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Back to Journals » International Journal of Nanomedicine » Volume 12
Nanoparticle–allergen complexes for allergen immunotherapy
Authors Di Felice G , Colombo P
Received 14 February 2017
Accepted for publication 11 April 2017
Published 19 June 2017 Volume 2017:12 Pages 4493—4504
DOI https://doi.org/10.2147/IJN.S134630
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Thomas J Webster
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Gabriella Di Felice,1 Paolo Colombo2
1National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, 2Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy
Abstract: Allergen-specific immunotherapy was introduced in clinical settings more than 100 years ago. It remains the only curative approach to treating allergic disorders that ameliorates symptoms, reduces medication costs, and blocks the onset of new sensitizations. Despite this clinical evidence and knowledge of some immunological mechanisms, there remain some open questions regarding the safety and efficacy of this treatment. This suggests the need for novel therapeutic approaches that attempt to reduce the dose and frequency of treatment administration, improving patient compliance, and reducing costs. In this context, the use of novel adjuvants has been proposed and, in recent years, biomedical applications using nanoparticles have been exploited in the attempt to find formulations with improved stability, bioavailability, favorable biodistribution profiles, and the capability of targeting specific cell populations. In this article, we review some of the most relevant regulatory aspects and challenges concerning nanoparticle-based formulations with immunomodulatory potential, their related immunosafety issues, and the nature of the nanoparticles most widely employed in the allergy field. Furthermore, we report in vitro and in vivo data published using allergen/nanoparticle systems, discuss their impact on the immune system in terms of immunomodulatory activity and the reduction of side effects, and show that this strategy is a novel and promising tool for the development of allergy vaccines.
Keywords: allergy, nanocarriers, immunotoxicity, immune modulation, immunotherapy, allergens
Allergic disorders are a growing global health problem affecting more than 25% of populations in industrialized countries,1,2 and there has been a significant worldwide increase in the prevalence of asthma and allergic rhinitis since 1960.3 Immunologically, allergic subjects manifest a higher frequency of allergen-specific CD4+ Th2 cells secreting IL-4, IL-5, and IL-13 than healthy subjects, leading to the production of allergen-specific immunoglobulin E (IgE) antibodies.4
Allergen-specific immunotherapy
To date, allergen-specific immunotherapy (AIT) has been the only treatment with the demonstrated capacity to ameliorate allergic symptoms, preventing the onset of new sensitizations to different allergens, as well as reducing the development of asthma in patients with allergic rhinitis.5
In particular, clinical trials using different pharmacological combinations and diverse routes of administration have demonstrated the crucial role of regulatory T- and B-cells (Treg and Breg, respectively)6,7 and the upregulation of IgG1, IgG4, IgA antibodies.8 The production of allergen-specific Treg is triggered by IL-109 and TGF-β10 which are induced during AIT due to the increase of CD25+ CD3+ FOXP3+ cells at the local and systemic level after immunotherapy.11,12 Furthermore, successful immunotherapy brings about a substantial reduction in the recruitment and activation of proinflammatory cells, including basophils, mast cells, and eosinophils in the skin, as well as in nasal or bronchial mucosae.13
Despite these advances in our understanding of the dynamics and functioning of AIT, there remain several problematic issues to resolve.
Market data show that only a limited number of patients suffering from allergic rhinoconjunctivitis decide to initiate immunotherapy, probably due to unfavorable conditions such as: 1) the high percentage of patients with local side effects,14,15 and 2) the duration of the treatment (up to 3 years) which causes low patient compliance and elevated costs.16 All of these points underline the importance of developing novel therapeutic approaches, improving the production of pharmaceutical products, and establishing optimal dosages and the more effective routes of administration in order to reduce the costs and duration of treatment and increase its safety.
Nanotechnology applied to immunotherapy
In the last decade, nanotechnologies have been applied to immunomodulatory therapies to enhance their efficacy and reduce potential side effects, mainly in addressing cancer and infectious diseases. In fact, in the last 30 years, a number of polymers have been used to design nanoparticles (NPs) that are capable of loading both proteins and nucleic acids for therapeutic applications.17,18 Although there is no universally accepted definition of NPs, they can be regarded as the primary component of a nanomaterial (NM), having defined physical limits and at least one dimension (or one diameter) in the nanoscale range.19 The definition of NMs recommended by the European Commission in 2011 is essentially based on size as the primary parameter to describe natural, incidental, or manufactured materials containing particles with any external dimension in the "nano" range (1–100 nm).20 A more comprehensive review, including recent scientific and technological developments, is underway.
NPs can take many different forms and have variable chemical compositions and physical properties, including their size/hydrodynamic radius, morphology, surface chemistry, solubility, and charge.21 These properties can be engineered to make them suitable for specific biomedical applications. The influence of physicochemical properties on the biocompatibility of NPs is critical for their use in biological applications and has been studied extensively. On the other hand, the biodistribution of NPs after entering the body through different routes, NP cellular uptake mechanisms, and their potential toxicity are primarily influenced by the physicochemical properties of the particles – especially size and surface characteristics.22
Regulatory issues
New nanotechnology-based medicinal products, developed for both therapeutic and diagnostic uses, can potentially yield innovative approaches to the field of drug delivery, improving the targeting, bioavailability, and transport of existing medicines across biological barriers or enabling new action mechanisms. The challenge for regulatory agencies is to ensure the proper evaluation of the quality, safety, and effectiveness of nanomedicines undergoing clinical development and market authorization. Since its 2006 Reflection Paper, the European Medicine Agency (EMA) has emphasized the complexity of nanomedicine properties and the consequent need to involve specialized experts in their evaluation (http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/01/WC500069728.pdf). Although the current regulatory framework appears sufficiently robust, several critical issues persist with regard to NP characterization, detection, fate, and persistence in human organs and tissues. Moreover, the suitability of current toxicological methods to facilitate satisfactory and exhaustive risk assessment remains under discussion.23,24
Nonetheless, a number of medicinal products containing NPs in the form of liposomes, polymer protein conjugates, polymeric substances or suspensions, and nanocrystals have already been granted Marketing Authorizations within the European Community and/or at the world level under the existing regulatory framework.18,23 Several nanodrugs are undergoing basic research and preclinical and clinical development, the entire process of which can take up to 20 years. Several specific safety issues can affect this process, primarily pertaining to: 1) the set-up and validation of standardized in vitro assays, with suitable reference materials; 2) the development of ex vivo/in vivo models relevant for the route of administration; 3) the generation of in silico approaches which are predictive for biological and toxicological responses; and 4) in vivo pharmacokinetic studies.25 Finally, the interactions of NM-based medicines with the major biological systems deserve particular attention from coordinated contributions of multidisciplinary competences.
Nanotoxicity assessment
Current approaches to assessing NM toxicity are based primarily on knowledge derived from chemical safety assessments. These methods may not adequately account for the unique properties of NMs compared to those of bulk materials/chemicals such as their small size, aggregation/agglomeration capacity, and reactivity in biological matrices. For instance, these properties may influence their absorption and transportability across membranes, persistence and accumulation in organs, entrance into blood circulation, or even crossing of biological barriers.
Although nanotoxicology has become an important topic of research with significant funding, as documented by the number of projects supported by FP6, FP7, and Horizon2020 European programs, the appropriateness of existing test methods for addressing NM safety remains under discussion among regulatory authorities and within the scientific community. The ad hoc Working Party on Manufactured Nanomaterials (WPMN) established by the Organization for Economic Cooperation and Development (OECD) has the major task of reviewing the suitability of standard chemical testing protocols for NM evaluation. Three main issues can be identified: the insufficient physicochemical characterization of NMs, the inadequate standardization and validation of toxicity assays, and the lack of reference materials. Other weaknesses that should be addressed are summarized in the following points: testing methods are often time-consuming, expensive, and/or require highly experienced specialists, thus limiting their applicability to the rapidly increasing number of novel entities that require assessment; testing tends to focus on single agents, but in many cases these agents are present as parts of mixtures, resulting in interactions that may affect biological outcomes; many existing methods, in particular in vitro assays based on cell culture models, are geared toward assessing acute responses, whereas effects of chronic and repeated exposure are much less accessible to testing; animal studies allow both longer term testing and access to intact tissues and organisms, but knowledge transfer to humans is problematic due to differences between species; moreover, the increasing need to test more different substances and mixtures rules out an upscaling of animal use for ethical, scientific, practical, and financial reasons.
An approach to overcoming these obstacles has been proposed, based on the development of an intelligent testing strategy (ITS) that would allow adequate safety evaluation of NMs.26 An ITS should integrate the characterization of physicochemical properties with in vivo and in vitro studies as well as in silico models, thus allowing the association of the intrinsic properties of an NM with its potential toxicity. A generally applied scheme encompasses some cellular assays and in vivo exposure studies in rodents, taking into account the different exposure scenarios. In vivo studies in appropriate animal models allow the evaluation of complex responses resulting from the involvement of the whole organism or its major systems, as well as the investigation of biokinetic and toxicokinetic mechanisms. Due to the complexity and the costly and time-consuming nature of in vivo studies, in vitro testing can be regarded as the first-line methodology for screening purposes in ITS and for refining the consequent evaluation steps. To this aim, the in vitro endpoints more frequently investigated include cytotoxicity, genotoxicity, inflammation, and immunotoxicity.
The assessment of the impact of NM-based medicines on the immune system in terms of immunotoxicity, and of their potential to modulate (intentionally or not) its function (suppression, adjuvance, and hypersensitivity),27 has particular relevance for the object of this review.
Until now, no specific regulatory documents have been developed to assess the immunotoxicity of nanomedicines, which are currently evaluated on the basis of guidelines, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Safety Guideline 8 (ICHS8) on immunotoxicity studies for human pharmaceuticals, which are in force for conventional medicinal products (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002851.pdf). The open question is whether the set of first- and second-level tests prescribed by these guidelines is capable of adequately evaluating the immunotoxic profile of complex and broadly heterogeneous NM-based medicines that result from the combined effects of the active pharmaceutical component, the nanocarrier, any potential coating, and the final formulation.28 A prudent response to this issue is that not all the immunotoxic properties of nanomedicines can be easily identified following the recommendations of the current guidelines. As a consequence, a specific testing battery, tailored to the different categories of NMs and the wide range of immunotoxic effects that they can cause, needs to be developed.
Therapeutic potential of nanoparticles for allergies
In recent years, various studies have demonstrated that the encapsulation of allergenic extracts or single allergens within NPs can beneficially affect the interaction of the encapsulated antigen with the immune system, as well as further improve the development of safer and more effective vaccines and immunosuppressive agents.
In the first case, immunostimulatory activity is required in order to enhance the quantity and quality of the cellular and humoral immune responses to the antigens in the vaccine. NPs can engage in such "adjuvant" activities through various mechanisms associated with the physicochemical characteristics of the NP and/or the possibility of incorporating specific ligands/agonists for the specific targeting of immune cells.29 Particle size, which affects tissue penetration and access to blood vessels and the lymphatic system, can be altered to modulate antigen delivery. The ability to protect antigens at the site of administration, maintaining their stability and conformation and allowing a gradual local release ("depot" effect), as well as the possibility of displaying their spatial organization in a highly repetitive way, are connected to characteristics of NPs, such as their chemical nature, solubility, and shape. The protection of the encapsulated payload from metabolic or immunologic degradation, together with the possibility to specifically target tissues or cells, allows the reduction of antigen/drug dose while maintaining high efficacy levels and containing unwanted side effects. This feature can be particularly favorable in the case of oral/mucosal administration where the antigen is highly exposed to enzymatic or pH-dependent destruction. The conjugation of NPs with ligands of Toll-like receptors (TLRs) or other receptors selectively represented on different populations of antigen-presenting cells (APCs) not only leads to the targeting of such cells but may also drive their functional response by activating differential signal transduction pathways and releasing soluble mediators with distinct immunomodulatory activity.30
In the second case, in addition to inducing immune tolerance, NPs can be therapeutically deployed to reduce or block the unwanted and detrimental immune responses that occur in autoimmunity and allergy by directly exerting immunosuppressive effects on immune cells (APCs and T and B lymphocytes) or improving the delivery of immunosuppressive compounds/drugs by increasing their solubility and bioavailability.29,31 The upregulation of cytokines such as TGF-β and IL-10, associated with Tregs which control the activity of effector cells and induce apoptosis, mediates the direct effects on immune cells.29
An example is shown by the fullerene spherical NPs. These have been shown to have immunosuppressive effects on anaphylaxis by decreasing in vitro IgE receptor-mediated signaling and the degranulation of human mast cells and basophils, as well as preventing histamine release and the lowering of body temperature after allergen challenge in an in vivo mouse model of anaphylaxis.32 A similar experimental approach has been applied to the evaluation of the antiallergenic potential of biodegradable poly(DL-lactide-co-glycolide) (PLGA) NPs.33 The ability of PLGA NPs to inhibit mast cell-mediated allergic responses was demonstrated in vitro on the antigen-induced activation and release of beta-hexosaminidase and histamine from the RBL-2H3 rat basophilic leukemia cell line (which possesses the phenotypic properties of mucosal mast cells) and on systemic anaphylaxis induced in mice. More recently, NP approaches have also been introduced in the field of allergy diagnosis, demonstrating that the encapsulation of hydrophobic allergens within poly-ε-caprolactone NPs can improve the diagnosis of allergic contact dermatitis.34 Moreover, NPs can be specifically designed to interact with the immune system, exploiting their immunomodulatory potential for therapeutic purposes, suggesting that new NP/allergen pharmacological preparations can open the way to alternative therapeutic options or administration routes.35
In accordance with the main focus of this review on NPs which have been engineered to act as adjuvants/carriers in allergy immunotherapy, in the following section, we briefly introduce the most common categories of NMs used in this field. NP–allergen complexes will then be described according to the origin of their allergenic component, together with an analysis of their immunological profile and immunomodulatory activities.
Categories of nanomaterials/nanoparticles applied in allergen immunotherapy
Different categories of NPs have been developed and studied as adjuvants/carriers to improve the efficacy and safety of allergy immunotherapy. Their classification is not univocal because overlapping criteria can be applied (size and morphology, physicochemical features, function, etc). An attempt to group NPs used for the preparation of allergen complexes according to their chemical nature could include these major classes of products: polyesters, polysaccharide polymers and carbohydrate-based particles, liposomes, protamine-based NPs, and polyanhydrides.
Polymeric nanocarriers have been investigated as vaccine delivery systems due to their ability to provide the controlled release of antigens or adjuvants.36,37 Polyesters are a group of molecules whose biocompatibility, safety, and biodegradability in human applications are well-documented and which have already been approved by the US Food and Drug Administration (FDA).38 Several applications have been described using PLGA particles in sutures and implants, and their use in humans has been proposed for decades.39,40 Poly(glutamic acid) (PGA) and PLGA have been primarily investigated as biodegradable synthetic polymer nanocarriers. It is possible to modify their size, surface properties, and release profile (in particular, the biodegradation rate) to affect the immunogenicity of the encapsulated antigens as well as to optimize delivery through different administration routes (oral, mucosal, and systemic).41
Polysaccharide polymers and carbohydrate-based particles
Another molecular group that has been studied in this context is polysaccharides, which are easily produced polymers derived from natural sources. In this respect, poly(D-glucosamine) (known as chitosan) is a very abundant natural polysaccharide which is derived from shrimp and other crustacean shells. Chitosan is composed of randomly distributed β-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit) and has several advantageous properties, such as low production costs, biocompatibility, biodegradability, and absence of toxicity.42 As a natural, nontoxic polysaccharide, it has already been approved for human use in the US and Europe for bandages and other hemostatic agents. Notably, for applications in the field of immunomodulatory agents, chitosan can provide a cationic charge that may facilitate endocytosis as well as adjuvance that acts by promoting the maturation of dendritic cells (DCs). Another important property of chitosan is its mucoadhesiveness that makes it particularly attractive for targeting mucosal tissues and promoting mucosal immunity.36,43 Other carbohydrate-based particles (Sepharose beads) have also been suggested as a novel particulate adjuvant to improve allergy vaccinations through the enhancement of antigen uptake by DCs.44
Liposomes are spherical vesicles composed of one or more bilayer phases of phospholipids encompassing aqueous compartments; this double chemical nature allows the entrapment and delivery of both hydrophobic and hydrophilic molecules. Due to their high biocompatibility and biodegradability, nanosized liposomes have found widespread application as drug and gene carriers.45 The major advantages of their application in drug delivery are the possibility of enhancing the solubility and bioavailability of the protein cargo, as well as its in vivo stability, to protect it from undesired interactions with other cells/molecules and optimize specific targeting of the action site of a drug.46
Protamine-based NPs
Protamines are biodegradable arginine-rich peptides of approximately 4 kDa that have been used for decades in human medications.47,48 Protamine NPs complexed with DNA or RNA oligonucleotides can be generated via electrostatic interaction, showing optimal biocompatibility and high stability. Moreover, since protamine contains a nuclear localization signal,49 protamine-based NPs can easily transport their content into the nucleus, thus improving the efficiency of specific gene therapy. In the context of this review, they are attractive elements for the formation of complexes with oligonucleotides, strong activators of Toll like receptors.
Polyanhydrides
Among biodegradable polymers, amphiphilic polyanhydride nanocarriers present unique properties in their capacity to modulate immune responses, together with a favorable safety profile. In fact, they have been demonstrated to be taken up by DCs and to induce antigen-specific proliferation of both CD4+ and CD8+ T cells.50 Their properties, such as release kinetics, antigen retention, and adjuvant effect, can be tailored based on polymer composition, with particular attention to the degree of hydrophobicity. Surface modifications can be introduced to enhance or reduce their mucus permeability and bioadhesion to specific target cells. For specific application in the field of allergy immunotherapy, Gantrez® AN 119 (poly[methyl vinyl ether-co-maleic anhydride]) has been investigated. In fact, Gantrez AN 119 is a copolymer of methyl vinyl ether and maleic anhydride that can easily react with amino groups, making it easy to load or link different types of proteins, including allergens.51
Nanoparticle-allergen complexes
Different classes of allergens have been studied in association with nanostructured adjuvants and/or carriers engineered for allergy immunotherapy. In vitro studies on human immune cells as well as mouse models of sensitization have been applied to the functional evaluation of such complexes. In the next section, these complexes have been categorized according to the origin of the allergenic molecules, putting special emphasis on the novel beneficial immunoregulatory properties introduced by their formation into complexes and investigating different routes of administration in vivo.
Pollen allergens
Birch pollen is a major allergenic source in Central Europe as well as in North America, and almost all birch allergic patients are sensitized to the Bet v 1 allergen; thus, the development of a product containing this molecule would be a useful drug for all birch allergic patients. In addition, the Bet v 1 allergenic molecule displays cross reactivity with several others allergens from different pollens and plant derived food. In particular, it has been reported that more than 70% of patients with birch pollen allergy react to at least 1 Bet v 1-associated allergenic food source, including vegetables, nuts, and legumes demonstrating the relevant role of this family of allergens.52 In a prophylactic experimental set-up, Schöll et al demonstrated that PLGA particles loaded with rBet v 1 (the major allergen of birch pollen) support the immunogenicity of the allergen in an animal system. This research group treated Bet v 1 allergic mice subcutaneously (SC) with different allergen formulations and evaluated their relative immunological properties. Bet v 1 allergen was encapsulated in PLGA in the presence or absence of Al(OH)3, or used absorbed in Al(OH)3 only, mimicking commercially available products. PLGA-entrapped Bet v 1 proved to be successful in modifying the ongoing Th2 response, leading to a decrease in IgG1 antibody production and an increase in IgG2a antibody titer after a few shots. These serological data were reinforced by the fact that allergen-loaded PLGA nanoparticles modulate the Th2 response (reduction of IgG1 antibodies) meanwhile IFN-γ and IL-10 were produced after the allergen-specific stimulation of splenocytes.53
Profilins are a widespread family of highly cross-reactive allergens which have been isolated in a large number of sources, so much so that this allergen is considered a true panallergenic molecule.54 Xiao et al synthesized a complex containing PLGA with a recombinant profilin from Caryota mitis (rCmP). The Authors showed that the rCmP-loaded PLGA NPs effectively inhibited the generation of allergen-specific IgE and the secretion of the pro-inflammatory Th2 cytokine IL-4, facilitating the generation of allergen-specific IgG2a and the secretion of the Th1 cytokines in vivo.55 The same NPs were employed in a different immunotherapy regimens by Salari et al, targeting another relevant cross-reactive allergen, Che a 3 protein belonging to the polcalcin family, an allergen showing high levels of identity with polcalcin from olive, birch, alder, rapeseed, and timothy grass pollens.54 BALB/c mice were sensitized to rChe a 3 and then treated sublingually, either with soluble rChe a 3 or PLGA-encapsulated rChe a 3. In vitro and ex vivo assays demonstrated significantly increased antigen-specific IgG2a. In addition, IL-4 levels in restimulated splenocytes were significantly reduced, while IFN-γ, IL-10, and TGF-β levels, as well as Foxp3 expression, were significantly higher than in control groups. This suggests that this formulation can induce a stronger Th1/Treg pathway than the purified allergen.56
A different strategy was proposed by Marazuela et al, describing the use of PLGA as a vehicle for the intranasal (IN) administration of the OLE109–130 peptide (a major Ole e 1 T cell epitope) in a mouse sensitization model. The pre-treatment of BALB/c mice with OLE109–130–PLGA complex before sensitization to the whole Ole e 1 (a major allergen of olive pollen, with a high degree of homology to allergens from other allergenic sources57) led to the significant inhibition of allergen-specific IgE and IgG1 levels, with a marked increase of specific IgG2a antibodies. Moreover, IL-5 and IL-10 levels in spleen cell cultures were suppressed in peptide-PLGA pre-treated mice, suggesting that pre-treatment with the OLE109–130–PLGA complex is effective at preventing subsequent allergic sensitization to Ole e 1.58,59
A different class of polymers belonging to this family of particles has also been tested by Broos et al, who demonstrated that 200 nm-sized biodegradable poly(g-glutamic acid) (γ-PGA) NPs activate human monocyte-derived dendritic cells (MoDCs). In this study, it was established that MoDCs from grass allergic patients stimulated with a mixture of γ-PGA and Phleum pratense extract augment the production of allergen-specific IL-10, a relevant cytokine for the induction of peripheral tolerance.60
Another polylactide particle used to generate new allergen complexes is poly(D,L-lactide-co-glycolide) (PLG). PLG microparticles were introduced in clinical contexts several years ago, exhibiting a capacity to slow the release of the entrapped antigens.61 In particular, Batanero et al used this polymer to entrap nOle e 1 allergen. The intraperitoneal (IP) immunization of such complexes in mice elicited high levels of specific IgG2a antibodies and low levels of both total IgE and specific IgG1 antibodies, demonstrating that this product induces a Th1-like immune response. On the other hand, immunization with nOle e 1 absorbed in alum only induced high levels of both specific IgG1 and total IgE, showing the adjuvancy capability of the particle in the context of the allergen specific immunological response.62
Carbohydrate-based particles (CBPs) covalently coupled to the timothy grass pollen allergen Phl p 5 (a major grass allergen) also exhibited desirable adjuvant properties. When compared with alum-absorbed Phl p 5, Grönlund et al reported that both adjuvants induced significantly increased allergen-specific antibody responses compared with soluble Phl p 5, but, unlike alum, CBP-Phl p 5 did not induce granulomatous tissue reactions. This demonstrated that this kind of formulation can reduce one of the most common local side effects observed following intradermal or subcutaneous injections.63
Recently, it has been demonstrated that liposomes coated with a neoglycolipid constructed from mannotriose and dipalmitoylphosphatidylethanolamine (Man3-DPPE) (oligomannose-coated liposomes, OMLs) can induce a strong Th1 immune response against encapsulated antigens in mice, with significant IFN-γ production and suppressed IL-4 production.64,65 These findings open the possibility that the administration of OMLs with entrapped allergens may control allergic reactions to Japanese cedars, using the major allergen Cry j 1, an allergen belonging to the Pectase lysase family. The pre-treatment of unsensitized mice with Cry j 1/OMLs blocked total and allergen-specific IgE levels in sera from Cry j 1 sensitized animals, with decreased IgG1 as well and significantly increased levels of specific IgG2a.66–68
Liposome-protamine-DNA (LPD) NPs are safe, effective, and non-toxic adjuvants that induce Th1-like immune responses. Nouri et al demonstrated that the encapsulation of rChe a 1, rChe a 2, and rChe a 3 allergens (produced in a recombinant hybrid form [rHM]) from Chenopodium album resulted in a reduction in specific IgE and a marked increase in IgG2a in a murine model. Furthermore, LPD-rHM induced allergen-specific responses with high IFN-γ production, as well as the expression of T-bet (a transcription factor that controls the expression of Th1 cytokines) in stimulated splenocytes.69
Gómez et al investigated the possibility of using a particle composed of Gantrez NPs with Lolium protein extract plus lipopolysaccharides (LPSs). The immunotherapeutic capacity of this formulation was evaluated in a model of mice which had been pre-sensitized to Lolium perenne. Once the animals were sensitized, allergens/NPs were administered and then mice were challenged with Lolium extract IP and the intensity of anaphylaxis was studied. After immunization, the animals treated with LPS–Lolium–NP showed IgG2a antibody levels 100-times higher than controls or Lolium–alum challenged mice. This observation demonstrated that the combination of the copolymer with LPS can induce a Th1 polarization that can counteract the existing Th2 polarization.70
Parietaria pollen is characterized by the presence of two major allergens which are capable of inducing IgE production in the majority of allergic patients. For this reason, recombinant Parietaria major allergens were entrapped within two independent classes of NPs whose bioavailability was evaluated by means of a basophil activation assay, showing that complex formation does not inhibit their availability to the IgE antibodies of allergic patients.71,72
Refer to Table 1 for a summary of this section.
Table 1 Pollen allergens nanocomplexes
Abbreviations: CBP, carbohydrate-based particle; OML, oligomannose-coated liposome; PLG, poly(glutamic acid); PLGA, poly(DL-lactide-co-glycolide); SLN, solid lipid nanoparticles; PHEA, poly(hydroxyethyl)aspartamide.
Arthropoda allergens
Joshi et al developed a strategy based on the co-encapsulation of PLGA with one of the major house dust mite (HDM) allergens (Der p 2) and unmethylated cytosine-phosphate-guanine (CpG) nucleotides.73 CpG oligonucleotides are known to be potent adjuvants, shifting immune responses to the Th1 type since they are TLR-9 agonists.74,75 The authors showed that the co-delivery of PLGA particles loaded with an antigen and CpG can stimulate a potent antigen-specific immune response, as well as that the magnitude of the immune response is correlated to the size of the PLGA particles used for immunization demonstrating that even the dimension of the NP can influence the allergen specific immune response.73
Comparable results using CpG oligonucleotides were further reported by Martìnez Gómez et al using the bee venom phospholipase A2 (PLA2) allergen as a model. Both naïve and bee venom allergic mice were immunized with microparticles containing only PLA2, showing that this treatment induced a weak antibody response. On the other hand, when PLA2-PLGA NPs were combined with CpG, a strong PLA2-specific antibody response was observed, and the presence of CpG was required for the induction of the Th1-associated isotype IgG2a. The effect of the CpG nucleotide was further strengthened when protamine was co-encapsulated for the complexation of CpG.76
Chitosan has been used for its mucoadhesiveness that makes this particle attractive for mucosal immunity.43 Following this line of evidence, Liu et al tested the immunotherapeutic efficiency of the IN administration of Dermatophagoides farinae extract (Der f) entrapped in chitosan microparticles. BALB/c mice were IP sensitized with Der f extract absorbed in alum, followed by IN treatment with PBS, chitosan, Der f or Der f-chitosan nano-vaccine for 6 weeks. The mice were subsequently challenged intranasally with Der f extract for 1 week, showing that this complex can induce immunological protection in a murine model of allergic asthma by inducing regulatory T cells and Th1-type reaction.77 In a similar way, Li et al entrapped a major epitope peptide of the mite group 2 allergen Der f 2 (Der f 2 47–67) in chitosan microparticles which were IP injected into BALB/c mice which had been previously intranasally challenged with a Der f extract allergen. Mice immunized with this protocol displayed decreased airway hyperreactivity, lung inflammation, and mucus production. Antibody production analysis showed a reduced serum level of Der f-specific IgE and increased specific IgG2a,78 Furthermore, another strategy utilizing chitosan was to mix it with hydroxybenzotriazole (HOBt), hydrophobic biomolecules, ie, phenylalanine (Phe), and hydrophilic polymers, ie, poly(ethylene glycol) methyl ether (mPEG), to produce positively charged NPs (20–50 nm in size) capable of entrapping negatively charged HDM extract (Dermatophagoides pteronyssinus). The HDM-entrapped CS-Phe-mPEG showed biocompatibility favoring T cell immune response and a synergistic effect of chitosan, Phe and mPEG with a clear increase in IFN-γ and IL-10 production in both allergic and healthy volunteers was reported.79
Liposomes have been complexed with cockroach allergens, a frequently cited source of severe asthma. Meechan et al studied the therapeutic efficacy of an IN liposome-adjuvant vaccine made of a refined Periplaneta americana arginine kinase (AK, Per a 9), compared to a liposome-entrapped P. americana crude extract (CRE) vaccine in adult BALB/c mice. The liposome-entrapped native AK attenuated airway inflammation after CRE provocation and caused a shift from Th2 to Th1 and Treg responses. Furthermore, this study demonstrated that IN liposome adjuvanted cockroach allergens containing native Per a 9 are more effective than complexes with liposome and crude extracts at attenuating allergy airway inflammation and allowing a more precise standardization of the product.80
Table 2 Arthropoda allergens nanocomplexes
Abbreviations: CpG, cytosine-phosphate-guanine; HDM, house dust mite; PLA2, phospholipase A2; PLGA, poly(DL-lactide-co-glycolide).
Other allergens (animal, food)
Thunberg et al showed that CBP-rFel d 1 (the major cat allergen) induces rapid allergen-specific antibody production and prevents the induction of allergic immune responses in mice sensitized to rFel d 1. Interestingly, in contrast to alum absorbed rFel d 1, CBPrFel d 1 remains at the injection site longer, enabling prolonged antigen exposure, working as an adjuvant for a safer and more efficient allergy vaccination.81
Another relevant feature of these types of complexes was introduced by Weinberger et al who showed that the coupling of a carbohydrate to a protein can mask B-cell epitopes, making the protein "hypoallergenic". In particular, they showed that the hypoallergenicity of neoglycoconjugates depends on the carbohydrate, the nature of the allergen, and the chemistry used for the coupling reaction, suggesting this strategy as a promising one that may lead to safer formulations.82
Food allergies affect approximately 5% of the population, severely impacting patient quality of life. Several strategies have been reported in the formation of NP complexes with single allergens or allergenic extracts.
Protamines have been used for a long time in clinical settings as molecules which are easy to handle in the making of complex nucleic acids via electrostatic interaction. For this reason, protamine-nAra h 2-CpG particles were prepared and injected SC into naïve BALB/c mice, showing an increase in Ara h 2-specific IgG2a with no detectable IgE specific antibodies, and, of particular interest, Pali-Schöll et al reported that granuloma formation was completely absent at injection sites.83
Furthermore, De S Rebouças et al suggested that poly(anhydride) NPs could be loaded with raw or roasted peanut proteins. These amphiphilic nanocarriers can modulate immune response per se, and their adjuvant capacity was evaluated in an animal model of food allergy. NP formulations were studied after oral immunization of C57BL/6 mice, showing low specific IgE induction. Furthermore, oral immunization with spray-dried NPs loaded with peanut proteins showed a significant decrease in splenic Th2 cytokines and the enhancement of both Th1 and regulatory cytokines.84
In a different way, Srivastava et al investigated the efficacy and safety of peanut oral immunotherapy using CpG-coated poly(lactic-coglycolic acid) NPs containing a peanut extract (CpG/PNNPs). In particular, C3H/HeJ mice were rendered peanut allergic by means of oral sensitization with peanut and cholera toxin. Mice were subjected to four weekly gavages with CpG/PN-NPs, vehicle (PBS), NPs alone, peanut alone, CpG NPs, or peanut NPs. Mice with peanut allergy treated with CpG/PN-NPs but not with a vehicle or other components were significantly protected from anaphylaxis. Treatment was associated with decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) but increased IFN-γ levels, together with decreased peanut-specific IgE/IgG1 levels and an increase in IgG2a levels.85
Table 3 Animal and food allergens nanocomplexes
Abbreviations: CBP, carbohydrate-based particle; CpG, cytosine-phosphate-guanine.
Several studies on allergen immunotherapy performed with commercially available products in comparison with pharmaceutical treatment have shown that immunotherapy may be very beneficial for patients and health care systems, reducing costs and bringing relief to patients.86 However, some questions still remain regarding the safety of these treatments and the need to reduce the dose and time of administration to improve patient compliance. In recent years, nanotechnologies have strongly emerged in vaccinology and, more currently, in the allergen immunotherapy field, with several studies in animals showing very promising future perspectives.35,87 Of particular interest in this field is how nanocarrier/allergen complexes can be formulated to obtain improved stability, slow release kinetics, selective targeting of specific immune cells, and lower immunotoxicity vs optimized immunomodulatory potential. Although such applications are still at an investigational stage, in vitro and in vivo studies have started to open the way to deeper knowledge about the interaction between the immune system and NPs/allergen complexes. The results suggest that several NP-based formulations can be applied in the near future to allergen immunotherapy to solve its unmet needs.
The authors report no conflicts of interest in this work.
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© 2017 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.


File Transfer Protocol (FTP) is an easy way to take you files and put them into you website. When you are using FileZilla, you can move thousands of files at once.
To start, login to FileZilla. Put in the login details into the top, host is ftp.yourdomain.com, the user and password are the same as you cPanel login.
Once that is successfull, you will see the box on the righ populate with files from you website server. The box on the left contains files from your computer. To transfer files, all you have to do is locate the files you wish to move, locate the folder you wish to move to on the remove server, and drag them over.


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Cahaba Pump Station
The Cahaba Pump Station, built in 1887-1890, is a working pump station owned by the Birmingham Water Works. The station is located on the banks of the Cahaba River at the former site of New Town at 4012 Sicard Hollow Road and consists of a Control Room Building, Boiler House, and two Pumphouses.
The original facility was designed by Elyton Land Company engineer Willis Milner for a capacity of 5 million gallons per day. Construction at the remote site began in 1887 and cost a half million dollars over the next three years. Another engineer, William Merkel, took charge of construction and superintended its operation afterward. The community of Merkel, named for him, grew up around the station to house workers.
A 1998 renovation and addition designed by KHAFRA engineers won a Preservation Award from the Birmingham Historical Society. Currently the station also functions as a museum with examples of early tools and equipment and a collection of historical photographs. The facility is also available as a meeting and conference space for business and civic groups of up to 100.
In 2009 the Water Works purchased 23 acres adjoining the station from Fleming Branch LLC in a deal that protects 50 additional acres bought by Alex Jones from high-density development.
Bryant, Joseph D. (October 23, 2009) "Birmingham Water Works buying land near major pump station." The Birmingham News
"How Local Communities Got Their Names" (1st Quarter 2014) The Jefferson Journal
Cahaba Museum page at bwwsb.com
Cahaba Pump Station postcard & photo at Postcard Birmingham
Retrieved from "https://www.bhamwiki.com/wiki/index.php?title=Cahaba_Pump_Station&oldid=150360"
Birmingham Water Works
Elyton Land Co. developments

redpajama_set_name: RedPajamaCommonCrawl


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Planning a Backpacking Trip in the US National Parks
By backcountrygear|2019-05-07T16:42:48-04:00June 14th, 2019|Backpacking|
U.S. National Parks receive over 330 million visits every year. [...]
The Rise of Indoor Climbing and Why You Should Try it
By backcountrygear|2019-05-07T16:39:59-04:00June 7th, 2019|Climbing|
There are estimates of more than 35 million climbers (both [...]
Lighten the Load: 20 Essential Backpacking Hacks
By backcountrygear|2019-05-05T15:49:19-04:00May 31st, 2019|Backpacking|
Sometimes there's nothing better than strapping on a backpack, walking [...]
Menu Item or Snowboarding Move? A Guide to Those Amazing Snowboard Tricks
By backcountrygear|2019-05-05T15:47:35-04:00May 24th, 2019|Snowboarding|
Over 2.2 million people are active snowboarders in the United [...]
10 Best Places to Ski in the US, 2019 Edition
By backcountrygear|2019-05-05T15:45:30-04:00May 17th, 2019|Skiing|
You're a keen skier, and hitting the slopes hard is [...]
Inside Out: A Complete Guide to Snowboarding Gear
Invented in 1965, the Snurfer consisted of two snow skis [...]
Stay Off the Slippery Slope and Start Cross-Country Skiing
By backcountrygear|2019-05-02T09:46:40-04:00May 2nd, 2019|Skiing|
Grab your skis and let's meet on the slopes! Skiing [...]
How To Buy A Kayak: Guide For First Timers
By backcountrygear|2018-06-05T18:58:40-04:00July 18th, 2018|Kayaking|
Are gearing up to spend your summer in the water? [...]
5 Essential Snowboarding Tips For Beginners
By backcountrygear|2018-06-01T09:53:35-04:00July 14th, 2018|Snowboarding|
Are you a snowboard newbie and want to be an [...]
Top 5 Outdoor Rock Climing Locations In The US
By backcountrygear|2018-05-28T13:49:23-04:00July 10th, 2018|Rock Climbing|
In 2015, more than 4.6 million people participated in either [...]
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Several changes have been made to the FIM Supersport 300 World Championship grid ahead of the sixth race of the season, scheduled to take place tomorrow at Misano World Circuit Marco Simoncelli.
At the start of the Superpole 1 session that took place on Saturday morning, fifteen riders did not respect the red light and red flag signal at the pit exit, heading out on track before the session was formally started. For this, all fifteen have been penalised to start from the back of the grid in tomorrow's race, in the order in which they had originally qualified.
The fifteen concerned are, in order of qualifying: Filippo Rovelli (Kawasaki ParkinGO Team), Imanuel Putra Pratna (TERRA E MOTO), Tom Edwards (Nutec – Benjan – Kawasaki), Walid Khan (Nutec – Benjan – Kawasaki), Hugo De Cancellis (Team Toth – Yart), Tomas Alonso (Samura-YART Racing), Maximilian Kappler (Freudenberg KTM WorldSSP Team), Tom Toparis (Motoport Kawasaki), Daniel Blin (Team Toth – Yart), Dino Iozzo (Racedays), Nicola Settimo (Scuderia Maranga Racing), Joseph Foray (ETG Racing), Samuel Aaron Lochoff (Samurai-YART Racing), Jared Schultz (Team Trasimeno), and Trystan Finocchiaro (Scuderia Maranga Racing).
As well as these fifteen riders, Mika Pérez (Kawasaki ParkinGO Team) has also been handed a six-place grid penalty after being found not in conformity with minimum weight requirements. The Spanish will thus start from ninth in tomorrow's race, after taking the third best time in the Superpole 2.


In Janod's Mistigri game the aim is to make up matching pairs of families from the 16 sets in the pack without being left with the cheeky black cat at the end of the game!
Mistigiri is an ideal matching game for the little ones, with it's simple rules and short rounds.
2 to 6 players from 4 years.


The Cross River Ripper Fat Bike Race, the first of its kind and promising to be a popular annual event at Nipika Mountain Resort in the future, will take place on a mixture of the resort's fat bike and ski trails, likely on the north side of the trail system. If so, it promises to be a veritable roller-coaster ride for participants.
Afterward, there will be a BBQ and awards ceremony at the Day Lodge. The cost of the BBQ is included in the race registration and additional tickets may be purchased at the event.


Power feeders have been the pride and joy of Co-matic for decades, and the AF48 Stock Feeder is the culmination of our experience. We constantly strive to improve the safety and functionality of our feeders, an approach which has yielded us an international reputation for quality and durability. All power feeders are made to meet or exceed the standards that both hobbyist and professional woodworkers have come to expect from our name.
By keeping your hands away from cutting edges, our AF48 Stock Feeder upholds Co-matic's reputation for setting and maintaining high standards in woodworking safety while still remaining easy to use.
Speed settings can easily be adjusted depending on your requirements. With a range of eight speeds and an interchangeable gear set, the AF48 provides a range of speed options for your stock feeding needs.
The rubber and polyurethane rollers that come with the AF48 can be removed with a minimum of effort. Replacement rollers can be purchased separately, with replacement times dependent on roller material, rate of use, and workpiece material.


Yogurt has nutritional benefits greater than milk. Consistent consumption of yogurt will bring you a variety of health benefits. It is particularly helpful for many intestinal conditions due to the "good bacteria" or probotics that it contains. All yogurts made with live cultures include probotics. Studies have also shown that the consumption of low fat yogurt can promote weight loss, increase your immune system and bring many health benefits. Many people who have moderate lactose intolerance can usually enjoy yogurt with no side effects. Due to the many healthy benefits that yogurt provides, it is frequently considered one of the top Super Foods.
You can use yogurt instead of mayonnaise in potato salad, chicken salad or with tuna.
It tastes great as a topping for baked potatoes or with tacos instead of sour cream.
Any creamy salad dressing can be made with yogurt as opposed to sour cream, real cream or mayonnaise.
Don't be afraid to experiment. Be creative. Anytime you can make a better choice you are improving your health. Small choices like putting yogurt on your sandwich or baked potato add up and contribute to your lifelong good health. Next time you pick up the mayonnaise jar, try a little yogurt instead. You can substitute yogurt entirely or try a blend. Living a healthy life and experiencing the benefits of lifelong good health is a choice that you make every day. Every diet choice is effecting your health.


Today's 5 star secret recipe comes from Magnolia Bakery in New York City. This chain of down-home bakeries specializes in a variety of creative cupcakes. They make a yummy vanilla cupcake that's light and moist with an irresistible vanilla buttercream icing.
Preheat oven to 350 degrees F. Line 2 (1/2 cup-12 capacity) muffin tins with cupcake papers.
In a small bowl, combine the flour, baking powder, and salt and set aside.
Add the dry ingredients in 3 parts, alternating with the milk and vanilla.
With each addition, beat until the ingredients are incorporated but do not over beat.
Carefully spoon the batter into the cupcake liners, filling them about 3/4 full.
Bake for 15-20 minutes, or until a cake tester inserted into the center of the cupcake comes out clean.
Cool the cupcakes in tins for 15 minutes.
Remove from the tins and cool completely on a wire rack before icing.
Add 4 cups of the sugar and then the milk and vanilla.
On the medium speed of an electric mixer, beat until smooth and creamy, about 3 to 5 minutes.
Gradually add the remaining sugar, 1 cup at a time, beating well after each addition (about 2 minutes), until the icing is thick enough to be of good spreading consistency.
You may not need to add all of the sugar. If desired, add a few drops of food coloring and mix thoroughly.
Use and store the icing at room temperature because icing will set if chilled.
Icing can be stored in an airtight container for up to 3 days.


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Ryanair expands Croatian hub and introduces 11 new connections
The Irish low-tariff airline Ryanair said on Wednesday that in 2020 it would restore its base in Zadar and introduce 11 new lines, predicting a 50% increase in the number of passengers.
The Zadar base will consist of three planes of Laudamotion, the Austrian low-tariff airline owned by Ryanair, which should help create 90 jobs, it was said at a news conference held by Ryanair and Zadar Airport officials.
The Irish airline had a base in Zadar until late 2018 and the company will again rent its old premises.
As regards the 2020 summer timetable, which goes into force in April, Ryanair will operate 31 lines at Zadar Airport and the new lines include the European destinations Aarhus, Bremen, Cork, Paris, Gdansk, Kaunas, Liverpool, Maastricht, Riga, Toulouse and Wroclaw.
Ryanair estimates that in 2020 it will transport 672,000 passengers, a 50% increase, which is expected to generate around 490 jobs in various services at Zadar Airport.
Ryanair executive director Eddie Wilson said that as of now Zadar residents and their guests could plan travel to 31 destinations in Europe until October 2020.
As of December 12, tickets will be sold at a promotional price of €21.99 for flights in May and June 2020.
Zadar Airport director Josip Klismanic said the return of Ryanair's base to Zadar with three aircraft was a major sign of recognition for Zadar as an airport and a destination.
Unemployment rate continuing to fall	Croatians around the world can vote for next President


Effectiveness of Back Massage on Sleep Pattern among Patients with Congestive Cardiac Failure | Sable | .
Background: Sleep plays an important role in congestive cardiac failure (CCF). Back massage reduces anxiety, discomfort, and physical suffering in CCF patients. Study objective is to assess sleep pattern in CCF patients before and after back massage.
Materials and Methods: A quasi‑experimental study was conducted in Pravara Rural hospital, Loni, India over 4 months in 2016. Thirty CCF patients were included in the study with purposive sampling. Nurse investigator performed 20‑min back massage thrice daily, 5 min for each step from the day of admission till discharge. In back massage, effleurage, stroking, kneading, and assessment of effectiveness was recorded using the Pittsburg sleep quality index.
Results: Thirty CCF patients were included, out of which individuals aged >65, 56–65, and 35–45 years age group were 40%, 24%, and 13%, respectively. Twenty‑four had left and 6 had right heart failure. Distribution of mean and standard deviation of pretest for sleep quality was 9.50 (3.14), indicating poor sleep quality. Posttest, the mean score was 4.47 (0.89), indicating good quality sleep. Eleven patients had >8 h of sleep, 15 patients had 6–8 h of sleep, whereas 4 patients had less than 6 h of sleep pretest. Posttest, 22 patients had >8 h and the remaining had 6–8 h of sleep.
Conclusions: Back massage technique is safe and cost‑effective in CCF patients, by which the quality and duration of sleep is improved. It can be a part of the standard treatment.
Dos Santos MA, da Cruz Dde A, Barbosa RL. Factors associated to sleep pattern in heart failure patients. Rev Esc Enferm USP 2011;45:1105‑12.
Vyas UK. Non‑pharmacological management of insomnia. BJMP 2013;6:a623.
Roger VL. Epidemiology of Heart Failure. Circulation 2013;113:646‑59.
Sivadasan Pillai H, Ganapathi S. Heart Failure in South Asia. Curr Cardiol Rev 2013;9:102‑11.
Jiménez JA, Greenberg BH, Mills PJ. Effects of Heart Failure and its Pharmacological Management on Sleep. Drug Discov Today Dis Models 2011;8:161‑6.
Vickers A, Zollman C, Reinish JT. Massage therapies. Western J Med 2001;175:202‑4.
Kong LJ, Zhan HS, Cheng YW, Yuan WA, Chen B, Fang M. Massage Therapy for Neck and Shoulder Pain: A Systematic Review and Meta‑Analysis. Evid Based Complement Alternat Med 2013;2013:613279.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Chapter 28, Sleep and Wakefulness.
Sharma B, McSharry D, Malhotra A. Sleep disordered breathing in patients with heart failure: Pathophysiology and management. Curr Treat Options Cardiovasc Med 2011;13:506‑16.
Sharma B. Sleep in Congestive Heart Failure. Med Clin North Am 2010;94:447‑64.
Chang BH, Jones D, Hendricks A, Boehmer U, Locastro JS, Slawsky M. Relaxation response for Veterans Affairs patients with congestive heart failure: Results from a qualitative study within a clinical trial. Prev Cardiol 2004;7:64‑70.
Mirzaaghazadeh M, Bahtouee M, Mehdiniya F, Maleki N, Tavosi Z. The Relationship between Nocturnal Hypoxemia and Left Ventricular Ejection Fraction in Congestive Heart Failure Patients. Sleep Disorders 2014;2014:978358.
Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, et al. Sleep disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011;306:613‑9.
Shinde MB, Anjum S. Effectiveness of Slow Back Massage on Quality of Sleep among ICU Patent's. IJSR 2014;3:292‑8.
Chen W‑L, Liu G‑J, Yeh S‑H, Chiang M‑C, Fu M‑Y, Hsieh Y‑K. Effect of Back Massage Intervention on Anxiety, Comfort, and Physiologic Responses in Patients with Congestive Heart Failure. J Altern Complement Med 2013;19:464‑70.


I know around my house at Christmas time there is a lot of teacher gift giving. Teacher's deal with our kiddos all year long and in my opinion have one of the hardest jobs beside being a mommy. They deserve a little treat come Christmas time. So I have found some of the best ideas for teacher gifts that I can think of. Check it out!!
This is a super cute idea. This is basically all of the ingredients to make cookies but in a jar. On the tag instead of putting girlfriend cookies you could put favorite teacher cookies. Check it out over at Loralee Lewis and she give a good idea on just how to make this one.
This is perfect and is a must. You can put this in a little basket or just give it to your teacher like it is.
Here is what it looks like. I love it.
I think this is my favorite idea yet. I got this idea at Bee In My Bonnet. Go over there and check it out. You can order these super cute apron's from her.
And this is what is in the jar.
I came over from linking up over at 'Serenity Now.' Very cute ideas, I'll have to use a couple of these ideas!
These are so cute! I love the Carmel apple jam!! Yummy!
Kelly thanks for stopping by. Let me know how they turn out if you make any of these.
Thanks for sharing these great ideas! I love the apron recipe. Too cute!
These are super cute. Thanks for linking up to Social Sunday.
I LOVE LOVE LOVE your ideas! Thank you so much for helping me think of gift ideas!
Fun! Love jars! And I like the Girlfriend Cookies, packaging makes all the difference! I've got to get better at presentation with my gifts.
Super cute ideas! I really want to try the gifts in a jar this year!
Hi! Hopped over here from The Sasse Life and I love this idea! As a teacher, I would love to get any of these gifts from my students, and I can think of a few teachers/friends who I want to make these for. Thanks for sharing this project!
Fabulous ideas! When I was teaching middle and high school English, I'd have loved to receive any of those great gifts! My fave is the mint hot cocoa! I'm pinning it! Would you pretty pleeease share it here at my holiday party?
Great ideas! My friend & I were talking the other day about making our own gifts this year, so I will have to let her know about some of these ideas & try them out!! Thanks! Now following, would love it if you came by for a visit & follow back!
Thanks for sharing these great ideas!! That apron is SO cute!!
Such a great collection of ideas! Thanks for sharing at Taking A Timeout Thursday. I can't wait to see what you share this week.
super cute!! Im in love with all of them!
Hey there. Look at you with 64 followers. So happy for you!
Thanks for linking this up last week on my mommy solution meme. This was the most clicked idea!
like the gift idea...really like it.
Send Gifts To Pakistan From Australia.
This is a great idea. I think homemade picture frames are always a nice gift for teachers. I used to get them a lot from my aunt. Should would create all different styles and design so my wife is trying to teach our kids to make them. However, I think these ideas are great gifts for anyone. I like to get people new technology gifts for Christmas. I guess you could call me a technology nerd but this sort of gift can always come in handy. Last year I got my brother the Spy Detector because it can help him track where his son is driving. He just got his license and I know here worries about him.


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Utrom Confirmed, but Not Really – Expanding Content on Nick's TMNT Site
Zach Gasior 2012-08-14
Zach Gasior · August 14, 2012
A quick hop over to Nickelodeon's TMNT site confirms that we will see the Utrom in the upcoming cartoon, but evidently they won't go by that name. Instead, brace yourself by an invasion of: the kraang. Not Krang, the Utrom-looking super-baddy from the 1980s TV series, but a whole race of renamed Utrom. They will be wielding blasters that look vaguely like those carried by the Triceratons in the original independent comic, plus the addition of a gears-of-war style chain bayonet.
New videos on the site profile three of the four turtles: Raphael, Donatello, and Leonardo. Additionally, they've added a weapons gallery that introduces a few changes to the Turtle's kit: Michelangelo now uses both nunchaku and kusarigama while Donatello will fight with his traditional bo and a naginata. Leonardo and Raphael still use katana and sai, respectively. Other profiled weapons include shredder's claws and splinter's staff.
The new character bios are concise, and don't tell us much of anything new. Leo is the leader, Mike's the fun one, Donnie's the brains, and Raph is tough. The "about" section also reiterates common knowledge about the turtle's origins (no mention of aliens, thankfully) and sets up their conflict with the Shredder.
The discussion forum is generally positive, which suggests that it's probably tightly moderated. After a few moments spent reading through the entries, it's easy to see that the forum is populated mostly by kids, and possibly by moderator sock puppets generating Astroturf. With topics like "I have a crush…on LEO AND RAPH!!!" and "urtwo fav turtles," it's a safe bet that the message boards at Nick 'toons aren't going to become your new source for hot TMNT news.
Overall the site gives a clear, if shallow, impression of what we can expect from the new series, but there's one particular stand-out feature: the flash game Dark Horizons. The game play is reasonably well developed as each of the four turtles do behave a bit differently based on their attributes (attack, defense, agility, and range), but the real standout is the visuals. The turtles in-game are highly stylized – all shadowy black with bold, character-appropriate weapons, masks, and kit. Fights are a bit button-mashy, but timing is an element, especially in the stages in which another turtle joins you. The levels are a bit difficult to navigate since some of them tend to look the same, but if you're looking for deep gameplay challenging navigation, well, this ain't it. This is a true side-scrolling slash 'em up, and worth a few minutes of your turtle-lovin' time.
Dark Horizons Game: http://www.nick.com/games/teenage-mutant-ninja-turtles-dark-horizons.html
Nick or Not – Another TMNT Trailer Released
Red, Purple, Orange, and Blue: TMNT Fashion Over Thirty Years
New Nickelodeon TMNT Books Now Available For Pre-Order
Tags:Dark HorizonsDonatelloKrangLeonardoMichelangeloNinja TurtlesRaphaelShredderTeenage Mutant Ninja TurtleTMNT
Zach Gasior
Zach Gasior is an author and English professor at Baton Rouge Community College in Louisiana. His short stories have been published around the world, and he has two non-fiction books in print. He has contributed articles to several different sites, and has been a fan of the turtles since he was two years old, and his favorite ninja turtle is Raphael.
Kevin Eastman to Both Write & Draw TMNT Annual 2012
Jessica Biel to Play April O'Neil in TMNT Reboot?


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Arthur Godfrey Kilner Brown (né le  à Bankura, en Inde - mort le  à Coneyhurst dans le Sussex) est un athlète britannique spécialiste du 400 mètres. Il est le frère de l'athlète Audrey Brown.

Carrière
Il se révèle durant l'année 1936 en remportant l'épreuve du 440 yards des Championnats du Royaume-Uni. Sélectionné pour les Jeux olympiques de 1936, il établit lors des demi-finales du 400 m un nouveau record d'Europe de la discipline en 47 s 3. Deux heures plus tard, en finale, Godfrey Brown remporte la médaille d'argent olympique en 46 s 7, ne s'inclinant que de deux dixièmes de secondes face à l'Américain Archie Williams, détenteur du record du monde. Aligné par ailleurs dans l'épreuve du relais 4 × 400 mètres, le Britannique s'adjuge le titre olympique aux côtés de ses compatriotes Frederick Wolff, Godfrey Rampling et William Roberts, devançant de deux secondes le relais des États-Unis.

En 1937, Godfrey Brown décroche trois médailles d'or lors des Jeux mondiaux universitaires de Paris, sur 400 m, 4 × 100 m et 4 × 400 m. Vainqueur des Championnats britanniques sur 440 yards en 1938 pour la seconde fois de sa carrière, il remporte la même année le titre du 400 m des Championnats d'Europe de Paris, devant le Néerlandais Karl Baumgarten. Il obtient également la médaille d'argent du relais 4 × 400 m dans lequel l'équipe du Royaume-Uni se voit devancer par l'Allemagne et une médaille de bronze sur 4 × 100 m derrière l'Allemagne et la Suède, qu'ils avaient devancé sur 4 × 400 m.

En 1939, Brown remporte sur 880 yd son troisième titre national.

Palmarès

Notes et références

Sources
 Robert Parienté et Alain Billouin, La Fabuleuse Histoire de l'athlétisme, Minerva, 2003

Liens externes

Sprinteur britannique
Coureur de 400 mètres
Relayeur (athlétisme)
Champion olympique britannique
Champion olympique d'athlétisme
Champion d'Europe d'athlétisme
Détenteur d'un record d'Europe d'athlétisme
Athlète (homme) aux Jeux olympiques d'été de 1936
Naissance au Bengale-Occidental
Naissance en février 1915
Décès en février 1995
Décès à 79 ans
Médaillé d'argent olympique britannique

redpajama_set_name: RedPajamaWikipedia


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Doctor Who: John Barrowman's most iconic appearances as Captain Jack Harkness returns for New Year special
Captain Jack Harkness has been an absolute staple of Doctor Who ever since he roared onto our screens in 2005.
Naturally, fans were over the moon when it was revealed that John Barrowman will be reprising the role for the 2021 New Year's special, Revolution of the Daleks.
From flirting with pretty much everyone in sight, including Christopher Ecclestone, David Tennant and Jodie Whittaker's Doctors, to saving the day with a side serving off sass, Jack's had quite the journey.
That's not even to mention starring in the wildly popular spin-off, Torchwod.
Basically, Jack's an all-round legend, so in celebration of our favourite immortal bisexual, we're toasting some of his greatest hits.
Jack first appeared in series one's The Empty Child, and was first seen spying on Rose Tyler (Billie Piper) as she clung onto a rope for dear life as she watched London being bombed during World War I.
He had a suitably flirty first line ('Excellent bottom!') and proceeded to catch Rose mid-air as she fell to the ground.
Little did we all know that it would begin the long-standing tradition of Jack strutting in to save the day.
Jack says goodbye
As it turns out, Captain Jack is just as good at goodbyes as he is at dramatic entrances.
His sweet farewell to the Ninth Doctor (Christopher) and Rose has been long-remembered as a matter-of-fact reference to his sexuality, as he kisses them both to say goodbye.
John's ability to simultaneously make us laugh and sob absolutely made the scene, as Jack told Nine: 'I wish I'd never met you, Doctor. I was much better off as a coward,' before jogging out of the TARDIS and declaring: 'See ya in hell!'
The race to the TARDIS
Weirdly enough, Jack's next appearance was pretty much in hell – well, the end of the world.
We next met Jack in series three, when he literally followed Ten (David Tennant) and Martha (Freema Agyeman) across time by clinging onto the TARDIS as it traveled through the Time Vortex.
Ten had a shady first reaction to Jack, intending to leave him behind as he raced towards the TARDIS, but clearly the time agent wasn't about to give up that easily.
Doctor Who/Torchwood crossover
We don't think too much about the end of series four if we can help it, because it simply HURTS TOO MUCH.
But, there is one moment that felt like Christmas for Whovians – when Torchwood and Doctor Who had a crossover.
Martha, Rose, Sarah Jane Smith (Elisabeth Sladen), and Harriet Jones (Penelope Wilton), all hopped on a conference call with Torchwood's Jack, Gwen Cooper (Eve Myles) and Ianto Jones (Gareth David-Lloyd) on the Subwave Network (a glorified version of Zoom) to contact the Doctor.
There was shade thrown between Rose and Martha, Jack flirting with Sarah Jane, Ianto taking control of the call – basically, it was glorious.
Series 12 return
We were a little spoilt with John's appearances in series one to four, but series five to 11 proved a no-go for Jack fans.
Of course, John was off appearing in Torchwood from 2006 to 2011, so we can't blame him for having a busy schedule!
However, Who fans were delighted when the star made a shock return in series 12, for Fugitive of the Judoon.
We won't have to wait too long to see Jack again for the New Year special and here's hoping he'll be around the save the day for years to come.
After all, John has insisted that he's happy to get back into his famous coat 'at the drop of a hat' – so we're going to hold him to that.
Revolution of the Daleks airs on New Year's Day at 6:45pm.
Doctor WhofollowJack HarknessJohn Barrowmanmycelebritylifetv
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text:
Announcement of public tenders in research, experimental development and innovation for the support of grant projects in basic research always takes place in the spring of the respective calendar year (usually at the turn of February and March).
Tender period is the same for all public tenders, starting the day after announcement of public tender and lasting at maximum 43 calendar days.
Evaluation period is the period during which the provider carries out evaluation of the project proposals, and decides on the results of the tender. The evaluation period starts the day following the end of the tender period and lasts at maximum 240 calendar days.
Announcement of the results of the tender takes place after the evaluation of project proposals, generally in December of the same calendar year the public tender was announced.
The expected date for launching of the projects is January 1st of the following year in which the tender was announced.
All information regarding the announced public project calls can be found in the Index of Public Tenders for Research, Experimental Development and Innovation (VES).
Terms and deadlines of LA project calls in 2021
Project proposals that are part of the Weave Initiative and where GACR is the Lead Agency can be submitted till April 22nd, 2021. Should GACR be in the role of partner agency, the deadline is given by the foreign agency.
Terms and deadlines for public project calls in 2021 (standard projects, JUNIOR STAR, POSTDOC INDIVIDUAL FELLOWSHIP, international – bilateral projects)
Project proposals may be submitted till April 22nd, 2021. Projects chosen for financial support from January 1st, 2022 will be announced on the 6th of December, 2021.


text:
Overview Of Activity For Year Ended
Appellate Courts
The 949 Petitions for Review and 55 Applications for Writs of Error filed during fiscal year 1998 represented a 2.1 percent increase from the 983 applications filed in fiscal year 1997, and was 0.2 percent lower than the 10-year average of 1,006.
The Court "passed on" (disposed of or otherwise acted upon) a total of 3,204 matters during fiscal year 1998, an increase of 5.5 percent from the 3,037 matters passed on in fiscal year 1997.
During fiscal year 1998, the justices of the Supreme Court wrote 222 opinions (or an average of 24.7 opinions each), 24 percent more than the 179 opinions written in fiscal year 1997 and 2.8 percent more than the 10-year average of 216. About 63.5 percent, or 141, of the opinions written in 1998 were deciding opinions which disposed of causes.
Court of Criminal Appeals
The 471 cases added to the docket of the Court of Criminal Appeals in fiscal year 1998 represented a decrease of 11.6 percent from the 533 cases added during fiscal year 1997.
Judges of the Court of Criminal Appeals wrote 652 opinions during fiscal year 1998, of which 417, or 64.0 percent, were "deciding" opinions disposing of cases. The remainder were dissents, concurrences, and opinions on rehearings. Of the deciding opinions, 131 were signed and 286 were per curiam. During 1997, members of the Court wrote 747 opinions, 75.6 percent of which were deciding opinions.
Courts of Appeals
The courts disposed of 11,736 total cases during the year, an average of 147 dispositions (88 criminal and 59 civil) per justice. The pending caseload increased from 10,809 at the beginning of the fiscal year 1998 to 11,575 at the end of the fiscal year.
A total of 12,502 cases were added to the dockets of the Courts of Appeals during the fiscal year, which included 7,144 criminal cases and 5,358 civil cases. This was an increase of 8.5 percent from the 11,523 total cases added in fiscal year 1997. Criminal cases increased 6.3 percent from the 6,718 added in fiscal year 1997 and civil cases increased 11.5 percent from the 4,805 added in fiscal year 1997.
The average lapse of time between the filing of a civil case in a Court of Appeals and its disposition ranged from 5.3 months in the Sixth Court of Appeals in Texarkana to 11.9 months in the Thirteenth Court of Appeals in Corpus Christi. The average lapse of time in the 14 courts for civil cases was 8.5 months.
The average lapse of time between the filing of a criminal case in a Court of Appeals and its disposition ranged from 7.6 months in the Tenth Court of Appeals in Waco to 20.3 months in the Fourteenth Court of Appeals in Houston. The average lapse of time for the 14 courts was 12.1 months.
In fiscal year 1998, the justices of the Courts of Appeals wrote 11,457 opinions, 9.3 percent more than the 10,480 written in 1997.
Thirty-six death sentences (compared to 34 in 1997) and 374 life sentences were assessed in the district courts during the year. Of the 211,630 criminal cases disposed by the district courts, 33 percent were disposed of in a period of less than two months from the date of indictment or information, 11 percent took two to three months, 9 percent took three to four months, and 47 percent took over four months.
Criminal cases added to the docket increased 0.6 percent in the ten urban counties during fiscal year 1998 as compared to 1997. This compares to 0.4 percent decrease in criminal filings for all other counties of the State. Criminal filings increased in six of the ten urban counties: Collin (20 percent), Nueces (9 percent), El Paso (6 percent), Travis (5 percent), Dallas (2 percent), and Tarrant (2 percent). Counties reporting a decrease in criminal cases added to the docket were Bexar (2 percent), Harris (3 percent), Denton (6 percent), and Hidalgo (1 percent).
Civil cases accounted for 443,095 or 64 percent of all cases added during the fiscal year. Family law matters other than divorce actions comprised the largest segment of civil cases added, with 36 percent of civil case additions.
During the fiscal year, the district courts disposed of 100.3 percent of the total criminal and civil cases added to their dockets, compared to 101 percent in 1997.
District courts handled 2 percent less divorce actions during 1998 than during 1997. During the fiscal year, 120,756 divorce cases were disposed, 27 percent of all civil (non-juvenile) cases handled by district courts. Seventeen percent of divorce cases were dismissed.
The 539,273 civil cases pending in the district courts on August 31, 1998 represent a 2 percent decrease over the 547,966 pending on August 31, 1997. Criminal cases pending increased 6 percent, from 177,236 to 188,329.
County-Level Courts
During the twelve-month reporting period, the county-level courts of the State disposed of 48 percent of the 1,409,962 total criminal, civil, and juvenile cases on their dockets (added during the year or carried over from the previous year).
From the number of cases reported, criminal cases constituted 74.9 percent (571,998) of the 763,941 cases added to the dockets of the county courts. This figure includes all criminal, civil, and juvenile cases added to the dockets, as well as cases filed under probate and mental health. Civil cases accounted for 13.5 percent (102,794), probate cases represented 7.2 percent (55,185), mental health cases represented 3.4 percent (26,063), and juvenile cases represented 1.0 percent (7,901) of the total.
Total cases pending on the dockets of the county-level courts increased by 4 percent from 730,068 on September 1, 1997, to 759,665 on August 31, 1998.
Return to 1998 Annual Report


text:
Folk Den is a folk music website founded in 1995 by Roger McGuinn, former front man of The Byrds. Hosted at the University of North Carolina at Chapel Hill's ibiblio, the site is intended to preserve and promote folk music and offers a new folk song on a monthly basis. Each posting provides an MP3 of a traditional folk song along with a descriptive paragraph, lyrics, guitar chords and related images. The site has received positive reviews from The New York Times, the Discovery Channel, and CNET.

CD releases
A selection of songs from Folk Den, with guest vocalists, was released on CD as Treasures from the Folk Den, which was nominated  for a Grammy Award in 2002 for  Best Traditional Folk Album. In November 2005, McGuinn released a four-CD box set containing one hundred of his favorite songs from the Folk Den.

References

Further reading

Interviews and reviews

External links

Folk music publications
Free music download websites
American music websites
Internet properties established in 1995


The world is your home. And while you're sightseeing in the city or hunting down a hostel in the back of beyond, the Jack Wolfskin Douglas Parka gives you the weather protection you need.
The hard wearing, wind and waterproof FUNCTION 65 fabric has a waxed finish that develops its own individual patina over time - a testament to all the adventures you've had together. The DOUGLAS PARKA has abrasion resistant reinforcements on the shoulders, so carrying a heavy pack on the way to the hostel or the airport is no problem.
Whether you're exploring the streets of Tokyo, harvesting apples in New Zealand or hiking through an Irish downpour, this parka fits the bill every time. It is happiest on long journeys and will develop its own individual look.


For more information about Financial Mathematics at University of Liverpool, please visit the webpage using the button above.
This cutting edge MSc programme will equip you with the mathematical, financial and computational skills needed to quantify and manage risk effectively in today's finance, investment and insurance industries. Such companies use advanced probabilistic models at the core of their business. They recruit people with the right mathematical, statistical and programming skills and financial knowledge who can understand, develop and implement such models. The course is also an excellent preparation for students wishing to embark upon research degree (PhD) in financial or actuarial mathematics. Working professionals who would like to move from their current field into finance or for finance professionals who would like to take their careers to the next level will also benefit greatly from this course.
The 12-month programme consists of seven taught compulsory modules plus one taught elective module, followed by a research project carried out over the summer period upon completion of Semester Two. The course is taught mainly by members of the Institute for Financial and Actuarial Mathematics (http://www.liv.ac.uk/ifam) which is part of the Department of Mathematical Sciences (http://www.liv.ac.uk/mathematical-sciences/). Some relevant modules are taught by the Management School (http://www.liv.ac.uk/management/).