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Review ARTICLE
HSP: bystander antigen in atopic diseases?
- 1 Department of Pediatric Immunology, Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands
- 2 Pediatric Intensive Care Unit, Sophia Children's Hospital, Rotterdam, Netherlands
Over the last years insight in the complex interactions between innate and adaptive immunity in the regulation of an inflammatory response has increased enormously. This has revived the interest in stress proteins; proteins that are expressed during cell stress. As these proteins can attract and trigger an immunological response they can act as important mediators in this interaction. In this respect, of special interest are proteins that may act as modulators of both innate and adaptive immunity. Heat shock proteins (HSPs) are stress proteins that have these, and more, characteristics. More than two decades of studies on HSPs has revealed that they are part of intrinsic, "natural" mechanisms that steer inflammation. This has provoked comprehensive explorations of the role of HSPs in various human inflammatory diseases. Most studies have focused on classical autoimmune diseases. This has led to the development of clinical studies with HSPs that have shown promise in Phase II/III clinical trials. Remarkably, only very little is yet known of the role of HSPs in atopic diseases. In allergic disease a number of studies have investigated the possibility that allergen-specific regulatory T cell (Treg) function is defective in individuals with allergic diseases. This raises the question whether methods can be identified to improve the Treg repertoire. Studies from other inflammatory diseases have suggested HSPs may have such a beneficial effect on the T cell repertoire. Based on the immune mechanisms of atopic diseases, in this review we will argue that, as in other human inflammatory conditions, understanding immunity to HSPs is likely also relevant for atopic diseases. Specifically, we will discuss why certain HSPs such as HSP60 connect the immune response to environmental antigens with regulation of the inflammatory response. Thus they provide a molecular link that may eventually even help to better understand the immune pathological basis of the hygiene hypothesis.
Over the last years insight in the complex interactions between innate and adaptive immunity in the regulation of an inflammatory response has increased enormously. This has revived the interest in stress proteins; proteins that are expressed during cell stress. As these proteins can attract and trigger an immunological response they can act as important mediators in this interaction. In this respect, of special interest are proteins that may act as modulators of both innate and adaptive immunity. Heat shock proteins (HSPs) are stress proteins that have these, and more, characteristics. More than two decades of studies on HSPs has revealed that they are part of intrinsic, "natural" mechanisms that steer an inflammatory response (Pockley, 2003; van Eden et al., 2005). This has provoked comprehensive explorations of the role of HSPs in various human inflammatory diseases. Most of these studies have focused on classical autoimmune diseases such as type I diabetes (IDDM), rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA; Abulafia-Lapid et al., 1999; de Kleer et al., 2003, 2004). This has led to the development of clinical studies with HSPs that have shown promise in Phase II/III clinical trials in both IDDM and RA (Albani et al., 1995a; Raz et al., 2001; Prakken et al., 2004).
Remarkably, only very little is yet known of the role of HSPs in atopic diseases. Based on the immune mechanisms of atopic diseases, in this review we will argue that, as in other human inflammatory conditions, understanding immunity to HSPs is likely also relevant for atopic diseases. Specifically, we will discuss why certain HSPs such as HSP60 connect the immune response to environmental antigens with regulation of the inflammatory response. Thus, they provide a molecular link that may eventually even help to better understand the immune pathological basis of the hygiene hypothesis: an important concept relating the increase in the prevalence of atopic disease with exposure to microbes or microbial products early in life.
Atopy is the predisposition to develop allergic diseases like atopic dermatitis, food allergy, asthma, and allergic rhinitis. It is characterized by a predominant typical T helper 2 (Th2)-like immune response (Umetsu et al., 2003). Firstly, an environmental allergen, like an inhalant or food allergen interacts with the innate immune system. After uptake by antigen-presenting cells, subsequent T cell priming leads to the stimulation of type 2 cytokines such as interleukin (IL)-4, IL-5, and IL-13. These cytokines interact with their receptors to induce a class switch toward IgE production and to increase the number of eosinophils and mast cells. In immediate hypersensitivity reactions IgE binds to its receptors and causes mast cells to degranulate. Apart from IgE, increased levels of IgG4 are often measured in allergic individuals. IgG4 is considered as an antibody with anti-inflammatory activity (van der Neut et al., 2007). The levels of IgG4 are usually elevated in serum from people that are repeatedly exposed to the same antigen, like beekeepers, or subjects receiving increased doses of antigen during specific immune therapy (SIT). In addition to this humoral immune response, allergy is characterized by a cellular response, mostly mediated by Th2 cells (Del Prete, 1992; Ozdemir et al., 2010), but also by Th1 cells (like in atopic dermatitis) and regulatory T cells.
The combination of these humoral and cellular responses, both innate and adaptive, leads to an allergic inflammatory reaction (Yazdanbakhsh et al., 2002). Here we will discuss various aspects of the allergic immune responses in the context of the possible role of environmental antigens such as HSPs in steering this immune response.
Allergy and the Hygiene Hypothesis
The prevalence of atopic disease has increased tremendously in the second half of the twentieth century (Peat et al., 1994). Although the cause of this increase is not known though, a genetic cause is unlikely due to the time span in which the increase took place. Therefore environmental changes are more likely causes of this observed increase. Strachan (1989) first proposed the concept of the hygiene hypothesis. This hypothesis states that the increase in the prevalence of atopic disease is due to a decreased exposure to microbes or microbial products early in life, especially in western societies. The concept was supported by the observation of an inverse association between both atopic dermatitis and hay fever and the number of children in a household. Although the hygiene hypothesis and its proposed immune mechanism are still under debate, in the 1990s numerous of studies have been published supporting this hypothesis. For example, these observations relate the number of siblings, the number of infections and exposure to endotoxins on the farm, with the incidence of atopic diseases (Jarvis et al., 1997; Bodner et al., 1998; von Mutius et al., 1999; Wickens et al., 1999; Braun-Fahrlander et al., 2002).
Immune Mechanisms of the Hygiene Hypothesis
What could be the immunological cause of this inverse relation between exposure to environmental antigens and the incidence of allergic disease? The explanation takes us back to the original observations in the eighties of Mosmann and Coffman who defined two main subtypes of helper T lymphocytes: Th1 and Th2 cells. Th2 cells are characterized by their production of cytokines like IL-4, IL-5, IL-9, and IL-13 and chemokines like TARC and MDC. They are involved in mediating allergic responses and host defense against parasitic infection (Mosmann and Coffman, 1989).
During fetal life and shortly after birth a predominant Th2 response is present (Wegmann et al., 1993). During life, a shift to a predominant Th1 response occurs in non-allergic subjects, but this shift may be incomplete in allergic individuals. As a consequence, an allergic individual will develop a Th2 response to an allergen leading to IgE production and typical type 2 cytokine production (IL-4, IL-5, and IL-13) and ultimately to a clinical allergic reaction, whereas non-allergic subjects develop a Th1 response leading to a protective IgG response and production of IFN-γ (Larche, 2007). This is the basis for the immunological explanation of the hygiene hypothesis, as exposure to microbes and microbial products would stimulate a Th1 response. Those individuals that were not enough exposed to these stress factors would be more prone to develop predominant Th2 responses, and thus an allergic response. Obviously this is still a simplification of the immune pathogenesis that does not explain all observations. For example, a Th1 response in allergic individuals would implicate the development of late hypersensitivity responses, whereas healthy individuals do not respond to allergens with a clinically noticeable response (Chen et al., 2004).
The hygiene hypothesis also does not explain why not only the incidence of allergic diseases is increasing but also that of auto immune diseases like RA and IDDM (Sheikh et al., 2003). These diseases are obviously known as typical Th1-like diseases.
Triggering an Allergic Immune Response
In order to fully assess and better appreciate the value of the hygiene hypothesis it is important to understand which cells are responsible for the initial trigger leading to the characteristic allergic immune response. First, naive T cells have to be activated, in a way that promotes the classical Th2 like response. There is recent evidence that basophils may play a crucial role in antigen recognition and processing. When recruited to lymph nodes they are able to induce Th2 cell differentiation through the release of IL-4 (Sokol et al., 2009; Falcone et al., 2011). Other cells also have the capacity to process and present allergens, including mast cells, macrophages, eosinophils, and natural helper cells. Natural helper cells are innate cell populations that include innate Th2 cells and are activated by IL-25 and IL-33 to secrete Th2 cytokines (Saenz et al., 2010).
There is an increasing realization that Th2 cells are not the only cells involved in the pathophysiology of allergic disease, as particularly in severe disease other cells than Th2 play a role in aggravating and perpetuating the immune response (Table 1; Lloyd and Hessel, 2010).
First of all, whereas Th2 cytokines have a clear role in initiating an allergic response, especially Th1 cells have been implicated in more chronic severe allergic disease, both in atopic dermatitis and allergic asthma (Krug et al., 1996; Ong and Leung, 2006; Yamanaka and Mizutani, 2011).
Secondly, in addition to the Th2 cytokines IL-4, IL-5, and IL-13, recently also IL-9 was shown to play an important role in asthma. At first IL-9 was discussed as a new Th2 cytokine. It was shown that Th9 cells are dependent on both IL-4 and transforming growth factor-beta (TGF-β) for their development. Interestingly, like Th2 cells, also Th9 cells are regulated by IL-25, predominantly seen in lung inflammation (Devos et al., 2006; Hauber et al., 2007; Soroosh and Doherty, 2009; Angkasekwinai et al., 2010). IL-25 (like IL-33 and thymic stromal lymphopoietin) is a type II initiating cytokine (Oliphant et al., 2011). In addition to the role of IL-25 in lung inflammation, it is also of importance in atopic dermatitis and food allergy (Aalberse et al. unpublished data; Hvid et al., 2011). Although IL-25 (also known as IL-17E) is a cytokine from the IL-17 family it has opposite effects of IL17A (IL-17).
Thirdly, Th17 cells (named after their main effector cytokine; IL-17) like Th1 cells may be associated with more severe asthma and mediate a more neutrophilic pattern of inflammation.
Fourthly, it was recently shown that IL-22 (also produced by Th17 cells), is produced by a distinct set of CD4+ cells, named Th22-cells. These cells have been implicated as being protective in a mouse model of allergic lung inflammation (Souwer et al., 2010) and may play a role in the severity of atopic dermatitis in humans (Nograles et al., 2009).
Finally, a lot of attention has recently focused on a subset of T cells with the capacity to suppress other T cells, namely regulatory T cells (Treg). Two types of regulatory T cells will be discussed below, namely IL-10 producing regulatory cells and FOXP3 expressing regulatory cells.
Regulatory T Cells
Here we will discuss two types of regulatory T cells; FOXP3 expressing Tregs and IL-10 producing regulatory T cells. However, it has to be emphasized that the distinction between these two types is not absolute, as for example FOXP3 expressing Tregs are also capable of producing IL-10. Moreover, many different regulatory T cells, may even act in concert in a single immune response.
IL-10 Producing Regulatory T Cells
As discussed above, exposure to an allergen leads to the development of sensitization in a susceptible individual. Upon a next encounter, a typical Th2 reaction will follow, including a humoral (IgE and IgG4) response. In contrast, when healthy (non-allergic) individuals are exposed to an allergen it was long thought that (in line with the Th1/Th2 dichotomy) instead of a Th2 response a Th1 response would develop. However it has become clear that, in fact, this is not the only difference between a normal and an allergic response to an allergen. Though indeed some IFN-γ responses to allergens are present in healthy individuals, a study by Akdis et al. (2004) showed that this is a simplification of the reality. They isolated CD4 T cells specific to several food- and aeroallergens from healthy and allergic individuals according to their IL-4, IFN-γ, and IL-10 secretion profile. Interestingly, allergen-specific T cells that belong to all three secretion profiles were detectable in both healthy and allergic individuals, with allergen-specific IL-10-secreting T cells being the predominant subset in healthy individuals. They regarded these IL-10 producing CD4+ T cells as T regulatory cell type 1 (Tr1 cells). Seemingly, low Tr1 numbers and high Th2 cell numbers resulted in an allergic response, whereas in healthy individuals a mixed Th1/Th2 response is associated with a strong IL-10 response (Larche, 2007). The crucial role for IL-10 in allergy is also suggested by other studies on food and inhalant allergies. In cow's milk allergy, T-cell clones derived from children that are persistently allergic produced Th2 cytokines (IL-4, IL-13), whereas allergic control subjects that are cow milk tolerant produced a mixed Th1/Th2 response associated with markedly elevated IL-10 levels (Tiemessen et al., 2004).
Similar observations of elevated IL-10 levels associated with less allergy symptoms were made in inhalation allergies. Children raised in a house with a cat are less likely to become allergic to cat allergen than those who only get indirect exposure. Many of these highly exposed children had an IgG and IgG4 response to the major cat allergen Fel d 1 without production of specific IgE. This induction of high levels of allergen-specific IgG4 in the relative absence of IgE has been referred to as a modified Th2 response (Platts-Mills et al., 2004). Interestingly also in the peripheral blood of these non-allergic children, T cell response to the allergens are characterized by an elevated level of IL-10. Comparable indications for a role for IL-10-producing Tr1 cells in the maintenance of tolerance to allergens can be found in individuals exposed to relatively high doses of allergen like bee keepers and allergic patients undergoing immunotherapy. Bee keepers with a repeated exposure to bee venom during the bee-keeping season demonstrate a marked increase in allergen-specific IL-10 secretion from peripheral blood T cells as the season progresses, while allergen-specific IgE is seen especially in the beginning of the season. Interestingly, reactions to stings disappear during the season, simultaneously with the increased IL-10 production by T-cells (Akdis and Blaser, 1999). Apart from IL-10, also TGF-β, another cytokine that can be produced by Tr1 cells, is reported to be induced by SIT, while both IL-10 and TGF-β are associated respectively with the blocking antibodies IgG4 and IgA (Larche et al., 2006; Taylor et al., 2006).
FOXP3 Regulatory T Cells
Not only IL-10 producing T cells but also FOXP3+ Tregare associated with an allergic response. The important role of the transcription factor FOXP3 for maintaining immune tolerance stems for multiple basic studies, mainly in experimental models. This importance of FOXP3+ Treg in human disease was underscored by the IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, X-linked). In IPEX patients a genetic mutation causes the FOXP3 transcription factor to be defective. Patients with IPEX have symptoms that fit both generalized autoimmunity and allergy (Bennett et al., 2001; Patel, 2001). The relevance of FOX P3 Treg has been extensively demonstrated in mice models, showing an inverse correlation to Treg and diseases like RA, inflammatory bowel disease, MS, and IDDM (Shevach, 2000; Fontenot et al., 2003; Sakaguchi, 2005). Not only in autoimmune diseases but also in allergic disease various studies have suggested a possible defective suppressive function of Tregs (Viglietta et al., 2004; Sakaguchi et al., 2006). In addition to the bee keeper model also the season-dependent antigen exposure during the pollen season offers a model to study responses in the same individuals with and without exposure. Whereas in several studies it was shown that both non-allergic as allergic individuals have CD4+CD25+ Treg, in the allergic subjects, these cells still produced IL-5 and IL-13 cytokines (Grindebacke et al., 2004; Ling et al., 2004). Further related experiments demonstrated that both dose and type of allergen appear to have effects on the ability of CD4+CD25+ T cells to suppress responses. At the time of these studies CD25b expression on CD4 T cells was used as a surrogate marker of FOXP3+ Treg. Later studies using FOXP3 as a direct marker seemed to confirm these data. During venom immunotherapy the increased allergen-specific IgG4 and reduced IgE correlated with circulating FOXP3 positive Treg (Pereira-Santos et al., 2008). A recent study even suggested that Treg function may be impaired in patients with allergic diseases and that this function can be enhanced by specific immunotherapy (Palomares et al., 2010).
Thus, altogether, there are ample suggestions that the presence of allergen-specific T cells with a regulatory phenotype (either expressing FOXP3, and/or capable of producing IL-10 and TGF-β) may have a beneficial effect on allergic diseases. However in some atopic diseases, like atopic dermatitis and asthma, the specific trigger is often not known. This raises the question whether methods can be identified to improve the Treg repertoire, when the triggering allergen is unknown. Studies from other inflammatory diseases, like JIA and RA, have suggested that a certain group of antigens, called HSPs, are present at the site of inflammation and may have such a beneficial effect on the T cell repertoire.
Heat Shock Proteins
The Treg repertoire is both formed in the thymus (so-called natural Treg) and generated in the periphery upon encounter with an antigen (induced or adaptive Treg). Both self and non-self antigens can induce Treg in the periphery, although the repertoire of Treg might be biased toward self antigens (Romagnoli et al., 2002).
In 1991, Cohen and Young (1991) proposed that a select group of self antigens is especially important for the maintenance of peripheral tolerance). He described the presence of auto reactive immune responses in a healthy individual to a limited set of self molecules, formed by auto reactive T cells and antibodies, which he called the immunological homunculus. The self antigens of this "homunculus" are all evolutionary highly conserved between the self and the non-self homolog of these proteins. According to Cohen, the immune system utilizes these self antigens to form an immunological picture of self which is crucial for the balance of the immune system. One of these homunculus' self proteins is human HSP60 (van Eden et al., 2005). HSPs are indeed evolutionarily highly conserved proteins and either present constitutively, functioning as chaperones, or induced upon cell stress caused by, for instance, heat, oxidative stress, and hypoxia (Craig et al., 1993). Several HSPs have been identified and, according to their size, organized into six families: HSP100, HSP90, HSP70, HSP60, HSP40, and HSP10. In this review we focus on the immune responses of HSP60 in atopic disease. It has to be stressed that as only very little data are available right now on HSPs and allergic disease, and thus we need to deduce the role of HSP in atopic disorders mostly on what is known about HSP reactivity on other diseases.
Immunity to HSPs and Inflammation
Humoral and cellular immune responses to HSP60 have been detected both in patients with an inflammatory disease, such as autoimmune and allergic diseases, as well as in healthy subjects. After these initial discoveries the perception was that HSP's may be involved in the development of autoimmunity through antigenis mimicry: an immune response toward a microbial HSP could lead to a cross-reactive response to a self-HSP and thus cause autoimmunity. However, after further studies it quickly became clear that the immune responses toward self HSP60 were more involved in the regulation and not in the induction of autoimmunity. Indeed, a wealth of data obtained in the last decade both in experimental models and from observations in human diseases point to a regulatory role of immunity to self HSP60 (van Eden et al., 2005).
The presence of self-HSP-reactive cells was first shown in animal studies by immunization of rats with mammalian HSP60 (Lopez-Guerrero et al., 1993). Though immunization could induce self-HSP-specific antibodies and T cells, a self-HSP-reactive immune repertoire was also shown to be present in the absence of immunization. The cause for this could be previous contact with homologous bacterial HSPs, for example in the mucosa of the gastro intestinal tract. The first report that immune responses to self HSP60 may have a regulatory role in inflammatory diseases was in mycobacteria-induced adjuvant arthritis. In this model the induction of a self HSP60, cross-reactive T cells response was responsible for the observed protection of HSP60 peptide immune therapy. After these initial findings, protective effects of various (conserved) microbial HSPs were seen in many other experimental disease models, including arthritis, atherosclerosis, allergic encephalomyelitis, and allergic asthma (Anderton et al., 1995; Birnbaum et al., 1998; Harats et al., 2002; Rha et al., 2002).
In vitro experiments show that immune responses modulated by HSPs can result in the induction of various cytokines like IFNγ and TNFα, as well as IL-10. HSPs are strong immune modulators and are able to influence the impact and direction of immune responses (Kaufmann et al., 1987). Moreover, HSP60 has the capacity to steer both innate and humoral immunity.
In human diseases, antibody responses to HSP60 were previously described in skin lesions of patients with Behçets disease, whereas HSP60 has been described as a target for T-cells in autoimmune diseases such as IDDM and JIA (Albani et al., 1995b; Ergun et al., 2001; Raz et al., 2001). Data in the experimental models have pointed out that the protective effect of HSP60 was independent of an antigenic relationship (antigen mimicry) between HSP60 and the disease-inducing antigen. Instead it seemed that HSP60 could confer protection through so-called bystander suppression (Horner et al., 2001; Larche et al., 2006). Inflammation causes local damage and cell stress leading to upregulation of stress proteins such as HSP60. Next, these bystander (self) antigens can become the target of subsequent, possibly suppressive immune responses. So, it is possible that immune responses to HSPs could be involved in the control of human chronic inflammatory diseases that have distinct, although as-yet-unknown, initiating auto-antigens, or even allergens.
HSP Responses in Early Life
Apparently, responses to HSP60 are important for maintaining peripheral tolerance in the adult immune system. It is unknown when during live these specific T cells arise. It would seem reasonable to expect that they are primed after birth upon encounter with homologous microbial HSP in the gut. However, there are indications that self HSP60 reactivity is present at birth. In a study by Ramage et al. (1999) it was shown that cord blood cells proliferate in response to an in vitro challenge with the self HSP60. This supported the hypothesis that this reactivity is part of the normal naive immune repertoire. A more recent study by Merbl et al. (2007) put these findings also in a different perspective. They found that normal cord blood contains IgM and IgA auto-antibodies directed against a relatively uniform set of auto-antigens, such as auto-antigens related to immune regulation such as HSP60. This obviously benign autoimmune self reactivity, present at birth, may have a dual function. On the one hand it may provide the basis for autoimmunity in later life, while on the other hand the "inborn" autoimmunity to regulatory self antigens such as HSP60 may actually serve to protect against autoimmune disease. Intrigued by these studies, we questioned whether CD4+ T cells specific for HSP60 are already detectable at birth before exposure to the microbial flora, and if so, to what type of immune response these "inborn" autoreactive CD4+ T cells have upon exposure to the self antigen HSP60. We found that HSP60 specific T cells are indeed present at birth. Moreover, stimulation of CBMC with HSP60 leads to CD4+ T cell proliferation and cytokine production, and induces T cells with an in vitro regulatory phenotype that are functionally suppressive (Aalberse et al., 2011).
HSP60 and Allergy
Thus, HSP60 is a self-protein, recognized already at birth in healthy subjects, but also in individuals with chronic inflammatory diseases. Thereby a correlation between self-HSP reactivity and diminished disease activity is seen both in experimental as in human autoimmunity. This has already led to the successful exploration of HSP60 immune therapy in human disease, firstly in IDDM. It is not known yet if the levels and responses to HSP60 are different in individuals developing chronic inflammatory disease later in life.
For once, priming of HSP60 T cell responsiveness takes places primarily in the gut through contact with microbial HSP60 (van Eden et al., 2005). Thus, priming of HSP60 immunity early in life through contact with microbiota leads to more self HSP60 mediated immune regulation. This could be one of possibly multiple mechanisms that explain why individuals exposed to more microbial triggers early in life, could be less prone to develop immune mediated diseases. Thus it may very well fit the concept of the hygiene hypothesis.
For that reason we set out to study the role of HSP60 immunity in human atopic diseases. Obviously the first pre-requisite for a potential role of self HSP60 in dermatitis is the (preferably increased) expression of HSP60 at the site of inflammation. Indeed we were able to show that self HSP60 is increased expressed in the skin of patients with atopic dermatitis (Kapitein and Aalberse submitted for publication). Moreover, in vitro stimulation with self HSP60 induced FOXP3 positive T cells, as well as T cells producing IL-10 and IFN-γ.
It has to be emphasized that this increased expression by no means is very specific for atopic diseases (Seung et al., 2007). Still it could be highly relevant for atopic disease as the characterization of an antigen present at the site of inflammation, without being the disease-causing antigen has therapeutic possibilities through, as previously mentioned, "antigen driven bystander suppression." Bystander suppression as a mechanism is especially important in human autoimmune diseases, because often the immunizing trigger is unknown.
Theoretically, in allergic diseases this could also be an interesting option for intervention. Although often at least one of the allergens triggering the disease is known, mono-sensitization is rare which would imply multi-antigen immune therapy. Immune therapy with a single bystander antigen might undermine this issue.
Novel Immune Therapeutic Possibilities in Allergic Disease
Various novel immune therapeutic approaches to diminish allergic symptoms have been or are being studied. Of these new interventions, blocking of effector cytokines (such as IL-4 and IL-5) and IgEis the most important. As IL-5 is important for the priming and survival of eosinophils and these cells play an important role in the pathophysiology of allergic disease, blocking IL-5 seemed logical. However only a highly selected patient group with severe asthma, shown as sputum eosinophilia, had profit from this therapy (Busse et al., 2010). Also blocking IL-4 and IL-13 has not yet been shown to be of clinical benefit in asthma (Oh et al., 2010). Thus, so far, the experiences with blocking antibodies to effector cytokines suggest that either the cytokines cannot be fully blocked or that not one of these cytokines is solely responsible for the allergic response. As mentioned above in recent years Th2 induction cytokines have been described among which IL-25. IL-25 is strongly elevated in a subgroup of peanut allergic subjects (Aalberse et al., submitted for publication). Moreover, in mouse models blocking IL-25 has a positive effect on bronchial hyper-reactivity (Ballantyne et al., 2007). Apart from blocking cytokines that are important in the pathophysiology of allergic disease, in the last decade various studies in asthmatic patients have been performed in which an IgE-blocker was used (Rodrigo et al., 2011). Although the first results look promising, the effect is not present in all patients, underlining again the complexity of chronic allergic diseases.
Antigen SIT, in which an allergic individual is exposed to increasing doses of the allergen triggering disease, has been used for over a century. It is one of the earliest and most effective forms of human immune therapy. Although for long the mechanisms behind this clearly effective immune intervention was not fully understood, we now know that IgG4, IL-10, and Treg probably play an important role. A disadvantage of this approach in which the eliciting protein is used, is the chance of a severe anaphylactic reaction, as has been described following immune therapy in peanut allergic subjects (Reid et al., 1993).
To tackle this issue, recent work has focused on allergy peptide therapy, showing good results. Mice studies showed that after immunization with Der p 2, the house dust mite allergen, downregulation of T cell and antibody responses was seen to Der p 2. Similar results were seen using Fel d 1 (cat allergen) and Bet v 1 (birch allergen) peptide therapy. As most patients are not sensitized to just one allergen, it is now studied if combination immune therapy is also effective. Another approach is the use of a peptide of an antigen present at the site of inflammation, without being the triggering antigen. This is the concept of the previous mentioned antigen bystander suppression model (Horner et al., 2001; Larche et al., 2006).
Based on the development of immune therapies usingHSP60 for other human inflammatory diseases and encouraged by recent data showing that HSP60 expression is increased in the skin in patients with atopic dermatitis, it is tempting to suggest that HSP60 may also be a potential candidate for bystander therapy in allergic diseases.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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de Kleer, I. M., Wedderburn, L. R., Taams, L. S., Patel, A., Varsani, H., Klein, M., de Jager, W., Pugayung, G., Giannoni, F., Rijkers, G., Albani, S., Kuis, W., and Prakken, B. (2004). CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J. Immunol. 172, 6435–6443.
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Keywords: allergic disease, atopic disease, stress proteins, heat shock protein, HSP60, regulatory T cells, hygiene hypothesis, inflammation
Citation: Aalberse JA, Prakken BJ and Kapitein B (2012) HSP: bystander antigen in atopic diseases? Front. Immun. 3:139. doi: 10.3389/fimmu.2012.00139
Received: 19 January 2012; Paper pending published: 16 February 2012;
Accepted: 14 May 2012; Published online: 31 May 2012.
Edited by:Willem Van Eden, Utrecht University, Netherlands
Reviewed by:Miriam Wittmann, University of Leeds, UK
Cristina Bonorino, Pontificia Universidade Catolica do Rio Grande do Sul, Brazil
Copyright: © 2012 Aalberse, Prakken and Kapitein. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
*Correspondence: Joost A. Aalberse and Berent J. Prakken, Wilhelmina Children´s Hospital, University Medical Centre, Department of Pediatric Immunology, Center for Molecular and Cellular Intervention, Eureka Institute for Translational Medicine, KC.03.063.0, PO Box 85090, Utrecht, The Netherlands. e-mail: firstname.lastname@example.com; email@example.com


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As we get towards golden days, we need to get our flexibility back. Especially when we are dealing with arthritis. It is a very difficult condition to handle, that's why some movement should relax the body. The appropriate moves should incorporate breathing exercises, stretches, and relaxation. Personally, I think that chair-based yoga is a perfect therapeutic way to handle the symptoms without drugs and other medical intervention.
Thus, I have for you 6 relaxing chair-based yoga poses for seniors with arthritis you should try right away!
1. Cat/Cow Stretch Pose
Image Credits: Cat/Cow Pose
Start by sitting near the front of the chair seat;
Place your feet at a hip distance apart;
Put them firmly under your knees;
Straighten your arms;
Place your hands on or near your knees;
Before moving into the pose, establish the lift of your spine, from your sitting bones through the crown of your head;
While inhaling, start moving from your pelvis, rocking your hips forward;
As you continue to inhale, gently lift your spine and lengthen into a gentle backbend;
Lift your breastbone forward and up and allow your head and neck to lengthen out and back;
Hold the pose for 2 breaths every time you switch.
2. Seated Boat Pose
Image Credits: Seated Boat Pose
Start the pose from a seated position on your chair;
Place your hands behind your hips;
Try to lift up your chest towards the ceiling, keeping your back flat;
Bring your legs straight up into the air by raising your feet slowly off the floor;
You should have a 45-degree angle between your thighs and the floor;
Keep your spine stiff and raise one arm extended over your head.
Continue to inhale slowly, holding the pose for 2 breaths;
Repeat the same movement for the other leg and arm.
3. Half-Locust Pose
Image Credits: Half-Locust Pose
Start by sitting on the edge of the chair.
Place the right arm long alongside the right ear with the left arm next to the left side of the body;
Inhale as you press your hips and pelvis lifting all extremities;
Make sure that you keep both hips on the chair rooting the tailbone down;
Lengthen from the core of the pelvis out through the inseam of the leg which should be straight but not locked;
While lifting, elongate from the low belly upward through the crown of the head.
Repeat on each side and hold the pose for 3 breath.
4. Forward Bend Pose
Image Credits: Forward Bend Pose
Start by sitting in the center of the chair;
Place your feet flat on the floor and about hip-width apart;
Position your knees directly above your feet, with your legs parallel to each other;
Tip forward from your hip joints, keeping your back as straight as possible;
Place your hands right under the chair, between your legs;
Hold this pose for 3 breath then gently lift your torso to the original position.
5. Bridge Pose
Image Credits: Bridge Pose
Start by sitting on the center of the chair;
Place your arms on the sides of the chair;
Exhale as you lengthen your spine and gently press with your arms;
Inhale as you press your feet into the floor and slowly lift your pelvis off the chair as high as possible;
While exhaling, come out of the pose and back to the original position;
Hold the pose for 3 breath before switching.
6. Raised Triangle Pose
Image Credits: Raised Triangle Pose
Start by sitting on the center of the chair;
Inhale as you raise your arms up to shoulder height;
Shift your hips right over the front extended leg extending the upper body;
Place the right hand into the hip cradle releasing the spine;
Place the left hand on the left hip and slightly rotate inward;
Slide the right hand down the leg to the shine;
Stack the left shoulder over the right shoulder and reach for the ceiling with the left hand;
The arms should be in a straight line with the head forming an even angle;
Keep your neck relaxed, your knees soft and your legs stretched but not strained.
Hold this pose for 6 breaths.

subset: commoncrawl


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Every great resident of Queens knows that the best Greek food is found in Astoria. There are a multitude of Greek havens found within a mile or so radius. We, of course, have our favorites.
Each one of the four we highlight here are special in their own way.
Taverna Kyclades
33-07 Ditmars Blvd, Astoria
Taverna Kyclades: Undoubtedly one of the most complete Greek meals you will find. They start you out with a whole loaf of crusty bread slathered in nutty olive oil and Greek seasonings. Try the calamari, it's some of the best I've ever had. Lightly battered and fried to perfection, it melts in your mouth. Enjoy a large Greek salad with the ripest tomatoes (I swear that the tomatoes in Astoria are PERFECT!) and creamy, salty feta cheese. Order their shrimp (either simply grilled, or prepared with tomatoes and feta) or the swordfish kebabs, perfectly grilled and succulent. They give you a free dessert of galakoboureko. This is one of the most popular restaurants for Greek food in Astoria, so either come early (around 6 or 7) and dine in an empty room or battle the crowds during the Greek dinner time of 8pm and beyond…..
19-06 Ditmars Blvd, Astoria
Agnanti: This small-plates Greek restaurant is located right on the edge of Astoria Park and has seating outside, cold or warm weather. There is usually a super-long wait as well, and people line the sidewalks for hours waiting to get in to try their tasty offerings. Stick to their small plates and askew the mains here……a basket of bread starts you out (pita by request), try the great eggplant dip, the fresh Greek salad, the shrimp wrapped in Phyllo with a mustard sauce, the Fava Beans are AMAZING and comforting after being stewed all day in tomato sauce, and the stuffed grape leaves are served with a giant scoop of Greek Yogurt in the middle. I also love their free dessert of grain cake and honey cake and a large scoop of Greek yogurt drenched in sweet and sour cherries. The house wine is cheep and flows plentifully and you have to hunt the waiter down after two or three hours to get your check!
29-09 23rd Avenue, Astoria
Stamatis: In our neck of the woods they just re-did the restaurant and they moved across the street, but luckily the food is the same. Large roasting pans stand in the front of the restaurant filled to the brim with slow-cooked Greek food. This is a family restaurant and is large and loud, filled to the brim with Greek families dining into the late hours of the night. Their small antipasto plate is a steal and comes full with eggplant dip, fishroe dip, yogurt sauce and a garlicky potato dip. The fresh crusty bread soaked with olive oil accompanies it well. Stick to the classics here and get the large plates of stews, pasticio, moussaka, and vegetables. Be warned that this is peasant style dining: the portions are large and soaked in olive oil! I would have to say that this is not the best quality Greek you'll find, but the portions are plentiful and certainly comforting.
Athens Tavern
23-01 31st Street, Astoria
Athens Tavern: This high-class Greek replaced one of our favorites (Anna's Corner RIP) but there is something interesting in having a High Class competitor using the same ingredients, but jazzing up the presentation (and the prices!). This restaurant is dimly lit and has white table clothes and votive candles abound. We went here with a group of 8 during the very first week it opened, and we look forward to going back. They give you fresh baked breads with small cups of dips to try to start. This is definitely a NYC restaurant in Astoria…..the service is classy and the food is complicated. The whole fish is recommended, as well as the rabbit. Be prepared to spend $75-100 depending on drinks for two.


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Granville Island is a classic location for both wedding and engagement sessions. There's good reason for it—it's a vibrant locale with as many variations on Vancouver as is possible in less than a kilometre of quasi-industrial buildings and greenery.
Getting to work with a fun couple in such a great location makes my job even easier. Ryan and Jacqueline's wedding ceremony is set for Cleveland dam this summer, so clearly these two have taste.


text:
A passionate advocate of growth mindset and grit—I believe that limitations are simply a choice. With the right education and tools, anyone can become an entrepreneur with location freedom and flexibility to sculpt their career around the life they desire and love.
I believe everything is "figureoutable" (Marie Forleo) and with a little guidance, ambition, and a solid game plan, you can tailor your situation and vision to create the vibrant and energized life you've been craving!


text: WASHINGTON (CBS.MW) -- The telecommunications sector opened Friday trading on the weak side, with the majority of stocks edging lower. The broadly based Nasdaq Telecommunications Index slipped 0.2 percent, as five of the six largest components declined. Among the few advancers, Ciena CIEN, -1.05% gained 3.6 percent and UTStarcom UTSI, +0.00% jumped 8 percent.


text:
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Hebei Dongshengyuan Trading Co.,Ltd.
|Payment Type:
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Packaging: waterproof paper inside,plastic film outside, or in pallets or as customers' requirements
Productivity: 5000 Square Meter/Square Meter
Brand: Dongshengyuan
Transportation: Ocean,Land,Air
Place of Origin: Hebei, China (Mainland)
Supply Ability: 5000 Square Meter/Square Meters per Week
Certificate: ISO SGS
Chicken Coop Hexagonal Wire Mesh
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Packaging Details: waterproof paper inside,plastic film outside, or in pallets or as customers' requirements
Delivery Detail: within 15-20 days after recieve the prepayment
Our Services
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2. Professional factory for 31 years with advanced facility.
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A. All products will have been strictly inspected by our inspector before packing.
B. Welcome you to our factory to supervise the production processing and inspect
the goods quality at any time.
C. After receipt of the goods within 15 days, have any quality problem,you could raise an objection.
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A. Sample order in stock, will be delivery within 3 to 7 days.
B. The goods will delivery on time according to the contract.
Product Categories : Wire Mesh > Hexagonal Wire Mesh


text:
An employee in California cannot be compelled by an agreement with his employer to limit his right of re-employment in the industry. The invalidity of such "non-compete" agreements is soundly fixed in California case law. A recent federal case in California however explores the sometimes overlapping and opposing interests of the employee and employer where the employer has a "trade secrets" agreement.
Calfornia courts uphold trade secret agreements, and will issue orders specifying the limitations of an employee's use of confidential information. A recent case [See full opinion below] has held that a "team member" [i.e., employee] can be restricted in contacting the other "team member's" [i.e., "employer's] clients when those clients were provided with newly developed software created by the efforts of both team members. The restriction was not a restraint of free competition, but was a restriction necessary, according to the court, to protect the trade secrets of the "team member" [employer] who owned the rights to the software.


text:
What is lung cancer?
Lungs tumors are malignant in over 90 percent of cases. They can basically develop in all lung sections, but most often they are found in the upper part of the lung. This region is more ventilated during respiration and thus comes increasingly in contact with harmful substances.
Lung cancer is one of the most common malignancies in Germany with about 40,000 deaths per year and is rarely curable. According to the Federal Statistical Office, 28,652 men and 10,634 women died of bronchogenic carcinoma in 2003. Lung cancer is the most common cause of death in men and the third most common cause of cancer death among women. Due to changing smoking habits, the number of deaths among women is currently on the rise, with a slight decline in men since the mid-1980s.
Lung cancer predominantly occurs from the age of 40 years. The risk of disease increases with age. Most lung cancer patients are around 65 years old on average.
lung cancer causes
Today, lung cancer is based on a multi-stage concept: on the first level, there is contact with a carcinogenic substance, such as tobacco smoke or asbestos (see also Risk Factors ). The second stage is caused by the carcinogen damage to the genetic material (so-called mutations) of the cells in the lower respiratory tract (bronchi) or in the lungs ( alveoli, ie alveoli ). On the third stage comes - after a certain period of rest ( latency) of up to 40 years or even earlier - to a degenerate, unchecked growth of the damaged cells. This is how malignant tumors and cancer develop. Cigarette smoking is both the most important trigger and the most important driver of the disease. Basically, cancer always seems to always start from one cell.
lung cancer risk factors
Many different factors can work together in the development of lung cancer. First and foremost, harmful substances in the respiratory air cause the mucosal cells of the bronchi to gradually transform into cancer cells. By far the most important risk factor for lung cancer is smoking. But pollutants at work and in the air are also considered risk factors. Furthermore, diet, infections and occupational disease (eg silicosis ) and possibly also hereditary preload play a role. Although there is no clear evidence for the latter, one can observe a familial accumulation of lung cancer.
Smoke & lung health
90 percent of lung cancer cases are attributable to smoking. The cigarette smoke contains numerous carcinogenic substances. The risk of developing bronchial carcinoma is for a smoker about 10-15 times as high as for a never-smoker. Of course, this risk increases with the number of cigarettes smoked daily and the duration of smoking. About every thirtieth smoker falls ill in the course of his life. For pipe and cigar smokers who do not inhale the smoke, the risk for lung cancer is significantly lower than for inhaled cigarette smoking, but still high compared to that of a non-smoker. However, there is a subgroup of cigars and pipe smokers who inhale like cigarette smokers. Here the risk is comparable to that of the cigarette smoker. Even passive smokers (people who do not smoke themselves, but stay in rooms where people smoke) have an increased risk of cancer: passive smoking increases lung cancer risk by a factor of 1.3.
Pollutants & lung health
The occupational lung cancer risk is significantly lower than the risk of smokers. About one percent of all cases of bronchogenic carcinoma is caused by the inhalation of substances that people have to deal with at their workplace. Asbestos is responsible for more than 90% of cases, but arsenic, beryllium, cadmium, chromium, nickel, aromatic hydrocarbons, and diesel exhaust also play a role. These substances are mainly used in metalworking, in coal gas and coke production, in foundries or in rubber production. Even with workers in uranium mines, the risk of lung cancer is due to contact with the naturally occurring radioactive noble gas radon elevated. Heavy air pollution - especially from diesel soot - can also increase lung cancer risk (1.5 times). Particularly in smokers pollutants - whether at work or in the outside air - lead to an additionally significantly increased lung cancer risk.
Nutrition & lung health
A low-vitamin diet increases the risk of developing lung cancer to about twice - especially among smokers. That's why it's important to eat fruits and vegetables regularly. For example, beta-carotene from leafy vegetables and carrots is said to have a protective effect against lung cancer. However, vitamins in the form of dietary supplements or high-dose supplements are not an alternative: In smokers, they do not seem to lower the risk of cancer, but even increase it. In relation to the damaging influence of smoking, however, the contribution of nutrition in the development of lung cancer is low overall.
lung Infections & injuries
Generally, scars in the lungs are associated with an increased risk of cancer due to previous inflammation or infection (such as tuberculosis or silicosis) or injuries. Because cancer develops preferentially in those areas of the lung, which are scarred as a result of tuberculosis or other illness. Here, too, smokers are additionally endangered.
Genetic strain
A hereditary bias can also increase the risk of lung cancer. If one parent suffers from a bronchial carcinoma, the risk of children increases by two to three times.
Genetic Lung disease
Different types of lung cancer
Physicians distinguish two types of lung cancer the small-cell lung cancer (SCLC: small cell lung cancer ) that is growing very quickly and accounts for about 15 percent of cases, and non-small cell lung cancer ( NSCLC: non-small cell lung cancer ), which with about 85 percent occurs most frequently.
Non-small cell lung cancer is further distinguished between what is known as squamous cell carcinoma (40-50% of all lung cancers), adenocarcinoma (10-15%) and large cell carcinoma(5-10 percent). Non-small cell bronchial carcinomas grow more slowly and therefore have a better overall prognosis. What type of tumor is involved can only be determined by a microscopic examination of the cancerous tissue.
All carcinomas rarely cause discomfort at the beginning of their growth. Therefore, they are almost always discovered at random at an early stage, for example in x-ray examinations performed for a different reason. It is only in advanced stages that symptoms may appear that may indicate a carcinoma but other causes are also conceivable.
Possible complaints in a bronchial carcinoma
Early signs that may indicate lung cancer are especially persistent cough for four weeks, wheezing and chest pain. However, such symptoms are firstly not necessarily typical for a tumor disease, secondly, they also occur in many other diseases. In this respect, lung cancer is often not discovered early enough. On the other hand, there are good chances of recovery only if a bronchial carcinoma is treated as early as possible. In advanced disease stages, there is often rapid weight loss, bloody sputum, difficulty breathing and/or fever, usually triggered by concomitant infections.
The following symptoms may indicate a bronchial carcinoma and should, therefore, be clarified by the doctor:
"Smoker's bronchitis" (ie a persistent cough with sputum due to years of cigarette smoking)
A stubborn cough that does not fade even after several weeks, and then suddenly changes
Persistent hoarseness
Bronchitis or a cold that does not improve despite treatment with antibiotics
difficulty in breathing
Constant pain in the chest
Nocturnal sweating
Expectoration with or without blood
Swelling of the neck and face
Loss of appetite or heavyweight loss
General malaise and decay of strength
Strong pain
Usually in later stages of the disease, especially in small cell bronchial carcinoma, cancer deposits in the brain (so-called brain metastases) can arise. Nerve damage causes headaches, nausea, impaired vision, and balance or even paralysis. Some tumors also release hormones into the blood and thus disrupt the natural hormone balance.
Grading & staging of a tumor
In a microscopic examination, not only the type of tumor but also the aggressiveness and growth rate of a tumor - and thus its prognosis - can be estimated. In the so-called "grading" the tumors are divided into four grades:
G1 tumors: very similar to their original tissue, still well differentiated, growing slowly and not as aggressive.
G2 tumors: moderately differentiated
G3 tumors: poorly differentiated
G4 tumors: undifferentiated, barely recognizable as a bronchial cell, grow rapidly and tend to grow aggressively into adjacent tissue.
However, information on the degree of differentiation due to "grading" only makes sense for squamous cell and adenocarcinomas. Large cell and small cell carcinomas always correspond to Grade 4 tumors.
The spread of lung cancer is assessed by "staging" according to the so-called TNM classification. The stage of cancer is characterized by the following three criteria:
the size and extent of the tumor (T1-4),
the number and location of the affected lymph nodes (English nodes, N0-3) and
the absence or presence of metastases (M0 or M1).
For example, small tumors (such as T1 and T2) with no lymph node involvement (N0) and no daughter tumors (M0) have a more favorable prognosis. In small cell lung cancer, physicians also distinguish between a limited and a more extensive disease. While in limited disease the tumor is limited to one lung, it is said to be of advanced disease when cancer has spread to adjacent tissue in the chest and other parts of the body.
Complications & effects
Depending on the position of the tumor, it can narrow the air or esophagus or even close the large bronchi. Frequently, lung cancer patients also develop pneumonia and tumor bleeding. Those affected spit blood and suffer from venous congestion in the head and neck area. There may be fistulas, accumulation of blood in the pericardium and pleural effusions - also due to lymphatic drainage disorders. Disintegrating cancer can cause a high fever.
Lung cancer prevention
If lung cancer is suspected , the patient is first questioned by the doctor in detail about his symptoms and possible risk factors, and then thoroughly examined physically. This involves examining both blood and sputum in the laboratory and x-raying his lungs. A subsequent bronchoscopy allows the doctor to look into the lungs. In some cases, he has to confirm his diagnosis with additional methods such as ultrasound , computed tomography (CT) or fine needle biopsy (see below), which may require the patient to be admitted to a pulmonary clinic.
If lung carcinoma has been diagnosed, further examinations should follow, which should show, in particular, how far the tumor has already spread, whether lymph nodes are affected or even secondary tumors ( metastases ) have formed in other parts of the body. The stage of cancer is crucial for choosing the treatment strategy.
laboratory examination
The blood values reflect the general condition of the patient and provide information about the functioning of individual organs such as kidneys and liver. In addition, the blood can be checked for the occurrence of so-called tumor markers - these are certain substances that are increasingly formed by tumor cells. However, as tumor markers can not be detected in all lung cancer patients and can also occur in healthy people, they do not play a major role in the diagnosis. They are more likely to be used in aftercare to control the disease process.
In a sputum examination , the patient's coughed mucus is examined under the microscope for abnormal cells. Such cells may indicate tumors that are not yet visible on the radiograph. However, their absence does not automatically mean all-clear. Therefore, this test can not be used for the early detection of lung cancer .
During bronchoscopy , the doctor introduces a flexible tube ( endoscope ) into the bronchial tubes via the nose and trachea to patients who are anesthetized locally or under anesthesia . Using an optical device at the end of the endoscope, the doctor can examine the mucous membranes and use a small forceps, which is located next to the optical unit, to take a tissue sample (biopsy). Only the microscopic examination of this sample reveals whether a malignant tumor is present - and if so, which form of cancer it is. During the same examination, the doctor can also aspirate secretions from deeper bronchial sections and examine them, similar to the sputum, under the microscope for cancer cells .
Fine-needle biopsy
If the cancerous area is unreachable due to its location for bronchoscopy, the doctor will perform a fine needle biopsy. He pushes from the outside a long, thin hollow needle through the patient's chest into the suspicious area and sucks some tissue. The whole thing happens today usually under ultrasound - or computer tomographic control. The tissue is then examined microscopically for the presence of cancer cells.
Computed tomography (CT)
With the help of this special X-ray method, the doctor examines the patient's body layer by layer. In the computer tomogram, he can detect the extent of the tumor and determine whether it has already affected adjacent organs. Thus, he receives important information about the extent to which vital organs are affected, whether the tumor can even be surgically removed and - if so - how extensive the operation is likely to be. In patients with bronchial carcinoma, computed tomography is also used to look for or eliminate the presence of cancer cells (metastases) in the head, but also in the chest and abdomen.
Magnetic Resonance Imaging (MRI)
Lying in a strong magnetic field, the patient is exposed to radio waves during this examination. The water molecules in the body "respond" to this signal at different speeds - depending on the type of tissue they are sitting in. From the resonance of their respective wave patterns, the computer calculates an image of the organs. In nuclear spin (as magnetic resonance tomography is also colloquially called) different structures stand out than with computed tomography. In addition, dislocations of cancer cells (metastases) in the brain, spinal cord and skeleton can be more clearly recognized. The waves and the magnetic field are innocuous for the patient.
Similar to magnetic resonance imaging ( MRI ), an ultrasound examination makes the internal organs visible without burdening the affected patient with harmful radiation. Using ultrasound, the doctor can determine whether the lung cancer has already spread to other organs such as the liver, kidneys, spleen and lymph nodes. An ultrasound examination of the heart can provide information about the performance of the heart muscle, which in turn is crucial for the choice of treatment method. Often affected people not only the lungs are damaged by regular tobacco consumption , but also their cardiac output (due to constricted coronary arteries).
Bone scintigraphy
With the help of bone scintigraphy, the doctor can detect whether the lung cancer has already spread secondary tumors into the bones (bone metastases). To do this, he injects small amounts of a radioactive substance into the bloodstream, which accumulates primarily in diseased bones. A camera recording radioactive radiation locates suspicious areas. A scintigraphic examination does not put a lot of strain on the patient as the radiation fades away very quickly.
Lung cancer often spreads through the lymphatics, and especially the lymph nodes of the mediastinum, which are close to the lungs, are particularly frequently attacked. In order to assess their condition, the physician must perform a mediastinoscopy : For this, he introduces the anesthetized patient via a small incision above the breastbone an optical probe in the space between the lungs. Using the endoscope, he can remove suspicious lymph nodes and then examine these tissue samples for the presence of cancer cells.
The choice of treatment depends on whether a small cell or non-small cell lung carcinoma is present and how far the disease has progressed. Since lung cancer patients almost always have a chronic inflammation of the bronchi with constriction, additional treatment of chronic bronchitis is very important in the treatment of bronchial carcinomas . Also respiratory distress, cough and pain can be alleviated.
Treatment of non-small cell lung cancer
In the treatment of non-small cell lung tumors, surgery and radiation are in the foreground: during surgery, the surgeon cuts out the tumor and a piece of adjacent healthy lung tissue. Frequently, the entire affected lung lobe (lobectomy) or a whole lung (pneumectomy) is removed, but in many cases can also be operated to maintain the organ. A surgical procedure is only possible if the general condition of the patient is good and the remaining lung sections can take over the respiratory function.
If this is not the case, or if the tumor already reaches neighboring, vital organs, radiotherapy must be performed. In this case, the cancer cells are irradiated from the outside with high-energy waves (taking advantage of the effect of ionizing radiation) and destroyed. Are being introduced X, Alpha, gamma or electron radiation. In the best case, the tumor is reduced by the radiation so far that it can still be surgically removed afterwards. Radiation therapy may also be performed following surgery (adjuvant radiotherapy) to destroy any remaining cancer cells. The prospect of success is limited, however, as often not all tumor cells can be destroyed or even the smallest tumor deposits have formed. In non-small cell lung cancer, chemotherapy is increasingly being used in combination with surgery and / or radiotherapy. The success of this treatment is currently being tested in clinical trials worldwide.
Treatment of small cell bronchial carcinoma
In small-cell bronchial carcinomas, which due to their rapid growth and early spread of secondary tumors (metastasis) can be operated on only rarely, chemotherapy is more effective than non-small cell carcinoma. The patient is given so-called cytostatics. These are drugs that inhibit cell division and act especially on the fast-growing cancer cells - less on healthy cells. Even if surgery is performed, chemotherapy is always performed before or after surgery to combat other possible (non-surgical) tumor cells. If distant metastases have already formed, the doctor tries to delay the course of the disease by means of chemotherapy. Thus, he can cure the patient only in a few cases, but possibly extend his life. As long as a small cell Lung cancer has a small extent, a combination of radiation and chemotherapy can be considered. Since small-cell lung tumors often form metastases in the brain, the patient's skull is sometimes irradiated preventively. This radiation should help prevent the onset of cancer in the brain.
Active substances in the chemotherapy of bronchial carcinomas
Non-small cell lung carcinoma
Small cell bronchial carcinoma
erlotinib + gefitinib
Treatment of tumor pain
In the advanced stages of lung cancer, the so-called tumor pain (for example, as a result of an infestation of the pleuraor the chest wall), and their control in the foreground. They often affect the quality of life of the person affected more than other effects of the tumor. The doctor has a range of painkillers to morphine injections available to relieve the suffering. For painful bone metastases sometimes helps a targeted irradiation. If the entire skeleton is affected by the tumor, the doctor can administer to the person concerned radioactive substances that accumulate in the diseased bone and irradiate it from the inside (radionuclide treatment). Also, chemotherapy can relieve tumor-related pain in more than half of the patients and prevent worsening of the general condition. However, healing is no longer possible at this time.
lung cancer prevention
About 85 to 90 percent of all malignant lung tumors are due to smoking . Therefore, one can prevent lung cancer still best when on tobacco use completely eliminated and not be gathered up in smoke filledrooms . Even at an advanced age and after many years of smoking it is worthwhile stopping for many reasons. Those who are in contact with carcinogenic substances at the workplace should strictly adhere to the safety precautions. A healthy, vitamin-rich diet helps the body fight against cancer. The risk prevention is in lung cancer especially important because its chances of recovery are rather poor and there is currently no one hundred percent safe screening for early detection.
Aftercare & rehab
The purpose of follow-up examinations for lung cancer is to detect and treat a possible recurrence of the tumor (recurrence) in good time. Follow-up visits often follow a set schedule of visits to the doctor in the first year at 1, 3, 6, 9 and 12 months, the second year every 3 months, then every 6 months. However, significant differences are possible depending on the individual course. Unfortunately, the prognosis of the patient (ie, his chance of survival) does not improve decisively simply by the control examinations - but without the symptoms changing. In addition to a detailed conversation and a physical examination, the blood is often analyzed during follow-up examinations and an X-ray of the chest (thorax)made. After surgery, sometimes bronchoscopy (lung reflection) may be useful at longer intervals .
Inpatient rehabilitation stays should preferably be sought at particularly experienced tumor after-care clinics that are familiar with the specific needs of lung cancer patients. The aim is to improve the overall quality of life of those affected - that is, physically, socially, psychologically and professionally. Whether a rehabilitation measure in individual cases makes sense and is possible, decides the treating pulmonologist.


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By Sean Booker
Apr 13, 2009 - 12:00
The game starts you off in your home town as a soon to be trainer in the Sinnoh region of the Pokémon universe. You get to choose a gender and name and after a few events unfold, you get your first Pokémon. Pokémon are pet-like creatures that you will collect and use to battle against rival trainers. From there you are asked to travel the world searching for new Pokémon and taking on new challenges. As you continue your journey you will encounter new enemies, friendly allies and loads of ways to enjoy yourself in Sinnoh.
Along with fighting your way through all the gyms and stray trainers who wish to take you on in the game, you also have several other choices of gameplay. The two more significant ones are Pokémon contests and the Underground area, but, apart from these two, there is also a new online multiplayer mode exclusive to Pokémon Platinum.
Pokémon contests have you select one of your Pokémon to go through a talent show like game in order to win ribbons. In each contest you will have to dress up your Pokémon, which requires selecting specific accessories that relate to the specified theme. You will have to make your Pokémon dance, which translates to a very basic
The Underground area is another fun way to spend time with your single player game or your friends, in multiplayer. Once you receive the Explorer's Kit in-game, you can head into what is essentially an underground maze that can be accessed almost anywhere in the Sinnoh region. In the Underground area, you can partake in treasure hunting mini-games along with building a secret base. Secret bases allow you to create a room and decorate it however you wish. When playing with friends, you will be able to see them in the underground maze as well, and from there you can interact with their character. One of the fun things to do is to try and steal your friends 'Flag' from their secret base and bring it to your own – almost like a 'capture the flag' style of game. To increase the difficulty of this game, players can set traps on the ground that will activate when stepped on. These traps can vary from sending someone on a track all the way west until hitting a wall or even covering their DS screen with bubbles that they must pop with their stylus.
The online mode is called the Wi-Fi Plaza and it is a new addition to Pokémon Platinum that can only be accessed if you have a wireless Internet connection. In the Plaza you can move around a room with other online players. However, your only option when trying to interact with them is asking pre-staged questions like "What's popular?" This causes the tasks of "talking" to people to become quite dull and pointless. You can also play a couple mini-games in here that involve using the stylus in certain ways. Playing these games well will upgrade your Tap Toy, an item you receive when first entering the room. The Tap Toy is an object shown on the bottom screen that, when tapped, will play a noise.
The graphics in Pokémon Platinum are great for the DS. It stays with the 2D side scrolling aspect but still looks great on the handheld. Though it does look identical to the landscapes and character models from Pokémon Diamond and Pearl. However, there are several minor differences added to Pokémon Platinum. The majority of these additions are some of the Pokémon stances are now different and some of the characters now wear different clothing. Overall, the graphics haven't changed much but they still look great.
The sound in Pokémon Platinum, like the graphics, remains the same as in the past couple Pokémon games on the DS. This is another one of Pokémon Platinum's disappointments as there wasn't really anything new in the way the game sounded. It even used some of the sounds that the Game Boy Pokémon games had. It would have at least been nice to hear some new music and sound effects when playing what could be your fifth or sixth Pokémon game.
When it comes to my verdict, I place it under both Buy It and Forget It. I only put it as Forget It for the people very familiar with either Pokémon Diamond or Pearl. They won't feel the game has enough in it to play through the same story again. However, I place it in the Buy It category for anyone who may have passed on playing those two. It's a great experience that is different enough from the other Pokémon games, just not the first two DS titles.
Overall: 9/10
Verdict: Buy It or Forget It
Verdict: Buy It or Forget It
Rating: 9 /10


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Marketers are increasingly finding that traditional marketing with its heavy focus on advertising no longer delivers the desired results. Customers simply don't want to be sold anymore; they want to be told.
The terms Content and Content Marketing are fast becoming the core of all that can be called marketing. In a business context, content is the information presented to an audience in a particular form and for a specific purpose.
Here's the thing, though; there is such a thing as good content and bad content.
There was a time (prior to Google's Panda update in 2011) when low quality content and spam sites used to rule the search results. But the Panda update and many other factors led to good quality content becoming more important (more on that in another post).
So what is good content and how is it different from bad content?
Simply put. Good content is content that is useful, relevant to users and solves their problem and most importantly it is content that is actually read by people.
On the other hand, bad content is quite simply bad (and in some cases evil), apart from lacking substance, being unreadable, stuffed with keywords or in some cases downright off-putting. All of us have come across it on the internet and we know bad content when we see it.
So why is it crucial to have high quality and authentic content about your business on websites, blogs, and social media? What nightmares can a business attract when it puts out low-quality or bad content? Read on to find out.
1. Poor Website Ranking
Today, it's all about visibility and popularity of your business website on search engines. Putting out bad content can be a big roadblock to achieving this. Through Search Engine Optimization (SEO), companies try to make their websites more visible on search engines with the help of keywords. These keywords are the most common words used by people to make a search on the web. So even if your content is technically and grammatically correct, without proper keywords, it will not make it to the search results and end up unseen and unknown. On the flipside, using too many keywords (known as keyword stuffing) too must be avoided at all costs!
2. Reduced Customer Engagement
How content is consumed and circulated is changing! Effective content is no longer only just text; rather people like content that is easy to understand, crisp and is supported by helpful pictures, illustrations, diagrams, charts, videos and other audio-visuals. The more relevant and fresh your content, the more it will lead to customer engagement. If you are still putting out only text-based content, people will no longer connect to you, period.
3. Reputation Loss
An oft-repeated excuse for putting out bad content is, "Why care about what is written? Who reads it anyway?" Well to put it squarely, people do read it and sending out bad content can lead to the loss of reputation often permanently.
When a business itself is not clear on how it is going to benefit customers or is vague in its content regarding the objective or the services it is going to provide, how can it expect customers to care about?
4. Lesser Brand Loyalty
Customers don't like to feel that they have been fooled. Poor quality content may bring you customers initially but those customers are not going to stay if they are fed with bad content again and again. When they find out that you are not worth it, they will leave. And there are plenty of competitors putting out good content, waiting to grab customers that could have been yours!
5. Financial Losses
Businesses tend to spend too much on the looks of their website, research reports, and other marketing materials, but they are generally less willing to spend on good quality content. They don't realize that customers are more attracted to the helpful information they are looking for instead of how the website looks.
Yes, sending out poor quality content may not cost you much initially but it will cost your business in the long run in the form of dissatisfied customers and financial losses.