Person: ERTEM ŞAHİNOĞLU, DENİZ
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ERTEM ŞAHİNOĞLU
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DENİZ
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Publication Open Access Mucus sialylation determines intestinal host-commensal homeostasis(2022-03-31) ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; ERTEM ŞAHİNOĞLU, DENİZ; Yao Y., Kim G., Shafer S., Chen Z., Kubo S., Ji Y., Luo J., Yang W., Perner S. P., Kanellopoulou C., et al.Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.Publication Open Access Phenotypic pattern of early versus later-onset pediatric inflammatory bowel disease in a eurasian country(2022-10-01) ERTEM ŞAHİNOĞLU, DENİZ; Akkelle B. S., Ertem D., Volkan B., Tutar E.Objectives: It is not clear whether the characteristics of pediatric inflammatory bowel disease (IBD) differ between Eastern and Western countries. The aim of this study was to analyze the characteristics of PIBD in Turkey, according to the age at diagnosis. Methods: The data of 176 children with IBD who were followed in our center were analyzed. Patients were divided into early (EO-IBD, onset at 2 to <10 years) and later-onset (LO-IBD, 10 to <= 17 years) IBD according to the age at diagnosis. Patients\" data with ulcerative colitis (UC) and Crohn\"s disease (CD) were compared. Results: Of 176 patients, 47 (26.7%) were diagnosed with EO-IBD. Patients with early-onset ulcerative colitis (EO-UC) had the highest rate of family history of IBD (17.6%). Pancolitis was the most common form of UC regardless of the age at onset. The rate of moderate-severe disease activity in later-onset UC (62.5%) was higher than in EO-UC (37.5%). A higher rate of extraintestinal manifestations was observed in EO-IBD patients, particularly in EO-UC (38.2%) than in LO-IBD patients. Patients with early-onset CD (EO-CD) had predominantly colonic involvement and nonstricturing, nonpenetrating disease behavior. The rate of perianal disease in patients with later-onset CD (LO-CD) (64.5%) was noticeably higher than those with EO-CD (23%). Conclusions: Our results suggest that patients with EO-UC represented a distinct phenotype with a mild disease activity, high rate of extraintestinal symptoms, and a high proportion of family history. The analysis of our IBD cohort also demonstrated remarkably high rate of perianal disease, particularly in patients with LO-CD.Publication Open Access Reactive oxygen species and chemokines: Are they elevated in the esophageal mucosa of children with gastroesophageal reflux disease?(W J G PRESS, 2008) ÇELİKEL, ÇİĞDEM; Tutar, Engin; Ertem, Deniz; Unluguzel, Goksenin; Tanrikulu, Sevda; Haklar, Goncagul; Celikel, Cigdem; Ademoglu, Evin; Pehlivanoglu, EnderAIM: To determine the role of inflammatory cytokines and reactive oxygen species (ROS) in childhood reflux esophagitis. METHODS: A total of 59 subjects who had complaints suggesting GERD underwent esophagogastroduoden oscopy. Endoscopic and histopathologic diagnosis of reflux esophagitis was established by Savary-Miller and Vandenplas grading systems, respectively. Esophageal biopsy specimens were taken from the esophagus 20% proximal above the esophagogastric junction for conventional histopathological examination and the measurements of ROS and cytokine levels. ROS were measured by chemiluminescence, whereas IL-8 and MCP-1 levels were determined with quantitative immunometric ELISA on esophageal tissue. Esophageal tissue ROS, IL-8 and MCP-1 levels were compared among groups with and without endoscopic/histopathologic esophagitis. RESULTS: Of 59 patients 28 (47.5%) had normal esophagus whereas 31 (52.5%) had endoscopic esophagitis. In histopathological evaluation, almost 73% of the cases had mild and 6.8% had moderate degree of esophagitis. When ROS and chemokine levels were compared among groups with and without endoscopic esophagitis, statistical difference could not be found between patients with and without esophagitis. Although the levels of ROS, IL-8 and MCP-1 were found to be higher in the group with histopathological reflux esophagitis, this difference was not statistically significant. CONCLUSION: These results suggest that the grade of esophagitis is usually mild or moderate during childhood and factors apart from ROS, IL-8 and MCP-1 may be involved in the pathogenesis of reflux esophagitis in children. (C) 2008 The WJG Press. All rights reserved.Publication Open Access Homozygous IL37 mutation associated with infantile inflammatory bowel disease(NATL ACAD SCIENCES, 2021-03-09) ÖZEN, AHMET OĞUZHAN; Zhang, Zinan Z.; Zhang, Yu; He, Tingyan; Sweeney, Colin L.; Baris, Safa; Karakoc-Aydiner, Elif; Yao, Yikun; Ertem, Deniz; Matthews, Helen F.; Gonzaga-Jauregui, Claudia; Malech, Harry L.; Su, Helen C.; Ozen, Ahmet; Smith, Kenneth G. C.; Lenardo, Michael J.Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1 beta stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.Publication Open Access Korozif-kostik madde maruziyeti nedeniyle başvuran çocuklarda endoskopik bulguların değerlendirilmesi: Retrospektif araştırma(2023-03-01) ŞAHİN AKKELLE, BİLGE; KARAOĞLU, SALİH; TUTAR, ENGİN; ERTEM ŞAHİNOĞLU, DENİZ; ŞAHİN AKKELLE B., Volkan B., Dursun C., Korkmaz B., KARAOĞLU S., TUTAR E., ERTEM ŞAHİNOĞLU D.Objective: Accidental caustic ingestions cause damagecomplications in the gastrointestinal tract. In our study, the characteristics of children who underwent endoscopy due to caustic ingestions were evaluated. Material and Methods: The demographic, clinic, endoscopic data of symptomatic children who underwent endoscopy due to caustic ingestions between 2016-2021 were reviewed. According to Zargar classification, patients with normal or mild findings on endoscopy were defined as Group 1; those with moderate/severe findings on endoscopy were defined as Group 2. The data of the two groups were compared. Results: The mean age of 284 patients included in our study was 42±41 months, and 58.4% of them were male. The most frequently exposed caustic agents were household cleaning chemicals (87.3%). Most of the caustic agents exposed were alkaline (78.9%) and 64.3% were in granule form. Esophageal corrosive damage compatible with at least Grade 2a was found in 26.1% of the patients. Complaints of drooling, dysphagia were more frequent in Group 2 compared to Group 1 (p<0.05). There was a statistically significant difference between the groups in terms of the chemical properties of exposed agents. In the follow-up, esophageal stenosis was detected in 2.8% of the patients and pyloric stenosis was detected in 1 patient. Conclusion: The results of our study showed that drooling and dysphagia symptoms are important in predicting esophageal damage in caustic ingestions, but oropharyngeal examination findings may be misleading. Preventive medicine approaches, inspections and sanctions for corrosive chemicals that are produced, sold, stored improperly are important in preventing these accidents.Publication Open Access Bowel Preparation for Colonoscopy in Children: 1 Day PEG-3350 with Bisacodyl versus 3 Day Sennosides(KARGER, 2019) ERTEM ŞAHİNOĞLU, DENİZ; Tutar, Engin; Bayrak, Nevzat Aykut; Volkan, Burcu; Ertem, DenizBackground and Objectives: Bowel preparation (BP) for colonoscopy is a challenging procedure in children and different regimens have been used for this purpose. Polyethylene glycol (PEG) is the most preferred agent in recent years. The primary aim of this study was to evaluate the efficacy of 1-day PEG-3350 with bisacodyl (PEG-B) and comparing it with 3-day sennosides A+B. Method: In this prospective, randomized, and single-blinded study, children aged 2-18 years were included in the PEG-B group for 1 day or in Senna group for 3 days. The effectiveness of BP was assessed according to the Ottawa and Boston BP scales, compliance and adverse effects were also recorded. Pre- and post-preparation biochemistry were obtained for investigation of safety of both regimens. Results: Successful BP was observed in 88.3% (n = 53/60) of PEG-B and 86% (n = 55/64) of Senna groups according to Boston scale, and it was 85% (n = 51/60) and 84.4% (n = 54/64), respectively, according to Ottawa scale. The cecal intubation rate was 96.7% (n = 58/60) in the PEG-B group and 93.8% (n = 60/64) in the Senna group. Ease of administration and disturbance in regular daily activities was better in the PEG-B group (p < 0.05). There was no major adverse event and biochemical abnormality in both groups. The correlation between Ottawa and Boston scales was found to be excellent (r(2) = -0.954, p < 0.01). Conclusions: The efficacy, safety, and adverse effect profile of 1-day BP with PEG-B regimen was found to be similar to 3-day sennosides regimen, however, the PEG-B regimen had advantages such as short duration, ease of administration, and better patient comfort. Also, high correlation rate between the Boston and Ottawa scales in pediatric patients was remarkable. (c) 2019 S. Karger AG, BaselPublication Open Access Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease(NATURE RESEARCH, 2021-02) ÖZEN, AHMET OĞUZHAN; Ozen, Ahmet; Kasap, Nurhan; Vujkovic-Cvijin, Ivan; Apps, Richard; Cheung, Foo; Karakoc-Aydiner, Elif; Akkelle, Bilge; Sari, Sinan; Tutar, Engin; Ozcay, Figen; Uygun, Dilara Kocacik; Islek, Ali; Akgun, Gamze; Selcuk, Merve; Sezer, Oya Balci; Zhang, Yu; Kutluk, Gunsel; Topal, Erdem; Sayar, Ersin; Celikel, Cigdem; Houwen, Roderick H. J.; Bingol, Aysen; Ogulur, Ismail; Eltan, Sevgi Bilgic; Snow, Andrew L.; Lake, Camille; Fantoni, Giovanna; Alba, Camille; Sellers, Brian; Chauvin, Samuel D.; Dalgard, Clifton L.; Harari, Olivier; Ni, Yan G.; Wang, Ming-Dauh; Devalaraja-Narashimha, Kishor; Subramanian, Poorani; Ergelen, Rabia; Artan, Reha; Guner, Sukru Nail; Dalgic, Buket; Tsang, John; Belkaid, Yasmine; Ertem, Deniz; Baris, Safa; Lenardo, Michael J.CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth. Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.Publication Open Access Evaluation of mucosal status in the follow-up of pediatric patients with celiac disease: the role of serology(2022-09-01) AY, NADİYE PINAR; ERTEM ŞAHİNOĞLU, DENİZ; ÇELİKEL, ÇİĞDEM; Sengul O. K., Akkelle B. S., Ay P., Volkan B., Tutar E., Celikel Ç., Ertem D.Recent guidelines suggest non-biopsy serology-based approach for the diagnosis of celiac disease; however, there is no evidence-based data regarding noninvasive follow-up of mucosal healing. The aim of this study is to investigate the efficacy of serology in reflecting mucosal status in the follow-up of pediatric patients with celiac disease. This is a validation study conducted at a university hospital. Patients who had biopsy proven celiac disease (Marsh III) at diagnosis, and had been followed-up for at least 12 months, were prospectively evaluated with duodenal biopsies. tTG-IgA and EMA tests were performed on the day of endoscopy. One hundred four patients with a mean age of 7.4 +/- 4.02 years were included in the study. The sensitivity and specificity of tTG-IgA were 85.2% and 61% respectively, with a high negative predictive value (NPV) of 92.2% but a very low positive predictive value (PPV) of 43.4%. We found that a cutoff value of 68.5 U/mL for tTG-IgA had a sensitivity, specificity of 85.2% and 85.7% respectively. The AUC was 0.891. The sensitivity and specificity of EMA was 77.8% and 87% respectively, with a high NPV of 91.8% but low PPV of 67.7%.Publication Open Access A rare and often unrecognized cause of hematochezia and tenesmus in childhood: Solitary rectal ulcer syndrome(AMER ACAD PEDIATRICS, 2002-12-01) ERTEM ŞAHİNOĞLU, DENİZ; Ertem, D; Acar, Y; Karaa, EK; Pehlivanoglu, ESolitary rectal ulcer syndrome (SRUS) is an unusual disorder of childhood, which usually presents with rectal bleeding, mucous discharge, prolonged straining, tenesmus, and localized pain in the perineal area. After the first description by Cruveilhier, Madigan and Morson further detailed the clinical and pathologic features of SRUS in 1969. The pathogenesis of the syndrome is not well-understood. The postulated mechanism responsible for rectal prolapse in most cases seems to be excessive straining efforts during which high intra-abdominal pressure forces the anterior rectal mucosa firmly into the contracting puborectalis muscle. The anterior rectal mucosa is frequently forced into the anal canal and as a consequence becomes strangulated, causing congestion, edema, and ulceration. Histologically, the presence of fibromuscular obliteration of the lamina propria with disorientation of muscle fibers is characteristic, which could be secondary to chronic mechanical and ischemic trauma and inflammation by hard stools, and intussusception of the rectal mucosa. Although the syndrome is well-recognized in adults, the pediatric experience with this condition is limited and often remains unrecognized or misdiagnosed. A misdiagnosis has been reported in one fourth of adult cases, and the correct diagnosis usually delayed approximately 5 to 7 years. There are few pediatric case reports in English literature. Here, we describe 2 children with SRUS, aged 11 and 14 years, whose SRUS was diagnosed 2 and 6 years, respectively, after the onset of the first signs and symptoms.Publication Open Access Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report(2021) ERTEM ŞAHİNOĞLU, DENİZ; Hatun, Şükrü; Dalgıç, Buket; Gökşen, Damla; Aydoğdu, Sema; Savaş Erdeve, Şenay; Kuloğu, Zarife; Doğan, Yaşar; Aycan, Zehra; Yeşiltepe Mutlu, Gül; Uslu Kızılkan, Nuray; Keser, Alev; Beşer, Ömer Faruk; Özbek, Mehmet Nuri; Bideci, Aysun; Ertem, Deniz; Evliyaoğlu, Olcay; Tipici, Beyza Eliuz; Gökçe, Tuğba; Muradoğlu, Serra; Taşkın, Orhun Çığ; Koca, Tuğba; Tütüncüler, Filiz; Baş, Firdevs; Darendeliler, Feyza; Selimoğlu, Mukadder AyşeIt is well-known that in children with type 1 diabetes (T1D), the frequency of celiac disease (CD) is increased due to unclear mechanisms including autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is gold standard, avoiding unnecessary endoscopy is crucial. Therefore, from the perspective of the clinicians and patients' families, the diagnosis of celiac disease remains challenging. With these in mind, a joint working group (Type 1 Diabetes and Celiac Disease Joint Working Group) was gathered, with the aim of reporting institutional data, as well as the current recommendations of international organizations, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tTG-IgA (tissue transglutaminase-Immunoglobulin A) and/or endomysial (EMA-IgA) antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision of endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are 7 times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.