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Review Article | Open Access
Laurindo Ferreira da Rocha Junior, Andréa Tavares Dantas, Ângela Luzia Branco Pinto Duarte, Moacyr Jesus Barreto de Melo Rego, Ivan da Rocha Pitta, Maira Galdino da Rocha Pitta, "PPAR Agonists in Adaptive Immunity: What Do Immune Disorders and Their Models Have to Tell Us?", PPAR Research, vol. 2013, Article ID 519724, 9 pages, 2013. https://doi.org/10.1155/2013/519724
PPAR Agonists in Adaptive Immunity: What Do Immune Disorders and Their Models Have to Tell Us?
Adaptive immunity has evolved as a very powerful and highly specialized tool of host defense. Its classical protagonists are lymphocytes of the T- and B-cell lineage. Cytokines and chemokines play a key role as effector mechanisms of the adaptive immunity. Some autoimmune and inflammatory diseases are caused by disturbance of the adaptive immune system. Recent advances in understanding the pathogenesis of autoimmune diseases have led to research on new molecular and therapeutic targets. PPARγ are members of the nuclear receptor superfamily and are transcription factors involved in lipid metabolism as well as innate and adaptive immunity. PPARγ is activated by synthetic and endogenous ligands. Previous studies have shown that PPAR agonists regulate T-cell survival, activation and T helper cell differentiation into effector subsets: Th1, Th2, Th17, and Tregs. PPARγ has also been associated with B cells. The present review addresses these issues by placing PPARγ agonists in the context of adaptive immune responses and the relation of the activation of these receptors with the expression of cytokines involved in adaptive immunity.
1. Introduction
Adaptive immunity is a very powerful and specialized tool of host defense. The T- and B-cell lymphocytes are classically involved in the adaptive immune system. Disturbances of the adaptive immunity results in autoimmunity. Immune dysfunction associated with autoimmune diseases was known to be caused by an imbalance between Th1 and Th2 cells. Autoimmune diseases could be categorized as predominantly Th1-driven if the major events were cell mediated in nature, or predominantly Th2 driven if antibodies and/or immune complexes served as the main mediators [1]. In the last years, a third subset named Th17 cells has been identified, and the Th1/Th2 imbalance hypothesis has shifted to an involvement of the Th1/Th2/Th17/regulatory T (Treg) lymphocytes with the same Th precursor cells [2]. B-cell activation and antibody production can be either an independent T-cell help process or B cells receiving help from follicular T cells. In autoimmune diseases, the contact with self-antigen leads to B-cell activation and, therefore, these lineage of cells are of great importance in adaptive immunity. Naive B cells develop into antibody-producing plasma cells through the contact with antigen in combination with TLR-agonists and cytokines. Activation of B cells also results in differentiation into plasma blasts and increased cytokine production [3].
The nuclear receptor (NR) superfamily is composed of 48 members and includes receptors for steroid hormones, thyroid hormone, various lipids, and oxysterols. NRs function as ligand-dependent transcription factors and share a modular domain structure [4]. PPAR-gamma (PPARγ) belongs to the nuclear receptor superfamily. These transcription factors function as receptors for various lipid-soluble, small molecules that are most commonly generated as hormones or in the intermediary metabolic pathways [5]. These receptors regulate gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. These genes are regulated through ligand-dependent transcriptional activation. Several of these target genes are involved in metabolic homeostasis [6]. The PPARγ express two isoforms, PPAR-γ1 and PPAR-γ2. PPAR-γ1 is expressed in macrophages, colonic epithelial cells, endothelial cells, and vascular smooth muscle cells. PPAR-γ2 is mainly expressed in adipose tissue and is involved in the regulation of adipogenesis [7]. PPARγ activation in immune cells predominantly results in another mechanism of action: transrepression of proinflammatory gene expression [8]. Transrepression does not involve binding of the nuclear receptor to its cognate DNA element, but here PPARγ operates by antagonizing signal-dependent activation of its target genes by other classes of transcription factors, including NF-κB and AP-1 proteins, thereby reducing inflammatory signaling pathways [9]. PPARγ expression in the monocyte/macrophage lineage was demonstrated by the suppression of the activation of monocyte/macrophages by PPARγ agonists. In Addition to their role in the anti-inflammatory response of innate immune cells, PPARs are involved in mediating the adaptive immune responses of T and B cells [10]. PPARγ is activated by diverse synthetic and naturally occurring substances. Many ligands that activate and modulate PPAR functions have been identified [10]. Naïve and activated T cells express PPARγ, and ligands for the receptor inhibit proliferation and significantly decrease cell viability [11]. Activated B cells upregulate their expression of PPARγ [12]. In this review, we will summarize the recent progress in PPARγ studies and the interplay of these nuclear receptors with adaptive immunity and T and B cells.
2. Th1 Lymphocytes
Th1 cells secrete interferon- (IFN-) γ, interleukin- (IL-) 2, and tumor necrosis factor (TNF) and control protection against infection with intracellular microbes. Maturation of Th1 cells is controlled by IL-12 and transcription factor T-bet. During Th1 cell differentiation, IL-12 signals via the IL-12R/STAT4-signalling pathway inducing IFN-γ expression, the secreted IFN-γ then signals through the IFN-γR/STAT1 pathway to further increase IFN-γ levels, forming a positive autoregulatory loop reinforcing Th1 differentiation. The signal transducer and activator (STAT) proteins STAT1 and STAT4 induce the expression of the Th1-specific transcription factor T-box expressed in T cells (T-bet) [13]. Inappropriate activation of Th1 cells in response to self-antigen or innocuous antigens leads to autoimmune states as well as to hypersensitive states in which T-cell tolerance to environmental antigens fails [14].
PPARγ agonists have been shown to decrease IL-2 production in activated T cells and thereby to enhance apoptosis. The modulation of T-cell activity is due to inhibition of IL-2 production in T-cell-receptor-stimulated Th cells and due to suppression of Th2 cell differentiation. The endogenous ligand 15-deoxy-Delta12, 14-prostaglandin J2(15d-PGJ2), and the synthetic ligand ciglitazone inhibit IL-2 secretion by T-cell clones in murine cells [6, 15]. High amounts of IL-2 and IFN-γ were detected in the supernatant of antigen stimulated splenocytes from PPARγ+/– mice [16]. Studies demonstrated that lymphocyte-derived IFN-γ interferes with PPARγ ligand regulation of MAPK activation in murine macrophages in vitro [17]. PPARγ ligands decreased the level of IFNγ production in splenocytes and T-cell clones isolated from SJL mice [15]. Treatment with pioglitazone changes the helper T-cell balance from Th1 to Th2 in the myocardium of rats with autoimmune myocarditis by upregulating the mRNA of Th2 cytokine IL-4 and by reducing the mRNA level of Th1 cytokine IFN-γ [18]. Pioglitazone also reduced IFN-γ production in a model of experimental autoimmune encephalomyelitis (EAE), the inflammatory demyelinating disease model of multiple sclerosis (MS) [19]. In vivo treatment with the PPAR-ligand THR0921 resulted in reduced production of TNF-α, IL-1β, and INF-γ by spleen cells cultured for 48 h with either lipopolysaccharide (LPS) or type II collagen (CII) compared with cells from vehicle-treated collagen-induced arthritis (CIA) mice [20]. PPARγ agonists decrease lupus-related nephritis through decreased IFN-γ and nitric oxide production in MRL/lpr mice in vivo [21]. Treatment of diabetic mice with rosiglitazone resulted in a significant decrease in the pancreatic level of TNF-α and IFN-γ compared to untreated diabetic mice [22].
In human cells, it has been demonstrated that nuclear factor of activated T cells (NFAT) is negatively regulated by PPARγ activation with troglitazone and 15d-PGJ2 through blockade of NFAT DNA binding and transcriptional activity and subsequent inhibition IL-2 production [23]. IL-2 protein expression was also downregulated by rosiglitazone [24]. The endogenous PPARγ agonist 13-hydroxyoctadecadienoic acid (13-HODE) downregulated IL-2 production by human peripheral blood T lymphocytes by reducing NFAT and NF-κB binding to the IL-2 promoter [25]. In PBMCs from patients with Hashimoto's thyroiditis (HT) and controls, rosiglitazone reduced IFN-γ expression by CD4+ and CD8+ T lymphocytes in a dose-dependent manner, but the degree of inhibition was significantly greater in healthy subjects than patients with HT. This in vitro resistance to immunomodulation might be due to the enhancement of mitogen-activated protein kinase (MAPK) pathway [26]. The CXC chemokines (CXCL9, CXCL10, and CXCL11), inducible by IFN-γ, are proinflammatory molecules with chemoattractant activity for Th1 lymphocytes secreting IFNγ [27]. Rosiglitazone has recently been shown to inhibit IFN-γ and TNF induction of α-chemokine CXCL10 release by cultured thyroid cells and orbital fibroblasts from patients with Graves' ophthalmopathy [28]. Troglitazone has been demonstrated to modulate the level of IFN-γ production [29, 30]. The deletion of PPARγ in CD4+ T cells results in enhanced antigen-specific proliferation and overproduction of IFN-γ in response to IL-12 highlighting the importance of expression of PPARγ in CD4+ T cells in downregulating excessive Th1 responses [31]. 15d-PGJ2 suppressed T-cell proliferation and IFN-γ secretion in vitro by both Con A- and myelin basic protein (MBP) Ac1–11 peptide-stimulated lymphocytes. MBP is used to induce EAE in rodents. The ability of T cells to adoptively transfer EAE is suppressed when these cells are cultured with 15d-PGJ2 in vitro [32]. 15d-PGJ2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. Microglia participate in pathology associated with multiple sclerosis (MS) [33]. The PPARγ ligands, 15d-PGJ2, troglitazone, and pioglitazone, can inhibit the IFN-γ-induced expression of the CXC chemokines inducing protein-10 and monokine induced by IFN-γ/IFN-inducible T-cell αchemoattractant by endothelial cells [34]. In addition, T-cell-specific PPARγ-deficient mice are suggested to be defective in accumulating T effector cells in secondary lymphoid organs and tissues and therefore in their ability to produce IFN-γ gamma and IL-17 in inflammatory sites [26, 35].
IL-12 plays a crucial role in the differentiation of T lymphocytes and immunity against pathogens. The development of EAE was also found to be associated with an increase in the expression of IL-12 in the central nervous system (CNS) and lymphoid organs [36, 37]. The PPARγ agonists 15d-PGJ2 and ciglitazone inhibit EAE by blocking IL-12 production in macrophage and microglial cells, IL-12 signaling, and Th1 cell differentiation [38, 39]. The endogenous ligand 9-hydroxyoctadecadienoic acid (9-HODE), a major oxidized lipid component of oxLDL, significantly inhibited IL-12 production in lipopolysaccharide- (LPS-) stimulated mouse macrophages and also suppressed NF-κB-mediated activation in IL-12 p40 promoter [40].
The inhibition of IL-12 production by dendritic cells through ligand-activated PPARγ, as well as the inhibition of IFNγ production by T cells, indicates that this nuclear hormone receptor might be involved in the differentiation of naive T cells into their effector subsets. These data highlight that PPARγ play important roles in Th1-cell survival, activation, and differentiation.
3. Th2 Cells
Th2 cells classically mediate host defense against extracellular parasites. They are also important in the induction and persistence of asthma and other allergic inflammatory diseases. Th2 cells can produce IL-4, IL-5, IL-9, IL-10, IL-13, and IL-25. IL-4 plays a positive feedback for Th2 cell differentiation through the transcription factor STAT-6 and expression of GATA-3 [41]. Although Th2 cells are not major effectors in the pathogenesis of most autoimmune diseases, in some instances induction of a Th2 response during ongoing autoimmune inflammation can be of therapeutic value, especially considering the potential of Th2 cells to modulate the generation of Th1 cells and their interactions with B cells. Th2 cytokines can stimulate proliferation, activation, and isotype switching of B cells and aid in the production of autoantibodies by providing help to autoreactive B cells [42, 43]. Futhermore, Th2 cytokines, like IL-5, can promote induction of Ag-specific Tregs, contributing to restore autoimmune tolerance [44].
Studies of gene expression have shown that polarized Th2 cells express greater levels of PPARγ2 mRNA than Th1 cells [45]. The exact interaction between PPARγ and IL-4 is not fully understood, and it seems to depend on the context and on the ligand type involved. Treatment with pioglitazone increased expression levels of IL-4 in a model of autoimmune myocarditis, and there was an amelioration of the inflammation [18]. This report agrees with previous description of improvement of acute colitis after thiazolidinic treatment (troglitazone, pioglitazone, and rosiglitazone) by decreasing TNFα and IFNγ and increasing IL-4, IL-10, and transcription factor GATA-3 expression [46, 47]. Recently, pioglitazone attenuated the neurological signs in a model of experimental autoimmune neuritis in rats by the inhibition of Th1 cytokines production (TNFα and IFNγ) and increased secretion of IL-4 [48]. In PBMC from Hashimoto's thyroiditis patients, rosiglitazone produced no inhibitory effect on IL-4 expression by CD4+ T lymphocytes [26].
On the other hand, significant inhibition of IL-4 production in T cells by natural and synthetic PPARγ agonists (15d-PGJ2 and ciglitazone) was reported [7]. In this study, the inhibitory effect was explained, at least in part, by downregulation of NF-AT (nuclear factor of activated T cells) activation, another proinflammatory signal transduction pathway [7]. This finding was subsequently confirmed by other authors [49, 50]. Furthermore, it was demonstrated that a nonthiazolidinedione PPARγ ligand (KR62980), but not rosiglitazone, decreased IL-4, IL-5, and IL-13 levels and Th2 cell differentiation in vitro, by reducing the expression of c-Maf, a Th2-specific transcription factor [51]. These findings suggest that PPARγ activation could have an anti-inflammatory effect on Th2-mediated diseases.
It was also demonstrated that IL-4 and IL-13 could upregulate PPARγ gene expression in CD4+ T cells, peripheral monocytes, peritoneal macrophages, and airway epithelial [52–55]. These authors also showed that IL-4 induces the expression and activity of 12/15-lipoxygenase, enzyme that catalyzes the synthesis of the PPARγ ligands 12-HETE, 15-HETE, and 13-HODE. This finding reinforces the important role of this cytokine in inflammation by coordinately inducing the expression of PPARγ receptor and its ligands and, consequently, proinflammatory gene repression [52, 53].
IL-10 is an anti-inflammatory cytokine that downregulates cellular immunity and allergic inflammation, by inhibiting activation and effector function of T cells, monocytes, and macrophages; downregulating IL-4 and IL-5 expression by T-helper type 2 cell lymphocytes and decreasing eosinophil survival and IgE synthesis [56, 57]. In a mouse model of asthma, the administration of rosiglitazone or pioglitazone increased IL-10 levels in lung tissue and decreased IL-4 and IL-5 levels, indicating a protective role for the receptor in inflammatory diseases [50]. The PPARγ agonists effects seem to depend on dose and cell type, since low concentrations of rosiglitazone induced production of IL-10 from mature dendritic cells and activated CD4+ T cells, but these effects were not identified with higher doses or in immature cells. This production was mediated by PPARγ receptors, and it was also described as a functional PPRE in the IL-10 gene promoter [58].
Some studies have suggested that PPARγ agonists may also have some proinflammatory activity in which 15d-PGJ2 can inhibit IL-10 action by blocking STAT1 and STAT3 activation. This inhibition was not specific for IL-10, as STAT activation by IFNγ or IL-6 is also inhibited by the compound [59]. Thus, some PPARγ ligands can exert their pro- or anti-inflammatory properties through a PPARγ-independent way.
IL-33 can act directly on Th2 cells increasing the secretion of Th2 cytokines such as IL-5 and IL-13 and can also act as a chemoattractant for Th2 cells [60, 61]. It was demonstrated that treatment with PPARγ agonists (15d-PGJ2 and rosiglitazone) could also reduce the production of IL-33, and they have been implicated in the pathogenesis of some inflammatory diseases mediated by eosinophils, like asthma [62].
In addition to downregulating Th1 proinflammatory cytokines, PPARγ ligands can presents anti-inflammatory effects by promoting the production of anti-inflammatory Th2 cytokines. Thus, PPARγ was suggested to modulate the orientation of immune responses in favor of Th2 responses, but the studies are not uniform.
4. Th17 Pathway
Recently, a new subset of Th cells has been identified named TH17 cells and characterized by the production of IL-17A, IL-17F, IL-21, IL-22, and IL-23R. Th17 cell differentiation is enhanced by the coordinated functions of distinct cytokines including TGFβ, IL-6, IL-21, and IL-23, whereas IL-2, IL-4, IFNγ, and IL-27 inhibit its differentiation. The IL-17A and IL-17F induce proinflammatory cytokines like IL-6, IL-1, TNF, and proinflammatory chemokines like CXCL1, GCP-2, and IL-8 and thus promote tissue inflammation and recruitment of neutrophils to the site of inflammation [63]. This cell population has been implicated in the development of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease and has been studied in mouse models of autoimmunity, such as experimental autoimmune encephalomyelitis, inflammatory bowel disease, and collagen-induced arthritis [64–67]. In several autoimmune diseases, Th17 cells are recruited to inflamed tissues and promote inflammation by enhancing cytokine production, which can in turn activate B-cell antibody production, activate dendritic cells, and stimulate resident cells in the target tissues [57].
Pharmacological PPARγ activation selectively impairs differentiation into Th17 cells. Under physiological conditions, the corepressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) is bound to the RORγt promoter and inhibits its transcription. PPARγ activation is thought to prevent removal of this corepressor complex, thus suppressing RORγt expression and RORγt-induced Th17 cell differentiation [67, 68]. In PPARγ knockout mice (PPARγ −/−), Th17 differentiation was strongly increased. In a model of EAE, characterized by increased infiltration of Th17 cells into the central nervous system, pioglitazone treatment alleviated the disease severity of EAE, and PPARγ −/− mice were reported to exhibit enhanced disease severity. In CD4+ T cells isolated from the central nervous system (CNS) of these EAE mice, endogenous (13-HODE) and synthetic (pioglitazone) PPARγ agonists suppressed Th17 differentiation, but not Th1, Th2, or Treg differentiation. A decreased expression of Th17 cytokines IL-17A, IL-17F, IL-21, IL-22, and IL-23R and a selective inhibition of TGFβ/IL-6-mediated expression of RORγt were also demonstrated [69].
IL-23 belongs to IL-12 cytokine family and represents an important cytokine implicated as being responsible for Th17 phenotype maintaining and survival [70, 71]. PPARγ agonists (15d-PGJ2 and rosiglitazone) inhibited the induction of IL-23 protein by LPS-stimulated CNS cells [72]. In models of allergic asthma, treatment with PPARγ agonists (15d-PGJ2 and rosiglitazone and pioglitazone) promoted the reduction of IL-17 and IL-23 [62, 73]. These studies demonstrate that PPARγ activation can regulate the differentiation and function of Th17 cells, by suppressing Th17 cell development and decreasing Th17 cytokines.
5. T Regulatory (Treg) Cells
Treg cells suppress autoimmune responses and also other aberrant or excessive immune responses to nonself-antigens. Depletion of CD25+CD4+ Treg cells, which constitute 5%–10% of CD4+ T cells, produces autoimmune diseases such as inflammatory bowel disease in normal mice [74]. Expression of PPARγ by macrophages and epithelial cells is required for protection against dextran sodium sulfate colitis [75, 76]. These Treg cells express FoxP3, a transcription factor essential for their development and function [77]. PPARγ-expressing Treg effectively reduce IFN-γ-producing CD4+ T cells. Therefore, the loss of PPARγ in Treg impairs their ability to control effector CD4+ T-cell responses preventing protection against colitis in a mouse model of intestinal inflammation suggesting that expression of PPARγ by Treg is required for optimal anti-inflammatory efficacy [31].
PPARγ deficiency leads to decreased numbers of CD4+Foxp3+ T cells and increased CD4+IFN-γ+ cells, suggesting that PPARγ plays a role in Treg survival and regulation of effector T-cell functions. Similarly, T-cell-specific PPARγ-deficient mice showed reduced Treg recruitment to mesenteric lymph nodes and increased expression of apoptosis-related genes [78]. In addition, ciglitazone or PGE2 treatment of naïve CD4+ T cells enhanced induction of Foxp3+ inducible regulatory T cells, suggesting that PPARγ may contribute to the quality and quantity of Treg functions in vivo. PPARγ regulates induction of Tregs through retinoic acid-mediated dendritic cells (DCs) [79, 80].
Foxp3+ Treg cells are abundant in visceral adipose tissue and have a different T-cell receptor repertoire compared with Treg cells in other tissues [81]. These cells specifically express the PPARγ and its stimulation by pioglitazone and increase Treg cell numbers in the visceral adipose tissue [82]. These findings suggest that PPARγ-expressing Treg cells in adipose tissue might control inflammation in obesity, providing a new link between immunoregulation and metabolic disease [83].
6. B Cells
The exact role of B cells in the pathogenesis of autoimmune diseases is still matter of research. One previous hypothesis proposed that autoimmune disease develops as a result of persistence of self-reactive clones of lymphocytes that should have been deleted via normal immune tolerance, although some had suggested that this could be an epiphenomena. The success of B-cell depletion therapy in autoimmune diseases, particularly in rheumatoid arthritis (RA) [84], systemic lupus erythematosus (SLE) [85], antineutrophil cytoplasmic antibody- (ANCA-) related vasculitides [86], and multiple sclerosis [87], reinforces the importance of B cells in the pathogenesis [88].
Papers discussing the role of PPARγ agonists in B cells focus on the induced apoptosis by natural and synthetic agonists. The PPARγ mRNA and protein expression in mouse B cells is described, and it has been suggested that PPARγ agonists (15d PGJ2) could be involved in the induction of apoptosis in B lymphocytes [89]. The same group demonstrated the nuclear and cytoplasmic expression of PPARγ in normal human B lymphocytes. An antiproliferative effect of natural (15d PGJ2) and synthetic PPARγ ligands (ciglitazone) on human B cells through inducing apoptosis is also shown [90].
On the other hand, PPARγ expression was increased in human activated B cells as compared to nonactivated cells. Using low doses of PPARγ ligands (15-d-PGJ2 and rosiglitazone), they found an increase of B-cell proliferation and IgM and IgG antibody production. These effects were related to activation of the cells: activated B cells, which had higher PPARγ levels, can respond to PPARγ ligands, while nonactivated B cells, with low PPARγ expression, were not able to activate PPARγ upon low-dose PPARγ ligand exposure. There was also a raise of stimulated memory B cells differentiation to plasma cells [12]. In an animal model of asthma, 15d-PGJ2 inhibited LPS-induced B cell proliferation [62], and, in peripheral blood mononuclear cells of atopic dermatitis patients, there was significant inhibition of IgE synthesis [49].
The role of PPARγ in B cells in autoimmune diseases is less well documented. In PPARγ heterozygote knockout mice (PPARγ+/–), in which PPARγ expression is reduced by 50%, B-cell proliferative response was enhanced, but not T cells. Furthermore, PPARγ+/− mice developed more severe antigen-induced arthritis, that was suggested to be due to B-cell hyperreactivity. However, the production of T-cell-derived cytokines was also enhanced, since higher amounts of both IL-2 and IFN-γ were detected in the supernatant of antigen stimulated splenocytes from PPARγ+/– mice, and it was suggested that the alteration in T-cell function caused by reduced PPARγ expression could be responsible for the results [16].
The interaction between T and B cells and the autoantibodies production are key elements in the SLE pathogenesis. Recently, some studies have suggested the PPARγ participation in this complex disease. An increased PPARγ expression in patients with active SLE was described [91]. PPARγ agonist rosiglitazone was shown to reduce autoantibody production and ameliorate renal disease in a murine SLE model [92]. Ciglitazone inhibited IgE production in nonallergic and atopic dermatitis models in vitro and in vivo [49]. Indeed, these effects are not proven directly mediated by activated B lymphocytes, but rather indirectly mediated via regulatory signal pathways of other cells types. Reduction in PPARγ expression increases T-cell proliferation and skews toward Th1 immune response, which includes increased IFNγ and IL-12 production [16, 38]. These cytokines can directly influence B-cell function, including plasma cell formation, proliferation, and antibodies production [93–95].
7. Perspectives
In conclusion, PPARγ agonists are important modulators of the inflammatory process and lymphocyte homeostasis. Currently, there is evidence to support that PPARγ is involved in Th lymphocyte differentiation, B lymphocyte effector functions, and cytokine expression. Figure 1 summarizes the effects of PPARγ agonists on cytokine expression and on T regulatory cells and B cells. PPARγ is expressed by the main cell types of adaptive responses. Natural and synthetic PPARγ ligands proved to be capable of inhibiting major signaling pathways of adaptive immunity, reducing or augmenting the expression of cytokines. In fact, PPARγ ligands were shown to inhibit the production of several proinflammatory cytokines. Thus, further studies are necessary to clarify the use of PPARγ antagonists in diseases driven by the Th imbalance such as autoimmune diseases. The actions of these compounds at the cellular levels and their proven immunomodulatory effects make it worth considering their use in clinical trials exploring the possibilities that these drugs might help in the treatment of immune diseases.
This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco (FACEPE), and Financiadora de Estudos e Projetos (FINEP).
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Elevating Compliance through Legal Expertise
Find out what you like doing best, and get someone to pay you for doing it.
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BCP Associates is also an Executive Placement firm and actively recruits for Senior Management positions in client organizations in the ER space.
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In the last decade, BCP Associates has grown into a leading Legal Audit firm conducting pan India audits. To serve clients in all industry segments, BCP Associates is looking for talented, qualified and motivated individuals with excellent communication skills. If you are interested in any of the job openings below, please email us at [email protected] with your resume and we will get back to you.

subset: commoncrawl


text:
If you only want to capture a screenshot of just
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screen image. You can take a few simple steps
just to capture that particular window.
Open the specific window. Make sure the window
that you want to screenshot is open and visible
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Press Command + Shift + 4. At the same time,
press the command, shift, and 4 buttons. This
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Press the Spacebar. This will now turn your
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Position the cursor. Move your cursor, and now
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Save and share. The image will be saved onto
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ChristineNZL:lanceanz: I put up with my T-Box for just under 2 years till I finally said "enough is enough". I've had a MySky+ for 2 1/2 weeks and it's even better than I hoped for. Responds to the remote quickly; don't have to point the remote very deliberately at the box; everything is faster; everything integrated into the one box (i.e. no external power supply and modem); I regularly browse the listings on my iPad and add recording-reminders from it; when I have a conflict (more than 2 recordings at the one time) it gracefully cancels one; it's not crashed or lost any recordings; the recordings are way better than what I was getting on my T-Box in the most recent month or two.
What's not better? I think the T-Box makes better use of HD screens for displaying the EPG and recording information. I think the T-Box picture was a wee bit better (and I'm talking generally as I've not experienced rain-fade yet). Also I'm paying a bit more. I now have a satellite dish, but it's barely visible from the street and the cabling was nicely done.
The straw that broke the camel's back was that the quality of recordings deteriorated so much. I'd have stuck with my T-Box a bit longer if not for that. But I'm very happy I did give up. Especially as I found it frozen on the morning that the Sky tech came. My TV viewing is now stress-free. Hope the T-Box fix delivers a decent improvement for everyone.
We've had our MySky for a couple of months now and I couldn't agree more. ?Have not regretted cancelling our T-Box one little bit. ?I only wish we had made the move sooner. ?I'm not sure rain fade is much of an issue these days. ?We have had some appalling weather and never experienced it.
We moved from Telstra to sky 2 years ago, with mysky hdi.
Only one instance of rain fade in the 2 years, it really is a non issue now.


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I was wondering what was up. Usually NYC debuts after Orange County in the Housewives line-up but all the promos show that New Jersey is following next month. I'm OK with this because I rot my brain with all of them but I really like NYC. Sure, it got crap reviews last season and views were way down but those crazy bitches grew on me just like Andy Cohen knew they would. But word on the street is the ladies are playing hardball for more money and Bravo's ready to cancel the whole show.
According to Page Six, the women aren't asking for an exorbitant amount of money just a little pay raise to help cover all the hair and make-up expenses that come out of the own pockets during filming. Strike that. Crazy eyes herself, Ramona Singer, was asking for a million this season but quickly backed down with Bravo laughed in her face. If the deal goes through she'll reportedly make $500,000 whereas the other women make anywhere from 65K and above. It pays to be bat-shit certifiable!
So what should Bravo do? Bring back Jill Zarin! I'm not gonna lie, I still miss that one. I can't believe they are asking all the ladies back from last year. Heather Thompson was a big yawn and Aviva Drescher's creepy dad made me uncomfortable. But I am in LOVE with Carole Radziwill. I got around to reading her book, "What Remains" and I was pretty blown away by how beautiful it was. If you have a thing for the Kennedys or have lost someone close in your life then you should check it out. Her writing is pretty outstanding.
So I'm in this for Carole. I want to see her again so I hope they get this cleaned up quickly. Besides, I don't know what I'll do if I don't have Ramona to watch and use to feel better about myself.
What do you think? Should the show be canceled? Real Housewives of New York City isn't as volatile as New Jersey but it has it's redeeming moments, right? Right??!
Photo Credit: Diane Cohen/FAMEFLYNET PICTURES
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Carnegie Hall, New York
This image appears in the gallery:
The world's best classical music venues
6. Carnegie Hall, New York
The iconic hall, built in 1891, is the subject of an anecdotal joke. A pedestrian reportedly stopped violinist Jascha Heifetz, and asked him how to get to Carnegie Hall. Heifetz replied: "Practice!"


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A few more photos from the beautiful island of Vlieland. During my hike the tide was out and these tidal flats were revealed. At other times of the day the boats would be rocking in the water, but now they were parked in the mud flats. It's quite spectacular to see how many different habitats exist on what is essentially quite a small island. This is yet another face of the many faces of Vlieland. It just can't get any more Dutch than this with the water, boats, dunes, mud flats, Frysian horses. Beautiful!
5 comments
Vlieland looks a beautiful place, San 🙂 I am curious about the green on the foreshore … is it sea weed? At first I thought it looked like moss! … but not in saltwater 🙂 I could imagine there are a lot of migrating birds turn up along the island coast.
It is s beautiful! 🙂 It looks like seaweed to me too. The texture does look like moss, but upon taking a closer look I have to agree that it's seaweed, which makes…eh…sense 😛
Lol! I was thinking…could it also be some type of algae? Is there such a thing as salt water algae? There's definetly seaweed in there, but I've just never seen such a solid cover of it. Wonder if it's mixed in with something else 😛
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Article tagged as: bed bugs emedicine, bed mites bites, beg bugs, parasitic bugs, what causes bed bugs


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Portman Opens Up About Call From Romney
Senator Rob Portman, R-OH, learned from Gov. Mitt Romney via telephone Friday evening that he was not picked to be the GOP running mate.
This morning, Portman managed to duck ABC News' camera as he left his hotel in downtown Columbus to join his biking team for the annual Pelotonia 100- Mile Ride to cure cancer - a charity event he does every year. In the middle of a sea of spandex and racing shirts, ABC News managed spot Portman and, for the first time, hear how the call from Romney went and how he was feeling. Portman, who is generally upbeat and cheery, was visibly somber.
Portman said Governor Romney called him last night around 7:15 p.m. ET - the exact time Portman was delivering remarks at the opening ceremony of the Pelotonia bike ride. Portman missed the call but was able to connect with Romney shortly after wrapping up his remarks.
"He couldn't have been more gracious," Portman said of their interaction. "And I told him I'm really excited about the prospect of working with him as president and implementing the changes that are definitely needed in this county on economic and fiscal issues."
Portman said that despite being passed over, he will continue spearhead to Romney's Ohio presidential effort.
"It was a great phone conversation overall and I really appreciate him giving me the heads up," Portman said.
Portman has told reporters in recent days he elected to not downloaded "Romney's VP" app. He said he second-guessed that decision once the call came from Romney.
"I thought, well, maybe I should get the app. Take angry birds off my phone."
ABC News asked Portman if he was disappointed. After a long pause, Portman answered:
"Well, I'll just say what I've been saying. That I'm happy where I am. I do feel fortunate to be where I am. I really do. And I've said from the outset I think I can help him where I am."
A fellow biker approached Portman told him, "I hope you're the VP. I really do."
"Thank you very much," Portman said.
After another lengthy pause, Portman emphasized again he thinks he can make an impact through his work in the U.S. Senate, that he loved his family and Ohio and that he really is happy where he is.
"I was honored to be a part of the mix. There. That's the first time I've said that," he said confirming for the first time that he had in fact been vetted by the Romney campaign.
When asked if he was surprised by Romney picking Rep. Paul Ryan, R-WI, Portman said he "really didn't know."
Portman departed the Commons Square in Columbus shortly after 7 a.m. ET with his 8 man team, including his older brother, Wym, and son, Will. They are all wearing "Team Portman" jerseys in honor of both Portman and his wife Jane's mothers, who died prematurely of cancer. Watching them, however, it was clear they also wear the Portman jersey in support of their brother, son, and friend.
UPDATE: Senator Portman issued the following statement shortly before Romney's official announcement that Ryan would be his #2 in Norfolk, Va:
"Mitt Romney has made a great choice in Paul Ryan. He is an accomplished public servant and a leading voice on the most pressing issues facing our country. Paul is one of my best friends in Congress and someone I have worked closely with as a former colleague on the House Ways & Means Committee.
"Jane and I wish Paul and Janna and their kids the very best. As the Chairman of the Romney campaign in Ohio, I look forward to working with Paul to ensure that the Romney-Ryan ticket carries Ohio and is victorious in November. Most importantly, as a member of the Senate, I look forward to working closely with a Romney-Ryan Administration to restore fiscal sanity and enact pro-growth policies to create jobs."


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Family Separation Sign-On Letter
June, 2018
Dear Secretary Nielsen and Attorney General Sessions:
As medical and mental health professionals and researchers working in the United States, we are gravely concerned about the Trump administration's practice of separating migrant and asylum-seeking families at the U.S.-Mexico border. Such a practice is profoundly harmful to children and to families, in addition to violating fundamental human rights. We urge you to immediately end forced separation of families at the border, and instead keep families together in community-based settings while their immigration proceedings are pending.
The Trump administration has stated that its goal in separating children from their parents is to deter people from crossing the border between ports of entry. According to statements by Attorney General Jeff Sessions, this policy is intended to be punitive, to serve as such deterrence.[i] The child welfare implications appear to be secondary at best. White House Chief of Staff and former Department of Homeland Security secretary John Kelly has stated, "The children will be taken care of — put into foster care or whatever. But the big point is they elected to come illegally into the United States and this is a technique that no one hopes will be used extensively or for very long.[ii]" Media reports indicate that government mechanisms for ensuring that parents and children are in contact and know each other's whereabouts are non-functional.[iii]
Using children as leverage to punish their parents is unconscionable, both with respect to the health and well-being of children and as treatment of migrants and asylum seekers. The right to family unity is enshrined in U.S. and international law, which recognize that families are the foundation of society. The relationship of children and parents is the strongest social tie most people experience, and a threat to that tie is among the most traumatic events people can experience. Forced separation of children and parents, especially in connection with the detention of a parent, can constitute an adverse childhood experience (ACE). ACEs are linked with disrupted neurodevelopment, resulting in social, emotional, and cognitive impairment,[iv] and have even been linked with negative intergenerational effects.[v] Extreme and repetitive stress -- known as toxic stress -- such as that experienced when a person is suddenly separated from parents, adversely affects brain development and is correlated with increased risk of developing chronic mental health conditions, such as depression and post-traumatic stress disorder (PTSD) and even physical conditions such as cancer, stroke, diabetes, and heart disease.[vi]
Separation from parents has been shown to be linked with higher rates of PTSD in the affected children.[vii] For children, separation results in a low-support environment which places them at increased risk of PTSD and depressive disorders.[viii] The negative impact on the cognitive and emotional functioning of the affected children can continue into adulthood, and contribute to lower academic achievement, attachment difficulties, and poor mental health.[ix]
Among refugees, one research study shows that individuals separated from their families had worse mental health outcomes in terms of depression, PTSD, and psychological quality of life than those who remained with their families, after controlling for trauma. After testing the contribution of 26 types of trauma to these outcomes, only the experience of being beaten and tortured had a similar impact on all three mental health measures as family separation.[x]
According to the new U.S. policy, children arriving with their parents will be placed in the custody of the Office of Refugee Resettlement in foster families after separation. However, foster care is not an appropriate substitute to a child remaining with his or her parents, and studies of refugee children in foster care have shown that children fare worse when placed in foster families than when cared for by their parents.[xi] Placing these children into foster care will strain the U.S. child welfare system and set these children up for worsened health and social outcomes.[xii]
The best interests of the child is the recognized legal standard for the treatment of children across a range of domains, including parental custody and immigration proceedings. This standard requires that children not be separated from their parents except in extreme circumstances, if required for the child's protection. Indeed, the literature shows that parents are a vital buffer for children coping with severe stress.[xiii] A strong predictor of successful adaptation for children is family support.[xiv] Separation from their parents denies these children this vital resource, leaving them alone to face extremely stressful and likely frightening conditions. It increases the risk that these children will experience severe and long-lasting psychological problems, and may even contribute to the development of physical health issues.[xv]
The United States should follow the "best interests of the child" standard and immediately stop the practice of forced separation. It should not be U.S. policy to traumatize children, especially not as a form of indirect punishment of their parents. The intentional infliction of pain on children and their families is not just inhumane, it also fails to meet the stated goals of deterrence. Punishing parents with family separation may cause damage to their children, and it will not change the realities that drove the parents to seek safe haven in the United States.
As experts committed to promoting health and well-being, including of children, we ask you to immediately end the practice of family separation and take all measures to ensure that currently separated families are reunited without delay.
[i] Attorney General Jeff Sessions, "Attorney General Sessions Delivers Remarks Discussing the Immigration Enforcement Actions of the Trump Administration." Speech, May 7, 2018. https://www.justice.gov/opa/speech/ attorney-general-sessions-delivers-....
[ii] John Kelly, "Transcript: White House Chief Of Staff John Kelly's Interview With NPR." NPR.org. Last modified May 11, 2018. https://www.npr.org/2018/05/11/610116389/transcript-white-house-chief-of....
[iii] Michael E. Miller, "'They just took them?' Frantic parents separated from their kids fill courts on the border." El Paso News (El Paso, TX), June 11, 2018.
[iv] Vincent J. Felitti, Robert Anda, et al, "Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study," American Journal of Preventive Medicine (1998) 14(4); Debora L. Oh, et al, "Systematic Review of Pediatric Health Outcomes Associated with Adverse Childhood Experiences," Pediatrics, January 2018, 141 (1 Meeting Abstract) 309; DOI: 10.1542/peds.141.1_MeetingAbstract.309.
[v] Felice Le-Scherban, et al, "Intergenerational Associations of Parent Adverse Childhood Experiences and Child Health Outcomes," Pediatrics, June 2018, 141 (6) e20174274; DOI: 10.1542/peds.2017-4274.
[vi] "Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults," American Journal of Preventive Medicine, 1998, Volume 14, pages 245 - 258.
[vii] Geltman PL, Grant-Knight W, Mehta SD, et al, "The 'lost boys of Sudan': functional and behavioral health of unaccompanied refugee minors re-settled in the United States," Archives of Pediatric and Adolescent Medicine 2005; 159: 585–91.
[viii] Hodes, M. (2008), "Psychopathology in refugee and asylum seeking children."
[ix] Bronstein, I., and Montgomery, P. (2011), "Psychological distress in refugee children: a systematic review," Clin Child Fam Psychol Rev, 14(1), 44-56. doi:10.1007/s10567-010-0081-0
[x] Miller, Alexander, Hess, Julia Meredith, Bybee, Deborah, Goodkind, Jessica R, (2018), "Understanding the mental health consequences of family separation for refugees: Implications for policy and practice," American Journal of Orthopsychiatry, Vol 88(1), 2018, 26-37, http://psycnet.apa.org/doiLanding?doi=10.1037%2Fort0000272
[xi] Holtan A, Rønning JA, Handegård BH, Sourander A, "A comparison of mental health
problems in kinship and nonkinship foster care," European Child & Adolescent Psychiatry
2005; 14(4): 200-207; Geltman PL, Grant-Knight W, Mehta SD, et al, "The 'Lost Boys of Sudan'"
[xii] Ahrens, K. R., Garrison, M. M., & Courtney, M. E. (2014, "Health outcomes in young adults from foster care and economically diverse backgrounds," Pediatrics, 134(6), 1067-1074; Dworsky, A., Napolitano, L., & Courtney, M. (2013, "Homelessness during the transition from foster care to adulthood," American Journal of Public Health, 103(S2), S318-S323.
[xiii] Bowlby, J. (1988), "A secure base: Parent-child attachment and healthy human development," New York: Basic Books; "Fostering resilience; protective agents, resources, and mechanisms for adolescent refugees' psychosocial well-being," Adolescent Psychiatry, 2014, Volume 4, Issue 4, pages 164-176.
[xiv] "Comparing psychological distress, traumatic stress reactions, and experiences of unaccompanied refugee minors with experiences of adolescents accompanied by parents," The Journal of Nervous and Mental Disease, April 2007, Volume 195, Issue 4, pages 288-297.
[xv] Shanta R. Dube, Vincent J. Felitti, et al, "The impact of adverse childhood experiences on health problems: evidence from four birth cohorts dating back to 1900," Preventive Medicine 37 (2003), 268–277.


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A Fairfield woman who allegedly filled at least 10 prescriptions using a stolen prescription pad and a doctor's license number was arrested by Westport Police.
Police learned of the incident when a Westport doctor reported the possible theft of a prescription pad by an employee, said the Westport Police.
He told police his office manager had received a call from a pharmacy regarding a prescription for an employee, Kristin Futia, 37.
The doctor told the pharmacy he did not prescribe anything to Futia and the prescription was not filled, police said.
He later learned Futia had allegedly previously filled 10 fraudulent prescriptions using his prescribing license number, two of which were filled in Westport, police said.
Futia was arrested on Friday, March 15, and charged with two counts of forgery. She was released on a promise to appear ticket and is scheduled to appear in court on March 26.
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Watch Now
Beat Bobby Flay not available on your favorite video service? Find something else you'll like!
12 Episodes
Videos: Trailers, Teasers, Featurettes
Streaming, rent, or buy Beat Bobby Flay – Season 23:
Currently you are able to watch "Beat Bobby Flay - Season 23" streaming on Hulu, fuboTV, Sling TV, DIRECTV, Food Network or buy it as download on Apple iTunes, Google Play Movies, Vudu, Amazon Video, FandangoNOW, Microsoft Store.


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Genetic variation and population structure in the endangered Houston toad in contrast to its common sympatric relative, the coastal plain toad
Metadata[+] Show full item record
I determined the number of populations, the levels of genetic diversity within and among populations, and migration/movement rates at the landscape and fine scales in the endangered Houston toad, Bufo houstonensis (Anura: Bufonidae) using mitochondrial sequence data and microsatellite loci. Genetic clustering analyses indicate nine populations across the range. The most divergent population was in Austin County, Texas. Genetic diversity was high across the range and within populations. I also examined population genetic structure and diversity in a common, sympatric congener, the coastal plain toad (Bufo nebulifer). Bufo houstonensis and B. nebulifer have comparable levels of genetic diversity, but B. nebulifer appears to migrate less frequently or over less distance than its endangered congener. Finally, I investigated the baseline levels of genetic admixture, or hybridization, in B. houstonensis. Admixture between B. houstonensis and two sympatric species (B. nebulifer and Bufo woodhousii) was detected. With continued habitat alteration and rising temperatures, both habitat isolation and offset breeding season have already partially broken down as isolating mechanisms and may deteriorate further; consequently, opportunities for hybridization events will increase. Conservation recommendations for B. houstonensis include supplementation programs to increase the number of individuals, preservation of all three habitat types (breeding/nursery, occupied, and dispersal), special attention towards the Austin County population, and involvement of the general public in conservation.
Ph. D.
Thesis Department
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.


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Steve Close is a qualified Dredge Master with over 17 years experience operating vessels on the water.
Steve has a Master Class 5 and Marine Engine Driver II. It's in Steve's blood to work on the water and he wouldn't do anything else! He has great pride in providing amazing service and making beautiful beaches for the properties he maintains.
Steve has been dredging Gold Coast Canals as part of The Gold Coast City Councils Maintenance Program and is now available for private hire anywhere on the Gold Coast.
Close Encounter Dredging currently conducts all maintenance dredging for Southport Yacht Club.


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An idea turned into reality
…And on December 18th we hosted our first charity drive, Santa for Seniors.
With the help of my AMAZING cousin, Kristie, founder of the non profit female empowerment group, Head Turners Ent., we collected blankets, pajamas, books, movies & lots more, all for old people!
The concept of Santa for Seniors came about because our grandmother lives in a nursing home. We love her very much, so we wanted to show our appreciation to a sometime forgotten, but important segment of people.
The most important thing for us was that the drive directly benefited the community we're from and live in, southeast Houston.
So after plenty of phone calls & false starts, we found the perfect home to accept our donations, the Mission Care Center.
This nursing home is located on the corner of Wayside Dr. and the South Loop East freeway. The friendly staff at Mission Care Center provides short and long term assistance to about 40 residents, and it is a Medicare-friendly facility.
As the event approached, I was a little nervous, but the love for what we were doing kept me going! And thanks to the kind people that came out and donated it actually went really well!
Dianne Mlih, Activity Director for the Mission Care Center, is passionate about her seniors and appreciated our contribution. What an amazing feeling!
(Shout out to my little cousin, Karter with the cameo. -__-)
This was probably the best Christmas ever and my cousin and I are so looking forward to doing this again.
Special thanks to Dianne Mlih, the Mission Care Center, and everyone that donated & showed their support!
Let me know below how you incorporate your brand during the holidays.
Merry Christmas + Happy New Years!


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Dad's Gift Bag SVG
Categories: Bags, Father's Day, Guys Tags: Father's Day, Gift Bag, Guy, Man, SVG, Sweater
- Product is provided in ZIP format and contains SVG files only. Product is 100% digital. Nothing physical will be mailed to you.
- 12"x12" cutting machine required (Recommended machines include Cricut Explore/Air/One, Cricut Explore Air Two, Cricut Maker, Brother ScanNCut, Silhouette CAMEO and Sizzix eclips2. For full list of compatible machines click here. Not fully compatible with 6"x12" or 8.5"x11" cutting machines. Items may be created with non 12"x12" cutting machines, but only at a smaller size.
- Cricut Design Space
- Silhouette Studio Designer Edition or Higher
- Sure Cuts A Lot 2 (may require manual sizing, not fully compatible with certain open path cuts)
- Sure Cuts A Lot 3 (may require manual sizing)
- Sure Cuts A Lot 4
- Sure Cuts A Lot 4 Pro
- Sure Cuts A Lot 5
- Sure Cuts A Lot 5 Pro
- eCAL (may require manual sizing)
- eCAL 2 & 3
- Make-The-Cut!
- Brother Canvas
(H)eight x (W)idth x (D)epth in Inches
- Dad's Gift Bag – 8″ H x 5.5″ W x 3.5″ D
Supply List
Dad's Gift Bag
- 1 Sheet Of 8.5X11 Lavender Cardstock
- 1 Sheet Of 8.5X11 White Cardstock
- 1 Sheet Of 8.5X11 Keylime Cardstock
- 1 Sheet Of 8.5X11 Lagoon Cardstock
- 3 Sheets Of 12X12 White Pattern Paper (Lawn Fawn Knit Picky Collection)
- 1 Sheet Of 8.5X11 Yellow Pattern Paper (Echo Park Dots and Stripes Collection)
- 1 Sheet Of 8.5X11 Argyle Pattern Paper
- 1 Sheet Of 8.5X11 Gold Foil Paper
- Fine Point Markers*
- 2 Yellow Buttons (0.375" In Dia.)
- Velcro Dots (0.375" In Dia.)
- Embossing Folder*
- Ink*
- Glue (Buy on Amazon)
All cardstock featured is AC Cardstock By American Crafts
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Far from the madding property crowd
If you really want to know what's happening next in the property market – just read the media.
Be it in a newspaper, a magazine or fresh onto your iPad, the mainstream media misreports facts so frequently, and with such fervor, that it's no wonder that their myths seem to magically become fact so often.
We live in a world of instant answers to the many questions we have, and these days, so many people rarely question the validity of the facts before them. We read the reports and suck up the information as if it were an informed forecast of the future or a fair and equitable reporting of the truth, and no longer question sources, slants, and facts.
Once upon a time
In the olden days, newspapers reported news of events that had already occurred – often days later after facts were carefully collected, sources analysed and stories prudently crafted to accurately report the event. Now though, much of what we read is a dissertation based on airy-fairy data, extrapolated out to represent future events, then reported as if these events are a sure thing.
Nowhere is this practice more prevalent than in the property industry, where daily we read of future booms, busting bubbles, oversupply, shortage – if it's about property it will be predicted and reported upon, often using the interpretation of a journalist who is most likely an excellent journalist, but not even the shadow of a property expert.
And the saddest part of this phenomena is that, like any self-respecting prediction, the 'forecast' event or fact becomes a self-fulfilling prophecy, as property investors everywhere take counsel and guidance from these often baseless reports and plan their entire investing strategy around them.
We see less of this on the share-market – that world is too fast paced to forecast, with T+3 meaning the tides can turn quicker than a newspaper can be printed, making any story about the future too easy to prove or disprove before the ink is dry. Yet where property is concerned, there is never any shortage of growth data, quickly consumed and then spat out by journalists to form a prediction of future events.
Which is madness, when you think about it, because as far as property is concerned, past growth is no indication of future growth! In fact I would go so far as to say that, in many areas, strong past growth is a sure fire sign to stay away – because you've missed it.
The boom boys (and girls)
Two years ago the media began predicting a boom in Sydney. It seemed to many to be an easy guess – so little had happened for so many years that it was well overdue for a catch up – but is this why it boomed? Or did it boom because of the copious amount of media stories stating that it would? Did the market move because it was value driven, or did it move because we were told it would, and everyone panicked that they would miss out, making it happen?
Now we see the pundits predicting the popping of the balloon – with dire warnings splashed across the headlines of the bloodbath to come. I'd like to bet that enough of these stories will make the average, risk averse property buyer take cover and hibernate till the worst is over – once again causing another flimsy prediction to come true.
This is why I stay away from much of what is reported on property markets – the ride is too nail biting and even I'm guilty of panicking whenever I see another dire headline. For me, it's just so much better to find an ordinary area, filled with ordinary people, who live in ordinary houses away from the madding crowd, where families flourish and councils provide a great lifestyle with infrastructure and services and where no one is interested in writing a property story because it's all too ordinary.
And you know what? So far I've hardly bought a property that hasn't doubled in its first five years and given me a great starting yield of at least 6%. It's terribly ordinary, I know, but it's easy, low risk and, even better, a darned good strategy.


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Marcopolis presents Nigeria Report focused on topics such as investments, power and hospitality, featuring interviews with Nigeria's leaders. The sectors under review in this issue are banking, construction, energy, industry, logistics, real estate, tourism and many more.
Lafarge Africa's brands in Nigeria include Ashaka Portland Limestone Cement, Elephant Cement, Powermax Cement, Supaset Cement, UniCem Cement, and Readymix Concrete and Aggregates.
"Combining our operations in Nigeria - 4.5MMT in WAPCO (with three plants in Ogun State), 1MMT in Ashaka Cement Plc (Gombe State), 2.5MMT in United Cement Company of Nigeria Limited (Cross Rivers State) and a terminal in Atlas Cement Company Limited (Rivers State) - with operations in South Africa 3.6MMT, Lafarge Africa Plc has a current installed cement capacity of 12MMT, which is expected to grow to 17.5MMT by 2017. This is in addition to strong market leading positions in aggregates, ready mix concrete and fly ash."
"We enjoy doing business in Nigeria and will continually invest in the Nigerian economy whilst building on its values to make the best aggregates, cement and concrete solutions available in all parts of the country."
All financial data are sourced from respective 2015 financial reports (12/2015).


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Dunford to lead Marine Corps
Gen. Joseph Dunford, Jr., the commander of international forces in Afghanistan, has been nominated by the president to be the next commandant of the Marine Corps, Secretary of Defense Chuck Hagel announced today.
Fellow Marines dubbed him "Fighting Joe" Dunford during the 2003 Iraq invasion, for his aggressive march to Baghdad as head of the 5th Marine Regiment.
In the 37 years since he was commissioned a Marine officer in 1977, Dunford's assignments have also included assistant commandant of the Marine Corps and commanding general of the West Coast Marine force headquartered in San Diego at Camp Pendleton, the 1st Marine Expeditionary Force.
The current commandant, Gen. James Amos, has said he expects to retire in October.
"Joe is one of the most knowledgeable and talented leaders and thinkers in the military today. He has commanded and excelled at every level. His tenure (in Afghanistan) … over the past 18 months has been extraordinary, and is testament to the full measure of the man," Amos said Thursday in a statement released by his spokesman.
"Our country and our Marine Corps will benefit greatly from his continued service."
Dunford is known among his peers as an unassuming workaholic and dedicated public servant who set aside his desire to retire and spend more time with family several times because of the needs of the Corps.
Lt. Gen. John Toolan has known Dunford since 1979 when they were fellow infantry platoon commanders. Dunford is a "blue collar guy," model father and husband, and die-hard Red Sox baseball fan who never forgave Babe Ruth, Toolan said in December 2012 when Dunford was selected for the Afghanistan job.
"He has an exceptional memory and superior intellect. Whatever schools he has attended he has consistently been among the top. He has been a fast mover through the ranks, skipping wearing two stars," Toolan said.
"There isn't a single person in or out of the Marine Corps that doesn't agree that he is among our best ever."
Dunford is a Boston native and son of a former deputy police superintendent and Marine veteran of the Chosin Reservoir battle of the Korean War.
The father of three married his wife Ellyn some 30 years ago and still vacations with his parents, a former staff member noted.
Dunford assumed command in February 2013 of the International Security Assistance Force (ISAF) and U.S. Forces – Afghanistan. He released a brief statement about his new job shortly after returning to Kabul from a defense minsters meeting in Brussels, saying: "I'm humbled to be nominated as the 36th Commandant of the Marine Corps."
His spokesman, Marine Lt. Col. Eric Dent, said Dunford is not media shy, merely busy and "so focused on our ISAF mission."
When he was selected in late 2012 to become the next commander in Afghanistan, several high-ranking Marines spoke about him to U-T San Diego on background because Dunford shuns the limelight.
He rarely grants media interviews unless it serves a strategic purpose, for instance over Christmas when he publicly pressed President Hamid Karzai to quickly sign the bilateral security agreement regarding a post-2014 force of U.S. troops in Afghanistan.
The timeline for Dunford to relinquish command in Afghanistan is undetermined, according to Army Col. Steve Warren, a Pentagon spokesman. His potential successor leading international forces has not been announced.
On Christmas Day at Camp Leatherneck, Dunford served the holiday dinner to Marines and other service members deployed to Helmand province. The NATO campaign needs a couple more years to develop the sustainability of the Afghan security forces, he said at the time in an interview with U-T San Diego.
"We don't need to help them fight. What we need to do is develop the capacity of the ministries to actually support the guys who are fighting," Dunford said.
This summer fighting season -- and the recent announcement by President Barack Obama that almost 10,000 U.S. troops will remain in Afghanistan after this year -- will be key to building the confidence of the Afghan forces, and stabilizing the country against the insurgency, Dunford predicted.
"In the summer of 2014 my sense is … the conditions will be such that we can begin a process for peace that will eventually direct Afghan reconciliation, which I think is necessary in the long term for our gains to be enduring," he said. "The campaign we are evolving right now is providing the time and a space within which those other things can take place."
Dunford was a political science major as an undergraduate at St. Michael's College. He earned a master's degree in government from Georgetown University and another in international relations from the Fletcher School of Law and Diplomacy.
He is a nimble thinker with a ravenous appetite for information whose aides in Afghanistan have been known to carry a voice recorder to keep up with his rapid-fire commands and observations.
As assistant commandant he held his own filling in for his boss "in the tank" among the Joint Chiefs of Staff, showing a knack for synthesizing information and "framing the strategic nugget," according to a former executive assistant.
Dunford is also a loyal champion for his staff, unless you "break covenant" with his high expectations. He is admired for his heartfelt concern for individual Marines, ruthless ability to roll heads when they let down the Corps and talent for cutting bureaucracy.
"He is not afraid to hold people accountable for what they do. But he also is not afraid to make the bureaucracy accountable. His personal integrity, his credibility with people is what gets the system to fix itself as well as the individual," a former staff member said.
Marine Brig. Gen. Paul Kennedy, who served with him in Iraq, said Dunford excelled in battle by treating his team like family, exercising and eating together.
"His regiment led all the way up to Baghdad," Kennedy recalled.
"When they launch across the line of departure, we're watching all three regiments on a big blue force tracker. You could see the lead elements of Gen. Dunford … as the other guys stopped, all you could see was his guys moving forward.
"He does all of this so fast that we basically weren't able to keep up with the plan. That's why they call him Fighting Joe."
Rep. Duncan Hunter, R-Alpine, a Marine veteran of Afghanistan and Iraq who serves on the House Armed Services Committee, said one of the Corps' best and most effective leaders had been nominated as commandant.
"It's reassuring to know that there will be a warfighter leading Marines," Hunter said in a statement released by his staff.
"With the drawdown in Afghanistan, the next several years will be a transformative time for the Marine Corps and Gen. Dunford is the right man to meet the challenges ahead. Gen. Dunford's steady hand and experience will be guiding forces for the Marine Corps."
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UK Charts: Saints Row 4 holds top, Lost Planet 3 and Killer is Dead place low
Saints Row 4 has held its position at top of the UK charts for a second week, while newcomers Lost Planet 3 and Killer is Dead fail to ignite healthy sales.
The full top 20 is below. Lost Planet 3 entered at 26, while Killer is Dead placed at 28.
I discussed Killer is Dead's controversial Gigolo missions and other gameplay elements here.
Missed our Saints Row 4 review round-up? Go here.
- Saints Row IV
- Tom Clancy's Splinter Cell: Blacklist
- Final Fantasy XIV: A Realm Reborn
- Disney Infinity
- Minecraft: Xbox 360 Edition
- Rayman Legends
- Madden NFL 25
- Call Of Duty: Black Ops II
- Payday 2
- Fifa 13
- Animal Crossing: New Leaf
- Lego Batman 2: DC Super Heroes
- The Last Of Us
- Max Payne 3
- Lego The Lord Of The Rings
- Tomb Raider
- Skylanders Giants
- Assassin's Creed III Xbox 360 Classics
- Grand Theft Auto IV Xbox 360 Classics
- Need For Speed Most Wanted


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My drawing is a spontaneous response to what I see, initiated from reality. It is not a demonstration of facility. It is not a literal description of surface qualities. It is a search for a internal reality that validates an object's reason for being. My work is a process of discovery through deconstruction. This process allows me to dignify the presence of the subject that I am working from, rather than to characterize it.
I maintain the aspect of the gesture in the approach to my work. This approach allows the drawing to live and to invoke a response.
My drawing is usually mixed media, although, not exclusively. The media I choose is dependent on the composition and statement that is being made. I approach my work intuitively. My work is not formulaic.
I succeed. I fail. I am the real deal.
Website: http://fineartbymichaelkelly.com


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RICE melamine cup - Yellow
By RICE
or make 4 interest-free payments of $1.98 fortnightly with More info
RICE's melamine cups are available in a rainbow of bright and cheery colours and prints. Mix and match to create your own unique colour combination.
The nitty gritty...
Made of 100% melamine
BPA free
Dishwasher friendly
Height: 9 cm
Diameter: 9cm
Complete your RICE style with matching melamine plates and bowls.
Neapolitan :: Colourful homewares and lifestyle products. www.neapolitan.net.au
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Today we celebrate Coast Guard Day. The Coast Guard can point to many achievements over its history, but for me, our greatest achievement was the Coast Guard's response to Katrina. I was out of the service by then, but I watched the news reports and felt immense pride in being associated with the service.
Katrina was ten years ago this month and a documentary will be aired late this month on PBS stations in Alabama, Mississippi, and Louisiana. The film is not a lavishly produced summer blockbuster, it is a student film, but was apparently a labor of love, the idea of a "Coast Guard brat." You can learn more about the film and its genesis here and here.


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Belvédères du Verdon
Castellane, gateway to the Verdon Gorge, is also an ideal starting-point for exploring the lakes and dams upstream and the range of mountains surrounding them.
After a first circuit towards the hilly hinterland of the Var, the path will climb onto a belvedere above Castillon Lake with breathtaking views. A trip to the Col St Barnabé and back will take you even higher, or you can plunge down towards the lake and back to Castellane. As you approach the town, the Chapel of Our Lady of the Rock, perched high on a spur, will definitely catch your eye.