George A. Stouffer, MD

• Henry A. Foscue Distinguished Professor of Medicine
• Chief of Clinical Cardiology
• Director, C.V. Richardson Cardiac Catheterization
• Laboratory
• Director, Interventional Cardiology
• Division of Cardiology
• University of North Carolina School of Medicine
• Chapel Hill, North Carolina

High soil salinity impedes plant growth anxiety symptoms skin rash generic sinequan 10mg mastercard, both by creating a water deficit in the soil and within the plant anxiety 9 to 5 buy sinequan 10 mg without prescription, as sodium ions impinge on many key bio chemical processes anxiety nursing interventions discount sinequan 75 mg with amex. Strategies to increase salt tolerance involve limiting exposure of cytoplasmic enzymes to the salt and may include blocking + + + Na anxiety symptoms quitting smoking safe sinequan 25mg, influx anxiety symptoms reddit buy sinequan 75 mg with mastercard, increasing Na efflux anxiety 247 discount sinequan, and compartmentalizing Na (Zhu, 2001). Successful transgenic approaches are described in detail in Yama guchi and Blumwald (2005). Many of these entail over-expressing the + + Arabidopsis vacuolar Na /H antiporter, which enhances tolerance to soil salinity, with few or no detrimental effects on seed quality or plant growth, in canola (Zhang et al. Sequestration of cations in the Arabidopsis vacuole, resulting in enhanced salt and + drought tolerance was also achieved by overexpressing the vacuolar H py rophosphatase (Gaxiola et al. Increased expression of a plasma + + + membrane Na /H antiporter augmented salt tolerance by limiting Na ac cumulation (Shi et al. Finally, tolerance in rice, resulting from ex + + pression of a bacterial Na /H antiporter, was accompanied by biosynthetic activation of the osmoregulatory molecule proline (Wu et al. Both freezing and high temperature cause damage to plant tissues and proteins, leading to diminished crop yield. A comprehensive listing of at tempts to enhance plant thermo-tolerance through genetic modification can be found in Sung et al. One of the earliest reports of altered chilling sensitivity resulted from engineering the degree of fatty acid saturation in tobacco membranes (Murata et al. In concluding this section on engineering tolerance to environmental constraints, it is important to recognize that reductions in crop viability and yield are compounded by combinations of abiotic stresses. Such combina tions can elicit plant responses that are not easily extrapolated from the plants response to each stress applied individually (Mittler, 2006). Strate gies designed to mitigate the effects of combinations of environmental stress conditions might, for example, target stress-responsive signal Agrobacterium and Plant Biotechnology 103 transduction pathways, which could exhibit synergistic or antagonistic cross-talk. Regardless of the approach taken, lab-based proof-of concept experiments must be complemented by testing under conditions that mimic the field environment (Mittler, 2006). In natu rally occurring ecosystems, elaborate networks of defenses function at many levels to protect plants from disease (Abramovitch and Martin, 2004). Elucidation of these defense pathways has recently become a par ticularly active area of research in plant molecular biology, and has led to our growing appreciation for the complex interplay between basal defenses and specific disease resistance (Feys and Parker, 2000). A major contribu tor to disease susceptibility is the reliance of industrial-scale agriculture on monocultures. Cultivation of plant lines bred for resistance to one or a few pathogens, often conferred by so-called R genes, can lead to the emergence of pathogens that have undergone natural selection to overcome the resis tance (Gurr and Rushton, 2005). Despite the potentially short-sighted na ture of such agricultural practices, identification of R genes has been the focus of considerable effort over the past decade (Baker et al. At least one such gene, the Bs2 gene from pepper, has been used successfully to engineer durable resistance to the agronomically significant bacterial spot disease in tomato (Tai et al. The Xa21 re sistance gene from rice, which provides wide-spectrum resistance to the devasting bacterial blight caused by Xanthomonas oryzae pathovar oryzae, has been introduced into a variety of rice cultivars using Agrobacterium mediated gene delivery (Wang et al. Likewise, broad spectrum re sistance to potato late blight is conferred by one of four R genes cloned from a wild, highly resistant, potato species (Song et al. Pyramiding of multiple R genes can confer resistance to a range of pathovars within a species. More recently, attention has shifted to the basal or non-host resistance plant defenses, which tend to target entire classes of pathogens. These pathways are generally activated in response to common patterns shared by many pathogens, such as fungal cell walls or bacterial flagellin. Elici tation of defense-related signal transduction pathways can be achieved by introduction or overexpression of receptor-like kinases (Gurr and Rushton, 2005) such as the receptor responsible for perception of the 104 Lois M. A related strategy involves engineering a plant to express a pathogen-derived elicitor of specific or basal defense responses (Keller et al. In this case, limiting the expression to sites of infection using pathogen-inducible promoters (Rushton, 2002) is essential, since constitutive activation of de fense pathways can lead to reductions in plant health and even cell death (Gurr and Rushton, 2005). Generic plant defenses include antimicrobial compounds such as de fensins and chitinases. Ectopic expression of plant-derived or synthetic an timicrobial peptides in transgenic potatoes provides robust resistance to bacterial and fungal pathogens (Gao et al. A variety of antibacterial proteins from sources other than plants have been used to confer resistance to bacterial diseases in several transgenic plants (reviewed in Mourgues et al. Arabidopsis plants expressing antifungal peptides fused to a pathogen specific recombinant antibody derived from chicken exhibited resistance to the fungal pathogen (Peschen et al. Finally, plant-derived defense molecules including proteinase inhibitors (Urwin et al. A third approach to engineering enhanced disease resistance takes ad vantage of the rapid expansion in our understanding of the pathways downstream of the initial pathogen perception events. Here, targets for ge netic manipulation include master-switch transcriptional regulators, par ticularly those that activate local or global resistance networks involving salicylic acid, jasmonate, pathogenesis-related proteins, and the systemic acquired resistance that primes defenses in uninfected areas of the plant (Gurr and Rushton, 2005). Plants engineered to produce ele vated levels of salicylic acid also exhibit enhanced disease resistance (Verberne et al. Finally, appreciation for the involvement of the iron-binding protein ferritin in the oxidative stress response and the central role of oxidative stress in plant defense responses led to the successful demonstration that ectopic expression of ferritin can enhance tolerance to viral and fungal pathogens (Deak et al. Given the explosion in knowledge of plant defense mechanisms over the past decade, as well as the continued reliance on approaches to industrial-scale cultivation that Agrobacterium and Plant Biotechnology 105 foment rampant pathogen spread, genetic engineering for disease resis tance promises to be a very active area of research in the near future. The quest to engineer virus resistance in plants stems from the proposal that expression of pathogen-derived genes within a plant can induce resis tance to the pathogen in question (Sanford and Johnston, 1985). The first successful validation of this concept was the creation of tobacco mosaic vi rus-resistant tobacco plants producing the virus coat protein (Powell-Abel et al. A multitude of virus-resistant plants have since been devel oped using the same strategy (reviewed in Lomonossoff, 1995 and Wilson, 1993). A markedly effective implementation of coat protein-mediated pro tection was instrumental in saving the Hawaiian papaya crop from the pa paya ringspot virus; the transgenic papaya has been commercialized and efforts are underway to transfer the technology to developing countries, which produce 98% of the worlds papaya crop (Gonsalves, 1998). Al though this particular application made use of particle bombardment rather than Agrobacterium to deliver the transgene, it serves as a convincing il lustration of the potential for achieving virus resistance in other highly susceptible crops. Production of viral proteins generally provides moderate levels of pro tection to a relatively broad spectrum of related viruses (Lomonossoff, 1995). In several cases, Agrobacterium-mediated expression of a viral rep licase gene (Baulcombe, 1994) or virus movement proteins. Unexpectedly, a number of researchers discovered that in some in stances, levels of resistance did not correlate with the amount of foreign protein produced; furthermore, translationally defective genes could also provide protection (reviewed in Lomonossoff, 1995). These observa tions coincided roughly with the initial reports of cosuppression (see section 2. In several instances, introduction of a defective or truncated protein-coding sequence has proven more effective than expres sion of an intact, functional version in inducing resistance (Uhrig, 2003). Furthermore, virus resistance achieved in the lab does not always translate into the field, where added environmental stresses compound the plants susceptibility (Wilson, 1993). This presents a potential problem for the use of silencing-based virus resistance in the field, where a secondary infection with a suppressor-carrying virus could allow the targeted virus to overcome the engineered resistance. Some at tempts to stack viral genes have been successful in achieving resistance to multiple, related, viruses (Prins et al. These observations suggest that virus-derived suppression of transgene expression, attributable to transcriptional or post transcriptional gene silencing, may prove to be a significant limitation in maintaining engineered traits in a field setting. The rationale is that these crops allow farmers to eliminate weeds with one broad-spectrum, somewhat less toxic, herbicide without damaging the crop. Banta and Maywa Montenegro genes encoding enzymes that are not susceptible to the action of the herbi cide (Comai et al. In addition, the bacterial bar gene product provides resistance to glufosinate ammonium by detoxifying it (De Block et al. The most widely planted herbicide-resistant crop plant is Monsantos Round Up Ready soybean; other glyphosate-resistant crops include maize, canola, oilseed rape, sugarbeet, tobacco, and cotton (Nottingham, 1998). Although many herbicide-resistant crops were initially developed using Agrobacte rium-mediated gene delivery, the current method of choice is particle bombardment. For this reason, these plants will not be discussed further here; the reader is referred to Nottingham (1998) for a more complete dis cussion of the private sector interests responsible for the development of these crops. By far the most widely used insect resistance traits are conferred by the cry genes, encod ing toxins derived from the soil bacterium Bacillus thuringiensis. Several different Bt toxin gene products have slightly different modes of action and target different orders of insects, but the general strategy is similar: the crystalline toxins bind to the membrane of the larval gut and prevent nutri ent uptake (Nottingham, 1998). Bt toxins are considered particularly at tractive because of their high specificity, biodegradable nature, and lack of toxicity for humans and other non-target animals. Agrobacterium was first used to introduce a Bt gene into tobacco and tomato in 1987 (Vaeck et al. The most widely planted Bt crops include maize (resistant to the European corn borer and/or southern corn rootworm), cotton (resistant to the cotton boll worm and the tobacco budworm), and potato (target pest is the Colorado potato beetle) (Shelton et al. Several other Bt crops, including ca nola, soybean, tomato, apple, peanuts, and broccoli are under development (Bates et al. A substantial body of literature exists on the economic impact of Bt crops in industrial and developing countries [see, for example, Morse et al. It should be noted that yield increases due to genetic modifications such as Bt transgenes are likely to be much higher in developing countries than in industrialized Agrobacterium and Plant Biotechnology 109 nations; this difference is attributable to high pest pressure, and low avail ability/adoption of chemical alternatives in areas such as south/southeast Asia and Africa, where farmers cannot afford chemical inputs (Qaim and Zilberman, 2003). In a clear validation of the original rationale for insecti cide-producing transgenic crops, Huang et al. Similar decreases in the use of pesticides have also been reported among farmers planting Bt cotton in India (Qaim and Zil berman, 2003). At the same time, effects such as the long-term regional declines in the pink bollworm population density attributed to the planting of Bt cotton (Carriere et al. Concern about the emergence of insect re sistance to Bt has led to a variety of insect resistance management strate gies including regulation of the toxin dosage, mandated planting of refuge regions, and temporal or tissue-specific toxin expression (Bates et al. Pyramiding two or more Bt toxin genes in the same transgenic plant has been demonstrated to delay the evolution of resistance (Zhao et al. However, selection for resistance will continue to occur even in plants with pyramided resistance genes as long as the transgenes are also used singly in other varieties; Pink and Puddephat (1999) have argued in stead for plant multilines that are heterogeneous with respect to the resis tance genes they carry, with the composition of the mixture commensurate with the frequency of the corresponding virulence alleles in the pathogen population. Additional non-Bt proteins that target non-Bt receptors under development include the Vip3A toxin (Moar, 2002) and toxin A from the bacterium Photorabdus luminescens (Liu et al. Other classes of in secticidal proteins are the protease inhibitors, produced by a wide variety of plants to inhibit animal or microbial digestive enzymes, and plant derived lectins (Nottingham, 1998). Agrobacterium-mediated introduction of the cowpea trypsin inhibitor gene has been shown to provide tobacco with increased resistance to the tobacco budworm (Hilder et al. Pyramiding cry genes with genes en coding lectins and/or protease inhibitors is an active area of research in many crops of import to developing world agriculture (see, for example, the report from the Indo-Swiss Collaboration in Biotechnology at iscb. In some cases, the goal is to improve nutritional value by removing naturally occurring, but harmful, substances. Perhaps the best-known cases are the toxic cyanogens found in the important staple food cassava. Labor-intensive processing is required to remove these cyanide precursors, which pose particular risks to indi viduals with protein-poor diets, from the tubers. By blocking the synthesis of the cyanogen precursors with antisense constructs, Siritunga and Sayre (2003) achieved a 99% reduction in root cyanogen levels, even though the Agrobacterium-mediated transgenic modification targeted the leaf-based biosynthetic pathway. More frequently, however, nutritional enhancement entails increasing the content of relatively rare constituents and/or creating a more balanced amino acid complement. Rice, for example, is a staple crop for over half the worlds population (Wang et al. The gene encoding a non-allergenic seed al bumin protein with a well-balanced amino acid content was introduced into potato (Chakraborty et al. Transgene-driven biosynthesis of naturally occurring or modified sulfur-rich proteins has been achieved in canola (Altenbach et al. Quantity and quality of starch are other targets of food-crop engineering (Slattery et al. Successful production of health promoting very long chain polyunsaturated (including omega-3) fatty acids in oilseed crops has recently been reported (Wu et al. Although accumulation of the desirable fatty acids in linseed is limited by the avail ability of biosynthetic intermediates, alternative strategies, including engi neering fatty acid production in green vegetables, have been proposed (Abbadi et al. If successful, such genetic modifications hold prom ise as a sustainable alternative to fish, which are prone to problems includ ing dwindling stocks and contamination with heavy metals and other pollutants (Qi et al. Agrobacterium and Plant Biotechnology 111 As might have been predicted from their roles in cancer prevention, in promoting immunity, and in slowing the progression of several degenera tive human diseases (Shintani and DellaPenna, 1998), augmentation of anti-oxidant levels in plants has been another attractive goal of food crop engineering. Biosynthesis of one such group of essential antioxidants, Vitamin E (Sattler et al. Production of other potent anti-oxidants in cluding lycopene has been increased through transgenic overexpression of relevant enzymes in tomatoes (Muir et al. Mineral fortification of crop plants through genetic alteration or selec tion has been envisioned as a way to address dramatic global dietary defi ciencies in iron, zinc, iodine, selenium and several other essential minerals. In the initial phase of this initiative, six crops (beans, cassava, maize, rice, sweet potato and wheat) are being targeted; an additional 11 subsistence crops will be added in phase 2. Transgenic approaches to increase bioavailability have targeted mineral uptake, transport to edible tissues, and augmented levels of organic compounds, including ascorbate and beta-carotene, that promote mineral absorption in humans (White and Broadley, 2005). Expression of the soybean iron storage protein ferritin in rice, for example, resulted in a three-fold rise in seed iron content (Goto et al. Alternative strategies include engineering plants to express phytase, thereby removing a key impediment in most animals to mineral uptake (Brinch-Pedersen et al. Beta-carotene and other carote noids are synthesized in plants from phytoene, and introduction of a phytoene synthase or desaturase from bacteria dramatically increased flux 112 Lois M. Banta and Maywa Montenegro through the carotenoid pathway in canola (Shewmaker et al. Vitamin A deficiency is a sig nificant health problem in much of the developing world, leading to an es timated 2 million deaths and 250,000 cases of childhood blindness each year (Ye et al. A public sector initiative to engineer the beta carotene biosynthetic pathway into rice endosperm resulted in the devel opment of golden rice in 1999. All three encoded enzymes car ried transit peptides targeting them to the plastid, the natural site of synthe sis of the phytoene precursor geranylgeranyl diphosphate (Ye et al.

Most propose and explain long-term management strategies patients with asthma have rhinitis anxiety disorder test order genuine sinequan, suggesting the concept to patients anxiety upper back pain purchase 25mg sinequan with amex, health care policy makers and government of one airway anxiety symptoms of going crazy buy sinequan with a visa, one disease anxiety job interview discount sinequan 10 mg online, although there are underlying authorities anxiety symptoms numbness in face purchase sinequan 25mg fast delivery. Introductionthe socio-economic consequence and impact of allergiesthe prevalence of allergic diseases anxiety 7 scoring interpretation generic sinequan 25 mg overnight delivery. Symptom control, improvement in quality of life and socio-economic levels and is increasing around the rehabilitation to normal (or almost normal) function can be world. Studies such as the International Study of Asthma achieved through modern pharmacological treatment. Oral H1-antihistamines have beenthe treatment of allergic diseases must be a personalized shown to be safe and effective in young children. Further studies may recommend the use of resources not available in the are required to substantiate this fnding and should focus family practice setting. Goals for the treatment of rhinitis include unimpaired sleep, Anti-H1 antihistamines are effective and safe as the frst line ability to perform normal daily activities (including work/school treatment in urticaria, controlling the skin fare and itching. It has attendance), and sport/leisure activities, with no or minimal side recently been proposed that higher doses of antihistamines (up effects of drugs. The goal of asthma treatment is to achieve and to 4-fold) can help in controlling severe urticaria not responding maintain clinical control of symptoms and normal (or near to to usual doses. This clinical control includes an absencethe second generation H1-antihistamines have a rapid onset of of daytime symptoms, with no limitations of activities including action with persistence of clinical effects for at least 24 hours, exercise, no nocturnal symptoms, normal or near-normal lung so these drugs can be administered once a day. Pharmacologic lead to the development of tachyphylaxis and show a wide treatment should take into account the effcacy, safety and therapeutic window. As it is also the case cost-effectiveness of medications, the patients preferences, with bilastine a recently 2nd generation anti-1 antihistamine and the presence of co-morbidities. The following section lists the most commonly used medications Although frst-generation oral H1-antihistamines are effective, for allergic diseases: they are not recommended when second-generation drugs are H1-antihistamines: H1-blockers or H1-antihistamines are available because of their sedative and anticholinergic effects. Over the past 30 administration in reducing itching, sneezing, runny nose and years, pharmacologic research has developed new compounds nasal congestion. They can be effective generation antihistamines (there is not yet a 3rd generation of within 20 minutes of administration. Topical H1-antihistamines antihistamines) induce little or no sedation or impairment. Intranasal glucocorticosteroids are are not anti-cholinergic and have no cardiac-adverse effects. Intra-nasal H1-antihistamines do not appear to metabolism via the cytochrome P450 system and are prone improve ocular symptoms. Although cardio-toxicity is not a class effect, in the past there have been major concerns about the Glucocorticosteroids: Intranasal glucocorticosteroids are the arrhythmogenic action of terfenadine, astemizole and high most effcacious anti-infammatory medication available for the doses of diphenhydramine, which in rare instances have been treatment of allergic and non-allergic rhinitis. The rationale for Copyright 2013 World Allergy Organization 116 Pawankar, Canonica, Holgate, Lockey and Blaiss using intranasal glucocorticosteroids in the treatment of allergic Anti-leukotrienes: Leukotriene receptor antagonists or rhinitis is that high drug concentrations can be achieved at anti-leukotrienes have been introduced in the last 15 years. Due to their mechanism of action, effcacy and asthma, montelukast was found to improve nasal and appears after 7-8 hours of dosing, but maximum effcacy may bronchial symptoms. Leukotriene receptor antagonists are more are well tolerated and adverse effects are few in number, mild effective than placebo, equivalent to oral H1-antihistamines in severity and have the same incidence as placebo. However, and inferior to intranasal glucocorticosteroids for treating there are differences in safety between molecules, those with low seasonal allergic rhinitis. Leukotriene modifers can also be for moderate intermittent and persistent rhinitis, for all nasal used as add-on therapy and may reduce the dose of inhaled symptoms, ocular symptoms, polyposis and sinusitis. Inhaled glucocorticosteroids are the most effective controller medications Bronchodilators: There are two kinds of bronchodilators, currently available in asthma. They are more medication (mainly long acting beta agonists or montelukast) is effective when combined with inhaled glucocorticosteroids. This strategy is preferredthe fxed available combinations improve symptom scores; over increasing the dose of inhaled glucocorticosteroids in decrease nocturnal asthma; improve lung function; and reduce order to avoid potential adverse effects. The regular countries, but its use is limited by the risk of signifcant adverse use of rapid-acting 2-agonists in both short and long acting effects. Early oral corticosteroid therapy is also recommended formulations may lead to relative refractoriness to 2-agonists. However, they do not improve nasal short term treatment with oral glucocorticosteroids. Systemic side effects with oral decongestants can include irritability, dizziness, headache, Anticholinergics: Inhaled anticholinergics are not recommended tremor, and insomnia, as well as tachycardia and hypertension. This fact suggests that therapeutic sodium in the long term treatment of asthma is limited. New technologies have to be anti-infamatory effect is weak and they are less effective than used to enhance education and increase compliance, and socio inhaled glucocorticosteroids. Cromoglycate and nedocromil economic disparities have to be overcome, but new medications are available as intranasal or ocular preparations. Its current indication Medication to prevent the inception of new disease is for patients with severe allergic asthma who are not controlled manifestations in allergic patients would be an important way by inhaled glucocorticosteroids and it can be used in severe to reduce the burden of these diseases and, in addition, since allergic rhinitis. In some countries Omalizumab is also approved allergic diseases are chronic, medications demonstrating long for moderate asthma. Low dose sustained Organization in association with national, local and release theophylline shows some anti-infammatory effects regional scientifc societies. Intravenous and adherence of patients in respect to different treatment adrenaline must only be used when the patient is monitored approaches. Advances in allergic skin disease, anaphylaxis, particularly advantageous in children and hypersensitivity reactions to foods, drugs, and insects in 2009. Consensus statements, evidence-based medicine and guidelines in allergic diseases. Asthma management and persisting changes in the immune response to pocket reference 2008. Allergy after discontinuation and in a disease-course modifying 2007; 62: 102-112 effect (prevention of the onset of asthma and of new 10. Despite this incorrect interpretation, at the time of this publication, no product has been licensed the subcutaneous injection of pollen extracts is capable for sublingual use. From the 1960s until the end of the 1980s, (epicutaneous, intralymphatic), new indications. Copyright 2013 World Allergy Organization 120 Pawankar, Canonica, Holgate, Lockey and Blaiss Table 2. Despite the heterogeneity of the trials, leading to a weakness estimated in less than 1 event per 2 million injections, and, in the of the meta analyses, the overall effcacy of the treatment on more recent surveys (last three years), no fatality was reported. Post-marketing surveillance reported a the escalating dose phase, and relatively increased with more rate of systemic reactions of 0. The latest safe treatment, although a quantifable risk of severe (even fatal) survey conducted in Italy in more than 2,000 patients reported reactions persists. It is currently recommended that systemic a rate of systemic side effects of 4% of patients and 0. Since then, a regulated by Th2 lymphocytes that produce a distinct profle of very large number of trials have been published, 60 reviewed in cytokines. Only 5 studies provided with an immune deviation in favour of Th1 responses with an totally negative results, and 8 inconclusive results. It is hypothesized reduced medication usage ranging between 20% and 35% that these regulatory T-cells act directly to suppress allergen compared to placebo, where also the placebo groups received specifc Th2 responses. This is of relevance, since the 20% Evidence suggests important biological effects of allergen cut-off is considered the threshold for a clinically relevant effect. Some meta-analyses (Table 2) were conducted with various selection criteria such as: rhinitis only, asthma only, conjunctivitis Long-lasting and preventive effect only, and asthma plus rhinitis, both in children and adults. This long-term or carry-over effect has been of numerous trials enabled the performance of meta-analyses described in both open and controlled studies with a number restricted to only one allergen (grass or mite). The long-lasting effect has been reported analyses, still showed a signifcant clinical effect on symptoms to persist for between 3 to 6 years, and a follow-up study in and medication scores for each allergen separately. After 3 years of represented by swelling/burning/itching of mouth, tongue and follow-up, the percentage of children developing asthma was lips, plus stomach-ache, nausea/vomiting or diarrhea. Systemic side effects (asthma, Controversial Aspects and Unmet Needs Of rhinitis, urticaria, hypotension) occur in less than 5% of patients. Finally, 2 post open, controlled trial, the rate of occurrence of new sensitizations marketing surveys performed in adults and children suggested was 5. Two studies, one in adults and one in greater than that of antihistamines and leukotriene modifers. The most relevant problem is the large variability of the doses used in clinical trials. Another study has investigated the possibility of vast majority of the trials utilized a pre-coseasonal regimen but a transdermal administration of allergens prepared as patches, this cannot be immediately extrapolated to all extracts and to and encouraging results have been obtained in animal models all patients. Similarly, the usefulness of a build-up phase is still a with the needle-free delivery of allergen nonoparticles. Adjuvants are non-immunogenic substances that, when coadministered with antigens, enhance their effects. One of the most intriguing sequences-oligodeoxynucleotide) was shown to be effective. One trial of 4 recombinant grass allergens resulted in a Figure 1 signifcant decrease in seasonal symptoms and medication requirements compared to placebo treatment. However, another trial reported that the recombinant Bet v 1 allergen does not perform better than the native extract. Conclusion In the last 20 years there has been an impressive development in the feld of allergen immunotherapy. Recombinant allergens for specifc be prescribed and administered only by trained physicians. Grading local side effects of sublingual immunotherapy for respiratory allergy: Speaking the same language. Specifc immunotherapy for respiratory allergy: state of the art according to current meta-analyses. Intralymphatic allergen administration renders specifc immunotherapy faster and safer: a randomized controlled trial. Epicutaneous allergen administration as a novel method of allergen-specifc immunotherapy. Copyright 2013 World Allergy Organization 126 Pawankar, Canonica, Holgate, Lockey and Blaiss but 5-10% of them have severe disease that responds Section 4. Biological Agents poorly and another sub-set have steroid resistance or Vesselin V. Holgate There is also an emerging view that asthma is not a Disclosure of potential confict of interest: V. Dimov has single disease entity but one with varying severity, natural no relevant consulting arrangements or other conficts 2 of interest. Casale has no relevant consulting history and response to individual therapies (endotypes). A study of 53 infants with atopic eczema QbG10 plus house dust mite for 10 weeks led to improvements caused by food allergies suggested that suplatast may be useful in both asthma and rhinitis symptoms. In trials of hypereosinophilic syndrome and it is currently undergoing severe asthma, these agents failed to reveal effcacy. Sixty one subjects with refractory airway remodelling through pro-fbrotic gene expression in lung eosinophilic asthma and a history of recurrent severe fbroblasts. Although not yet published, quality of life, and lowered eosinophil counts in the blood and preliminary reports for some trials have shown relatively weak sputum. The second study included in clinical trials, and further studies are needed to evaluate the asthmatic patients with persistent sputum eosinophilia and utility of this strategy. Nine patients were assigned to receive mepolizumab (administered in fve monthly Lebrikizumab infusions of 750 mg each) and 11 patients to receive placebo. A randomized, double-blind, placebo-controlled exacerbations, lower prednisone requirements, and a decrease study of lebrikizumab included 219 adults who had asthma in sputum and blood eosinophils. Patients with high pretreatment levels of serum be screened to fnd patients with sputum eosinophil counts periostin had greater improvement in lung function with greater than 3% which limits the effectiveness to a small subset lebrikizumab than did patients with low periostin levels43. Despite a reduction in exacerbations, meaningful changes in symptoms and spirometry were generally lacking. A multicentre, double-blind, placebo-controlled trial Dupilumab in 13 countries included 621 adults with severe eosinophilic Dupilumab is fully human monoclonal antibody to the alpha asthma who were randomly assigned to receive one of three subunit of the interleukin-4 receptor that was evaluated in doses of intravenous mepolizumab (75 mg, 250 mg, or 750 52 patients with persistent, moderate-to-severe asthma and mg) or matched placebo. Patients received 13 infusions at elevated eosinophil levels who used medium-dose to high 4-week intervals.

The saying that cleanliness is next to godliness expresses a deeply rooted belief anxiety 19th century discount sinequan uk. It seems as if we cannot control our bodies or our impulses or hide the deep parts of ourselves that others manage to keep out of sight anxiety symptoms high blood pressure buy sinequan 10 mg cheap. Were we purely rational beings anxiety symptoms 4dp3dt order sinequan 10mg visa, disease would seem a bodily problem to be treated and survived anxiety 7 reasons order sinequan with paypal, no more and no less anxiety feeling order sinequan 75mg. However anxiety scale 0-10 purchase sinequan 25mg on-line, none of us are such beings: our emotions are what make us human, and shame, guilt, anger, and despair are part of the heritage. The physical toll of skin disease is bad enough and its emotional turmoil compounds the pain. Spare yourself the added burden of blame for feeling what anyone else would feel in your place. Different skin diseases carry their own brands of torment: a person with genital Find out more at. People with psoriasis and ichthyosis, which are hereditary, may rage against their parents. Pain, itching, marred appearance, and disability can provoke a deep anger against the disease and the world of "normal" people. While few people are at risk of killing themselves, a far more common danger is fractional suicide. Despairing sufferers kill off little pieces of themselves: a passion is allowed to cool; a hobby is abandoned; an opportunity for pleasure or success is ignored. Many people resigned from clubs and organizations when symptoms started, exchanging social activities for solitary pursuits, such as walking, stamp collecting, and reading. A lengthening history of unsuccessful treatments deepens this sense of hopelessness. Preexisting sexual problems, depression, and anxiety are easily lumped together as the fault of the illness, making it doubly difficult to relieve either skin symptoms or real-life problems. Less dramatically, the anxiety-disease-anxiety cycle can simply prevent symptoms from getting better. Only the most philosophical of us can hope to ride through illness without emotional turmoil. The more you learn to understand these feelings, however, the better control you can achieve over them. Anyone may suffer embarrassment when he or she must present a blemished face to the world, but a person whose self-esteem is low to begin with will endure a special distress. If your upbringing made you uncomfortable about your sexual needs, genital warts or herpes may provoke an extra dose of agony. Knowing why you suffer your larger than-life torments is the first step toward cutting them down to size. Colligan,the Healer Within:the NewMedicine of Mind and Body (New York: Dutton, 1986), for a masterful review of the area. Nakagawa, "A Psychosomatic Study of Contagious Dermatitis" Kyushu Journal of Medical Science 13 (1962): 335-350. Typically, a doctor will have positive results with a previously successfully treated patient, and a more "scientific" approach with college sophomores or other, much less interested and motivated. Hall, Clinical Hypnosis Principles and Applications (New York: Grune and Stratton, 1975); and L. Hoff, "Uberpsychogene Entstebung des Herpes Labialis", Medizinische Klinik 24 (1928): 1472. Takaishi, "Psychosomatic Studies on Chronic Urticaria," Folia Psychiatrica et Neurological Japonica 17-1 (1963): 16-24. Bettley, "Psychiatric Treatment of Eczema: A Controlled Trial," British Medical Journal (June 26, 1971): 729-734. Nadelson, "Emotional Aspects of Cutaneous Disease," in Dermatology in General Medicine, edited T. Van Keep, "The Influence of Skin Disease on Social Relationships," International Journal of Dermatology 15 (1976):446-449. It is part of a complex mind-body organism, designed above all for survival, and survival for any organism means satisfying basic needs. Skin symptoms may irritate, inconvenience, or even torment you but they are often attempts to obtain what you need, biologically and emotionally, in order to flourish. In a famous study, the French psychoanalyst Rene Spitz observed infants in an orphanage. Institutionalized babies, for one thing, are far more prone to eczema than others. Our needs are most dramatically visible in our totally dependent first years, but they persist throughout life. Just as we never outgrow our needs for food, water, and warmth, we always need three of emotional nourishment: love, respect, and protection. Love is the emotional equivalent of food, the nurturing gift of a world that supports life. We also need respect; love, food, and the rest are given as we require them, not arbitrarily or impersonally. As adults, the respect of family and friends confirms us as independent human beings who deserve recognition. We need protection from emotionally intense extremes, as well as extremes of temperature, if we are to grow and flourish. In time, just as we learn to keep ourselves comfortably warm or cool, we learn to protect ourselves against emotional overload. Even skin problems that strike previously healthy people in their later lives may have psychological roots in the long-ago days when needs were strongest. In fact, indications are that the roots of such ills may extend back before birth: infants born with allergies or eczema may be at risk from heredity or may have been subjected to unusual prenatal stress. Troubled skin is like a loyal but not very bright servant who refuses to quit until he accomplishes what he was ordered to do. One of my patients, starved of emotional nurturing as a child, carried into adulthood an insatiable need to be cared for. Her raw inflamed skin got the soothing attention her organism craved but at a high price: normal life was impossible. Try to shut it up with medications or stoic indifference and it may simply cry louder. The alternative is to give your inner self what your skin is asking for, and when that is impossible, to face the pain of frustrated needs squarely and work to resolve it directly. The first step in treating the problem under your skin is relabeling it in psychological terms. Is it trying to satisfy the primary needs of love, respect, and protection or to resolve problems that arose when these needs were frustrated long ago To start relieving your skin of its emotional burden, you must identify and understand the tasks it is laboring to accomplish. The vast majority of parents do the best they can in nurturing and protecting their children, but human beings are imperfect, and life in the world is difficult. A mother may be the victim of a poor upbringing that crippled her ability to give love. A major upheaval (death in the family or abandonment, perhaps) may deny the baby adequate love and protection. Many families are so impoverished that the struggle for bread makes proper nurturing impossible. A failure to satisfy these early needs leaves an emptiness within: a voracious emptiness, in fact; an emotional black hole that absorbs all the love, respect, and protection we get later and that cries insatiably for more. We keep on trying to fill this emptiness with misguided attempts at self-feeding Find out more at. The alcoholic and the drug addict are mired in a doomed and destructive attempt at self feeding. They require the chemical illusions of love, protection, and respect because they still suffer from an early deprivation of the real thing. Her mother, emotionally devastated herself, simply could not provide her baby with sufficient love and nurturing. Lacking the words to express her needs, the infant Joan let her skin do the talking: severe infantile eczema gave voice to her pain and loneliness. The adult Joan, married and a mother, remained plagued by troubled skin, which continued to cry out for the love and attention absent from her earliest years. Being in the hospital for Joan meant a return to childhood: she was exempted from the demands and responsibilities of daily life and was mothered by nurses who bathed and comforted her tormented skin. Even lesser episodes treated at home enabled Joan to self mother her skin with cortisone creams and special baths. At an extreme is the parent who beats his child, giving him much to be angry about while intimidating him into denying his anger. Instead of feeling our anger and expressing it as directly as possible (recognizing our rage at an unfair boss without punching him in the nose), we often suppress it or turn it inward. The "passive-aggressive" person means to feel no anger at all but has developed the sophisticated ability to arouse it in others. He satisfies his need to vent anger by provocative behavior that infuriates; not only does this strike out more effectively Find out more at. Unfelt, unexpressed anger is the most common psychological mechanism beneath troubled skin. Alternatively, the skin becomes the voice of anger that the child within the adult was forbidden to express. They had appeared mysteriously, had worsened inexorably, and seemed determined to stay. His parents were responsible and dutiful, but they both had to work, leaving the task of caring for him and his four brothers and sisters to Grandma, an efficient but undemonstrative woman. The last year, he admitted, had been difficult: his neighborhood buddies had departed, one after another, for the army, for jobs elsewhere, for marriage. He had enjoyed his job until he was arbitrarily shifted to another part of the plant six months ago. Instead, anger was turned inward, where George himself would suffer but do harm to no one else. When his hands could strike out legitimately, his skin no longer had the task of expressing his rage. From our earliest days, we must be acknowledged as independent beings, not mere extensions of our parents. Our own selfhood must be respected and the boundary that sets us off from the rest of the world must be recognized. When parents give love and attention on their own schedule, according to their own needs, they withhold this respect. The father who arranges every detail with the injunction that "father knows best" is doing the same thing: refusing to respect the autonomy of his child. The stubbornly independent child who digs in her heels and automatically says no Find out more at. She fights to secure the boundaries of herself, to protect the basic integrity of her soul. People not given respect as children may spend their later lives turning the tables on the world. Others develop a repertoire of ways for getting others to do what they want indirectly and often are labeled manipulative. This pejorative term is unfair because it ignores the underlying struggle to maintain integrity as an autonomous human being. In the effort to control the world around them, they may employ argumentative verbal arts and such indirect arm twisting as flirtatiousness, intimidation, or guilt. She was a fragile woman who loved her son but had found it hard to cope with his independence and kept a tight rein on his behavior. As his mother had ruled his childhood, Peter tried unconsciously to control the adult world with his allergies. He remains rather controlling verbally, but his sense of humor about it makes him easier to live with. The ability to temper and postpone our urges is one thing that distinguishes humans from lower animals. The internal policeman that restrains us from grabbing immediate gratification (what Freud called the "superego") can grow so strong that it forbids the satisfaction of perfectly legitimate needs and desires. The conflict may also be played out in the body, where the skin plays policeman to the "criminal" heart. A major skin problem is an effective turnoff, a flag that says, "Count me out sexually. He maintained a dispassionate, cool posture toward his life; his relationship with his live-in lover was best described as "slightly committed.

Cheap 10 mg sinequan with visa. How to Overcome Test Anxiety.

Cooling should be accomplished salads anxiety x rays cheap 10 mg sinequan visa, should be treated so as to as quickly as possible by the use Transporting containers and vehi minimize its bacterial content by of an ice water bath anxiety symptoms early pregnancy order sinequan now, fans anxiety nos icd 10 cheap sinequan 25 mg line, refrig cles should be clean and of sani immersing the chopped celery in eration anxiety symptoms 247 generic sinequan 10mg on line, etc anxiety natural treatment purchase discount sinequan on-line. The mixing opera Contact of ready-to-eat foods tion is to be completed as quickly as tures and conditions anxiety symptoms for hours buy sinequan 25 mg low price. Food Processing Techniques for Do not place packing cases and Specific Types of Service cans on food work surfaces. Additional Instructions for Displayed Food Specific Salads When it is necessary to taste (Buffet, Smorgasbord, etc. Fast chilling and utensils (pots, pans, spoons, can be accomplished by the same spatula, etc. Stainless steel utensils and from Steam-tables or Warming equipment are preferred in prepara Devices tion of these foods. Schedule the cooking of meats so 3) Clean hands, fingernails, and they will be completed as close as arms thoroughly with soap and hot possible to desired time of service. However, it is at ingredient: using shellfish from neered by the Pillsbury Company in the steps that are determined to be unapproved source or meat and the 1960s. During this period, the critical control points that some meat products from uninspected space program was escalating and action must be taken. Some Frequently Found Hazards tainers: storing barbecue sauce in this system involves following Microorganisms are allowed to grow by: galvanized containers. Not only the ingredients are studied Microorganisms, chemicals and foreign but the analysis includes the avail 3) Institute control measures matter are allowed to contaminate food by: able equipment, personnel and the and devise criteria to establish population to be served. Failure to do allowed to work while suffering this is also called the critical limit. The fourth step is to monitor depending on the food ingredients, Cross-contamination: allowing what is being done at each critical method of preparation and whether ready-to-eat foods to come into control point to determine whether it is a hot or cold food. In every contact with raw foods or conta the hazards are controlled by the food preparation process, some minated equipment. The sixth step is to review the of Health and Mental Hygiene are system to ensure that it is working,the following diagrams illustrate familiar with this food safety system that hazards are identified, correc the process generally involved in the and are willing to provide guidance. If potentially hazardous foods are left in the Temperature Danger Zone for more than two hours, what corrective action should be taken When making cold salads such as tuna, it is recommended that ingredients be pre-chilled. Storage Insufficient refrigeration space No Check food and Place thermometer in Provide more refrigeration Improper equipment temperature refrigerator refrigerated equipment space and efficient units Raw stored over cooked temperatures Check food temperature Discard food if temp. Another good reason sanitation helps manage flies is that fourth stage larva typically est control is a major concern Flies: Life cycle leave their breeding area and move Pfor the operator of a food ser-the life cycle of a house fly con away to some distance before they vice establishment. Therefore, Flies the females can be seen in clusters frequent and thorough cleaning isthe flying insects in the restau of up to 50 individuals. The female an extremely important fly manage rant industry include the house fly house fly lays individual eggs that ment tool. The house fly poses pile up in masses of 75 to 150 eggs; the gravest risk to food safety among in her lifetime, a single female Flies: Control all of the pests. Screen house flies are categorized as patho In warm weather, the white pupae windows, roof vents and other genic or disease-causing flies, (or maggots) emerge from their eggs openings with 18 mesh screens. They of any buildup that can attract or Since flies cannot chew the food, have been known to travel over 100 provide breeding grounds. We must they re-gurgitate or throw-up on feet to locate a suitable place to recognize the importance of humid the food to dissolve or soften it pupate. The pupa transforms into ity and warm temperatures for flies before eating again. Ensuring that there are no an adult in as little as 3 days or as that one live fly may carry as many damp areas in a food facility, and long as 5 weeks. This pupation as 28 million bacteria on its body improving drainage will often aid period varies with temperature and alone, and another 5 million inside. Since the filth fly can travel to all areas especially clogged drains, can pro of a food establishment relatively vide an excellent damp environ Flies: Habitat quickly and easily, it has the poten ment for the flies to breed in. The House flies prefer decaying tial to contaminate many foods, fly breeding areas can be eliminated organic materials, such as garbage, food areas and food contact surfaces. Traps can be an addi are the most basic and critical step tional management tool to pre to managing these pests as this will vent solitary flies from wandering decrease food and breeding sites. Both cles need regular washing as flies kinds of traps use ultra violet may find ample breeding media light to attract flies. When placed and piles where fruits and vegetables are the bottom of the trap (fly catcher). Fruit fly larvae living inthe use of fly zappers in a food ing insects, these can also be fruit which is eaten can cause establishment is a very high risk effective in keeping out dust and intestinal discomfort and diarrhea. The use of fly catcher on effective in the long term elimina measure about 1/8 inch in the other hands is relatively safe tion of this annoying pest. The red eyes of the fruit fly as the flies are merely stunned and removing the breeding areas, taking are key identifying characteristics. Roaches carry disease when fruits and vegetables are inside, install them so that they causing bacteria on their bodies and improperly stored or allowed to cannot be seen from the outside. Garbage that contains fruit If the flies can see these traps their excreta and body contact. They peels also will be a frequent target from outside, theyll be automati have been linked to allergies in humans of these flies. Roach sonous fly baits can be extremely Some of the obvious places to check dust is a very strong asthma trigger. Although these are able to rapidly include garbage cans, underneath kill a large number of flies, their and behind low laying kitchen German cockroach effectiveness may be short-lived. These tiny Cover food contact surfaces before spaces can harbor thousands of fly application. All small cracks and crevices may have to be cleaned prior to at floor level need to be inspected facility start up. Air curtains, depend Once, one of the breeding ing on the season, are simply a sources has been located, continue blast of steady cold or hot air that to look for more. Fruit flies easily flows from a device installed above follow air currents and usually have doorways. Originally designed to several breeding places in any struc cut down on energy costs, these ture. Young roaches are days, and nymphs develop in 40 to sion of a food establishment with wingless and nearly black with a 125 days. Female roaches live about insects, especially roaches that may single light stripe running down the 200 days, with males living not come from an adjoining building or middle of the back, and the adults quite as long. The emphasis must be placed on are light tan in color and usually American Cockroach elimination of harborage and breed yield about 36 baby cockroaches. Adult American cockroaches are 1 ing places within the establishment and 1/2 inches long (38mm), mak German cockroaches are the most as well as extermination. Most cockroaches walls and ceilings should be elimi brown, fully developed wings, the have a flattened, oval shape, spiny nated by filling with cement, plaster, American cockroaches have a yel legs, and long, filamentous anten putty or plastic wood. Immature roaches are smaller, tures and equipment should receive body region behind the head. Immature cock kinds and may hitchhike into the placed flush against the wall and roaches resemble adults except that food service establishments on egg floor; if not, then a sufficient dis they are wingless. In food establishments, these generally develop their population stagnant water, should be eliminat cockroaches live in basements, around in kitchens and bathrooms. Garbage should be kept in tight pipes and sewers, and may move the day, these roaches may be found ly covered metal cans, and the cans outdoors into yards during warm hiding behind baseboard moldings, should be thoroughly cleaned after weather. The room, in which common in basements, crawl spaces, or pantries, and in and under stoves, garbage is kept, prior to removal, cracks and crevices of porches, microwave ovens, refrigerators, dish should be constructed of impervi foundations, and walkways adjacent washers, and other restaurant equip ous washable material, preferably to buildings. The presence of German cement, and should have facilities to ness for sewers, large populations of roaches during the daytime is usually wash garbage cans. If this room can American cockroaches will be seen an indication of a severe roach be refrigerated, the cold temperature in many cities after heavy rains or infestation. Due to the large size and very near to the food and water and odors from decomposing slow development of American source. The food establish during certain times of the year, their abdomen until the eggs are ment and equipment therein should these cockroaches may move inside about to hatch. During the last three be completely cleaned each night food establishments from outside or four days prior to dropping her before closing, not only for good sources. For example, in winter egg case, the female German cock sanitation, but to remove all grease, these cockroaches may move roach does not seek any food or food encrustation, and food particles indoors, seeking warmer tempera water. Cockroaches may secluded location, with the nymphs In addition, roaches can be enter food establishment through emerging sometimes within the destroyed with effective insecticides sewer connections, under doors, hour or as long as a week. A female applied by a licensed pest control around utility pipes, air ducts, or may produce four to six cases dur operator. Operators of food burrows can usually be found in remain in and around the food service establishments must ensure parks or near vegetation, under establishments and yards which pro that the establishment remains free buildings and other structures, vide their necessities, and unless of pests and must use the methods beneath concrete slabs, along stream they are disturbed, they do not described in the sections above to banks, in garbage dumps, and at move to greater distances. Additionally, other locations where suitable food, they may use glue traps and baited water, and shelter are present. However, they may not use They may also make their burrows Norway rats can and will eat pretty chemical pesticides of any kind in beneath sidewalks and along the much any food. Additionally, a choice, they select a nutritionally possess certification as a commercial an unkempt open space with clutter balanced diet. This applies even to may also encourage rats to make Their preferable diet includes aerosol cans of pesticides, available their burrows. The water require Cockroaches, particularly Germanthe rat burrows are typically ment, however, is dependant on the cockroaches, have been identified as located within 25 to 125 feet radius type of food being consumed. There are close to a dozen proteins linked to cast skins, droppings or frass or whole bodies that can cause allergies in humans. One study showed that 40 60% of people with asthma also have a serious allergy to cockroaches. Norway Ratthe Norway rat (rattus norvegi cus), the most common rodent in New York City, is a burrowing mammal. A burrow is a hole or tun nel dug into the ground by the rodent to create a space suitable for habitation. This small mammal is not indigenous to the United States, but is believed to have come on the ships from Central Asia around 1700s. Their fur is coarse and the upper body is usu ally brownish or reddish-gray, while the belly is whitish-gray. They can easily urinates over 100 times a night and House Mouse: Habitat detect stale and contaminated each micro droplet of urine con-the house mouse lives in and foods, and often choose fresh items tains various markers or messages. In this manner, the Norway rats, homes, as well as in any cluttered Tip: Pay close attention to garbage relying on their sense of smell, can locations. They are capable of living as it offers a very balanced diet and recognize pathways, locate foods outdoors, however; they must seek also satisfies their water needs. In captivity, they may live members of their own colonies and although may eat a variety of differ for up to 3 years. These are very curious gestation is roughly 21 to 22 days Norway rats use hearing to locate mammals and are not hesitant to and litters of 8 to 12 pups are born. They are considered nibblers can eat solid food when theyre 2 to with their touch sensitivity can pin as they nibble on every food in their 3 weeks old. They become com point the location of the object to path, thus leading to the contami pletely independent at about 3 to 4 within six inches. Norway rats have nation and destruction of many food weeks and become sexually active at a highly developed sense of touch items. Their mon to see them foraging during has 4 to 7 litters per year and may movement in an area relies heavily the day time. Their appearance during reproduce as many as 60 to 70 or on their senses of touch and smell the day time does not necessarily more offspring annually. Like the though most of these pups will not learned by exploration and knowl rats, mice also have poor eyesight, survive, but on average, about 20 or edge of its terrain. Like most rodents, Norway rats also like to rub their bodies against When shelter inside the food are nocturnal. They usually become a wall when moving from one loca establishment becomes scarce, house active at night, when they start tion to another.