Non-IgE-Mediated Gastrointestinal Food Protein-Induced Allergic Disorders. Clinical Perspectives and Analytical Approaches.

Non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) is the name given to a series of pathologies whose main entities are food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy (FPE), and food protein-induced enterocolitis syndrome (FPIES). These are more uncommon than IgE-mediated food allergies, their mechanisms remain largely unknown, and their diagnosis is mainly done by clinical history, due to the lack of specific biomarkers. In this review, we present the latest advances found in the literature about clinical aspects, the current diagnosis, and treatment options of non-IgE-GI-FAs. We discuss the use of animal models, the analysis of gut microbiota, omics techniques, and fecal proteins with a focus on understanding the pathophysiological mechanisms of these pathologies and obtaining possible diagnostic and/or prognostic biomarkers. Finally, we discuss the unmet needs that researchers should tackle to advance in the knowledge of these barely explored pathologies.

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss.

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/- mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

Poor prognosis of food protein-induced enterocolitis syndrome to fish.

BACKGROUND: Fish is the most common causative food of food protein-induced enterocolitis syndrome (FPIES) in Southern Europe. In children with FPIES, the development of tolerance varies according to the culprit food and specifically fish seems to have a poorer prognosis than other solid foods. We sought to evaluate the fish-FPIES resolution rate in children. METHODS: A descriptive retrospective analysis of children with fish-FPIES, followed during the last 20 years, was performed. The offending fish, age and symptoms at onset, the coexistence of atopic diseases and FPIES to other foods were registered. All the children included had undergone an oral food challenge (OFC) with the offending fish. We recorded those children that overcame their fish-FPIES and those that did not outgrow the disease. RESULTS: Seventy children were enrolled in this study (median age: 9 yo; IQR 6.4-13.8). Forty-two (60%) achieved tolerance to the offending fish with a median age of 4 years (IQR: 3-5). Among children ≤5 yo (n = 40), 35 (87.5%) developed tolerance; among 6-8yo (n = 14), 40% developed tolerance; and only 12.5% among those ≥9 yo (n = 16) developed tolerance. Twenty-eight children did not outgrow the disease (median age: 8.9 yo; IQR: 9-13.8). We did not find any statistical differences regarding the offending fish, presence of single vs multiple fish-FPIES, symptoms at the beginning, coexistence of other atopic diseases or the coexistence of other FPIES, between the children who overcame the disease and those who did not. CONCLUSION: One in five children with FPIES to fish will not overcome the disease during childhood.

AR101 Oral Immunotherapy for Peanut Allergy.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

[123I]Ioflupane imaging in Caucasians and non-Caucasians: Are there any differences?

PURPOSE OF THE REPORT: To compare diagnostic performance of [123I]ioflupane SPECT imaging in different racial groups. In previous registration trials of [123I]ioflupane, 99% of the subjects enrolled were Caucasians. MATERIALS AND METHODS: A multicenter retrospective case-control study was conducted to evaluate whether the diagnostic performance of [123I]ioflupane SPECT imaging is different in non-Caucasians than in Caucasians matched by age, sex, and final clinical diagnosis. Subjects who had received an initial diagnosis of suspected Parkinson's disease (PD) or essential tremor (ET) and then underwent [123I]ioflupane SPECT imaging to assist with the subject's final clinical diagnosis were enrolled. Each subject's image was rated as normal or abnormal by 3 blinded expert readers. The majority interpretation was then compared with the final clinical diagnosis. Diagnostic performance of [123I]ioflupane SPECT imaging (as measured by positive percent agreement (equivalent to sensitivity), negative percent agreement (equivalent to specificity), overall percent agreement (OPA), and measures of inter-rater agreement) were compared between the Caucasian and non-Caucasian groups. RESULTS: In total, 102 non-Caucasians (58 with PD and 44 with ET as a final clinical diagnosis) and 102 Caucasians (58 with PD, 43 with ET, and 1 with "other") were included in the intent-to-diagnose (ITD) population. There was no significant difference between Caucasians and non-Caucasians in the diagnostic performance of [123I]ioflupane SPECT imaging as measured by sensitivity, specificity, OPA, and measures of inter-rater agreement. CONCLUSION: In this study, the diagnostic performance of [123I]ioflupane SPECT imaging was comparable between Caucasians and non-Caucasians.

Rhodiola rosea Exerts Antiviral Activity in Athletes Following a Competitive Marathon Race.

Rhodiola rosea, a medicinal plant with demonstrated adaptogenic properties, has recently been reported to contain active compounds with antimicrobial activity. The goal of this study was to measure the antiviral and antibacterial properties of the bioactive metabolites of Rhodiola rosea in the serum of experienced marathon runners following supplementation. Marathon runners, randomly divided into two groups, ingested 600 mg/day of Rhodiola rosea (n = 24, 6 female, 18 male) or placebo (n = 24, 7 females, 17 males) for 30 days prior to, the day of, and 7 days post-marathon. Blood serum samples were collected the day before, 15 min post-, and 1.5 h post-marathon. Serum from Rhodiola rosea-supplemented runners collected after marathon running did not attenuate the marathon-induced susceptibility of HeLa cells to killing by vesicular stomatitis virus. However, the use of Rhodiola rosea induced antiviral activity at early times post-infection by delaying an exercise-dependent increase in virus replication (P = 0.013 compared to placebo). Serum from both groups collected 15 min post-marathon significantly promoted the growth of Escherichia coli in culture as compared to serum collected the day before the marathon (P = 0.003, all subjects). Furthermore, the serum from subjects ingesting Rhodiola rosea did not display antibacterial properties at any time point as indicated by a lack of group differences immediately (P = 0.785) or 1.5 h (P = 0.633) post-marathon. These results indicate that bioactive compounds in the serum of subjects ingesting Rhodiola rosea may exert protective effects against virus replication following intense and prolonged exercise by inducing antiviral activity.

Gene silencing of SOCS3 by siRNA intranasal delivery inhibits asthma phenotype in mice.

Suppresors of cytokine signaling (SOCS) proteins regulate cytokine responses and control immune balance. Several studies have confirmed that SOCS3 is increased in asthmatic patients, and SOCS3 expression is correlated with disease severity. The objective of this study was to evaluate if delivering of SOCS3 short interfering RNA (siRNA) intranasally in lungs could be a good therapeutic approach in an asthma chronic mouse model. Our results showed that intranasal treatment with SOCS3-siRNA led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion, a reduction in lung collagen, which are prominent features of airway remodeling. The mechanism implies JAK/STAT and RhoA/Rho-kinase signaling pathway, because we found a decreasing in STAT3 phosphorylation status and down regulation of RhoA/Rho-kinase protein expression. These results might lead to a new therapy for the treatment of chronic asthma.

Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon.

Adaptogens modulate intracellular signaling and increase expression of heat shock protein 72 (HSP72). Rhodiola rosea (RR) is a medicinal plant with demonstrated adaptogenic properties. The purpose of this study was to measure the influence of RR supplementation on exercise-induced muscle damage, delayed onset of muscle soreness (DOMS), plasma cytokines, and extracellular HSP72 (eHSP72) in experienced runners completing a marathon. Experienced marathon runners were randomized to RR (n=24, 6 female, 18 male) or placebo (n=24, 7 female, 17 male) groups and under double-blinded conditions ingested 600mg/day RR extract or placebo for 30days prior to, the day of, and seven days post-marathon. Blood samples were collected, and vertical jump and DOMS assessed the day before, 15min post- and 1.5h post-marathon. DOMS was also assessed for seven days post-marathon. Marathon race performance did not differ between RR and placebo groups (3.87±0.12h and 3.93±0.12h, respectively, p=0.722). Vertical jump decreased post-marathon (time effect, p<0.001) with no difference between groups (interaction effect, p=0.673). Post-marathon DOMS increased significantly (p<0.001) but the pattern of change did not differ between groups (p=0.700). Myoglobin (Mb), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), granulocyte-colony-stimulating factor (G-CSF), C-reactive protein (CRP), and eHSP72 all increased post-marathon (all p<0.001), with no group differences over time (all p>0.300). In conclusion, RR supplementation (600mg/day) for 30days before running a marathon did not attenuate the post-marathon decrease in muscle function, or increases in muscle damage, DOMS, eHSP72, or plasma cytokines in experienced runners.

Exploring new applications for Rhodiola rosea: can we improve the quality of life of patients with short-term hypothyroidism induced by hormone withdrawal?

Patients treated for differentiated thyroid cancer (DTC) are subjected to periodic surveillance that includes serum thyroglobulin measurements followed by radioiodine administrations for diagnostic and therapeutic purposes if necessary. Both procedures require adequately elevated blood levels of thyroid-stimulating hormone (TSH), which can be achieved by two approaches: parenteral administration of recombinant human TSH (rhTSH) or stopping thyroid hormone replacement until optimal levels of endogenous TSH are achieved. Although rhTSH administration does not require hormone withdrawal, it is not inexpensive and carries the risk of secondary effects. The latter option is simpler but induces a profound state of hypothyroidism, which results in physical and mental complaints that may interfere severely with the patient's activities of daily living. Rhodiola rosea is a popular plant in traditional medical systems in Eastern Europe and Asia with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, and eliminating fatigue, all features of clinical hypothyroidism. Investigators have also suggested additional benefits such as cardioprotection or even tumor growth inhibition. Here, we propose R. rosea as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients with DTC who require hormone withdrawal.

A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice.

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1(-/-) null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1(+/+) and null Igf1(-/-) mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1(-/-) null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1(+/+) wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1(-/-) null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.

Impact on allergic immune response after treatment with vitamin A.

BACKGROUND: Vitamin A may have some influence on the immune system, but the role in allergy modulation is still unclear. OBJECTIVE: To clarify whether high levels of retinoic acid (RA) affects allergic response in vivo, we used a murine experimental model of airway allergic disease. METHODS: Ovalbumin (OVA)-immunization/OVA-challenge (OVA/OVA) and house dust mite (HDM)-immunization/HDM-challenge (HDM/HDM) experimental murine models of allergic airway disease, using C57Bl.10/Q groups of mice (n = 10) treated subcutaneously with different concentrations of all-trans RA (0, 50, 500 and 2,500 ug) every 2-days were used to assess the allergic immune response. RESULTS: Levels of total and specific-IgE in sera were increased in all groups of RA treated OVA/OVA and HDM/HDM mice. Percentage and total amount of recruited eosinophil in airways by bronchoalveolar lavage fluid (BALF) were significantly enhanced in groups treated with 50, 500 and 2,500 ug of RA compared to non-treated mice. However, the group of mice treated with 2,500 ug had less eosinophil recruitment than the other two groups (50 and 500 ug). In parallel, levels of IL-5 and total IgE in BALF were also significantly diminished in the group treated with 2,500 ug compared to the other 2 groups (50 and 500 ug). Finally, total lung resistance was decreased in group treated with 2,500 ug compared to non-treated mice. CONCLUSION: Our results suggest that retinoic acid directly enhances allergic response in vivo, but in higher doses may produce of immune suppression.

Inhibition of chronic airway inflammation and remodeling by galectin-3 gene therapy in a murine model.

We previously demonstrated that treatment of acute asthmatic rats with gene therapy using plasmid-encoding Galectin-3 (Gal-3) resulted in an improvement of cellular and functional respiratory parameters. The next question that we wanted to clarify was if in a chronic situation where the treated animal continues to inhale the Ag, does this procedure prevent the chronicity and the remodeling? Chronic inflammation was induced by intranasal administration of OVA over a period of 12 wk. In the treated group, the Gal-3 gene was introduced by intranasal instillation in 50 mul of plasmid-encoding Gal-3. Noninvasive airway responsiveness to methacholine was tested at different times. Cells were obtained by bronchoalveolar lavage and used for RNA extraction and cytometric studies. Eosinophils were counted in blood and bronchoalveolar lavage fluid. Real-time PCR was used to measure Gal-3 and cytokine mRNA expression in lung. Lungs were paraffined and histologic analyses were performed (H&E, periodic acid-Schiff, and Masson Trichrome stain). Our results showed that 12 wk after the first intranasal Ag instillation in chronically asthmatic mice, treatment with the Gal-3 gene led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion and subepithelial fibrosis in the chronically asthmatic mice, with a quantitatively measured reduction in lung collagen, a prominent feature of airway remodeling. Plasmid-encoding Gal-3 acts as a novel treatment for chronic asthma in mice producing nearly complete blockade of Ag responses with respect to eosinophil airway accumulation, airway hyperresponsiveness, and remodeling.

The economic impact of 18FDG positron emission tomography in the surgical management of colorectal cancer with hepatic metastases.

BACKGROUND: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is recognized as a powerful tool in the management of patients with recurrent and/or metastatic colorectal cancer. The aim of this was was to analyze costs from the payer's perspective, of adding FDG-PET to a computed tomography (CT) scan preoperatively in colorectal cancer patients with resectable hepatic metastases. METHODS: CT with and without FDG-PET were compared among patients with colorectal cancer in staging for surgical resection of hepatic metastases. Outcomes included uncomplicated surgery, complicated surgery, or death. Extrahepatic disease occurrence rates and diagnostic accuracy of CT and FDG-PET were obtained from published sources. Complication rates and costs for CT, FDG-PET, and surgical procedures were obtained from Healthcare Finance Administration data. RESULTS: The average expected surgical cost per patient when FDG-PET was used to determine the presence of extrahepatic disease was 16,278 dollars compared to 21,547 dollars for conventional management-a net savings of 5,269 dollars. CONCLUSIONS: Integration of FDG-PET into the presurgical evaluation of patients with hepatic metastases could substantially reduce overall costs and patients' morbidity. This substantial net saving results from the unique ability of FDG-PET in excluding patients with extrahepatic disease, and avoiding unnecessary surgical expenses.

Allergy to lingonberry: A case report.

Past few years cranberry/lingonberry products have been incorporated as healthy products to the US and European market as prophylaxis of recurrent urinary tract infections in young women as well as in chronic infections in elderly which because of there are many biological activities attributed to the that fruit is a very popular additive to the new diets. To the best of our knowledge, this is the first case of allergy to lingonberry. We speculate that previous exposure to lingonberry products could be sensitising. The symptoms, timing of the episode, positive skin test, IgE-ELISA and western-blot strongly support the role of lingonberry as the causative agent.

Clinical applications of (18)F-FDG in oncology.

PET has emerged as a powerful diagnostic tool for the evaluation of cancer patients. Currently, most of these studies are performed with the glucose analog (18)F-FDG, which has been shown to accumulate avidly in most tumors. (18)F-FDG PET is now routinely used in the diagnosis, staging, and posttherapy evaluation of oncologic patients. After reading this paper, the reader should understand the physiologic basis of using (18)F-FDG in patients with different tumors, describe the role of this radiopharmaceutical in the management of oncologic patients, and identify those malignancies for which (18)F-FDG has proved to be effective in diagnosis and follow-up.