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Fatal anaphylaxis in humans is rare and unpredictable. We note a trend to provide allergic individuals with care plans that recommend immediate use of epinephrine autoinjectors if allergen ingestion is suspected, even in the absence of any allergic symptoms, without any supporting evidence base. Instructions to use an autoinjector device, irrespective of reaction severity and especially when symptoms are actually absent, are likely to add to parental and patient anxiety. Of greater concern is the possibility of epinephrine being administered "too early" to treat initial, mild symptoms that then progress to severe anaphylaxis. It is not hard to visualize a scenario where one or both epinephrine autoinjectors have been deployed for mild symptoms, yet the reaction progresses to a severe reaction and no further epinephrine is available for administration. Epinephrine needs to be available as a rescue treatment for anaphylaxis, potentially buying valuable minutes while emergency medical services are activated to attend. Food-allergic individuals and their carers need to be provided with more constructive strategies and support than merely being told to "use your pen.", (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The observed increase in incidence of allergic disease in many regions over the past 3 decades has intensified interest in understanding the epidemiology of severe allergic reactions. We discuss the issues in collecting and interpreting these data and highlight current deficiencies in the current methods of data gathering., Recent Findings: Anaphylaxis, as measured by hospital admission rates, is not uncommon and has increased in the United Kingdom, the United States, Canada, and Australia over the last 10-20 years. All large datasets are hampered by a large proportion of uncoded, 'unspecified' causes of anaphylaxis. Fatal anaphylaxis remains a rare event, but appears to be increasing for medication in Australia, Canada, and the United States. The rate of fatal food anaphylaxis is stable in the United Kingdom and the United States, but has increased in Australia. The age distribution for fatal food anaphylaxis is different to other causes, with data suggesting an age-related predisposition to fatal outcomes in teenagers and adults to the fourth decade of life., Summary: The increasing rates of food and medication allergy (the latter exacerbated by an ageing population) has significant implications for future fatality trends. An improved ability to accurately gather and analyse population-level anaphylaxis data in a harmonized fashion is required, so as to ultimately minimize risk and improve management.

Aim: Cryopyrin-associated periodic syndromes (CAPS) encapsulate three auto-inflammatory conditions, ranging in severity from mild (familial cold auto-inflammatory syndrome: FCAS), moderate (Muckle-Wells syndrome: MWS) and severe (neonatal onset multi-inflammatory disorder: NOMID). We aimed to describe the epidemiology, clinical features and outcomes of Australian children and adults with CAPS., Methods: Patients were identified and clinical data collected through a questionnaire sent during 2012-2013 to clinicians reporting to the Australian Paediatric Surveillance Unit and subscribing to the Australasian Societies for Allergy/Immunology, Rheumatology and Dermatology., Results: Eighteen cases of CAPS were identified (8 NOMID; 8 MWS, 2 FCAS); 12 in children <18 years of age. The estimated population prevalence of CAPS was 1 per million persons. Diagnostic delay was frequent, particularly in those with milder phenotypes (median diagnostic delay in MWS/FCAS 20.6 years compared with NOMID 2.1 years; P = 0.04). Common presenting features included urticaria (100%), periodic fever (78%), arthralgia (72%) and sensorineural hearing loss (61%). Almost all (90%) MWS patients had a family member similarly affected compared with none in the NOMID group (P = 0.004). A significant proportion of patients on anti-interleukin (IL)-1 therapy (n = 13) no longer had systemic inflammation. Only 50% with sensorineural hearing loss had hearing restored on anti-IL-1 therapy., Conclusions: Although CAPS are rare, patients often endured prolonged periods of systemic inflammation. This is despite almost all MWS patients having family members with similar symptoms and children with NOMID presenting with chronic infantile urticaria associated with multi-system inflammation. Hearing loss in NOMID/MWS was frequent, and reversible in only 50% of cases., (© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Anaphylaxis has been defined as a 'severe, life-threatening generalized or systemic hypersensitivity reaction'. However, data indicate that the vast majority of food-triggered anaphylactic reactions are not life-threatening. Nonetheless, severe life-threatening reactions do occur and are unpredictable. We discuss the concepts surrounding perceptions of severe, life-threatening allergic reactions to food by different stakeholders, with particular reference to the inclusion of clinical severity as a factor in allergy and allergen risk management. We review the evidence regarding factors that might be used to identify those at most risk of severe allergic reactions to food, and the consequences of misinformation in this regard. For example, a significant proportion of food-allergic children also have asthma, yet almost none will experience a fatal food-allergic reaction; asthma is not, in itself, a strong predictor for fatal anaphylaxis. The relationship between dose of allergen exposure and symptom severity is unclear. While dose appears to be a risk factor in at least a subgroup of patients, studies report that individuals with prior anaphylaxis do not have a lower eliciting dose than those reporting previous mild reactions. It is therefore important to consider severity and sensitivity as separate factors, as a highly sensitive individual will not necessarily experience severe symptoms during an allergic reaction. We identify the knowledge gaps that need to be addressed to improve our ability to better identify those most at risk of severe food-induced allergic reactions., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A number of point-of-care diagnostic tests are commercially available in the UK, however, not much is known regarding GPs' desire for these tests or the clinical areas of interest., Objective: We sought to establish for which conditions point-of-care tests (POCTs) would be most helpful to UK GPs for diagnosis, reduction of referrals, and monitoring of chronic conditions., Methods: A total of 1635 regionally representative GPs were invited to complete an online cross-sectional survey between 31 September and 16 October 2012., Results: A total of 1109 (68%) GPs responded to the survey. The most frequently cited conditions were urinary tract infections for diagnosis (47% of respondents), pulmonary embolism/deep vein thrombosis for referral reduction (47%) and international normalized ratio/anticoagulation for monitoring (49%)., Conclusions: This survey has identified the conditions for which UK GPs would find POCTs most helpful. Comments by respondents suggest that quite radical system-level adjustments will be required to allow primary care clinicians to capitalize on the potential benefits of POCTs., (© The Author 2016. Published by Oxford University Press.)

Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health-related quality of life. In the last decade, research into disease-modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks-months. OIT has proven effective to induce immune modulation and 'desensitization' - that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short- and long-term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long-term adherence is unclear, which rises concerns given the low rates of long-term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti-IgE, pre-/probiotics). Biomarkers of safe/successful OIT are also under investigation., (© 2015 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.)

Ventilatory sensitivity to hypoxia increases in response to continued hypoxic exposure as part of acute acclimatisation. Although this process is incompletely understood, insights have been gained through studies of the hypoxia-inducible factor (HIF) hydroxylase system. Genetic studies implicate these pathways widely in the integrated physiology of hypoxia, through effects on developmental or adaptive processes. In keeping with this, mice that are heterozygous for the principal HIF prolyl hydroxylase, PHD2, show enhanced ventilatory sensitivity to hypoxia and carotid body hyperplasia. Here we have sought to understand this process better through comparative analysis of inducible and constitutive inactivation of PHD2 and its principal targets HIF-1α and HIF-2α. We demonstrate that general inducible inactivation of PHD2 in tamoxifen-treated Phd2(f/f);Rosa26(+/CreERT2) mice, like constitutive, heterozygous PHD2 deficiency, enhances hypoxic ventilatory responses (HVRs: 7.2 ± 0.6 vs. 4.4 ± 0.4 ml min(-1) g(-1) in controls, P < 0.01). The ventilatory phenotypes associated with both inducible and constitutive inactivation of PHD2 were strongly compensated for by concomitant inactivation of HIF-2α, but not HIF-1α. Furthermore, inducible inactivation of HIF-2α strikingly impaired ventilatory acclimatisation to chronic hypoxia (HVRs: 4.1 ± 0.5 vs. 8.6 ± 0.5 ml min(-1) g(-1) in controls, P < 0.0001), as well as carotid body cell proliferation (400 ± 81 vs. 2630 ± 390 bromodeoxyuridine-positive cells mm(-2) in controls, P < 0.0001). The findings demonstrate the importance of the PHD2/HIF-2α enzyme-substrate couple in modulating ventilatory sensitivity to hypoxia., (© 2015 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

A functional role for the mitochondria in acute O2 sensing in the carotid body (CB) remains undetermined. Whilst total inhibition of mitochondrial activity causes intense CB stimulation, it is unclear whether this response can be moderated such that graded impairment of oxidative phosphorylation might be a mechanism that sets and modifies the O2 sensitivity of the whole organ. We assessed NADH autofluorescence and [Ca2+]i in freshly dissociated CB type I cells and sensory chemoafferent discharge frequency in an intact CB preparation, in the presence of varying concentrations of nitrite (NO2 −), a mitochondrial nitric oxide (NO) donor and a competitive inhibitor of mitochondrial complex IV. NO2 − increased CB type I cell NADH in a manner that was dose-dependent and rapidly reversible. Similar concentrations of NO2 − raised type I cell [Ca2+]i via L-type channels in a PO2-dependent manner and increased chemoafferent discharge frequency. Moderate inhibition of the CB mitochondria by NO2 − augmented chemoafferent discharge frequency during graded hypoxia, consistent with a heightened CB O2 sensitivity. Furthermore, NO2 − also exaggerated chemoafferent excitation during hypercapnia signifying an increase in CB CO2 sensitivity. These data show that NO2 − can moderate the hypoxia sensitivity of the CB and thus suggest that O2 sensitivity could be set and modified in this organ by interactions between NO and mitochondrial complex IV.

Study Question: How safe is live attenuated influenza vaccine (LAIV), which contains egg protein, in young people with egg allergy?, Methods: In this open label, phase IV intervention study, 779 young people (2-18 years) with egg allergy were recruited from 30 UK allergy centres and immunised with LAIV. The cohort included 270 (34.7%) young people with previous anaphylaxis to egg, of whom 157 (20.1%) had experienced respiratory and/or cardiovascular symptoms. 445 (57.1%) had doctor diagnosed asthma or recurrent wheeze. Participants were observed for at least 30 minutes after vaccination and followed-up by telephone 72 hours later. Participants with a history of recurrent wheeze or asthma underwent further follow-up four weeks later. The main outcome measure was incidence of an adverse event within two hours of vaccination in young people with egg allergy., Study Answer and Limitations: No systemic allergic reactions occurred (upper 95% confidence interval for population 0.47% and in participants with anaphylaxis to egg 1.36%). Nine participants (1.2%, 95% CI 0.5% to 2.2%) experienced mild symptoms, potentially consistent with a local, IgE mediated allergic reaction. Delayed events potentially related to the vaccine were reported in 221 participants. 62 participants (8.1%, 95% CI for population 6.3% to 10.3%) experienced lower respiratory tract symptoms within 72 hours, including 29 with parent reported wheeze. No participants were admitted to hospital. No increase in lower respiratory tract symptoms occurred in the four weeks after vaccination (assessed with asthma control test). The study cohort may represent young people with more severe allergy requiring specialist input, since they were recruited from secondary and tertiary allergy centres., What This Study Adds: LAIV is associated with a low risk of systemic allergic reactions in young people with egg allergy. The vaccine seems to be well tolerated in those with well controlled asthma or recurrent wheeze., Funding, Competing Interests, Data Sharing: This report is independent research commissioned and funded by a Department of Health policy research programme grant to the National Vaccine Evaluation Consortium. Additional funding was provided by the NIHR Clinical Research Networks, Health Protection Scotland (Edinburgh site), and Health & Social Care Services in Northern Ireland (Belfast site). PJT and MEL had support from the Department of Health for the submitted work; PJT has received research grants from the Medical Research Council and NIHR. No additional data available.Study registration ClinicalTrials.gov (NCT02111512) and the EU Clinical Trials Register EudraCT (2014-001537-92)., (© Turner et al 2015.)

Background: Food allergy is a common cause of anaphylaxis, but the incidence of anaphylaxis in food allergic people is unknown., Methods: We undertook a systematic review and meta-analysis, using the inverse variance method. Two authors selected studies by consensus, independently extracted data and assessed study quality using the Newcastle-Ottawa assessment scale. We searched Medline, Embase, PsychInfo, CINAHL, Web of Science, LILACS and AMED between January 1946 and September 2012 and recent conference abstracts. We included registries, databases or cohort studies which described the number of food anaphylaxis cases in a defined population and time period and applied an assumed population prevalence of food allergy., Results: We included data from 34 studies. There was high heterogeneity between study results, possibly due to variation in study populations, anaphylaxis definition and data collection methods. In food allergic people, medically coded food anaphylaxis had an incidence rate of 0.14 per 100 person-years (95% CI 0.05, 0.35; range 0.01, 1.28). In sensitivity analysis using different estimated food allergy prevalence, the incidence varied from 0.11 to 0.21 per 100 person-years. At age 0-19, the incidence rate for anaphylaxis in food allergic people was 0.20 (95% CI 0.09, 0.43; range 0.01, 2.55; sensitivity analysis 0.08, 0.39). At age 0-4, an incidence rate of up to 7.00 per 100 person-years has been reported. In food allergic people, hospital admission due to food anaphylaxis had an incidence rate of 0.09 (95% CI 0.01, 0.67; range 0.02, 0.81) per 1000 person-years; 0.20 (95% CI 0.10, 0.43; range 0.04, 2.25) at age 0-19 and 0.50 (0.26, 0.93; range 0.08, 2.82) at age 0-4., Conclusion: In food allergic people, the incidence of food allergic reactions which are coded as anaphylaxis by healthcare systems is low at all ages, but appears to be highest in young children., (© 2014 John Wiley & Sons Ltd.)

Background: Live attenuated influenza vaccine (LAIV) is an intranasal vaccine recently incorporated into the United Kingdom immunization schedule. However, it contains egg protein and, in the absence of safety data, is contraindicated in patients with egg allergy. Furthermore, North American guidelines recommend against its use in asthmatic children., Objective: We sought to assess the safety of LAIV in children with egg allergy., Methods: We performed a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom. Children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited. LAIV was administered under medical supervision, with observation for 1 hour and telephone follow-up 72 hours later., Results: Four hundred thirty-three doses were administered to 282 children with egg allergy (median, 4.9 years; range, 2-17 years); 115 (41%) had experienced prior anaphylaxis to egg. A physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. There were no systemic allergic reactions (upper 95% CI for population, 1.3%). Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%; 95% CI for population, 6.2% to 13.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze. None of these episodes required medical intervention beyond routine treatment., Conclusions: In contrast to current recommendations, LAIV appears to be safe for use in children with egg allergy. Furthermore, the vaccine appears to be well tolerated in children with a diagnosis of asthma or recurrent wheeze., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous work has shown patients commonly misuse adrenaline autoinjectors (AAI). It is unclear whether this is due to inadequate training, or poor device design. We undertook a prospective randomized controlled trial to evaluate ability to administer adrenaline using different AAI devices., Methods: We allocated mothers of food-allergic children prescribed an AAI for the first time to Anapen or EpiPen using a computer-generated randomization list, with optimal training according to manufacturer's instructions. After one year, participants were randomly allocated a new device (EpiPen, Anapen, new EpiPen, JEXT or Auvi-Q), without device-specific training. We assessed ability to deliver adrenaline using their AAI in a simulated anaphylaxis scenario six weeks and one year after initial training, and following device switch. Primary outcome was successful adrenaline administration at six weeks, assessed by an independent expert. Secondary outcomes were success at one year, success after switching device, and adverse events., Results: We randomized 158 participants. At six weeks, 30 of 71 (42%) participants allocated to Anapen and 31 of 73 (43%) participants allocated to EpiPen were successful - RR 1.00 (95% CI 0.68-1.46). Success rates at one year were also similar, but digital injection was more common at one year with EpiPen (8/59, 14%) than Anapen (0/51, 0%, P = 0.007). When switched to a new device without specific training, success rates were higher with Auvi-Q (26/28, 93%) than other devices (39/80, 49%; P < 0.001)., Conclusions: AAI device design is a major determinant of successful adrenaline administration. Success rates were low with several devices, but were high using the audio-prompt device Auvi-Q., (© 2015 The Authors Allergy Published by John Wiley & Sons Ltd.)

Peanut and tree nut allergies are the commonest cause of life-threatening food-allergic reactions and significantly affect quality of life in children and their families. Dietary nut avoidance and provision of emergency medication is currently the mainstay of treatment. Nut avoidance has consequences on both quality of life and nutrition. We review the terminology that may cause confusion and lead to unnecessary dietary restrictions. In peanut or tree nut-allergic children, introduction of specific nuts to which the child is not allergic may improve quality of life and should be considered in patients with multiple foods allergies, vegan or ethnic-specific diets, in whom nuts are an important source of protein. Nut-allergic consumers do not just need to avoid foods containing nuts as an ingredient, but also contend with pre-packed foods which frequently have precautionary allergen labelling (PAL) referring to possible nut contamination. Although the published rate of peanut contamination in 'snack' foods with PAL (see Box ) ranges from 0.9-32.4%, peanut contamination in non-snack items with PAL is far less common. We propose that in some peanut-allergic patients (depending on history of reactivity to trace levels of peanut, reaction severity, other medical conditions, willingness to always carry adrenaline, etc.), consideration may be given to allow the consumption of non-snack foods containing PAL following discussion with the patient's (and their family's) specialist. More work is needed to provide consumers with clearer information on the risk of potential nut contamination in pre-packed food. We also draw attention to the change in legislation in December 2014 that require mandatory disclosure of allergens in non-pre-packed foods., (© 2014 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.)

Background: The incidence of anaphylaxis might be increasing. Data for fatal anaphylaxis are limited because of the rarity of this outcome., Objective: We sought to document trends in anaphylaxis admissions and fatalities by age, sex, and cause in England and Wales over a 20-year period., Methods: We extracted data from national databases that record hospital admissions and fatalities caused by anaphylaxis in England and Wales (1992-2012) and crosschecked fatalities against a prospective fatal anaphylaxis registry. We examined time trends and age distribution for fatal anaphylaxis caused by food, drugs, and insect stings., Results: Hospital admissions from all-cause anaphylaxis increased by 615% over the time period studied, but annual fatality rates remained stable at 0.047 cases (95% CI, 0.042-0.052 cases) per 100,000 population. Admission and fatality rates for drug- and insect sting-induced anaphylaxis were highest in the group aged 60 years and older. In contrast, admissions because of food-triggered anaphylaxis were most common in young people, with a marked peak in the incidence of fatal food reactions during the second and third decades of life. These findings are not explained by age-related differences in rates of hospitalization., Conclusions: Hospitalizations for anaphylaxis increased between 1992 and 2012, but the incidence of fatal anaphylaxis did not. This might be due to increasing awareness of the diagnosis, shifting patterns of behavior in patients and health care providers, or both. The age distribution of fatal anaphylaxis varies significantly according to the nature of the eliciting agent, which suggests a specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Prediction of postoperative facial appearance after orthognathic surgery can be used for communication, managing patients' expectations,avoiding postoperative dissatisfaction and exploring different treatment options. We have assessed the accuracy of 3dMD Vultus in predicting the final 3-dimensional soft tissue facial morphology after Le Fort I advancement osteotomy. We retrospectively studied 13 patients who were treated with a Le Fort I advancement osteotomy alone. We used routine cone-beam computed tomographic (CT) images taken immediately before and a minimum of 6 months after operation, and 3dMD Vultus to virtually reposition the preoperative maxilla and mandible in their post operative positions to generate a prediction of what the soft tissue would look like. Segmented anatomical areas of the predicted mesh were then compared with the actual soft tissue. The means of the absolute distance between the 90th percentile of the mesh points for each region were calculated, and a one-sample Student's t test was used to calculate if the difference differed significantly from 3 mm.The differences in the mean absolute distances between the actual soft tissue and the prediction were significantly below 3 mm for all segmented anatomical areas (p < 0.001), and ranged from 0.65 mm (chin) to 1.17 mm (upper lip). 3dMD Vultus produces clinically satisfactory 3-dimensional facial soft tissue predictions after Le Fort I advancement osteotomy. The mass-spring model for prediction seems to be able to predict the position of the lip and chin, but its ability to predict nasal and paranasal areas could be improved.

The identity of the oxygen sensor in arterial chemoreceptors has been the subject of much speculation. One of the oldest hypotheses is that oxygen is sensed through oxidative phosphorylation. There is a wealth of data demonstrating that arterial chemoreceptors are excited by inhibitors of oxidative phosphorylation. These compounds mimic the effects of hypoxia inhibiting TASK1/3 potassium channels causing membrane depolarisation calcium influx and neurosecretion. The TASK channels of Type-I cells are also sensitive to cytosolic MgATP. The existence of a metabolic signalling pathway in Type-1 cells is thus established; the contentious issue is whether this pathway is also used for acute oxygen sensing. The main criticism is that because cytochrome oxidase has a high affinity for oxygen (P50 ≈ 0.2 mmHg) mitochondrial metabolism should be insensitive to physiological hypoxia. This argument is however predicated on the assumption that chemoreceptor mitochondria are analogous to those of other tissues. We have however obtained new evidence to support the hypothesis that type-1 cell mitochondria are not like those of other cells in that they have an unusually low affinity for oxygen (Mills E, Jobsis FF, J Neurophysiol 35(4):405-428, 1972; Duchen MR, Biscoe TJ, J Physiol 450:13-31, 1992a). Our data confirm that mitochondrial membrane potential, NADH, electron transport and cytochrome oxidase activity in the Type-1 cell are all highly sensitive to hypoxia. These observations not only provide exceptionally strong support for the metabolic hypothesis but also reveal an unknown side of mitochondrial behaviour.

Background: Most children with egg allergy tolerate egg in baked foods, such as cake, but tolerance cannot be predicted with conventional allergy testing. We hypothesized that the skin prick test (SPT) wheal to unprocessed raw egg might predict tolerance of baked egg at formal oral food challenge (OFC)., Methods: We conducted a retrospective chart review to assess the utility of SPT wheal to egg extract (EE), raw egg (RE), and the ratio of EE:RE in predicting outcome of baked-egg OFC in children presenting to our tertiary referral centers with a physician diagnosis of egg allergy and following complete egg avoidance in their diet, between 2009 and 2013. OFC were performed following a standardized protocol using baked egg in cake, to a total dose equivalent to 3g egg protein., Results: Data were analyzed from 186 completed challenges: OFC was positive in 64 (34%) children and negative in 122 (66%). Six children experienced anaphylaxis at OFC. Children tolerant to baked egg were more likely to have a lower SPT to egg extract/raw egg and EE:RE (median 0.56) than their allergic counterparts (0.70, p < 0.05). However, ROC curve analysis demonstrated poor predictivity of challenge outcome, with AUC for SPT to egg extract, raw egg and EE:ER equal to 0.71, 0.63 and 0.60, respectively., Conclusion: EE:RE was not helpful in predicting outcome of baked-egg OFC. Indeed, SPT to egg extract was slightly better at predicting outcome than either SPT to raw egg or EE:RE. Unfortunately, tolerance to baked egg can only be predicted from previous history or through controlled exposure., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate PO2 led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Background: Many children with IgE-mediated allergy to cow's milk (CM) can tolerate CM in baked foods., Objective: To define the clinical characteristics and severity of reactions to baked CM in children with CM allergy (CMA) at an oral food challenge (OFC)., Methods: Children with CMA presenting to a tertiary clinic from 2010 through 2013 with complete dietary CM avoidance were offered a baked CM OFC. Challenges were performed with incremental dosages to a total of 1 baked muffin., Results: Seventy children with CMA underwent a baked CM OFC. Fifty-one children (73%) passed the OFC and successfully incorporated baked CM into their diet. Nineteen children (27%) reacted to their challenge. Of reactors, 4 (21%) developed anaphylaxis and required intramuscular adrenalin. Predictors of clinical reactivity to baked CM were asthma, asthma requiring preventer therapy, IgE-mediated clinical reactions to more than 3 food groups, and those with a history of CM anaphylaxis., Conclusion: This study identified factors that were predictors of clinical reactivity to baked CM in this cohort of children with CMA. These risk factors do not represent contradictions to a baked CM challenge but may allow for risk stratification of challenges. Given the potential for anaphylaxis, an OFC to baked CM should be done under medical supervision in those children with CMA who have been strictly avoiding all CM., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Food allergy and anaphylaxis occur most commonly in children under five, the majority of whom attend preschool and early childcare. Children under five differ significantly from school-aged children, as do their care environments, yet specific strategies for managing food allergies in early childcare settings are generally lacking in existing guidelines and legislation. In this review, we outline the scope of the problem, the unique challenges encountered in the preschool environment and existing policy and legislation in Australia, the US, Canada and the UK. We outline the management guidelines and resources available from specialist societies, and the evidence base for specific management strategies including voluntary versus legislative approaches, staff training and education, banning of foods, and availability of multiple and generic adrenaline auto-injectors. We call for greater uniformity and consistency of policy in regards to the recognition and management of infants and children with food allergy in the preschool environment and specific programmes and policies tailored to this environment.

Purpose of Review: Food allergy affects up to 10% of preschool children, and continues to increase in prevalence in many countries, resulting in a major public health issue, with practical implications for the food industry, educational establishments and healthcare systems., Recent Findings: The need to distinguish between food allergen sensitization and true clinical reactivity remains crucial in diagnosis, often requiring formal food challenge to avoid unnecessary dietary elimination. Epicutaneous exposure in the absence of oral tolerance induction during infancy may be an important risk factor for food allergy. Mounting evidence suggests that for milk and egg allergens, many children are able to tolerate the food when heat-modified, and that this may hasten resolution of the allergy., Summary: These developments will hopefully result in a lower adverse impact on quality of life for food-allergic individuals and their families.

Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this.

The hypoxia-inducible factor (HIF) family of transcription factors coordinates diverse cellular and systemic responses to hypoxia. Chuvash polycythemia (CP) is an autosomal recessive disorder in humans in which there is impaired oxygen-dependent degradation of HIF, resulting in long-term systemic elevation of HIF levels at normal oxygen tensions. CP patients demonstrate the characteristic features of ventilatory acclimatization to hypoxia, namely, an elevated baseline ventilation and enhanced acute hypoxic ventilatory response (AHVR). We investigated the ventilatory and carotid-body phenotype of a mouse model of CP, using whole-body plethysmography, immunohistochemistry, and electron microscopy. In keeping with studies in humans, CP mice had elevated ventilation in euoxia and a significantly exaggerated AHVR when exposed to 10% oxygen, with or without the addition of 3% carbon dioxide. Carotid-body immunohistochemistry demonstrated marked hyperplasia of the oxygen-sensing type I cells, and the cells themselves appeared enlarged with more prominent nuclei. This hypertrophy was confirmed by electron microscopy, which also revealed that the type I cells contained an increased number of mitochondria, enlarged dense-cored vesicles, and markedly expanded rough endoplasmic reticulum. The morphological and ultrastructural changes seen in the CP mouse carotid body are strikingly similar to those observed in animals exposed to chronic hypoxia. Our study demonstrates that the HIF pathway plays a major role, not only in regulating both euoxic ventilatory control and the sensitivity of the response to hypoxia, but also in determining the morphology of the carotid body.

Background: Food allergy is a common cause of anaphylaxis, but the incidence of fatal food anaphylaxis is not known. The aim of this study was to estimate the incidence of fatal food anaphylaxis for people with food allergy and relate this to other mortality risks in the general population., Methods: We undertook a systematic review and meta-analysis, using the generic inverse variance method. Two authors selected studies by consensus, independently extracted data and assessed the quality of included studies using the Newcastle-Ottawa assessment scale. We searched Medline, Embase, PsychInfo, CINAHL, Web of Science, LILACS or AMED, between January 1946 and September 2012, and recent conference abstracts. We included registries, databases or cohort studies which described the number of fatal food anaphylaxis cases in a defined population and time period and applied an assumed population prevalence rate of food allergy., Results: We included data from 13 studies describing 240 fatal food anaphylaxis episodes over an estimated 165 million food-allergic person-years. Study quality was mixed, and there was high heterogeneity between study results, possibly due to variation in food allergy prevalence and data collection methods. In food-allergic people, fatal food anaphylaxis has an incidence rate of 1.81 per million person-years (95%CI 0.94, 3.45; range 0.63, 6.68). In sensitivity analysis with different estimated food allergy prevalence, the incidence varied from 1.35 to 2.71 per million person-years. At age 0-19, the incidence rate is 3.25 (1.73, 6.10; range 0.94, 15.75; sensitivity analysis 1.18-6.13). The incidence of fatal food anaphylaxis in food-allergic people is lower than accidental death in the general European population., Conclusion: Fatal food anaphylaxis for a food-allergic person is rarer than accidental death in the general population., (© 2013 The Authors Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.)

Background: Many children with IgE-mediated egg allergy can tolerate products containing extensively heated (baked) egg. Aside from food challenge, there are no tests which reliably predict tolerance to baked egg in egg-allergic individuals., Objectives: To determine if skin prick test (SPT) to baked egg (muffin) and ovomucoid can predict the outcome of baked egg challenges in egg allergic patients., Methods: In this prospective study, children with a recent history of immediate allergic reactions to egg [and corroborative positive SPT or serum-specific IgE (ssIgE) to egg] or those with SPT/ssIgE > 95% PPV for egg allergy were invited to undergo an open standardized baked egg (muffin) challenge. SPT to egg white, ovomucoid, and fresh muffin were performed immediately prior to challenge., Results: One hundred and forty-three egg allergic children underwent baked egg challenge and of these, 90 (63%) tolerated 1 g of egg protein in a baked muffin. Of the 53 positive challenges, eight (15%) had respiratory and/or cardiovascular symptoms. The median SPT diameters in positive challenges compared with negative challenges were baked muffin - 6.0 mm/4.0 mm and ovomucoid 7.5 mm/5.0 mm respectively. Receiver operating characteristic (ROC) curves were generated for SPT to baked egg and ovomucoid. The area under the curve was 0.68 for baked egg, and 0.67 for ovomucoid. A muffin SPT of < 2 mm had a negative predictive value of 88% and an ovomucoid SPT ≥ 11 mm had a positive predictive value of 100%., Conclusions and Clinical Relevance: A SPT of < 2 mm to muffin had a high negative predictive value to baked egg challenge. Ovomucoid SPT ≥ 11 mm was very likely to predict a reaction to baked egg. In these children, deferring the challenge would be appropriate., (© 2013 John Wiley & Sons Ltd.)

Background: Many children with IgE-mediated allergy to egg can tolerate egg in baked foods. However, the clinical characteristics and severity of reactions of egg-allergic children who react to baked egg at open food challenge (OFC) are not well defined., Methods: Children presenting to our tertiary referral clinic with a diagnosis of egg allergy and following complete egg avoidance in their diet were offered OFC to baked egg. Challenges were performed with incremental dosages to a total of one baked muffin containing 1/6 egg (equivalent to 1 g egg protein) following a standardized protocol. Data were collected prospectively from 2009-2012., Results: Open food challenge to baked egg were carried out on 236 egg-allergic children who had been strictly avoiding egg in their diet. A total of 150 children (64%) passed and successfully incorporated baked egg into their diet. Eighty-six children (36%) reacted to their challenge. Of these, 12 (14%) experienced anaphylaxis (according to WAO criteria), including four to <100 mg extensively heated egg protein. Intramuscular adrenaline was administered to 5 of the 12 children, one of whom required a second dose due to persistent hypotension. Skin prick testing, asthma, or prior egg anaphylaxis were not predictive of challenge outcome., Conclusion: The majority of children with IgE-mediated allergy to egg were able to tolerate 1 g of baked egg protein, but the outcome of OFC remained unpredictable, and 14% of children who failed OFC reacted with anaphylaxis. We recommend that OFC to baked egg should take place under medical supervision., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The mechanism of oxygen sensing in arterial chemoreceptors is unknown but has often been linked to mitochondrial function. A common criticism of this hypothesis is that mitochondrial function is insensitive to physiological levels of hypoxia. Here we investigate the effects of hypoxia (down to 0.5% O2) on mitochondrial function in neonatal rat type-1 cells. The oxygen sensitivity of mitochondrial [NADH] was assessed by monitoring autofluorescence and increased in hypoxia with a P50 of 15 mm Hg (1 mm Hg = 133.3 Pa) in normal Tyrode or 46 mm Hg in Ca(2+)-free Tyrode. Hypoxia also depolarised mitochondrial membrane potential (m, measured using rhodamine 123) with a P50 of 3.1, 3.3 and 2.8 mm Hg in normal Tyrode, Ca(2+)-free Tyrode and Tyrode containing the Ca(2+) channel antagonist Ni(2+), respectively. In the presence of oligomycin and low carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP; 75 nm) m is maintained by electron transport working against an artificial proton leak. Under these conditions hypoxia depolarised m/inhibited electron transport with a P50 of 5.4 mm Hg. The effects of hypoxia upon cytochrome oxidase activity were investigated using rotenone, myxothiazol, antimycin A, oligomycin, ascorbate and the electron donor tetramethyl-p-phenylenediamine. Under these conditions m is maintained by complex IV activity alone. Hypoxia inhibited cytochrome oxidase activity (depolarised m) with a P50 of 2.6 mm Hg. In contrast hypoxia had little or no effect upon NADH (P50 = 0.3 mm Hg), electron transport or cytochrome oxidase activity in sympathetic neurons. In summary, type-1 cell mitochondria display extraordinary oxygen sensitivity commensurate with a role in oxygen sensing. The reasons for this highly unusual behaviour are as yet unexplained.

Oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor (HIF) by a set of closely related prolyl hydroxylase domain enzymes (PHD1, 2 and 3) regulates a range of transcriptional responses to hypoxia. This raises important questions about the role of these oxygen-sensing enzymes in integrative physiology. We investigated the effect of both genetic deficiency and pharmacological inhibition on the change in ventilation in response to acute hypoxic stimulation in mice. Mice exposed to chronic hypoxia for 7 days manifest an exaggerated hypoxic ventilatory response (HVR) (10.8 ± 0.3 versus 4.1 ± 0.7 ml min(-1) g(-1) in controls; P < 0.01). HVR was similarly exaggerated in PHD2(+/-) animals compared to littermate controls (8.4 ± 0.7 versus 5.0 ± 0.8 ml min(-1) g(-1); P < 0.01). Carotid body volume increased (0.0025 ± 0.00017 in PHD2(+/-) animals versus 0.0015 ± 0.00019 mm(3) in controls; P < 0.01). In contrast, HVR in PHD1(-/-) and PHD3(-/-) mice was similar to littermate controls. Acute exposure to a small molecule PHD inhibitor (PHI) (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid) did not mimic the ventilatory response to hypoxia. Further, 7 day administration of the PHI induced only modest increases in HVR and carotid body cell proliferation, despite marked stimulation of erythropoiesis. This was in contrast with chronic hypoxia, which elicited both exaggerated HVR and cellular proliferation. The findings demonstrate that PHD enzymes modulate ventilatory sensitivity to hypoxia and identify PHD2 as the most important enzyme in this response. They also reveal differences between genetic inactivation of PHDs, responses to hypoxia and responses to a pharmacological inhibitor, demonstrating the need for caution in predicting the effects of therapeutic modulation of the HIF hydroxylase system on different physiological responses.

Objective: The purpose of this cross-sectional survey was to evaluate the psychosocial impact of tooth agenesis in children and to investigate the potential influence of gender, socioeconomic status, severity of tooth absence, and the number of retained primary teeth on their quality of life., Materials and Methods: A total of 86 children (36 male, 50 female) with tooth agenesis, aged 11-14 years were recruited from the Birmingham Dental Hospital, United Kingdom. Thirty subjects with a complete dentition and having a low treatment need acted as controls. Children completed the validated Child Perceptions Questionnaire (CPQ) and their parents completed the Parental-Caregiver Perceptions Questionnaire (P-CPQ)., Results: The median number of missing teeth in the sample population was 6. There were significant differences in the oral symptoms, functional limitations and the social and emotional well-being reported between the agenesis and control groups. The overall CPQ scores were significantly higher in children with tooth agenesis (P<0·001). No significant correlation was detected between the number of missing teeth and the quality of life score. There was no influence found on the CPQ score from gender, socioeconomic status, the site of agenesis or the presence of retained primary teeth. There was moderate correlation between parental and child reported quality of life., Conclusions: Tooth agenesis can have a significant impact on the quality of life of children, resulting in oral symptoms, functional limitation and also affecting emotional and social well-being. This does not appear to be related to the number of missing teeth. This study has implications for our understanding of the effect of tooth absence on the quality of life of children and their parents and addressing these reported impacts may help to improve patient satisfaction.

This article reviews the recent advances in the diagnosis and management of IgE mediated food allergy in children. It will encompass the emerging technology of component testing; moves to standardization of the allergy food challenge; permissive diets which allow for inclusion of extensively heated food allergens with allergen avoidance; and strategies for accelerating tolerance and food desensitization including the use of adjuvants for specific tolerance induction.

Pacifiers, otherwise known as dummies, have been around for many centuries. They have, however, taken many different forms, shapes and sizes. Their use is increasing and has remained controversial, with both potential risks and benefits identified in the medical and dental literature. The purpose of this article is to review some of the evidence available for and against the use of pacifiers and make recommendations for their application, maintenance and weaning. CLNICAL RELEVANCE: Dental healthcare professionals need to consider the evidence available for and against pacifiers when making recommendations to patients and their parents.

CeCoIn₅ is a heavy fermion superconductor with strong similarities to the high-Tc cuprates, including quasi-two-dimensionality, proximity to antiferromagnetism and probable d-wave pairing arising from a non-Fermi-liquid normal state. Experiments allowing detailed comparisons of their electronic properties are of particular interest, but in most cases are difficult to realize, due to their very different transition temperatures. Here we use low-temperature microwave spectroscopy to study the charge dynamics of the CeCoIn₅ superconducting state. The similarities to cuprates, in particular to ultra-clean YBa₂Cu₃O(y), are striking: the frequency and temperature dependence of the quasiparticle conductivity are instantly recognizable, a consequence of rapid suppression of quasiparticle scattering below T(c); and penetration-depth data, when properly treated, reveal a clean, linear temperature dependence of the quasiparticle contribution to superfluid density. The measurements also expose key differences, including prominent multiband effects and a temperature-dependent renormalization of the quasiparticle mass.

Allergic rhinitis affects up to 40% of children but is commonly undiagnosed. Careful assessment of nasal symptoms allows for the most appropriate therapeutic options to be chosen. Allergen avoidance is often difficult in practice. Antihistamines are of limited benefit in allergic rhinitis caused by house dust mite and other perennial allergens, where symptoms, predominantly nasal obstruction, are not histamine mediated. In contrast, symptoms triggered by pollen, such as nasal itch, rhinorrhoea and sneezing, are relieved by antihistamines. Intranasal steroids are the treatment of choice for persistent moderate-severe allergic rhinitis and are more effective than antihistamines for relief of nasal obstruction. Failure to respond to intranasal medications is often caused by poor compliance or inefficient use of nasal sprays. Immunotherapy may be a useful, if expensive, option, particularly where symptoms are because of a specific pollen. The benefits of immunotherapy in house dust mite-induced rhinitis and asthma remain controversial., (© 2010 The Authors. Journal compilation © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Montelukast was effective in treating refractory abdominal and urinary symptoms in a child with systemic mastocytosis., (© 2011 Wiley Periodicals, Inc.)

Severe cases of atopic dermatitis (AD) may require systemic immunosuppression to achieve disease control. Unfortunately, some cases continue to be refractory to management or develop unacceptable adverse effects. There are limited reports of the use of intravenous immunoglobulin (IVIg) in the treatment of severe AD, but results are inconsistent. In a retrospective study, we report 10 children with severe AD refractory to systemic immunosuppression and maximal topical therapy who were treated using IVIg. The children received monthly IVIg for an average of 24 months. This resulted in a significant improvement in symptoms, with fewer infection-related exacerbations and hospitalizations, allowing systemic immunosuppression to be tapered. The effect was associated with a significant decrease in serum immunoglobulin E and was sustained after cessation of IVIg in 50% of cases. No significant side effects attributable to the IVIg infusions were noted. In this cohort of children with severe AD and recurrent cutaneous infections, IVIg provided an effective treatment with minimal side effects and significant benefits in school attendance and quality of life., (© 2011 Wiley Periodicals, Inc.)

'Food intolerance' is often confused with a range of adverse symptoms which may be coincidental to ingestion of food. 'Food intolerance' is defined as a reaction in which symptoms must be objectively reproducible and not known to involve an immunological mechanism. A more precise term is non-allergic food hypersensitivity, which contrasts with food allergies which are due to an immunological mechanism. Some children will experience food reactions to food additives. Reported symptoms range from urticaria/angioedema to hyperactive behaviours. While parents/carers report that over one fifth of children experience of food reaction, only 1 in 20 of these are confirmed to have a non-allergic food hypersensitivity on testing., (© 2010 The Authors. Journal of Paediatrics and Child Health © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)