]

Background: Although abnormalities of various chemokines are detected in systemic sclerosis (SSc), there are few findings concerning Th1 or Th2 chemoattractants. Objective: To determine whether serum levels of chemokines preferentially chemotactic for Th1 cells (IP-10 and MIG) and predominantly chemotactic for Th2 cells (TARC and MDC) are elevated and whether they correlate with clinical features in patients with SSc. Methods: Serum samples from patients with diffuse cutaneous SSc (dSSc; n=34), limited cutaneous SSc (lSSc; n=30), dermatomyositis (DM; n=15), systemic lupus erythematosus (SLE; n=22), and normal controls (n=30) were examined by sandwich ELISA. Results: Serum TARC levels were significantly elevated in dSSc patients (P<0.0002) and lSSc patients (P<0.0001) compared with normal controls. Similarly, serum MDC levels were significantly increased in patients with dSSc (P<0.02) or lSSc (P<0.05) relative to normal controls. In addition, serum IP-10 was detected significantly more frequently in patients with dSSc (44%), lSSc (30%), or DM (53%) than normal controls (0%) and patients with SLE (0%). Furthermore, elevated TARC levels correlated with the presence of pitting scars and anti-topoisomerase I antibody, increased titers of anti-topoisomerase I and antinuclear antibody, and decreased glomerular filtration rate. Increased MDC levels were associated with pitting scars and younger ages at onset. Conclusion: These results suggest that both Th2 chemoattractants, TARC and MDC, and a Th1 chemoattractant IP-10 play a role in the development of SSc. [Copyright &y& Elsevier]

We investigated 4-heptyloxy-4′-n-cyanobiphenyl (7OCB) Langmuir films by monolayer compression using Maxwell displacement current (MDC) and optical second harmonic generation (SHG) measurements. In the region with a slope in the surface pressure – area (π-A) isotherm, it was found that the s-s and p-s SH signals were suddenly generated by monolayer compression, although the change of MDC was very gentle. This result reveals the appearance of phase transition accompanying the monolayer structural change from C∞v to Cs-symmetry, due to the shear induced azimuthal in-plane reorientation in monolayers. [ABSTRACT FROM AUTHOR]

Using Maxwell displacement current (MDC) and optical second harmonic generation (SHG) measurements, the orientational order parameters S1 and S3 of 4-octyl-4′-n-cyanobiphenyl (8CB) monolayers on the water surface were determined by monolayer compression. [ABSTRACT FROM AUTHOR]

Background: Macrophage-derived chemokine (MDC) is a Th2 type chemokine and its receptor CC chemokine receptor 4 (CCR4) is preferentially expressed on Th2 cells. Recent reports demonstrated that MDC is expressed not only by macrophages, dendritic cells and lymphocytes, but also by cultured human keratinocytes (KCs). However, the regulation of MDC production in KCs by various cytokines has not been well documented. Objective: In this study, we investigated how Th1/Th2 cytokines regulate MDC production in a human KC cell line, HaCaT cells. Methods: HaCaT cells were cultured with or without various cytokines for 24 h and RT-PCR was performed using these cells to evaluate MDC mRNA levels. ELISA was carried out using supernatant of HaCaT cells to calculate secreted MDC protein levels. Results: MDC mRNA was weakly expressed in HaCaT cells, and upon stimulation with TNF-α or IFN-γ, MDC expression was strongly upregulated. The supernatant MDC levels when stimulated with TNF-α or IFN-γ were significantly higher than those without stimulation, and were synergistically increased when stimulated with a combination of TNF-α and IFN-γ. Both interleukin-4 (IL-4) and IL-13 inhibited TNF-α and IFN-γ enhanced MDC production in HaCaT cells in a dose-dependent manner. Conclusion: Th2-type cytokines IL-4 and IL-13 downregulate the production of MDC, a Th2 type chemokine, by KCs. This may partially contribute to maintaining Th1/Th2 balance in inflammatory skin diseases like atopic dermatitis. [Copyright &y& Elsevier]

This study presents an optimal rapid epithermal neutron activation analysis (ENAA) technique, using a 1 mm Cd filter in reactor neutron flux, to analyze 80Br and 128I in the roots, stems, and leaves of health food Angelica keiskei (AK). Various sample weights of lichen (IAEA-336) for each portion of AK, under various periods of irradiation and counting, were used to optimize the elemental analysis. Selecting the analytical conditions depends on the minimum detectable concentration (MDC), required sensitivities and the quantitative accuracy of Br and I elements. These findings imply that the MDCs of Br and I, measured under 10 min activation and 5 min counting followed by 10 min decaying, using 350 mg of lichen are ideal for elemental analysis. Moreover, each portions of AK were analyzed under optimal conditions. The elemental concentrations of Br, Cl, I, Mg, Mn and Na and their implications are discussed. [Copyright &y& Elsevier]

ADAM11 is the prototype member of the predominantly CNS-associated clade of the ADAM metalloprotease-disintegrins that has been implicated in neural adhesion and axon guidance. The present study describes the spatiotemporal expression pattern of the ADAM11 gene in adult and developing mouse, and identifies the cells expressing the gene. In the adult CNS, ADAM11 mRNA was present throughout the forebrain, including different cortical fields and diencephalic nuclei. In brainstem, low to moderate expression was detected in certain midbrain nuclei, while several pontine and medullary nuclei showed a very strong signal. High expression was observed in the cerebellar cortex and spinal cord. In addition, ADAM11 was expressed in ganglia of the peripheral nervous system (PNS), retinae, testes, liver, and at lower levels in epidermal and mucosal epithelia, kidney, and salivary gland. The expression was localized to neurons in all examined CNS and PNS subfields. During pre- and perinatal development, ADAM11 was differentially expressed both in the developing PNS and CNS, as well as in heart, kidney, eyes, and brown fat.The present results suggest a widespread involvement of ADAM11 in neuron–neuron or neuron–glial cell interactions during development as well as in the adult nervous system. They provide novel complementary information to recently accumulated data on CNS integrin gene expression and offer useful clues for further studies of the neural functions of ADAMs and integrins. [Copyright &y& Elsevier]

SUMMARY Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by the predominant infiltration of T cells, eosinophils and macrophages in lesional skin. Recently, macrophage-derived chemokine (MDC)/CCL22, a CC chemokine, was identified as a selective chemoattractant for CC chemokine receptor 4 (CCR4)-expressing cells, in addition to thymus and activation-regulated chemokine (TARC). We have previously reported that serum TARC levels correlate with the severity of AD. In this report, we investigated the participation of MDC in AD. First, we measured serum MDC levels in 45 patients with AD, 25 patients with psoriasis vulgaris and 25 healthy controls. Serum MDC levels in AD patients were significantly higher than those in healthy controls and psoriasis patients. Furthermore, the increases in serum MDC levels in AD patients were greater in the severely affected group than in the moderate or mild groups. We compared serum MDC levels in 11 AD patients, before and after treatment, and observed a significant decrease after treatment. Moreover, the serum MDC levels significantly correlated with the Scoring AD (SCORAD) index, serum soluble (s) E-selectin levels, serum soluble interleukin-2 receptor (sIL-2R) levels, serum TARC levels and eosinophil numbers in peripheral blood. Our study strongly suggests that serum MDC levels have a notable correlation with disease activity and that MDC, as well as the CC chemokine TARC, may be involved in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Cofilin-1 interacts with actin to regulate cell movement. The importance of cofilin-1 in immunity has been established, and its involvement in a number of autoimmune diseases has been confirmed. However, its role in severe aplastic anaemia (SAA) remains elusive. Thus, the aim of the current study was to investigate the role of cofilin-1 in patients with SAA. Flow cytometry, Western blotting and real-time quantitative reverse transcription-polymerase chain reaction were performed to detect the mRNA and protein expression of cofilin-1 in myeloid dendritic cells (mDCs) from patients with SAA. The expression of cofilin-1 was then suppressed via siRNA, and its effects on mDCs and downstream effector T-cell function were evaluated. Cofilin-1 expression was higher in mDCs from patients with SAA and correlated with routine blood and immune indexes. Moreover, cofilin-1 knockdown in mDCs from patients with SAA reduced their phagocytic capacity, migration capacity, and CD86 expression through F-actin remodelling, downregulating the stimulatory capacity of mDCs on CD4 + and CD8 + T lymphocytes. Collectively, these findings indicate that cofilin-1 participates in the hyperfunction of mDCs in patients with SAA and that the downregulation of cofilin-1 in mDCs from patients with SAA could be a novel treatment approach for SAA., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Purpose: To evaluate the longitudinal validity and responsiveness of the Persian version of Patient-Rated Tennis Elbow Evaluation (PRTEE) and the Disabilities of the Arm, Shoulder, and Hand (DASH) in patients with lateral elbow tendinopathy (LET)., Methods: Sixty-four patients with LET completed the PRTEE, DASH, and Global Rating of Change Scale (GRC) at baseline and six weeks. The external and internal responsiveness, floor and ceiling effects, minimal detectable change (MDC) and minimal clinically important difference (MCID) were calculated., Results: No ceiling and floor effects were detected for either the PRTEE or DASH. External responsiveness as an indicator to detect the relationship between change in the measured and external indicator of change was acceptable for both, but higher for the PRTEE (AUC = 0.90; CI: 0.83-0.97) vs. DASH (AUC = 0.80; CI: 69-90). Internal responsiveness to detect intervention related changes indicated slightly superiority in responsiveness for PRTEE. The relative efficiency (1.21), standard effect size (1.14 PRTEE vs. 1.03 DASH), and standard response mean (1.34 PRTEE vs. 1.10 DASH). The MDC were 11 and 12, and MCID were 20 and 18 for the PRTEE and DASH, respectively., Conclusions: Both the DASH and PRTEE were responsive in detecting improvement in patients with LET. The PRTEE was shorter, more efficient, and slightly more responsive which supports its use as a core outcome measure in evaluating patients with LET.Implications for RehabilitationThe Patient-Rated Tennis Elbow Evaluation (PRTEE) compared with the Disability of the Arm, Shoulder, and Hand (DASH) is a shorter questionnaire with higher psychometric and clinimetric properties for evaluating the patients with lateral elbow tendinopathy.This supports the use of the PRTEE in evaluating patients with elbow tendinopathy.

Pralsetinib (PRL) is a selective Rearranged during Transfection (RET) inhibitor, developed by Blueprint Medicines Corporation for the treatment of RET fusion non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), and medullary thyroid carcinoma (MTC). RET is a known proto-oncogene found in NSCLC, PTC, and MTC. PRL was recently granted accelerated USFDA approval with the brand name GAVRETO™ on 4 September 2020 to treat metastatic RET fusion-positive NSCLC and was updated on 1 December 2020 with the addition of advanced and metastatic RET-altered MTC and PTC in the USA. On 19 November 2021, the European Commission granted conditional marketing authorization to PRL for use as a single agent in adult patients with RET fusion-positive advanced NSCLC. They were not previously treated with an RET inhibitor. This review article summarizes the milestones in the development of PRL, chemistry, chemical (synthesis) research and development, characterization and identification of PRL-resistant RET mutants, the structural basis of resistance to PRL, mechanism of action, pharmacokinetics, pharmacodynamic, adverse effects, and regulatory status, including ongoing clinical trial of PRL and other potential drug candidates, leading to this first approval of PRL for the treatment of various solid tumors (RET fusion NSCLC, MTC, and PTC)., (© 2022. The Pharmaceutical Society of Korea.)

One way hash functions are an important cryptographic primitive, and can be used to solve a wide variety of problems involving authentication and integrity. It would be useful to adopt a standard one-way hash function for use in a wide variety of systems throughout the world. Such a standard one-way hash function should be easy to implement, use, and understand; resistant to cryptographic attack, and should be fast when implemented in software. We present a candidate one-way hash function which appears to have these desirable properties. Further analysis of its cryptographic security is required before it can be considered for widespread use. [ABSTRACT FROM AUTHOR]