Specific oral immunotherapy in food allergic patients: transient or persistent tolerance?

INTRODUCTION: The first therapeutic choice for food allergy is avoidance of the responsible food, but when this approach is not possible, specific oral desensitization could be considered as a good alternative. It is not clear yet whether the acquired tolerance is transient or persistent. AIM: We report on a subset of 13 patients of a larger study, treated successfully with specific oral tolerance induction who experienced secondary loss of tolerance after a period of allergen avoidance. MATERIAL AND METHODS: Thirteen patients affected by IgE-mediated food allergy: to cow milk (3 patients), to hen egg (3 patients), to cod fish (2 patients), to peanuts (1 patient) and to corn (1 patient) confirmed by a complete allergological workup and a double-blind placebo-controlled food challenge (DBPCFC), were treated with sublingual-oral desensitization. After the interruption of the maintenance phase, the laboratory tests were performed and 12 of 13 patients underwent DBPCFC. RESULTS: Oral specific desensitization was completed successfully in all the 13 reported patients. At different times after the end of treatment, they decided, on their own initiative, to stop the ingestion of incriminated food. A new food allergen re-exposure caused adverse reactions in 12 of 13 patients. The detection of specific IgE and IgG4 during the period of allergen avoidance showed an increase in or a stable level of specific IgE and a decrease in specific IgG4 in 8 patients. CONCLUSIONS: According to our experience, the tolerance obtained through the desensitizing treatment is transient and so the regular allergen intake is necessary for its maintenance.

Hypersensitivity to major panallergens in a population of 120 patients.

INTRODUCTION: Lipid transfer proteins (LTP), profilin and PR-10 are the most important panallergens in central and southern Italy. Lipid transfer proteins are stable molecules, predominantly present in the fruit peel, which can induce systemic symptoms after ingestion of vegetables. Profilin and PR-10 are randomly distributed in the pulp and peel. Both are labile proteins and usually determine reactions restricted to the oral cavity. Panallergens-specific IgE may cross-react with homologues from different plant sources, due to their conserved structure. AIM: To assess the pattern of sensitization to panallergens and the correlation with the clinical history and the allergological evaluation of food and aeroallergens. MATERIAL AND METHODS: One hundred and twenty patients with adverse reactions after vegetables ingestion underwent skin prick tests (SPT) with commercial extracts of plant-derived foods and inhalant allergens and commercial extracts of LTP, profilin and PR-10. RESULTS: Many patients presented positive SPT with different plant-food allergens. We found that 76 patients were sensitized to LTP, 14 to profilin and 5 to PR-10. In the LTP-sensitized group, 64 (84%) patients suffered from systemic symptoms while the patients sensitized only to profilin referred the oral allergy syndrome. CONCLUSIONS: This study shows a high rate of sensitization to LTP in our population according to the literature about food allergy in our geographical area and confirms the literature data about the symptoms referred by patients with sensitization to panallergens. Panallergens should be considered as clinically relevant food allergens.

Rio1 downregulates centromeric RNA levels to promote the timely assembly of structurally fit kinetochores.

Kinetochores assemble on centromeres via histone H3 variant CENP-A and low levels of centromere transcripts (cenRNAs). The latter are ensured by the downregulation of RNA polymerase II (RNAPII) activity, and cenRNA turnover by the nuclear exosome. Using S. cerevisiae, we now add protein kinase Rio1 to this scheme. Yeast cenRNAs are produced either as short (median lengths of 231 nt) or long (4458 nt) transcripts, in a 1:1 ratio. Rio1 limits their production by reducing RNAPII accessibility and promotes cenRNA degradation by the 5'-3'exoribonuclease Rat1. Rio1 similarly curtails the concentrations of noncoding pericenRNAs. These exist as short transcripts (225 nt) at levels that are minimally two orders of magnitude higher than the cenRNAs. In yeast depleted of Rio1, cen- and pericenRNAs accumulate, CEN nucleosomes and kinetochores misform, causing chromosome instability. The latter phenotypes are also observed with human cells lacking orthologue RioK1, suggesting that CEN regulation by Rio1/RioK1 is evolutionary conserved.

Evidence of a maturational disruption in non-rapid eye movement sleep slow wave activity in youth with attention-deficit/hyperactivity, learning and internalizing disorders.

BACKGROUND: Sleep slow wave activity (SWA) peaks during childhood and declines in the transition to adolescence during typical development (TD). It remains unknown whether this trajectory differs in youth with neuropsychiatric disorders. METHODS: We analyzed sleep EEGs of 664 subjects 6 to 21 y (449 TD, 123 unmedicated, 92 medicated) and 114 subjects 7-12 y (median 10.5 y) followed-up at 18-22 y (median 19 y). SWA (0.4-4 Hz) power was calculated during non-rapid eye movement sleep. RESULTS: TD and unmedicated youth showed cubic central and frontal SWA trajectories from 6 to 21 y (p-cubic<0.05), with TD youth showing peaks in central SWA at 6.8 y and frontal at 8.2 y. Unmedicated attention-deficit/hyperactivity (ADHD) and/or learning disorders (LD) showed peak central SWA 2 y later (at 9.6 y, coinciding with peak frontal SWA) than TD, followed by a 67% steeper slope by 19 y. Frontal SWA peak and slope in unmedicated ADHD/LD, and that of central and frontal in internalizing disorders (ID), were similar to TD. Unmedicated ADHD/LD did not differ in the longitudinal SWA percent change by 18-22 y; unmedicated ID showed a lower longitudinal change in frontal SWA than TD. Medicated youth showed a linear decline in central and frontal SWA from 6 to 21 y (p-linear<0.05). CONCLUSIONS: ADHD/LD youth show a maturational delay and potential topographical disruption in SWA during childhood and steeper decline throughout adolescence, suggesting faster synaptic pruning. Youth with ID experience less changes in frontal SWA by late adolescence. Psychotropic medications may impact the maturational trajectory of SWA, but not the magnitude of developmental decline by late adolescence.

Association of a novel EEG metric of sleep depth/intensity with attention-deficit/hyperactivity, learning, and internalizing disorders and their pharmacotherapy in adolescence.

STUDY OBJECTIVES: Psychiatric/learning disorders are associated with sleep disturbances, including those arising from abnormal cortical activity. The odds ratio product (ORP) is a standardized electroencephalogram metric of sleep depth/intensity validated in adults, while ORP data in youth are lacking. We tested ORP as a measure of sleep depth/intensity in adolescents with and without psychiatric/learning disorders. METHODS: Four hundred eighteen adolescents (median 16 years) underwent a 9-hour, in-lab polysomnography. Of them, 263 were typically developing (TD), 89 were unmedicated, and 66 were medicated for disorders including attention-deficit/hyperactivity (ADHD), learning (LD), and internalizing (ID). Central ORP during non-rapid eye movement (NREM) sleep was the primary outcome. Secondary/exploratory outcomes included central and frontal ORP during NREM stages, in the 9-seconds following arousals (ORP-9), in the first and second halves of the night, during REM sleep and wakefulness. RESULTS: Unmedicated youth with ADHD/LD had greater central ORP than TD during stage 3 and in central and frontal regions during stage 2 and the second half of the sleep period, while ORP in youth with ADHD/LD on stimulants did not significantly differ from TD. Unmedicated youth with ID did not significantly differ from TD in ORP, while youth with ID on antidepressants had greater central and frontal ORP than TD during NREM and REM sleep, and higher ORP-9. CONCLUSIONS: The greater ORP in unmedicated youth with ADHD/LD, and normalized levels in those on stimulants, suggests ORP is a useful metric of decreased NREM sleep depth/intensity in ADHD/LD. Antidepressants are associated with greater ORP/ORP-9, suggesting these medications induce cortical arousability.

Trajectories of Insomnia Symptoms From Childhood Through Young Adulthood.

OBJECTIVES: Insomnia symptoms are transdiagnostic to physical and mental health disorders. Given the lack of population-based cohorts with objective sleep measures and long-term follow-ups, little is known about the chronicity of childhood insomnia symptoms. We determined the developmental trajectories of insomnia symptoms, their evolution into adult insomnia, and the role of objective sleep duration in the transition to adulthood. METHODS: A total of 502 children (median 9 years old, 71.7% response rate) were studied 7.4 years later as adolescents (median 16 years old) and 15 years later as adults (median 24 years old). Insomnia symptoms were ascertained as moderate-to-severe difficulties initiating and/or maintaining sleep via parent- or self reports at all 3 time points, adult insomnia via self-report in young adulthood, and objective short-sleep duration via polysomnography in childhood and adolescence. RESULTS: Among children with insomnia symptoms, the most frequent trajectory was persistence (43.3%), followed by remission (26.9% since childhood, 11.2% since adolescence) and a waxing-and-waning pattern (18.6%). Among children with normal sleep, the most frequent trajectory was persistence (48.1%), followed by developing insomnia symptoms (15.2% since adolescence, 20.7% in adulthood) and a waxing-and-waning pattern (16.0%). The odds of insomnia symptoms worsening into adult insomnia (22.0% of children, 20.8% of adolescents) were 2.6-fold and 5.5-fold among short-sleeping children and adolescents, respectively. CONCLUSIONS: Early sleep interventions are a health priority because pediatricians should not expect insomnia symptoms to developmentally remit in a high proportion of children. Objective sleep measures may be clinically useful in adolescence, a critical period for the adverse prognosis of the insomnia with short-sleep duration phenotype.

Sex and Pubertal Differences in the Maturational Trajectories of Sleep Spindles in the Transition from Childhood to Adolescence: A Population-Based Study.

Sleep spindles, bursts of electroencephalogram (EEG) activity in the σ-frequency (11-16 Hz) range, may be biomarkers of cortical development. Studies capturing the transition to adolescence are needed to delineate age-related, sex-related, and pubertal-related changes in sleep spindles at the population-level. We analyzed the sleep EEG of 572 subjects 6-21 years (48% female) and 332 subjects 5-12 years (46% female) followed-up at 12-22 years. From 6 to 21 years, spindle density (p quadratic = 0.019) and fast (12-16 Hz) spindle percent (p quadratic = 0.016) showed inverted U-shaped trajectories, with plateaus after 15 and 19 years, respectively. Spindle frequency increased (p linear < 0.001), while spindle power decreased (p linear < 0.001) from 6 to 21 years. The trajectories of spindle density, frequency, and fast spindle percent diverged between females and males, in whom density plateaued by 14 years, fast spindle percent by 16 years, and frequency by 18 years, while fast spindle percent and spindle frequency continued to increase until 21 years in females. Males experienced a longitudinal increase in spindle density 31% greater than females by 12-14 years (p = 0.006). Females experienced an increase in spindle frequency and fast spindle percent 2% and 41% greater, respectively, than males by 18-22 years (both p = 0.004), while males experienced a 14% greater decline in spindle power by 18-22 years (p = 0.018). Less mature adolescents (86% male) experienced a longitudinal increase in spindle density 36% greater than mature adolescents by 12-14 years (p = 0.002). Overall, males experience greater maturational changes in spindle density in the transition to adolescence, driven by later pubertal development, and sex differences become prominent in early adulthood when females have greater spindle power, frequency, and fast spindle percent.

Maturational trajectories of non-rapid eye movement slow wave activity and odds ratio product in a population-based sample of youth.

BACKGROUND: Brain maturation is reflected in the sleep electroencephalogram (EEG) by a decline in non-rapid eye movement (NREM) slow wave activity (SWA) throughout adolescence and a related decrease in sleep depth. However, this trajectory and its sex and pubertal differences lack replication in population-based samples. We tested age-related changes in SWA (0.4-4 Hz) power and odds ratio product (ORP), a standardized measure of sleep depth. METHODS: We analyzed the sleep EEG of 572 subjects aged 6-21 y (48% female, 26% racial/ethnic minority) and 332 subjects 5-12 y followed-up at 12-22 y. Multivariable-adjusted analyses tested age-related cross-sectional and longitudinal trajectories of SWA and ORP. RESULTS: SWA remained stable from age 6 to 10, decreased between ages 11 and 17, and plateaued from age 18 to 21 (p-cubic<0.001); females showed a longitudinal decline 23% greater than males by 13 y, while males experienced a steeper slope after 14 y and their longitudinal decline was 21% greater by 19 y. More mature adolescents (75% female) experienced a greater longitudinal decline in SWA than less mature adolescents by 14 y. ORP showed an age-related increasing trajectory (p-linear<0.001) with no sex or pubertal differences. CONCLUSIONS: We provide population-level evidence for the maturational decline and sex and pubertal differences in SWA in the transition from childhood to adolescence, while introducing ORP as a novel metric in youth. Along with previous studies, the distinct trajectories observed suggest that age-related changes in SWA reflect brain maturation and local/synaptic processes during this developmental period, while those of ORP may reflect global/state control of NREM sleep depth.

Influence of Antihistamines on Basophil Activation Test in Food Allergy to Milk and Egg.

BACKGROUND: The basophil activation test (BAT) is used to improve the accuracy of food allergy diagnosis. To date, the influence of antiallergic drugs on BAT reactivity is poorly investigated. The aim of the study was to investigate if BAT results were influenced by antihistamine intake for 3 months in a cohort of patients with IgE-mediated food allergy to milk or egg. METHODS: A retrospective, single-center, observational study was performed. We enrolled subjects with history of hypersensitivity reaction after specific food ingestion, positive skin prick tests and specific IgEs, concomitant allergic rhinitis, and, contraindication to the double-blind, placebo-controlled food challenge due to personal history of systemic reactions related to the ingestion of culprit food. Validated allergens (α-lactoalbumin, ß-lactoglobulin, casein, egg white, and yolk) for BAT were used. RESULTS: Thirty-nine patients with well-documented food symptoms and positive allergological workup were included in the study. BAT was positive in 29 patients. The mean percentages of CD63+ expression to specific culprit allergen did not change after the administration of drugs. CONCLUSIONS: This was the first study assessing the effects of oral antihistamines on basophil reactivity in cow's milk and egg food allergy. Antihistamines do not interfere with BAT results.

Impact of nickel oral hyposensitization on quality of life in systemic nickel allergy syndrome.

Nickel (Ni) oral hyposensitization treatment (NiOHT) is an effective management approach for Ni allergy. No health-related quality of life (HRQoL) data exist for the pre- and post-treatment with NiOHT in systemic nickel allergy syndrome (SNAS). The aims of this study were (a) to explore HRQoL in SNAS patients, (b) to assess changes of HRQoL after 1 year of NiOHT; (c) to evaluate psychological status of patients. SNAS patients completed the Short-Form 36-Item Health Survey and Psychological General Well-Being Index before and 1 week after the end of NiOHT. Moreover, psychological state was assessed with the Minnesota Multiphasic Personality Inventory (MMPI-2). A total of 52 patients self-reported pre- and post-treatment questionnaires. HRQoL was poor at baseline. After 1 year of NiOHT, all outcome measure scores improved by about 20% with respect to baseline data (P < 0.01 for all indices, except depressed mood). Finally, 33 patients performed the MMPI-2. High rates for hypochondriasis and depression were noted. Furthermore, most of the patients had high scores for anxiety, depression, and health concerns. This is the first study showing that NiOHT improves HRQoL of SNAS patients, which can be considered a "personalized medicine" approach.

Benefits and risks of long-term recycling of pharmaceutical sewage sludge on agricultural soil.

European policy is direct towards increasing the agricultural reuse of sludge on soil for improving the fertility; however, the effects of long-term pharmaceutical sewage sludge (PSS) application on soil properties are still unknown. Thus, the aim of this work was to evaluate the agronomic and environmental effects on soil after 17 years of organic amendment with PSS derived from daptomycin production. Five different doses of PSS were spread on lands located in Anagni, Central Italy. Physico-chemical soil properties were investigated, as well as total and bioavailable heavy metals, changes in the soil organic matter quality and biochemical functioning. PSS application showed a positive agronomic potential, improving SOM quality, increasing soil humified organic matter and raising plant nutrients. SOM dynamic was different at low and high PSS supplies, as confirmed by the chemical and biochemical analysis (e.g. C biomass, FDA hydrolysis activity, basal respiration, dehydrogenase, urease and phosphatase activities). However, in a long-term agricultural reuse, environmental risks of PSS recycling were related to the increase of some heavy metals (Hg, Zn and Cu) and exchangeable Na.

Evaluation of benefits and risks associated with the agricultural use of organic wastes of pharmaceutical origin.

Industrial fermentations for the production of pharmaceuticals generate large volumes of wastewater that can be biologically treated to recover plant nutrients through the application of pharmaceutical-derived wastes to the soil. Nevertheless, benefits and risks associated with their recovery are still unexplored. Thus, the aim of the present work was to characterize three potential organic residues (sludge, anaerobic digestate and compost) derived from the wastewater generated by the daptomycin production process. The main parameters evaluated were the physico-chemical properties, potential contaminants (heavy metals, pathogens and daptomycin residues), organic matter stabilization and the potential toxicity towards soil microorganisms and plants. The results showed that all the studied materials were characterized by high concentrations of plant macronutrients (N, P and K), making them suitable for agricultural reuse. Heavy metal contents and pathogens were under the limits established by European and Italian legislations, avoiding the risk of soil contamination. The compost showed the highest organic matter stabilization within the studied materials, whereas the sludge and the anaerobic digestate were characterized by large amounts of labile organic compounds. Although the pharmaceutical-derived fertilizers did not negatively affect the soil microorganisms, as demonstrated by the enzymatic activities, the sludge and the anaerobic digestate caused a moderate and strong phytotoxicity, respectively. The compost showed no toxic effect towards plant development and, moreover, it positively affected the germination and growth in lettuce and barley. The results obtained in the present study demonstrate that the valorization of pharmaceutical-derived materials through composting permits their agricultural reuse and also represents a suitable strategy to move towards a zero-waste production process for daptomycin.

Multi-approach characterization of organic sediment produced by an anaerobic digestion plant fed with pig slurry and stored for a long term in a lagoon.

This study combined different approaches to characterize organic sediments produced by an anaerobic digestion plant feed with pig slurry, and accumulated for many years in a lagoon. The results of all analyses identified a certain homogeneity of the sediments. As a consequence of the pig diet, the sediment contained an high concentration of Zn (about 4gkg-1) and Cu (about 1.2gkg-1), which were mostly associated to the particles with a size ranging from 2 to 53µm. The sediment was made of large amount of organic matter, mostly cellulose and recalcitrant molecules, and 30-40% mineral fraction. XANES and XES spectroscopies indicated the presence of zinc phosphate (38%), zinc sulfide (32%), zinc carbonate (19%), and zinc oxide (11%). The presence in the sediment of forms characterized by a very scarce solubility, as also confirmed by the Zn and Cu chemical speciation, indicated a low bioavailability of these metals. However, although their low mobility, the high concentrations of Zn and Cu allowed to consider the sediment not suitable to use as a fertiliser due to the potential risk of metal interaction with the food chain.

Utility of Basophil Activation Test for monitoring the acquisition of clinical tolerance after oral desensitization to cow's milk: Pilot study.

OBJECTIVE: The quantification of basophil activation by flow cytometry is a useful tool for the assessment of immediate-type responses to food allergens and the prediction of clinical tolerance in food allergy patients. The aim of this study is to investigate how the analysis of allergen-induced CD63 up-regulation by flow cytometry can be effective in monitoring the acquisition of clinical tolerance by specific oral desensitization in food allergy. To our knowledge, this is the first study to examine this topic. MATERIALS AND METHODS: Three male patients affected by cow's milk allergy underwent successful oral desensitization to cow's milk. In order to monitor the acquired clinical tolerance that occurred after treatment, we performed laboratory tests for total and specific IgE, specific IgG4 and the Basophil Activation Test (BAT) both at baseline and at the end of the desensitization protocol. RESULTS: Using a fluorescent enzyme immunoassay, the comparison of specific cow's milk antibodies before and after treatment showed a decrease of specific IgE levels, without reaching normal values, and an increase of specific IgG4 levels. A complete suppression of cow's milk proteins (α-lactoalbumin, ß-lactoglobulin and casein) induced CD63 regulation was observed in all three reported cases. CONCLUSIONS: Using flow cytometry, food allergen-specific basophil responses could be monitored in order to identify an acquired tolerance induced by desensitization treatment. Although further studies are needed to develop this important new topic, it was interesting to note that the BAT seemed to be more sensitive and characterized by a close correlation with clinical tolerance.

'Empty sella syndrome': a case of a patient with sodium succinate hydrocortisone allergy.

OBJECTIVE: We present the case of a woman with 'empty sella syndrome' who experienced generalized urticaria after the administration of sodium succinate hydrocortisone in two episodes. METHODS: The patient underwent an allergological evaluation (prick, intradermal, and patch tests) with hydrocortisone sodium succinate, hydrocortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, methylprednisolone hemisuccinate, methylprednisolone, and preservatives held in the formulation of sodium succinate hydrocortisone (sodium phosphate and methyl-p-oxybenzoate). The basophil activation test (BAT) was also performed with hydrocortisone. The single-blind i.m. challenge test was performed with hydrocortisone sodium phosphate in 4 days. RESULTS: Skin test with hydrocortisone sodium succinate and methylprednisolone hemisuccinate was positive. On the contrary, allergological tests performed with other formulations of the same steroids and preservatives were negative. These results showed an immediate-type allergy to succinate ester. BAT was not helpful to improve our diagnostic work-up because our patient was a 'nonresponder.' Therefore, the patient underwent successfully to a challenge test with hydrocortisone sodium phosphate. CONCLUSIONS: Patients with succinate ester allergy can tolerate alternative corticosteroids without ester.