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Background: The Learning Early About Peanut allergy (LEAP) study has shown the effectiveness of early peanut introduction in prevention of peanut allergy (PA). In the Enquiring About Tolerance (EAT) study, a statistically significant reduction in PA was present only in per-protocol (PP) analyses, which can be subject to bias., Objective: The aim of this study was to combine individual-level data from the LEAP and EAT trials and provide robust evidence on the bias-corrected, causal effect of early peanut introduction., Method: As part of the European Union-funded iFAAM project, this pooled analysis of individual pediatric patient data combines and compares effectiveness and efficacy estimates of oral tolerance induction among different risk strata and analysis methods., Results: An intention-to-treat (ITT) analysis of pooled data showed a 75% reduction in PA (p < .0001) among children randomized to consume peanut from early infancy. A protective effect was present across all eczema severity groups, irrespective of enrollment sensitization to peanut, and across different ethnicities. Earlier age of introduction was associated with improved effectiveness of the intervention. In the pooled PP analysis, peanut consumption reduced the risk of PA by 98% (p < .0001). A causal inference analysis confirmed the strong PP effect (89% average treatment effect relative risk reduction p < .0001). A multivariable causal inference analysis approach estimated a large (100%) reduction in PA in children without eczema (p = .004)., Conclusion: We demonstrate a significant reduction in PA with early peanut introduction in a large group of pooled, randomized participants. This significant reduction was demonstrated across all risk subgroups, including children with no eczema. Furthermore, our results point to increased efficacy of the intervention with earlier age of introduction., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Primary hazelnut allergy is a common cause of anaphylaxis in children, as compared to birch-pollen associated hazelnut allergy. Population-based data on hazelnut and concomitant birch-pollen allergy in children are lacking. We aimed to investigate the prevalence of primary and pollen-associated hazelnut allergy and sensitization profiles in school-aged children in Berlin, Germany., Methods: 1570 newborn children were recruited in Berlin in 2005-2009. The school-age follow-up (2014-2017) was based on a standardized web-based parental questionnaire and clinical evaluation by a physician including skin prick tests, allergen specific immunoglobulin E serum tests and placebo-controlled double-blind oral food challenges, if indicated., Results: 1004 children (63.9% response) participated in the school-age follow-up assessment (52.1% male). For 1.9% (n = 19, 95%-confidence interval 1.1%-2.9%) of children their parents reported hazelnut-allergic symptoms, for half of these to roasted hazelnut indicating primary hazelnut allergy. Symptoms of birch-pollen allergy were reported for 11.6% (n = 116 95%-CI 9.7%-13.7%) of the children. Both birch-pollen allergy and hazelnut allergy associated symptoms affected 0.6% (n = 6, 95%-CI 0.2%-1.3%) of children. Assessment of allergic sensitization was performed in 261 participants and showed that almost 20% of these children were sensitized to hazelnut, being the most frequent of all assessed food allergens, or birch-pollen, the majority to both., Conclusions: Based on parental reports hazelnut-allergic symptoms were far less common than sensitization to hazelnut. This needs to be considered by physicians to avoid unnecessary changes in diet due to sensitization profiles only, especially when there is a co-sensitization to hazelnut and birch-pollen., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan-European, population-based birth cohort study have been lacking. This study compares the prevalence and early-life risk factors of these diseases in European primary school children., Methods: In the prospective multicentre observational EuroPrevall-iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC-based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these., Results: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family-allergy-score, odds ratio (OR) 1.50 (95% CI 1.32-1.70) per standard deviation; early-life allergy symptoms, OR 2.72 (2.34-3.16) for each symptom; and caesarean birth, OR 1.35 (1.04-1.76). Female gender, OR 0.72 (0.58-0.90); older siblings, OR 0.79 (0.63-0.99); and day care, OR 0.81 (0.63-1.06) were protective factors., Conclusion: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early-life factors are modifiable and may be considered for prevention strategies., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The prevalence of food allergy (FA) among European school children is poorly defined. Estimates have commonly been based on parent-reported symptoms. We aimed to estimate the frequency of FA and sensitization against food allergens in primary school children in eight European countries., Methods: A follow-up assessment at age 6-10 years of a multicentre European birth cohort based was undertaken using an online parental questionnaire, clinical visits including structured interviews and skin prick tests (SPT). Children with suspected FA were scheduled for double-blind, placebo-controlled oral food challenges (DBPCFC)., Results: A total of 6105 children participated in this school-age follow-up (57.8% of 10 563 recruited at birth). For 982 of 6069 children (16.2%), parents reported adverse reactions after food consumption in the online questionnaire. Of 2288 children with parental face-to-face interviews and/or skin prick testing, 238 (10.4%) were eligible for a DBPCFC. Sixty-three foods were challenge-tested in 46 children. Twenty food challenges were positive in 17 children, including seven to hazelnut and three to peanut. Another seventy-one children were estimated to suffer FA among those who were eligible but refused DBPCFC. This yielded prevalence estimates for FA in school age between 1.4% (88 related to all 6105 participants of this follow-up) and 3.8% (88 related to 2289 with completed eligibility assessment)., Interpretation: In primary school children in eight European countries, the prevalence of FA was lower than expected even though parents of this cohort have become especially aware of allergic reactions to food. There was moderate variation between centres hampering valid regional comparisons., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Hen's egg is the most common cause of food allergy in early childhood., Objective: We investigated the efficacy and safety of early hen's egg introduction at age 4 to 6 months to prevent hen's egg allergy in the general population., Methods: This randomized, placebo-controlled trial included 4- to 6-month-old infants who were not sensitized against hen's egg, as determined based on specific serum antibodies (IgE). These infants were randomized to receive either verum (egg white powder) or placebo (rice powder) added to the first weaning food 3 times a week under a concurrent egg-free diet from age 4 to 6 until 12 months. The primary outcome was sensitization to hen's egg (increased specific serum IgE levels) by age 12 months. Hen's egg allergy (secondary outcome) was confirmed by double-blind, placebo-controlled food challenges., Results: Among 406 screened infants, 23 (5.7%) had hen's egg-specific IgE before randomization. Seventeen of 23 underwent subsequent double-blind, placebo-controlled food challenges, and 16 were confirmed as allergic, including 11 with anaphylactic reactions. Of the 383 nonsensitized infants (56.7% male), 184 were randomized to verum and 199 to placebo. At 12 months of age, 5.6% of the children in the verum group were hen's egg sensitized versus 2.6% in the placebo group (primary outcome; relative risk, 2.20; 95% CI, 0.68-7.14; P = .24), and 2.1% were confirmed to have hen's egg allergy versus 0.6% in the placebo group (relative risk, 3.30; 95% CI, 0.35-31.32; P = .35)., Conclusion: We found no evidence that consumption of hen's egg starting at 4 to 6 months of age prevents hen's egg sensitization or allergy. In contrast, it might result in frequent allergic reactions in the community considering that many 4- to 6-month-old infants were already allergic to hen's egg., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Many infants with atopic dermatitis (AD) are sensitized against food or airborne allergens. The severity of AD, using the SCORAD, seems to correlate with elevated serum levels of TARC/CCL17. Other chemokines, such as CCL20 or CCL25, have been described in the context of allergic inflammation. The aim of this study was to analyze whether chemokine serum levels differ within a cohort of infants suffering from varying severities of AD with or without allergic sensitization., Methods: Chemokine serum levels (CCL8, CCL17, CCL20, CCL25) as well as food and airborne allergen-specific IgE were analyzed in infants with AD., Results: About 60.9% (78/128) infants with AD (median age 8.8 months, 49 (38%) girls and 79 (62%) boys) showed a positive screening test to common food allergens and 26.6% to common airborne allergens. There was a strong correlation between serum levels of CCL17 and SCORAD in food-sensitized infants (r(s) = 0.646, p = <1e-04) and airborne-sensitized infants (r(s) = 0.587, p = 0.00065) in contrast to non-sensitized ones. Moreover, food-sensitized infants showed significantly higher levels of CCL25 compared to non-food-sensitized ones (p = 0.007)., Conclusion: The strong correlation between TARC/CCL17 and SCORAD in infants with specific sensitizations may be accounted for by the impaired skin barrier. As TARC/CCL17 has been found mainly in the (inflamed) skin but not in the gut, the detection of significantly higher levels of CCL25, ligand of CCR9, localized primarily in the gastrointestinal tract, suggests its impact on food allergen-induced inflammation processes in food-sensitized infants., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: CD24 expression has been described as a significant prognostic factor in multiple solid tumours. Most of these studies have, however, been undertaken using the Ab-2 antibody (clone SN3b), which detects a CD24-associated carbohydrate, and not the CD24 protein itself. Although its biological identity remains unclear, its prognostic significance means that detection of this carbohydrate may, nonetheless, be clinically relevant., Methods: 133 breast carcinomas were selected (pT1-2 pN0-2 M0, no secondary carcinoma, no contralateral carcinoma) from a previous SN3b expression study on a larger cohort of breast carcinomas. After updating data on follow-up observations, we carried out univariate and multivariate analysis of the prognostic significance of SN3b for total and breast cancer-specific survival., Results: A statistically significant correlation between cytoplasmic SN3b immunoreactivity and positive node status was found. Cytoplasmic SN3b also has node status-independent prognostic significance. Total survival exhibits a statistically significant dependency on cytoplasmic SN3b even for pN0 cases., Conclusion: The independent prognostic value of CD24 as detected by Ab-2/clone SN3b could replace the diagnostic axillary dissection in breast carcinoma patients if this was confirmed in further studies. Also, clarifying the exact epitope of this interesting antibody is more than warranted.

Background: Apart from a number of cases of inaccurate prognosis in regard to individual patients, the inter- and intra-observer variability of the classical, histological prognosis parameters have been under repeated discussion. For this reason, a long-term analysis was carried out in regard to overall survival by means of automated microscopic image analysis of the nucleolar organizer regions (AgNORs) to objectify tumour grading in the case of breast carcinoma.This consists of a selective representation of argyrophilic proteins that are associated with the nucleolus organising regions., Methods: The evaluation included 244 female patients with an average age of 59.3 years. The characterisation of the histological sections was carried out on the basis of the AMBA/R system. With this software the histometric characterisation level was evaluated in terms of the nucleolus organizer regions. The post-observation data were obtained from the clinical register and were complemented by mortality data from the cancer registers and by data supplied by the residents' registration office of Berlin., Results: The average post-observation period was 106.6 months. With the Cox-Regression the influence of the co-variables (conventional prognosis parameters and AgNOR parameters) were examined. In the model, only the parameters pN, G and various AgNOR parameters remain present., Conclusion: There is a strong correlation between survival and selected AgNOR parameters. These could replace the conventional grading as the standard measure for the mitosis rate together with the pleomorphism level. Instead of the-time consuming AMBA/R system originally used, a new implementation of AgNOR quantification with modern VM systems could be applied., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1449591192859058.

For breast centre certification, follow-up care data have to be presented, although the further treatment is carried out outside of the hospital. An analysis of 2062 patients with their first operation (breast cancer and carcinoma in situ) occurring between 1.1.1984 and 31.12.1998 has been conducted. The tracking of follow-up results ended on 1.7.2007. The survival of breast cancer patients appears to be superior in the pure clinical register than with cross-linking with additional registers (Epidemiological Cancer Register and registration of address office). The outcome of this is that the completed feedback of the cases of death (Cancer Register) and of living patients (registration of address office) increases the qualitative statement. The compliance with the data security laws may be ensured by pseudo-anonymisation., (Georg Thieme Verlag Stuttgart, New York.)

Gross cystic disease fluid protein (GCDFP-15) and mammaglobin are both widely used and accepted markers for epithelia of breast origin. We aimed to evaluate their relation of expression on parallel whole tissue sections in primary breast cancer by immunohistochemistry and also to correlate it with clinico-pathological parameters including patient survival. Primary breast carcinomas from 165 patients with a mean clinical follow-up of 73 months were immunostained using commercially available antibodies against GCDFP-15 and mammaglobin. An immunoreactive score (IRS) was calculated based on the cytoplasmic staining intensity and the number of cells stained. Cytoplasmic expression of GCDFP-15 and mammaglobin was observed in 73.3% and 72.1% of invasive breast carcinomas respectively. 91.8% of breast cancer cases expressed at least one of both markers. Both markers strongly correlated with each other and were significantly associated with lower tumour grading. Additionally, GCDFP-15 negativity was significantly associated with shortened disease-free survival times in univariate and multivariate analyses. We demonstrated the strong correlation of GCDFP-15 and mammaglobin with each other and showed that only very few primary breast cancers are completely negative for both markers. The significantly longer disease free survival times for patients with GCDFP-15 positive tumours clearly warrants further study.

Purpose: CD24 is a cell adhesion molecule that has been implicated in metastatic tumor progression of various solid tumors. We aimed to clarify the expression patterns of CD24 in colorectal cancer and to correlate these to clinicopathologic variables including patient survival., Experimental Design: 147 colorectal carcinomas and two colon carcinoma cell lines were immunostained for CD24. Cytoplasmic and membranous immunoreactivity were semiquantitatively scored. Fisher's exact test, chi(2) test for trends, Kaplan-Meier analysis, and Cox's regression were applied., Results: The cell line CX-2 showed only a minimal membranous CD24 immunoreactivity, in contrast to HT29, which stained strongly in the cytoplasm. In colorectal cancer, 68.7% of the tumors showed membranous CD24 staining, whereas 84.4% showed cytoplasmic staining. In 10% of cases, an exceptionally strong cytoplasmic CD24 expression was observed. The latter significantly correlated to higher tumor stages (Dukes and pT), nodal or systemic metastasis, and higher tumor grade. In survival analysis, strong cytoplasmic CD24 expression correlated significantly (Cox's regression: P = 0.012, relative risk = 3.7) to shortened patient survival in the group of cases without distant metastases., Conclusions: CD24 is commonly up-regulated in colorectal cancer and is a new independent prognostic marker which corroborates the importance of CD24 in tumor progression of this disease.

Background/aims: CD24 is expressed in hematological malignancies as well as in a large variety of solid tumors and is often associated with a more aggressive course of the disease. We aimed to evaluate CD24 protein expression in pancreatic adenocarcinomas and to correlate it to clinicopathological data including patient survival., Methods: 95 primary adenocarcinomas of the pancreas were immunostained using a monoclonal CD24 antibody (Ab-2, clone 24C02). Staining was evaluated as negative versus positive for statistical analysis., Results: CD24 expression was observed in 71.6% of cases with a heterogeneous distribution, and a significantly higher rate of positivity in high grade (G3) tumors. In univariate survival analyses, no association of CD24 expression with shortened overall survival of the patients could be demonstrated., Conclusion: CD24 is commonly expressed in adenocarcinomas of the pancreas, preferentially high-grade tumors and thus might be a marker of disease progression., (Copyright 2004 S. Karger AG, Basel and IAP)

Purpose: CD24 is expressed in hematological malignancies as well as in a large variety of solid tumors including breast cancer. We aimed to evaluate CD24 protein expression in breast cancer and to correlate to clinicopathological data including patient survival., Experimental Design: Primary breast carcinomas (201) with a mean clinical follow-up time of 53 months were immunostained using a monoclonal CD24 antibody (Ab-2, clone 24C02). The staining was evaluated as negative versus positive for statistical analysis., Results: In invasive breast carcinomas, CD24 expression was observed in 84.6% of cases. In univariate survival analyses, a significant association of CD24 expression with shortened patient overall survival (5-year survival rate 91.9% versus 83.8%; P = 0.031; log rank test) and disease-free survival (5-year progression rate 88.3% versus 57.0%; P = 0.0008) was demonstrated. In multivariate analyses CD24, tumor grading and nodal status were significant prognostic parameters for shortened disease-free survival., Conclusions: Our data suggest that CD24 expression in primary breast cancer as detected by immunohistochemistry might be a new marker for a more aggressive breast cancer biology.

Ultrasonic tissue characterization is based on the assumption that microscopic tissue structures are identifiable by their acoustic properties. Our study group consisted of 23 cardiac recipients. Two-dimensional images were obtained within 2 hours of endomyocardial biopsy. The end-diastolic echo frames were digitized into the matrix of an image-processing system. A region of interest was placed into the anteroseptal segment of the left ventricle. The texture within the region of interest was analyzed using four major groups of texture analysis (first-order histogram, co-occurrence matrix, run-length statistic, and power spectrum). A total of 408 echocardiographic examinations were compared with histologic findings. The 117 initially calculated texture parameters were reduced incrementally using a series of discriminant analyses. A set of three texture parameters (inverse difference moment undirected, run-length nonuniformity vertical, and sector sum) was able to describe changed echocardiographic texture when rejection occurred. Using these three parameters, echocardiographic sensitivity was 89.0% and specificity was 83.6% for moderate rejection. We conclude that cardiac rejection is associated with echocardiographic texture alterations and that serial echocardiographic texture analysis can reliably identify rejection.

The aim of the study was to assess the usefulness of M-mode echocardiography for noninvasive diagnosis of cardiac rejection. For this purpose, 292 M-mode images of 26 heart transplant recipients were analyzed. The echocardiographic images were digitized into an image analysis system. The curves of left ventricular diameter changes were obtained and its first differential calculated. A total of 23 parameters were measured. The most important parameters were: peak velocity of systolic diameter change, peak velocity of diastolic diameter change, time to peak velocity of systolic diameter change, time to peak velocity of diastolic diameter change (TPEAK-D), isovolumetric relaxation time (IVRT), rapid filling time (RFT), shortening fraction (SF), and mean velocity of circumferential fiber shortening (MVCF). The echocardiographic parameters were compared to biopsy results. In 18 patients, 23 biopsy-proven moderate rejections occurred. When rejection occurred, IVRT decreased 23% +/- 6% (P < 0.05), SF decreased 13% +/- 14% (P<0.05), MVCF decreased 18% +/- 18% (P<0.05), and TPEAK-D increased 27% +/- 27% (P<0.05). We concluded that the analysis of digitized M-mode images can identify heart transplant rejection.

Due to contrary results concerning the interaction of cholecystokinin and dopamine (CCK/DA) circadian variations in CCK/DA concentration were investigated in forebrain nuclei of rats (Nc. accumbens, striatum) in order to assess the influence of time of day on neurotransmission. CCK was determined by a radioimmunoassay, DA was measured by electrochemical detection after HPLC separation. A distinct circadian rhythm, superimposed by harmonics (12 h, 6 h) was found in the content of both DA and CCK. A trough was shown for CCK during the light phase and a crest during the late afternoon and the dark phase, respectively. For DA the opposite was found. Caused by a phase-shift of about 3-4 h, the CCK/DA rhythms are negatively correlated. The differences are significant at 11.00 h, 13.00 h, 21.00 h, and 03.00 h. The results indicate that circadian processes are involved in neuronal transmission of CCK and DA.

Oculocardiac reflex (OCR) is a frequently occurring complication in eye operations. It is a trigemino-vagal reflex characterised by the clinical occurrence of bradycardia and other cardiac rhythm disturbances following manipulations on the eye and its surroundings especially after traction of the external eye muscles. In this paper based on an analysis of 402 anaesthesia records, a bradycardia frequency (f = less than 60/min) of 31.8% was noted while other rhythm disturbances occurred in 5.7%. Predisposition facts were identified as age over 50, hypertension and cardiac diseases requiring medication with cardiac drugs. The frequency of OCR is considerably lowered by diabetes mellitus. Examination of 159 traction measurements made at the lateral rectus muscle revealed that the first manipulation made at the rectus bulbi superior muscle resulted in a statistically significantly stronger reflex activity than at the other muscles. In a further series of investigations in which rectus bulbi superior muscle was tested last, this muscle again showed the biggest frequency deviation. Only determination of the percentage heart rate decrease is suitable for characterising reflex activity. The frequency of the reflex occurring in our study was 71.7%, the result being reduced by the high proportion of diabetics, who are relatively reflex insensitive.

In Golgi-Kopsch impregnated pyramid neurons of the neocortex (regio precentralis agranularis and area striata) of adult rats the individual variability was investigated. As parameters served the dendritic lengths, spine numbers and spine densities along the dendritic orders (basal and apical), within single dendritic fields, the apical and basal parts of the dendritic tree and of the whole neuron. The statistical tests gave the following results: Pyramid neurons in the regio precentralis agranularis are more variable than pyramid neurons in the area striata. Within the area striata the lamina III-pyramid neurons are more invariable than the lamina V-pyramid neurons. The basal dendrites are statistically more invariable than the apical dendrites. The dendritic lengths are less variable than the spine values. In general, the variability is different in particular subdivisions of the neurons analyzed as well as for the parameter chosen. The variability of neuronal structures depends from genetical factors and from a functional training. The knowledges about this variability are still insufficient. They are of considerable importance for the planning of experiments followed by statistical analyses.

Lamina V-pyramidal neurons of regio precentralis agranularis in Golgi-Kopsch impregnated frontal series of the brains of four adult male rats were analyzed quantitatively in order to estimate the degree of individual variability. As parameters served the dendritic lengths, spine numbers and spine densities along the dendritic orders, within single dendritic fields and within the apical and basal parts of the dendritic tree or of the whole neuron. The significance of individual differences in these parameters between the animals was proven by the tests of Mann and Whitney or of Kruskal and Wallis. The variability turned out to be different in particular subdivisions of the neuron analyzed as well as for the parameter chosen. The basal single dendritic field showed a relative high degree of constancy in its data and the dendritic lengths were statistically more invariable than the spine values. The knowledge about high or less variable parameters in strictly selected neurons is of considerable importance for the planning of experiments followed by quantitative analyses of neurons. The application of the most suitable statistical method is also discussed.