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1,3,4-thiadiazole derivatives. Synthesis, structure elucidation, and structure-antituberculosis activity relationship investigation
(AMER CHEMICAL SOC, 2004) Oruc, EE; Rollas, S; Kandemirli, F; Shvets, N; Dimoglo, AS
A series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized, the compounds structures were elucidated and screened for the antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. Among the tested compounds, 2-phenylamino-5-(4-fluorophenyl)-1,3,4-thiadiazole 22 showed the highest inhibitory activity. The relationships between the structures of compounds and their antituberculosis activity were investigated by the Electronic-Topological Method (ETM) and feed forward neural networks (FFNNs) trained with the back-propagation algorithm. As a result of the approach, a system of pharmacophores and anti-pharmacophores has been found that effectively separates compounds of the examination set into groups of active and inactive compounds. The system can be applied to the screening and design of new active compounds possessing skeletons similar to those used in the present study.
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17 beta-estradiol increases intracellular free calcium concentrations of human vascular endothelial cells and modulates its responses to acetylcholine
(INFORMA HEALTHCARE, 1997) Moini, H; Bilsel, S; Bekdemir, T; Emerk, K
In this study, we have investigated the effect of (17)beta-estradiol (E2) on intracellular free calcium concentrations ([Ca2+](i)) in human umbilical vein endothelial cells (HUVEC) using fura-2 fluorescence, E2 at concentrations of 1nM-1 mu M was added subsequently to HUVEC cultures which were either deprived of estrogens or preincubated with E2 (100 nM) for 23 hours, In both groups of cultures, E2 stimulated significant increases in [Ca2+](i) in a dose-dependent manner, The effects were more prominent in E2-deprived cells, Preincubation of cells with tamoxifen or the presence of it in the buffer during the experiments did not inhibit the response of the cells to E2, Experiments performed in Ca2+ free/EGTA buffer yielded transient increases in [Ca2+](i) suggesting release of Ca2+ from intracellular stores was responsible for the initial peak, while sustained elevations were supported by Ca2+ influx from the extracellular space, Addition of La3+ abolished the sustained [Ca2+](i) elevations, Carbachol (CCh) (1nM, 100 nM) did not induce changes in [Ca2+](i) of estrogen-deprived cells but produced significant increases in [Ca2+](i) of the same cells after incubation with E2 for 30 minutes, The cultures which were preincubated with E2 for 24 hours responded to carbachol directly, The results of our study indicate that E2 may modulate the functions of endothelial cells after only a brief exposure and also may be necessary for the response to acetylcholine especially at low concentrations.
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17Beta-estradiol modulates endothelin-1 expression and release in human endothelial cells
(2000) ÖZER, SIDIKA AYŞE; Bilsel, A. S.; Moini, H.; Tetik, E.; Aksungar, F.; Kaynak, B.; Ozer, A.
OBJECTIVE: In this study the role of 17beta-estradiol (E2) in the regulation of endothelin-1 (ET-1) mRNA expression and secretion was investigated in cultured human umbilical vein endothelial cells (HUVECs). METHODS: Endothelial cells were either deprived of or treated with 17beta-estradiol (10(-9), 10(-7) M) for 48 h. After the incubation, the effect of E2 on ET-1 gene expression was evaluated by Northern blot analysis. ET-1 release into the media was measured by radioimmunoassay after 6 h of incubation under basal conditions and upon stimulation with thrombin (4 U/ml). In addition, the cyclic guanosine 5'-monophosphate (cGMP) content of cells was assayed by immunoassay. In order to exclude the role of nitric oxide (NO) in E2-induced effects on endothelin-1 gene expression and secretion, nitric oxide synthase (NOS) inhibitor, N-nitro L-arginine methyl ester (1 mM) (L-NAME) was added to the media of some cultures. RESULTS: Incubation of HUVECs with 10(-9) and 10(-7) M E2 for 48 h resulted in a 30 and 47% inhibition of ET-1 mRNA expression, respectively. Incubation with E2 also decreased the basal and thrombin-stimulated ET-1 release while increasing the cGMP content of cells significantly. NOS inhibitor L-NAME increased the release of ET-1 from E2-incubated cells but did not alter the ET-1 release from hormone-deprived cells. However, ET-1 secretion of E2-treated cells were significantly less than the deprived ones. Northern blot analyses also demonstrated that inhibition of NOS only partly attenuated the effect of E2 on ET-1 gene expression. In the presence of L-NAME, treatment with 10(-7) M E2 caused a 12% decrease in ET-1 gene expression. CONCLUSION: The results demonstrate that E2 may play both direct and indirect role in regulation of ET-1 gene expression and production in human endothelial cells. E2-induced increase in NO but decrease in ET-1 production may partly explain the mechanism of the protective effects of the hormone on the cardiovascular system.
Open Access
18 F-FDG PET/CT imaging of a Grade 3 lymphomatoid granulomatosis in an immunocompromised pediatric patient
(2023-02-01) KESİM, SELİN; ÖZGÜVEN, SALİH; ÖNEŞ, TUNÇ; KESİM S., Şen F., ÖZGÜVEN S., ÖNEŞ T.
Lymphomatoid granulomatosis is a rare extranodal Epstein-Barr virus-driven B-cell lymphoproliferative disease, involving predominantly lung, less often skin, kidney, and central nervous system. Here, we present a pediatric case with primary immunodeficiency, diagnosed with pathologically proven pulmonary grade-III lymphomatoid granulomatosis.18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging demonstrated18F-FDG avid pulmonary masses with central air-bronchograms and cavitations. Although the definitive diagnosis depends on biopsy,18F-FDG PET/CT serves as a complementary imaging tool to evaluate the extent of the disease and response to treatment.
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18F-FDG PET / CT findings of Rosai Dorfman Disease withdiffuse extranodal involvement
(2020-10-22) FİLİZOĞLU, NUH; KESİM, SELİN; ENGÜR, CEREN ÖZGE; ÖZGÜVEN, SALİH; ÖNEŞ, TUNÇ; TUROĞLU, HALİL TURGUT; ERDİL, TANJU YUSUF; FİLİZOĞLU N., KESİM S., ŞAHİN C. Ö., Öksüzoğlu K., ÖZGÜVEN S., ÖNEŞ T., TUROĞLU H. T., ERDİL T. Y.
Aim/Introduction: Rosai Dorfman disease (RDD) is a rare benign disease characterized by permanent massive lymphadenopathy mimicking malignant tumors. Extranodal involvement, including the skin, upper respiratory tract, salivary gland, bone, central nervous system and rarely kidneys, may occur in approximately 43% of patients. Although RDD can usually recover spontaneously, it may persist in some patients and mimic lymphoproliferative disorders clinically and visually. We present the 18F-FDG PET / CT findings of the patient with RDD with diffuse extranodal involvement. Materials and Methods: An 18F-FDG PET / CT examination was performed to investigate malignancy in a 57-year-old male patient with multiple cervical lymph nodes. Results: 18F-FDG PET / CT demonstrated 2.5 cm sized intense hypermetabolic lymph nodes in the bilateral cervical chain. Intense hypermetabolic soft tissue density lesions were observed in the subcutaneous fatty plans of the T12 vertebra left posterolateral section and the right lower quadrant of the abdomen. 12 mm sized mild hypermetabolic soft tissue density nodular lesion was seen in the right adrenal gland medial crust and 3x2.5 cm sized mild hypermetabolic soft tissue density nodular lesion was found in the left adrenal gland corpus. In the skeletal system, intense hypermetabolic lytic lesions compatible with metastasis were observed in the left occipital condyle, the posterior elements of the T6 vertebra, the C1 vertebra transvers process, the posterior part of the right acetabulum and the posterior part of the right iliac bone. Excisional biopsy was performed on the lymph node in the submandibular area and the lesion observed in the subcutaneous fatty plan in the right lower quadrant of the abdomen and the histopathology was found compatible with Rosai Dorfman disease. Conclusion: RDD, first described by Rosai and Dorfman in 1969, is a rare benign lymphoproliferative disease. RDD is usually manifested by cervical lymphadenopathy and typically mimics lymphoma. Diseases such as lymphoma, tuberculosis, sarcoidosis, reactive hyperplasia and nasopharyngeal carcinoma can be considered in the differential diagnosis. Extranodal disease is observed in approximately 43% of cases, most commonly in the skin, nasal cavity, eyes and bone. Although Rosai-Dorfman disease is usually self-limited, patients with extranodal involvement may have a more fulminant course and need active treatment. Since lesions show increased FDG uptake, 18F-FDG PET-CT may be useful in determining the extent of the disease, including lymph node involvement. Therefore, the present case emphasized the importance of 18F-FDG PET-CT scan in the diagnosis, staging and treatment selection of the disease. References: None
Open Access
2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography after breast conserving surgery: Correlation with molecular markers of breast cancer
(MEDKNOW PUBLICATIONS & MEDIA PVT LTD, 2016) TUROĞLU, HALİL TURGUT; Ozguven, Salih; Inanir, Sabahat; Turoglu, Halil Turgut; Erdil, Tanju Yusuf; Ugurlu, Mustafa Umit; Gulluoglu, Bahadir
Aim: To investigate the role of 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT) early after breast-conserving surgery (BCS) in patients with breast cancer (BC) and whether we can determine which molecular biomarkers of breast carcinoma put the patients at risk. Materials and Methods: This retrospective study involved 88 patients with histologically proven T1 or T2 BC, who were treated with BCS and underwent F-18-FDG PET/CT study. The correlation between biological markers (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 [HER2], and Ki-67) of the primary tumor and F-18-FDG PET/CT findings was analyzed. Results: F-18-FDG PET/CT demonstrated the presence of BC disease (locoregional disease [LRD], distant metastases, or contralateral BC) in 26 of 88 patients (29.5%). Regarding immunohistochemical profiles, BC expressing high levels of Ki-67 were associated with an increased percentage of LRD, which was the major recurrence pattern on F-18-FDG PET/CT. Although the BC disease was observed more commonly in patients with HER2 positivity compared to those of HER2 negative, the difference did not reach statistical significance. The patients with T2 tumor or a higher histopathological grade had a higher percentage of BC disease. Conclusions: This study demonstrated that patients with early stage BC treated with BCS have a remarkable risk of the presence of BC even early after surgery, and there was a clinically important relationship between F-18-FDG PET/CT findings and biological markers of BC. These findings suggest that high-risk molecular biomarkers (Ki-67, HER2) can be taken into account in the decision-making the process for both preoperative imaging and planning of the surgical approach.
Open Access
2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase
(ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2013-11) TATAR, ESRA; Kucukguzel, Ilkay; Satilmis, Gokhan; Gurukumar, K. R.; Basu, Amartya; Tatar, Esra; Nichols, Daniel B.; Talele, Tanaji T.; Kaushik-Basu, Neerja
Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4-thiazolidinone scaffold as inhibitors of HCV NS5B polymerase. Eleven compounds tested were found to inhibit HCV NS5B with IC50 values ranging between 19.8 and 64.9 RM. Compound 24 was the most active of this series with an IC50 of 5.6 mu M. A number of these derivatives further exhibited strong inhibition against HCV lb and 2a genotypes in cell based antiviral assays. Molecular docking analysis predicted that the thiazolidinone derivatives bind to the NS5B thumb pocketII (TP-II). Our results suggest that further optimization of the thiazolidinone scaffold may be possible to yield new derivatives with improved enzyme- and cell-based activity. (C) 2013 Elsevier Masson SAS. All rights reserved.
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2-mercaptoethane sulfonate (MESNA) protects against biliary obstruction-induced oxidative damage in rats
(ELSEVIER IRELAND LTD, 2006) ERCAN, FERİHA; Sener, G; Kabasakal, L; Sehirli, O; Ercan, F; Gedik, N
The aim of this study was to assess the antioxidant and antifibrotic effects of chronic administration of 2-mercaptoethane sulfonate (MESNA) on oxidative liver damage and fibrosis induced by biliary obstruction in rats. Liver fibrosis was induced in male Wistar albino rats by bile duct ligation and scission (BDL). MESNA (150 mg/kg, i.p.) or saline was administered for 28 days. At the end of the experiment, rats were killed by decapitation. Serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were determined to assess liver function. Tumor necrosis factor-alpha (TNF-alpha) and lactate dehidrogenase (LDH) were also assayed in serum samples. Liver tissues were taken for determination of the free radicals, hepatic malondialdehyde (MDA) levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant; myeloperoxidase (MPO) activity, as an indirect index of neutrophil infiltration. Hepatic collagen content, as a fibrosis marker was also determined. Serum AST, ALT, LDH and TNF-alpha levels were elevated in the BDL group as compared to control group, while this increase was significantly decreased by MESNA treatment. BDL caused a significant (p < 0.05-0.001) decrease in GSH levels while MDA levels and MPO activity were increased in the liver tissue. These changes were reversed by MESNA treatment. Collagen contents of the liver tissue was increased by BDL (P < 0.001), and reversed back to the control levels with MESNA. Since MESNA administration alleviated the BDL-induced oxidative injury of the liver and improved the hepatic functions, it seems likely that MESNA with its antioxidant and antifibrotic properties, may be of potential therapeutic value in protecting the liver fibrosis and oxidative injury due to biliary obstruction. (c) 2006 Published by Elsevier Ireland Ltd.
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2-mercaptoethane sulfonate (MESNA) protects against burn-induced renal injury in rats
(ELSEVIER SCI LTD, 2004) YEGEN, BERRAK; Sener, G; Sehirli, O; Erkanli, G; Cetinel, S; Gedik, N; Yegen, B
Animal models of thermal injury implicate oxygen radicals as causative agents in local wound response and distant organ injury following burn. In this study we investigated the putative protective effects of 2-mercaptoethane sulfonate (MESNA) against oxidative kidney damage in rats with thermal injury. Under ether anaesthesia, shaved dorsum of the rats was exposed to 90 degreesC bath for 10 s to induce burn injury. Rats were decapitated either 6 or 24 h after burn injury. MESNA was administered i.p. immediately after burn injury. MESNA injections were repeated once more 12 h after the first injection in the 24 h burn group. In the control group the same protocol was applied except that the dorsum was dipped in a 25 degreesC water bath for 10 s. Kidney tissues were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, protein oxidation (PO), myeloperoxidase (MPO) activity and collagen contents. Creatinine, urea concentrations (BUN) and lactate dehydrogenase (LDH) in blood were measured for the evaluation of renal functions and tissue damage, respectively. Tissues were also examined microscopically. Severe skin scald injury (30% of total body surface area) caused significant decrease in GSH level, significant increase in MDA level, protein oxidation (PO), MPO activity and collagen content of renal tissue. Serum creatinine was slightly increased at the early phase of thermal trauma but not changed in 24 h groups. On the other hand BUN and LDH were significantly elevated by thermal trauma in both 6 and 24 h of burn groups. Treatment of rats with MESNA significantly increased the GSH level and decreased the MDA level, PO, MPO activity, collagen contents, BUN and LDH. Since MESNA reversed the oxidant responses seen in burn injury, it seems likely that MESNA could protect against thermal trauma-induced renal damage. (C) 2004 Elsevier Ltd and ISBI. All rights reserved.
Open Access
2016 ESC and ACC/AHA/HFSA heart failure guideline updates: Changes, similarities, differences, and unresolved isssues
(TURKISH SOC CARDIOLOGY) SARI, İBRAHİM; Sari, Ibrahim; Cavusoglu, Yuksel; Temizhan, Ahmet; Yilmaz, Mehmet Birhan; Eren, Mehmet
Open Access
2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis
(BMJ PUBLISHING GROUP, 2018-09) DURUÖZ, MEHMET TUNCAY; Osthoff, Anne-Kathrin Rausch; Niedermann, Karin; Braun, Juergen; Adams, Jo; Brodin, Nina; Dagfinrud, Hanne; Duruoz, Tuncay; Esbensen, Bente Appel; Guenther, Klaus-Peter; Hurkmans, Emailie; Juhl, Carsten Bogh; Kennedy, Norelee; Kiltz, Uta; Knittle, Keegan; Nurmohamed, Michael; Pais, Sandra; Severijns, Guy; Swinnen, Thijs Willem; Pitsillidou, Irene A.; Warburton, Louise; Yankov, Zhivko; Vlieland, Theodora P. M. Vliet
Regular physical activity (PA) is increasingly promoted for people with rheumatic and musculoskeletal diseases as well as the general population. We evaluated if the public health recommendations for PA are applicable for people with inflammatory arthritis (iA
Open Access
2021 Guideline for the Management of COPD Exacerbations: Emergency Medicine Association of Turkey (EMAT) / Turkish Thoracic Society (TTS) Clinical Practice Guideline Task Force
(WOLTERS KLUWER MEDKNOW PUBLICATIONS, 2021) AKOĞLU, HALDUN; Dogan, Nurettin Ozgur; Varol, Yelda; Kokturk, Nurdan; Aksay, Ersin; Alpaydin, Aylin Ozgen; Corbacioglu, Seref Kerem; Aksel, Gokhan; Baha, Ayse; Akoglu, Haldun; Karahan, Sevilay; Sen, Elif; Ergan, Begum; Bayram, Basak; Yilmaz, Serkan; Gurgun, Alev; Polatli, Mehmet
Chronic obstructive pulmonary disease (COPD) is an important public health problem that manifests with exacerbations and causes serious mortality and morbidity in both developed and developing countries. COPD exacerbations usually present to emergency departments, where these patients are diagnosed and treated. Therefore, the Emergency Medicine Association of Turkey and the Turkish Thoracic Society jointly wanted to implement a guideline that evaluates the management of COPD exacerbations according to the current literature and provides evidence-based recommendations. In the management of COPD exacerbations, we aim to support the decision-making process of clinicians dealing with these patients in the emergency setting.
Open Access
2022 American college of rheumatology/EULAR classification criteria for giant cell arteritis
(2022-12-01) DİRESKENELİ, RAFİ HANER; Ponte C., Grayson P. C., Robson J. C., Gribbons K. B., Judge A., Craven A., Khalid S., Hutchings A., Watts R. A., Merkel P. A., et al.
Objective: To develop and validate updated classification criteria for giant cell arteritis (GCA). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 6 phases: 1) identification of candidate items, 2) prospective collection of candidate items present at the time of diagnosis, 3) expert panel review of cases, 4) data-driven reduction of candidate items, 5) derivation of a points-based risk classification score in a development data set, and 6) validation in an independent data set. Results: The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C-reactive protein ≥10 mg/liter (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging, and fluorodeoxyglucose–positron emission tomography activity throughout the aorta (+2 each). A patient could be classified as having GCA with a cumulative score of ≥6 points. When these criteria were tested in the validation data set, the model area under the curve was 0.91 (95% confidence interval [95% CI] 0.88–0.94) with a sensitivity of 87.0% (95% CI 82.0–91.0%) and specificity of 94.8% (95% CI 91.0–97.4%). Conclusion: The 2022 American College of Rheumatology/EULAR GCA classification criteria are now validated for use in clinical research.
Open Access
2022 American college of rheumatology/EULAR classification criteria for Takayasu arteritis
(2022-12-01) DİRESKENELİ, RAFİ HANER; Grayson P. C., Ponte C., Robson J. C., Gribbons K. B., Judge A., Craven A., Khalid S., Hutchings A., Danda D., Luqmani R. A., et al.
Objective: To develop and validate new classification criteria for Takayasu arteritis (TAK). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 6 phases: 1) identification of candidate criteria items, 2) collection of candidate items present at diagnosis, 3) expert panel review of cases, 4) data-driven reduction of candidate items, 5) derivation of a points-based classification score in a development data set, and 6) validation in an independent data set. Results: The development data set consisted of 316 cases of TAK and 323 comparators. The validation data set consisted of an additional 146 cases of TAK and 127 comparators. Age ≤60 years at diagnosis and imaging evidence of large-vessel vasculitis were absolute requirements to classify a patient as having TAK. The final criteria items and weights were as follows: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of ≥20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1), and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as having TAK with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the model area under the curve was 0.97 (95% confidence interval [95% CI] 0.94–0.99) with a sensitivity of 93.8% (95% CI 88.6–97.1%) and specificity of 99.2% (95% CI 96.7–100.0%). Conclusion: The 2022 American College of Rheumatology/EULAR classification criteria for TAK are now validated for use in research.
Open Access
2022 american college of rheumatology/european alliance of associations for rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis
(2022-03-01) DİRESKENELİ, RAFİ HANER; Grayson P. C., Ponte C., Robson J. C., Craven A., Judge A., Khalid S., Hutchings A., Luqmani R. A., Watts R. A., Merkel P. A., et al.
Objective: To develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate criteria items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. Results: The development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1 × 109/liter (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti–proteinase 3 ANCA positivity (−3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1), and hematuria (−1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% confidence interval [95% CI] 77–91%) and the specificity was 99% (95% CI 98–100%). Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for EGPA demonstrate strong performance characteristics and are validated for use in research.
Open Access
2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Granulomatosis With Polyangiitis
(2022-03-01) DİRESKENELİ, RAFİ HANER; Robson J. C., Grayson P. C., Ponte C., Craven A., Judge A., Khalid S., Hutchings A., Watts R. A., Merkel P. A., Luqmani R. A., et al.
Objective: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate criteria items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. Results: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting, or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti–proteinase 3 ANCA positivity (+5); pulmonary nodules, mass, or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (−1); and eosinophil count ≥1 × 109/liter (−4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% confidence interval [95% CI] 87–96%) and the specificity was 94% (95% CI 89–97%). Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research.
Open Access
2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis
(2022-03-01) DİRESKENELİ, RAFİ HANER; Robson J. C., Grayson P. C., Ponte C., Craven A., Khalid S., Judge A., Hutchings A., Merkel P. A., Luqmani R. A., Watts R. A., et al.
Objective: To develop and validate classification criteria for microscopic polyangiitis (MPA). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. Results: The development set for MPA consisted of 149 cases of MPA and 408 comparators. The validation set consisted of an additional 142 cases of MPA and 414 comparators. From 91 candidate items, regression analysis identified 10 items for MPA, 6 of which were retained. The final criteria and their weights were as follows: perinuclear antineutrophil cytoplasmic antibody (ANCA) or anti–myeloperoxidase-ANCA positivity (+6), pauci-immune glomerulonephritis (+3), lung fibrosis or interstitial lung disease (+3), sino-nasal symptoms or signs (−3), cytoplasmic ANCA or anti–proteinase 3 ANCA positivity (−1), and eosinophil count ≥1 × 109/liter (−4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having MPA with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 91% (95% confidence interval [95% CI] 85–95%) and the specificity was 94% (95% CI 92–96%). Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for MPA are now validated for use in clinical research.
Open Access
22q11 deletion syndrome: current perspective
(DOVE MEDICAL PRESS LTD, 2015-05) Hacihamdioglu, Bulent; Hacihamdioglu, Duygu; Delil, Kenan
Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome ( 22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems
Open Access
3-pyridinylboronic acid ameliorates rotenone-induced oxidative stress through nrf2 target genes in zebrafish embryos
(2022-06-01) ALTURFAN, EBRU IŞIK; MEGA TİBER, PINAR; Üstündağ F. D., Ünal İ., Üstündağ Ü. V., Cansız D., Beler M., Karagöz A., Kara Subaşat H., Alturfan A. A., Mega Tiber P., Emekli-Alturfan E. I.
Parkinson\"s disease (PD) is one of the most common forms of neurodegenerative diseases and research on potential therapeutic agents for PD continues. Rotenone is a neurotoxin that can pass the blood-brain barrier and is used to generate PD models in experimental animals. Boron is a microelement necessary for neural activity in the brain. Antioxidant, non-cytotoxic, antigenotoxic, anti-carcinogenic effects of boric acid, the salt compound of boron has been reported before. Boronic acids have been approved for treatment by FDA and are included in drug discovery studies and pyridine boronic acids are a subclass of heterocyclic boronic acids used in drug design and discovery as substituted pyridines based on crystal engineering principles. The aim of our study was to determine the effect of 3-pyridinylboronic acid in rotenone-exposed zebrafish embryos, focusing on oxidant-antioxidant parameters and gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes gclm, gclc, hmox1a, nqo1, and PD related genes, brain-derived neurotrophic factor, dj1, and tnfa alpha. Zebrafish embryos were exposed to Rotenone (10 mu g/l); Low Dose 3-Pyridinylboronic acid (100 mu M); High Dose 3-Pyridinylboronic acid (200 mu M); Rotenone + Low Dose-3-Pyridinylboronic acid (10 mu g/l + 100 mu M); Rotenone + High Dose-3-Pyridinylboronic acid (10 mu g/l + 200 mu M) in well plates for 96 h post-fertilization (hpf). Our study showed for the first time that 3-pyridinylboronic acid, as a novel sub-class of the heterocyclic boronic acid compound, improved locomotor activities, ameliorated oxidant-antioxidant status by decreasing LPO and NO levels, and normalized the expressions of bdnf, dj1, tnf alpha and Nrf2 target genes hmox1a and nqo1 in rotenone exposed zebrafish embryos. On the other hand, it caused the deterioration of the oxidant-antioxidant balance in the control group through increased lipid peroxidation, nitric oxide levels, and decreased antioxidant enzymes. We believe that these results should be interpreted in the context of the dose-toxicity and benefit-harm relationship of the effects of 3-pyridinylboronic.
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3-Pyridinylboronic acid normalizes the effects of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure in zebrafish embryos
(TAYLOR & FRANCIS LTD) ALTURFAN, EBRU IŞIK; Ustundag, Fumet Duygu; Unal, Ismail; Cansiz, Derya; Ustundag, Unsal Veli; Subasat, Hulya Kara; Alturfan, A. Ata; Tiber, Pinar Mega; Emekli-Alturfan, Ebru
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that damages dopaminergic neurons. Zebrafish has been shown to be a suitable model organism to investigate the molecular pathways in the pathogenesis of Parkinson's disease and also for potential therapeutic agent research. Boron has been shown to play an important role in the neural activity of the brain. Boronic acids are used in combinatorial approaches in drug design and discovery. The effect of 3-pyridinylboronic acid which is an important sub-class of heterocyclic boronic acids has not been evaluated in case of MPTP exposure in zebrafish embryos. Accordingly, this study was designed to investigate the effects of 3-pyridinylboronic acid on MPTP exposed zebrafish embryos focusing on the molecular pathways related to neurodegeneration and apoptosis by RT-PCR. Zebrafish embryos were exposed to MPTP (800 mu M); MPTP + Low Dose 3-Pyridinylboronic acid (50 mu M) (MPTP + LB) and MPTP + High Dose 3-Pyridinylboronic acid (100 mu M) (MPTP + HB) in well plates for 72 hours post fertilization. Results of our study showed that MPTP induced a P53 dependent and Bax mediated apoptosis in zebrafish embryos and 3-pyridinylboronic acid restored the locomotor activity and gene expressions related to mitochondrial dysfunction and oxidative stress due to the deleterious effects of MPTP, in a dose-dependent manner.

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