The opportunistic human pathogen Pseudomonas aeruginosa exhibits great resistance to antibiotics; so, new therapeutic agents are urgently needed. Since polyamines levels are incremented in infected ...tissues, we explored whether the formation of a toxic aldehyde in polyamines degradation can be exploited in combating infection. We cloned the gene encoding the only aminoaldehyde dehydrogenase involved in P. aeruginosa polyamines‐degradation routes, PaPauC, overexpressed this enzyme, and found that it oxidizes 3‐aminopropionaldehyde (APAL) and 3‐glutamyl‐3‐aminopropionaldehyde (GluAPAL) − produced in spermine (Spm), spermidine (Spd), and diaminopropane (Dap) degradation, as well as 4‐aminobutyraldehyde (ABAL) and 4‐glutamyl‐4‐aminobutyraldehyde (GluABAL) − formed in putrescine (Put) degradation. As the catalytic efficiency of PaPauC with APAL was 30‐times lower than with GluAPAL, and GluAPAL is predominantly formed, APAL will be poorly oxidized ‘in vivo’. We found polyamines‐induced increases in the PaPauC activity of cell crude‐extracts and in the expression of the PapauC gene that were diminished by glucose. Spm, Spd, or Dap, but not Put, were toxic to P. aeruginosa even in the presence of other carbon and nitrogen sources, particularly to a strain with the PapauC gene disrupted. APAL, but not GluAPAL, was highly toxic even to wild‐type cells, suggesting that its accumulation, particularly in the absence of, or low, PaPauC activity is responsible for the toxicity of Spm, Spd, and Dap. Our results shed light on the toxicity mechanism of these three polyamines and strongly support the critical role of PaPauC in this toxicity. Thus, PaPauC emerges as a novel potential drug target whose inhibition might help in combating infection by this important pathogen.
In Pseudomonas aeruginosa, spermine (Spm), spermidine (Spd), and diaminopropane (Dap) degradation produces the highly toxic 3‐aminopropionaldehyde (APAL) and its non‐toxic, glutamylated form (GluAPAL). Both are oxidized by the aminoaldehyde dehydrogenase PaPauC, which has a preference for GluAPAL over APAL. PaPauC inhibition causes the build‐up of APAL, leading to important increases in Spm, Spd, and Dap toxicity. Thus, PaPauC emerges as a novel potential drug target against P. aeruginosa infections.
Allergen immunotherapy (AIT) is a safe, effective treatment for allergic rhinoconjunctivitis and allergic asthma. However, AIT's clinical effect is still contested—primarily due to heterogeneity in ...clinical trial designs, study populations, therapeutic formulations, and efficacy criteria. After discussing current concepts and unmet needs, an international panel of experts made several recommendations: (i) explore and validate definitions for (clinical) responders in AIT trials; (ii) use of well‐documented, standardized provocation tests prior to inclusion of subjects with relevant diseases in AIT trials; (iii) monitoring neo‐sensitizations and occurrence of new allergy in extended AIT trials, and exclusion of polyallergic participants; (iv) validation of allergen exposure chambers with regard to natural exposure; (v) in studies of seasonal allergies, focus on peak exposure but also consider organizing two parallel, geographically distinct but otherwise identical trials; (vi) discuss adaptive trial designs with the regulatory authorities; (vii) use e‐health and m‐health technologies to capture more information on individual exposure to allergens; (viii) initiate research on potential psychological, biochemical, immune, neural, and even genomic markers of the placebo response; (ix) identify trial designs and primary endpoints that will give children with allergies easier, faster access to AIT formulations; and (x) promote and apply standardized methods for reporting systemic and local adverse events. The latest technologies and trial designs may provide novel, ethical ways of reducing bias and heterogeneity in AIT clinical trials. There is scope for physicians, patient organizations, companies, and regulators to improve clinical trials in AIT and, ultimately, to provide patients with better treatments.
Food allergy (FA) is an important atopic disease although its precise burden is unclear. This systematic review aimed to provide recent, up‐to‐date data on the incidence, prevalence, time trends, and ...risk and prognostic factors for FA in Europe. We searched four electronic databases, covering studies published from 1 January 2000 to 30 September 2012. Two independent reviewers appraised the studies and qualified the risk of bias using the Critical Appraisal Skills Programme tool. Seventy‐five eligible articles (comprising 56 primary studies) were included in a narrative synthesis, and 30 studies in a random‐effects meta‐analysis. Most of the studies were graded as at moderate risk of bias. The pooled lifetime and point prevalence of self‐reported FA were 17.3% (95% CI: 17.0–17.6) and 5.9% (95% CI: 5.7–6.1), respectively. The point prevalence of sensitization to ≥1 food as assessed by specific IgE was 10.1% (95% CI: 9.4–10.8) and skin prick test 2.7% (95% CI: 2.4–3.0), food challenge positivity 0.9% (95% CI: 0.8–1.1). While the incidence of FA appeared stable over time, there was some evidence that the prevalence may be increasing. There were no consistent risk or prognostic factors for the development or resolution of FA identified, but sex, age, country of residence, familial atopic history, and the presence of other allergic diseases seem to be important. Food allergy is a significant clinical problem in Europe. The evidence base in this area would benefit from additional studies using standardized, rigorous methodology; data are particularly required from Eastern and Southern Europe.
Background
Occurrence, elicitors and treatment of severe allergic reactions are recognized and reported differently between countries. We aimed to collect standardized data throughout Europe on ...anaphylaxis referred for diagnosis and counselling.
Methods
Tertiary allergy, dermatology and paediatric units in 10 European countries took part in this pilot phase of the first European Anaphylaxis Registry, from June 2011 to March 2014. An online questionnaire was used to collect data on severe allergic reactions based on the medical history and diagnostics.
Results
Fifty‐nine centres reported 3333 cases of anaphylaxis, with 26.7% below 18 years of age. Allergic reactions were mainly caused by food (children and adults 64.9% and 20.2%, respectively) and insect venom (20.2% and 48.2%) and less often by drugs (4.8% and 22.4%). Most reactions occurred within 30 min of exposure (80.5%); a delay of 4+ hours was mainly seen in drug anaphylaxis (6.7%). Symptom patterns differed by elicitor, with the skin being affected most often (84.1%). A previous, usually milder reaction to the same allergen was reported by 34.2%. The mainstay of first‐line treatment by professionals included corticoids (60.4%) and antihistamines (52.8%). Only 13.7% of lay‐ or self‐treated reactions to food and 27.6% of insect anaphylaxis received on‐site adrenaline.
Conclusion
This pilot phase of a pan‐European registry for severe allergic reactions provides for the first time data on anaphylaxis throughout Europe, demonstrates its potential functionality and allows a comparison of symptom patterns, elicitors and treatment habits between referral centres and countries.
Allergic rhinitis and asthma constitute two clinical expressions of a single‐condition, respiratory allergy. Allergen immunotherapy (AIT) is a form of treatment specifically aimed at modifying the ...response to sensitizing allergens. The inherent potential benefit of AIT is the simultaneous treatment of all clinical expressions of respiratory allergy. Current data support the effectiveness of subcutaneous and sublingual immunotherapy in rhinitis. Studies also provide proof for a beneficial effect in allergic asthma. Even more, substantial evidence points to the preventive effect on the progression from rhinitis to asthma. Despite the current knowledge on the basic mechanisms underlying the immunological effect of AIT is vast, the specific mechanisms for the preventive effect of primary sensitization or new sensitizations are poorly understood. This review aimed to provide a critical overview of the current knowledge on the effectiveness of AIT and its potential role in secondary prevention of respiratory allergy progression.
Background
Anaphylaxis is an acute, potentially fatal, multi‐organ system, allergic reaction caused by the release of chemical mediators from mast cells and basophils. Uncertainty exists around ...epidemiological measures of incidence and prevalence, risk factors, risk of recurrence, and death due to anaphylaxis. This systematic review aimed to (1) understand and describe the epidemiology of anaphylaxis and (2) describe how these characteristics vary by person, place, and time.
Methods
Using a highly sensitive search strategy, we identified systematic reviews of epidemiological studies, descriptive and analytical epidemiological investigations, and studies involving analysis of routine data.
Results
Our searches identified a total of 5 843 potentially eligible studies, of which 49 satisfied our inclusion criteria. Of these, three were suitable for pooled estimates of prevalence. The incidence rates for all‐cause anaphylaxis ranged from 1.5 to 7.9 per 100 000 person‐years. These data indicated that an estimated 0.3% (95% CI 0.1–0.5) of the population experience anaphylaxis at some point in their lives. Food, drugs, stinging insects, and latex were the most commonly identified triggers.
Conclusions
Anaphylaxis is a common problem, affecting an estimated 1 in 300 of the European population at some time in their lives. Future research needs to focus on better understanding of the trends across Europe and identifying those most likely to experience fatal reactions.
The Future of the Allergists and Specific Immunotherapy (FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review ...developments in the field of allergen immunotherapy (AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future.
Co-factor-enhanced food allergy Cardona, V.; Luengo, O.; Garriga, T. ...
Allergy (Copenhagen),
October 2012, Letnik:
67, Številka:
10
Journal Article
Recenzirano
Background
Alcohol, exercise or non‐steroidal anti‐inflamatory drugs (NSAID) are frequently mentioned as amplifiers of food allergic reactions but only individual cases or small series have been ...previously published.
Methods
Descriptive study including 74 cases of suspected co‐factor enhanced food allergy, assessed by skin‐prick tests, specific IgE and oral challenges.
Results
Anaphylaxis accounted for 85.1% of reactions. In 99% of cases culprit food allergens were plant‐derived, mainly vegetables and cereals. NSAID were involved in 58%, exercise in 52.7% and alcohol in 12.2%. Lipid transfer protein was the most frequently involved allergen.
Conclusions
Co‐factor enhanced food allergy should be considered when assessing food, alcohol, exercise and NSAID allergic reactions.
Allergen immunotherapy was introduced by Leonard Noon 100 years ago and is the only disease‐modifying treatment for allergic individuals. Improved understanding of immunology has taught us a great ...deal about the underlying mechanisms involved in allergen immunotherapy; however, despite these developments, a number of important questions remain unanswered. Several of these questions relate to the practice of allergen immunotherapy in the clinic, such as: Is it possible to unify units of allergen potency? Which treatment schedules are best? Is allergen immunotherapy effective in all patient groups? Is there a dose–response relationship for efficacy and safety?, and Is there evidence for long‐term effects following allergen immunotherapy? Others are related to new developments, such as new indications, or developments in the production of allergens. On the centenary of Noon's discovery, European experts in the field of immunotherapy met in Geneva under the aegis of the EAACI to discuss these controversial issues. This study presents outcomes and conclusions from these discussions.
Background
Food allergies can have serious physical, social, and financial consequences. This systematic review examined ways to prevent the development of food allergy in children and adults.
...Methods
Seven bibliographic databases were searched from their inception to September 30, 2012, for systematic reviews, randomized controlled trials, quasi‐randomized controlled trials, controlled clinical trials, controlled before‐and‐after studies, interrupted time series studies, and prospective cohort studies. Experts were consulted for additional studies. There were no language or geographic restrictions. Two reviewers appraised the studies using appropriate tools. Data were not suitable for meta‐analysis due to heterogeneity, so were narratively synthesized.
Results
Seventy‐four studies were included, one‐third of which were of high quality. There was no good evidence to recommend that pregnant or breastfeeding women should change their diet or take supplements to prevent allergies in infants at high or normal risk. There were mixed findings about the preventive benefits of breastfeeding for infants at high or normal risk, but there was evidence to recommend avoiding cow's milk and substituting with extensively or partially hydrolyzed whey or casein formulas for infants at high risk for the first 4 months. Soy milk and delaying the introduction of solid foods beyond 4 months did not have preventive benefits in those at high or normal risk. There was very little evidence about strategies for preventing food allergy in older children or adults.
Conclusions
There is much to learn about preventing food allergy, and this is a priority given the high societal and healthcare costs involved.
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