Gluten intolerance. Celiac disease

Universitatea de Stat de Medicină şi Farmacie „Nicolae Testemiţanu”, Chişinău, Republica MoldovaIntroduction. Celiac disease (CD) is an immune-mediated inflammatory condition of the small intestine that occurs in genetically predisposed individuals when they are exposed to gluten (a plant-based protein component found in grains). The disease has a variable incidence, with a worldwide prevalence of approximately 1:100; Statistics have shown that 70% of patients reported with celiac disease are female. Distribution of population groups, reported that HLA DR3 Phenotype occurs in 70-90% of patients. Aim of study. Celiac disease is an autoimmune disorder and an inflammatory disease that manifests itself upon ingestion of gluten in the upper small intestine and is characterized by the gradual deterioration of the intestinal mucosa. Biochemically, it highlights an immune reaction, which is mediated by certain cells of the immune system, which attack the cells of the small intestine. Methods and materials. It has been scientifically proven that the prevalence of celiac disease in the majority of the population ranges from 0.5% to 1%. Medical science researchers have determined that the incidence is higher among people with autoimmune disorders. Patients with type 1 diabetes are prone to celiac disease, and in the last 20 years there has been a considerable increase in cases. Results. Inflammation and nutrient malabsorption, in addition to diarrhea, distention and abdominal pain, lead to damage to many organs and systems such as: iron deficiency leading to anemia, vitamin deficiencies, osteoporosis, dermatitis herpetiformis, tooth enamel defects, chronic fatigue, joint pain, poor growth, delayed puberty, infertility or repeated miscarriages, and other autoimmune disorders. A number of neurological problems have also been associated with celiac disease; these include migraines, depression, attention deficit/hyperactivity disorder and epilepsy. The diagnosis of celiac disease is established: a) upon the histological finding of an increased number of intraepithelial T lymphocytes; of crypt hyperplasia; of the expansion of regenerative epithelial crypts until the total disappearance of villi; b) positive serological testing (IgA tissue transglutaminase, anti-deamidated gliadin-related peptides IgA and Ig G, IgA antibodies); c) by molecular genetic testing of HLA-DQA1 and HLA-DQB1 which can be determinant or of HLADQ2 and HLA-DQ8) which can be used to exclude celiac disease. Conclusion. Celiac disease (CD) is a very common disorder but in most cases it starts silently. Many of the patients are identified through screening of at-risk groups or after the onset of symptoms of malabsorption, rarely for complications associated with the disease. The diagnosis of CD and its differential diagnosis is made from integrations between typical histological findings and clinical, serological and immunological features. The Corazza-Villanacci system is a useful method to assess mucosal damage and response to gluten-free diet in patient follow-up. intestine that occurs in genetically predisposed individuals when they are exposed to gluten (a plant-based protein component found in grains). The disease has a variable incidence, with a worldwide prevalence of approximately 1:100; Statistics have shown that 70% of patients reported with celiac disease are female. Distribution of populati on groups, reported that HLA DR3 Phenotype occurs in 70-90% of patients. Aim of study. Celiac disease is an autoimmune disorder and an inflammat ory disease that manifests itself upon ingestion of gluten in the upper small i ntestine and is characterized by the gradual deterioration of the intestinal mucosa. Biochemi cally, it highlights an immune reaction, which is mediated by certain cells of the immune system, whi ch attack the cells of the small intestine. Methods and materials. It has been scientifically proven that the prevalence o f celiac disease in the majority of the population ranges from 0.5% to 1%. Medi cal science researchers have determined that the incidence is higher among people with aut oimmune disorders. Patients with type 1 diabetes are prone to celiac disease, and in the l ast 20 years there has been a considerable increase in cases. Results. Inflammation and nutrient malabsorption, in addition to di arrhea, distention and abdominal pain, lead to damage to many organs and systems such as: iron deficiency leading to anemia, vitamin deficiencies, osteoporosis, dermatitis he rpetiformis, tooth enamel defects, chronic fatigue, joint pain, poor growth, delayed puberty, infertility or repeated miscarriages, and other autoimmune disorders. A number of neurological problems ha ve also been associated with celiac disease; these include migraines, depression, attention defi cit/hyperactivity disorder and epilepsy. The diagnosis of celiac disease is established: a) upon the histological finding of an increased number of intraepithelial T lymphocytes; of crypt hyperp lasia; of the expansion of regenerative epithelial crypts until the total disappearance of villi; b) positive serological testing (IgA tissue transglutaminase, anti-deamidated gliadin-related peptides IgA and Ig G, IgA antibodies); c) by molecular genetic testing of HLA-DQA1 and HLA-DQB1 which can be determinant or of HLADQ2 and HLA-DQ8) which can be used to exclude celiac disease. Conclusion. Celiac disease (CD) is a very common disorder but in mos t cases it starts silently. Many of the patients are identified through screening of at- risk groups or after the onset of symptoms of malabsorption, rarely for complications as sociated with the disease. The diagnosis of CD and its differential diagnosis is made from integr ations between typical histological findings and clinical, serological and immunological features. Th e Corazza-Villanacci system is a useful method to assess mucosal damage and response to gluten-free diet in patient follow-up

Prävalenz von Antidrug-Antikörpern und antinukleären Antikörpern sowie deren Relevanz für den Wirkverlust von Systemtherapien bei Patienten mit Psoriasis

Die Psoriasis ist eine chronische inflammatorische Erkrankung, welche vor allem die Haut und in bis zu 30 % auch die Gelenke betrifft. Hinzu kommen häufige Komorbiditäten wie Herzerkrankungen, chronisch entzündliche Darmerkrankungen, Hypothyreose und Depression. Pathophysiologisch wird die Psoriasis von Th-17-Zellen und den Zytokinen IL-17, -22, -23 und TNF dominiert. Seit Beginn des neuen Jahrtausends wurden zunehmend mehr und effektivere Systemtherapien für Patienten mit schweren Verläufen entwickelt, allen voran die Gruppe der Biologika, welche monoklonale Antikörper und Fusionsproteine umfasst. Diese Biopharmazeutika richteten sich zunächst gegen TNF und wurden in den letzten 5 Jahren um IL-17- und -23-Inhibitoren ergänzt. Die neuen Behandlungen erwiesen sich klinisch als sehr effektiv und sicher bei den meisten Patienten. Es wurde jedoch ebenso beobachtet, dass es Patienten gab, welche entweder nicht auf die Therapie ansprachen oder im Verlauf einen Wirkverlust entwickelten. Diese Phänomene wurden häufig mit gegen die einzelnen Biologika gerichteten Antikörpern, sogenannten Anti-drug antibodies (ADA), in Verbindung gebracht. Ziel dieser Studie war es, die Prävalenz von ADA bei Patienten mit Wirkverlust unter Systemtherapie zu untersuchen, sowie deren Status hinsichtlich antinukleärer Antikörper (ANA), anderen Autoantikörpern (AAK) und IgE-Antikörpern. Von März 2015 bis September 2017 wurde eine Datenbank von Patienten mit Wirkverlust unter Systemtherapien im Rahmen der Psoriasis- und Autoimmunsprechstunde der Universitäts-Hautklinik Tübingen aufgebaut. Diese Datenbank wurde hinsichtlich des Vorhandenseins von ADA, ANA, AAK und IgE untersucht. 82 Patienten mit Wirkverlust unter Systemtherapien wurden eingeschlossen. 15 waren Biologika-naiv, 67 hatten einen Wirkverlust unter mindestens einem Biologikum erlitten. Unter dem Patienten mit einem Biologika-Wirkverlust fanden sich ADA bei 32,8%, 35,9% der auf ADL-ADA-untersuchten und 26,7% der auf IFX-ADA-untersuchten Patienten waren positiv. Es konnten keine ADA gegen ETN oder UTK nachgewiesen werden. Bei der ANA-Diagnostik aller Patienten war die IIF an HEp2-Zellen deutlich häufiger positiv (53,7%) als der ANA-CTD-Screening-ELISA (9,7%). AAK konnten selten nachgewiesen werden, am häufigsten aPL. Beim tIgE zeigte sich eine weite Spanne von 2,7-2672 kUA/L, 74,4% wiesen einen Titer >100 kUA/L auf. Patienten mit Gelenkbeteiligung (57,3%) neigten häufiger zur Bildung von ADA (34,0%), wiesen häufiger ANA auf HEp2-Zellen ≥ 1:640 (25,5%) auf und hatten häufiger ein tIgE > 100kUA/L (29,8%), als Patienten mit rein kutanen Psoriasis (ADA 17,1%; HEp2≥1:640 17,1%; tIgE>100kUA/L 20,0%). Aufgrund der niedrigen Patientenzahl von 82 Patienten konnten keine statistischen Signifikanzen dargestellt werden. Die beschriebenen Trends deuten allerdings darauf hin, dass die Grundhypothese eines Zusammenhangs von Wirkverlust mit dem Vorhandensein von ADA, einer höheren Prävalenz von ANA und bei Gelenkbeteiligung richtig ist. Sie lässt sich jedoch nicht monozentrisch beweisen. Multizentrische Studien mit großen Fallzahlen und langen Beobachtungsperioden, beispielsweise als Registerstudien, wären ein möglicher Ansatz, um diese Fragen hinreichend zu beantworten

Definition of treatment goals for moderate to severe psoriasis: a European consensus

Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) <= 10 and psoriasis area and severity index (PASI) <= 10 and dermatology life quality index (DLQI) <= 10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (Delta PASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is >= 75%. The treatment regimen should be modified if improvement of PASI is <50%. In a situation where the therapeutic response improved >= 50% but <75%, as assessed by PASI, therapy should be modified if the DLQI is >5 but can be continued if the DLQI is <= 5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians

Determining the role of basophil activation testing in reported type 1 allergy to beta-lactam antibiotics

Background: Allergy to beta-lactam antibiotics (BLA), especially to penicillin, is the most commonly reported drug allergy by patients. Alternative antibiotics can yield negative consequences, such as extended hospitalization days due to less efficacy and overall higher costs. The basophil activation test (BAT) is an in vitro assay, in which activation of an individual's own basophils is quantified by flow cytometry. It is an increasingly applied in vitro method in allergy testing that is also gaining traction in drug allergies. Methods: We correlated 37 BAT results with skin test results. The cohort exclusively included patients with suspected type I BLA allergy. In addition, we examined the concordance of these results with clinical symptoms reported in the BLA patients’ medical histories. Results: BLA-BAT revealed a high specificity of 92.3% [95% confidence interval (CI) 66.7–98.6] but a low sensitivity of only 20.8% (95% CI 9.24–40.47) using BLA-skin tests as a comparator. Negative BLA-BAT in patients with a history of grade I anaphylaxis yielded doubt on the assumption of grading. The exclusion of grade I BLA anaphylaxis increased the sensitivity to 29.4% (95% CI 13.28–53.13) with a still high specificity of 85.7% (95% CI 48.69–97.43). When ImmunoCAP was available, we compared specific IgE and BAT results by using Cohens' kappa (κ) and revealed a moderate level of agreement (κ = 0.538, p = 0.029). Conclusion: BAT reveals specific positive results exclusively in patients with cephalosporin anaphylaxis. However, these findings could not be generally confirmed in the heterogeneous group of BLA

Simple and efficient expression of Agaricus meleagris pyranose dehydrogenase in Pichia pastoris

Pyranose dehydrogenase (PDH) is a fungal flavin-dependent sugar oxidoreductase that is highly interesting for applications in organic synthesis or electrochemistry. The low expression levels of the filamentous fungus Agaricus meleagris as well as the demand for engineered PDH make heterologous expression necessary. Recently, Aspergillus species were described to efficiently secrete recombinant PDH. Here, we evaluate recombinant protein production with expression hosts more suitable for genetic engineering. Expression in Escherichia coli resulted in no soluble or active PDH. Heterologous expression in the methylotrophic yeast Pichia pastoris was investigated using two different signal sequences as well as a codon-optimized sequence. A 96-well plate activity screening for transformants of all constructs was established and the best expressing clone was used for large-scale production in 50-L scale, which gave a volumetric yield of 223 mg L−1 PDH or 1,330 U L−1 d−1 in space–time yield. Purification yielded 13.4 g of pure enzyme representing 95.8% of the initial activity. The hyperglycosylated recombinant enzyme had a 20% lower specific activity than the native enzyme; however, the kinetic properties were essentially identical. This study demonstrates the successful expression of PDH in the eukaryotic host organism P. pastoris paving the way for protein engineering. Additionally, the feasibility of large-scale production of the enzyme with this expression system together with a simplified purification scheme for easy high-yield purification is shown

Impactos Psicossociais e na Qualidade de Vida do Tratamento Oncológico em Crianças e Adolescentes

Introdução: Tão importante quanto o diagnóstico e o tratamento do câncer pediátrico são os cuidados relacionados ao impacto psicossocial, educacional e emocional. Objetivo: Avaliar em crianças e adolescentes com diagnóstico de câncer os impactos psicossociais, de qualidade de vida e da presença de acompanhante durante os procedimentos. Método: Estudo transversal, descritivo, com pacientes de 8 a 18 anos e diagnóstico de neoplasia maligna. Os pacientes responderam aos questionários: PedsQL 4.0 Qualidade de Vida (8 a 12 anos), PedsQL 3.0 Módulo de Câncer (8 a 12 anos), PedsQL 4.0 Qualidade de Vida (13 a 18 anos), PedsQL 3.0 Módulo de Câncer (13 a 18 anos) e outro sobre acompanhantes elaborado pelos autores. Resultados: Foram incluídos 25 pacientes pediátricos oncológicos que se sentiam mais felizes na presença de um acompanhante e menos ansiosos durante os procedimentos. Foi percebido grande impacto na qualidade de vida. No questionário Qualidade de Vida, não houve diferença significativa (p=0,627) entre os grupos de pacientes com 8 a 12 anos e 13 a 18 anos, porém o grupo com 8 a 12 anos teve impacto significativamente maior no questionário Módulo de Câncer (p=0,0094). Conclusão: O impacto psicossocial e na qualidade de vida é razoavelmente grande em pacientes pediátricos oncológicos. Além disso, os mais jovens parecem sofrer um impacto psicossocial maior. Os pacientes se dizem mais felizes com a presença de acompanhante, e mais ansiosos na sua ausência

A phase 2b basket trial approach to treat multiple rare and fibrotic skin diseases

Fibrotic skin diseases are rare, chronic, and often debilitating conditions characterized by excessive extracellular matrix deposition, leading to tissue scarring and functional impairment. Despite their severity, diseases—such as lichen sclerosus et atrophicus (LSA), frontal fibrosing alopecia (FFA), radiation-induced skin fibrosis (RISF), eosinophilic fasciitis (EF), pansclerotic disabling morphea (PDM), and linear circumscript sclerodermia (LCS)—lack approved therapies and are underrepresented in clinical research. This phase 2b multicenter basket trial proposes a novel approach to evaluate a common antifibrotic therapy across these diverse but pathophysiologically related conditions. The trial employs a two-stage Simon design to address the statistical challenges posed by small patient populations, allowing the inclusion of ultra-rare diseases while maintaining analytical rigor. LSA and FFA serve as primary study groups due to higher prevalence, while EF, RISF, PDM, and LCS are included as exploratory arms. The study aims to assess the efficacy, safety, and tolerability of the selected therapy, while also providing mechanistic insights into fibrosis through molecular analyses. The primary endpoint is a ≥ 1-point improvement in the Investigator Global Assessment (IGA) at 24 weeks. Secondary endpoints at 52 weeks encompass quality of life (Dermatological Life Quality Index (DLQI), EuroQol Group Quality of Life Questionnaire (EuroQol five dimensions (EQ-5D))), symptom relief (itch and pain Numeric Rating Scale (NRS)), and disease-specific clinical scores. The trial excludes a placebo arm due to ethical considerations in progressive, untreated diseases but allows rescue therapies for disease progression. This design not only facilitates access to treatment for underserved populations but also leverages shared clinical and molecular features to enhance statistical power. By integrating disease-specific and global outcome measures, the study aims to generate robust evidence for repurposing existing therapies. If successful, this trial could serve as a model for future research in rare fibrotic diseases, accelerating drug development and improving patient outcomes

Loss of MTAP expression is a negative prognostic marker in Ewing sarcoma family of tumors.

AIM: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. METHODS: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival(OS). RESULTS: Loss of MTAP expression was significantly associated with lower OS in both univariate and multivariate analyses. CONCLUSION: Loss of MTAP expression is an independent negative prognostic biomarker in ESFT.Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP) and CNPq grants to RM Reis. WP Menezes is recipient of a FAPESP fellowship (2016/06833–2). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.info:eu-repo/semantics/publishedVersio