Malignant melanoma and bone resorption

The cellular and humoral mechanisms accounting for osteolysis in skeletal metastases of malignant melanoma are uncertain. Osteoclasts, the specialised multinucleated cells that carry out bone resorption, are derived from monocyte/macrophage precursors. We isolated tumour-associated macrophages (TAMs) from metastatic (lymph node/skin) melanomas and cultured them in the presence and absence of osteoclastogenic cytokines and growth factors. The effect of tumour-derived fibroblasts and melanoma cells on osteoclast formation and resorption was also analysed. Melanoma TAMs (CD14+/CD51−) differentiated into osteoclasts (CD14−/CD51+) in the presence of receptor activator for nuclear factor κB ligand (RANKL) and macrophage-colony stimulating factor. Tumour-associated macrophage-osteoclast differentiation also occurred via a RANKL-independent pathway when TAMs were cultured with tumour necrosis factor-α and interleukin (IL)-1α. RT–PCR showed that fibroblasts isolated from metastatic melanomas expressed RANKL messenger RNA and the conditioned medium of cultured melanoma fibroblasts was found to be capable of inducing osteoclast formation in the absence of RANKL; this effect was inhibited by the addition of osteoprotegerin (OPG). We also found that cultured human SK-Mel-29 melanoma cells produce a soluble factor that induces osteoclast differentiation; this effect was not inhibited by OPG. Our findings indicate that TAMs in metastatic melanomas can differentiate into osteoclasts and that melanoma fibroblasts and melanoma tumour cells can induce osteoclast formation by RANKL-dependent and RANKL-independent mechanisms, respectively

The economic costs of alcohol consumption in Thailand, 2006

<p>Abstract</p> <p>Background</p> <p>There is evidence that the adverse consequences of alcohol impose a substantial economic burden on societies worldwide. Given the lack of generalizability of study results across different settings, many attempts have been made to estimate the economic costs of alcohol for various settings; however, these have mostly been confined to industrialized countries. To our knowledge, there are a very limited number of well-designed studies which estimate the economic costs of alcohol consumption in developing countries, including Thailand. Therefore, this study aims to estimate these economic costs, in Thailand, 2006.</p> <p>Methods</p> <p>This is a prevalence-based, cost-of-illness study. The estimated costs in this study included both direct and indirect costs. Direct costs included health care costs, costs of law enforcement, and costs of property damage due to road-traffic accidents. Indirect costs included costs of productivity loss due to premature mortality, and costs of reduced productivity due to absenteeism and presenteeism (reduced on-the-job productivity).</p> <p>Results</p> <p>The total economic cost of alcohol consumption in Thailand in 2006 was estimated at 156,105.4 million baht (9,627 million US$PPP) or about 1.99$ PPP), followed by cost of productivity loss due to reduced productivity (45,464.6 million baht/2,804 million US$PPP), health care cost (5,491.2 million baht/339 million US$ PPP), cost of property damage as a result of road traffic accidents (779.4 million baht/48 million US$PPP), and cost of law enforcement (242.4 million baht/15 million US$ PPP), respectively. The results from the sensitivity analysis revealed that the cost ranges from 115,160.4 million baht to 214,053.0 million baht (7,102.1 - 13,201 million US$ PPP) depending on the methods and assumptions employed.</p> <p>Conclusions</p> <p>Alcohol imposes a substantial economic burden on Thai society, and according to these findings, the Thai government needs to pay significantly more attention to implementing more effective alcohol policies/interventions in order to reduce the negative consequences associated with alcohol.</p

Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases

Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with HLA region polymorphisms. To determine if associations can be explained by classical HLA determinants we studied Italian 676 cases and 1440 controls with genotyped with dense single nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (p = 1.59 × 10(−11)) was the strongest predisposing allele where as DRB1*11 (p = 1.42 × 10(−10)) was protective. Additionally DRB1*14 and the DPB1 association (DPB1*03:01) (p = 9.18 × 10(−7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC

Impact of comorbid conditions on asthmatic adults and children

Comorbid conditions (comorbidities) can complicate the diagnosis and management of asthma. In different age groups, comorbid conditions can present varying challenges, including diagnostic confusion due to mimicking asthma symptoms, exacerbation of asthma symptoms, therapy for comorbid conditions affecting asthma or therapy for asthma affecting these conditions. This review aims to summarise some common comorbid conditions with asthma, such as rhinitis, vocal cord dysfunction, gastro-oesophageal reflux, psychiatric disorders, obesity and obstructive sleep apnoea, and discuss their prevalence, symptoms, diagnosis and treatment, highlighting any differences in how they impact children and adults. Overall, there is a lack of data on the impact of treating comorbid conditions on asthma outcomes and further studies are needed to guide age-appropriate asthma management in the presence of these conditions.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.A.K. reports personal fees from AstraZeneca, Behring, Boehringer Ingelheim, GlaxoSmithKline, Griffols, Teva, Novartis, Novo Nordisk, Paladdin, Pfizer, Purdue, Sanofi and Trudel, outside the submitted work. D.M.G.H. reports personal fees from AstraZeneca, Chiesi and Pfizer and grants and personal fees from Boehringer Ingelheim, GlaxoSmithKline and Novartis, outside the submitted work. S.J.S. reports fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Propeller Health, Regeneron and Sanofi, outside the submitted work all paid to the University of Colorado School of Medicinepublished version, accepted version, submitted versio

Transit Heimat: Translation, Transnational Subjectivity and Mobility in German Theatre

Deposited with permission of Transit.This paper is interested in themes of translation, transnational subjectivity and mobility in German theatre between 1994 and 2004. It is set within the broader context of the expansion of Europeanisation that followed German reunification and the lifting of the Iron Curtain in central and eastern Europe. It is therefore especially concerned with theatre that responds to the issues that arise with the opening of Europe’s eastern borders and the tensions associated with increased cross-border movement.Some of the developing tensions will involve the changed status of nations in post-communist Europe, the future of national identity and culture and the formation of transnational or post-national subjectivities. Anna Langhoff’s 1994 Transit Heimat/gedeckte tische is the primary example used in this paper. It is a play about central and eastern European refugees written and performed in the critical early years of reunification that brings an early example of the changing face of Europe to the German stage. It is the little-known but important precedent for later more boisterous German-language treatments of the theme of refugees and xenophobia such as Christoph Schlingensief’s provocative Bitte Liebt Österreich (Vienna, 2000). Foreign subjects also find their counterparts in Heiner Müller’s posthumously performed Germania 3 Ghosts at Dead Man (Berlin 1996) and Germania Stücke (2004). The paper argues that these theatrical and performance pieces represent the downside of transnational or post-national subjectivities as experienced by the new Europe’s poor and powerless. In danger of falling into an underclass of stateless and itinerant welfare recipients, the characters display the trauma of the transition from the old communist regimes to the neoliberal economies of western Europe. It concludes that the play offers a timely reflection on the state of foreignness showing it as a transnational subjectivity produced by entrenched nationalist perspectives