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The diagnosis of celiac disease (CD) at the first diagnostic step requires the detection of specific class A antibodies to tissue transglutaminase type-2 (TG2 IgA) and the measurement of total immunoglobulin A (tIgA) to exclude IgA deficiency. The aim of the study was to evaluate the new quantitative immunoassay panel allowing for the detection of celiac-specific antibodies with the simultaneous determination of tIgA from the same sample of blood at one time. This retrospective study included 104 pediatric patients divided into groups with recognized CD and IgA deficiency (n = 20; 19%), immunocompetent children with CD (n = 28; 27%), children with IgA deficiency and without CD (n = 28; 27%), and the control group of immunocompetent children without CD (n = 28; 27%). Intestinal biopsy with histopathological evaluation (except five patients with CD who were diagnosed without biopsy) and measurement of reference celiac specific antibodies were performed in all children. Multiparametric quantitative immunoassay Polycheck® Celiac IgA plus total IgA test was used to evaluate its usefulness in CD screening and IgA deficiency diagnosis. The statistical analysis showed the high sensitivity and specificity of both TG2 IgA and tIgA on the multiparametric panel (sensitivity 96% and 100%; specificity 100% and 79%, respectively). The accuracy and area under the ROC curve for tIgA were 0.904 and 0.955, while for TG2 IgA they were 0.982 and 1.000, respectively. Although the sensitivity of IgA antibodies against deaminated gliadin peptides was low (20%), the specificity reached 100%. The study showed that Polycheck® Celiac IgA plus total IgA test is a specific and sensitive tool for simultaneous serological CD screening and recognition of IgA deficiency.

The pathogenesis of biliary atresia (BA) is still not clear. The aim of this study was to evaluate the expression of selected immunological parameters in liver tissue in BA children based on CMV/EBV infection status. Eight of thirty-one children with newly diagnosed BA were included in this prospective study and assigned to two groups (I with active infection, II without active or past infection). All studies were performed on surgical liver biopsies. To visualize CD8+ T cells and CD56 expression, immunohistochemical staining was performed. The viral genetic material in the studied groups was not found, but CMV infection significantly affected the number of CD8+ lymphocytes in both the portal area and the bile ducts. The average number of CD8+ cells per mm2 of portal area in Groups I and II was 335 and 200 (p = 0.002). The average number of these cellsthat infiltrated the epithelium of the bile duct per mm2 in Group I and II was 0.73 and 0.37 (p = 0.0003), respectively. Expression of CD56 in the bile ducts corresponded to the intensity of the inflammatory infiltrate of CD8+ cells. Our results suggest that active CMV infection induces an increased infiltration of CD8+ lymphocytes, which could play a role in BA immunopathogenesis. Increased CD56 expression can be a sign of a newly formed bile structure often without lumen, suggesting inhibition of the maturation process in BA.

Small Intestinal Bacterial Overgrowth (SIBO) is a form of dysbiosis that involves increased bacterial colonization of the small intestine with some of the bacteria more characteristic of the colon microbiota. The prevalence of SIBO over recent decades has been estimated to range from 2.5 to 22% (depending on the source) and to increase with age and among individuals with comorbidities. Recently, an increase in the number of diagnosed SIBO cases has been observed, which is primarily due to the availability of noninvasive breath tests that facilitate the diagnostic process. However, SIBO is still both a diagnostic and a therapeutic problem. This review presents the pathophysiology, manifestations, diagnostics, and recommended management of SIBO.

Hydrogen sink is a beneficial process, which has never been properly examined in chickens. Therefore, the aim of this study was to assess the quantity and quality of microbiota involved in hydrogen uptake with the use of real-time PCR and metagenome sequencing. Analyses were carried out in 50 free-range chickens, 50 commercial broilers, and 54 experimental chickens isolated from external factors. The median values of acetogens, methanogens, sulfate-reducing bacteria (SRB), and [NiFe]-hydrogenase utilizers measured in the cecum were approx. 7.6, 0, 0, and 3.2 log10/gram of wet weight, respectively. For the excreta samples, these values were 5.9, 4.8, 4, and 3 log10/gram of wet weight, respectively. Our results showed that the acetogens were dominant over the other tested groups of hydrogen consumers. The quantities of methanogens, SRB, and the [NiFe]-hydrogenase utilizers were dependent on the overall rearing conditions, being the result of diet, environment, agrotechnical measures, and other factors combined. By sequencing of the 16S rRNA gene, archaea of the genus Methanomassiliicoccus (Candidatus Methanomassiliicoccus) were discovered in chickens for the first time. This study provides some indication that in chickens, acetogenesis may be the main metabolic pathway responsible for hydrogen sink.

Biochemical abnormalities in the course of type 1 diabetes (T1D) may cause the production/activation of various proteins and peptides influencing treatment and causing a risk of complications. The aim of this study was to assess concentrations of selected serum substances involved in the pathogenesis and course of T1D and to correlate their concentrations with the duration of T1D. The study included patients with T1D (n = 156) at the age of 3–17, who were divided according to the duration of the disease into those newly diagnosed (n = 30), diagnosed after 3–5 (n = 77), 6–7 (n = 25), and over 7 (n = 24) years from the onset of T1D, and age-matched healthy controls (n = 30). Concentrations of amylin (IAPP), proamylin (proIAPP), catestatin (CST), chromogranin A (ChgA), nerve growth factor (NFG), platelet-activating factor (PAF), uromodulin (UMOD), and intestinal fatty acid binding protein (I-FABP) were measured in sera using immunoenzymatic tests. There were significant differences in concentrations of all the substances except UMOD and NGF between T1D patients and healthy children. The duration of the disease affected concentrations of CST, ChgA, PAF, and NGF, i.e., proteins/peptides which could have an impact on the course of T1D and the development of complications. In long-term patients, a decrease in concentrations of CST and ChgA, and an increase in PAF concentrations were found. In the case of NGF, a decrease was observed after the initial high values, followed by an increase over 7 years after T1D diagnosis. Concluding, the results show that concentrations of selected serum indicators may change in the course of T1D. Further studies are needed to establish whether these indicators could be used in the context of predicting long-term complications.

The diagnosis of celiac disease (CD) may be delayed due to non-specific clinical symptoms. The aim of the study was to evaluate the clinical manifestation and diagnostic process of CD in Polish children and adults. Methods: The members of the Polish Coeliac Society (n = 2500) were asked to complete a questionnaire on socio-demographic factors, clinical and diagnostic aspects of CD. The analysis was based on 796 responses from patients with confirmed CD diagnosis, and included 224 (28.1%) children and 572 (71.9%) adults. Results: The mean duration of symptoms prior to CD diagnosis in children was significantly shorter than in adults (p < 0.001), and amounted to 3.1 and 9 years respectively. The most frequent symptoms before CD diagnosis were abdominal pain and bloating in children (70.4%), and chronic fatigue in adults (74.5%). Although almost all CD patients claimed to strictly avoid gluten after CD diagnosis, symptoms were still present in the majority of these respondents. No comorbid diseases were reported by 29.8% of children and by 11.7% of adults (p < 0.001). Conclusions: the results indicate that CD diagnosis is delayed in Poland, especially in adults, and clinicians should be aware of the diversity in CD presentation.

Patients with type 1 diabetes (T1D) are at higher risk of celiac disease (CD). Recently, intestinal fatty acid binding protein (I-FABP) has been shown to be a serological biomarker of impaired intestinal barrier in CD. Thus, the aim of this study was to verify whether I-FABP could be an early marker of CD in pediatric T1D patients. I-FABP was measured in sera of patients with T1D (n = 156), active CD (n = 38), T1D with active CD (T1D-CD, n= 51), and age-matched healthy children (n = 55). Additionally, I-FABP was determined in T1D patients with negative CD serology at least one year before CD diagnosis (T1D-CD-1, n = 22), in CD patients on a gluten-free diet (CD-GFD, n = 36), and T1D-CD patients on GFD (T1D-CD-GFD, n = 39). Sera were tested using immunoenzymatic assay. Significantly increased levels of I-FABP were found in the T1D, active CD, and T1D-CD groups (1153 ± 665, 1104 ± 916, and 1208 ± 878, respectively) in comparison to healthy with controls (485 ± 416, p < 0.05). GFD induced a significant decrease in I-FABP levels in CD and T1D-CD groups (510 ± 492 and 548 ± 439, respectively). Interestingly, in T1D-CD-1 and T1D, I-FABP levels were comparable (833 ± 369 vs. 1153 ± 665), and significantly increased in relation to healthy controls and T1D-CD values on GFD. The results indicate that the epithelial barrier is disrupted in T1D patients independently of CD development; therefore, I-FABP cannot serve as an early marker of CD in T1D patients. Although GFD can improve epithelial recovery, the question remains as to whether GFD could exert beneficial effects on the intestinal barrier in early stages of T1D.

The diagnosis of celiac disease (CD) may be delayed due to non-specific clinical symptoms. The aim of the study was to evaluate the clinical manifestation and diagnostic process of CD in Polish children and adults. Methods: The members of the Polish Coeliac Society (n=2 500) were asked to complete a questionnaire on socio-demographic factors, clinical and diagnostic aspects of CD. The analysis was based on 796 responses from patients with confirmed CD diagnosis, and included 224 (28.1%) children and 572 (71.9%) adults. Results: The mean duration of symptoms prior to CD diagnosis in children was significantly shorter than in adults (p < 0.001), and amounted to 3.1 and 9 years respectively. The most frequent symptoms before CD diagnosis were abdominal pain and bloating in children (70.4%), and chronic fatigue in adults (74.5%). Although almost all CD patients claimed to strictly avoid gluten after CD diagnosis, symptoms were still present in the majority of these respondents. No comorbid diseases were reported by 29.8% of children and by 11.7% of adults (p < 0.001). Conclusions: The results indicate that CD diagnosis is delayed in Poland, espe-cially in adults, and clinicians should be aware of the diversity in CD presentation.

A high quality of knowledge and how it is communicated by healthcare professionals (HCPs) let the patient understand coeliac disease (CD) and result in better adherence to therapeutic recommendations. Therefore, the aim of the current study was to assess the opinion of Polish respondents with CD on the comprehension of CD among Polish HCPs. The analysis was based on 796 responses from patients (the members of the Polish Coeliac Society) with confirmed CD diagnosis (224; 28.1% children and 572; 71.9% adults). The most frequently consulted HCPs regarding CD symptoms in the analysed group were gastroenterologists, and various support groups and associations for CD patients. Furthermore, their comprehension of CD was rated best, as 89.3% (n = 552) of the patients who had contact with support groups and associations classified their knowledge on CD as good. More than a half of the respondents (n = 310, 56.6%) who had contact with general practitioners (GPs) due to their symptoms, rated the doctor’s knowledge on CD as bad. Nurses’ comprehension on CD was classified as bad by 45 (52.3%) respondents who had contact with a nurse. Out of 294 Polish patients with CD who had contact with a dietician, 247 (84.0%) assessed that the dietician communicated their knowledge on CD well. The respondents rated that GPs and nurses communicated their knowledge on CD in the worst manner (60.4% and 58.1%, respectively). Out of 796 respondents, 792 (99.5%) provided information about the number of appointments with GPs due to symptoms that occurred prior to CD diagnosis. The respondents had contact with GPs 13 863 times before obtaining a CD diagnosis due to their symptoms. After the establishment of a CD diagnosis, the number of appointments with GPs decreased to 3850, and the average number of appointments decreased from 17.8 to 5.1. The respondents assessed that the knowledge on CD of HCPs is not satisfactory. The work of support groups and associations on CD, who promote reliable CD diagnosis and treatment methods, should be promoted. The cooperation between various HCPs needs to be encouraged, which may lead to better compliance.

In order to answer the question if an IgE-mediated allergy (A-IgE) may occur in subjects with celiac disease (CD), a systematic review was performed of available publications collected in the United States National Institute for Biotechnology Information/National Institutes of Health/National Library of Medicine/PubMed database up to 28 December 2022, with the use of the following keywords “allergy&celiac/coeliac”, “sensitization&celiac/coeliac”, and “anaphylaxis&celiac/coeliac” compared in the form of a conjunction. In total, the search returned 2013 publications from these keywords in any section of the article. As numerous review articles included the above-mentioned entries in the abstract, we decided to focus on the publications with the entries only in the title (n = 63). After rejecting studies unrelated to the topic, narrative reviews, book chapters, conference abstracts, symposium reports, letters to the editor, or non-English articles, 18 publications (6 observational original studies and 12 case reports describing a total of 15 cases of A-IgE developed after a diagnosis of CD) were included to this review. Our study is the first systematic review on allergy occurrence in CD patients. The analysis indicated that the possibility of a coexistence of A-IgE with any food and inhalant allergens in subjects diagnosed with CD should be considered. A sensitization to wheat was the most frequently described in subjects with CD. The clinical manifestation of A-IgE in CD was similar to that in subjects without CD; e.g., with possible atopic dermatitis, vomiting, urticaria, angioedema, or anaphylactic shock. Screening for allergies in subjects with CD should be considered, especially in those cases where symptoms persist after introducing a gluten-free diet. The elimination of wheat from the diet of patients with CD may lead to a loss of immune tolerance and to the development of sensitization, which may even manifest as anaphylaxis. In conclusion, although there are few studies assessing the occurrence of A-IgE in subjects with CD, they show the possibility of a coexistence of both diseases and the high clinical significance of this phenomenon, which indicates the need for further studies.

The allergic march is a progression of naturally occurring symptoms whose nature changes with age. The classic allergic march typically begins in infancy and manifests in the form of atopic dermatitis and food allergy. As immune tolerance develops over time, these conditions may resolve by the age of 3–5 years; however, they may evolve into allergic rhinitis and bronchial asthma. Traditional diagnostic assessments, such as skin prick testing or serum allergen-specific immunoglobulin E (sIgE) level testing, are conducted to introduce effective treatment. Recent years saw the emergence of precision allergy molecular diagnosis (PAMD@), which assesses sIgE against allergenic molecules. This new technology helps more accurately evaluate the patient’s allergy profile, which helps create more precise dietary specifications and personalize allergen-specific immunotherapy. This review presents possible predictions regarding the allergic march and the means of controlling it based on PAMD@ results.

Background Irritable bowel syndrome (IBS) is a functional gastrointestinal disease in the pathogenesis of which the gut dysbiosis may play an important role. Thus, probiotics, prebiotics or microbiota metabolites such as butyric acid are considered to be an effective therapy in IBS, however still there is no trials presented efficacy of these three biotic components delivered to the patient simultaneously. This study aims to evaluate the effects of the combined formulation comprising sodium butyrate, probiotics and short chain fructooligosaccharides (scFOS) on the severity of clinical IBS symptoms and the quality of patients’ life (IBS-QOL). Methods This is randomized double-blind placebo-controlled trial included adults with IBS diagnosed according Rome IV criteria. Patients will be randomized in ratio 1:1 into the intervention group receiving a preparation of 300 mg of colon-targeted microencapsulated sodium butyrate, the mixture of Lactobacillus strains (L. rhamnosus and L. acidophilus) and Bifidobacterium strains (B. longum, B. bifidum, B. lactis) and 64mg of scFOS or into the control group receiving placebo containing maltodextrin. After 12 weeks of intervention the primary outcome will measure changes in IBS symptoms with the use of IBS-Symptom Severity Score (IBS-SSS), IBS-Global Improvement Scale (IBS-GIS), IBS-Adequate Relief (IBS-AR), and IBS-QOL. The secondary outcomes will be: type of stools, symptoms assessed in a patients’ diary, adverse events, anthropometric and nutritional measurements, levels of inflammatory cytokines. Discussion The findings will provide the first evidence for the use of a combination of three biotic compounds in IBS. Trial registration: The study was registered in the clinicaltrials.gov registry under the number NCT05013060.

Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through Janus kinase signal transducers and activators of transcription pathway (JAK/STAT) activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve–Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186_Tyr190del variant present constitutively. Tyr186_Tyr190del was found by exome sequencing and was shown to be de novo (absent in proband’s parents and siblings) and mosaic (present in approximately 15–40% of cells depending on the tissue studied—blood, urine sediment, hair bulbs and buccal swab). Functional studies were performed in the Epstein–Barr virus-immortalized patient’s B cell lymphoblastoid cell line, which carried the variant in approximately 95% of the cells. Western blot showed that the patient’s cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3, which is indicative of IL6-independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1, we speculate that these drugs may be effective in the treatment of our patient’s condition.

The purpose of the randomized double-blind placebo-controlled trial was to assess the effectiveness of synbiotic preparation containing probiotic Lactobacillus rhamnosus FloraActive™ 19070-2, Lactobacillus acidophilus DSMZ 32418, Bifidobacterium lactis DSMZ 32269, Bifidobacterium longum DSMZ 32946, Bifidobacterium bifidum DSMZ 32403 and fructooligosaccharides in adult patients with diarrhea-dominant IBS (IBS-D). The study included eighty patients with moderate and severe IBS-D who were randomized to receive synbiotics or placebo for eight weeks. Finally, a total of sixty-eight patients finished the study. The primary endpoints included the assessment of the symptoms’ severity with IBS symptom severity scale (IBS-SSS), an improvement of IBS global symptoms with Global Improvement Scale (IBS-GIS) and adequate relief of symptoms after four and eight weeks of therapy. Secondary endpoints, which were collected by telephone interviewers three times a week included the assessment of individual IBS symptoms and adverse events. Synbiotic treatment in comparison to placebo significantly improved IBS-GIS (p = 0.043), and IBS-SSS score inducing a decrease in the total IBS-SSS (p = 0.042) and in domain-specific scores related to flatulence (p = 0.028) and bowel habit (p = 0.028) after four and eight weeks. Patients treated with synbiotics reported in weekly observations a significant amelioration in a feeling of incomplete bowel movements, flatulence, pain, stool pressure and diarrheal stools compared to those receiving placebo. There were no differences in adverse events between both groups. Concluding, the multi-strain synbiotic preparation was associated with a significant improvement in symptoms in IBS-D patients and was well-tolerated. These results suggest that the use of synbiotics offers a benefit for IBS-D patients. [Clinicaltrials.gov NCT04206410 registered 20 December 2019].

Patients with type 1 diabetes (T1D) are at increased risk for developing celiac disease (CD). The aim of the study was to assess the usefulness of celiac-specific human leukocyte antigen (HLA) haplotype and the rs3130484 variant of MSH5 gene, a previously described non-HLA variant associated with CD in the Polish population as a first-line screening for CD in T1D pediatric patients. Serological CD screening performed in the T1D group (n = 248) and healthy controls (n = 551) allowed for CD recognition in 20 patients (8.1%) with T1D (T1D + CD group). HLA-DQ2, HLA-DQ8 and the rs3130484 variant were genotyped with TaqMan SNP Genotyping Assays. The T1D + CD group presented a higher, but not statistically significant, frequency of HLA-DQ2 in comparison with T1D subjects. Combining the rs3130484 with HLA-DQ2/HLA-DQ8 typing significantly increased the sensitivity of HLA testing from 32.7% to 68.7%, and the accuracy of estimating CD prediction from 51.7% to 86.4% but decreased the specificity from 100% to 78.2%. The receiver operating characteristic curve analysis confirmed the best discrimination for the combination of both genetic tests with an area under curve reaching 0.735 (95% CI: 0.700–0.7690) in comparison with 0.664 (95% CI: 0.632–0.696) for HLA typing alone. Results show the low utility of HLA-DQ2/HLA-DQ8 typing for CD screening in T1D pediatric patients. Combination of the rs3130484 variant of the MSH5 gene and HLA testing increases both the sensitivity and the predictive value of the test accuracy, but still, the obtained values are not satisfactory for recommending such testing as the first-line screening for CD in T1D patients.

Introduction: Hypersensitivity to ionising radiation is most often observed in the course of primary immunodeficiency diseases, which are associated with dysfunctional DNA repair, especially with the repair of double-strand breaks. Due to phenotypic similarities between primary immunodeficiency diseases, radiosensitivity testing can prove useful in early differential diagnosis, when attempting to identify patients with increased toxic reactivity to radio- and chemotherapy, and can have an impact on the process of their preparation for stem cell transplantation. Aim: The aim of the study was to assess the radiosensitivity in vitro of patients with ataxia-telangiectasia (A-T) syndrome, and their parents, carriers of one copy of the mutated ATM gene. Material/Methods: Lymphoblastoid cell lines (LCLs) from 15 A-T patients (remaining under the care of the Immunology Clinic and Immunology Outpatient Clinic of the Children’s Memorial Health Institute) and 11 mothers and 11 fathers of A-T patients, were used for radiosensitivity assessment. A standard colony survival assay (CSA) was applied in the tests. Results: A markedly decreased survival fraction (SF) of LCLs after in vitro exposure to X-rays was observed in all A-T patients when compared to control cells. A clear diversification of radiosensitivity to ionising radiation was observed among obligate heterozygotes. SF for heterozygotes was between 1% and 53%, i.e. varied from the values in healthy individuals to the extreme values observed in A-T patients. Conclusion: The assessment of cell radiosensitivity in A-T patients using CSA may be a useful additional test for confirming a clinically suspected disease. In heterozygous carriers, it can be an indicator of increased risk of carcinogenesis, and in both A-T patients and their parents can be helpful in making decisions with regard to radio- and/or chemotherapy.

Medulloblastoma, the most common malignant pediatric brain tumor, is a heterogeneous disease, with the existence of at least four molecular types: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 tumors. The latter two groups, which can be identified by an application of multi-gene expression or methylation profiling, show sometimes ambiguous categorization and are still classified for diagnostic reason as non-SHH/non-WNT medulloblastomas in updated WHO 2016 classification. In order to better characterize non-SHH/non-WNT tumors, we applied the method based on the Nanostring nCounter Technology, using the 26 genes codeset in 68 uniformly treated medulloblastoma patients. This allowed for identification of tumors, which shared common Group 3 and Group 4 gene signatures. We recognized three transcriptional groups within non-WNT/non-SHH tumors: Group 3, Group 4 and the Intermediate 3/4 Group. Group 3, in line with previously published results, showed poor prognosis with survival rate

Celiac disease (CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Before activating the immune system, gluten peptides are transferred by the epithelial barrier to the mucosal lamina propria, where they are deamidated by intestinal tissue transglutaminase 2. As a result, they strongly bind to human leucocyte antigens (HLAs), especially HLA-DQ2 and HLA-DQ8, expressed on antigen-presenting cells. This induces an inflammatory response, which results in small bowel enteropathy. Although gluten is the main external trigger activating both innate and adaptive (specific) immunity, its presence in the intestinal lumen does not fully explain CD pathogenesis. It has been hypothesized that an early disruption of the gut barrier in genetically susceptible individuals, which would result in an increased intestinal permeability, could precede the onset of gluten-induced immune events. The intestinal barrier is a complex functional structure, whose functioning is dependent on intestinal microbiota homeostasis, epithelial layer integrity, and the gut-associated lymphoid tissue with its intraepithelial lymphocytes (IELs). The aim of this paper was to review the current literature and summarize the role of the gut microbiota, epithelial cells and their intercellular junctions, and IELs in CD development.

The increase in allergy prevalence observed in recent decades may be a consequence of early intestinal dysbiosis. The intestinal microbiota is formed in the first 1000 days of life, when it is particularly sensitive to various factors, such as the composition of the mother’s microbiota, type of delivery, infant’s diet, number of siblings, contact with animals, and antibiotic therapy. Breastfeeding and vaginal birth favorably affect the formation of an infant’s intestinal microbiota and protect against allergy development. The intestinal microbiota of these infants is characterized by an early dominance of Bifidobacterium, which may have a significant impact on the development of immune tolerance. Bifidobacterium breve is a species commonly isolated from the intestines of healthy breastfed infants and from human milk. This review outlines the most important environmental factors affecting microbiota formation and the importance of Bifidobacterium species (with a particular emphasis on Bifidobacterium breve) in microbiota modulation towards anti-allergic processes. In addition, we present the concept, which assumes that infant formulas containing specific probiotic Bifidobacterium breve strains and prebiotic oligosaccharides may be useful in allergy management in non-breastfed infants.

Purpose Impaired angiogenesis is one of the most common findings in preeclamptic placentas. A new angiogenetic role of fractalkine (CX3CL1) is recently recognized apart from inflammatory activity. In this study, a link between CX3CL1 and the development of placental vasculature in preeclampsia was examined. Methods The study comprised 52 women allocated to Group 1 (normotensive, n = 23) and Group 2 (preeclampsia, n = 29). In each group Doppler parameters, serum levels of CX3CL1, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) were assessed between 30 and 32 week of pregnancy. After the delivery, placental samples were taken and the vascularization and expression of CX3CR1 receptor were assessed after immunostaining. Results CX3CL1 and sFlt-1 serum levels were significantly higher levels in Group 2 vs Group 1, while PlGF serum levels was significantly lower in Group 2. Lower cerebroplacental ratio (CPR) was observed in Group 2. The vascular/extravascular tissue index (V/EVTI) was significantly lower in Group 2, while compared to Group 1, with the lowest value in the fetus growth restriction (FGR) subgroup (0.18 ± 0.02; 0.24 ± 0.03; 0.16 ± 0.02, respectively). The expression of examined CX3CR1 was higher in Group 2, while compared to Group 1, reaching the highest values in FGR subgroup. There was a moderate negative correlation between birth weight, V/EVTI and CX3CL1 serum level and CX3CR1 placental expression in the group of pregnancies complicated with preeclampsia. Conclusion The significant underdevelopment of placental vascular network in preeclampsia is associated with the change in the CX3CL1/CX3CR1 system, especially in FGR complicated pregnancies.

Probiotics seem to have promising effects in the prevention and treatment of allergic conditions including atopic dermatitis (AD) and food allergy. The purpose of this multicenter randomized placebo-controlled trial was to evaluate the effectiveness of a probiotic preparation comprising Lactobacillus rhamnosus ŁOCK 0900, Lactobacillus rhamnosus ŁOCK 0908, and Lactobacillus casei ŁOCK 0918 in children under 2 years of age with AD and a cow’s milk protein (CMP) allergy. The study enrolled 151 children, who—apart from being treated with a CMP elimination diet—were randomized to receive the probiotic preparation at a daily dose of 109 bacteria or a placebo for three months, with a subsequent nine-month follow-up. The primary outcomes included changes in AD symptom severity assessed with the scoring AD (SCORAD) index and in the proportion of children with symptom improvement (a SCORAD score decreased by at least 30% in comparison with that at baseline). After the three-month intervention, both the probiotic and placebo groups showed a significant (p &lt, 0.0001) decrease in SCORAD scores, which was maintained nine months later. The percentage of children who showed improvement was significantly higher in the probiotic than in the placebo group (odds ratio (OR) 2.56, 95% confidence interval (CI) 1.13–5.8, p = 0.012) after three months. Probiotics induced SCORAD improvement mainly in allergen sensitized patients (OR 6.03, 95% CI 1.85–19.67, p = 0.001), but this positive effect was not observed after nine months. The results showed that the mixture of probiotic ŁOCK strains offers benefits for children with AD and CMP allergy. Further research is necessary to assess the effect of probiotic supplementation on the development of immune tolerance. (ClinicalTrials.gov NCT04738565)

The purpose of the randomized double-blind placebo-controlled trial was to assess the effectiveness of synbiotic preparation containing probiotic Lactobacillus rhamnosus FloraActive&trade, 19070-2, Lactobacillus acidophilus DSMZ 32418, Bifidobacterium lactis DSMZ 32269, Bifidobacterium longum DSMZ 32946, Bifidobacterium bifidum DSMZ 32403 and fructooligosaccharides in adult patients with diarrhea-dominant IBS (IBS-D). The study included eighty patients with moderate and severe IBS-D who were randomized to receive synbiotics or placebo for eight weeks. Finally, a total of sixty-eight patients finished the study. The primary endpoints included the assessment of the symptoms&rsquo, severity with IBS symptom severity scale (IBS-SSS), an improvement of IBS global symptoms with Global Improvement Scale (IBS-GIS) and adequate relief of symptoms after four and eight weeks of therapy. Secondary endpoints, which were collected by telephone interviewers three times a week included the assessment of individual IBS symptoms and adverse events. Synbiotic treatment in comparison to placebo significantly improved IBS-GIS (p = 0.043), and IBS-SSS score inducing a decrease in the total IBS-SSS (p = 0.042) and in domain-specific scores related to flatulence (p = 0.028) and bowel habit (p = 0.028) after four and eight weeks. Patients treated with synbiotics reported in weekly observations a significant amelioration in a feeling of incomplete bowel movements, flatulence, pain, stool pressure and diarrheal stools compared to those receiving placebo. There were no differences in adverse events between both groups. Concluding, the multi-strain synbiotic preparation was associated with a significant improvement in symptoms in IBS-D patients and was well-tolerated. These results suggest that the use of synbiotics offers a benefit for IBS-D patients. [Clinicaltrials.gov NCT04206410 registered 20 December 2019].

The aim of the study was to investigate the toxic effects of aflatoxin B1 (AFB1) and efficacy of a probiotic preparation containing L. reuteri, L. plantarum, L. pentosus, L. rhamnosus and L. paracasei and Saccharomyces cerevisiae yeasts to ameliorate their effects in broiler chickens. A total of 168 one-day-old female Ross 308 broilers were randomly allocated to six groups. Three wheat and soybean meal-based diets were prepared: Control diet and diets contaminated with 1 or 5 mg/kg AFB1 supplied in moldy wheat. All diets were unsupplemented or supplemented with probiotic, cold pelleted and fed from 1 to 35 day of life. Feeding diet with 1 mg AFB1/kg did not affect performance, but a diet with 5 mg AFB1 resulted in a significant reduction of feed intake and BWG, both diets induced liver and kidneys enlargement. The probiotic supplementation of the diets partially ameliorated those negative effects and resulted in a significant increase of AFB1 excretion. It was accompanied by the reduced level of AFB1 residues in the liver from 8.9 to 3.7 and from 11.8 to 5.9 &micro, g/kg, in kidneys from 7.9 to 2.5 and from 13.7 to 4.1 &micro, g/kg in birds fed the less and more contaminated diets, respectively. AFB1 exposure caused many severe histopathological changes in the liver and kidneys of broilers, probiotic supplementation significantly reduced the changes of these organs. It may be concluded that the probiotic supplementation can be used to alleviate the negative effects of contamination of broiler feed with AFB1 on bird health and product security.

The “microbiota hypothesis” ties the increase in allergy rates observed in highly developed countries over the last decades to disturbances in the gut microbiota. Gut microbiota formation depends on a number of factors and occurs over approximately 1000 days of life, including the prenatal period. During this period the microbiota helps establish the functional immune phenotype, including immune tolerance. The development of immune tolerance depends also on early exposure to potential food allergens, a process referred to as nutritional programming. This article elaborates on the concepts of microbial and nutritional programming and their role in the primary prevention of allergy.

Oxidative stress (OS) has been recently implicated in the disease pathogenesis in inflammatory bowel disease (IBD). The aim of the study was to evaluate oxidative and antioxidative stress status and the risk of the atherosclerotic process in children with IBD and functional gastrointestinal disorders (FGID). The prospective study included a group of 71 children during a period of 2 years. In all children, laboratory tests were performed and intima-media complex in the carotid artery was measured (IMC). Low values of OS were more frequent in children with IBD than in the FGID group. The average concentration of oxidized lipoprotein with average density (oxLDL) was lower in patients with IBD. Among patients with IBD, higher concentrations of oxLDL were recorded in patients with longer-duration disease and with higher concentrations of total cholesterol. In the IBD group, more often, higher concentrations of anti-oxLDL were recorded among patients with longer-duration disease. The obtained results did not support the hypothesis of total antioxidant capacity depletion and greater overall OS in patients with IBD. Patients with IBD with a longer duration of the disease have higher concentrations of oxLDL and anti-oxLDL.

Introduction The results of studies assessing whether patients with Down syndrome have increased risk of coeliac disease are contradictory. The prevalence of coeliac disease in patients with Down syndrome is estimated at a wide range between 1% to as much as 18.6%. Aim To assess coeliac disease prevalence in patients with Down syndrome in Poland. Material and methods The study enrolled 301 patients with Down syndrome from six centres in Poland (Wroclaw, Sandomierz, Rzeszow, Grudziadz, Katowice, and Bydgoszcz). We measured the concentration of anti-tissue transglutaminase IgA antibodies and anti-deamidated gliadin peptide IgG antibodies in all patients. Patients with abnormal positive (> 10 U/ml) or inconclusive (7–10 U/ml) result of the serological test were offered endoscopic biopsy of the small intestine in the main centre. Results In 31 (10.3%) patients increased concentrations of the investigated antibodies were found, including 19 (6.3%) patients with increased tTg-IgA concentration, 27 (8.97%) patients with increased concentration of DGP-IgG, and 15 (4.98%) patients with increased concentration of both types of antibodies. Endoscopic biopsy of the small intestine was planned for all 31 patients with abnormal results of at least one antibody test and for 2 patients with inconclusive results. One of them suffered from previously diagnosed and histologically confirmed coeliac disease. Biopsy was not conducted in 9 patients due to contraindications, lack of their consent, or introduction of a gluten-free diet by the parents before the examination. In a group of 23 patients who underwent endoscopic biopsy of the small intestine, in 15 patients the histopathological picture of the small intestinal mucosa was typical for coeliac disease, 2 patients were diagnosed with lesions of grade 1 according to the classification by Marsh-Oberhuber, 1 patient was diagnosed with focal shortening of villi and hypertrophy of the crypts with no intraepithelial lymphocytosis (remains under gastrological observation), 2 patients were diagnosed with mucosal inflammation of the duodenum, and 3 patients were found to have a normal histopathological picture of the small intestine. Analysis of the data included in the questionnaires of all patients showed no statistically significant differences in the body height, body mass index, prevalence of abdominal pain, diarrhoea, constipations, recurrent stomatitis, enamel hypoplasia, thyroid diseases, or hypertransaminasaemia between the groups of patients with normal and abnormal serological test results. Significantly higher prevalence of abdominal flatulence (p < 0.05) and epilepsy (p < 0.05) was found in the group of patients whose serological test results were negative. Conclusions Patients with Down syndrome are a high-risk group for coeliac disease in the Polish population, with an estimated prevalence of at least 5.4%. Serological tools based on tTG-IgA and DGP-IgG tests are useful for the diagnosis of coeliac disease in Down syndrome patients. tTG-IgA test may be superior to DGP-IgG test in patients with normal total IgA level. Tests for coeliac disease should be carried out in all Polish patients with Down syndrome, regardless of the clinical picture.

Background Anti-liver kidney microsome (anti-LKM) autoantibodies are a distinguishing feature of type II autoimmune hepatitis (AIH-2). However, the levels of anti-LKM-1 in adult AIH-2 patients and their role in liver immunopathology remain equivocal. The aim of the study was to survey the autoantibody profile and the activity of liver disease in adult patients diagnosed with AIH-2 at childhood. Methods The autoantibody profile of adults was compared with the autoantibodies of the pediatric period. Liver function test, Immunoglobulin G (IgG), and gamma globulins were evaluated at the AIH presentation, at the age of 18 years, and at the current adult visit. Results All ten patients tested positive for LKM-1 at least once during the pediatric period. At the adult visit, four patients lost autoantibody positivity. LKM-1 was positive in four, liver cytosol antigen 1 (LC-1) in two, soluble liver antigen in one, and antinuclear antigen in one patient. Additionally three patients with LKM-1 and one patient without LKM-1 were positive for AMA-M2 (where AMA is antimitochondrial antibodies) Immunoglobulin M (IgM). Liver function markedly improved at 18 years and adult visit compared with initial diagnosis of AIH with only a mild decrease of IgG. The six adult patients positive for at least one autoantibody had statistically lower aspartate aminotransferase (AST) and gamma-glutamyltranspeptidase (GGTP) than the four patients autoantibody negative (AST: 52 vs. 88 IU/l, P < 0.05; GGTP 19 vs. 163 IU/l, P < 0.05). Conclusion LKM-1 positivity is not a stable condition in all patients with AIH-2. Patients who remained autoantibody positive had better liver function tests than those who lost their positivity. The presence of AMA-M2 autoantibodies suggest that development of AIH/Primary Biliary Cirrhosis (PBC) overlap syndrome should be considered.

Here, we report the extensive bioinformatic and functional analyses of the unusual pLOCK 0919, a plasmid originating from the probiotic Lactobacillus casei LOCK 0919 strain. This plasmid is atypical because it harbors the spaCBA-srtC gene cluster encoding SpaCBA pili. We show that all other spaCBA-srtC sequences of the Lactobacillus genus that have been previously described and deposited in GenBank are present in the chromosomal DNA. Another important observation for pLOCK 0919 is that the spaCBA-srtC gene cluster and its surrounding genes are highly similar to the respective DNA region that is present in the most well-known and active SpaCBA pili producer, the probiotic Lactobacillus rhamnosus GG strain. Our results demonstrate that the spaCBA-srtC clusters of pLOCK 0919 and L. rhamnosus GG are genealogically similar, located in DNA regions that are rich in transposase genes and are poorly conserved among the publicly available sequences of Lactobacillus sp. In contrast to chromosomally localized pilus gene clusters from L. casei and Lactobacillus paracasei, the plasmidic spaC of L. casei LOCK 0919 is expressed and undergoes a slight glucose-induced repression. Moreover, results of series of in vitro tests demonstrate that L. casei LOCK 0919 has an adhesion potential, which is largely determined by the presence of the pLOCK 0919 plasmid. In particular, the plasmid occurrence positively influenced the hydrophobicity and aggregation abilities of L. casei LOCK 0919. Moreover, in vivo studies indicate that among the three Lactobacillus strains used to colonize the gastrointestinal tract of germ-free mice, already after 2 days of colonization, L. casei LOCK 0919 became the dominant strain and persisted there for at least 48 days.

There is evidence that children with autism spectrum disorders (ASDs) display an increased immune reactivity against gluten, which is supposed to be the effect of intestinal barrier abnormalities. The aim of study was to evaluate the relation of antibody induced by gluten to zonulin and intestinal fatty acid binding proteins (I-FABP), that is, serological markers of an impaired gut barrier. The study included 77 patients with ASDs. Zonulin, I-FABP, celiac-specific antibodies, anti-gliadin antibodies (AGA), and antibodies against neural transglutaminase 6 (TG6) of immunoglobulin (Ig) A and IgG classes were detected in sera. Celiac-specific antibodies were negative in all ASD children, four children (5.2%) had positive anti-TG6 antibodies, and increased AGA-IgG production was found in 21 patients (27.3%). Mean levels of zonulin and I-FABP in ASD patients were similar to those found in healthy controls and revealed a negative correlation with age, whereas regression analysis revealed a significant positive relationship between antibody production and the age. Serum concentrations of zonulin and I-FABP showed no statistically significant association with antibody positivity. An increased production of antibodies related to gliadin and neural TG6 in ASD children is not related to serological markers of an impaired intestinal barrier.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Celiac disease (CD) is a lifelong condition and it often involves impaired nutrition, wide spectrum of symptoms and it requires constant dietetic treatment. The impact of the gluten-free diet on patients’ nutritional status and on the other biochemical parameters is being widely investigated. In this article we looked into particular risk factors that might lead to increased prevalence of atherosclerosis in CD patients, including nutritional status, gluten-free diet, lipids profile and concomitant disease—type 1 diabetes mellitus. Here, we present the current data and research on these risk factors of atherosclerosis with respect to celiac disease.

Introduction: In the last decade we can observe a gradual increase in the incidence of autoimmune diseases. The aetiology of chronic pancreatitis (CP) in children is varied and includes gene mutations, anatomic anomalies and others. The reported paediatric experience with chronic CP is scarce and little is known about the role of autoimmune pancreatitis (AIP). Aim: To assess the frequency of autoimmune markers in children with CP. Material and methods: One hundred and twenty-nine children hospitalised between 2005 and 2012 at the Department of Gastroenterology, The Children’s Memorial Health Institute, were examined for the presence of AIP; the level of IgG4 was determined, and tests for anti-tissue antibodies (ANA, ASMA, AMA, ANCA, AHA) were conducted. Clinical data were recorded and analysed. Results: Anti-tissue antibodies were detected in 75/129 children (58%), and 24/68 patients (35.3%) showed an increased IgG4 level. Based on the International Association of Pancreatology criteria, a suspicion of AIP was raised in 6 patients (4.6%). We found gene mutations predisposing to CP in 32/75 (42.6%) patients with autoimmune markers. In 16/75 children (21.3%), anatomic anomalies were found. There was no difference in the severity of the disease and clinical course between children with evidence of autoimmune process and patients without autoimmune markers (p = NS). Conclusions: In children with CP, similarly to adults, there is a high frequency of biochemical markers of autoimmunity. It is worth remembering that AIP can occur in children.

The aim of the study was to investigate the effects of beetroot juice fermented by Lactobacillus brevis 0944 and Lactobacillus paracasei 0920 (FBJ) on carcinogen induction of aberrant crypt foci (ACF) in rat colon. 2-Amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) was used as carcinogen, which was administrated intragastrically at a dose of 10 μg/day, every day of the experiment. Additionally, we investigated the cytotoxicity and genotoxicity of fecal water from experimental animals in the Caco-2 cell line, evaluated by MTT test and the comet assay, respectively, as well as by the count of bacteria adhered to colon epithelium assessed by fluorescence in situ hybridization. Oxidative stress in rats was expressed by measuring serum antioxidant status and the level of malondialdehyde in the kidneys and liver. The experimental rats were divided into four groups based on diet type: basal diet, basal diet supplemented with FBJ, basal diet and PhIP treatment, and basal diet supplemented with FBJ and PhIP treatment. FBJ significantly reduced the number of ACF in PhIP-treated rats (from 59 ± 18 to 26 ± 4). Moreover, the number of extensive aberrations (more than 4 crypts in a focus) decreased from 52 ± 18 to 18 ± 4. Fecal water obtained from rats fed with a PhIP-containing diet induced pronounced cytotoxic and genotoxic effects in Caco-2 cells, but FBJ supplementation of the diet abolished these effects. In groups fed dietary PhP and FBJ the latter was found to increase the antioxidant status of serum from 40% to 66% depending on the fraction. Reduced concentration of malondialdehyde was found only in the kidneys of rats fed with PhIP and FBJ. FBJ present in the diet of rats causes a reduction of MDA in the kidneys from 118.7 nmol/g tissue to 100 nmol/g tissue. The presence of FBJ in the diet of rats significantly increased the count of bacteria, including Lactobacillus/Enterococcus and Bacteroides-Prevotella group adhered to colonic epithelium. In conclusion, supplementation of the diet with lactofermented beetroot juice may provide protection against precancerous aberrant crypt formation and reduce the cytotoxic and genotoxic effects of fecal water and improve the oxidative status of the organism.

Gut microbiota was analyzed in children, aged 6-18 months and suffering from atopic dermatitis before and after 3 month supplementation of their diet with Lactobacillus casei DN--114001 in a dose of 109 cells daily. On completion of this period the total number of fecal Lactobacillus sp. cells decreased from 7.86 Log10 CFU/g to 6.40 Log10 CFU/g. After the next 5 months (without dietary supplementation with the probiotic bacteria) the level of Lactobacillus sp. cells was maintained at the latter value. During the dietary supplementation with the probiotic strain, the level of Bifidobacterium cells was maintained at 6.15-6.89 Log10 CFU/g while after 5 months it decreased to 5.57 Log10 CFU/g. The population of Clostridium sp. was reduced after 3 months of dietary supplementation from 6.49 to 5.83 Log10 CFU/g and was maintained at the latter level during the next 5 months. The dietary supplementation had no effect on populations of Bacteroides sp., Enterococcus sp. and Enterobacteriaceae. Supplementation of children who developed atopic dermatitis with the preparation of Lactobacillus casei DN - 114001 positively affected their gut microbiota in terms of bifidobacteria and clostridia populations.

Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited.Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation.The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed.None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus.Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS)