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Almost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules with antibiotic activity have been isolated from animals, insects, plants and bacteria, and their use has revolutionised clinical medicine. So far, more than 1200 types of peptides with antimicrobial activity have been isolated from various cells and tissues, and it appears all living organisms employ these antimicrobial peptides (AMPs) in their host defense. In the last decade, innate AMPs produced by mammals have been shown to be essential for the protection of skin and other organs. Their importance is due to their pleiotrophic functions to not only kill microbes but also control host physiological functions such as inflammation, angiogenesis and wound healing. Recent advances in our understanding of the function of AMPs have associated their altered production with various human diseases such as psoriasis, atopic dermatitis and rosacea. In this review, we summarize the history of AMP biology and provide an overview of recent research progress in this field.
The antimicrobial peptides (AMPs) have redefined the way we think about immune defense and human disease. Unfortunately, this name is misleading as the term "antimicrobial" describes more about their history of discovery than the potent influence these molecules have on cell behavior. As such, alternative terms for AMPs have also appeared. These include better descriptive terms such as "host defense peptides", "alarmins" and even "defensins" (used in a broad context instead of the gene family). However, to appreciate the history of the discovery of these molecules as well their common unifying function to kill microbes, the term AMPs will be used in this review.
Over the last two decades more than 1200 AMPs have been identified or predicted from various organisms. For a partial list of these, see the Antimicrobial Peptide Database (APD: http://aps.unmc.edu/AP/main.php). AMPs in general consist of 10–50 amino acid residues. These peptides lack any specific consensus amino acid sequences that are associated with biological activity, but most of them maintain certain common features, such as containing positive charge and relatively hydrophobic and amphipathic structure. Based on their amino acid composition, size and conformational structures, AMPs can be divided into several categories, such as peptides with α-helix structures, peptides with β-sheet structures stabilized by disulfide bridges or peptides with extended or loop structures, reviewed in (Lai and Gallo, 2009). Classic AMPs, such as LL-37 and human β-defensins (hBDs), are amphipathic molecules that possess clusters of positively charged and hydrophobic charged amino acid chains. This amphipathic feature is thought to allow them to interact with negatively charged phospholipid head groups and hydrophobic fatty acid chains of microbial membranes, resulting in pore formation on the microbial membrane and release of cytosol components (Glaser et al., 2005; Wimley, 2010). It is the membrane active nature of the AMPs that likely controls their function, but as we continue to study these molecules we learn that their function is much more than originally expected.
Many immunologists consider the study of AMPs as a relatively new topic that led the way towards recognition of our modern understanding of innate immunity. AMPs are a primary effector system that acts with the detection system generated by microbial pattern recognition genes such as the toll-like receptors (TLRs). However, the history of discovery of innate antimicrobials goes back much further in history. Alexander Fleming first recognized the presence of a soluble antimicrobial substance produced by humans about 90 years ago. Fleming observed the bactericidal and bacteriostatic activities of nasal secretions from a patient suffering from acute coryza when he treated bacterial culture plates with this material (Fleming, 1922). He named the activity lysozyme because of its capacity to "lyse" bacterial lawns on a dish. Subsequently, he found lysozyme activity in various human physiological fluids and tissues of animals, as well as egg whites. Such observations indicated to him that lysozyme performed a wide range of functions as a part of our immune system. In 1928, Fleming subsequently discovered that penicillin extracted from the culture of green mold, Penicillium notatum, stopped the growth of various bacteria (Fleming, 1929). In the 1940's, Howard Florey and Ernst Chain brought penicillin's potential for medical use to fruition. They shared the 1945 Nobel Prize for Medicine along with Fleming for the discovery of penicillin and its therapeutic effects. About forty years after Fleming's lysozyme discovery, the primary structure of egg white lysozyme was characterized (Canfield, 1963), but by this point the interest in natural host antibiotics had decreased and the importance of this immune defense strategy was all but forgotten.
Antibiotics were also recognized in prokaryotic cells at an early stage in modern medicine. In 1939, René Dubos isolated antimicrobial substances, named gramicidin, from culture supernatant of soil bacteria, Bacillus brevis. Gramicidin exhibited bactericidal or bacteriostatic activity against a wide-range of Gram-positive bacteria in vitro and in vivo (Dubos, 1939a, b). Gramicidin was later shown to be a heterogeneous mixture of six AMPs that was identified as N-formylated polypeptides with alternating L- and D-amino acids (Sarges and Witkop, 1965a, b, c). In addition, application of gramicidin on infected wounds on guinea-pig skin rapidly disinfected pathogenic bacteria and successfully suppressed infection, indicating the therapeutic potential of gramicidin for clinical use (Gause and Brazhnicova, 1944). To our knowledge, gramicidins were the first AMPs for which the primary structures were characterized and the first antibiotics to be commercially manufactured. This is available today as an over-the-counter antibiotic.
AMPs are now known to exist in all kingdoms. In contrast to the large size of lysozymes, relatively small antimicrobial molecules were observed to be induced in the hemolymph of wax moth larvae after challenging with Pseudomonas aeruginosa (Stephens and Marshall, 1962). Remarkably, normal larvae that had received hemolymph from pathogen-challenged larvae exhibited passive protection against bacterial infection, thus proving these innate protective molecules were soluble. In 1981, Hans Boman at the Karolinska Institute pioneered the field of modern innate immunity by seeking to identify the structure of innate insect antimicrobial defense molecules. Initially, Steiner et al., characterized primary structures of two AMPs, named cecropins A and B, in hemolymph of the cecropia silk moth, Hyalophora cecropia (Steiner et al., 1981). Later, an AMP was isolated from pig small intestines which showed a high similarity with the insect cecropins, therefore it was named cecropin P1 (Lee et al., 1989). However, the research group that discovered the peptide later corrected their original conclusion and discovered that this peptide in fact originated from parasite Ascaris nematodes (Andersson et al., 2003).
AMPs are also an integral part of the immune systems in plants. In the early 1940's, Stuart and Harris demonstrated that a crystalline protein isolated from wheat flour exhibited antimicrobial effects against some human pathogenic bacteria and yeast (Stuart and Harris, 1942). It was a low molecular weight proteinaceous material with high sulfur content and named purothionin (Balls et al., 1942). In the 1990's, a group of small basic proteins was isolated from wheat endosperm and characterized as purothionin homologs, so they are called γ-purothionins (Colilla et al., 1990). However, subsequent study has established that purothionins and γ-purothionins are structurally unrelated (Bruix et al., 1993). Considering that γ-purothionins show a high structural analogy with insect defensins, adapting β-sheets and a single α-helix structures stabilized by an eight cysteine-motif, they are renamed as plant defensins (Broekaert et al., 1995) (see below for defensins). Transgenic plants over-expressing AMPs have been explored for decades as a mechanism for disease resistance. For example, expression of defensins in plants confers enhanced resistance to phytopathogen attacks (De Coninck et al., 2010; Jha et al., 2009).
The discoveries of defensins and cathelicidins led the way for the emergence of our appreciation of AMPs in mammals. Arginine-rich cationic peptides possessing potent antimicrobial activity against both Gram-positive and Gram-negative bacteria were first identified in the lysosomal fraction of guinea-pig polymorphonuclear leukocytes by mobility to the cathode (Zeya and Spitznagel, 1963). Selsted et al. characterized primary structures of the six cationic AMPs purified from rabbit neutrophils and named these defensins (now classified as α-defensins) (Selsted et al., 1985; Selsted et al., 1984). The research group subsequently identified three defensins from normal human neutrophils and also demonstrated that the peptides directly inactivated herpes simplex virus (Ganz et al., 1985). These defensins have a characteristic six-cysteine motif which forms three intramolecular disulfide bonds (Cys1–Cys6, Cys2–Cys4 and Cys3–Cys5). Selsted et al. isolated and characterized 13 AMPs with 38–42 amino acid residues and the six-cysteine motif of defensin in bovine granulocytes (Selsted et al., 1993). However, these defensin-like AMPs differed from α-defensins by relatively longer amino acid residues and different disulfide pairings (Cys1–Cys5, Cys2–Cys4 and Cys3–Cys6), therefore they were newly classified as β-defensins. Genomic-based approach have identified 28 human and 43 mouse β-defensin genes (Schutte et al., 2002). Tang et al., characterized an AMP in the leukocytes of rhesus monkey, which consisted of 18 amino acid residues with the six-cysteine motif of defensin, and in which the peptide backbone is naturally cyclized (Tang et al., 1999). This AMP was classified as θ-defensin. Interestingly, θ-defensin mRNA transcripts are present in human bone marrow, spleen, thymus, testis, and skeletal muscle, but a premature stop codon aborts their translation (Nguyen et al., 2003). In addition to the antibacterial activity, defensins also offer effective antiviral and antifungal activities through multiple modes of action. Mammalian defensins exhibit strong viral neutralizing activities by directly interacting with viral envelope proteins (Doss et al., 2009; Hazrati et al., 2006). In addition, α- and θ-defensins directly interact with specific viral receptors on the host cell, antagonizing viral attachment, entry, or intracellular shuttling (Cole et al., 2002; Furci et al., 2007). α-defensins also kill Candida albicans by lysing cells, possibly in a similar way to their antibacterial activity (Lehrer et al., 1985; Patterson-Delafield et al., 1980).
Zanetti et al. cloned a full-length cDNA of Bac5, a proline-rich AMP which had previously been isolated from bovine neutrophils (Frank et al., 1990), from myeloid bone marrow cell mRNA (Zanetti et al., 1993). The region upstream of mature Bac5 peptide was found to share high homology to cathelin (more than 70% identity), an inhibitor of the cysteine proteinase cathepsin L isolated from pig leukocytes (Kopitar et al., 1989). Bovine or porcine leukocytes both contained at least 10 structurally-diverse AMPs composed of 12–100 amino acid residues whose precursor proteins have cathelin-like domains in the N-terminal, therefore these AMPs were named cathelicidins (Zanetti et al., 1995). Interestingly, the number of different cathelicidins varies substantially among species. In contrast to the multiplicity of cathelicidins in bovine and porcine neutrophils, the human and murine neutrophils express only a single cathelicidin gene (CAMP) that encodes an inactive precursor proteins, hCAP18 in human and CRAMP in mouse (Agerberth et al., 1995; Cowland et al., 1995; Gallo et al., 1997). Post-transcriptional processing cleaves out the C-terminal cathelin domain from cathelicidin precursor protein and makes the active AMP. In human, for example, active AMP composed of 37 amino acids beginning with two leucines, named LL-37, is generated from hCAP18 (Zanetti, 2004). hCAP18 is cleaved extracellularly by proteinase 3 or kallikrein family serine proteases to generate the active LL-37 peptides (Sorensen et al., 2001; Yamasaki et al., 2006). After the cleavage, the N-terminal cathelin domain also exhibits antimicrobial activity (Zaiou et al., 2003). The cathelicidin AMPs generated from CAMP genes found between species show little similarity to each other and are referred to as a group solely because of the similarity of the precursor protein that is predominated by the large cathelin domain. In addition, they are remarkably variable in secondary structures. Many of them adopt an α-helical structure followed or not by a hydrophobic unstructured tail (human LL-37, mouse CRAMP, rabbit CAT-18), while others are proline/arginine-rich (bovine Bac-5 and porcine PR-39), tryptophan rich (bovine indolicidin and porcine tritrpticin), and β-hairpin-like structure (porcine protegrins) (Bulet et al., 2004; Lehrer and Ganz, 2002). The cathelicidins have been cloned not only mammals, but also fish (Chang et al., 2005; Maier et al., 2008), chicken (van Dijk et al., 2005), snakes (Wang et al., 2008; Zhao et al., 2008) and hagfish (Uzzell et al., 2003).
As described above, in the early 1990s AMPs were being discovered in a wide range of organisms and cell types. Despite this, we were surprised to discover that AMPs were abundantly present in mammalian skin (Gallo et al., 1994). These observations were first made in pig wounds with the discovery of the porcine cathelicidin PR-39. Following this discovery, Harder et al. described the production of hBD-2 in human skin, lung, uterus and trachea epitheliums, and elevated hBD-2 expression in human keratinocytes exposed to pathogenic bacteria (Harder et al., 1997). Subsequent work from our group and others demonstrated that AMPs are induced in the skin by injury and are abundantly found in some inflammatory processes such as psoriasis (Dorschner et al., 2001; Frohm et al., 1997). The unique inflammatory environment of psoriasis has been subsequently exploited for discovery of multiple AMPs including α-and β-defensins, psoriasin and RNase7 (Harder and Schroder, 2005). A key advance for the field came with the capacity to not only purify and test antimicrobial activity of isolated AMPs, but also to apply modern mouse molecular genetic approaches to evaluation of their function. These studies led the way to revise perceptions of AMPs as evolutionarily ancient molecules that have relatively insignificant roles in organisms that have developed adaptive immune defense systems. The key initial finding was that targeted deletion of cathelicidin proved this AMP was essential to the normal immune response and resistance to bacterial skin infection (Nizet et al., 2001). This critical role for cathelicidin has been now shown in many tissues, mucosa and body fluids, and for a wide range of pathogenic bacteria, several viruses and funguses as well as Leishmania (Doss et al., 2010; Gallo et al., 1997; Gordon et al., 2005; Gutner et al., 2009; Kulkarni et al., 2011). Targeted deletion of other molecules involved in pattern recognition and processing of AMPs have shown similar results (Takeuchi et al., 2000). Although similar in vivo data with defensins have been more difficult to generate due to the extensive gene duplication of the α- and β-defensin gene families, several reports have successfully demonstrated an important roles for defensins in host defense against bacteria and some viruses in vivo. Metalloprotease-7-deficient mice, lacking all mature α-defensins due to the loss of the protease required for proteolytic cleavage, displayed a reduced clearance of bacteria and higher mortality rates upon pathogen challenge (Wilson et al., 1999). Mouse β-defensin-1 knockout mice showed earlier weight loss and higher mortality after influenza virus infection than wild-type mice (Ryan et al., 2011). Conversely, transgenic over-expression and knock-in of AMPs further supported these conclusions by showing that the addition of excess AMPs can increase resistance to some microbes (Lee et al., 2005; Salzman et al., 2003).
Today, cathelicidins and β-defensins are the most well characterized AMPs found in the human skin (Lai and Gallo, 2009; Wiesner and Vilcinskas, 2010). hBD-1 is constitutively expressed in keratinocytes, but exhibits only minor antibiotic killing activity in comparison with other defensins (Yadava et al., 2006; Zaalouk et al., 2004). More recently, the reduced form of hBD-1 has been shown to become a potent antimicrobial peptide, of which reduction is catalyzed by thioredoxin expressed in the epidermis (Schroeder et al., 2011). This suggests that the redox regulation is crucial for the innate immune protection by hBD-1. The expression levels of hBD-2, hBD-3, and human cathelicidin in keratinocytes are very low at the steady state and typically upregulated during infection, inflammation and wounding (Froy, 2005; Gallo et al., 2002). This suggests that with these AMPs it is the secondary response of increasing expression that serves to limit the severity of clinical symptoms when the primary line of defense (constitutive expression of AMPs) fails. Human keratinocytes also express many molecules that were first discovered for reasons other than action as an AMP, but subsequently found to also inhibit microbial growth. Once example of these are the ribonucleotidases (RNases). Of these, RNases 5 and 7 exhibit antimicrobial activity against many pathogenic microorganisms independent of the RNase activity (Abtin et al., 2009; Huang et al., 2007; Zanger et al., 2009). The antimicrobial activity of those RNases is inhibited by RNase inhibitor protein expressed in epidermal keratinocytes, and, in turn, activated when the RNase inhibitor is cleaved by stratum corneum serine proteases (Abtin et al., 2009). An antimicrobial heterodimeric complex, S100A8/S100A9 (calprotectin), is induced in epidermal keratinocytes during Gram-negative bacteria infection and sensing of bacterial flagellin by TLR5 is critical for the regulation of calprotectin (Abtin et al., 2010). Cathelicidin, hBD-2 and -3 and antimicrobial histone H4 are detected in the cultured human sebocytes, and their expression levels are upregulated in the presence of Gram positive bacteria or sebum free fatty acids (Lee et al., 2009a; Nagy et al., 2006; Nakatsuji et al., 2010). Large amounts of psoriasin antimicrobial peptide accumulate in the epidermis of sebaceous skin as well as sebaceous glands and secreted to the external skin surface (Glaser et al., 2005). Sweat eccrine glands are also known as an important supplier of AMPs to the epidermal surface. Dermcidin is an AMP constitutively expressed as a small precursor protein in eccrine sweat glands and secreted into sweat where active AMPs are proteolytically generated (Schittek et al., 2001).
The skin provides a rapid first-line of immune defense against invading pathogens from outside environments by constitutively and actively producing various AMPs. In human skin, the main cellular sources of AMPs are keratinocytes, mast cells, neutrophils, sebocytes and eccrine epithelial cells (Figure 1). This layered system of deployment functions well because of the dual action of AMPs. First, as we have thus far described, the secretion or release of these peptides provides innate antibiotic-like action against infectious pathogens. However, a key component of the overall defense strategy of skin and other epithelial organs is that alternate defense systems are activated to provide protection in the event that microbes evade the first system. Clearly, microbes are well adapted to develop antimicrobial resistance, and many microbes are human pathogens because they have succeeded in doing this. AMPs such as Cathelicidins and Defensins therefore appear to have maintained their relevance because they also contribute to host defense by triggering inflammatory cell recruitment and cytokine release. This system often involves signaling mediated by pattern recognition receptors such as TLRs or responses to pro-inflammatory cytokines. The AMPs amplify defense by calling for help.
As a result of the inherent association of AMPs with inflammation, recent evidence indicates that abnormal production of AMPs affects the pathogenesis of diseases such as psoriasis, rosacea, and atopic dermatitis (Yamasaki and Gallo, 2008). These observations have two important consequences. First, they have further demonstrated the relevance of these evolutionarily ancient genes to human health. Secondly, the role of some AMPs in human disease appears to depend more on the actions of these peptides beyond those as an antibiotic. It is in this context that the alternative terms such as "host defense peptide" or "alarmin" are most appropriate.
Cathelicidins and hBDs were well known to be strongly induced in psoriatic lesions in comparison with normal skin, and this degree of induction mimicked expression expected when normal skin was injured. However, the induction of some AMPs such as cathelicidin and hBD-2 and 3 was found to be lower in atopic dermatitis lesions than expected, despite the presence of skin inflammation (Hata et al., 2010; Lande et al., 2007; Mallbris et al., 2010; Ong et al., 2002). In contrast, RNase7 and psoriasin are induced in atopic dermatitis lesional skin and in this case AMP induction is appropriately upregulated by barrier disruption (Harder et al., 2010). The defective expression of some AMPs in atopic dermatitis has been linked to a higher propensity to Staphylococcus aureus colonization, which is known to play important roles in the exacerbation of the infection and is correlated with its extent and severity of atopic lesions (Miller et al., 2005). Thus, in this situation, a lack of the antimicrobial function of the AMP may lead to disease. An informative contrast to the observations in atopic dermatitis can be made in analysis of the diseases rosacea and psoriasis. Our group showed that an excess of cathelicidin in the form of LL-37 exists in rosacea, and this drives inflammation and abnormal blood vessel growth by mechanisms of cell activation not related to antimicrobial action (Yamasaki et al., 2007). High amounts of LL-37 appear to result from the abnormal function of innate immune pattern recognition by TLRs, and proteases that process hCAP18 (Bensch et al., 1995; Jugeau et al., 2005; Yamasaki et al., 2007; Yamasaki et al., 2010). In psoriasis and systemic lupus erythematosus, the excess presence of LL-37 enables recognition of self-nucleic acids by both plasmacytoid dendritic cells (Lande et al., 2011; Lande et al., 2007) and keratinocytes (Morizane et al., 2011). Thus, under these conditions AMPs may be exacerbating inflammation and contributing to disease by permitting auto-inflammatory signaling. Expression of AMPs is also associated with viral infectious diseases such as mollusca contagiosm (Meyer-Hoffert et al., 2010), condyloma acuminatum, and verruca vulgaris (Conner et al., 2002), as well as autoimmune diseases, such as cutaneous lupus erythematosus (Kreuter et al., 2011).
As introduced by the proceeding discussion of AMPs in human diseases, these molecules have several important physiological and immunomodulatory functions. Some α- and β-defensins are chemotactic for T lymphocytes, monocytes and immature DCs, and can induce cytokine production by monocytes and epithelial cells (Yang et al., 2004). hBD-2 activates immature dendritic cells through TLR4-dependent mechanisms, inducing a robust Th1 response (Biragyn et al., 2002). Cathelicidin triggers inflammatory cell recruitment and cytokine release through various mechanisms. LL-37 is a potent chemoattractant for mast cells, monocytes, T lymphocytes and neutrophils through activating formyl peptide receptor–like 1(FPRL1) (De et al., 2000; Niyonsaba et al., 2002). The complex of LL-37 with self-DNA or self-RNA released from dead cells activates dendritic cells by triggering TLR9 or TLR7/8, respectively, leasing productions of proinflammatory cytokines and type-I interferons (Ganguly et al., 2009; Lande et al., 2011; Lande et al., 2007). These immunomodulatory properties of AMPs can contribute to host defense against infections by attracting and activating various immune cells as well as by their direct antimicrobial activity.
LL-37 contributes to cutaneous wound healing by stimulating re-epithelialization (Heilborn et al., 2003). LL-37 also induces neovascularization which is mediated by FPRL1 signaling in endothelial cells, and the cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization (Koczulla et al., 2003). Furthermore, LL-37 induces proliferation and migration by human endothelial cells (Ramos et al., 2011). In fact, accumulation of cathelicidin has been observed in epidermal wound and blister fluid (Dorschner et al., 2001; Frohm et al., 1996; Gallo et al., 1994).
A surprising recent revelation is that the AMPs that directly contribute to our skin innate immune defense are made not only by our own cells, but also in prokaryotic organisms that inhabit our epidermis. Our group has proposed that the unique peptides phenol-soluble modulin (PSM)γ and PSMδ produced by Staphylococcus epidermidis (S. epidermidis) could be beneficial to the host and thus serve as additional AMPs on normal skin surface (Cogen et al., 2010b). Although we know today from 16S sequencing approaches that the microbiome of human skin is diverse (Grice et al., 2009), S. epidermidis was of high interest because it is the predominant bacteria that can be cultured from healthy human skin, and thus known to thrive on the epidermis (Kloos and Musselwhite, 1975). PSMs caused membrane leakage and membrane perturbation in bacteria as well as classic AMPs such as LL-37 and hBDs, suggesting that these peptides function in a similar mechanistic manner as that of innate cutaneous AMPs. These peptides selectively exhibited bactericidal activity against skin pathogens, such as Staphylococcus aureus (S. aureus), Group A Streptococcus (GAS) and Escherichia coli, whereas they are not active against S. epidermidis. Moreover, inoculating PSMs on the mouse skin surface reduced the survival of GAS but not S. epidermidis. This selective activity is likely to be an important part of a normal microbial defense strategy against colonization. In addition, PSMs enhance the capacity of bacterial killing activity by human neutrophils by inducing their neutrophil extracellular traps (Cogen et al., 2010a). These lines of discovery are only at the very early stages, and considering the diversity of the human microbiome it is likely that many other microbial AMPs that benefit our immune defense will be discovered.
The important pleiotropic actions of AMPs, the many examples of relevance in animal models, and their associations with human disorders, all point towards this class of molecules as a new target for therapy. In cases where increasing AMP expression would be beneficial, such as when attempting to treat or prevent infectious disease, a simple therapy has shown promise. Vitamin D, long suspected of having health benefits in infectious diseases such as influenza and tuberculosis, has been shown to be a potent stimulus of AMPs (Beard et al., 2011). Experiments with cultured cells have shown that 1–25-dihydroxyvitamin D3 enhances the expression of cathelicidin and hBD-2 by normal human keratinocytes, resulting in an enhanced antimicrobial function against S. aureus in vitro (Schauber et al., 2008; Wang et al., 2004). Pilot studies have attempted to compensate for the defective expression of AMPs in the skin of patients suffering from atopic dermatitis by administering vitamin D (Hata et al., 2008). Analysis of killing of Mycobacterium tuberculosis by monocytes has shown improvement with vitamin D (Liu et al., 2006). However, most clinical trials have not shown a conclusive association between vitamin D and infections in humans. It is possible that this lack of an ability to observe an association reflects the influence of other variables not yet understood. In psoriasis patients, decreased expression of hBD-2 and hBD-3 were observed in lesional skin following topical administration with calcipotriol, a vitamin D analog, despite increased expression of cathelicidin (Peric et al., 2009). The suppression of AMP expression was accompanied by decreased expression of interleukins-17 and -8 that play important roles to cause psoriatic inflammation. Thus, ameliorating AMP expression is also a novel therapeutic approach for the treatment of skin diseases with disturbed AMP expression such as psoriasis, rosacea or atopic dermatitis.
AMPs have been known for some time, but their discovery in the skin and associations with disease are a relatively recent advance that has opened a new chapter in immunology. AMPs mediate the host innate immune defense through various modes of action. A variety of factors influence AMP expression and function. For example, a recent study from our group demonstrated that a small molecule of <10 kDa secreted from S. epidermidis, the predominant commensal in healthy human skin, increased expression of hBDs in murine skin and human keratinocytes through activation of TLR2 signaling (Lai et al., 2010). Similarly, co-cultivation of differentiated human primary keratinocytes with live S. epidermidis, but not heat-inactivated bacteria, enhanced production of hBD-2, hBD-3 and RNase7. In addition, keratinocytes pre-incubated with S. epidermidis-conditioned media strongly enhanced AMP production induced by S. aureus, suggesting that S. epidermidis sensitizes human keratinocytes toward pathogenic bacteria and amplifies the innate immune response (Wanke et al., 2011). These results suggest that the recognition of Staphylococcal molecules by TLR2 may be involved in the steady-state production of AMPs in keratinocytes and enhances resistance to infection by bacterial, fungal and viral pathogens. Thus, the correlation between AMP expression and commensal microbiota may be very important to maintaining skin homeostasis. Imbalanced skin microflora would alter AMP expression in the skin, which is critical in the pathogenesis of psoriasis, rosacea, and atopic dermatitis. Indeed, many lines of evidence suggest a role for the imbalanced cutaneous microflora with pathogenicity of these disorders (Gallo and Nakatsuji, 2011). Understanding and control of AMPs is an exciting new part of the immunological revolution taking place today.
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Darla Peel and Sir Ian Shag are assigned by S to assassinate the double agent from Vermont who is a crooked CIA agent who sells stolen diamonds and illegal assault weapons to the Mafia and to the Soviet Union and to Communists and Nazi businessmen. He even travels to China and Cambodia and to South America in Chili to do his crooked dealings too. Back to the Soviet Union, S assigns Darla Peel and Sir Ian Shag to assassinate him. Do they accomplish the mission? Read and find out.
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Swiss artisan watchmaker F.P. Journe unveil their first sports watch venture using titanium with the new limited-edition Octa Sport Titanium timepiece. Featuring a titanium crown, aluminum dial, 5-day power reserve, and an in-house caliber FPJ 1300-3 movement, the Octa Sport Titanium watch combines a lightweight sleek black exterior with a free-sprung balance that includes four adjustable inertias. Buyers also get a state of the art aerodynamic and comfortable fit. Find the Octa Sport Titanium here at select retailers with rubber strap ($27,500) or titanium bracelet ($32,000).
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Have you ever driven on University Avenue in Provo? It is a high traffic street serving many businesses and also many many BYU students. If you are from a city and have had the treat of driving in this area you might have noticed
that people walk right out in front of you. It seems as though they have no idea that you are in a 3000 lbs or more box of steel on wheels and they are 200 lbs or less of flesh. I have noticed this phenomenon for the past ten years and have wondered what would motivate someone to walk out in front of a car?
I wonder if they feel because pedestrians have the right of way they should let everyone know of their legal protection by sacrificing their well being and maybe a few weeks time in the hospital? "If they hit me...I WILL SUE" I think might be the mentality? I have served my time in a few traffic schools and a good line I always take from them is, "You can be right, or you can be DEAD right!" So caution to any driver around that area! You need to always be watching for these lemmings and their death wishes. Please watch the video and please hone your skills of animal avoidance! Any comments on why this happens?


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36, 123 lbs. Can Super Sagging 34A Breast Fixed With Lollipop Lift and No Implants? (photo)
Doctor Answers 14
Improving Asymmetry
Breasts are often asymmetric. They can be lifted differently. One side can be reduced or the breasts can have different size implants, but without your desire for implants different amounts of fat can be added to improve symmetry.
36, 123 lbs. Can Super Sagging 34A Breast Fixed With Lollipop Lift and No Implants?
Kenneth Hughes, MD
Beverly Hills, CA
Breast lift with implants
All the best,
Dr. Results
Miami, FL
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Breast lift
- A full mastopexy raises the breasts by removing excess skin and tightening the surrounding tissue to reshape and support the new breast contour.
Sometimes the areola becomes enlarged over time, and a breast lift will reduce this as well
- A breast lift can rejuvenate your figure with a breast profile that is more youthful and uplifted
- A woman's breasts often change over time, losing their youthful shape and firmness.
- Is up to you to consider the combination of Breast Lift and Breast Implants- When the Nipple-Areola is below the crease under your breast and the breast gland has deflated a combination Breast Lift and Breast Augmentation is often required.
Implants with lift yields more youthful breast contours
Hi, I have attached a link that might be helpful...
Hi goddesslubana. Thank you for sharing your photos. You will have a more youthful breast appearance with both implant and lift. However, you would benefit from a lift regardless of an implant-the implant will provide you with upper and inner fullness that is difficult to create without enough breast tissue. You can always have the lift and place implants later, but the cost of two recoveries and two surgeries is more than a single operation. Fat grafting is an option but may not be less expensive, requires enough donor fat, and successful grafting is highly technique dependent. Inquire about financing options. Good luck!
Learn more: http://www.changeisbeautiful.com/breast-procedures-jacksonville/breast-lift
You Need a full anchor mastopexy. Fat grafting is good if you want to add volume.
I'm not sure that fat grafting will save you money however since this also adds time and expense to the procedure, similar to that of an implant.
Good luck
Full mastopexy
Lollipop Lift and No Implants?
Learn more: Http://www.nelson-center.com/breast-lift.html
36, 123 lbs. Can Super Sagging 34A Breast Fixed With Lollipop Lift and No Implants?
Lift and Implants? What's the best option?
A detailed consultation with a board certified plastic surgeon is important to establish your postoperative goals and determine what would be best for you. In my practice I like to review different photos of my patients to establish what shape and volume they seem to like most. It is also very important to perform a detailed exam to evaluate the thickness of your breast tissue, skin tone and the dimensions of your chest. I like to have my patients try on sizers to get a feel for what they may look like and also appreciate how heavy the implants might feel. It is also useful to incorporate some additional 3-D imaging to get a sense for the subtle change between different implant types.
The advice I give to my patients focuses on 3 key elements.
1. Select a board certified plastic surgeon that you can communicate with comfortably to establish your desired look.
2. Establish that your plastic surgeon has your best interest in mind and make sure that they can explain your procedure to you in a way that makes sense and makes you comfortable. I want my patients to walk out of my consults and feel like they "get it" with respect to their surgical plan. I want to make sure that my patients can understand what a specific implant may deliver in regard to their results. This is common when we are trying to determine the size a patient desires, and also whether or not to select a shaped highly cohesive implant compared to a round silicone gel or saline implant.
3. Make sure that you understand what to expect in terms of your recovery and postoperative instructions. In my practice I give my patients additional instructions and tools to help them recover. In addition, I follow all of my patients closely after surgery and visit with them at 1 week and 3 weeks after surgery to make sure they are healing as expected.
Best wishes and cheers!!! Steven Camp MD #HappyCamperMD
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.


text:
Ace Attorney/Tiger & Bunny crossoverAug. 1st, 2014 03:36 am
Title: In the Flesh
Fandom: Ace Attorney
Characters: Nathan/Edgeworth
Word count: 440 words
Rating: PG
Warnings: Nope
Summary: Gymnophoria - The sensation that someone is mentally undressing you.
Notes: For the Tumblr vocabulary meme.
This wasn't, Miles Edgeworth reminded himself, the first time he'd ever encountered a superhero, even if the other occasions had all involved accusations of murder, or the masked presence of Larry Butz. And Nathan Seymour was here, and a witness to the crime, in his civilian capacity; it wasn't like he'd be meeting Fire Emblem. Or seeing the signature car, regrettably. Most likely it never left Stern Bild.
No, this was just an ordinary interview with a witness, but Edgeworth still took advantage of the elevator ride to indulge in a moment's giddiness, which was preferable to the way he usually spent elevator rides.
When the doors opened, he straightened his cravat, brushed himself off, shot his cuffs, and approached the office door, which to his surprise was propped open. A moment later, as an acrid stench reached his nostrils, he understood why. He must have grimaced, because when he met the eyes of the young woman sitting behind the desk outside the office door, she was smiling sympathetically. "Opening the window didn't help," she said. "We just have to let it air out."
"I take it when Mr. Seymour 'gave chase,' it was less literal than I imagined." The police report had clearly erred on the side of discretion.
"Have you ever tried running in heels?" There was only one person to whom that voice — deeper than Edgeworth had expected — could belong, an imposingly-built black man with close-cropped pink hair. Nathan Seymour was, indeed, wearing heels, though he had to stand over six feet even without them.
"I can't say I've ever had the opportunity," Edgeworth said, smiling slightly, as he took Seymour's proffered, impeccably manicured hand. The nails were nearly the same shade of fuchsia as Edgeworth's own suit, as was the silky-looking, boat-neck shirt under Seymour's dark suit jacket. Without the Fire Emblem cowl, Seymour's face was androgynously handsome, though the feminine cut of his clothes did nothing to minimize his powerful build. His handshake was firm but not aggressive, and perfectly businesslike, but Edgeworth couldn't shake a familiar sensation at the sight of the man's broad smile.
"A cravat," he said happily. "I really like your style. Come right in," he added, standing aside to let Edgeworth through the door. Which meant Seymour was standing behind him while Edgeworth surveyed the charred and dampened wreckage of what had once been a tastefully-appointed office, before superpowered pursuit and a sprinkler system intervened.
And the wreckage was extensive, so Seymour was standing back there for quite some time.Edgeworth shrugged mentally. It was significantly more pleasant being undressed by the eyes of a superhero than of Wendy Oldbag.


text:
Student Employment Update
Jobs will open to students with Federal Work Study for the Fall 2017 next month. Being awarded FWS does not guarantee that you will be able to obtain employment for 2017-2018 but gives you the opportunity to apply for jobs. Students without a work program will not be able to apply for on campus jobs until further notice. If you have any questions, please contact our office.
How to Apply
Employment listings are updated continuously throughout the year and are separated by grade level (Undergraduate or Graduate). Listings include a description of the position, required qualifications, and pay rate. The search process works much like a real-life job search. You decide which positions interest you, and then apply for the positions through MyBentley.
If you have never worked on campus before, you will need to complete a federal I-9 form at the Student Employment Office, Rauch 104 before you can begin working. Use the Forms tab for copies of all available documents.
Many positions fill quickly, so plan to start your job search process early in the semester. If you are having difficulty finding a job, the Student Employment Office staff will make every effort to assist you.
View Job Listings
ACADEMIC YEAR JOB LIST (Sorted by Department)
SUMMER JOB LIST (Sorted by Department)
Dining Services
Having trouble finding a job on campus? Sodexo is looking for student employees.They will consider all applicants regardless of FWS eligibility. If interested in their opportunities please view their Sodexo Flyer.pdf for more information and how to apply.
For More Information
- To access S.E.A.S. on MyBentley. Log in to MyBentley > Student Self Service > Main menu > Undergrad menu > Student services > S.E.A.S.
- S.E.A.S. Tutorial (pdf) on how to apply for the jobs
- If you still have questions, contact the Student Employment staff.


text:
|iPhone apps
If you want to listen latest music from Czech Republic (more then 128 stations), this application is for you
* download list of radio stations
* stream from radio station (MP3/AAC+/WMA/OGG format supported)
* play music in background (MP3&AAC+)
* details of each radio stations (contact, link to web site with built in web browser)
* failback streaming
* create your own favourites list
* sleep function (1 to 210 min, with fade out volume)
* wake up function (fail-safe wake up if stream or Internet is not available)
* refresh full list of radio station from web
* add your own radio stations
* edit all radio stations and tweak it for your own use
* add/edit/delete your own favourites list through web site
* traffic counter (3G/Edge and Wifi)
* change volume with built-in control
* show song title and artist if supported by the stream
* update your Twitter status directly from application
What's New in Version 3.8
- iOS9 support
iPhone Screenshots
Video Reviews
No video review.
Customer reviews
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Be the first question this app.
Users Community
The information may be outdated (2017-03-08 18:04:25). For actual information go to iTunes


text:
BERLIN (Jul. 18)
With the Reichstag elections only two weeks off, it is apparent today that not a single Jewish candidate is listed by any of the parties with the exception of that of the extreme Left.
In the Reichstag elections of 1930, all the parties not anti-Semitic in their program, had Jewish candidates on their lists.
The "Israelitisches Familienblatt," commenting on this fact, explains that the lack of Jewish candidates is due to the strength of the anti-Semitic issue and no party is willing to risk being accused by the Nazis of being pro-Jewish.
The Nazis have spread throughout the city thousands of reprints of their bill and the measure as passed by the Prussian Diet regarding the confiscation of the property of East European Jews.
The reprints are part of the election propaganda of the Nazis.
The Nazi press carries daily attacks upon the Jews which are reiterated in special pamphlets.


text:
McMahon Tomlinson Nursing Center
Talk to a Family Advisor:
Reviews of McMahon Tomlinson Nursing Center
Susan2016 February 18, 2017
I am a friend or relative of a current/past resident
My mother was on the skilled nursing unit and received the wrong seizure medication even after family members tried to correct it several times. As a result , she had 3 seizures and her discharge was delayed by one week.
BRHPAIH May 11, 2016
I am a friend or relative of a resident
Right now my mother is in McMahon-Tomlinson Nursing Center, and we're not really happy with the place. The skilled part of it is doing fine and seem to be really attentive in taking good care of her. We're unhappy with the food because she doesn't like it. Some of the staff members are excellent; others are lazy. The dining room is restaurant style, but she's only had one opportunity to go to the cafeteria because they're bringing her food to the room. There are some exceptionally good nurses and assistants and all those folks that are caring for her, but then on the other side of it, there are those that act like they're put out when you need something. Some are excellent and some are the opposite; it's just a matter of who's on shift.
Write a Review
About McMahon Tomlinson Nursing Center
McMahon Tomlinson Nursing Center is a nursing home in Lawton, OK that provides patients with skilled nursing care as well as private or shared accommodations. Contact McMahon Tomlinson Nursing Center for more details on housing, services, and rates.
Features of McMahon Tomlinson Nursing Center
Medicare (ratings last updated: 06/16/17)
- Health:
- Overall:
- Quality:
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- Medicare Provider Number: 375562
- Ownership Type: Government County
- Date Certified: 05/01/2017
- Resident Capacity: 135
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text:
- Artist
- Period Active
30 Nov 1999 KOREA, REPUBLIC OF
- Type
Male Group
- Genre
K-POP > Dance
- Debut
26 Jul 2000 UNITED N-GENERATION
- Members
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the VirtualBoy Encyclopedia Book
Paperback, 38 Pages
List Price: $15.40
Price: $9.24
You Save: $6.16 ( 40% )
Prints in 3-5 business days
This is a book on the Virtual Boy. The book cover every licensed VB game and include screenshots, information, cover art, checklists, etc.
Ratings & ReviewsLog in to review this item
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Product Details
- 9781329988460
- Copyright
- DaddaRuleKonge (Public Domain)
- Edition
- First (Second) Edition
- Publisher
- DaddaCorp.
- Published
- March 21, 2016
- Language
- English
- Pages
- 38
- Binding
- Perfect-bound Paperback
- Interior Ink
- Full color
- Weight
- 0.49 lbs.
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- 8.5 wide x 8.5 tall
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Right planting methods will help reduce pollution
The damage that cyclone Vardah caused to the green cover of Chennai can be taken as a lesson to rectify past defects and improve on future tree plantation measures. Before the authorities take up massive tree planting, there are a few important issues that should be considered for getting the maximum benefits out of the plantation.
A perfect tree plantation is achieved by three factors -correct choice of tree species, correct planting techniques and consideration of environmental needs.
While selecting trees for plantation, the usual trend is to pick the one that is easily available. This, however, results in wrong species being planted in wrong places. While selecting the species for plantation in urban areas one should consider whether the species comes under the evergreen species, is wind resistant, drought hardy, fast growing, has aesthetic value and the capacity to tolerate water logging among other factors.
A study revealed that correct planting techniques were not followed in more than 90% cases of the urban tree plantings. While planting a tree, one should ensure that the ball of earth bearing the seedling is rested on the hard bottom of the pit. The sides around the ball should be furrowed for easy spread of new roots and the refilled earth should be a mixture of about 70% of the original soil and 30% compost.
In polluted cities like Chennai, trees enrich the oxygen content of the atmosphere, reduce carbon dioxide pollution and control hazardous trace chemicals, gases and particulate matters in the atmosphere. Plants absorb carbon dioxide to prepare food and release oxygen as a byproduct.Trees also respire by taking oxygen from the air and release carbon dioxide. However, trees take more CO2 and release less of it but take less oxygen and release more of it.Thus, more oxygen is added to the atmosphere and more carbon dioxide is absorbed.The carbon dioxide absorbed is sequestrated in their wood as carbon reserve, thus reducing CO2 pollution in air.
According to a study , the average number of trees needed to offset the annual oxygen consumption of one adult was 30 trees. This means, the number of trees needed to offset the human oxygen requirement would be thirty times of the total human population.It is very difficult to achieve the offset number in a city. But our atmospheric content of oxygen is constantly high at 20% that cannot be depleted at any condition. Therefore, enriching oxygen with more number of trees may improve only the local environment and may have seldom impact on the total oxygen content of the environment.
Although the total CO2 content is very little (0.03%), the atmosphere is very sensitive even to a small change in CO2 content.Therefore, reducing the CO2 content of the environment is imperative in order to reduce the global warming and other ill effect on human health conditions. For Chennai which has a population of 98 lakh, the total number of trees required to offset the total CO2 production of the city would be about 5.17 lakh or 30 treesHa.
Urban forest carbon sequestration and air pollution removal along with other environmental impacts of urban forests (e.g.water quality improvement, reduced ultraviolet radiation loads etc.) need to be incorporated within the urban development planning efforts to improve environmental quality and enhance the quality of urban life.


text:
VCSU plant science
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Information about VCSU plant science, and registering for discussion sections. Which college degrees give you the best chances of finding employment after graduation? Completion of an accredited nursing program or other medical training can qualify you to start working in a private hospital immediately. Concentrating on VCSU plant science, for example, you may gain an advantage in job recruiting on-campus. Check with the botany department for course registration deadlines, and plant biology program requirements. Please use the form above to request admissions info for VCSU.
Agricultural biotechnology, and crop science in general, includes plant cross-breeding techniques, trait selection, and genetic engineering in some cases. Biotech crops can make farming more profitable by increasing crop quality and may in some cases increasing crop yields. Where biotech crops are grown in proximity to related plants, the potential for the two plant species to exchange traits via pollen must be evaluated. In fact, according to the USDA National Agricultural Statistics Service (NASS), herbicide-tolerant crops are particularly compatible with reduced-tillage commercial agriculture systems that help preserve topsoil from erosion.
USDA researchers seek to solve major agricultural problems and to better understand the basic plant biology relating to crop science. Researchers may use biotechnology processes to discover things that may not be possible by more conventional means. This includes introducing new or improved traits in plants, animals, and microorganisms and creating new biotechnology-based products such as more effective diagnostic tests, improved farm animal vaccines, and better antibiotics. The USDA Economic Research Service (ERS) conducts research on the economic aspects of the use of genetically engineered plants, including the rate of adoption of biotechnology by farmers. The regulation of genetic engineering aims to assess and manage the risks of developing genetically modified organisms (GMO), including commercial food crops and fish. Beyond major requirements within the botany department, you may consider Umpqua Community College medical laboratory technology as a complementary elective to your primary course of study.
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text:
So, this apartment is a little bit smaller than my last one. To be specific, 100 square feet smaller. All of my stuff has managed to fit in, even though the kitchen only has one (tiny) drawer! I really like the layout of this apartment. I also like that it is on the second floor and only shares a wall with one other apartment.
I would like to give myself a pat on the back for how fast I was able to get everything set up. This apartment came together a lot faster than the last one, because I already had everything and already knew furniture arrangements that I liked.
Look at all of this nice, natural light!
That bathroom is tiny and has no storage, so I just threw everything in that basket above the towels. Good thing I'm tall and can reach everything without having to take it down!


text:
Kanebo Face Brush
3 reviews
66% would repurchase
Package Quality: 3.7
Price: $$$$
Package Quality: 3.7
Price: $$$$
Where to Buy
- When you make a purchase through these links, we may receive a commission from the eBay Partner Network or other affiliates.
Start your review
Age: 36-43
Skin: Combination, Fair-Medium, Cool
Hair: Black, Relaxed, Medium
Eyes: Brown
💖 I use this brush as a finishing blush because of its wider coverage and the cloudy plushness that just makes me smile. Because it is less dense that Chikuhodo Z-1, it is more feathery so you have to do the circular motion quite a few times unless you have heavier pigmented blush colour. Lunasol Powder Brush N is made from hair collected on the ground from blue squirrel (in 2011) and now in April 2017 [RM254] from mixture of gray squirrel and goat according to ther their website: www.lunasol-net.com. Difference is in the colour of the bristles whereby the mixed hair is dyed pitch balck compared to just pure dark brown/hazel blue squirrel hair only. Softness wise you can only feel the difference if you forcibly tap the tip against your cheeks, otherwise in strippling or circular motions, more psychological difference in softnest i guess 😍
My recommendations if you wish to feel:-
Velvety medium dense brush: Chikuhodo Z-1 (US$146), Z-8 (US$96)
Super soft yet heavenly dense brush: koyudo Fu-pa 14 (US$110) and 01 (US$39)
Age: 36-43
Skin: Dry, Fair-Medium, Neutral
Hair: Brunette, Straight, Fine
Eyes: Blue
Seriously - this is high quality stuff. I am not kidding - I have had this brush (actually 2 of them so I had already re-purchased) since the late 1980ies (sic!) and used it extensively (this goes for the eye shadow brush as well). At that time the handle was made from a transparent china red plastic, very 80ies indeed. It still looks like new. I take very good care of my brushes, but still - we are talking about 20 years of heavy duty use... In my stash I also have brushes from other brands (e.g. MAC, Bobbi Brown, Chanel, Youngblood) as well. It will be interesting to see how they compare when I have had them as long as the Kanebo ones :-). This brush is a natural hair brush (I cannot remember what hair but it could be sable) and I have used in primarily as a blush brush.
Age: 36-43
Skin: Dry, Fair, Neutral
Hair: Brown, Curly, Coarse
Eyes: Brown
This brush is great. It looks quite small, so I bought it initially to use for blush. The bristles are super soft and the long handle looks very elegant, although I could live with it being slightly shorter, since it's kind of hard to fit it into my makeup bags. Anyway, I've started using this brush for my mineral foundation (Everyday Minerals, great, great products). I felt doubtful it would work at first, since this brush is nothing like a kabuki, nor is it very big. But I was wrong. This works great as a face brush for minerals, and its small size is actually ideal to use in the EM lid. I "pump" the bristles full of minerals and then apply like I would do with a kabuki, only this brush actually controlls application much better. Despite its size it can hold the same amount of minerals as the EM kabuki. I'm so glad I gave it a go with EM!
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text:
Will doxycycline hyclate help an upper respatory infection or bronchitis ?
- Asked
- 23 Jan 2013 by Kflowers61
- Active
- 23 Jan 2013
- Topics
- infections, bronchitis, doxycycline
Responses (1)
Upper respiratory infections are usually a virus, and antibiotics don't help that. It may help if its a bacterial infection you have.
Further Information
- Doxycycline Information for Consumers
- Doxycycline Information for Healthcare Professionals (includes dosage details)
- Side Effects of Doxycycline (detailed)
Search for questions
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text:
Call us toll free at 1.888.600.6988
In Texas, RV consignment is getting to be an effective way to sell a recreational vehicle. While not everyone knows about this great manner of marketing your motorhome, it is quickly catching on. Here are a few reasons why it would behoove you to sell your RV using the services of the leader in Texas RV consignment dealers, sellmyrvtoday.com:
Texas is a big state, and there is a lot of RV travel. Needless to say, there are constantly RVs for sale, and there are just as many people looking to buy an RV. The leader of Texas RV consignment sales is sellmyrvtoday.com. They offer fair prices to purchase your RV outright, or they will take it to their consignment lot located in Tucson, Arizona and see if they can draw an even better price for you.
Sellmyrvtoday.com purchases late model recreational vehicles and motorhomes, such as Class A, Class B and Class C RVs. They also purchase 5th wheels, travel trailers and toy haulers. They have a large customer base of RV shoppers that continually peruse their inventory.
A simple call to the leader in Texas RV consignment sales, Sellmyrvtoday.com, will put the wheels in motion (literally) to getting the best deal for you in a quick, safe and reputable fashion.
I thought everything went perfectly in dealing with Sellmyrv. The process was easy and went very smoothly. I would definitely recommend your dealership to anyone wanting to sell their RV fast and with very little hassle!
Thank you very much, your teams service was very professional. I have no complaints at all.
Thanks, Mike. Honestly, it was a pleasure working with you and your team as well. Everybody was very thorough and professional during the process. You eliminated my initial concerns with transacting business on-line and I felt you covered everything, again giving me peace of mind…
Thanks for the follow up. Just another example of the good service I received from Sellmyrv. Thanks for your flexibility when my bank was not responsive within the time frame of your initial offer. All aspects of the sale were handled quickly and efficiently.
I would like to say that it was a pleasure working with you. Everything was explained up front and all questions were answered promptly. I would recommend you to anyone looking to sell their RV.
SellMyRVToday.com is a division of Pedata Resales Inc. © 2010 –2017 Pedata Resales Inc.
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text:
Lamp Assist touch-lighting on headboard; The Bancroft collection comes in a Java finish; With poplar solids and alder veneer Queen Sleigh Headboard Queen Sleigh Headboard I08-400 65"Wx58"Hx7"D Queen Bed Side Rails Queen Bed Side Rails I08-402 82"Wx8"Hx3"D Queen Low Profile Footboard Queen Low Profile Footboard I08-403 67"Wx19"Hx5"D KingCal King Sleigh Headboard KingCal King Sleigh Headboard I08-404 81"Wx58"Hx7"D King Bed Side Rails King Bed Side Rails I08-406 82"Wx8"Hx3"D KingCal King Low Profile Footbaord KingCal King Low Profile Footboard I08-407 83"Wx19"Hx5"D Cal King Bed Side Rails Cal King Bed Side Rails I08-410 86"Wx8"Hx3"D
Please note that the finish or fabric of this product in-store may be different than the photo currently pictured. Please contact your local store to confirm product pricing, availability, finish and fabric colors and promotional dates.
|Model Number
|Bed Rails
|Bedroom » Beds


text:
And if there is a anyone, anyone at all, who already does all of these things on a regular basis, you win a bajillion brownie points. You're also probably a much better/more organized human being than I am.
• Press down very gently. Your eyelash and eyelid are very fragile. There's no need to squeeze roughly. Multiple light squeezes are more effective.
• Learn more than one technique. There are hundreds of different methods. None of them are right or wrong, unless they're not working for you personally. Luckily, there are tons of blog and Youtube tutorials that specially feature eyelash curling.
• Properly store while traveling. Eyelash curlers are delicate. That frame can break or get bent out of shape easily. Remember, if the frame gets off a bit, you could end up chopping off your eyelashes the next time you go to curl them.
• Keep out of reach of children. SO many curlers come with this warning on the packaging and with good reason. Sharp metal tools for your eyes do not make good toys.
• Replace the rubber pad if it gets torn, cracked or broken in anyway.
• Clean with soap and water, just like you would your brushes, at least once a week.
See what you can learn from reading product instruction manuals? You obviously can use your eyelash curler however you want! These are just a few tips that might help you trouble shoot if your curler isn't working the way you want.
Anyone else have any tips and tricks to get the most out of this beauty tool?
Also, does anyone really replace them every single year? Pretty sure I used the same curler from middle school all the way up to last year. Oops!


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Suicide is a problem for us all
Today The Press publishes, for the first time ever in such detail, the statistics behind New Zealand's hidden tragedy.
The Coroner has agreed to the publication of horrifying statistics that plainly show the cost in lives each year of our suicide toll.
The 540-odd lives lost each year easily outpaces the road toll. Yet little mention is made publicly of our silent killer.
Partly that is because of New Zealand's relatively strict laws around the reporting of suicide. Health professionals have also long argued that detailed discussion of suicide can lead to "copycat'' or additional needless death.
Yet given the numbers of suicides have remained high, by international comparisons, The Press believes it is time to again ask the question: Should we be more open in talking about such a deadly disease?
The editor of The Press, Andrew Holden, said he welcomed the release of the suicide statistics. "Suicide is clearly a significant health issue for New Zealand, yet the imposed silence around its coverage in the media does not appear to have reduced the problem.
"This paper understands the sensitivities around reporting specific cases, such as detailing the method used by a particular person, and the worry that this can trigger copycat suicides.
"But brushing the issue under the carpet clearly is not working either. As a community, we need to accept the scale of the problem, and have an open and honest debate about it."
What do you think? Should suicide be discussed more openly? Are we brushing it under the carpet? Have your say. Comment below or email us at email@example.com and we will publish your thoughts.
The Press


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Give us a call to get our secret deals 1-800-468-3578
Property Location
With a stay at Fiorentini Residence, you'll be centrally located in Naples, steps from Piazza Matteotti and minutes from Fontana di Monteoliveto. This townhouse accommodation is within close proximity of Castel Nuovo and Naples Town Hall.
Make yourself at home in one of the 10 air-conditioned rooms featuring refrigerators. Rooms have private balconies. Complimentary wireless Internet access is available to keep you connected. Bathrooms have showers and hair dryers.
Make use of convenient amenities, which include complimentary wireless Internet access and concierge services.
Business, Other Amenities
Featured amenities include a computer station, express check-in, and dry cleaning/laundry services. Self parking (subject to charges) is available onsite.


text:
- UnitedHealthcare Pro Cyclists and mascot Dr. Health E. Hound lead
fun-filled afternoon with helmet giveaway designed to promote safe,
active and healthy lifestyles
BOISE, Idaho–(BUSINESS WIRE)–More than 100 kids at the Boys & Girls Club at Hawthorne Elementary took
part in a special event today, each receiving their own professional
bike helmet donated by UnitedHealthcare.
UnitedHealthcare Pro Cycling team members Carlos Alzate, Greg Henderson,
Tanner Putt and Daniel Eaton, who are participating in the Downtown
Boise "Twilight Criterium" cycling race, helped lead bike/helmet safety
lessons and provided stretching tips to encourage kids to be safe, stay
active and participate in events like the Kids'
Ride at the annual event. UnitedHealthcare's mascot Dr. Health E.
Hound was on hand to help kids decorate their helmets with decals and
hand out healthy snacks.
About UnitedHealthcare
UnitedHealthcare is dedicated to helping people nationwide live
healthier lives by simplifying the health care experience, meeting
consumer health and wellness needs, and sustaining trusted relationships
with care providers. The company offers the full spectrum of health
benefit programs for individuals, employers, military service members,
retirees and their families, and Medicare and Medicaid beneficiaries,
and contracts directly with more than 1 million physicians and care
professionals, and 6,000 hospitals and other care facilities nationwide.
UnitedHealthcare is one of the businesses of UnitedHealth Group (NYSE:
UNH), a diversified Fortune 50 health and well-being company. For more
information, visit UnitedHealthcare at www.uhc.com
or follow @myUHC on Twitter.
here to subscribe to Mobile Alerts for UnitedHealth Group.
Trevor Hayes, 702-308-9993


text:
Panama Negotiates Double Taxation Agreement with Mexico
Both countries will begin negotiations for a double taxation agreement on November 11th.
Friday, November 6, 2009
Panama's economy vice minister, Frank de Lima, who leads the negotiating team, has also contacted France, Germany, Australia, Japan, Holland, Switzerland, Norway, Island, Lichtenstein and England in order to negotiate double taxation agreements.
Source: Critica.com.pa
Panama and South Korea Sign Tax Agreement
October 2010
The country completed 9 of 12 agreements required by the OECD to remove it from the tax haven gray-list.
Panama Negotiates Double Taxation Agreement with Portugal
July 2010
Both countries have taken steps toward signing a double taxation agreement.
Panama and Netherlands Negotiate Double Taxation
April 2010
Starting today and until Wednesday, representatives from both countries will negotiate a Double Taxation Agreement in Panama City.
Panama Seeks Tax Agreements
September 2009
Panama is en route to sign double taxing agreements with Spain, Italy, Holland and Mexico.


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This property has been removed by the agent. It may be let or temporarily removed from the market
Property Description
Letting information:
|Reduced on Rightmove:
|20 October 2016 (341 days ago)
Key features
- Garden
- Two bedroom terraced house
- Within walking distance of the Town Centre and local amenities
Full description
Please quote reference 3021197 when enquiring about this property.
First month's rent is half price!
This fantastic terraced house is situated in a quiet sought-after residential area, close to main bus road and shops, and within approximate 10-minute walking distance of the Town Centre and five-minute walk of the park.
The property has been recently redecorated throughout and benefits from gas central heating covered by British Gas break-down cover scheme. It comes unfurnished and comprises two bedrooms, kitchen, living room and a bathroom.
- No DSS
- No smokers
- No pets
- No students accepted
- Six months minimum tenancy
- 460 GBP deposit required
- References will be required
EPC Rating: D
Please quote reference 3021197 when enquiring about this property.
Energy Performance Certificate (EPC) graphs
Map & Street View
View in fullscreenView in fullscreen
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Disclaimer - Administration fees may apply when renting a property in England, Wales or Northern Ireland. For more details, please contact the agent.
Property reference 3021197. The information displayed about this property comprises a property advertisement. Rightmove.co.uk makes no warranty as to the accuracy or completeness of the advertisement or any linked or associated information, and Rightmove has no control over the content. This property advertisement does not constitute property particulars. The information is provided and maintained by EasyProperty.com, National.
Please refer to our Renting Guides for further information on how to safely rent a property.
Map data ©OpenStreetMap contributors.


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Little Drummer Girl
A little drummer boy looks towards a fellow classmate while performing for a crowd of parents, grandparents and teachers at this years carol festival in the Provost Public School. ©Provost News Photo. Print version in December 24 edition of
The Provost News
. Want to Subscribe to
The Provost News
Click here.
Editors 2003 Christmas Wish List
Some snow for the snowmobilers.
A huge U.S. market for live cattle returned to livestock growers.
A lump of coal for those who insist on putting paint on buildings that dont belong to them.
An improved Provost News.
That economic report called Rural Alberta: Land of Opportunity dealing with East Central Alberta that was promised us by our MLA Doug Griffiths and our deputy premierway back in September.
Continued activity in the local oil patch.
The purchase of all those Empress of Ireland artifacts by Canadians not foreignersso the owner of them can take his money and retire.
More beautiful spaces built for an aging population so our friends and relatives dont have to move to other centres for care.
The cloning of mosquitoes that cant carry West Nile Virus. Or better yet, just no mosquitoes.
Camp Qualitys return to rural Alberta where so much care and devotion by local volunteers was put towards it.
Poison that really works wonders to get rid of those billions of grasshoppers.
Another successful motorcycle rally here.
No smoking in all tax-payer operated buildings.
More provincial and national wins or achievements by so many people from the area.
More students to take advantage of the Provost Outreach School.
Less spam for e-mail users. But a long distance thank you to Telus who has figured out a way to
detect and mark most of those absolutely silly e-mail messages that were just holding our breath to receive.
A joyous reflection and celebration of the birth of Jesus Christ.
Full story and pictures in December 24 edition of The Provost News.
Want to Subscribe to
The Provost News
Click here.
M.D. OKs fire Pumper Truck for Hughenden
Full story in December 24 edition of The Provost News.
Want to Subscribe to
The Provost News
Click here.
Summary of Events for the Year 2003
From the files of
The Provost News
Full article in December 24 edition of The Provost News.
Want to Subscribe to
The Provost News
Click here.
Street Spokesman
This week we asked:
"What Should Santa Get for Christmas?"
. . . and we heard opinions from Joriann Chopek, Erika Kloberdanz, Nelson Heisler, Deanna Gourlay and Santa Claus.
Check out the
December 24
edition of The Provost News for their answers.
Want to Subscribe to
The Provost News
Click here.
This, along with many other stories and pictures can be found in this week's edition of The Provost News.
Subscribe to the award winning paper by clicking on this link and following the instructions on our secure on-line ordering centre.
Take me to the Secure On-Line Ordering Centre


text:
DC Joinery31 Feedback reviews, 100% positive
Hi, my name is Dean. I have been a joiner for 30+ years, dealing in all aspects of joinery and much more. In my spare time I make bespoke wooden picture frames. I am happy to take on projects of all sizes, from small handyman jobs to all carpentry work including kitchen...
Latest Carpentry & Joinery feedback review:
By charlotte9093 on 10th Aug, 2017
N.A and sons carpentry and electrical8 Feedback reviews, 100% positive
Hi. my business includes me and my two sons, i am qualified to level 3 CNG in electrical engineering, and level 2 CNG in site carpentry, i have years of experience since 1982. my oldest son has a level 3 CNG in site carpentry and my middle son has a btec level 3 in...
Latest Carpentry & Joinery feedback review:
By benlewis432 on 6th Mar, 2016
sjm joinery services ltd148 Feedback reviews, 97% positive
We are a hard working small local company who pride ourselves in excellent workmanship, outstanding customer care and who always strive to provide a very competative quotation. The majority of our customers have had repeat work and go on to recommend us to friends.We have...
Latest Carpentry & Joinery feedback review:
By jjb_46 on 30th May, 2017
CT Joinery65 Feedback reviews, 100% positive
FULLY BOOKED UNTIL DECEMBER. Sole trader working with friendly, reliable team which work to the standards you expect. Over 15 years in the industry and covering all aspects of Domestic/Commercial Joinery.
Latest Carpentry & Joinery feedback review:
By emma_1v2d on 25th Jul, 2017
GO LOCKSMITHS & PROPERTY SERVICES75 Feedback reviews, 100% positive
My name is Gareth, im a fully qualified locksmith and joiner\handyman. I've been doing this job for over 20years. I thoroughly enjoy my job and take pride in all of my work.
Latest Carpentry & Joinery feedback review:
By klb17588 on 24th Feb, 2017
Spectrum building and joinery29 Feedback reviews, 100% positive
At Spectrum Building & Joinery, we strive to to deliver 100% satisfaction by ensuring perfection in all our work. The entire team of trades are trustworthy, hard working, reliable and will go the extra mile to ensure we meet your expectations. We take pride in all our work...
Latest Carpentry & Joinery feedback review:
By suet_46 on 3rd Aug, 2016
Johnston Joinery22 Feedback reviews, 100% positive
I am a 30 year old Joiner with 16 years of professional joinery experience. Great knowledge and passion for the trade. Fully qualified NVQ Level 3 in Carpentry and Joinery and currently finishng a HNC in construction. New build site and commercial experience as well as...
Latest Carpentry & Joinery feedback review:
By helen_from_wakefield on 19th Sep, 2017
HARRIS Damp- Proofing & Property Maintenance12 Feedback reviews, 100% positive
Formerly worked under and eventually alongside father in damp-proofing and property maintenance business straight from school at the age of 16 in Aberystwyth. Have since started own business in Wakefield. Have experience in working in maintenance of rental accommodation...
Latest Carpentry & Joinery feedback review:
By pauldamien on 25th Feb, 2017
JF Joinery10 Feedback reviews, 100% positive
JF joinery is a solo trader that can fit all kind of aspects of joinery. Joinery work undertaken is never too small or big. I have fitted work from skirting boards an architrives upto roofs and kitchens. I have full NVQ level 2 joinery and worked in the trade 4 years. JF...
Latest Carpentry & Joinery feedback review:
By missellis on 14th Sep, 2017
Tim Healey14 Feedback reviews, 100% positive
Over 30 years experience of being a Carpenter. City and Guilds certified. Was self employed for Eleven years, then entered into teaching in the further education sector. I have now relocated to West Yorkshire and I am now self employed again.
Latest Carpentry & Joinery feedback review:
By lianner_14 on 1st Sep, 2017
J K Joinery8 Feedback reviews, 100% positive
I've been in the building trade for 13 years. Working mainly in carpentry and joinery but have experience in all aspects of building work. I work by myself for myself. No job too small and all work considered.
Latest Carpentry & Joinery feedback review:
By libby_74 on 5th Jul, 2016
A R Rowley Joinery10 Feedback reviews, 100% positive
I have always been interested and enjoyed working within the building industry and since starting my own business five years ago I have developed and honed skills needed for doing the work I enjoy. My work is my passion, I pride myself in a high quality and standard of work...
Latest Carpentry & Joinery feedback review:
By donna_876 on 4th Sep, 2016
Lionheart Builders18 Feedback reviews, 100% positive
plastering/electrics/plumbing work/maintenance/fencing/brickwork.all general building work...i have been a plasterer for 10+years. along the way i have learnt all aspects of building work. also my parntner which as been a bricklayer for 5 years. together thers nothing really...
Latest Carpentry & Joinery feedback review:
By linda_379 on 4th Aug, 2017
Pineridge Joinery7 Feedback reviews, 100% positive
Pineridge Joinery prides it self on delivering quality works at affordable prices. I take great pride in my work and always try and delight the customer where possible. I am a time served joiner with over 21 years experience and have had my own business for over 10 years.
Latest Carpentry & Joinery feedback review:
By joanne_woods_97 on 20th Aug, 2017
P B joinery4 Feedback reviews, 100% positive
30 years experience in joinery 20 years of that on new build 10 yrs running my own business .
Latest Carpentry & Joinery feedback review:
By nalawole on 5th Jun, 2017
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text:
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it's an internet thing!
"I love the song 'El Rey.' And for years, I never knew what the song was totally about. It was something new for me. I'd never sung a song in Spanish before. Then I got the translation and saw what a really cool song it was."
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"Rather be dead than cool."George Strait on Kurt Cobain
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text:
Chris Pyle , one of a couple of dishwasher specilists in the business – with manufacturer technician time at both Hobart and Meiko, has held a number of additional dishwasher master-classes for our trainees and improvers. With the sun shining, his latest group of students were given the opportunity to undertake the session outside.
In January, a cohort of 6 trainee engineers joined McFT to embark on a 2 year development plan, during which time they will become fully trained as competent, professional engineers, able to meet the exacting standards required of a McFT engineer.
McFT began to provide its services nationally in 2015, with great success with our Northern and Midlands growing substantially.
McFT are delighted to be featured as part of the Fleet Operators Recognition Scheme current advertising programme: the Art of Good Vanmanship.
McFT welcomed six new trainees on Monday 16th January - the first of two cohorts planned for this year. Ahead of them lies a couple of years of intensive training – mixing classroom with site experience – and mixing technical skills with soft skills – CQ anyone ? – along with commercial insights – from working safely to industry knowledge.
Dan and his team, along with Craig Atkins and the gang at 1-Fix who provide our hardware and systems support, have achieved our accreditation to the Government supported Cyber Essentials programme – the first stage of an externally-approved cyber security programme for 2017.
The office really looked in the Christmas Spirit with everyone wearing their best Christmas jumpers for Save the Children – Raising £32.8
We've found over the years that we can develop really good technicians – from absolute beginners.
If you were at the Maidenhead United game this Saturday, you may have seen the McFT logo around.
McFT joins a select band of fewer than 20 employers in the UK - out of 40,000 accredited to Investors in People - to achieve Platinum Status.


text:
Originally posted on On Art and Aesthetics:
Sam Shendi Carefully situated between 'representation' and 'abstraction', the candy-coloured figures of Yorkshire-based Egyptian-born sculptor Sam Shendi easily resemble children's toys. Made of steel and aluminium, they are minimalistic projections of human bodies…
Heads together
This gallery contains 2 photos.
My husband seems to be able to tap into some subliminal subconscious web of communication. There have been several times where he has been working on something which parallels what is happening else where. These heads were created at the … Continue reading