Nasal IL-13 production identifies patients with late-phase allergic responses.

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. OBJECTIVE: We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. METHODS: In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n = 20) or placebo (n = 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. CONCLUSIONS: IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Polyunsaturated Fatty Acid Intake during Complementary Feeding and Neurodevelopmental Outcome in Very Low Birth Weight Infants.

Polyunsaturated fatty acids (PUFAs) are vital for brain development, yet limited knowledge exists regarding PUFA intake during complementary feeding (CF) and its impact on neurodevelopmental outcomes in very low birth weight (VLBW) infants. This secondary analysis of a randomized intervention trial, aimed to investigate the association between dietary intake of total PUFAs, arachidonic acid (AA), and docosahexaenoic acid (DHA) during CF and neurodevelopmental outcomes at 12 and 24 months of corrected age (CA). Dietary intakes were assessed using monthly 3 day dietary protocols from 3 to 12 months CA. Neurodevelopmental outcome was evaluated using the Bayley Scales of Infant Development-III. Among the 177 randomized patients, PUFA intake and neurodevelopmental outcomes were evaluated in 140 (79%) infants. Higher total PUFA and DHA intakes significantly correlated with improved cognitive and motor function at 12 months CA, while increased AA intake notably enhanced motor scores at 12 months CA. However, median dietary intakes of AA and DHA (AA: 53.50-84.25 mg/d; DHA: 51.47-76.23 mg/d) fell short of recommended levels (AA: 140 mg/d; DHA: 100 mg/d) at any of the investigated timepoints. These findings emphasize the need to enhance total PUFA, DHA and AA intakes during CF, ensuring adherence to guidelines and unlocking the potential to improve neurodevelopmental outcomes in VLBW infants.

Effects of early introduction of solid foods on nutrient intake in preterm infants during their 1st year of life: a secondary outcome analysis of a prospective, randomized intervention study.

Very low birth weight (VLBW) infants have higher nutritional needs even after hospital discharge. However, data concerning current nutrient intakes at different time points after the introduction of solid foods and whether dietary reference values are being met are scarce. To adress this issue, this secondary analysis of a prospective, two-arm interventional study in 177 VLBW infants 21 investigates dietary intake comparing early and late (early: 10-12 weeks corrected for gestational age, late: 16-18 weeks corrected for gestational age) introduction of standardized complementary food during the first year of life. Nutritional intake was assessed using self-reported monthly 3-day dietary records from 3 until 12 months, corrected for gestational age. The time point of the introduction of solid foods did not influence nutrient intake, but the early introduction of solids tended toward a higher proportional intake of protein and carbohydrates and a lower intake of fat as a percentage of total energy) during the 1st year of life, corrected for gestational age. The results of this study indicate that this standardized feeding concept was sufficient for zinc, calcium, and phosphorus intake. However, dietary iron and vitamin D intakes did not meet the recommendations. Thus, prolonged iron supplementation should be considered beyond the introduction of meat and vitamin D supplementation at least until 12 months, corrected for gestational age. Trial registration number: ClinicalTrials.gov: NCT01809548.

Effect of Regular Electrotherapy on Spinal Flexibility and Pain Sensitivity in Patients with Chronic Non-Specific Neck Pain and Low Back Pain: A Randomized Controlled Double-Blinded Pilot Trial.

Background and Objectives: Chronic neck pain and low back pain are common conditions in high-income countries leading to social and medical problems such as invalidity and decreased quality of life. The aim of this study was to investigate the effect of supra-threshold electrotherapy on pain level, subjective feeling of disability, and spinal mobility in patients with chronic pain in the spinal cord. Materials and Methods: 11 men and 24 women with a mean age of 49 years were randomly divided into three groups: group 1, "therapy": supra-threshold electrotherapy was applied on the whole back after electrical calibration; group 2, "control": electrical calibration without successive electrotherapy; group 3, "control of control": no stimulation. Sessions were performed once a week and six times in total, each lasting 30 min. The numeric pain rating scale (NRS), cervical and lumbar range of motion (ROM), as well as disability in daily live were investigated before and after the sessions using questionnaires (Neck Disability Index, Roland Morris Questionnaire, Short-form Mc Gill Pain Questionnaire (SF-MPQ)). Results: Spinal mobility improved significantly in the lumbar anteflexion (baseline mean, 20.34 ± SD 1.46; post session mean, 21.43 ± SD 1.95; p = 0.003) and retroflexion (baseline mean, 13.68 ± SD 1.46; post session mean, 12.05 ± SD 1.37; p = 0.006) in the group receiving electrotherapy. Pain levels measured by the NRS and disability-questionnaire scores did not differ significantly before and after treatment in any of the groups. Conclusions: Our data indicate that regular supra-threshold electrotherapy for six times has a positive effect on lumbar flexibility in chronic neck pain and low back pain patients, whereas pain sensation or subjective feeling of disability remained unchanged.

Longitudinal Assessment of Serum 25-Hydroxyvitamin D Levels during Pregnancy and Postpartum-Are the Current Recommendations for Supplementation Sufficient?

(1) Background: Pregnant women are at risk of vitamin D deficiency. Data on pregnancy outcomes in women with vitamin D deficiency during pregnancy are controversial, and prospective longitudinal data on vitamin D deficiency with consistent definitions in pregnant women are scarce. (2) Methods: The aim of this prospective longitudinal cohort study was to investigate 25-hydroxyvitamin D levels over the course of pregnancy and postpartum in singleton and twin pregnancies with regard to dietary and supplemental vitamin D intake and environmental factors influencing vitamin D levels, evaluated by a standardized food frequency questionnaire. (3) Results: We included 198 healthy singleton and 51 twin pregnancies for analysis. A total of 967 study visits were performed over a 3-year period. Overall, 59.5% of pregnant women were classified as vitamin D deficient in the first trimester, 54.8% in the second trimester, 58.5% in the third trimester, 66.9% at birth, and 60% 12 weeks postpartum, even though 66.4% of the study population reported daily pregnancy vitamin intake containing vitamin D. Dietary vitamin D intake did not affect vitamin D levels significantly. (4) Conclusions: The majority of pregnant women evaluated in this study were vitamin D deficient, despite administration of pregnancy vitamins containing vitamin D. Individualized vitamin D assessment during pregnancy should be considered to ensure adequate supplementation and prevention of hypovitaminosis D.

Metabolome and lipidome derangements during a severe mast cell activation event in a patient with indolent systemic mastocytosis.

BACKGROUND: The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. OBJECTIVE: Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. METHODS: A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography-mass spectrometry. RESULTS: A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase. CONCLUSIONS: Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events.

Two years of treatment with the recombinant grass pollen allergy vaccine BM32 induces a continuously increasing allergen-specific IgG4 response.

BACKGROUND: BM32, a grass pollen allergy vaccine containing four recombinant fusion proteins consisting of hepatitis B-derived PreS and hypoallergenic peptides from the major timothy grass pollen allergens adsorbed on aluminium hydroxide has been shown to be safe and to improve clinical symptoms of grass pollen allergy upon allergen-specific immunotherapy (AIT). We have investigated the immune responses in patients from a two years double-blind, placebo-controlled AIT field trial with BM32. METHODS: Blood samples from patients treated with BM32 (n = 27) or placebo (Aluminium hydroxide) (n = 13) were obtained to study the effects of vaccination and natural allergen exposure on allergen-specific antibody, T cell and cytokine responses. Allergen-specific IgE, IgG, IgG1 and IgG4 levels were determined by ImmunoCAP and ELISA, respectively. Allergen-specific lymphocyte proliferation by 3H thymidine incorporation and multiple cytokine responses with a human 17-plex cytokine assay were studied in cultured peripheral blood mononuclear cells (PBMCs). FINDINGS: Two years AIT comprising two courses of 3 pre-seasonal injections of BM32 and a single booster after the first pollen season induced a continuously increasing (year 2 > year 1) allergen-specific IgG4 response without boosting allergen-specific IgE responses. Specific IgG4 responses were accompanied by low stimulation of allergen-specific PBMC responses. Increases of allergen-specific pro-inflammatory cytokine responses were absent. The rise of allergen-specific IgE induced by seasonal grass pollen exposure was partially blunted in BM32-treated patients. INTERPRETATION: AIT with BM32 is characterised by the induction of a non-inflammatory, continuously increasing allergen-specific IgG4 response (year 2 > year1) which may explain that clinical efficacy was higher in year 2 than in year 1. The good safety profile of BM32 may be explained by lack of IgE reactivity and low stimulation of allergen-specific T cell and cytokine responses. FUNDINGS: Grants F4605, F4613 and DK 1248-B13 of the Austrian Science Fund (FWF).

Selection for atrial fibrillation ablation: Importance of diastolic function grading.

BACKGROUND: Pulmonary vein isolation (PVI) has become an accepted therapy for patients with atrial fibrillation (AF) and the indications have widened to include non-paroxysmal AF-patients. Maintenance of sinus rhythm after PVI can be adversely affected by clinical or echocardiographic parameters, which should be clearly identified. METHODS AND RESULTS: After baseline clinical and echocardiographic evaluations, PVI was performed in patients with paroxysmal or non-paroxysmal AF. The follow-up strategy after PVI included: (1) clinical follow up, 12-lead electrocardiography (ECG) and 24-h ECG every 3 months, (2) trans-telephonic ECGs twice daily and when symptomatic (over 4 weeks) every 3 months, or (3) continuous monitoring via implanted devices. A recurrence was an atrial arrhythmia lasting >30s. All 340 PVI procedures of 229 patients were analyzed. On average, 1.5 PVI procedures per patient (range, 1-6 PVI) were performed. The mean age was 58±11 years (73% male) with 109 paroxysmal and 120 non-paroxysmal AF cases. Clinical follow-up with 12-lead ECGs, 24-h ECGs, trans-telephonic ECGs, and implanted devices was complete in 100%, 63%, 51%, and 16% of cases, respectively. The overall one-year recurrence rate of 59% (range, 24-82%) was dependent on grades of diastolic function (normal - dysfunction grade III) in a multivariable analysis model. Patients with normal diastolic function had the lowest recurrence rates of 24% and 49% after 1 and 3 years of follow-up, respectively (p<0.0001). CONCLUSION: Diastolic function could serve as a simple summary predictor for AF recurrence, and would facilitate clinical decision-making in AF treatment.

Thymoquinone attenuates tumor growth in ApcMin mice by interference with Wnt-signaling.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are at increased risk for the development of colorectal cancer. Surgery and chemoprevention are the most effective means to prevent cancer development. Thymoquinone (TQ) is considered the main compound of the volatile Nigella sativa seed oil and has been reported to possess anticarcinogenic properties. In this study we evaluated the chemopreventive properties of TQ in a mouse model of FAP. METHODS: APCMin mice were fed with chow containing 37.5 mg/kg or 375 mg/kg TQ for 12 weeks. H&E stained intestine tissue sections were assessed for tumor number, localization, size, and grade. Immunohistochemistry for ß-catenin, c-myc, Ki-67 and TUNEL-staining was performed to investigate TQ's effect on major colorectal cancer pathways. TQ's impact on GSK-3ß and ß-catenin were studied in RKO cells. RESULTS: 375 mg/kg but not 37.5 mg/kg TQ decreased the number of large polyps in the small intestine of APCMin mice. TQ induced apoptosis in the neoplastic tissue but not in the normal mucosa. Furthermore, upon TQ treatment, ß-catenin was retained at the membrane and c-myc decreased in the nucleus, which was associated with a reduced cell proliferation in the villi. In vitro, TQ activated GSK-3ß, which induced membranous localization of ß-catenin and reduced nuclear c-myc expression. CONCLUSIONS: In summary, TQ interferes with polyp progression in ApcMin mice through induction of tumor-cell specific apoptosis and by modulating Wnt signaling through activation of GSK-3ß. Nigella sativa oil (or TQ) might be useful as nutritional supplement to complement surgery and chemoprevention in FAP.