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Int. J. Mol. Sci. 2014, 15, 4965-4976; doi:10.3390/ijms15034965
International Journal of
Molecular Sciences
ISSN 1422-0067 www.mdpi.com/journal/ijms
P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases
Andrea Picchianti-Diamanti 1, *, Maria Manuela Rosado 2 , Marco Scarsella 2 , Bruno Laganà 1 and Raffaele D'Amelio 1
1 Department of Medical Sciences, Sapienza University of Rome, 2nd School of Medicine, Sant' Andrea University Hospital, 00189 Rome, Italy; E-Mails: email@example.com (B.L.); firstname.lastname@example.com (R.D.A.)
2 Research Center Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy; E-Mails: firstname.lastname@example.com (M.M.R.); email@example.com (M.S.)
* Author to whom correspondence should be addressed; E-Mail: email@example.com; Tel.: +39-06-3377-6043; Fax: +39-06-3377-5331.
Received: 7 February 2014; in revised form: 6 March 2014 / Accepted: 13 March 2014 / Published: 20 March 2014
Abstract: Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.
Int. J. Mol. Sci. 2014, 15
Keywords: p-glycoprotein; autoimmune diseases; multidrug resistance; lymphocytes
1. Introduction
In the last decade, the growing knowledge of the molecular and cellular pathways involved in the development and progression of systemic autoimmune disorders combined with the advances in monoclonal antibody technology [1] have led to a better therapeutic management of autoimmune diseases. Despite these efforts, a significant percentage of patients do not respond, or develop a secondary failure to conventional treatment regimens. It has been hypothesized that therapeutic
unresponsiveness may be caused by various mechanisms such as the rapid degradation of corticosteroids (CCS), the release of neutralizing antibodies against biological agents such as infliximab, or other unidentified factors [2]. More recently, unresponsiveness to CCS has been correlated to the expression of multidrug resistance gene (MDR-1) on a subset Th17 inflammatory lymphocytes [3]. MDR-1 encodes for
a transmembrane P-glycoprotein (P-gp), of 170-kD belonging to the superfamily of ABC
(ATP binding cassette) transporters [4] that plays an important role in controlling drug uptake and excretion [5]. Initially studied in the context of tumor therapy, P-gp over-expression or hyper-function has been proposed, more recently, as a possible mechanism of drug resistance in patients with systemic autoimmune diseases [6,7]. In this review we will focus on the role of P-gp expression/function in the development of drug resistance in patients affected by systemic autoimmune diseases in particular systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) and will discuss how P-gp may be a therapeutical target in the control of abnormal immune response and inflammation.
2. P-gp Expression and Function in the Immune System
At least 48 human ABC transporters have been described, however only three have been linked to a role in mutidrug drug resistance (MDR) to anti-cancer, anti-inflammatory and anti-viral drugs [8]:
the multidrug resistance associated protein 1 (MRP1 or ABCC1), the breast cancer resistance protein (BCRP or ABCG2) and P-gp also called transmembrane small-molecule pump (ABCB1). P-gp is one
of the most studied MDR family members for its function in extruding various cytotoxic compounds
out of the cells [9] but also for its role in modulating inflammation by direct or indirect tuning the secretion of cytokines, chemokines and other small peptides [10–12]. P-gp is widely present in different normal tissues such epithelial cells of the kidney, liver, intestine and in endothelial cell of the brain and of the placenta [13,14]. P-gp is also present at different stages
of the lymphoid cell development [15–17] but its role on the maturation and function of each cell
subset has not been completely revealed. Recently, studies in the mouse have shown that P-gp expression is required for dendritic cell (DCs) migration to lymph nodes [18] as well as for DCs development and maturation [19]. In fact, the down-modulation of P-gp on DCs, after venlafaxine (VLX) treatment, dampens surface expression of co-stimulatory molecules and reduces cytokine production impairing T cell proliferation in an allogenic mixed lymphocyte reaction (MLR) assay.
In mice, the ablation of the MDR-1a gene [20,21], that codes for P-gp, always leads to the spontaneous development of T-cell mediated colitis with no other autoimmune disorder being reported [22,23]. Recently this mouse model for colitis has been the target of a new study in which the role of P-gp expression and the homeostasis of the regulatory T cell compartment was investigated [24–27]. It was found that P-gp is important for the generation, at the mucosal site, of inducible regulatory T cells (iTreg) from naïve MDR-1a deficient T cells. Thus, lack of P-gp on CD4+ T cells compromises the suppressive function and the anti-inflammatory role played by iTreg cells in the intestine finally resulting in the development of chronic inflammation and colitis [28]. As in the mouse, in humans, the expression of P-gp in the T cell compartment seems to be tightly regulated. P-gp is highly expressed by bone marrow multipotent stem cells in humans [29]; its expression lowers in the early bone marrow and thymocyte precursor cell compartments to increase again in the thymus following T cell maturation [30,31]. Peripheral blood T- and B-lymphocytes express modest levels of P-gp [32–35] that can be up-regulated upon lymphocyte activation in particular on CD4+ T cells. P-gp expression can be measured by flow-cytometry using specific antibodies (CD243), and, its function, using rhodamine-123 (Rh-123) dye [14]. Rh-123 molecules enter living cells by passive effusion and are actively pumped out by P-gp. Thus, bigger is the loss of Rh-123 fluorescence higher is the function of the P-gp pumps. Because Rh-123 extrusion directly depends on P-gp, it can be blocked by verapamil, hydroxycloroquine, tacrolimus or cyclosporine that are P-gp inhibitors [36]. P-gp was first described to confer resistance to several chemotherapeutic drugs [37] or antagonizing caspase-3 dependent apoptosis in tumors [33,38]. More recently, P-gp function has been studied in multiple conditions in which patients develop resistance to therapy, for example P-gp expression has been correlated to the efficacy of highly active antiretroviral therapy (HAART) on HIV infection [39,40] and to the lack of response to CCS in autoimmune patients [41]. Although, genetic studies have shown that several polymorphisms on the MDR-1 gene result in altered function of P-gp and increased susceptibility to develop colonic inflammatory diseases such as ulcerative colitis [42] no similar correlation has been exploited for other systemic autoimmune diseases. The complex link between autoimmunity and P-gp function has been recently investigated by Ramesh et al. [3]. They showed that P-gp is a useful marker to distinguish a subgroup of pro-inflammatory human Th17 cells [43] from non-pathogenic Th17 cells; these lymphocytes produce both IL-17A, IL-17F, IL-22 and IFN-γ cytokines upon T cell receptor (TCR) stimulation and do not express IL-10 or other anti-inflammatory molecules. They also demonstrated that these Th17 cells expressing P-gp are refractory to several CCS and accumulate in the gut of Crohn's disease patients.
3. Therapeutic Management and Drug Resistance in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA)
The prototype of systemic autoimmune disease is SLE. SLE is a chronic autoimmune inflammatory disease of unknown etiology characterized by protean clinical manifestations that can involve different organs, such as kidney, heart, brain, skin and by the production of several autoantibodies against various self-molecules [44].
SLE emerges with a rate of 0.65/patient/year and has an increased mortality due to lupus activity, long lasting sequelae and heavy side effects caused by the present therapies, as compared to the general population [45,46]. Different immunosuppressant drugs can be implemented to control disease activity depending on the severity of and type of organ damage, particularly, nephritic versus neurological. Hydroxicloroquine (HYQ) and low dose of CCS are commonly effective in patients with mild SLE, whereas a mono or combined therapy of: azathioprine, methotrexate (MTX), mycophenolate mofetil and cyclophosphamide with high doses of CCS are used in active, severe or refractorySLE [47,48]. Cyclosporine (CsA) has been introduced in 1981 by Isenberg et al. [49] for patients with active SLE; 2.5–5 mg/kg/day may provide adequate disease control and behave as CCS-sparing drug [50]. CsA binds to cyclophilin with the synergistic action of calcium and suppresses activation of calcium-dependent phosphatase calcineurin, thus leading to the block of T cell activation and cytokine release, such as IL-2 [51]. CsA also represents a substrate and competitive inhibitor of the P-gp function [5]. Despite all the efforts, long term treatment of SLE still remains a major challenge for clinicians that have to face the constant fluctuation between remission and flares over time, drug unresponsiveness and side effects. RA and PsA are chronic, inflammatory autoimmune diseases potentially leading to functional disability, deterioration in patients' health-related quality of life and life expectancy [52]. There is strong evidence that the highest joint inflammation, observed in these patients, occurs in the first 2 years and that prompt treatment is able to slow down the progression of diseases reducing the inflammatory events associated with structural and functional joint impairment. Therapeutic weapons for RA and PsA are very similar and their number constantly increasing, as a consequence of a better knowledge of disease pathogenesis and of the advances in monoclonal antibody technology. Disease modifying anti rheumatic drugs (DMARDs), also called synthetic immunosuppressive agents, such as HYQ, sulfasalazine (SSA), leflunomide, MTX and CsA were, until 10 years ago, the most commonly used drugs to treat these patients. Nowadays they are often replaced or supported by the introduction of biological agents that target cytokines such as TNF-α, IL-6 or can inhibit T cell activation and B cell function. The gold standard therapeutic regimen for RA and PsA patients is represented by the early introduction of MTX plus low dose CCS, non responding patients can be treated with a combination of synthetic DMARDs or switched to a biological agent [53]. Although these treatment strategies have shown good efficacy, up to 40% of the patients may not benefit from the therapy because lack of efficacy, development of resistance [54] or treatment related adverse events [55]. Furthermore, this growing availability of therapeutic weapons is not supported by validate clinical/immunological predictive markers that can help the clinicians in the adoption of the best personal "targeted therapy". CsA is a drug often used in PsA patients because it demonstrated to have good efficacy and high tropism for the skin [56,57]; however, it is important to note that also RA patients may benefit of a therapy using CsA specially in combination with MTX. In fact, a recent study by Migliore et al. [58] has shown that MTX + CsA was able to control disease activity and maintain clinical remission in RA patients more efficiently than therapy with MTX alone.
4. P-gp and Mutidrug Drug Resistance (MDR) in SLE, RA and PsA
The association between P-gp and MDR-1 has been extensively evaluated in oncology, whereas the
studies on autoimmune diseases are scarcer and the few that do exist are mainly focused on patients with SLE and RA [54]. The first description, for a role of P-gp on autoimmunity, was reported in 1990 by a French group in which the authors described an overexpression of P-gp on the surface of peripheral lymphocytes of RA patients treated with CCS [59]. Later on, another group, Yudoh et al. in
1999 [60], showed an increased expression of P-gp on TH1 cells isolated from 22 RA patients not
responding to SSA therapy. Hider et al. [61] found that MTX treatment in newly diagnosed RA patients resulted in the down regulation of P-gp expression on circulating mononuclear cells. In 2008 Tsujimura et al. [62] analysed P-gp expression on lymphocytes isolated either from healthy donors or from RA patients under therapy for at least 2 years and found that P-gp was overexpressed by lymphocytes from RA patients. Moreover, expression of P-gp positively correlated with disease activity and CCS treatment, whereas it reduced with MTX and with the use of infliximab, a chimeric monoclonal anti-TNF-α antibody. The same group reported similar results in 2010, this time analyzing 11 RA patients treated with the anti-TNF-α soluble receptor, etanercept [63]. Etanercept ensued a good disease control and was able to reduce P-gp expression on CD4+ T cells and on B cells (CD19+) in RA patients not responding to MTX as well as in two patients in which infliximab has failed.
Agarwal et al. [64] evaluated P-gp expression in a group of 25 RA patients some of which were naïve and others were resistant to MTX therapy; the authors showed a significant positive correlation between high expression of P-gp and disease activity, whereas no association was found among high P-gp expression and unresponsiveness to MTX therapy. In contrast, Suzuki et al. [65] using the calcineurin inhibitor tacrolimus [66,67] (that works also as inhibitor of P-gp function) in 113 RA patients refractory to MTX or other DMARDs showed that 22 patients achieved good clinical responses correlated with a reduction of P-gp expression/function on peripheral lymphocytes. Interestingly Kis et al. in 2009 demonstrated that BCRP could play an important role in the development of resistance to leflunomide by using an ATPase assay, whereas neither leflunomide nor its active metabolite were capable of stimulating the basal activity of P-gp transporter, suggesting that the ABC proteins do not present DMARDs substrate profiles completely comparable [68]. Finally, we recently analyzed P-gp expression on three PsA patients with a secondary failure to MTX, before and after combined therapy with CsA and found that the introduction of CsA resulted in a good clinical outcome and a reduction on P-gp function on CD3+ T cells, particularly ascribed to the contribution of P-gp functional reduction on CD8+ T cells [69]. Several groups have invested considerable efforts on the study of the relationship between disease activity and P-gp expression levels/function in SLE patients [50]. In 2000, Llorente et al. [70] studied P-gp expression and function in the peripheral blood lymphocytes isolated from 30 SLE patients and showed that the mean percentage of lymphocytes with high P-gp activity was increased as compared to the healthy controls; moreover, lymphocytes from SLE patients in clinical remission had a lower P-gp activity than those with active disease. Similar results were obtained by the group of Tsujimura et al. in
2005 [71]. This group analyzed the expression of P-gp on peripheral lymphocytes from SLE and
healthy controls and found significantly higher levels of P-gp on lymphocytes of 80 SLE patients with
active disease than in normal controls. In addition, P-gp expression was increasing with the rise of
disease activity and decreasing by immunosuppressive therapy. P-gp was expressed on both CD4+ and CD8+ T cells and strongly expressed by CD19+ B cells in patients with impaired response to CCS. The same group also demonstrated, first in vitro and then in vivo, that CsA is able to inhibit CCS excretion in freshly isolated lymphocytes from SLE patients and overcome CCS resistance once patients were treated with a combined therapy (CCS + CsA) [41]. More recently, Henmi et al. [72] confirmed that hyper function of P-gp on CD4+ T cells of 12 SLE patients correlated with a poor clinical response to CCS and Zhang et al. [73] corroborated the correlation between high P-gp expression in the peripheral blood lymphocytes and increased severity of SLE disease. It is important to mention that P-gp expression/function has also been analyzed in other systemic autoimmune disorders such as idiopathic thrombocytopenic purpura (ITP) [74–76] and, more recently, inflammatory bowel diseases (IBD) [77]. Although they are few and involve only a small number of patients, the studies on IPT agree that resistance to CCS therapy is associated to hyper function of P-gp. As for IBD, the present data are often contradictory and need further elucidation. Indeed, a P-gp hyperexpression in circulating lymphocytes and epithelial cells of patients affected by Crohn's disease and ulcerative colitis resistant to CCS has been described [78]. However, other authors did not find association between MDR-1 polymorphism and response to therapy in a large cohort of pediatric patients with Crohn's and ulcerative colitis [79].
5. Conclusions
ATP-binding cassette (ABC) transporters, including the P-gp transmembrane pump inequivocally play an important role in regulating intracellular drug concentrations. Several studies on patients with systemic autoimmune diseases in particular SLE, RA and PsA have demonstrated a significant correlation between P-gp expression/function, disease activity and the development of resistance to immunosuppressive therapy. Furthermore, P-gp inhibition/reduction by CsA or anti-TNF-α agents can overcome drug resistance, thus ameliorating patients outcome. In conclusion, although the matter deserves further studies, mainly as far as the new therapies are concerned, existing data already suggest that the measurement of P-gp expression/function could be a useful biomarker to evaluate drug resistance in these autoimmune conditions.
We thank Valentina Germano and Claudio Pioli for the critical reading of the manuscript.
Author Contributions
A. Picchianti Diamanti and M.M. Rosado have most contributed to the drafting of the manuscript; R. D'Amelio and B. Laganà carefully read and gave a relevant help in the revision; and M. Scarsella wrote the bibliography of the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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51. Caccavo, D.; Lagana, B.; Mitterhofer, A.P.; Ferri, G.M.; Afeltra, A.; Amoroso, A.; Bonomo, L. Long-term treatment of systemic lupus erythematosus with cyclosporin A. Arthritis Rheumatol. 1997, 40, 27–35.
52. Picchianti Diamanti, A.; Germano, V.; Ferlito, C.; Migliore, A.; D'Amelio, R.; Lagana, B. Health-related quality of life and disability in patients with rheumatoid, early rheumatoid and early psoriatic arthritis treated with etanercept. Qual. Life Res. 2010, 19, 821–826.
53. Smolen, J.S.; Landewe, R.; Breedveld, F.C.; Dougados, M.; Emery, P.; Gaujoux-Viala, C.; Gorter, S.; Knevel, R.; Nam, J.; Schoels, M. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann. Rheum. Dis. 2010, 69, 964–975.
54. Van der Heijden, J.W.; Dijkmans, B.A.; Scheper, R.J.; Jansen, G. Drug insight: Resistance to methotrexate and other disease-modifying antirheumatic drugs—From bench to bedside. Nat. Clin. Pract. Rheumatol. 2007, 3, 26–34.
55. Day, R. Adverse reactions to TNF-α inhibitors in rheumatoid arthritis. Lancet 2002, 359, 540–541.
56. Fraser, A.D.; van Kuijk, A.W.; Westhovens, R.; Karim, Z.; Wakefield, R.; Gerards, A.H.; Landwew, R.; Steinfeld, S.D.; Emery, P.; Dijkmans, B.A.C.; et al. A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis. Ann. Rheum. Dis. 2005, 64, 859–864.
57. Mazzanti, G.; Coloni, L.; de Sabbata, G.; Paladini, G. Methotrexate and cyclosporin combined therapy in severe psoriatic arthritis. A pilot study. Acta Derm. Venereol. Suppl. 1994, 186, 116–117.
58. Migliore, A.; Bizzi, E.; Massafra, U.; Vacca, F.; Martin, L.S.; Ferlito, C.; Podesta, E.; Granata, M.; Lagana, B. Can Cyclosporine-A associated to methotrexate maintain remission induced by anti-TNF agents in rheumatoid arthritis patients? (Cynar pilot study). Int. J. Immunopathol. Pharmacol. 2010, 23, 783–790.
59. Maillefert, J.F.; Maynadie, M.; Tebib, J.G.; Aho, S.; Walker, P.; Chatard, C.; Dulieu, V.; Bouvier, M.; Carli, P.M.; Tavernier, C. Expression of the multidrug resistance glycoprotein 170 in the peripheral blood lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes expressing glycoprotein 170 is increased in patients treated with prednisolone. Br. J. Rheumatol. 1996, 35, 430–435.
60. Yudoh, K.; Matsuno, H.; Nakazawa, F.; Yonezawa, T.; Kimura, T. Increased expression of multidrug resistance of P-glycoprotein on Th1 cells correlates with drug resistance in rheumatoid arthritis. Arthritis Rheumatol. 1999, 42, 2014–2015.
61. Hider, S.L.; Owen, A.; Hartkoorn, R.; Khoo, S.; Back, D.; Silman, A.J.; Bruce, I.N. Down regulation of multidrug resistance protein-1 expression in patients with early rheumatoid arthritis exposed to methotrexate as a first disease-modifying antirheumatic drug. Ann. Rheum. Dis. 2006, 65, 1390–1393.
62. Tsujimura, S.; Saito, K.; Nawata, M.; Nakayamada, S.; Tanaka, Y. Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis. Ann. Rheum. Dis. 2008, 67, 380–388.
63. Tsujimura, S.; Saito, K.; Nakayamada, S.; Tanaka, Y. Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis. Mod. Rheumatol. 2010, 20, 139–146.
64. Agarwal, V.; Mittal, S.K.; Misra, R. Expression of multidrug resistance-1 protein correlates with disease activity rather than the refractoriness to methotrexate therapy in rheumatoid arthritis. Clin. Rheumatol. 2009, 28, 427–433.
65. Suzuki, K.; Saito, K.; Tsujimura, S.; Nakayamada, S.; Yamaoka, K.; Sawamukai, N.; Iwata, S.; Nawata, M.; Nakano, K.; Tanaka, Y. Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis. J. Rheumatol. 2010, 37, 512–520.
66. Choe, J.Y.; Park, K.Y.; Park, S.H.; Lee, S.I.; Kim, S.K. Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes. Arthritis Res. Ther. 2013, 15, R26:1–R26:12.
67. Kang, K.Y.; Ju, J.H.; Song, Y.W.; Yoo, D.H.; Kim, H.Y.; Park, S.H. Tacrolimus treatment increases bone formation in patients with rheumatoid arthritis. Rheumatol. Int. 2013, 33, 2159–2163.
68. Kis, E.; Nagy, T.; Jani, M.; Molnar, E.; Janossy, J.; Ujhellyi, O.; Nemet, K.; Heredi-Szabo, K.; Krajcsi, P. Leflunomide and its metabolite A771726 are high affinity substrates of BCRP:
Implications for drug resistance. Ann. Rheum. Dis. 2009, 68, 1201–1207.
69. Picchianti Diamanti, A.; Rosado, M.; Germano, V.; Scarsella, M.; Giorda, E.; Podesta, E.; D'Amelio, R.; Carsetti, R.; Lagana, B. Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthritis by cyclosporine A: Modulation of P-glycoprotein function. Clin. Immunol. 2010, 138, 9–13.
70. Llorente, L.; Richaud-Patin, Y.; Diaz-Borjon, A.; Alvarado de la Barrera, C.; Jakez-Ocampo, J.; de la Fuente, H.; Gonzalez-Amaro, R.; Diaz-Jouanen, E. Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part I: Increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis patients might influence disease outcome. Jt. Bone Spine 2000, 67, 30–39.
71. Tsujimura, S.; Saito, K.; Nakayamada, S.; Nakano, K.; Tanaka, Y. Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2005, 52, 1676–1683.
72. Henmi, K.; Yoshida, M.; Yoshikawa, N.; Hirano, T. P-glycoprotein functions in peripheral-blood CD4+ cells of patients with systemic lupus erythematosus. Biol. Pharm. Bull. 2008, 31, 873–878.
73. Zhang, B.; Shi, Y.; Lei, T.C. Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control. Exp. Ther. Med. 2012, 4, 705–710.
74. Levy, A.S.; Cunningham-Rundles, S.; Mazza, B.; Simm, M.; Gorlick, R.; Bussel, J. High P-glycoprotein-mediated export observed in patients with a history of idiopathic thrombocytopenic purpura. Br. J. Haematol. 2002, 118, 836–838.
75. Lopez-Karpovitch, X.; Graue, G.; Crespo-Solis, E.; Piedras, J. Multidrug resistance-1 in T lymphocytes and natural killer cells of adults with idiopathic thrombocytopenic purpura: Effect of prednisone treatment. Arch. Med. Res. 2008, 39, 541–545.
76. Ruiz-Soto, R.; Richaud-Patin, Y.; Lopez-Karpovitch, X.; Llorente, L. Multidrug resistance-1 (MDR-1) in autoimmune disorders III: Increased P-glycoprotein activity in lymphocytes from immune thrombocytopenic purpura patients. Exp. Hematol. 2003, 31, 483–487.
77. De Iudicibus, S.; Franca, R.; Martelossi, S.; Ventura, A.; Decorti, G. Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease. World J. Gastroenterol. 2011, 17,
78. Potocnik, U.; Ferkolj, I.; Glavac, D.; Dean, M. Polymorphisms in multidrug resistance 1 (MDR-1) gene are associated with refractory Crohn's disease and ulcerative colitis. Genes Immun. 2004, 5,
79. Cucchiara, S.; Latiano, A.; Palmieri, O.; Canani, R.B.; D'Inca, R.; Guariso, G.; Vieni, G.; de Venuto, D.; Riegler, G.; de'Angelis, G.L. Polymorphisms of tumor necrosis factor-α but not MDR-1 influence response to medical therapy in pediatric-onset inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 2007, 44, 171–179.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license


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Our research investigates the genetic basis of phenotypic evolution. The evolution of development, especially mechanisms controlling gene regulation, are of particular interest. Molecular and developmental biology, population and quantitative genetics, genomics and bioinformatics are integrated in this work.
For details of our current research, please see the RESEARCH page.
Lab Olympics September 2016
Back row: Patty Simmer, Bing Yang, Joe Walker, Jon Massey, Petra Vande Zande, Ali Farhat, Fabien Duveau Middle Row: Rebecca Tarnopol, Abby Lamb, Andrea Hodgins-Davis, Hannah Shuman, Jennifer Lachowiec, Alisha John, Trisha Wittkopp Front row: Daayun chung, Jade Diaz, Morgan!, Elizabeth Walker
Not shown: Lisa Kim, Kiran Ajani, Tricia Lybrook, Madison Drye
Biological Sciences Building, University of Michigan
- Department of Ecology and Evolutionary Biology (EEB)
- Department of Molecular, Cellular, and Developmental Biology (MCDB)
- Program in the Biomedical Sciences (PIBS)
- Center for Computational Medicine and Biology (CCMB)
- Center for Statistical Genetics (CSG)
- Researching Evidence Based Undergraduate Instructional and Learning Developments (REBUILD)
Lab members may link to our Lab Wiki

subset: commoncrawl


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Adding stone to your interior will enhance the look of your home. Stones provide a natural beauty, are long-lasting, and are non-combustible and they're easy to install and clean. Their versatility allows them to adapt to a wide variety of applications for homes. Adding our custom stonework to the indoors of your home is a great way to add a cozy and elegant feel while increasing the curb appeal and value of your home.
Castle Pines Basement and Remodeling specializes in designing and installing beautiful stonework inside your home. Our projects have ranged from building fireplace and stove enclosures as well as adding it to your the walls of our customers homes.
Castle Pines Basement and Remodeling is licensed and insured & have been in business since 1989. Our dedicated work to remodeling kitchens includes quality, speed and affordability to all of our customers.
If you would like to discuss adding custom interior stonework to your home, we will gladly meet you at your home to get a full understanding of your personal style, what your budget is and will create a timeline to suit your needs.
To schedule a free consultation please contact us here.


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RATEC 107 Positioning & Related Anatomy I • 2 Cr.
Presents basic positioning principles and terminology. Students get demonstration and film evaluation experience in positioning and related anatomy of the chest, abdomen, and upper extremities. Format includes one hour lecture and two hours lab each week. Prerequisite: Acceptance into program or permission of instructor.
After completing this class, students should be able to:
- Define the terminology used to describe body planes, body part location, patient/part positioning, and body movement.
- Describe the appropriate steps for completion of a radiographic examination to include room/patient/equipment preparation, appropriate use of lead identification markers, and post-examination procedure.
- Identify and describe the basic anatomy of the respiratory system and the abdominopelvic cavity.
- Identify and describe the bones of the fingers, hand, wrist, and distal forearm.
- Locate and name surface markings found on the phalanges, metacarpals, carpals, distal radius, and ulna.
- Classify the articulations of the phalanges, metacarpals, carpals, distal radius, and ulna; and identify their type of movement.
- List and describe the basic and supplemental positions/projections of the chest, abdomen, hand, and wrist to include preferred type and size of image receptor, central ray location, and structures best visualized.
- Describe equipment considerations and exposure factors relative to radiography of the chest, abdomen, hand, and wrist.
- Demonstrate the basic positions/projections of the chest, abdomen, hand, and wrist.
- State the criteria used to determine positioning accuracy on radiographs of the upper extremity, lower extremity, and pelvic girdle.
- Evaluate radiographs of the chest, abdomen, hand, and wrist in terms of positioning, centering, image quality, radiographic anatomy, and simple pathology.


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Proactive vs. Reactive Pond Management
Up until the last few years, most pond owners have relied on REACTIVE pond management practices to keep their ponds clean of excessive, unwanted, aquatic growth. They've traditionally waited for the problem to appear then treated it chemically. Although sometimes necessary as a management tool, chemical applications can be bandages for the real problem and can actually contribute to the problem by adding more nutrient rich muck and increasing the overall
nutrient load.
With the introduction of the Airmax Ecosystem program, pond owners, have now been able to convert to, and rely on, PROACTIVE pond management practices. With the use of aeration, 100% natural bacteria and/or pond dyes, they've been able to get directly at the SOURCE of their problems; excessive nutrients in the water column and in the muck at the bottom on the pond. By providing microbial competition for the nutrients, they've successfully maintained healthy, clear ponds for all, including the fish, to enjoy.
Airmax Aeration Works!
Airmax to the Rescue!
Airmax Aeration Systems utilize a shore-mounted air pump that delivers compressed air to a synergistic diffuser plate on the pond's bottom. As the air rises from the diffuser plate at the bottom, it creates a convection current that slowly and steadily turns the water body over. Bringing the bottom waters up to the top to interact with the atmosphere not only adds oxygen to the water but circulates as well. It is this interaction that lies at the heart of the Airmax Aeration System.
Healthy, Clear and Circulated Water Column
The circulation created by the Airmax Aeration System eliminates the thermocline (water separated into multiple layers based on temperature). When the thermocline is eliminated, oxygen is allowed to the pond's bottom, creating a perfect environment for aerobic beneficial bacteria such as PondClear and MuckAway to thrive. With the help of these bacteria, the water column will become clear while the muck is reduced off the pond's bottom.
Preventing Winter Fish Kill
Keeping the aerator running in colder climates (where an ice layer may form) will greatly reduce the chances of a winter fish kill. Dying or dead vegetation will cause toxic gases to build up underneath the ice during the winter months. These toxic gases can displace the oxygen causing a winter fish kill. The Airmax Aeration System can prevent this by circulating the water column and pumping oxygen into the pond or lake. Circulating the water column will also maintain an open hole in the ice, allowing the toxic gases to safely escape.
Stronger Fish Population
In a thermally stratified state, the bottom half of your pond becomes almost uninhabitable to fish. The low oxygen and high amount of toxins drive your fish into the much warmer top half of the pond. The Airmax Aeration System de-stratifies the water column, creating optimal conditions for fish to inhabit the entire
body of water.


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Tripoli Death Toll Hits 7 as Clashes Renew at Night and Army Arrests Gunmenإقرأ هذا الخبر بالعربية
Clashes renewed on Wednesday evening in the rival Tripoli neighborhoods of Bab al-Tabbaneh and Jabal Mohsen after a brief lull, as the army made contacts with the warring parties and fired back at the sources of gunfire, especially sniper fire.
An Energa-type rifle-launched grenade fell in the vicinity of al-Mallouleh area and was followed by an exchange of gunfire between Jabal Mohsen and Bab al-Tabbaneh, LBCI television reported.
A security official told Agence France Presse that sniper fire killed seven civilians in on Tuesday and Wednesday in the two rival districts.
The security official said four were killed on Wednesday, while three others died the day before.
"Khodr Hanoub, a man in his 40s, was killed at dawn Wednesday in the district of Bab al-Tabbaneh," the official said, adding that Ali Habbabeh was killed in the adjacent district of Jabal Mohsen.
The official also reported the killing in Bab al-Tabbaneh of Zakaria Othman and Mehdi al-Beik on Wednesday, while Khaled Salem, 27, was killed overnight.
They died a day after kiosk owner Mohammed Ibrahim, 65, was killed in Jabal Mohsen by a sniper operating from across the street-turned-front line separating the two impoverished neighborhoods.
Also on Tuesday, Bab al-Tabbaneh resident Abdul Rahman Nassouh was shot dead.
While there was a lull in fighting on Wednesday, snipers held their positions and continued to shoot, an AFP correspondent at the scene said.
The official reported 57 people wounded altogether, including two soldiers.
The National News Agency said that the armed clashes intensified during day hours between fighters in the areas of Qobbeh, al-Mankoubin, Mallouleh, Bab al-Tabbaneh, and Syria Street and others in Jabal Mohsen.
The army has been returning fire against the sources of gunshots.
The Army Command said in a statement its troops "staged patrols, erected checkpoints and fired back immediately at the sources of gunfire," noting that five people were arrested on suspicion of involvement in the shooting and that a quantity of weapons and ammunition was found in their possession.
"Two soldiers were wounded in the security operations as some military vehicles sustained material damage," said the statement.
The detainees and the confiscated items were handed over to the relevant judicial authorities, according to the statement.
Light and medium weapons could be heard in the battles, as well as sounds of rocket-propelled grenades.
Earlier on Wednesday, a meeting was held at the residence of al-Mustaqbal MP Mohammed Kabbara to discuss the developments in the northern city.
The meeting was held in the presence of State Minister Ahmed Karami, Ahmed al-Safadi representing Finance Minister Mohammed al-Safadi, MPs Samir al-Jisr, Moein al-Merehbi, Khaled al-Daher and several other officials.
The attendees urged the rival neighborhoods to end all the armed clashes under the auspices of the army, calling on it to control the situation in the city.
"We should find a permanent solution to the recurrence of the incidents," Kabbara told reporters after the meeting.
He also called on the government to compensate all the families affected by the gun battles.
The clashes broke out over the weekend in wake of the announcement of the death of a number of Lebanese Islamist fighters, who mainly hail from the North, in the border region of Tall Kalakh in Syria on Friday.
Media outlets had conflicting information about the number of people who died and those who survived the attack.
While the Syrian Observatory for Human Rights reported that a group of 30 rebels "were caught in an ambush by government troops in the area of Tall Sarin near the town of Tall Kalakh", Voice of Lebanon radio (100.5) said the ambush left 20 Lebanese men dead, adding that they hail from Akkar's Fnaideq and Tripoli's Bab al-Tabbaneh and al-Mankoubin neighborhoods.
Amazing country. Leaders slugging it by making speeches, while their followers translating it with bullets.
Hizbala, Berri and Aoun are the causes of all the ills of Lebanon...they arm any faction that supports Assad or Iran...
ft, that was a good movie actually..did your general Aoun cast for the lead role???
ft, okay we're even :)
Snipers are cowards. They should die the death of 1000 cuts. The "leaders" who encourage these worthless killers to murder unarmed people should be used for target practice themselves. It's a terrible thing that these young killers are out in the street with nothing in their heads except hatred and vengence. They feed off of lies and death. They aren't smart enough to know why they in such a cycle and don't want to know. Kill,baby,kill.
The best thing would be to send them directly to Syria where they can fight for their beloved FSA and the Baath Regime.
I live only a few miles away from Tripoli in Koura. Every time the Hariri salafites are upset with something that happens in Syria, they start burning homes and businesses of Aliwites in areas they control and shooting at Jabal Mohsin. There is a campaign of ethnic cleansing of Alewites in tripoli and the western "human rights" organizations have been silent for political reasons. Alewites, whether they support the Syrian regime or not have been murdered, driven out of their homes and businesses in Tripoli, and Jabal Mohsin is now their only refuge. This is happening hear in Lebanon. Shame on those who have been silent.
Proof?...It has been documented several times in the indendent Leftist Al-Akhbar and the burning of businesses and homes in Nahar. There used to be several thousand Alewites in Qobe and Tal section of Tripoli living next to Christians. Go and ask the few Christians still living there, what happened to the Alewite neighbors.
Sorry....Assuming you live in Lebanon
ya accordionman, are confused? I didn't say anything about whipping someone ass!!! what's wrong with you and yes jibleh shi manouchih bi zaatar halabi maa naanan, hurry up ya ammour enta wa walad...
lets recapitulate:
1)there is hizballah fighters fighting FSA ON SYRIAN LAND to defend lebanese shia living on syrian land
2)there is sunni lebanese armed fighters on SYRIAN LAND fighting the regime syrian army to defend their sunni brothers..
3)what's next????? more popcorn pse.....
ASSad is heading down. The Alawites in Tripoli are suffering the same frustration as Flame Retardant and his M8 friends. Their world will be upside down soon.
This article says Bashar is looking for political asylum in Latin Americs and one of the commie countries. http://english.alarabiya.net/articles/2012/12/05/253495.html
There is not fire without smoke. He is looking to jump off the sinking ship. They keep losing bases. It is over.
Guys in Tripoli- pls calm it down. This isn't 1975. Haven't we learned something from 15 years of war?
But I don't blame them. I blame their leaders. And the army should totally interfere and stop this & arrest these people to jail. If not now, when?


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Sansevieria zeylanica - 10" Pot
We love the dark green green foliage on this Sansevieria (Dracaena) cultivar. Tolerates low light, but can handle even some direct sun! A great, low-maintenance, beginner's plant.
Multiple plants available - yours may not be the exact one shown in photo.
This item is available for pick-up only, and cannot be shipped.
Local pick-up info
Pickup orders are available at our warehouse location in North Portland. Please use any Oregon address during the check-out process to see the free "pickup at warehouse" option
We are currently offering pickup on Tuesdays and Fridays from 12:00pm - 6:00pm
You'll get an email as soon as your order is ready to be picked up, and we'll include detailed instructions about when and where your order will be waiting for you. Out of safety precautions, we will be making every effort to follow best practices for social distancing, and your pickup will be "contactless." More Info


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Throughout the year, all escorts experience a period of burn-out, distraction or over scheduling that creates obstacles to success in their careers. For many, fall is a season with unlimited distractions that create challenges in focus, marketing and booking. From the change in weather to new attitudes associated with the time of year, autumn may be a difficult time to escort successfully. Continue reading
Tag: allergy
12 things every successful escort knows about perfume
Scent is a natural part of sexual attraction, so it an expectation that escorts are concerned with the proper use of perfume and other fragrances as a useful tool for their professions. However, with awareness of scent sensitivities becoming more prevalent, it may leave escorts in a quandary about how to incorporate perfume into their beauty routines without offending clients. Continue reading


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What season is the best for traveling?
|Posted by electronics51 under Sport, Travel
Traveling is the best way to relaxing for our body.
Traveling can expand our insights.
Traveling can learn things that we cannot usually learn.
Traveling can keep us a positive attitude, let us love life more, So that we can enjoy the beauty of life.
Personally, I like traveling very much. So in a year, I would choose one or two places toi go where I like. Two month ago, I had a very nice trip to Yunnan with my good friends.
However, you may want to ask: What season is best for travel? And what kind of people to travel with? How much do we need to prepare to arrange a pleasant trip? You may have all kinds of questions.
In my opinion, there is no need to consider too many questions. Bring a certain amount of money, start to go with about three or two friends.
As long as you have an idea in your heart, you can come and go on a trip in different seasons. Because in some places, all seasons are warm and beautiful like spring and very suitable for traveling.
Which vehicle to choose? Airplane or train even self-driving, it depends on personal preference. If you hope to visit more attractions place and enjoy the scenery, suggest you to choose Airplane which can save more time. If you prefer more economical, save money, train is a better transportation tool. If you want to freedom and start at any time, then self-driving tour is your best choice. However, if you choose Airplane or train, I suggest you to prepare a short-term travel tool, this will be very convenient for your short trip. Just like longboard electric skateboard. Also you need to have one to experience riding and freedom. Skateboarding is characterized by a slippery behavior, advocating a free movement, experiencing and creating a feeling of supergravity, bringing joy and creativity to the skater.
Koowheel remote control skateboard, it's 7 layers of Canadian Maple Panels, better elasticity and toughness, Board without splicing, using CNC trimming and grinding process, Allows riders to have more traction while riding this motorized skateboard.
New 350W x 2 Motors with Replaceable PU Wheels, unique design will help motors cooling maximumly, Koowheel is the fastest electric longboard manufacturer China, max Speed can reach 24.8 mph (variable depending on various factors such as weight, slope steepness, temperature, speed,etc.),Even in high-speed, it could keep sufficient stability and balance to ensure the safety and a good riding experience.


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1 Item(s)
Grid List
Standard-grade no trespassing signs protect your facility and employees from intruders. No trespassing signs limit access and clearly indicate restricted areas. Emedco signs are heavy duty and can stand up to all weather conditions.
1 Item(s)
Grid List
All signs are manufactured using durable materials with your choice of a Duroshield coating.
You can also customize your own sign using your special wording if you cannot find what you need from our stock-worded options. A reflectorized finish is also available so your signs are seen even at night.


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GLENDALE, Ariz. – Following tonight's Versus-televised WEC 55 event, officials host a post-event press conference, and you can watch a live video stream of the proceedings here on MMAjunkie.com at approximately midnight ET (10 p.m. MT local time).
The event and post-fight presser take place at Jobing.com Arena in Glendale, Ariz.
Scheduled to appear at the press conference are WEC General Manager Reed Harris, headliners Benson Henderson and Anthony Pettis, and winning fighters from the night's main card.
For the latest on WEC 53, stay tuned to the MMA Rumors section of MMAjunkie.com.
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Crime Watch
RCPC takes crime in Rockridge very seriously. If you want to contact us regarding crime issues you should contact the Public Safety Committee.
Additionally, a great resource to the community is the Rockridge Neighborhood Crime Prevention Council. They hold regular monthly meetings and provide the community a forum in which to discuss issues not only with your neighbors but Oakland police officers as well.


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As a side project, I have been designing and building these bent wood bicycle trays. Needless to say, I've spent a lot of time in the wood shop working with a variety of wood working tools. It has been a while since I have used a bandsaw and table router. It feels so satisfying to be making something tangible with my hands. Like most designers, I spend a lot of time in front of my laptop or reading and talking about design.
Where GlassyBaby's Are Born
Out on another tour of an amazing local startup, GlassyBaby in the Madrona neighborhood in Seattle, WA. If you haven't heard of them, you should look them up. They are a high end, beautiful, glass tea light candles. Originally created as small gifts for friends, GlassyBaby has quickly grown to a large studio.
Touring GrayPants Seattle Studio
On a cold and wet Thursday morning, I made my way down to the SoDo neighborhood in Seattle WA, to tour the GrayPants studio. Deep inside the industrial neighborhood, tucked in behind large anonymous buildings sits an old wooden building previously used for boat building. This is the home of GrayPants.
News Journals / Primary Research — Thesis Update #2
The first phase of my primary research for my master thesis project started with some making. After getting a quick refresher tutorial from designer Abigail Steinem, I designed and made hand bound journals for my research participants to record their news consumption habits for a week and a half. I recruited (with the help of Kristine Matthews, my thesis chair) a class of juniors at the University of Washington. The journals were an interesting challenge. In order for them to not become a chore they needed to be simple and straight forward. They also were made small and sturdy so that the students could easily keep the journals on them at all times.


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John Portman, a prominent twentieth-century architect,...
William Jay (ca. 1792-1837)
William Jay was an English-trained architect who, from 1817 to 1820, practiced in Savannah, where
Jay was born in 1792 or 1793 in Bath, England, to a family of stonemasons. From 1807 to 1813 he apprenticed in London with the architect David Riddall Roper, who built mostly in the Greek revival and Gothic revival styles. Jay's only known commission in London is the neoclassical-style Albion Chapel (1816), Moorgate, a square-shaped church with a recessed Ionic entry and a Pantheon-like dome.
In December 1817 Jay arrived in Savannah as the city's premier architect and one of the best-trained architects in America. The Owens-Thomas House (1819), a commission he received through a family connection, was the first of a series of neoclassical-style mansions Jay designed and features a Regency-style side porch supported by foliated consoles (leaf-shaped decorative brackets). The interior plans of the William Scarbrough House (1819), which later became the headquarters for the Historic Savannah Foundation (1976-1991) and the Ships of the Sea Museum (1996-present), and the Alexander Telfair House (1819), which later became part of Telfair Museums, are configured in circular, oval, and elliptical shapes. In the Bulloch House (1818-19) Jay called for a dramatic spiral stair surrounded by Corinthian columns. Jay's last commission in Savannah was the Bank of the United States (1821), an early Greek revival–style
After returning to England in 1822, Jay produced designs for Pittville Parade, a large, six-unit row house. When the speculative Pittsville development failed in 1829, Jay went bankrupt and in 1836 was forced to accept the position of colonial architect and civil engineer on the island of Mauritius in the Indian Ocean east of Madagascar. Jay worked on the island until his death in 1837 in Port Louis, Mauritius.
Media Gallery: William Jay (ca. 1792-1837)
Further Reading
Hanna Hryniewiecka Lerski, William Jay: Itinerant English Architect, 1792-1837 (Lanham, Md.: University Press of America, 1983).
James Vernon McDonough, "William Jay, Regency Architect in Georgia and South Carolina" (Ph.D. diss., Princeton University, 1950).
James Vernon McDonough, "William Jay, Regency Architect in Georgia and South Carolina" (Ph.D. diss., Princeton University, 1950).
Cite This ArticleMoffson, Steven H. "William Jay (ca. 1792-1837)." New Georgia Encyclopedia. 26 March 2020. Web. 18 October 2020.
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Los Angeles Estates & Luxury Homes – Location (1st in Series)
There seems to be growing international interest in Los Angeles' luxury real estate market right now and asking prices have declined significantly since last year. Many prospective buyers may have only heard of the the famous communities like Hollywood, Beverly Hills, or Malibu that they are considering making their new home. This first in a series of articles is an overview of where you can find the finest properties for sale in Los Angeles.
When it comes to finding estates and luxury homes in Los Angeles, the old real estate cliche in the title holds true. While you'll certainly find extraordinary luxury homes in all of the areas that will be discussed here, you can also find fabulous listings for these throughout the city. The art of finding great estates with an amazing compound and usable acre or more is easier to define because there are fewer of these magnificent properties and they're usually grouped in specific areas.
There are two main areas where you'll find the majority of Los Angeles' exclusive residential listings. The first is a broad band that includes much of the Hollywood Hills and surrounding communities along the north end of the L.A. Basin which extends for fifteen miles from Griffith Park by Downtown, west to the Pacific Ocean. Predictably enough, the other area includes the beach cities from Malibu to Palos Verdes.
Since true estate properties require a lot of land and privacy, the largest estates are found in and around the hills from Los Feliz to West Hollywood, Beverly Hills, Bel Air, Brentwood and Pacific Palisades by the beach (Malibu is in a category by itself.) These luxury properties and full-blown estates are truly the epicenter of high end real estate in Southern California and there is no shortage of the spectacular, sweeping views from Downtown to the sea that Los Angeles is known for.
Opulent properties built during Hollywood's Golden Era in the 1920's & 30's line the base of the hills and lower elevations, particularly in the older parts of town to the east around Griffith Park & Hollywood. This is also true of Beverly Hills and Bel Air, and there are several charming villages dating from the period along Sunset & San Vicente Boulevards to the west in Brentwood & Pacific Palisades.
Older styles of architecture found in these areas tend towards the Spanish and Mediterranean with a lot of other traditional styles from Chateau and Tudor, to Neo-Classical and Georgian mixed in.
Newer homes and estate properties which were built from the 1940's and 50's up to the present tend to dominate as you move farther west and up into the hills. More Ranch homes and cleaner modern and contemporary architectural styles tend to be found here, along with a generous helping of thematic eclecticism and over-the-top excess.
Mulholland Drive runs the length of the Hollywood Hills along the crest which separates these L.A. communities to the south, from the San Fernando Valley to the north. About 75% …


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Constructive dismissal claims takes place when an employee is forced to leave the job as a result of their employer's conduct. The employee must prove that the employer committed a serious breach of contract and that they felt forced to leave because of that breach and that they have not done anything to indicate that they have accepted this breach or a change in employment conditions.
Constructive dismissal claims are notoriously difficult to prove but you need to guard against them because if successful they can give rise to damages for wrongful dismissal and (after 12 months of employment) unfair dismissal.
What Can Employers Do To Guard Against Constructive Dismissal Claims?
One of the first things you should do is review your policies, management systems and procedures and ensure that you look after and engage your staff. By creating an open and transparent workplace, where everybody knows what they are doing, you are less likely to have to deal with difficult employees.
Create And Implement Staff Appraisals And KPI's
Create and implement staff appraisals and KPIs if you haven't already done so and look to brand your business as an open and progressive organisation. Your business will avoid problematic situations with staff by establishing and maintaining a positive and forward-thinking approach.
Ensure that you have sound internal policies and that your managers know how to deal with disciplinary and grievance procedures. Train your staff on regulatory procedures and other rules such as equal opportunities, and ensure that knowledge is shared across the organisation.
Quite often constructive dismissal claims in adverts and only arise by virtue of a failure to properly apply procedures. It is also worth reviewing the emotional intelligence of your line managers: do they need further training to develop their soft skills to sensitively deal with staff issues?
Create A Staff Handbook
Create a staff handbook which includes both internal policies and procedures together with the relevant legislative frameworks which apply to your organisation. Ensure that your handbook is clear, easy to use and up to date so that both staff and employees know what to do in any given situation.
Having a comprehensive and well drafted staff handbook will also put you in good stead if an issue does end up being heard before a tribunal.
Ensure that you carefully consider how best to structure and implement organisational change. Changing an employee status or duties can lead to a constructive dismissal situation. In particular you should seek specialist legal advice if you are thinking about changing an employee's job location, title or terms and conditions of these are the most common areas which usually give rise to a claim.
Fair And Reasonable Approach
Adopt a fair and reasonable approach when making decisions about your staff. Always ensure that you consider the health, safety and welfare of your staff since issues which may cause stress or illness can result in a constructive dismissal situation.
Grievance procedures enable line managers to deal with potential issues objectively and support an employee who is unhappy with a specific situation.
Keep talking! Communicate with disgruntled employees and always try to amicably resolve or mediate a difficult situation. Even if your powers of persuasion do not ultimately work, a tribunal will take the historical conduct of an employer into account when making a decision.
Final Words: Protecting Your Business Against Constructive Dismissal Claims
We've given you a general overview of how to protect your business against constructive dismissal claims. One important way to do this is via a bespoke Staff Handbook and we can create this for you. Click below and order your customised Staff Handbook today, which will help reduce incidences of constructive dismissal claims in your business.


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Passion, experience and intuition combine to bring to life head-turning pieces you'll love forever.
The pure artistry of the A.G workshop comes alive when designing one off signature pieces.
Being drawn by hand or designed using the latest technology, even the smallest details are possible, ensuring your piece is as distinctive as you are. Only the highest quality metals and individually selected stones from across the globe enter the A.G workshop ensuring each piece is a rare and timeless beauty.


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Property Fraud & Identity Documents Property, as with any asset, is subject to the threat posed by unscrupulous parties looking to defraud people or to launder money. Property frauds are increasingly sophisticated and the nature of the attempts are constantly evolving. It is important that individuals are aware of the potential threats. Every buyer expects… Learn more
Joint Ownership We all know that buying a property can be a stressful time but also a very exciting time as it is a new chapter in your life. We would like to make that process as easy as possible for you especially when you are purchasing a property with your partner, spouse, family… Learn more
Selling a property through Probate, or Lasting Power Of Attorney. Top Facts about Probate Sales; Technically you cannot sell a property before the probate is granted, unless your name is already on the deed. The Probate takes around eight weeks to come back and if you sell your house in the meantime this could hold… Learn more
Is this a question that has been playing on your mind? Is Help to Buy only for New Homes? Help to Buy is a government scheme which was introduced to offer help to first time home buyers purchase a property. This was brought about by offering government loans which were more attainable, such as… Learn more
Protecting your intellectual property – what is it and how can it be done? It is a common saying that imitation is the best form of flattery, however, this is not the case where such imitation causes a loss to your business! What is intellectual property? Intellectual property (IP) is a creation of… Learn more
Shared ownership: A Current Explanation Often when purchasing a property, we do not do it alone. Our reasons may differ, for example a couple may wish to start a family or business partners may seek to make an investment but the law that governs how we recognise ownership of property stays the same. Explaining property… Learn more
In the tax year 2016/2017 the amount of Inheritance Tax (IHT) paid to HMRC was in excess of £4.7billion. Official bodies have also calculated that in the next five years this figure could increase by up to a third, this is a payment of up to £6.1billion. The reason for this increase is a… Learn more
Radon Radon is a noble gas which has been classified as "carcinogenic to humans" by the International Agency for Research on Cancer. It is the second largest cause of lung cancer, being a factor in 1,100 deaths annually nationwide. It is odourless, tasteless and colourless making it impossible for those without specialised equipment to detect… Learn more
Voluntary Registration of Unregistered Land Over 80% of land in England and Wales is now registered with the Land Registry, meaning there is a clear, permanent electronic record of who owns what. Where land has not been registered, we refer to this as being 'unregistered' whereby ownership to the land is evidenced by paper… Learn more
Why make a will? You spend your lifetime carefully managing your money and building up your estate but imagine if on your death it is all given to someone you never intended to inherit it and potentially leaving out your loved ones. Without a Will, your assets will be shared according to… Learn more


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The second reshuffle or rejig in the Union Council of Ministers by the Prime Minister Man Mohan Singh on July 12, 2011 is disappointing, to say the least. The first such reshuffle was effected in January 2011. Both taken together and as announced by the Prime Minister that it would be the last shuffling of the UPA-11 Government before the next General Elections to the Lok Sabha in May 2014 have come as a damp squib. It seems the UPA-11 has lost the will to govern much less take decisive measures to stem the rots of corruption, inflation and ability to reassure the people, the ultimate sovereign masters that the Government is business like and not adrift. Added to this, the Government appears to have lost the plot.
In the scheme of the Constitution of India, the Government set up under clause (3) of Article 77, is one body and soul with different limbs in the form of various Ministries/Departments to provide specialized services to the nation. This means that the Government is cohesive to provide integrated coordinated approach to the issues of governance and intended solutions to the problems facing the nation. The drift in the form of inertia and stand still in the Government do not appear to have been addressed in the reshuffle.
The fact that the big four Ministers- Home, Finance, Defence and External Affairs- have been left untouched shows the incompetence of the Government in dealing with the emerging challenges. External Affairs Minister S.M.Krishna, rated on the laurels of Bangalore having emerged as the Silicon Valley of India on account of his initiatives as the Chief Minister of Karnataka, has grown old enough with a poor reflex system as can be seen from his last performances in the United Nations and tackling the issue of Indian hostages held by the Somali pirates in the high seas, the two recent examples giving the impression of his growing ineffectiveness in the days to come.
The emerging challenges before the nation are India as a rightful destination for foreign investments at a time of the economic downturn of the developed world and geo-political interest of the country vis-à-vis neighbouring countries and others in the emerging economies. One wonders how will Krishna be able to take up such daunting tasks? This vital Ministry surely needed a younger and more articulate Minister with fresh ideas and approach to steer India clear at international fora and in the comity of nations.. Similarly, Defence Minister A.K.Antony, a man of unimpeachable integrity and probity, perceived publicly to be conservative and impeding or slowing the process of modernization of our defence forces, should have been replaced by a younger and more active person who could guide the destiny of India's defence in keeping with the nuances of the globalised world. The oligarchy of the big four oldies is discomforting to the well-meaning people.
At a time when media have emerged all-in-one out and out negative and as complainant, prosecutor and judge with the public perception of the UPA-11 Government as the most corrupt one with its ability to tackle grave issues like price rise, corruption and unemployment under cloud, the Minister of Information and Broadcasting Ambika Soni needed to be axed for her inept handling of the media.. She has become a dead wood and has outlived her utility. She should have been replaced by a younger and articulate person who could generate ideas to keep official media heads on tenterhooks by tightening screws against them in order to deliver by disseminating information and publicity in the positive light to fill the space that are currently filled by negative news and false information.
So many things are happening in the Government on developmental front and people needed to be informed about such development as a hallmark of responsive and caring Government. But nothing goes home to them. Only negative propaganda and campaign against the Government appear to be the order of the time. Over and above, the State Governments are taking credit by default for various flagship programmes in the infrastructural and social sectors as the money allocated for such welfare programmes is spent through the State Government agencies, which generally siphon off money, fudge data and send bogus utilization certificates to the Government of India. Official media could be made to play primordial role in countering ill-conceived propaganda of the States.
The one and only good thing that has happened is elevation and shifting of hyperactive, action oriented, hard task and responsive Jairam Ramesh as the Minister of Rural Development, with his ability to deliver. He is a man of ideas and expected to oversee effective implementation of flagship rural welfare programmes. He will ensure effective implementation of rural development by keeping the state governments' agencies on tenterhooks so that they are not able to siphon off allocated funds, fudge the data by giving bogus completion and utilization certificates. The other redeeming feature is transfer of Salman Khurshid as Minister of Law and Justice. He is a balanced man with his ability to maintain a perfect equilibrium between the three organs of the state- executive, legislature and judiciary- unlike his immediate predecessor Veerapa Moily, who had penchant for shooting his mouth on all issues while letting the integrated coordinating machinery of his Ministry slip away from under his feet despite the fact that he is a well meaning political leader with proven ability.
All said, the reshuffle is an opportunity lost and at that an ill-conceived exercise though not ill timed. One can understand the art of political balancing, expediency and coalition compulsions. What one cannot understand is inability of the leadership of the dominant Congress party to axe some more of its nonperforming Ministers to come out unscathed to refurbish and make over its sagging public image that the Government is responsive and not adrift!
Writer Mr. M Y siddiqui is former director of Public Relation for Law and justice & Railways, Govt of India.


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YouTube and Editing
I have been doing a lot of recording and editing lately for Let's Plays and Literal Torture videos and I came to two realizations:
1. I have no idea what I am doing.
2. It doesn't matter, because I'm having fun.
I have jumped headfirst into learning programs that I'm sure can take years to master, and people actually go to school to use, with the end goal of making a final product that looks and sounds worthwhile. This goes along with learning very basic usage of Photoshop to create the intro images and thumbnails for the episodes. I know that pretty much every YouTube personality out there has probably done the same and some have even become extremely successful with their craft, and I am finally coming to terms with how difficult it really is to make this sort of thing a reality. I love playing games, and sharing my experiences with people makes me very happy, so keeping the videos coming on YouTube is overall an enjoyable experience for me.
Before I start rambling more than I already have, I just wanted to say thanks to everyone who has supported me in this new thing (especially the gorgeous Lady Crass) and I hope that people are enjoying the videos as much as I have enjoyed creating them.
- Mark
Mark Boutet is more or less three quarters of the hosts of The Digital and Dice Podcast. He is most decidedly NOT a goat or a robot. He acquired his skin fair and square as all other humans do.
February 2020


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PHOENIX – Sixteen states have filed suit against President Donald Trump's national emergency declaration last week, but Arizona isn't among them.
The attorneys general of California, Colorado, Connecticut, Delaware, Hawaii, Illinois, Maine, Maryland, Minnesota, Nevada, New Jersey, New Mexico, New York, Oregon, Virginia and Michigan filed a complaint on Monday opposing the national emergency declaration, which the president declared after Congress refused to fully fund his request for barriers along the southern border.
California Attorney General Xavier Becerra is leading the state lawsuit, which comes on the heels of lawsuits filed last week by several activist groups.
Of the four border states, New Mexico joined California, while Texas remained on the sidelines with Arizona.
Arizona Attorney General Mark Brnovich did not respond to a request for comment.
After reaching an agreement on a spending bill to avoid another government shutdown, Trump announced that $6.6 billion in military and drug-interdiction funds would be made available to build a border wall, which has been his key campaign promise.
"Such use would divert counter-drug programming funds directed to the states, and military construction funds to be spent in the states," the 16 plaintiffs assert.
U.S. Rep. Tom O'Halleran, D-Ariz., has said the funding would consist of $3.5 million from the Pentagon's military construction fund, $2.5 billion from the Pentagon's drug interdiction initiative and $600 million from the Department of Treasury's drug-forfeiture program.
Gil Kerlikowske, an Obama appointee as commissioner of U.S. Customs and Border Protection, from 2014 to 2017, said he does not see an emergency at the U.S.-Mexico border.
"Well, we know that the drugs, especially marijuana seizures, along the border have gone down for a pretty good number of years," he said. "We also know that the people aren't attempting to evade the Border Patrol, they're people that essentially turn themselves into the Border Patrol trying to make a claim of credible fear."
While working in the Obama administration, Kerlikowske said, CBP processed 68,000 unaccompanied children at the U.S. -Mexico border.
"They were able to handle that, and there's really no reason that they shouldn't be able to handle this also," he said.
Kerlikowske also said increased technology use by CBP officials has led to a safer border.
"The technology, I think, has been far more effective at reducing the numbers though then a barrier than a wall."
A main point of contention involving the construction of a physical barrier is how it would be paid for.
In a tweet Friday, Sen. Martha McSally, R-Ariz., publicly addressed the concern over cuts to military funding in Arizona.
"I support @POTUS's goal, which is to further fund border security," McSally said. "I will continue to study the emergency declaration and additional funding proposal to ensure it increases border security while not adversely impacting our military."
(2/2) I support @POTUS's goal, which is to further fund border security. I will continue to study the emergency declaration and additional funding proposal to ensure it increases border security while not adversely impacting our military.
— Martha McSally (@SenMcSallyAZ) February 16, 2019
Gov. Doug Ducey apparently doesn't share that concern. He tweeted his support for the president on Friday, saying, "Arizona has watched for decades as Washington has failed to prioritize border security. It's unfortunate it has come to this rather than Congress doing its job. But action is needed. I support President Trump's plan to secure our border."
The Department of Justice has not publicly commented on the lawsuits.'
– Video by Austin Westfall/Cronkite News


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Iraqi Governing Council
The Iraqi Governing Council (IGC) was the provisional government of Iraq from July 13, 2003 to June 1, 2004. It was established by and served under the United States-led Coalition Provisional Authority (CPA). The IGC consisted of various Iraqi political and tribal leaders who were appointed by the CPA to provide advice and leadership of the country until the June 2004 transfer of sovereignty to the Iraqi Interim Government (which was replaced in May 2005 by the Iraqi Transitional Government, which was then replaced the following year by the first permanent government).
The Council's ethnic and religious breakdown included 13 Shias, five Sunnis, five Kurds (also Sunnis), one Turkmen and an Assyrian. Three of its members were women.
In September 2003, the Iraqi Governing Council gained regional recognition from the Arab League, which agreed to seat its representative in Iraq's chair at its meetings. On June 1, 2004, the Council dissolved after choosing member Ghazi Mashal Ajil al-Yawer as the president of the new Iraq interim government. Full sovereignty was transferred to the interim government (and the CPA dissolved) on June 28.
General information
Though subject to the authority of the CPA administrator Paul Bremer, the council had several key powers of its own. Their duties included appointing representatives to the United Nations, appointing interim ministers to Iraq's vacant cabinet positions, and drafting a temporary constitution, the Transitional Administrative Law (TAL). The TAL spelled out the provisions which were to govern the Iraqi Interim Government, and the timeline for holding elections to a National Assembly, drafting of a permanent constitution to be voted on by the Iraqi people, and elections to a permanent government.
Despite having to answer to the CPA, different factions took on controversial stands. Religious hardliners won a solid victory when Directive 137 was passed on December 29, 2003. Passed by the council in less than 15 minutes, it replaced Iraq's former secular family law code with Shari'a family law. This move met with wide protest among many Iraqi women fearful of how it will affect their freedom to make their own decisions about marriage, alimony, and many other issues where Iraq used to be a leader in the Arab world for women's rights. Other legislation passed by the council included declaring the day that Baghdad fell to be a national holiday, voting to establish a tribunal to try former government leaders, and banning television stations which are deemed to be supportive of the resistance. A new flag chosen by the council for post-Saddam Iraq created much controversy, in part because of the similarity of color and design with the flag of Israel, and the flag was not adopted.
According to the Law of Administration for the State of Iraq for the Transitional Period, the interim constitution that the Council approved, the Council would cease to function after June 30, 2004, at which point full sovereignty would return to Iraq, and the government will be handed over to a new, sovereign interim government. Instead, the council chose to dissolve itself prematurely.
Presidents of the Iraqi Governing Council
|Took office
|Left office
|Political party
|Mohammed Bahr al-Uloum (1st time, acting)
|13 July 2003
|31 July 2003
|Ibrahim al-Jaafari
|1 August 2003
|31 August 2003
|Islamic Dawa Party
|Ahmed Chalabi
|1 September 2003
|30 September 2003
|Iraqi National Congress
|Iyad Allawi
|1 October 2003
|31 October 2003
|Iraqi National Accord
|Jalal Talabani
|1 November 2003
|30 November 2003
|Patriotic Union of Kurdistan
|Abdel-Aziz al-Hakim
|1 December 2003
|31 December 2003
|Supreme Council for the Islamic Revolution in Iraq
|Adnan Pachachi
|1 January 2004
|31 January 2004
|Assembly of Independent Democrats
|Mohsen Abdel Hamid
|1 February 2004
|29 February 2004
|Iraqi Islamic Party
|Mohammed Bahr al-Uloum (2nd time)
|1 March 2004
|31 March 2004
|Massoud Barzani
|1 April 2004
|30 April 2004
|Kurdistan Democratic Party
|Ezzedine Salim
|1 May 2004
|17 May 2004
|Islamic Dawa Party
|Ghazi Mashal Ajil al-Yawer
|17 May 2004
|1 June 2004
Council Members
The presidency of Iraq rotated monthly among nine members of the council. A (p) marks those members above. (See President of Iraq.)
On September 1, 2003, the council named its first cabinet. They were:
- Minister of Communications — Haidar al-Abbadi
- Minister of Public Works — Nesreen Mustafa Sidiq Berwari
- Minister of Construction and Housing — Bayan Baqir Solagh
- Minister of the Environment — Abdul-Rahman Sidiq Kareem
- Minister of Trade — Ali Abdul-Amir Allawi
- Minister of Planning — Mahdi al-Hafidh
- Minister of Education — Alaudin Abdul-Saheb al-Alwan
- Minister of Higher Education — Zeyad Abdul-Razzaq Mohammed Aswad
- Minister of Culture — Mofeed Mohammed Jawad al-Jazaeri
- Minister of Human Rights — Abdul-Basit Turki (resigned April 2004)
- Minister of Foreign Affairs — Hoshyar Zebari
- Minister of Interior — Nori al-Badran (resigned April 2004 and replaced by Samir Sumaidaie)
- Minister of Agriculture — Abdul-Ameer Abboud Rahima
- Minister of Sport and Youth — Ali Faik al-Ghadban
- Minister of Health — Dr. Khudayer Abbas
- Minister of Industry and Minerals — Mohammed Tawfik Raheem
- Minister of Justice — Hashim Abdul-Rahman al-Shibli
- Minister of Science and Technology — Rashad Mandan Omar
- Minister of Work and Social Affairs — Sami Izara al-Majoun
- Minister of Electricity — Ayham al-Samaraie
- Minister of Finance — Kamil Mubdir al-Gailani
- Minister of Immigration and Refugees — Mohammed Jassem Khudair
- Minister of Water Resources — Abdul-Latif Rashid
- Minister of Oil — Ibrahim Mohamed Bahr al-Uloum
- Minister of Transport — Behnam Zayya Polis
The Saddam-era positions of Minister of Defense and Minister of Information were dissolved.
External links
|Preceded by
Ba'athist Iraq
|Government of Iraq
with Coalition Provisional Authority
July 13, 2003 - June 1, 2004
| Succeeded by
Iraqi Interim Government


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Run Because You Can // Muscle Tank // Gold Imprint
$ 24.99
Product Details
Our signature finisher muscle tank is a sheer jersey that offers extreme comfort, softness with instant touchability.
**If you like this design but want it on a different color and style. Email email@example.com and we can source it out for you.
Availiable: Black, Maroon, and Navy
See Picture below for Sizing.
Care Instructions:
Machine wash cold. Do not bleach. Tumble dry low.


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Computer Maintenance Technician
Are you using an old computer or a brand new model computer? It doesn't matter to us what model computer you are using. We provide computer maintenance services through talented and efficient computer maintenance technicians. We are 247techies and we are Microsoft Gold Certified Professionals. We adhere to Microsoft's most stringent standards. 247techies never give up until they find the root cause for your tech problem. We understand that your computer plays an important role in your routine life. Unlike the computer repair shops we troubleshoot your computer efficiently. Don't rely on unreliable sources to repair your PC. Dial 1-951-225-4557 to contact us immediately and receive world's best tech support.
Computer Maintenance Technicians for Your PC
Computer is an electronic machine. It needs regular maintenance services. You may have noticed that your computer won't perform as well as it performed when it was brand new. Computer's performance may depend on your computer's specifications and usage period. But frequent maintenance services can optimize your computer's performance. So are you going to hire a computer maintenance technician? Why don't you do it via online because remote computer support is easier, cheaper, faster and reliable? 247techies are well trained and experienced computer maintenance technicians. We will be at your service around the clock anytime and anywhere.
Services Offered By Computer Maintenance Technicians
- Unlimited tech support throughout the year
- Free up hard disk space
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- Optimizing Windows start-up programs
- Backup support for emails, browsers and for storage devices
- Wireless and wired network installation and troubleshooting support
- System recovery and backup services
- Secure browsing
- Fixing blue screen errors
- Laptop repairs
- And many other services as you require
Just give us a call at 1-951-225-4557 for immediate tech support


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When my daughter asked me if we had a water filter for shower, I had no idea what she was talking about. I told her that we use filtered water for drinking, but that filter is in the kitchen. She asked me about the water in the shower though and how we are filtering it. Again, I had no idea what she was even asking because I had just never heard of people filtering their shower water. She explained what she had learned in school that week, which was how all kinds of pollutants get into our water.
Most kids had water filters in their kitchens at home, but only a couple knew that they had a shower filter. I still was not sure what a water shower filter would do, so I went online to learn more about it. I was really surprised with what I found out too. I had no idea that there were so many things in the shower water. I had never really thought about it before, but I guess I just figured it was all okay because none of the water goes into our bodies. That is where I was wrong though.
I paid attention the next time I took my shower, and I did notice water droplets going into my mouth. It is really inevitable, and I was surprised at the amount that I could tell was going into my mouth. After reading about the things that can be found in shower water like chlorine, metals, bacteria and so much more, I knew this was something we had to start taking seriously. I ordered a shower filter that same day, and it was so easy to install when it arrived that I didn't even need any help. Now we are all taking much nicer showers knowing it is there!


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By KTVI
House Springs, MO (KTVI) — A Cedar Hill man is arrested after an employee of a store located a video recording device in the ceiling of the women's restroom. The employee was able to identify the man from photos obtained from the recording device.
Authorities say Frank Fuchs, 51, allegedly placed a video recording device in the ceiling of the female restroom at Price Shopper located in the 4600 block of Gravois Road in House Springs.
Fuchs was detained by store employees and upon the arrival of deputies Fuchs was taken into custody.
The Jefferson County Prosecuting Attorney's Office has issued a charge of Invasion of Privacy of Multiple Individuals against Fuchs.
Fuchs is incarcerated in the Jefferson County Jail on a $50,000 cash bond.
It is believed that Fuchs may have attempted to video other victims as well.


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The Turkish Escalation
It is hard to explain the attitude made by Turkish Prime Minister Recep Tayyip Erdogan toward the crisis in Syria, unless we read the Turkish Political calculations and study Erdogan's dreaming project.
Erdogan wants to lead the Islamic world by using new Sultanate concepts and the new Islamic movements (Muslim Brotherhood) in the region.
These Islamic movements removed and mounted on the popular movement in many Arabs countries.
A new pact between U.S.A and Emerging Islamic movements (Muslim Brotherhood) was made to create a new middle east, this pact had been prepared since Obama speech in 2009.
Obama speech described the smooth power, the American values and Abandonment of military power to keep the U.S. strategic interests and American National Security.
This pact will become future US strategy to serve the new American strategy in our region.
U.S.A. uses another way to do this strategy; this way has less economic, human cost by using regional powers (Turkey) instead of Israel, because Israel is not qualified any longer to do this role due to the public mood and its negative attitude in the region.
American strategy and Erdogan's dreams met at this point because Erdogan's dream has an opportunity and momentary historical chance especially that Arab's region lives in unstable conditions.
We don't underestimate the street against some corrupt regimes in other countries, but we focus on the way especially that Emerging Islamic movements which hijacked the popular movement.
Former U.S. Secretary of State, Condoleezza Rice, had talked about the unstable conditions (Creative chaos).
The only obstacle against the pact among US and western powers and the Emerging Islamic movements (Muslim Brother hood) will be Syria, so they (USA and Turkey) are trying to shift the Syrian from playing the role of Resistance.
The Turkish role comes here through the intervention of Syrian internal affairs by pushing situations to further escalation and blocking any opportunities for political solutions and taking the Syrian to the point of irreversibility. They believe this will lead to the fall of the Syrian political regime and will destroy the Syrian state through its depletion economically, militarily and socially; and this will pave the way for foreign opposition forces to gain power and implement strategies of the Western world (US-Israeli camp).
US, Western powers and Turkey were unable to defeat Syria by using the hard and soft powers, so they are waving the direct use of military force by installing Patriot missiles in Turkish land.
The missiles aim to achieve several objectives: first to protect Israel and Turkey from any attack (Syria, Iraq and Iran) and second to use Turkey as a platform for NATO against Russia and that will lead the region to cold war again.
This, however, will be reflected negatively on Turkish people and will serve US and Israel for free, and will push the people in the region for Conflict, infighting and rivalry.
Dr. Khalf al-Miftah
Translation: M.T