ISSN: 2687 - 5365
International Journal of Academic
Medicine and 20 2 1 Pharmacy
amp
www.academicmed.org [email protected] Editörden;
Sayın Jamp okuyucuları…
Dergimize olan ilgiden dolayı büyük mutluluk duymaktayız. Dergimizi takip eden, kıymetli eleştiri ve tavsiyelerini eksik etmeyen bilim insanlarına ayrıca teşekkür ederiz. Sonraki sayılarımızda çok daha geniş bir indeks ağı ile okuyucularımıza ulaşacağız. Görüşmek üzere…
From the Editor;
Dear Jamp readers…
We are very pleased with the interest in our journal. We would like to thank the scientists who are follow- ing our journal and make their valuable criticism and advice. In the following issues, we will reach our readers with a much wider index network. Kindest regards…
Baş Editör / Chief Editor Necati OZPINAR, PhD., Assoc. Prof.
Editör Yardımcıları / Assistant Editors Savas KARAKUS, MD., Assoc. Prof.
Ceylan HEPOKUR, PhD., Asst. Prof.
www.academicmed.org editö[email protected]
International Journal of Academic Medicine and Pharmacy (Jamp), temel ve klinik tıp, eczacılık ve diğer sağlık alanları ile ilgili bilimsel makalelerin yayınlanması için açık erişimli ve hakemli bir akademik dergidir. Jamp yayımlamak için orijinal araştırma makaleleri, derlemeler, olgu sunumlarını bilimsel makale olarak kabul etmektedir. Jamp’de, tüm klinik ve temel tıp bilimleri alanlarından, tüm eczacılık alanlarından ve ayrıca biyoterapi, tıbbi öneme sahip ekto ve/veya endo parazitler ve mikrobio- tadan makaleler kabul eder. Jamp'de yayınlanacak tüm makaleler, gerekli süreyi geciktirmeksizin hakem tarafından gözden geçirilir ve yayın süreci tamamlandıktan sonra anında erişim ve alıntı için çevrimiçi olarak yayınlanır. Ocak, Mayıs ve Eylül aylarında yılda üç kez yayınlanan Jamp'nin sadece akademiye değil, sektöre, medyaya ve halka ulaşması hedeflenmektedir.
Yazarlardan veya okuyuculardan herhangi bir ücret talep edilmez.
International Journal of Academic Medicine and Pharmacy (Jamp) is an open-access and peer-reviewed academic journal for the publication of scientific articles on health sciences, especially in basic and clinical medicine and pharmacy. Jamp accepts original research articles, reviews, and case reports for publication. Jamp accepts articles from all areas of clinical and basic medical sciences, all pharmaceutical fields, as well as those on biotherapy, ecto- and endoparasites of medical importance, and microbiota. All articles to be published in the Jamp are peer-reviewed without delay and are published online for immediate access and citation after the publication process is completed. Jamp, is published twice a year (June and December), and is aimed to reach not only the academy but also the sector, the media and the public.
No fees are charged to the authors or readers.
Baş Editör / Chief Editor Necati OZPINAR, PhD., Assoc. Prof.
Editör Yardımcıları / Assistant Editors Savas KARAKUS, MD., Assoc. Prof.
Ceylan HEPOKUR, PhD., Asst. Prof.
www.academicmed.org editö[email protected]
BAŞ EDİTÖR
Necati ÖZPINAR, Doç. Dr.
Hatay Mustafa Kemal Universitesi, Hatay, Türkiye [email protected]
YARDIMCI EDİTÖR
Savaş KARAKUŞ, Doç. Dr.
Sivas Cumhuriyet Üniversitesi, Tıp Fakültesi, Kadın Doğum ve Jinekoloji AD., Sivas, Türkiye [email protected]
Ceylan HEPOKUR, Dr. Öğr. Üyesi
Sivas Cumhuriyet Üniversitesi, Eczacılık Fakültesi, Farmasötik Biyokimya AD., Sivas, Türkiye [email protected]
TIP ALAN EDİTÖRLERİ ECZACILIK ALAN EDİTÖRLERİ
Kosta Y. MUMCUOGLU, Prof. Dr. Nuraniye ERUYGUR, Doç. Dr.
Kudüs Hebrew Üniversitesi, Tıp Fakültesi, Selçuk Üniversitesi Eczacılık Fakültesi, Mikrobiyoloji ve Moleküler Genetik Bölümü Farmakognozi Anabilim Dalı, Kudüs, İsrail Konya, Türkiye [email protected] [email protected]
Alexandros GEORGAKILAS, Doç. Dr. Tülay OYMAK, Doç. Dr.
Atina Ulusal Teknik Üniversitesi, Sivas Cumhuriyet Üniversitesi, Eczacılık Fakültesi, DNA Hasar Laboratuvarı, Analitik Kimya AD., Atina, Yunanistan Sivas, Türkiye [email protected] [email protected]
ii
Gulnaz CULHA, Prof. Dr. Mohammad Omar FARUQUE, Doç. Dr. Hatay Mustafa Kemal Üniversitesi, Tıp Fakültesi, Chittagong Üniversitesi, Botanik Bölümü Tıbbi Parazitoloji AD. Chattogram, Bangladeş Antakya, Türkiye [email protected] [email protected]
Saliha ÖZPINAR, Doç. Dr. Seifu Juneidi KEDIR, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Adama Bilim ve Teknoloji Universitesi, Tıp Fakültesi, Halk Sağlığı AD, Uygulamalı Doğa Bilimleri Fakültesi Alanya, Türkiye Adama, Ethiopia [email protected] [email protected]
Rukiye YASAK GÜNER, Dr. Öğr. Üyesi Ahmad ALI, Dr. Öğr. Üyesi
Sivas Cumhuriyet Üniversitesi, Mumbai Üniversitesi, Tıp Fakültesi, Dermatoloji AD, Yaşam Bilimleri Bölümü Sivas, Türkiye Mumbai, Hindistan [email protected] [email protected]
Faten Mohamed Ibrahim MANSOUR, Doç.Dr. İshak Suat ÖVEY, Dr. Öğr. Üyesi Tıbbi Aromatik Bitkiler Araştırma Merkezi Alaaddin Keykubat Üniversitesi, Tıp Fakültesi İlaç Endistrüsi Araştırma Bölümü, Fizyoloji AD., National Research Center Alanya, Türkiye Mısır [email protected] [email protected]
Sharida FAKURAZİ, Prof.Dr. Emrah DURAL, Doç. Dr.
Putra Malaysia Üniversitesi, Tıp Fakültesi Sivas Cumhuriyet Üniversitesi, Eczacılık Fakültesi, Anatomi AD, Farmasötik Toksikoloji AD., Selangor, Malezya Sivas, Türkiye [email protected] [email protected]
Fawzi M. MAHOMOODALLY, Doç. Dr. Amar Mohamed ISMAIL, Dr.
Mauritius Üniversitesi, Hücre ve Moleküler Biyoloji Lab. Bşk. Halk Sağlığı Anabilim Dalı Africa City of Technology Reduit, Mauritius Sudan [email protected] [email protected]
Gogineni Subash BABU, Prof. Dr. Hülya ÖZPINAR, Dr. Öğr. Üyesi
A.B. Shetty Memorial Diş Hekimliği Enstitüsü Sivas Cumhuriyet Üniversitesi, Eczacılık Fakültesi Oral Tıp ve Radyoloji AD., Farmasötik Botanik AD., Mangalore, Hindistan Sivas, Türkiye [email protected] [email protected]
iii
İSTATİSTİK ALAN EDİTÖRÜ
Emre DÜNDER, Dr. Öğr. Üyesi
Ondokuz Mayıs Üniversitesi, Fen Edebiyat Fakültesi, İstatistik Bölümü, Samsun, Türkiye [email protected]
İNGİLİZ DİLİ ALAN EDİTÖRÜ
Eyüp GÜNDÜZ, Öğr. Gör.
Sivas Cumhuriyet Üniversitesi, Edebiyat Fakültesi, İngiliz Dili ve Edebiyatı Bölümü, Sivas, Türkiye [email protected]
DİJİTAL PAZARLAMA VE SOSYAL MEDYA EDİTÖRÜ
Selçuk Yasin YILDIZ, Dr. Öğr. Üyesi
Sivas Cumhuriyet Üniversitesi, Cumhuriyet Sosyal Bilimler MYO, Pazarlama Bölümü, Sivas, Türkiye [email protected]
SEKRETERYA
Hasan YÜCEL, Araş. Gör.
Hatay Mustafa Kemal Üniversitesi, Sağlık Bilimleri Fakültesi, Hatay, Türkiye [email protected]
iv
EDITOR IN CHIEF
Necati Ozpinar, PhD., Assoc. Prof.
Hatay Mustafa Kemal University, Hatay, Turkey [email protected]
ASSİSTANT EDITOR
Savas Karakus, MD, Assoc. Prof.
Sivas Cumhuriyet University, Faculty of Medicine, Department of Obstetrics and Gynecology, Sivas, Turkey [email protected]
Ceylan Hepokur, PhD., Asst. Prof.
Sivas Cumhuriyet University, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Sivas, Turkey [email protected]
MEDICAL FIELD EDITORS PHARMACEUTICAL FIELD EDITORS
Nuraniye Eruygur, PhD., Assoc. Prof. Kosta Y. Mumcuoglu, PhD., Prof. Dr. Selcuk University, Faculty of Pharmacy, Hebrew University of Jerusalem, Department of Pharmacognosy, Department of Microbiology and Molecular Genetics, Konya, Turkey Jerusalem, Israel [email protected] [email protected]
Alexandros Georgakilas, PhD., Assoc. Prof. Tulay Oymak, PhD., Assoc. Prof.
DNA Damage Laboratory, Sivas Cumhuriyet University, Faculty of Pharmacy, National Technical University, Department of Analytical Chemistry, Athens, Greece Sivas, Turkey [email protected] [email protected]
v
Gulnaz Culha, PhD., Prof. Dr. Mohammad Omar Faruque, PhD., Assoc. Prof.
Hayat Mustafa Kemal University, Faculty of Medicine, University of Chittagong, Department of Medical Parasitology, Department of Botany Antakya, Turkey Chattogram, Bangladesh [email protected] [email protected]
Saliha Ozpinar, PhD., Assoc. Prof. Seifu Juneidi Kedir, PhD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Adama Science and Technology University, Department of Public Health, School of Applied Natural science Alanya, Turkey Adama, Ethiopia [email protected] [email protected]
Rukiye Yasak Guner, MD, Asst. Prof. Ahmad Ali, PhD., Asst. Prof.
Sivas Cumhuriyet University, Faculty of Medicine, University of Mumbai, Department of Dermatology, Department of Life Sciences Sivas, Turkey Mumbai, India [email protected] [email protected]
Ishak Suat Ovey, PhD., Asst. Prof. Faten Mohamed Ibrahim Mansour, PhD., Assoc. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Medicinal and Aromatic Plants Research Department, Department of Physiology, Drug Pharmaceutical industry Research Division, Alanya, Turkey National Research Center [email protected] Egypt [email protected]
Sharida Fakurazi, PhD., Prof.Dr. Emrah Dural, PhD., Assoc. Prof.
Universiti Putra Malaysia, Faculty of Medicine and Sivas Cumhuriyet University, Faculty of Pharmacy, Health Sciences Department of Pharmaceutical Toxicology, Department of Human Anatomy, Sivas, Turkey Selangor, Malaysia [email protected] [email protected]
Fawzi M. Mahomoodally, PhD., Assoc. Prof. Ammar Mohamed Salih Lubeiny, PhD.
University of Mauritius, Faculty of Science Head of Cell and Molecular Biology Lab. Department of Health Sciences Africa City of Technology Reduit, Mauritius Sudan [email protected] [email protected]
Hülya Ozpinar, PhD. Asst. Prof. Gogineni Subash Babu, Prof. Dr. Sivas Cumhuriyet University, Faculty of Pharmacy, A.B. Shetty Memorial Institute of Dental Science Department of Pharmaceutical Botany, Department of Oral Medicine and Radiology, Sivas, Turkey Mangalore, India [email protected] [email protected]
vi
STATISTICS FIELD EDITOR
Emre Dunder, PhD., Asst. Prof.
Ondokuz Mayıs University, Faculty of Arts and Sciences, Department of Statistics, Samsun, Turkey [email protected]
ENGLISH LANGUAGE EDITOR
Eyup Gunduz, Lecturer
Sivas Cumhuriyet University, Faculty of Letters, Department of English Language and Literature, Sivas, Turkey [email protected]
DIGITAL MARKETING AND SOCIAL MEDIA EDITOR
Selcuk Yasin Yildiz, Asst. Prof.
Sivas Cumhuriyet University, Cumhuriyet Social Science Vocational School, Department of Marketing, Sivas, Turkey [email protected]
SECRETARIAT
Hasan Yucel, Research Assistant
Hatay Mustafa Kemal University, Faculty of Health Sciences, Hatay, Turkey [email protected]
vii
BİLİM KURULU
Semra ÖZÇELİK, Prof. Dr.
Bezmialem Universitesi, Tıp Fakültesi, Istanbul, Türkiye
Ahmet ÖZBİLGİN, Prof. Dr.
Manisa Celal Bayar Universitesi, Tıp Fakültesi, Manisa, Türkiye
Zeynep SÜMER, Prof.Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Haldun SÜMER, Prof.Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Serpil DEGERLI, Prof. Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Hediye Nese ÇINAR, MD, PhD.,Research Biologist
US Food and Drug Administration, Washington DC, USA
Yasemin ÖZTOP, Prof. Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Melih AKYOL, Prof. Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Funda DOGRUMAN AL, Prof. Dr.
Gazi Universitesi, Tıp Fakültesi, Ankara, Türkiye
Sahin YILDIRIM, Prof. Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Ramazan GÜNEŞAÇAR, Prof. Dr.
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Şafak TANER, Prof. Dr.
Ege Üniversitesi Tıp Fakültesi, İzmir, Türkiye
Gönül DİNÇ HOROSAN, Prof. Dr.
İzmir Ekonomi Üniversitesi, Tıp Fakültesi, İzmir, Türkiye
Nuran GÜLER, Prof. Dr.
Sivas Cumhuriyet Üniversitesi, Sağlık Bilimleri Fakültesi, Sivas, Türkiye
viii
İlhan YAYLIM, Prof. Dr.
Aziz Sancar Deneysel Tıp Araştırma Enstitüsü, Moleküler Tıp AD., Istanbul. Türkiye
Gulay YILDIRIM, Doç. Dr.
Sivas Cumhuriyet Universitesi, Tıp Fakültesi, Sivas, Türkiye
Adalet KOCA KUTLU, Doç. Dr.
Manisa Celal Bayar Universitesi, Sağlık Bilimleri Fakültesi, Manisa, Türkiye
Kıvan ÇAVİK, Doç. Dr.
Manisa Celal Bayar Universitesi, Sağlık Bilimleri Fakültesi, Manisa, Türkiye
Figen YARDIMCI, Doç. Dr.
Manisa Celal Bayar Universitesi, Hemşirelik Fakültesi, Manisa, Türkiye
Gülengül MERMER, Doç. Dr.
Ege Üniversitesi, Hemşirelik Fakültesi, İzmir, Türkiye
Tutku TUNÇ, Dr. Öğr. Üyesi
Sivas Cumhuriyet Universitesi, Eczacılık Fakültesi, Sivas, Türkiye
Seda AVNİOĞLU, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Büşra CANDAN, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
İbrahim Aydın CANDAN, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Hasan Basri SAVAŞ, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Durkadın DEMİR EKŞİ, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
İsmail SARIKAN, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Ersin SAYAR, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Erkan MAYTALMAN, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
ix
Dilek ERDEM, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Gözde ORHAN KUBAT, Dr. Öğr. Üyesi
Alanya Alaaddin Keykubat Üniversitesi, Tıp Fakültesi, Alanya, Türkiye
Ümmühan YÜCEL, Dr. Öğr. Üyesi
Ege Üniversitesi, Sağlık Bilimleri Fakültesi, İzmir, Türkiye
Dilay AÇIL, Dr. Öğr. Üyesi
Manisa Celal Bayar Üniversitesi, Sağlık Bilimleri Fakültesi, Manisa, Türkiye
Vasviye BAYRAM, Dr. Öğr. Üyesi
Mardin Artuklu Üniversitesi, Sağlık Bilimleri Fakültesi, Mardin, Türkiye
Devrim DEMIR DORA, Dr. Öğr. Üyesi
Akdeniz Üniversitesi, Tıp Fakültesi, Antalya, Türkiye
Semire UZUN GÖÇMEN, Dr. Öğr. Üyesi
Hatay Mustafa Kemal Üniversitesi, Tıp Fakültesi, Hatay, Türkiye
Mehmet Emre YURTTUTAN, Uzm. Dr. Dt.
Ankara Üniversitesi Diş Hekimliği Fakültesi, Ankara, Turkiye
x
SCIENTIFIC COMMITTEE
Semra OZCELIK, PhD., Prof. Dr.
Bezmialem University, Faculty of Medicine, Istanbul, Turkey
Ahmet OZBILGIN, PhD., Prof. Dr.
Manisa Celal Bayar University, Faculty of Medicine, Manisa, Turkey
Zeynep SUMER, MD., Prof.Dr.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Haldun SUMER, MD., Prof.Dr.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Serpil DEGERLI, PhD., Prof. Dr.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Hediye Nese CINAR, MD
Research Biologist, US Food and Drug Administration, Washington DC, USA
Yasemin OZTOP, PhD., Prof. Dr.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Melih AKYOL, MD., Prof. Dr.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Funda DOGRUMAN AL, MD., Prof. Dr.
Gazi University, Faculty of Medicine, Ankara, Turkey
Sahin YILDIRIM, MD., Prof. Dr.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Ramazan GUNESACAR, PhD, Prof. Dr.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Safak TANER, MD, Prof. Dr.
Ege University, Faculty of Medicine Izmir, Turkey
Gonul DINC HOROSAN, MD, Prof. Dr.
Izmir Universty of Economics, Faculty of Medicine, Izmir, Turkey
Nuran GULER, PhD., Prof. Dr.
Sivas Cumhuriyet University, Faculty of Health Sciences, Sivas, Turkey
xi
Ilhan YAYLIM, MD, Prof. Dr.
Aziz Sancar Experimental Medicine Research Institute, Department of Molecular Medicine Istanbul. Turkey
Gulay YILDIRIM, PhD., Assoc. Prof.
Sivas Cumhuriyet University, Faculty of Medicine, Sivas, Turkey
Adalet KOCA KUTLU, PhD., Assoc. Prof.
Manisa Celal Bayar University, Faculty of Health Sciences, Manisa, Turkey
Kivan CEVIK, PhD., Assoc. Prof.
Manisa Celal Bayar University, Faculty of Health Sciences, Manisa, Turkey
Figen YARDIMCI, PhD., Assoc. Prof.
Ege University, Faculty of Nursing, Izmir, Turkey
Gulengul MERMER, PhD., Assoc. Prof.
Ege University, Faculty of Nursing, Izmir, Turkey
Tutku TUNC,PhD., Asst. Prof.
Sivas Cumhuriyet University, Faculty of Pharmacy, Sivas, Turkey
Seda AVNIOGLU, Ph. D., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Busra CANDAN, PhD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Ibrahim Aydin CANDAN, PhD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Hasan Basri SAVAS, MD, PhD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Durkadin DEMIR EKSI, MD, PhD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Ismail SARIKAN, MD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Ersin SAYAR, MD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Erkan MAYTALMAN, PhD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
xii
Dilek ERDEM, MD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Gozde ORHAN KUBAT, MD., Asst. Prof.
Alanya Alaaddin Keykubat University, Faculty of Medicine, Alanya, Turkey
Ummuhan YUCEL, PhD., Asst. Prof.
Ege University, Faculty of Health Sciences, Izmir, Turkey
Dilay ACIL, PhD., Asst. Prof.
Manisa Celal Bayay University, Faculty of Health Sciences, Manisa, Turkey
Vasfiye BAYRAM, PhD., Asst. Prof.
Mardin Artuklu University, Faculty of Health Sciences, Mardin, Turkey
Devrim DEMIR DORA, PhD., Asst, Prof.
Akdeniz University, Faculty of Medicine, Antalya, Turkey
Semire UZUN GOCMEN, PhD., Asst. Prof.
Hatay Mustafa Kemal University, Faculty of Medicine, Hatay, Turkey
Mehmet Emre YURTTUTAN, Dt., PhD.
Ankara University, Faculty of Dentistry, Ankara, Turkey
xiii İÇİNDEKİLER / CONTENTS
ARAŞTIRMA MAKALESİ / RESEARCH ARTICLE
Gastroprotective Effects of Pear (Pyrus Communis L.) Extract on Ethanol Induced Gastric Ulcer in Rats 1-6 Ersen Eraslan, Ayhan Tanyeli, Mehmet Ramazan Bozhüyük, Mustafa Can Güler, Erdem Toktay, Nezahat Kurt, Gülay Özkan, Esra Çapanoğlu Güven
Results of Prolonged Use of Intrauterine Device in Endometrium and Eosinophil Leukocytes 7-10 Ayşe Nur Uğur Kılınç, Sevcan Sarıkaya, Melike Geyik Baran, Yaşar Ünlü
Combination of Strontium Chloride 5% and Licorice 1% Solution Compared Mometasone Furoate Solution 0.1% for Dandruff 11-15 Rukiye Yasak Güner, Mustafa Tosun, Melih Akyol, Selim Çam
Evaluation of Pain and Anxiety Levels of Tooth Extraction 16-21 Ahmet Barışık, Mehmet Esen, Mehmet Kemal Tümer, Yunus Balel
Hesperidin Attenuates Oxidative Ovarian Damage Induced by Ischemia Reperfusion: An Antioxidant, Antiautophagic and Antiapoptotic Agent 22-28 Fazile Nur Ekinci Akdemir, Ayhan Tanyeli, Derya Güzel, Mustafa Can Güler, Ersen Eraslan, Selim Çomakli
Estimation of Tibia Length in Turkish Adults Using the Artificial Neural Network Method 29-34 Özhan Pazarcı, Yunis Torun
Prevalence of Fibromyalgia Syndrome in Infertile Women and Its Effects on Quality of Life and Sleep 35-42 Sevil Ceyhan Doğan, Çağlar Yıldız, Gonca İmir Yenicesu, Özlem Şahin
Hip Pain associated with High Risk of Metastasis in Elderly Population 43-46 Hüseyin Sina Coşkun, Hikmet Çinka, Nevzat Dabak, Ferhat Say, Hasan Göçer
Obsesif-Kompulsif Bozukluk Tanısı Almış Yetişkin Bireylerde Benlik Saygısı ile Anksiyete arasındaki İlişkinin İncelenmesi 47-51 Ahmet Aytaş, Habib Erensoy
Antioxidant Activity of Apocynin against Intestinal Ischemia-Reperfusion Induced Oxidative Damage in Lung and Intestinal Tissues 52-57 Derya Güzel Erdoğan, Ayhan Tanyeli, Ersen Eraslan, Mustafa Can Güler
Tweak Levels in Rheumatic Inflammatory Diseases 58-63 Demet Yalcin Kehribar
www.academicmed.org editö[email protected]
Neuroimaging Manifestations of Behcet’s Disease: A Retrospective Study from the Eastern Mediterranean Region of Turkey 64-69 Gülen Burakgazi, Fatma Duman
Evaluation of the Relationship Between Epicardial Fat Tissue Area and Coronary Atherosclerosis 70-75 İnan Korkmaz, Ali Balcı, Sinem Karazincir, Hanifi Bayaroğulları
Student Opinions About Anatomy Education From Past to Future 76-81 Erengül Boduç
The Relationship Between Systemic Immune-Inflammation Index and TNM Stage in Patients Underwent Pancreatic Cancer Surgery 82-87 Meriç Emre Bostancı, Kürşat Karadayı
DERLEME MAKALE / REVİEW ARTICLE
Preventive Nutritional Style for New Type 2019 Coronavirus SARS-CoV-2 (COVID-19) Pandemic 88-91 Hasan Basri Savaş, Mehmet Enes Sözen
OLGU SUNUMU / CASE REPORTS
Association of Communicating Extralobar Bronchopulmonary Sequestration with Intralobar Sequestration in a Patient Who had Anal Atresia 92-94 İbrahim Karaman, Selma Uysal Ramada, Ayşegül Zenciroğlu, Özlem Balcı, Ayşe Karaman
Development of Acute Generalized Exanthematous Pustulosis due to Hydroxychloroquine Use for COVID-19 Treatment 95-96 Mustafa Tosun
2 Int J Acad Med Pharm, 2021; 3 (1); 1-6
International of Academic Medicine and Pharmacy
Gastroprotective Effects of Pear (Pyrus Communis L.) Extract on Ethanol Induced Gastric Ulcer in Rats
Ersen Eraslan 1*, Ayhan Tanyeli 2, Mehmet Ramazan Bozhüyük 3, Mustafa Can Güler 4, Erdem Toktay 5, Nezahat Kurt 6, Gülay Özkan 7, Esra Çapanoğlu Güven 8
1 Department of Physiology, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey 2,4 Department of Physiology, Faculty of Medicine, Atatürk University, Erzurum, Turkey 3 Department of Horticulture, Faculty of Agriculture, Iğdır University, Iğdır, Turkey 5 Department of Histology and Embryology, Faculty of Medicine, Kafkas University, Kars, Turkey 6 Department of Biochemistry, Faculty of Medicine, Erzincan Binali Yıldırım Üniversitesi, Erzincan, Turkey 7,8 Department of Food Engineering, Chemical and Metallurgical Engineering Faculty, Istanbul Technical University, Istanbul, Turkey
ORCID; 0000-0003-2424-2269, 0000-0002-0095-0917, 0000-0001-5021-6019, 0000-0001-8588-1035, 0000-0002-7447-6023, 0000-0002-1685-5332, 0000-0002-6375-1608, 0000-0003-0335-9433
Article info Research article
Received :21.07.2020 Abstract;Various natural molecules have been examined against ethanol-induced gastric ulcer up to present. Pear, Received in revised form :29.09.2020 Pyrus communis L. (PYR), includes various antioxidant and anti-inflammatory features. Current study was planned to find Accepted :02.11.2020 out potential preventive properties of PYR extract against gastric ulcer induced by ethanol in rats. 32 rats were assigned to Available online :05.01.2021 4 groups (n=8). Group I was sham, group II was ulcer group. Groups III and IV were 4 and 8 ml/kg PYR groups. Group I, normal saline was administered and group II, III and IV were administered ethanol (5 ml/kg) by oral gavage to rats. Phenolic substances in PYR content were detected via high-pressure liquid chromatography (HPLC). CUPRAC, ABTS Keywords and FCR amounts of PYR extract were determined. Gastric tissue was evaluated through macroscopic and immunohistochemical methods. NF-kB and caspase-3 expressions increased in ulcer group but PYR treatment reversed Pear these levels. PYR extract performed protective effects against ethanol-induced gastric ulcer by decreasing NF-kB and Ethanol caspase-3 expressions and preventing gastric mucosal injury. As a result, PYR extract has been shown to have a strong Ulcer therapeutic effect against gastric ulcer. Therefore, we propose PYR as a potential antiulcer drug. HPLC NF-kB Caspase-3 Rat
INTRODUCTION Peptic ulcer is a serious health condition worldwide 1. Peptic upregulation of pro-inflammatory mediators. For this reason, ulcer can be observed in esophagus, stomach or small intestine inhibition of NF-kB activity can alleviate the severity of which is characterized with irritating symptoms such as inflammatory diseases such as gastric ulcer 5,7,8. heartburn, nausea, vomiting or bloating 2. Acute gastric ulcer is Various agents were examined against gastric ulcer in often initiated with excessive alcohol consumption or high previous studies 9. Pyrus communis l. is within Rosaceae family doses of nonsteroidal anti-inflammatory drug (NSAID) usage and grows widely around the world 10. PYR tree is common in 3,4. Ethanol not only directly damages the gastric mucosa, but Turkey and Europe. Fruits are yellowish green color and also sensitizes the mucosa against injury 5. Ethanol can induce 2-4 cm long 11,12. Phenolic molecules are one of the major gastric ulcer through different ways. Ethanol increases the active ingredients in PYR and the anti-ulcer properties of generation of reactive oxygen species (ROS) by enhancing the phenolics on PYR has also been stated. Initial studies have cytochrome P450 enzyme activity and changing the levels of shown that the main phenolics in PYR are leukocyanidine, certain materials 6. In addition, it has been stated that some quercitrin, catechin, chlorogenic acid, epicatechin and inflammatory cytokines can play crucial roles in acute phase quercetin 13. Many researchers have shown that phytochemicals inflammation as well as in maintaining and regulating the in fruits and vegetables are important for the against chronic severity of gastric ulcers. Over-expression and translocation of diseases including obesity, diabetes mellitus, cardiovascular nuclear factor kappa-B (NF-kB) subunits promote the diseases and cancer 1,4,7,14,15. Here, it was investigated the
*Corresponding author: Ersen Eraslan, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.45434
1 beneficial effects of PYR on gastric ulcer through calibration curves were prepared by using gallic acid, ethanol-induced gastric ulcer model in rats. 4-hydroxy benzoic acid, caffeic acid, vanillic acid, catechin, p-coumaric acid, chlorogenic acid, ferulic acid, syringic acid, MATERIALS and METHODS delphinidin-3-glucosidase and cyanidin-3-glucosidase. These
samples and stock solutions were filtered through a 0.45-µm Animals Wistar albino rats (female, 250-280 g) were procured from membrane filter and 1 mL of the filtered sample was placed Atatürk University Medical Experimental Application and into vials and analyzed in a Waters W600 HPLC system with Research Center (Erzurum, Turkey) and experimental studies PDA (Waters 996) detector, for each sample. Luna C18 column were carried out in this center. All the procedures carried out in (Phenomenex, Utrecht, The Netherlands), heated to 40 °C, was this study were carried out in line with the permission obtained used as the stationary phase. Chromatograms were recorded at from Atatürk University Animal Experiments Local Ethics 280, 312, 360, and 520 nm. Identification was based on the Committee (Protocol no:19.04.2016/70). All rats were exposed retention times and characteristic UV spectra and quantification to a 12 hours/12 hours light/dark cycle in rooms with constant was done by external standard curves 20. temperature and humidity control. Rats were free access to water and food. Spectrophotometric assays (evaluation of the content of PYR) Free radical clearance activity was evaluated with 2,2-azino-di- Groups and drug administration (3-ethylbenzothialozine-sulphonic acid (ABTS). ABTS activity There were 4 groups composed of 32 female Wistar (n=8) as measurement was modified according to previous studies 21. group I (sham group), group II (ulcer group), group III and IV Antioxidant features of PYR content was evaluated with cupric (PYR 4 ml/kg and PYR 8 ml/kg groups). In group I, the reducing antioxidant capacity (CUPRAC) analysis 22. Total animals were administered normal saline by oral gavage. In phenolic content was analyzed with Folin–Ciocalteu reagent other groups, 5 ml/kg 99% ethanol (absolute ethanol) (FCR) and the method developed by Folin and Singleton 23,24. (Sigma-aldrich, USA) was administered to animals by oral gavage to establish ulcer model as described in previous studies Immunohistochemical examination 16,17. All interventions in groups lasted ten days. On the Gastric tissues were cut along the large curvature, washed with eleventh day of the study, the animals were kept away from saline and photographed. After the imaging process was food for 8 hours, but they were allowed access to water. After completed, the tissues were placed in a 10% formalin 90 minutes, animals were sacrificed, gastric tissues were (Sigma -aldrich, USA) solution and fixed. Then, they were removed and examined to determine gastric lesions. embedded in paraffin and 5 µm sections were taken with microtome (Leica RM2235, Germany). Immunohistochemical Plant material (IHC) and hematoxylin and eosin (H&E) staining were carried The pears (Pyrus communis L.) used in the research belong to out. IHC staining was done using Caspase-3 (Novus Santa Maria cultivar and obtained from Goksun district Bursa Biological, USA) and NF-κB (Abcam, England) antibodies. province of Turkey. Pears were harvested in July and stored in The samples were examined under light microscope (Olympus controlled atmospheric warehouses then served to the market in BH-40, Japan). August. Fresh pear fruits were washed and cleaned then cut into small pieces and their seeds were removed. A homogenizer Statistical analysis was used to extract pulpy pear juices 18,19. Statistical analysis was done using SPSS v.20.0 software (SPSS Inc., USA). The treatment groups were compared with HPLC analysis of PYR profile ulcer group. One-way analysis of variance (ANOVA) and Phenolic profiles of PYR were evaluated by HPLC coupled to a Tukey post hoc test were performed. Statistical significance photodiode array (HPLC-PDA). HPLC-PDA results of PYR was accepted as p<0.05. All data were expressed as sample were given as mg/100 mL samples for all. Standard mean±standard deviation (SD).
2 RESULTS widespread edema and leukocyte infiltration were observed. On the other side, mucosal damage decreased in PYR groups HPLC Results compared to ulcer group. Decline in mucosal damage was Determination of the phenolic compounds of the PYR content supported by decreased ulcer area, edema and leukocyte was measured using HPLC and the results were given as Infiltration. average (ppm) ± SD in table 1. In immunohistochemical evaluation of caspase-3 and
Table 1. PYR phenolic ingredient contents (average±SD) NF-κB immunopositivity, the group with ulcer had higher immunopositivity compared to sham group. Moreover, PYR Phenolic Substances Value (ppm) (Average ± SD) treatment groups demonstrated lower immunopositivity Gallic acid 5,24 ±0,15 compared to ulcer group. The most significant difference was
4-Hydroxybenzoic 10,94 ±0,89 noted in the groups in which 8ml/kg PYR was applied.
Catechin 34,10 ±1,64
Vanillic acid 0,91 ±0,07 DISCUSSION
Syringic acid 2,93 ±0,31 Peptic ulcer appears due to disruption/loss of the mucosal
Arbutin 0,33 ±0,06 integrity. The main cause of mucosal damage is the disruption Isorhamnetin 3-o-rutinoside of the balance between mucous protective and aggressive 31,92 ±4,16 25 Abscisic acid mechanisms . Ethanol-induced gastric ulcer leads to 25,65 ±5,40 p-coumaric acid inflammatory response which is characterized with increased 1,55 ±0,01 neutrophil infiltration, thereby disrupting the oxidant/ Chlorogenic acid 0,49 ±0,06 antioxidant balance 26. Ethanol injury begins with Caffeic acid 0,16 ±0,03 microvascular damage including edema formation, surface Rutin 0,44 ±0,06 epithelium disruption and necrotic lesions which penetrate deep Antioxidant Properties of PYR into the mucosa. It can also lead to vascular permeability and The antioxidant capacity of PYR samples was found out even cell lysis 27. Ethanol-induced gastric ulcer in experimental according to two different procedures (CUPRAC and ABTS). animals is one of the most common ulcer models examining The total phenolic content was detected according to the Folin various compounds for determining antiulcer effects 16. The Ciocalteu Reactive (FCR) method. All values were current study revealed that PYR has preventive activity against demonstrated in table 2. ethanol-induced gastric ulcer. We detected several phenolic
Table 2. CUPRAC, ABTS and FCR values (average±SD) compounds from PYR via HPLC measurements. Direct and indirect effects of some of these molecules on gastric ulcer Value Analysis (Average ± SD) have been investigated. Gallic acid, arbutin, isorhamnetin CUPRAC (mg TEAC/100ml) 4,46 ± 2,18 3-o-rutinoside, p-coumaric acid, caffeic acid, chlorogenic acid, ABTS (mg TEAC/100ml) 239,96 ± 15,25 routine and catechin molecules have been reported to mediate FCR (mg GAE/100 ml) 11,51 ± 0,56 antiulcer mechanisms in experimental ulcer models 28-36.
Trolox equivalent antioxidant capacity (TEAC), Gallic acid equivalents Protective effects of p-coumaric acid 37-39, gallic acid 40 and (GAE). chlorogenic acid 41,42 were examined in previous studies. In Histopathological and Immunohistochemical Assessment addition, ABTS and CUPRAC values indicate that the PYR In figure 1, macroscopic and histopathological views of extract contains powerful antioxidant compounds. stomach samples of all groups were presented. Hemorrhagic NF-kB is an important transcription factor involved in and ulcerative lesions were not observed in the control group. the inflammatory response process and production of several In ulcer group, hemorrhagic ulceration lesions were observed. cytokines. NF-κB is activated in gastric ulcer, promoting the Serious erosion with hemorrhagic lesions extending deep into production of a number of pro-inflammatory cytokines. the mucosa was demonstrated in histological evaluation of the Suppression of the NF-κB pathway is considered a target for stomach. Additionally, histopathological findings such as gastric ulcer treatment 43,44. The reduction of NF-κB
3 immunoreactivity by PYR administration may show that it has As a result, especially 8ml/kg PYR extract contributes gastroprotective effects by decreasing cytokine production. more to the preservation of mucosal integrity, decreases NF-κB Apoptosis cascade is a significant pathway mediating and caspase-3 expression, and exerts antioxidant effects in ethanol-induced gastric ulcer, which is also associated with ethanol-induced gastric ulcer and exhibits gastroprotective inflammatory response and oxidative stress 45. In this regard, effect. Thus, new studies will be necessary to evaluate PYR as ethanol-induced gastric ulcer enhances caspase-3 expression 16. an anti-ulcer drug. Caspase-3 inhibitory effects of PYR were presented in current data. Although the decline in caspase-3 expression can be Conflict of interest attributed to PYR, the main responsible molecules for this The authors declare that they have no conflict of interest. decrease are phenolic compounds in the extract content.
Figure 1. Macroscopic and histopathological images of stomach tissues A) sham, B) ulcer C) PYR 4 ml/kg and D) PYR 8 ml/kg.
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6 Int J Acad Med Pharm, 2021; 3 (1); 7-10
International of Academic Medicine and Pharmacy
Results of Prolonged Use of Intrauterine Device in Endometrium and Eosinophil Leukocytes
Ayşe Nur Uğur Kılınç 1*, Sevcan Sarıkaya 2, Melike Geyik Baran 3, Yaşar Ünlü 4
1,4 Konya Training and Research Hospital, Department of Pathology, Konya, Turkey 2,3 Konya Training and Research Hospital, Department of Gynecology and Obstetrics, Konya, Turkey
ORCID; 0000-0002-0439-0101, 0000-0002-0922-4671, 0000-0003-0008-2205, 0000-0002-3951-8881
Article info Research article
Received :09.08.2020 Abstract;We aim to evaluate the effects of prolonged use of IUD (Intrauterine device) in endometrium curettage materi- Received in revised form :29.09.2020 als and the relationship between the use of IUD and eosinophils. Between 2018 and 2020, the pathology preparations of 38 Accepted :02.11.2020 patients who applied to our hospital with abnormal uterine bleeding and had IUD, and 30 patients with abnormal uterine Available online :05.01.2021 bleeding alone as the control group were examined by a single pathologist. Histopathological diagnosis in the curettage materials with a light microscope, eosinophil leukocyte, neutrophil, plasmocyte counts, and accompanying histopathologi- cal findings were re-evaluated in 10XHMF (High magnification fields) in compact areas without destruction findings. In Keywords our study, the eosinophil presence rate of 38 patients using IUD was 81%. The average duration for IUD use in these patients was seven years. The average duration of IUD use for seven patients who had no eosinophils detected was two Intrauterine device years. The average duration of IUD use for 31 patients with eosinophils was 7.5 years. In the control group patients who Eosinophils were not using IUD with abnormal uterine bleeding, the eosinophil presence rate was found to be 36%. The use of IUD Endometrium does not always cause an increase in eosinophils in the endometrium but is accompanied by high rates. However, we can say that the number of eosinophils increases as the IUD carrying time increases. It should be kept in mind that eosinophil leukocytes, monitored by gynecopathologists in curettage materials, may be associated with prolonged IUD use.
INTRODUCTION MATERIAL and METHOD It is known to all gynecopathologists that the use of IUD (intrauterine device) causes histopathological changes in the Ethical approval endometrium. The histological features associated with the use This study was approved by the Ethical Committee in Konya of IUD are usually due to mechanical action. The Training and Research Hospital, Turkey (02 July 2020, micropapillary formation, focal reactive changes, nuclear 48929119/774) enlargement, mild nuclear atypia, small nucleoli, and cytoplasmic vacuolization, as well as rarely stromal Patients and study design microcalcification, can be seen on the surface. Polymorphs, A single pathologist reviewed pathology preparations of 68 lymphocytes, histiocytes, plasma cells, foreign body type giant patients (38 using IUD and 30 not using IUD) who had cells, and inflammatory cell infiltration can also be seen. abnormal uterine bleeding during the reproductive period and Long-term use of IUD may also be associated with applied to our hospital between 2018-2020. Histopathological actinomyces infection 1. diagnosis in the curettage materials with a light microscope, Until today, there were several studies about the eosinophil leukocyte, neutrophil, plasmocyte counts, and number of eosinophils in the endometrium. accompanying histopathological findings were re-evaluated in These studies were generally performed in 10 high magnification fields from compact areas without endometritis to help configuring out the confusion between destruction findings. The methodology of this study is plasma cells, which are the diagnostic cell of endometritis, and descriptive-analytical method, and data is analyzed using the plasmacytoid stroma cells 2-3. statistical software SPSS 20. However, the relationship of eosinophil leukocytes with IUD has never been studied in the literature.
*Corresponding author: Ayşe Nur Uğur Kılınç, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.45696
7 RESULTS (figure 1). While the average number of eosinophils observed In this study, a total of 68 patients with abnormal uterine in 10 HMF is 5.8 in patients with endometritis, it is 5 in bleeding in the reproductive period were examined. Thirty patients without endometritis. The average duration of IUD use patients were not using IUD, while 38 had IUD. The patients' for eight patients who were observed to have no eosinophils age range was between 25 and 46 years, with a mean age of 37. was two years. The average duration of IUD use for patients In the histopathological diagnosis of 38 patients using who were found to have eosinophils was six years. In addition IUD during curettage; endometritis was detected in 13 patients, to these findings, actinomyces were observed in 2 patients proliferative endometrium in 5 patients, disorder proliferative (figure 2). Enterobius vermicularis was detected in 1 patient. endometrium in 4 patients, early secretory endometrium in 3 Metaplastic changes were observed in 17 of our patients 14 patients, endometrial polyp in 4 patients, progesterone effect in eosinophilic, two squamous, one tubal) (figure 3). One patient 3 patients, glandular stromal destruction in 3 patients, had dystrophic calcification (figure 3). Pigment-laden Enterobius vermicularis infestation in 1 patient. Six of our histiocytes draw attention in 8 patients. (Table 1-2) patients used the Mirena coil, while 32 of them used Eosinophils were observed in 11 (36%) of 30 patients copper-wire IUD. The duration of IUD use in our patients in the control group with abnormal uterine bleeding who did varied between 3 months and 15 years, and the mean use was not use IUD. Histopathological diagnoses in the control group seven years (Table 1). In 31 of 38 patients (81%) with were found as proliferative endometrium in 20 patients and abnormal uterine bleeding and using IUD, eosinophils were disordered proliferative endometrium in 10 patients. Eleven detected in curettage materials. Among them, eosinophils were patients who had eosinophils in the control group had an detected in 85% (11/13) of cases, which were detected to have eosinophil average of two in 10 HMF. endometritis and in 80% (20/25) of cases without endometritis
Table 1. Results of our patients using IUD
IUD-Usage-duration M-C-IUD Pathologic diagnosis NPL/10 HPF Plasmocyte/10 HPF EOS/ 10 HPF Metaplasia 10 year + Progesterone effect 0 0 8 0 10 year Endometritis 15 5 5 Squamous metaplasia 3 year DPE 5 0 5 Eosinophilic metaplasia 2 year + Progesterone effect, endometritis 0 2 0 Tubal metaplasia 3 month Endometrial polyp 5 0 0 0 12 year Proliferative endometirum 10 0 3 Eosinophilic metaplasia 3 year Endometritis 5 5 3 0 4 year + Progesterone effect 3 1 3 0 9 year Early secretory endometrium 5 0 3 Eosinophilic metaplasia 1 year Endometrial polyp 10 0 0 0 5 year Endometritis 1 3 1 Eosinophilic metaplasia 2 year DPE 5 0 0 Eosinophilic metaplasia 14 year Endometritis 20 20 15 Squamous metaplasia 5 year Early secretory endometrium 20 5 10 0 10 year DPE 20 5 5 0 7 year + Progesterone effect 10 3 10 0 12 year Endometritis 5 4 5 Eosinophilic metaplasia 15 year Endometritis 10 10 10 Eosinophilic metaplasia 4 year Endometritis 10 5 5 Eosinophilic metaplasia 4 year Endometritis 10 10 3 Eosinophilic metaplasia 3 year + Progesterone effect 5 5 5 0 4 year Endometritis 10 5 15 Eosinophilic metaplasia 5 year Endometritis 10 5 10 0 4 year + Progesterone effect 0 0 0 0 3 year Endometrial polyp 10 5 10 Eosinophilic metaplasia 1,5 year Endometrial polyp 15 2 10 0 5 year PE 5 0 5 0 7 year Endometritis 5 5 5 0 1 year Endometrial polyp 5 3 5 0 4 year Early secretory endometrium 1 2 4 0 1.5 year PE 5 5 0 0 5 year PE 5 2 7 0 4 year Endometritis 2 7 2 Eosinophilic metaplasia 18 year DPE 10 2 10 Eosinophilic metaplasia 2 year G/S br. 0 0 0 Eosinophilic metaplasia 11 year G/S br. 5 5 5 Eosinophilic metaplasia 10 year G/S br. 7 5 3 0 5 year PE 5 0 4 Eosinophilic metaplasia
(M-C-IUD: Mirena- coil intrauterine device, PE: Proliferative endometrium, DPE:Disorder proliferative endometrium, G/S br.(Glandulo stromal breakdown)
8 Table 2. Pathological effects of long-term use of IUD
Metaplasic changes 19/38 cases Eosinophilic metaplasia 15
Squamous metaplasia 2
Tubal metaplasia 1
Hemosiderin pigments 8/38 cases
Actinomyces 2/38 cases (5 and18 years usage of copperwire coil)
Distrophic calcification 1/38 case (four years usage of mirena coil)
Endometritis 13/38 cases
Enterobius vermicularis 1/38 case (four years usage of mirena coil)
Hyperplasia-malignancy None
Figure 1. Eosinophil on the pr oliferative endometrium background (red arrow) 400X H&E Stain
Figure 2. Squamous metaplasia of the endometir um (red ar row) 100X H&E Stain ,after usage of ten years copper -wire coil (a) Colonies of actinomyces (blue arrow) after usage of ten years copper-wire coil 100X H&E Stain (b)
be involved in allergy-related responses. However, eosinophils are also known to play an important role in the pathogenesis of late-type inflammation. Previous studies have shown that eosinophils are absent in the normal endometrium, except for immediately before menstruation, or they may be associated with endometrial instrumentation 3. Also, inflammatory infiltration can sometimes be accompanied by eosinophils in endometritis 2-3. Adegboyega et al. stated that eosinophil leukocyte infiltration in the endometrium may occur in curettage materials after surgical intervention and may sometimes be seen without an underlying abnormality. In the study of Phillips et al., only patients using Mirena coils were Figure 3. Microcalcifications of the endometrium (red arrows), after usage of four years Mirena coil 200X H&E Stain examined, and it was found that 59 of 75 samples had stromal inflammatory cell infiltration, which is usually with a mixture of lymphocytes, neutrophils, histiocytes, and eosinophils 4. DISCUSSION In the study in which Perlman et al. aimed to find the Eosinophils are inflammatory cells that are popularly known to 9 rate of eosinophils in endometritis, eosinophils were found in IUD has not been previously defined2-7. 68% in the endometritis group and 38% in the control group Although at low rates, hyperplasias have been (1). In our study, this rate was found to be 85% in the reported in the literature related to Mirena coil use. There were endometritis group who were using IUD, and 80% in the group no findings suggesting malignancy or hyperplasia in our using IUD without endometritis. patients 5. The eosinophil presence rate (36%) found in our Our study is valuable since it is the first study in the control group was found to be similar to that of the control literature investigating the number of eosinophils in curettage group in the study of Perlman et al. In our study, the rate of materials of patients using an intrauterine device (IUD). eosinophil monitoring rate of 36% for non-endometritis and non-IUD control group indicates that IUD use alone may cause CONCLUSION an increase in the number of eosinophil leukocytes without The prolonged use of IUD causes many histopathological endometritis. The reason for separately evaluating endometritis changes in the endometrium. According to the results of our and non-endometritis groups in the group using IUD is to study, the use of IUD does not always cause an increase in eo- prevent misleading because eosinophils may accompany sinophils in the endometrium but is accompanied by high rates. plasma cells in endometritis. Also, we can say that the number of eosinophils increases as As per our findings, the average duration of IUD use the IUD usage time increases. It should be kept in mind that for seven patients, for whom no eosinophils were detected in increased eosinophil leukocytes monitored by gyneco- the histopathological examination, was two years. The average pathologists in curettage materials, may be associated especial- duration of IUD for patients who had eosinophils was 7.5 ly with prolonged IUD use. years. Although the use of IUD does not always cause an increase in eosinophils in the endometrium, we can say that the Conflict of interest rate of eosinophils increases as the duration of IUD use The authors declare that they have no conflict of interest. increases. In our study, we added neutrophils along with REFERENCES eosinophils and observed that neutrophils usually accompany 1. Kurman RJ, Ellenson LH, Ronnett BM Blaustein’s Pathology of the (30/31) eosinophils. However, we know that lymphocytes and Female Genital Tract 6thedition Benign diseases of endomet- neutrophils may be a regular component of the endometrium, rium Mc Cluggage WG 2011 Springer pp349-350 depending on the menstrual cycle stage. Also, we did not detect 2. Perlman B, Goldsmith L, Wang Q, Heller DS. Are eosinophils a any eosinophilic micro-abscess in any of our patients. specific marker of chronic endometritis? Journal of Gynecologic In addition, metaplastic changes have been observed Surgery. 2016;32(6):345-7 in 17 of our cases, and 8 of them had hemosiderin 3. Adegboyega PA, Pei Y, McLarty J. Relationship between eosinop- hils and chronic endometritis. Human Pathology. 2010;41(1):33- pigment-laden histiocytes, and in the literature, metaplastic 7. changes and hemosiderin pigments were associated with the 4. Phillips V, Graham C, Manek S, McCluggage W. The effects of the use of IUD in endometrial curettage materials 5. levonorgestrel intrauterine system (Mirena coil) on endometrial The dystrophic calcification observed in one of our morphology. Journal of Clinical Pathology. 2003;56(4):305-7. cases was found to be seen in 10% of the patients using Mirena 5. Hejmadi RK, Chaudhri S., Ganesan R, Rollason TP. Morphologic coil in the literature. In our results, it was observed in only one Changes in the Endometrium Associated With the Use of the out of six patients who were using the Mirena coil 5. In a Mirena Coil: A Retrospective Study of 106 Cases. International recent study, they stated that endometrial benign calcifications Journal of Surgical Pathology, 2007; 15(2), 148–154. may be multifactorial but progesterone plays an important role 6. AbdullGaffar B, AlMulla A. Endometrial Calcifications. Internatio- 6 . The fact that the only case we detected calcification used nal Journal of Surgical Pathology. 2020;28(6):590-599 mirena coil for four years supports this thesis . 7. Ng YW, Ng SB, Low J. Enterobius vermicularis infestation of the Once again, Enterobius vermicularis was present in endometrium-a cause of menstrual irregularity and review of one of our cases, which was associated with chronic pelvic literature. Annals of the Academy of Medicine, Singapore. inflammatory diseases in the literature, and its association with 2011;40(11):514. 10 Int J Acad Med Pharm, 2021; 3 (1); 11-15
International of Academic Medicine and Pharmacy
Combination of Strontium Chloride 5% and Licorice 1% Solution Compared Mometasone Furoate Solution 0.1% for Dandruff
Rukiye Yasak Güner 1*, Mustafa Tosun 2, Melih Akyol 3, Selim Çam 4
1,2,3 Cumhuriyet University School of Medicine, Dermatology Department, Sivas, Turkey 4 Cumhuriyet University School of Medicine, Hospital Statistics, Sivas, Turkey
ORCID; 0000-0002-5154-4652, 0000-0002-6189-8016, 0000-0001-7912-0651, 0000-0001-8688-9434
Article info Research article
Received :15.09.2020 Abstract; Pityriasis capitis simplex (Dandruff) is one of the most common scalp disorders with poor quality of life and Received in revised form :19.11.2020 pityriasic desquamation and pruritus on scalp. The main treatment options are antifungal agents and topical steroids. The Accepted :02.11.2020 aim of this study was to compare the clinical and symptomatic efficacy of strontium chloride hexahydrate 5% + licorice Available online :05.01.2021 1% combination (Storice®) with mometasone furoate 0.1%, a topical corticosteroid, in cases of pityriasis capitis simplex. 80 patients with a diagnodis of pityriasis capitis simplex were enrolled. 40 patients (20 males (50%), 20 females (50%)) were included in the mometasone furoate 0.1% group, and the remaining 40 patients (19 males (47.5%), 21 females Keywords (52.5%)) were included in the group of topical treatment agent (Storice®) consisting of strontium chloride hexahydrate 5% + licorice 1% combination. The clinical and symptomatic efficacy (pruritus and desquamation on scalp and life Pityriasis capitis simplex quality) of both agents were evaluated. Strontium chloride hexahydrate 5% + licorice 1% significantly reduces pruritus Dandruff and improves quality of life by reducing clinical symptoms. Pruritus Desquamation Life quality Strontium Licorice
INTRODUCTION patient group and causes the development of emotional The prevalence of seborrheic dermatitis is 3% and it can make problems such as impaired self-esteem 5. In the USA, people a peak in the 3rd to 4th decade of lifetime. This skin disease is spent 300 million dollars annually on "over-the-counter" more common in men. Use of neuroleptics, Parkinson's disease products to relieve the complaints of squams and pruritus on and HIV are factors that facilitate seborrheic dermatitis 1. the scalp 2. Pityriasis capitis simplex (Dandruff) can be considered as the Since pityriasis capitis simplex is a chronic disease mild form of seborrheic dermatitis, especially affecting the with recurrent attacks, the main purpose of treatment is to scalp. Unlike seborrheic dermatitis, it affects 50% of the relieve symptoms. Prevention of erythema, desquamation and general population 2. pruritus on the scalp construct the basis of the treatment. Etiopathogenesis of seborrheic dermatitis is not clear. Topical or systemic treatments are used for this purpose. Indirect evidence pointed out that Malassezia spp. may have a Topical antifungal (ketoconazole) shampoos and role. Endocrinopathies and metabolic changes were claimed to corticosteroids are the main treatment approaches. Selenium be associated with seborrheic dermatitis 3. In a study conducted sulfide and zinc pyrithion-containing shampoos are also used in in our clinic, we reported that in patients with seborrheic treatment. Systemic antifungal agents (fluconazole) may also dermatitis, a positive family history for metabolic syndrome be used in treatment of unresponsive or resistant cases. Topical and low HDL levels were associated with the presence of the calcineurin inhibitors (pimecrolimus, tacrolimus) can also be disease 4. used in treatment of cases where topical corticosteroids cannot In cases of pityriasis capitis simplex, squams and be used or unresponsive cases, but scalp preparations of these pruritus on the scalp are the most basic clinical findings. This drugs do not exist. Only topical corticosteroid lotions and some clinical state significantly affects the quality of life in this tars are available as treatment options on the scalp 6-9.
*Corresponding author: Rukiye Yasak Güner, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.48372
11 Recurrent topical treatments in cases proceeding as agent (Storice®) consisting of strontium chloride hexahydrate attacks may cause side effects especially related to topical 5% + licorice 1% combination was given to one group and steroids. Therefore, there is a need for different topical mometasone furoate 0.1% hair lotion to the other group, to be treatment options to control the symptoms of the disease applied on the scalp twice a day by the patients. The clinical besides the current treatments. Pruritus control is important in and symptomatic efficacy of both agents were compared. this patient group as in other similar diseases. Topical Visual Analogue Scale (VAS) was applied to evaluate pruritus treatments that can actively control pruritus are significant for (scalp pruritus score) (SPS Score). Dermatology Life Quality the control of pityriasis capitis simplex and to improve the Index (DLQI), which is commonly used in dermatological quality of life in patients. Preparations in the form of topical diseases, was used to evaluate the quality of life. The amount hair lotion containing strontium chloride hexahydrate and/or of desquamation in the scalp of the patient was determined by licorice, which are known to have anti-inflammatory and the physician using the scalp lesion score (SLS Score) 12. prominent antipruritic properties, can be used in the control and Visual Analogue Scale (VAS, SPS Score) and scalp maintenance of these symptoms by preserving the moisture and lesion score were evaluated before treatment, in the first week barrier integrity of the scalp. These topical preparations do not of treatment and after treatment, and DLQI was evaluated have any known side effects in long-term use 10, 11. before and after treatment. The aim of this study was to compare the clinical and symptomatic efficacy of strontium chloride hexahydrate 5% + Statistical analysis licorice 1% combination (Storice®) with mometasone furoate The data obtained from our study were evaluated by uploading 0.1%, a topical corticosteroid, in cases of pityriasis capitis to the SPSS (V22.0) software. Since the data did not conform simplex. to the normal distribution according to the normality test (Shapiro-Wilk) and there were three repetitive measurements, MATERIAL and METHODS the Friedman test, a non-parametric test, was used. Wilcoxon test was used to compare two dependent groups. Mann Ethics committee approval Whitney U test was used to compare two independent groups. Ethics committee approval of the study was obtained from The level of error was taken as 0.05. Cumhuriyet University Clinical Research Ethics Committee with the decision numbered 2020-10/03. RESULTS Of the 80 patients (41 females (51%), 39 males (49%) ) with a Patients and study design diagnosis of pityriasis capitis simplex who participated in our The presence of a comorbid disease in the patients was study, 40 patients (20 males (50%), 20 females (50%) ) were determined by the history of patient and hematological included in the mometasone furoate 0.1% group, and the examinations that are routinely used in examination and follow remaining 40 patients (19 males (47.5%), 21 females (52.5%) ) -up of these patients. For this purpose, hemogram, complete were included in the group of topical treatment agent biochemistry, sedimentation, CRP and TSH levels were (Storice®) consisting of strontium chloride hexahydrate 5% + checked. Patients with a history of hypertension or an licorice 1% combination. endocrinopathy, pediatric patients, pregnant women, patients The mean age of the patients was 30.6 ± 12.25 years, over 65 years of age, patients diagnosed with neurological and the mean disease duration was 7.9 ± 7.5 months. The mean diseases, HIV positive patients were not included in the study. age was 30.3 ± 11.8 years in the patient group using Eighty patients who applied to the Dermatology mometasone furoate 0.1%, and 30.9 ± 12.8 years in the patient outpatient clinic of Sivas Cumhuriyet University Faculty of group using strontium chloride hexahydrate 5% + licorice 1% Medicine and were diagnosed with pityriasis capitis simplex, (Storice®). The mean disease duration was 6.2 ± 5.08 months who had not been treated for the last four weeks, participated in in the patient group using mometasone furoate 0.1%, and 9.6 ± the study. The patients included in the study were randomly 9.1 months in the patient group using strontium chloride divided into two age- and gender-matched treatment groups. hexahydrate 5% + licorice 1% (Storice®). Table 1 shows the After obtaining the consent of the patients, topical treatment results of statistical analysis (Figure 1-3). 12 Table 1. The results of the statistical analysis in both gr oups.
Treatment groups
Mometasone furoate Strontium chloride p Measurements 0.1% hair lotion 5%+licorice 1% hair lotion (Storice®) Median±IQR (Percentile 25- Median±IQR (Percentile 25-Percentile Percentile 75) 75) DLQI before treatment 9±3,5(8-11,5) 11±7(9-16) 0,096 DLQI after treatment 3,5±4(2-6) 5±4(4-8) 0,002 p <0,001 <0,001 SLS Scores before treatment 13±13,5(8,5-22) 14±15,5(8,5-24) 0,569 SLS Scores first week 7±6(5-11) 9,5±10(7-17) 0,006 SLS Scores after treatment 2±4(1-5) 6±10(2-12) 0,001 p <0,001 <0,001 SPS Scores before treatment 7±3(5-8) 6,5±3(5-8) 0,807 SPS Scores first week 2±1,5(1,5-3) 2±2(1-3) 0,634 SPS Scores after treatment 1±1(1-2) 0,5±1(0-1) <0,001 p <0,001 <0,001 *p< 0.05 significant
Figure 1. SLS scores in patients gr oups Figure 2. SPS scores in patient gr oups
play an important role in the pathogenesis of the disease 2, 13, 14. As a matter of fact, obtaining a successful clinical response in patients who receive only antifungal therapy may not be possible 14. Basic treatment options include antifungal agents, keratolytics and keratostatics, anti-inflammatory agents, anti-sebum agents, and immunomodulators 15. The most commonly used anti-inflammatory agents are topical corticosteroids. For this purpose, low and mid-potency strength topical steroids can be used in the form of hair lotion. Although Figure 3. DLQI scores in patient gr oups they have an important role in the control of pityriasic desquamation and pruritus with their rapid effects, DISCUSSION development of atrophy and similar side effects with long and Pityriasis capitis simplex is a chronic, recurrent inflammatory frequent use of topical corticosteroids is possible. Therefore, in disease of the scalp. It is characterized by pityriasic the treatment of pityriasis capitis simplex located on the scalp, desquamation and itching of the scalp and affects a significant particular anti-inflammatory and antipruritic effective options part of the world population. Various internal and external are needed in addition to topical corticosteroids. As an factors are responsible for the development of the alternative to topical steroids, there are immunomodulatory disease 2, 13, 14. effective calcineurin inhibitors such as pimecrolimus and Although Malassezia is an important factor, tacrolimus, but the lack of appropriate topical forms for the inflammatory responses related to personal predisposition also scalp limits their use 13-16. 13 Strontium is a trace element and a competitive and licorice (Storice®) significantly reduces pruritus and inhibitor of calcium. It inhibits the flow of calcium into the cell improves quality of life by reducing clinical symptoms in and may indirectly reduce the expression of proinflammatory cases of pityriasis capitis simplex, which is a frequently cytokines 10,17,18. In a study conducted in our clinic, we have recurring chronic inflammatory disease. The results of our shown that strontium chloride hexahydrate 5% cream study point out that this combination may be used safely and suppresses the inflammatory phase in the wound healing model effectively to provide maintenance alone or in combination 10. Strontium salts are also effective in reducing skin irritation with topical steroids or after topical steroids in the cases with and can effectively block the burning-stinging sensation and pityriasis capitis simplex, especially in cases requiring itching 19, 20. long-term treatment in clinical practice. Licorice is a perennial herb. One of the major components of Licorice root extract is 18b-Glycyrrhetinic acid. Conflict of interest Glycyrrhetinic acid can be used effectively in suppressing the Melih Akyol, who is one of the authors of this publication, has inflammatory response and reducing pruritus in eczema 21-24. a commercial relationship with Drogsan medicine company In this comparison study of topical Strontium chloride through “Cumhuriyet Teknokent.” hexahydrate and licorice combination with topical mometasone in pityriasis capitis simplex cases with anti-inflammatory and REFERENCES antipruritic effects, similar clinical and symptomatologic 1. Collins CD, Hivnor C. Seborrheic dermatitis. In: Fitzpatrick’s efficacy emerged in both treatment groups at the end of two Dermatology in General Medicine. Goldsmiths LA, Katz SI, weeks of treatment. Gilchrest BA, et al (eds), Eight edition, The McGraw-Hill Companies, Inc., New York, 2012, p: 259-66. In our study, mometason furoate 1% is more effective 2. Borda LJ, Wikramanayake TC. Seborrheic Dermatitis and than Strontium chloride and licorice combination (Storice®) in Dandruff: A Comprehensive Review. J Clin Investig Dermatol reducing scalp desquamation. On the other hand,it is 2015; 3(2): 10.13188/2373-1044.1000019. remarkable that the combination of Strontium chloride 3. Linder D, Drehier J, Zampatti A, Sampagna F, Cohen AD. hexahydrate and licorice has a significant effect especially in Seborrheic dermatitis and hypertension in adults: a cross the control of pruritus. The antipruritic effect of this sectional study. J Eur Acad Dermatol Venerol. 2014;28:1450-5. combination can be explained by two mechanisms: 4. İmamoğlu B, Berksoy Hayta S, Güner R, Akyol M, Özçelik S. 1- Antipruritic effect of strontium salts blocking of Metabolic syndrome may be an important comorbidity in patients calcium-mediated P substance release 20, 2- Indirect antipruritic with seborrheic dermatitis. Arch Med Sci Atheroscler Dis. 2016;1 (1): e158–e161. effect of licorice with its anti-inflammatory effects 25. 5. Xuan M, Lu C, He Z. Clinical characteristics and quality of life Quality of life is an important factor in the treatment in seborrheic dermatitis patients: a crosssectional study in China. of this community-common disease. Significant improvements Health Qual Life Outcomes. 2020;18(1):308. doi: 10.1186/ were observed in dermatological quality of life scores in both s12955-020-01558-y. treatment groups. Although the control of the pruritus of 6. Danby FW, Maddin WS, Margesson LJ, Rosenthal D. A Strontium chloride hexahydrate and licorice combination randomized, double-blind, placebo-controlled trial of (Storice®) significantly affects the quality of life positively, ketoconazole 2% shampoo versus selenium sulfide 2.5% our results shows that mometasone furoate effect is more shampoo in the treatment of moderate to severe dandruff. J Am pronounced in improving the quality of life. Acad Dermatol 1993; 29:1008. 7. Schwartz JR. Zinc Pyrithione: A Topical Antimicrobial With In the present study, no significant adverse effects Complex Pharmaceutics. J Drugs Dermatol 2016;15:140. were noted in either treatment group. 8. Piérard-Franchimont C, Piérard GE, Vroome V, et al. The limitations of this study are that the placebo group Comparative anti-dandruff efficacy between a tar and a non-tar was not used and the long-term treatment effects such as shampoo. Dermatology 2000;200:181. maintenance, recurrence and side effects were not evaluated. 9. Gupta AK, Richardson M, Paquet M. Systematic review of oral The combination of Strontium chloride hexahydrate treatments for seborrheic dermatitis. J Eur Acad Dermatol Venereol 2014;28:16.
14 10. Berksoy Hayta S, Durmuş K, Altuntaş EE, Yıldız E, 18. Korgali E, Dundar G, Coskun KA, et al. Effect of strontium Hisarcıklıoğlu M, Akyol M. The reduction in inflammation and chloride on experimental bladder inflammation in rat. Int Sch Res impairment in wound healing by using strontium chloride Notices 2014;2014:369292. hexahydrate. Cutan Ocul Toxicol. 2018;37(1):24-28. doi: 19. Zhai H, Hannon W, Hahn GS et al. Strontium nitrate suppresses 10.1080/15569527.2017.1326497. chemically-induced sensory irritation in humans. Contact 11. Hahn GS. Strontium is a potent and selective inhibitor of sensory Dermatitis 2000;42: 98-100. irritation. Dermatol Surg. 1999;25(9):689-94. doi: 10.1046/j.1524 20. Akyol M, Güner R. [General approach and topical treatment for -4725.1999.99099.x. pruritus]Pruritusta genel yaklaşım ve topikal tedavi. Şavk E, 12. Bacon, R. A., Mizoguchi, H., & Schwartz, J. R.. Assessing thera- editör. Pruritus. 1. Baskı. Ankara: Türkiye Klinikleri; 2019. p.73- peutic effectiveness of scalp treatments for dandruff and seborr- 7. heic dermatitis, part 1: a reliable and relevant method based on 21. Yang R, Wang L-Q, Yuan B-C, Liu Y. The pharmacological the adherent scalp flaking score (ASFS). J Dermatol Treat, activities of licorice. Planta Med 2015; 81:1654–1669. 2014;25(3), 232-236. 22. Kowalska A, Kallinowska-Lis U. 18b-Glycyrrhetinic acid: its 13. Sheth U, Dande P. Pityriasis capitis: Causes, pathophysiology, core biological properties and dermatological applications. Int J current modalities & future approach. J Cosmetic Dermatol 2020. Cosmetic Science, 2019,1-7. doi: 10.1111/jocd.13488. 23. Angelova-Fischer I, Neufang G. Jung K, Fischer TW, Zillikens 14. Wei S-Y, Zhang H-Y, Yin Y-T, et al. actor analysis approach D. A randomized, investigator-blinded efficacy assessment study unveils the influencing factors of dandruff in the normal teenage of stand-alone emollient use in mild to moderately severe atopic population. Dermatol Ther 2020;33(4): e13690. doi: 10.1111/ dermatitis flares. JEADV 2014, 28 (Suppl. 3), 9–15. dth.13690. 24. Wang Y, Zang Y, Peng G, Han X. Glycyrrhizin ameliorates 15. Mariappan PM, Sabesan G, Babu K, Ranjith M. Herbal vs. atopic dermatitis-like symptoms through inhibition of HMGB1. chemical substances as antidandruff ingredients: which are more Int Immunopharmacol 2018;60:9-17. doi: 10.1016/ effective in the management of Dandruff?-An overview . Egypt J j.intimp.2018.04.029. Dermatol 2010;5(2): 8. 25. Saeedi M, Morteza-Zemnani K, Ghoresihi M-R. The treatment of 16. Salgado A, Raposo S, Marto J et al. Mometasone furoate atopic dermatitis with licorice gel. J Dermatol Treat 2003;14:153- hydrogel for scalp use: in vitro and in vivo evaluation. Pharm 157. Dev Technol 2014; 19(5): 618-22. doi: 10.3109/10837450.2013.819012. 17. Kurt A, Soylu S, Şahin İnal ZD et al. Effects of strontium ranilate and Hypericum perforatum extract on experimental colitis model in rats. CMJ 2018;40:194-200.
15 Int J Acad Med Pharm, 2021; 3 (1); 16-21
International of Academic Medicine and Pharmacy
Evaluation of Pain and Anxiety Levels of Tooth Extraction**
Ahmet Barışık 1*, Mehmet Esen 2, Mehmet Kemal Tümer 3, Yunus Balel 4
1,3,4 Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tokat Gaziosmanpasa University, Tokat, Turkey 2 Department of Emergency Medicine, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey
ORCID; 0000-0002-7785-0033, 0000-0003-2180-6946, 0000-0002-6250-0954, 0000-0003-0496-8564
Article info Research article
Received :02.09.2020 Abstract; The anxiety observed in patients before and during dental treatments is defined as a complex behavior pattern Received in revised form :21.11.2020 related to physiological activation against internal or external stimuli. Anxiety formation is common before dental Accepted :02.11.2020 treatments, especially before tooth extraction. In this study, we were aimed to evaluate the anxiety, preoperative / Available online :05.01.2021 postoperative pain levels and the relationship of various variables (age, smoking, etc.) with tooth extraction, which is one of the most basic procedures of oral and maxillofacial surgery. During the study process, 982 patients applied, 312 patients were identified according to the inclusion criteria, and the study was conducted with 210 patients who volunteered to Keywords participate in the study. There were significant differences between the groups in terms of marital status, educational status, history of previous tooth extraction and tooth brushing frequency (p <0.05). The level of anxiety increases towards Tooth extraction posterior teeth (mean: 37.38 ± 7.40 for anterior teeth, mean: 44.40 ± 10.43 for molar teeth with complications). When the Pain VAS scores were examined, the pain increased significantly from the anterior teeth to the posterior teeth (r: 0.568, p Anxiety <0.05). There were statistically significant differences in terms of Penn State Worry Questionnaire (PSWQ) total scores when the groups that had tooth extraction were compared. Although smoking causes an increase in the incidence of alveolar osteitis, it has been observed that it causes less pain (low VAS score) in patients who undergo tooth extraction.
INTRODUCTION vicious circle will occur due to this fear and anxiety 7. Patients The anxiety observed in patients before and during dental avoid dental treatments for these reasons and this causes dental treatments is defined as a complex behavior pattern related to problems to become more complex. This situation may lead to physiological activation against internal or external stimuli 1. A more intense and potentially more traumatic treatment high level of fear of dental treatment is widely observed all requirements in the future 8. over the world, studies conducted in different countries indicate Postoperative pain reaches its peak between the first that the anxiety rates in dental treatments are between 4.2% and 6th and 8th hours with the disappearance of the local anesthetic 20.9% 2,3. effect. Pain occurs when inflammatory mediators and algogenic Dental anxiety prevents the realization of planned substances secreted by surgical injury stimulate the treatments and increases the incidence of diseases in non - myelinated C fibers of the trigeminal nerve. These surrounding tissues 4. Although various levels of anxiety are stimulating substances are bradykinin and prostaglandin felt in patients before treatment in dental treatments, oral secreted from damaged cells, and leukocytes, lymphocytes, surgical procedures are associated with the highest levels of mast cells, eozonophils and leukotrienes that reach the injured anxiety 5. In the study conducted by Muğlalı and Kömerik, area in the inflammatory process. The stimulated peripheral 30% of the patients undergoing minor oral surgical procedures nerves release substance P and send nociceptive pain signals to had mild, moderate anxiety levels in 40%, high levels in 14% the central nervous system and simultaneously cause and very high levels of anxiety in 11% and the level of patients vasodilation, local proinflammatory symptoms such as edema who did not feel any anxiety remained around 5% 6. in the area by exiting the plasma from the vein. Peripheral If the anxiety and worry related to dental treatment fibers that carry pain enter the brainstem directly from the pons observed in patients are not managed properly, it is likely that a and stimulate the neurons in the spinal trigeminal nucleus.
*Corresponding author: Ahmet Barışık, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.46109 **This study has been prepared as a Master of Science thesis
16 After this stage, the impulse travels to the thalamus and reaches Patients who did not agree to be included in the study the regions that process the nociceptive senses, such as the Patients with incomplete demographic data somatosensory cerebral cortex and the limbic forebrain, Patients with incomplete postoperative follow-up creating the sensation of pain 9. Bisphosphonate use history In this study, it was aimed to evaluate the anxiety, The patients were divided into 7 groups according to the preoperative / postoperative pain levels and the relationship of tooth to be extracted: Anterior, Canine, Premolar, Molar, various variables (age, smoking, etc.) with tooth extraction, Complicated Molar, 3rd Molar Tooth with Mucosa Retention which is one of the most basic procedures of oral and and 3rd Molar Tooth with Bone Retention. All tooth maxillofacial surgery. extractions were done by the same Oral and Maxillofacial
surgeon(YB). Non-Steroid Anti-Inflammatory Drugs MATERIAL and METHOD (NSAIDs) at a dose of 2x1 for 3 days were prescribed to all
groups. Ethical approval
This study was approved by the Tokat Gaziosmanpaşa Surveys applied University Non-Interventional Clinical Research Ethics Patients; Demographic Data Form (with information on age, Committee on 22.11.2019, with the meeting number 2019/17, gender, smoking status, etc.), Penn State Worry Questionnaire project number 19-KAEK-241 and the decision number (PSWQ), Pain Catastrophizing Scale (PCS-T) and Visual 83116987-859. Analogue Scale (VAS) were applied.
Demographic Data Form: The patient demographic Study design data questionnaire aims to obtain information by including Between 2019 and 2020, it was held in Tokat Gaziosmanpaşa questions about the current systemic status, educational status, University Faculty of Medicine, Department of Emergency social character and medical history of the patients Medicine and Tokat Gaziosmanpaşa University Faculty of participating in the study. The content of this questionnaire, Dentistry, Department of Oral and Maxillofacial Surgery. which is not based on literature data, was determined by the During the study process, 982 patients applied, 312 patients researchers who participated in the study. It does not contain were identified according to the inclusion criteria, and the study any scoring system. It is mainly for obtaining information was conducted with 210 patients who volunteered to participate about the patients participating in the study. in the study. Penn State Worry Questionnaire (PSWQ): PSWQ has Inclusion criteria applied: been used in different medical branches for many years to 18-65 years old measure the anxiety level of the patient. The presence of worry ASA (American Society of Anesthesiologists) -I systemic factor consists of 11 items expressed positively, while the status absence of worry factor consists of the remaining 5 items Not having a previous psychiatric disorders written in a negative way 10. While 11 existing items are scored Not being diagnosed with a current psychiatric disorder positively, the remaining 5 items (items 1, 3, 8, 10 and 11) and not receiving any treatment require reverse scoring. Scoring with a minimum of one and a maximum of 5 points is required for each item in the total Not having a history of any trauma to the maxillofacial 16-item survey scoring. According to the scoring results of all area. items, patients have a scoring score between 16 and 80. No major surgery in the maxillofacial region Increasing the scoring score means that the patient's anxiety Exclusion Criteria Applied: level increases. The scale is filled by the patients in the Having a history of psychiatric disorders preoperative period. PSWQ reported adequate internal Having a psychiatric treatment history consistency, with consistencies ranging from 0.86 to 0.95 in Having a systemic condition other than ASA – I both clinical and non-clinical samples 11. In addition, test-retest reliability of PSWQ in different time intervals varies between 17 0.74 and 0.93 in three independent university samples 12. of variables showing normal distribution, and t-test was used Pain Catastrophizing Scale (PCS-T): PCS-T is used to for paired comparisons. Kruskal Wallis test was used for assess the patient's feelings, thoughts, and senses about pain comparison between variables that did not show normal and disaster. It is a self-administered questionnaire with 13 distribution, Mann-Whitney U test for paired comparisons, items and 3 subscales: helplessness, magnification, and Chi -Squared test for comparisons, and Pearson correlation test rumination. A 5 point scale is used for each item, higher values was used to determine the relationships between variables. mean greater disaster. Of the 13-item questions, PCS-T scored Tukey and Games-Howell tests were used in post hoc analysis. between 0 and 52 in total. Higher scores mean patients are P <0.05 was considered statistically significant. more catastrophic. The scale is filled by the patient in the preoperative period. It was reported that the inter-item and item RESULTS -total correlations of the Turkish version of the scale were A total of 118 women (mean age 35.71 ± 14.76), 92 men (mean between 0.488 and 0.848, and the intraclass correlation age 40.58 ± 14.63) were included in the study. The coefficient was 0.830 13. demographic information obtained from the patients is summarized in table 1. There were significant differences Statistical analysis between the groups in terms of marital status, educational In this study, statistical analyzes were carried out using SPSS status, history of previous tooth extraction and toothbrushing 22.0 (IBM Company, United States) statistical package frequency (p <0.05, Table 1). In the post hoc analysis, it was software. While analyzing the data, one-way analysis of seen that 3rd molar teeth with Bone / Mucosa Retention variance (ANOVA) was used in addition to descriptive differed from other groups. statistics (mean, standard deviation) for intergroup comparisons
Table 1. Distribution of demographic characteristics by gr oups
Groups p Anterior Canine Premolar Molar C.Molar MR 3rd BR 3rd (n=30) (n=30) (n=30) (n=30) (n=30) (n=30) (n=30) Male 14 17 11 14 13 12 11 Gender 0,733 Female 16 13 19 16 17 18 19 Married 25 27 27 19 18 12 12 Marital status <0,01* Single 5 3 3 11 12 18 18 Primary Education 16 14 21 11 10 6 3 High school 9 11 2 11 6 11 12 Education status <0,01* Undergraduate 5 5 7 7 13 12 11 Post Graduate 0 0 0 1 1 1 4 Previous Tooth Extraction Yes 29 29 27 23 21 22 20 0,03* Experience No 1 1 3 7 9 8 10 No 5 3 2 3 1 2 0 Tooth Brushing Frequ- Once a week 7 9 8 5 3 3 4 0,023* ency Once a day 10 11 13 11 18 8 13 Twice a day 8 7 7 11 8 17 13 Yes 10 14 9 10 10 7 6 Smoking 0,411 No 20 16 21 20 20 23 24 Data are shown as n (%). Test: One Way ANOVA * p value is significant at the 0.05 level., C.Molar:Complicated Molar , MR 3rd: 3rd molar tooth with Mucosal Retention , BR 3rd: 3rd molar tooth with Bone Retention Quantitative changes are shown in table 2. There were VAS scores were examined, the pain increased significantly significant differences between the groups in terms of age, PCS from the anterior teeth to the posterior teeth (r: 0.568, p <0.05). -T and PSWQ (p <0.05). The level of anxiety increases towards There was no significant relationship between tooth posterior teeth (mean: 37.38 ± 7.40 for anterior teeth, mean: brushing frequency and PCS-T and PSWQ scores (p> 0.05). 44.40 ± 10.43 for molar teeth with complications). When the
Table 2. Distribution of quantitative values by groups
Groups p
Anterior (n=30) Canine (n=30) Premolar (n=30) Molar (n=30) C.Molar (n=30) MR 3rd (n=30) BR 3rd (n=30) Age 49,46±13,39 52,53±10,20 43,33±13,22 34,33±12,69 33,40±11,38 25,10±7,45 27±8,40 <0,01* Penn State Worry 37,83±7,40 39,06±8,43 40,33±12,15 41,56±10,09 44,40±10,43 44,96±10,41 43,26±8,88 <0,01* Questionnaire PCST Pain Scale 12,26±6,07 15,56±8,76 19,03±9,80 20,70±10,41 22,13±12,26 18,33±10,94 14,76±6,25 <0,036* Score Data are shown as Mean ± SD. Test: One Way ANOVA * p value is significant at the 0.05 level., C.Molar:Complicated Molar , MR 3rd: 3rd molar tooth with Mucosal Retention, BR 3rd: 3rd molar tooth with Bone Retention 18 While there was no significant relationship between smoking social-cultural conditions. The minimum amount of the and PCS-T and PSWQ scores, there was a significant stimulus that triggers the pain is different for each patient. Pain relationship between VAS scores (Tables 3 and 4). The average disaster is considered a marker of pain. It is defined as VAS scores of smokers were lower than non-smokers (4.06 ± exaggerated negative reactions to a painful stimulus. The 1.71 versus 6.12 ± 1.52). However, the incidence of alveolar severity of the pain experienced by the individual plays an osteitis in smokers was 1.3 times higher than in non-smokers. important role in the formation of the thought of
Table 3. Relationship between smoking and Penn State Worry catastrophizing the event. In a study involving 92 patients, Questionnaire and PCST Pain Scale Score Altan et al.16 investigated the effect of preoperative PCS-T
Smoking score on postoperative analgesic use using the pain disaster t p Yes (n=66) No (n=144) scale. Although it was not statistically significant according to 36,66±8,63 42,39±10,53 Penn State Worry Questionnaire -1,217 0,224 the results of the study, it was observed that the use of 16,31±8,87 18,10±10,29 PCST Pain Scale Score -1,840 0,067 analgesics was statistically higher in patients with higher Data are shown as Mean ± SD. Test: Independent Sample T Test * p value is significant at the 0.05 level PCS-T scores. They concluded that the preoperative anxiety level was significantly higher in female patients compared to Table 4. Distribution of VAS scores by smoking use male patients 16. The results of the present study showed that Smoking t p postoperative analgesic use may be higher in patients with high Yes (n=66) No (n=144) VAS Score 6 Hours After PCS-T scores. The data in the present study are in agreement 4,06±1,71(a) 6,12±1,52(a) 8,115 0,003* Tooth Extraction 16 VAS Score 24 Hours After with the data in Altan et al. study. When the groups were 1,14±1,51(b) 2,95±1,62(b) 7,697 0,003* Tooth Extraction VAS Score 72 Hours After examined, it was observed that PCS-T values were 0,17±0,55(c) 0,63±1,01(c) 3,340 0,003* Tooth Extraction Time: F= 102,160; p<0,001* significantly higher in those who drank more than one TimexGroups: F=7,535; p=0,003* painkiller per day. Patients with medical disaster fear that a medical DISCUSSION emergency such as cardiac arrest might develop during The concept of dental anxiety, which is widely observed, treatment 17. Usually, such patients report that they are allergic includes a complex behavioral model associated with or react to local anesthetics, especially those containing physiological activation that occurs in response to cognitive epinephrine or similar vasoconstrictors. In addition, placing and somatic internal stimuli or environmental external stimuli instruments in the mouth during treatment triggers concerns that patients may experience before or during dental treatment about suffocation. In the event of a reaction due to local 1. Fear and anxiety observed in dentistry often cause anesthesia, the patient may show symptoms such as heart psychosocial problems such as poor oral hygiene, poor quality palpitations or shortness of breath due to increased epinephrine of life, low self-esteem and mental collapse, which occur as a levels. Patients tend to interpret these symptoms as anesthetic result of inadequate oral health 14. McGrath and Bedi reported allergy. The expectation of the patient to have a similar that low oral and dental health was observed in patients with reaction at the next appointment where the anesthetic is used high dental treatment anxiety 15. In the present study, PCS-T may lead to an increase in anxiety level. When anxiety-induced scores were observed to be lower in patients with high oral autonomic arousal or any condition associated with epinephrine hygiene who had regular tooth brushing habits, and conversely, is experienced, the patient may believe that this condition will PCS-T scores were observed to be lower in patients with poor worsen over time. It is important to distinguish these and oral hygiene, although it was not statistically significant. similar situations in terms of effective anesthesia depth. Pain is a difficult symptom to live with and often Otherwise, insufficient anesthesia depth will manifest itself in needs treatment. It is also defined as unpleasant sensory and the form of an increased risk of pain and an increased level of emotional experiences associated with actual or potential tissue anxiety. When dealing with this type of fear, it is important to damage. After tooth extraction, the pain reaches its maximum provide a detailed medical history. The actual prevalence of level as the effect of local anesthetic disappears. Pain allergies to local anesthetics is extremely low. It has been perception is associated with many mechanisms, including determined that most negative responses are associated with environmental stimuli, cognitive and emotional processes, and 19 anxiety. Even in cases where a patient's true allergy to local extraction groups (Molar and 3rd molar teeth), the average age anesthetics does not seem likely, consulting the patient with an of the patients increased towards the anterior. immunology-allergist can completely eliminate patient anxiety, There were statistically significant differences in in order to eliminate this concern completely. Patients with this terms of PSWQ total scores when the groups that had tooth fear do not respond well to assurances that such allergy stories extraction were compared. Higher PSWQ scores were observed are rare. In cases where the dentist takes the patient's anxiety in the 3rd molar tooth extraction group and compared to the seriously, it is observed that the patients respond well. After molar tooth group. It was observed that the anxiety level was excluding an allergy history, briefing about the nature and higher in patients with posterior tooth extraction compared to effects of epinephrine can enable the patient to relate their the anterior region. When the two groups were compared in symptoms 17–20. terms of PCS-T scores, statistically insignificant higher scores In the present study, alveolar osteitis was observed 1.3 were observed in patients with complicated molar teeth and times more in smokers compared to non-smokers. This those requiring extraction of 3rd molar teeth. situation supports previous studies, but the mechanism of Although smoking causes an increase in the incidence smoking on alveolar osteitis has not been clearly explained. of alveolar osteitis, it has been observed that it causes less pain The most accepted theory suggests that mechanical clot (low VAS score) in patients who undergo tooth extraction. dislodgement occurs with the suction movement while smoking, but the effect of nicotine contained in cigarette smoke Conflict of interest on the formation of granulation tissue or the reduced local The authors declare that they have no conflict of interest immune and inflammatory response due to smoking may also lead to alveolar osteitis 21–23. REFERENCES Dental anxiety and dental phobia in oral surgical 1. López-Jornet P, Camacho-Alonso F, Sanchez-Siles M. 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21 Int J Acad Med Pharm, 2021; 3 (1); 22-28
International of Academic Medicine and Pharmacy
Hesperidin Attenuates Oxidative Ovarian Damage Induced by Ischemia Reperfusion: An Antioxidant, Antiautophagic and Antiapoptotic Agent
Fazile Nur Ekinci Akdemir 1, Ayhan Tanyeli 2*, Derya Güzel 3, Mustafa Can Güler 4, Ersen Eraslan 5, Selim Çomakli 6
1 Department of Nutrition and Dietetics, High School of Health, Ağrı İbrahim Çeçen University, Ağrı, Turkey 2,4 Department of Physiology, Faculty of Medicine, Atatürk University, Erzurum, Turkey. 3 Department of Physiology, Faculty of Medicine, Sakarya University, Sakarya, Turkey. 5 Department of Physiology, Yozgat Bozok University, Faculty of Medicine, Yozgat, Turkey. 6 Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum, Turkey.
ORCID; 0000-0001-9585-3169, 0000-0002-0095-0917, 0000-0002-7618-5043, 0000-0001-8588-1035, 0000-0003-2424-2269, 0000-0002-8744-7686
Article info Research article
Received :21.07.2020 Abstract; In the current study, it was examined the possible protective properties of hesperidin (HES), an antioxidant, Received in revised form :29.09.2020 antiautophagic, and antiapoptotic molecule, against ovarian injury caused by ischemia reperfusion. 24 healthy rats were Accepted :02.11.2020 grouped as the group I (sham), group II (ischemia reperfusion (I/R)) and group III (I/R+HES) (n=8). In the sham group, Available online :05.01.2021 the only abdominal incision was performed and closed. In the I/R group, following the incision, the I/R model was carried out. In the I/R+HES group, HES was administered intraperitoneally to the animals at the dose of 100 mg/kg approximately Keywords 1 hour before reperfusion. All the experimental procedures were performed under anesthesia. Following reperfusion, ovarian tissues were removed, and then some antioxidant, oxidant, autophagic and apoptotic parameters were evaluated. Hesperidin The oxidant parameters elevated, and antioxidant parameters declined in the I/R group. On the other side, antioxidant Ovary parameters were raised and oxidant parameters diminished in the I/R+HES group. Besides, it was observed that Light chain 3 (LC3) B, caspase-3, and Nuclear factor-kappa Bp50 (NF-kBp50) immunopositivity were fairly intensive in the I/R Oxidative stress group while it was less in the I/R+HES group. A single dose of HES is quite efficient against I/R-induced oxidative Autophagy ovarian injury. Apoptosis
Abbreviations: IR: Ischemia reperfusion, HES: Hesperidin, TAS; Total antioxidant status, TOS; Total oxidant status, OSI: Oxidative stress index, NF- κB: Nuclear factor- kappa B, LC3: Light chain 3, SOD: Superoxide dismutase, MDA: Malondialdehyde, MPO: Myeloperoxidase
INTRODUCTION properties such as anti-allergic, anti-carcinogenic, Ovarian torsion (OT) is the primary and most common reason anti-inflammatory, and strong antioxidant effects. One of the for the pathological condition leading to ischemia reperfusion basic properties of HES is scavenging the radicals. Thus, HES (I/R) in the ovaries. The situations such as ovarian cysts, applied cells indicated less oxygen-derived radicals and devel- pregnancy, polycystic over syndrome are classified among the oped the antioxidant system 9-11. causes of OT 1, 2. The inability of the tissue feeding due to the Different agents with anti-inflammatory, antioxidant, restriction of the tissue blood flow is called ischemia, and and radical scavenging features performed beneficial effects in reperfusion is the condition of restoring the blood flow. The the alleviation or elimination of I/R injuries 5, 6. It was planned reperfusion phase damages the tissues more than ischemia 3. to find out the potential protective effects of HES, an The physiopathology of the ovarian damage has not been fully antioxidant, antiautophagic and antiapoptotic agent against clarified yet 4. Besides, it is possible that oxygen-derived ovarian damage induced by I/R. radicals are responsible for the I/R injury 3. Early and rapid intervention to ischemia may prevent ovarian injury and MATERIAL and METHODS infertility. Nowadays, physiopathology of I/R injury and the different treatment methods are being improved and researched Animals and ethical approval as experimental 5-7. The present search was admitted by Atatürk University Hesperidin (HES), a flavonoid, is found in various Experimental Animal Ethics Committee (date:30.03.2018- fruits such as lemon and orange 8. It has several biological number:75). Experimental steps were established at Atatürk
*Corresponding author: Ayhan Tanyeli, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.45782
22 University Experimental Animals Research and Application (MDA) level 19. Myeloperoxidase (MPO) activity in the Center (ATADEM). Wistar type female rats, weighing 220-230 ovarian tissue was determined through the methods described g, acquired from ATADEM. Rats were housed in regular cages by Bradley et al. 20. with laboratory mediums including 12 light/12 darkness, the temperature of 22±2°C and humidity of %55±5. They were Immunohistochemical assessments supplied standard rat feed and tap water. All animals were Upon completion of the experiment, the ovarian samples were deprived of food 12 hours prior to the experiment but were taken into 10% neutral formalin solution. Then, they were allowed to drink water. washed in tap water and embedded in paraffin blocks following tissue processing procedures. Following the deparaffinization,
Groups and experimental design they were kept in 3% H2O2 for 10 min to inactivate the All rats were fixed in the supine position. The lower abdominal endogenous peroxidase and then washed in phosphate-buffered region was shaved and disinfected with povidone-iodine. All saline (PBS). The tissues were heated for 10 min at 500W into surgical procedures were performed under anesthesia. 60 mg/ an antigen retrieval solution (citrate buffer, pH 6.0) to retrieve kg intraperitoneal (i.p.) ketamine (Ketalar®, Pfizer, Istanbul) antigens and washed again in PBS. Protein block solution was and 10 mg/kg i.p. xylazine hydrochloride (Rompun®, Bayer, used to avoid nonspecific binding and washed in PBS. NF-kB İstanbul) were preferred as anesthetic. HES was obtained from (Abcam, Cat. No: ab7971, Dilution:1/150), caspase-3 (Novus Sigma-Aldrich Co, USA. HES was prepared by dissolving in Biological, Cat. No: NB600-1235, Dilution:1/100), and LC3B 0.5% sodium carboxymethylcellulose as described in a (Abcam, Cat. No: ab48394 Dilution:1/200) primary antibodies previous study 12. were used for 1 hour at room temperature to the sections. 24 female, Wistar-Albino rats were separated into 3 Finally, it was followed by the procedure described by the groups (n=8): sham group; 2 cm incision was performed in the expose mouse and rabbit specific HRP/DAB detection IHC kit midline of the lower abdominal region and then, the incision (abcam: ab80436). The 3,3'-diaminobenzidine chromogen was was repaired with 3/0 silk suture. I/R group; Following the in- used and counterstained with hematoxylin. The intensity of cision, as described in previous studies 13, 14, uterine horns and immunopositivity was evaluated as no (-), mild (+), moderate adnexa were fixed with a microvascular clamp for 3 hours (++), and severe (+++) 21. (ischemic phase). After ischemia, 3 hours of reperfusion was applied by releasing the clamps. I/R+HES group; All proce- Statistical analysis dures in group II was performed and in addition, 100 mg/kg i.p. For the biochemical evaluation, all results were presented as HES was administered one hour prior to reperfusion stage. The Means±SD analyzed using One-way ANOVA. Tukey test was dose of HES was adjusted according to a previous I/R study 15. preferred for pairwise comparisons of the groups. The The ovaries were cleaned in cold saline and then kept differences were accepted as significant when p<0.05. at -80 °C for biochemical measurements. A part of the ovarian SPSS 16.0 program was preferred for statistical tissue samples was also stored in 10% formaldehyde for im- evaluation in immunohistochemistry results. The difference munohistochemical assessments. between groups was determined by the Kruskal Wallis test and Mann–Whitney U-test followed it. p<0.05 value was accepted Biochemical assessments significant statistically. Immunohistochemistry data were Total antioxidant status (TAS) level was detected with the expressed as Means±SEM. commercial kit (Rel Assay Diagnostics, Product Code: RL0017). Total oxidant status (TOS) value was gauged with an RESULTS appropriate kit (Rel Assay Diagnostics, Product Code: RL024) 16, 17. TOS to TAS ratio represents the oxidative stress index Biochemical results (OSI). The evaluation of superoxide dismutase (SOD) depends TAS, TOS, OSI, SOD, MDA, and MPO data were presented on the production of superoxide radicals 18. Lipid peroxidation (figure 1). TOS and OSI levels elevated in the I/R group when in ovarian tissue was measured by assessing malondialdehyde it was compared to the sham group. MDA level and MPO
23 activity raised significantly in the I/R group compared to the group compared to the I/R group (p<0.05). TAS value and sham group (p<0.05). HES treatment diminished TOS, MDA, SOD activity elevated significantly in the I/R+HES group OSI levels and MPO activity significantly in the I/R+HES when it was compared to the I/R group (p<0.05).
Figure 1. Effect of HES on (a) TAS, (b) TOS, (c) OSI, (d) SOD, (e) MDA and (f) MPO levels in ovarian tissues. *p<0.05 compared to sham group, #p<0.05 compared to I/R group
Immunohistochemical results LC3B immunopositivity was not found in the sham group NF-kBp50 immunopositivity was not found in the sham group (figure 4a). Conversely, in the I/R group, intense LC3B im- (figure 2a). In the I/R group, intensive immunopositivity was munopositivity was detected in the interstitial area and luteal observed in the interstitial area (figure 2b). In the I/R+HES cells (figure 4b). In the I/R+HES group, there was mild im- group, there was mild immunopositivity in the interstitial tissue munopositivity in the luteal cells (figure 4c). and luteal cells (figure 2c). NF-kBp50, caspase 3, and LC3B positivity were im- In the sham group, caspase-3 immunopositivity did munohistochemically different between groups (p<0.05, table not occur (figure 3a), but in the I/R group, intense caspase-3 1). There was a difference between the sham group and the immunopositivity was observed in the interstitial area and lute- other groups. A difference also occurred between the I/R and I/ al cells (figure 3b). In the I/R+HES group, the severity of im- R+HES groups. (P<0.05, table 1). munopositivity decreased in both areas (figure 3c).
24
Figure 2. A) Sham group B) I/R group, intensive NF-kB immunopositivity in interstitial region (arrow) C) I/R+HES group, mild NF-kB immunopositivity (arrow) in luteal cells
Figure 3: A) Sham group B) I/R gr oup, in luteal cells (ar row) and interstitial area (star) intense caspase-3 immunopositivity C) I/R+HES group, mild caspase-3 immunopositivity in luteal cells (arrow) and interstitial area (arrowhead)
Figure 4. a) Sham group b) I/R group, intensive LC3B immunopositivity in luteal cells (arrow) and interstitial area (arrowheads) c) I/R +HES group, mild LC3B (arrow) immunopositivity in luteal cells
Table 1. NF-kB, Caspase-3, and LC3B immunopositivity among different groups.
Groups NF-kB caspase-3 LC3B
Sham 0.25±0.16a 0.25±0.25 a 0.50±0.26 a
I/R 2.75±0.16b 2.62±0.18 b 2.87±0.12 b
I/R+HES 1.50±0.42c 1.75±0.25 c 1.37±0.18 c
Data were expressed as means+SEM. Groups with different letters (a,b,c) in columns are significantly different from each other (p<0.05). Sham group performed significant difference compared to I/R and I/R+HES groups (a,b and a,c , p<0.05). On the other side, a difference also occured between the I/R and I/R+HES groups (b,c, P<0.05).
25 DISCUSSION HES was effective in alleviating ovarian I/R injury 41. Ischemia is defined as the loss of oxygen and lack of nutrition One of the experimental ovarian I/R studies showed as a result of mechanical reasons or clot. Adenosine that lipid peroxidation significantly increased, but the triphosphate (ATP) production ceases in cells due to hypoxic antioxidant defense system was inadequate 42. In another study genesis resulting from ischemia. Only the current ATP about I/R injury in ovaries, lipid peroxidation increased continues to be used, and the adenosine breaks down. dramatically due to I/R, whereas antioxidant enzyme level Adenosine diffuses out of the cell, the formation of inosine and decreased 43. TOS and OSI values elevated, and TAS level hypoxanthine is shaped 22, 23. In oxygen deficiency, xanthine declined in the I/R group in a previous ovarian I/R study 44. dehydrogenase enzyme can’t be activated, so hypoxanthine is MPO activity is an essential marker for the neutrophil metabolized by xanthine oxidase, and xanthine occurs. Free infiltration in tissues 45. In an ovarian I/R injury study, it was oxygen radicals are released as a result of these reactions 24, 25. detected an increase in MPO activity and a significant decrease The recovery of blood flow is called reperfusion. The damage in SOD antioxidant enzyme activity 46. Consistent with all after the reperfusion is a pathophysiological process that has these literature studies, in this study, MDA level, MPO activity, not yet been fully understood. In this process as a result of the TOS, and OSI values increased in the I/R group. In the HES various mechanisms such as the increase of nitric oxide treatment group, these parameters returned to normal levels. synthase levels, free oxygen radicals, lipid peroxidation, Autophagy is a physiological process in living activation of leukocytes and cellular signal pathways, elevation organisms. Uncontrolled autophagy is initiated in various in intracellular Ca2+ ion level, impairment of Na+-K+ pump in situations, including chemotherapeutics, reactive oxygen the membrane, activation of protein kinase C (PKC) and species (ROS), hypoxia, starvation, intracellular pathogens, mitogenic activating protein kinase may cause pathologic growth factor deprivation, and DNA damage 47. Hitherto, conditions that result in necrosis or apoptosis in cells 26-29. microtubule-related protein 1 LC3 has been detected on the During I/R injury, free oxygen radicals occur and may lead to autophagosomal inner membrane. LC3B immunoblotting is a oxidative damage in various cellular biomolecules containing method and commonly used for the determination of proteins, lipids, and DNA 30. SOD and CAT, other similar autophagic activity 48. Programmed cell death or apoptosis is a antioxidant enzymes, convert the superoxide radicals to physiologic process that is known as a staminal ingredient of hydrogen peroxide and scavenge lipid peroxides 31, 32. many biologic procedures of the organism 49, 50. NF-kBp50 is a Derogating the activities of SOD has been connected with free nuclear transcription factor and takes a role in differentiation, oxygen-mediated pathologies 33. Different agents with various tumorigenesis, neurodegeneration, immunity, apoptosis, features, including anti-inflammatory, antioxidant, and radical inflammation, and cell growth 51. ROS formation induces the scavenging properties, have been found beneficial in the activation of NF-kBp50. Previous studies demonstrated a alleviation or elimination of I/R injuries 3, 5-7. HES has strong correlation between autophagic response and vasodilating activities, antioxidant, anti-inflammatory, NF -kBp50transcription 52, 53. Here, the immunopositivity of anticarcinogenic, and antimicrobial properties 10, 34. Numerous LC3B, NF-kBp50, and caspase-3 were determined intensively studies have been conducted to reduce oxidative stress by HES in the I/R group when it was compared to sham group. But all administration in different experimental models 9, 35, 36. It has the immunopositivity were less observed in the I/R+HES group been shown by Banji et al. that HES performed protective compared to the I/R group. effects against D-galactose-induced apoptosis in rat brain by In the current study, ovarian I/R injury led to dramatic decreasing the MDA level and increasing the antioxidant increases of MDA level, MPO activity, TOS, and OSI values activities 37. HES performed hepato-ameliorative effect in rats while it causes a decrease in SOD activity and TAS value. HES intoxicated by the mercuric chloride 38. In addition, HES treatment effected in the positive direction the changes of protected the liver against valproate-caused toxicity 39. In MDA, TOS, OSI, and MPO, stimulated an overproduction of another study, it was determined by İskender et al. that HES enzymatic antioxidant SOD activity, and increased TAS value. demonstrated protective effects against oxidative injury in STZ Thereby, a single dose of HES significantly derogated ovarian -induced diabetic model 40. In a previous ovarian I/R study, tissue injury.
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International of Academic Medicine and Pharmacy
Estimation of Tibia Length in Turkish Adults Using the Artificial Neural Network Method
Özhan Pazarcı 1*, Yunis Torun 2
1 Department of Orthopedics and Traumatology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey 2 Department of Electrical and Electronics Engineering, Robolab, Sivas Cumhuriyet University, Sivas, Turkey . ORCID; 0000-0002-2345-0827, 0000-0002-6187-0451
Article info Research article
Received :05.09.2020 Abstract; Of all the long bones in the human skeleton, the bone fractured most often is the tibia. In Received in revised form :16.11.2020 the surgical treatment of shaft fractures, the use of the correct length nail is important. Therefore, Accepted :02.11.2020 the length of the tibia is crucial during orthopedic surgery and in forensic science, anatomy and Available online :05.01.2021 anthropology. In this study, the Artificial Neural Network (ANN) method was applied to obtain a correct estimation of the tibia length from its proximal measurements. The inputs of the ANN, which are independent parameters of the problem, are the age of the subject, the tibia side, top measurement, middle measurement, bottom measurement and fibula length. A total of 193 tibia Keywords bone measurements were taken from an adult Turkish population. Five different input parameter combinations were tried for the correct determination of the tibia length. According to these Tibia, fracture combinations, the root mean square error (RMSE) values and correlation coefficients ® were Artificial neural network obtained as 21.27, 17.60, 19.56, 18.39, 6.14 and 0.66, 0.78, 0.72. 0.76, 0.98 for the training data Estimation of ANN, respectively. For the test data these values were 21.81, 21.53, 23.32, 21.50, 9.26 for RMSE and 0.51, 0.56, 0.44, 0.55, 0.93 for values. The correlation coefficients showed a moderate correlation between data in the ANN estimation, and according to the RMSE values, the error in the estimations was at the level of approximately 5%.
INTRODUCTION has the advantage of reducing costs and the need for additional The tibia is the bone most frequently fractured of all the long radiological imaging. bones 1. Intramedullary nailing is the most preferred surgical In recent years, the artificial neural network (ANN) treatment for shaft fractures 1. In this operation, the use of the method has been used in the field of orthopedics 6. In the correct length nail is important for satisfactory results. medicine field, several examples can be given for ANN, such Although there is no standard method for measuring tibial as the neural network prediction of the movement of the lower length 2, many methods for tibial length measurement have extremities using angle-angle diagrams 7, medical imaging 8, been defined in the literature. These are mainly intraoperative medical disease prediction 9, automated detection and techniques, radiological techniques and anthropometric classification of proximal humerus fracture 10, improving bone measurement techniques 3. The length of the tibia is as strength prediction in human proximal femur specimens 11, important during orthopedic surgery as in other disciplines, bone fracture healing assessment 12, determination of patellar primarily forensic medicine, anatomy and anthropology. position 13, and estimation of femur length from the proximal Accurate measurement of tibia length or estimation of this measurements 14. The ANN method is a mathematical model length is used in many other places such as body length that mimics the human brain functionality. In the method, there calculation from the bone 4. is no need for any relationship between the input and output The proximal tibia is the region less affected by the data. In the current study, six measurements of the tibia bone trauma of shaft fracture 1. In addition, the proximal tibia is one were collected to set feature set combinations that were used as of the skeletal regions that is well preserved after death. input parameters for ANN. The main task was to obtain tibia Information obtained from body parts can be important in the length (TL) according to the given independent variables. identification of disaster victims 5. The calculation of full body According to the results, the ANN method was seen to be height from the same AP radiological image of the tibia also suitable for prediction of the tibia length. The second aim of the
*Corresponding author: Özhan Pazarcı, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.47374
29 study was to show the utility of the method in the orthopedics for almost all problems. The hidden neuron number is field. determined after several trials because there is no rule for this determination. One of the ANN structures used in this study is MATERIAL and METHODS shown in Fig.2. The input neurons (FL- fibula length, A- age, S - side, T- top measurement, M- middle measurement and Ethics approval B- bottom measurement) correspond to different variables for Approval for the study was granted by the Local Ethics the problem. Committee (Sivas Cumhuriyet Univercity no: 2019-10/32, The ANN method is composed of two main steps. In date: 09,10,2019). the training step, the weights are modified until an acceptable error level is reached by given input and output data to the Samples and measurements network. In this study, the error function which measures the Evaluations were made of 220 tibia AP radiographs. Any difference between desired and network outputs was the root radiographs that were not completely AP or were not taken mean square error (RMSE) given by the equation (1). from the appropriate distance were excluded. Finally, 193 tibia bone measurements were used, which had been taken from an adult Turkish population. The measurements were taken on the radiological images of the tibia AP view (Fig. 1). Of the total where yi and fi are the neural network and actual outputs, samples, 106 were of the right leg and 87 of the left leg. The respectively, N is the total number of samples. After the measurements were taken as 3 transverse diameters and 2 cm determination of the final weights in the training step, the ANN full-length measurements of the tibia and fibula, starting at the is constructed. In the second step of ANN which is the test top of the tibia AP radiograph. step, ANN is tested using the previously unseen test data. If the results are good, it is said that the constructed ANN has Artificial neural network (ANN) generalized the data, and the constructed ANN can be Artificial neural network (ANN) 15 is a mathematical model confidently used as appropriate for another set of data related to that mimics the human brain functionality and nervous system the given problem. in order to perform estimations for given problems. ANN consists of neurons which are the main processing units. The neurons are grouped in three different layers of input, hidden and output layers, with input, hidden and output neurons. Each neuron is connected to all the next layer neurons via adjustable synaptic weights. Data is transmitted from one neuron to another through these connections. For each independent variable of the problem there is an input neuron. After transmitting the data to hidden neurons, the data is summed and activated by the appropriate functions. The output of the hidden neurons is transmitted to output neurons and the dependent results are obtained, which is the aim of the calculations. In the hidden neurons, generally a sigmoid-like activation function is used. In this study, the tangent hyperbolic (tanh = (ex - e-x)/ (ex + e+x)) activation function was used for hidden neuron activation. The numbers of the input and output neurons are related to the independent and dependent variables, whereas the numbers of hidden layers and their neurons depend on the Figure 1. Radiological images of the tibia AP view. Tibia Length (TL), nature of the problem. Generally, one hidden layer is enough top measurement (T), middle measurement (M), bottom measurement (B) and fibula length (FL). 30 training and test steps were obtained as 383.84 and 390.72 mm, respectively. The corresponding root mean square errors were 14.0 and 14.5 mm in the measurements of the radiological im- ages, corresponding to an average error of approximately 3.5%. In Type-1 ANN calculations, the RMSE value was obtained as 21.27 mm for the training data. In the left upper panel of Fig.2, the differences between measured TL and ANN estimated TL are shown. It can be seen from the figure that the maximum and minimum deviations from the measured values are 43.07 and 0.12 mm, respectively. The correlation coefficient for the training data was 0.66. For TYPE-II calculations (right upper panel of Fig.2), age information was added to the inputs. In this case, the maximum and minimum Figure 2. The 4-2-3-1 structure of ANN that was used deviations from the measured values were 43.01 and 0.08 mm, respectively. The correlation coefficient for the training data RESULTS and DISCUSSION was 0.78. The RMSE value was obtained as 17.60 mm. After several trials for this problem, it was seen that two hidden According to the result, it can be said that the age information layers with two and three neurons structure gave the best improves the results. In the next calculation (Type-III), the results. Layered feed-forward ANN was used to estimate the information of the side of the bones was added. The maximum length of the tibia (TL). All possible inputs were the age of the and minimum deviations from the measured values were subject (A), the side of the tibia (S), top measurement (T), obtained as 46.28 and 0.13 mm, respectively. The RMSE value middle measurement (M), bottom measurement (B) and fibula was determined as 19.56 mm. The correlation coefficient for length (FL). Different input combinations (Table 1) were tested the training data was 0.72. As can be seen in the left middle and the results of all of these are presented. The total number panel of Fig.2, adding the side information to Type-I worsened of synaptic weights was calculated according to Eq. (2). the results. For TYPE-IV calculations (right middle panel of Fig.2), A, S, T, M, B data were the inputs. In this case, the
maximum and minimum deviations from the measured values where p, h1, h2 and r are neuron numbers in input, first hidden, were 42.57 and 0.16 mm, respectively. The correlation second hidden and output layers, respectively. coefficient for the training data was 0.76. The RMSE value was
Table 1. Different ANN properties used in this study obtained as 18.39 mm. According to the result, it can be said that adding age and side information simultaneously caused Name Inputs* Outputs Total ANN weights Structure worse results. In the final calculation of Type-V at the bottom Type-I T, M, B TL 15 3-2-3-1 Type-II A, T, M, B TL 17 4-2-3-1 of Fig.2, very good results were obtained after including FL Type-III S, T, M, B TL 17 4-2-3-1 data to the inputs. The maximum and minimum deviations Type-IV A, S, T, M, B TL 19 5-2-3-1 Type-V FL, A, S, T, M, B TL 21 6-2-3-1 were 21.34 and 0.0008 mm, respectively. The RMSE value *Tibia length (TL), age (A), side (S), top measurement (T), middle measurement (M), bottom measurement (B) and fibula length (FL). was 6.14 mm and the correlation coefficient for the training *Tibia length (TL), age (A), side (S), top measurement (T), middle data was 0.98. measurement (M), bottom measurement (B) and fibula length (FL). To be able to see the overall success of the ANN All data were partitioned into two separate sets, for method in TL estimation, the constructed ANN was tested on training and test stages. In this study, 80% of all data (153 data the test data which had not been used in the training process. points) was used for training and 20% (40 data points) was For Type-1 ANN calculations, the RMSE was 21.81 mm. In used for the test. In the ANN training stage of this study, a the left upper panel of Fig.3, the ratio of measured TL to ANN 16, 17 back-propagation algorithm with Levenberg-Marquardt estimated TL is given. It can be seen from the figure that the was used. The average values of the tibia length used in the maximum and minimum deviations from the measured values
31 were 51.90 and 0.073 mm, respectively. The correlation panel of Fig.2), A, S, T, M, B data were used as inputs. In this coefficient for the test data was 0.51. In TYPE-II calculations case, the maximum and minimum deviations from the (right upper panel of Fig.3) with age information added to the measured values were 50.85 and 0.075 mm, respectively. The inputs, the maximum and minimum deviations from the correlation coefficient for the test data was 0.55. The RMSE measured values were 50.24 and 0.25 mm, respectively. The value was obtained as 21.50 mm. In the final calculation of correlation coefficient for the data was 0.56. The RMSE value Type-V at the bottom of Fig.3, very good results were obtained was obtained as 21.53 mm. According to the result, it can be after including FL data to the inputs. The maximum and said that the age information had no effect on the results in the minimum deviations were 22.45 and 0.28 mm, respectively. test data. In the next calculation (Type-III), information of the The RMSE value was obtained as 9.26 mm. The corresponding side of the bones was included. The maximum and minimum correlation coefficient for the test data in this case was 0.93. It deviations from the measured values were 50.26 and 1.22 mm, was observed in the test data that the results from the first four respectively. The RMSE value was obtained as 23.32 mm. The types of ANN according to the different input parameters used correlation coefficient was 0.44 which showed that adding side in this study were quite similar to each other. Thus, with the information to Type-I slightly worsened the results (left exception of FL, adding parameters to the inputs did not middle panel of Fig.3). For TYPE-IV calculations (right middle improve the estimations.
Figure 3. Differences between measured and estimated TL for training data
32
Figure 4. Ratio of measured and estimated TL according to the measured TL for test data
CONCLUSION 2. Galbraith JG, O’Leary DP, Dailey HL, Kennedy TE, Mitra A, Harty In this study, the ANN method was applied for the first time for JA. Preoperative estimation of tibial nail length - Because size the estimation of tibia length from proximal tibial transverse does matter. Injury. 2012;43(11):1962-8 diameter. The algorithm used here has the potential to be used 3. Venkateswaran B, Warner RM, Hunt N, Shaw DL, Tulwa N, in the tibia length estimation in fractures. According to the Deacon P. An easy and accurate preoperative method for deter- results, the deviations from actual tibia length were mining tibial nail lengths. Injury. 2003;34(10):752-5. approximately 5%. As the method is reliable, easy to apply, 4. Chibba K, Bidmos MA. Using tibia fragments from South Africans of European descent to estimate maximum tibia length and non-invasive and the results are quickly available, this tibia stature. Forensic Sci Int. 2007;169(2–3):145–51. length estimation method can reduce radiation exposure and 5. Blau S, Briggs CA. The role of forensic anthropology in Disaster cost. The biggest problem in the length calculation method Victim Identification (DVI). Forensic Sci Int. 2011;205(1-3):29-35. from direct AP graph is magnification. Although full AP and 6. Cabitza F, Locoro A, Banfi G. Machine Learning in Orthopedics: A films not taken from the appropriate distance were excluded in Literature Review. Front Bioeng Biotechnol. 2018;75. this study, this problem has been reported in the literature 18. 7. Kutilek P, Farkasova B. Prediction of lower extremities’
movement by angle-angle diagrams and neural networks. Acta Conflict of interest Bioeng Biomech. 2011;13(2):57–65. The authors have no conflicts of interest to declare. 8. Erickson BJ, Korfiatis P, Akkus Z, Kline TL. Machine Learning for
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34 Int J Acad Med Pharm, 2021; 3 (1); 35-42
International of Academic Medicine and Pharmacy
Prevalence of Fibromyalgia Syndrome in Infertile Women and Its Effects on Quality of Life and Sleep
Sevil Ceyhan Doğan 1*, Çağlar Yıldız 2, Gonca İmir Yenicesu 3, Özlem Şahin 4
1,4 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey 2,3 Department of Obstetrics and Gynecology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey
ORCID; 0000-0002-1852-7981, 0000-0003-3150-3340, 0000-0002-7865-1466, 0002-9346-5477
Article info Research article
Received :09.09.2020 Abstract; Infertility is a very common problem which may have social, cultural, and economical consequences. Received in revised form :23.10.2020 Fibromyalgia also frequently affects women of reproductive age. Both conditions impair quality of life and adversely Accepted :02.11.2020 influence sleep quality, as well. The aim of this study was to evaluate the association between female infertility and Available online :05.01.2021 fibromyalgia as well as their effects on quality of life, sleep quality, and several reproductive hormones. This study included 52 infertile women and 38 women who attended to the obstetrics and gynecology outpatient clinic for family planning purposes. The diagnosis of fibromyalgia was made as per American College of Rheumatology (ACR) criteria. Study participants were asked to complete Pittsburgh Sleep Quality Index (PSQI), the 36-item Short Form Health Survey Keywords (SF-36), and fibromyalgia impact questionnaire (FIQ). The frequency of fibromyalgia was not significantly different between the groups. Infertile women in this study were younger, had significantly lower educational status, and less likely Fibromyalgia to be employed compared with the control group. Among the SF-36 subscales physical functioning, role physical, vitality, Infertility mental health, social functioning, and bodily pain scores were lower in the control group than the infertile group. PSQI Quality of life total score was not different between the groups. Although infertility is known to be stressful, the burden of caring for Anti-Mullerian hormone small children is also high for mothers which should be taken into consideration while evaluating the effects of infertility, and motherhood on quality of life and sleep quality of women at childbearing age.
INTRODUCTION development of both conditions 7. The association between A formal definition of infertility is “the failure to achieve a fibromyalgia and infertility has rarely been investigated successful pregnancy after 12 months or more of appropriate, previously. In women with myofascial face pain, reduced timed unprotected intercourse or therapeutic donor fecundity was found in the group with fibromyalgia 8. Also a insemination”1. Infertility is a prevalent problem affecting 1 in previous study in endometriosis patients, which is a common every 7 marriages worldwide 2. Infertility is a stressful and cause of infertility, found a higher rate of FM 9. High levels of traumatic condition which may have social, cultural, and stress in infertile women may cause de novo or exacerbate economical consequences 3. Especially social pressure may be existing fibromyalgia by means of HPA axis or other endocrine stressful for infertile women, which may trigger several pathways. psychosomatic problems 4. Approximately 80% of fibromyalgia patients report Fibromyalgia (FM) is characterized by chronic poor sleep. In the fibromyalgia population there is a strong and widespread pain, tiredness, and sleep disturbance 5. Anxiety, dose dependent association between fibromyalgia symptoms depression, and impairment in activities of daily living also and sleep quality. Few research studies have been conducted on accompany this disorder. Although the exact etiology is yet to sleep disturbances in infertility. Pal et al. studied sleep be known, disturbance in the regulation of the autonomic and disturbances in infertile women using single item query “do neuro-endocrine systems seems to be crucial considering you experience disturbed sleep?”, and got positive answers characteristic sleep pattern changes and alterations in from 34% of the participants 10. The authors found that after neuroendocrine neurotransmitters such as serotonin, cortisol, controlling for race, body mass index, and vasomotor substance P, and growth hormone 6. Fibromyalgia has a symptoms, probability of sleep disturbance was 20 times higher frequent co-occurrence with mood disorders, moreover among women with diminished ovarian reserve. Lin et al. also hypothalamic pituitary adrenal (HPA) axis is implicated in the evaluated infertile women receiving intrauterine insemination
*Corresponding author: Sevil Ceyhan Doğan, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.46857
35 and showed that greater than 35% of women reported sleep tient clinic of Cumhuriyet University hospital for family disturbances 11. The most plausible pathway accounting for the planning purposes. relationship between sleep disturbance and infertility is the HPA activation. Method Fibromyalgia has many chronic somatic and The patients and the controls who accepted to participate in the psychological symptoms which may cause poorer health study were seen once to complete the study surveys and related quality of life (HRQOL). HRQOL of fibromyalgia evaluation for fibromyalgia. Age, weight, height, and the cause patients has been compared with many other disease states of infertility were recorded. Blood samples were obtained and including rheumatoid arthritis, chronic obstructive pulmonary prolactin, follicular stimulating hormone (FSH), luteinizing disease, congestive heart failure, hypertension, and diabetes hormone (LH), and AMH levels were measured. Patients and and was found to be worse than those disorders 12. Infertility is control subjects were asked to complete Short Form-36 also associated with impaired HRQOL. Infertile women (SF -36), fibromyalgia impact questionnaire (FIQ), and reported poorer marital adjustment and HRQOL compared with Pittsburgh Sleep Quality Index (PSQI). controls. Diagnosis of fibromyalgia was made by a physical Anti-Mullerian hormone (AMH) is secreted by the therapy and rehabilitation specialist as per American College of granulosa cells of early antral follicles. AMH level shows a Rheumatology (ACR) 2010 FM diagnostic criteria 14. Symptom strong correlation with the number of primordial follicles severity index (SSI) and widespread pain index (WPI) scores of remaining in ovaries 13. Serum AMH level is used as a marker the subjects who were diagnosed with FM were recorded. for reproductive potential for women and as a reliable predictor when a woman will reach menopause. AMH levels were Surveys assessed in several musculoskeletal disorders. In women with Short Form-36 (SF-36): This is a valid and frequently used rheumatoid arthritis, spondyloarthritis, or Behcet’s disease, questionnaire to evaluate quality of life. SF-36 was developed AMH levels were found to be lower than controls. by Ware et al 15. Validity and reliability of its Turkish version The aim of this study was to investigate the frequency was studied 16. It is not specific to an age, disease, or treatment of FM in female patients attending an infertility clinic and to group. It includes general health concepts. It is developed to be determine the associations between infertility, FM, life quality, used in clinical practice and research. It includes 36 items in 8 sleep, and several reproductive hormones, including AMH. subscales, namely physical functioning, role physical, bodily pain, role emotional, social functioning, general health, mental MATERIALS and METHODS health, and vitality. The total score for each component ranges between 0-100 and higher scores indicate higher quality of life. Patients and controls Pittsburgh Sleep Quality Index (PSQI): This This study included women of reproductive age (15-49) who self-report scale was developed by Buysse et al. to assess sleep were assessed at the fertility clinic of Cumhuriyet University quality in clinical populations over a 1 month period. It hospital due to infertility between January to March 2018. includes nineteen individual items which generate seven Screening interviews were performed with 85 infertile patients. “component” scores: subjective sleep quality, sleep latency, Among them 13 patients refused to participate in the study. sleep duration, habitual sleep efficiency, sleep disturbances, use Eight patients were excluded because their ages were not of sleep medication, and daytime dysfunction 17. Each appropriate for the study. A patient was excluded because she component is scored between 0-3. Higher scores indicate worse was illiterate. History of major depression or systemic diseases sleep quality. Validity and reliability study of the Turkish were also exclusion criteria and eleven patients were excluded version of PSQI was performed by Agargun et al. 18. because they had previous diagnoses of major depressive disor- Fibromyalgia Impact Questionnaire (FIQ): The FIQ der or they were using antidepressant treatment. The control was developed by Burchardt et al. to evaluate current health group included women at the same age period who had at least status of women with FM 19. It consists of 10 items. The 1 child and admitted to the Obstetrics and Gynecology outpa- questionnaire measures physical functioning, work status,
36 depression, anxiety, morning tiredness, pain stiffness, fatigue, lower in the control group than the infertile group (Table 2). and well being over the past week. Each item is scored on a PSQI total score was not different between the groups. Among scale between 0-10 (the total score may be between 0-100). PSQI subdomains median score in sleep duration domain was FIQ is a self rated scale. Validity and reliability study of the higher (p=0.036) in the control group than in the infertile Turkish version of the scale was performed by Sarmer et al. 20. group. Other PSQI subdomain scores were similar between the groups (Table 2). Statistical analysis Comparisons were made according to the presence of To summarize the data obtained from the study the results were FM. The median age, height, weight, BMI, education status, presented as mean ± standard deviation or median and and employment status were similar between the patients with interquartile range. Categorical variables were summarized as and without FM (Table 3). FSH, LH, and AMH levels weren’t number and percentage. Normality checks of the numerical statistically significantly different. Among the SF36 domains data were performed by the Kolomogorov Smirnov test. the median values for Physical Functioning, Role Physical, Chi-square test and Fisher Freeman Halton tests were used to Bodily Pain, and Change in Health were significantly lower in compare education status, employment status, and FM rates FM patients (p=0.002, p=0.002, p<0.001, and p=0.036; according to infertility status. Independent Samples t test was respectively). PSQI total score and its subjective sleep quality, used for continuous variables when the data demonstrated and sleep disturbance subscales were higher in FM patients normal distribution and Mann-Whitney U test was used when (p=0.040, p=0.046, and p=0.005, respectively) (Table 3). the distribution was not normally distributed. “sm.ancova” Correlation analyses were performed to assess the function in “sm” package of R software was used to control the relationship between the levels of reproductive hormones such effect of age on several SF-36 components and “Raov” as FSH, LH, and AMH in infertile women and clinical function in “Rfit” package was used to control the effects of parameters for fibromyalgia, quality of life and sleep quality. working status and education. Spearman’s Rho correlation Positive and significant correlations were found between AMH coefficient was used to evaluate the association between levels and role emotional, and bodily pain components of numerical variables. Univariate and multiple logistic regression SF-36 and habitual sleep efficiency component of PSQI models were used to investigate the risk factors that affect FM (r=0.314, r=0.278, and r=0.407; respectively). A positive and the results were given as odds ratio and 95% confidence correlation was also found between LH level and bodily pain interval. Jamovi software was used for the statistical analyses Table 1. Comparison of several sociodemographic variables among wom- en with and without infertility and p<0.05 was accepted as statistically significant.
Infertility RESULTS No (n=38) Yes (n=52) p This study included 52 infertile women and 38 controls. The Age 32.8 ± 5.9 29.4 ± 4.8 0.005 mean age of infertile women (29.4 ± 4.8 years) was lower (32.8 Weight 68.2 ± 12.9 66.2 ± 10.4 0.450 ± 5.9) than controls (p=0.005). The mean weight, height, and Height 162.0 ± 6.2 160.6 ± 6.4 0.321 body mass index (BMI) were similar between the patient and BMI 26.0 ± 4.7 25.7 ± 3.9 0.756 control groups. The control group had a significantly higher Education Level (%) Secondary School 9 (23.7) 27 (51.9) educational status (p=0.003) and more likely to be employed High School 9 (23.7) 15 (28.8) 0.003 (p<0.001) than the infertile group (Table 1). University 20 (52.6) 10 (19.2) The frequency of FM was not different between the Employment Status (%) infertile (11/52) and the control (9/38) groups (p=0.977). The Unemployed 9 (23.7) 42 (80.8) <0.001 29 (76.3) 10 (19.2) median SSS was significantly higher in the control group Employed (p=0.007) while the median WPI was not different between the Statistics for normally distributed variables were given as mean (± standard deviation). Descriptive statistics for categorical variables were given as groups. FIQ was also not different between the groups. Among number (%). P values in bold were accepted as statistically significant (p<0.05). the SF-36 subscales physical functioning, role physical, *: Independent Samples t test was used. **: Pearson Chi-Square test was used. vitality, mental health, social functioning, and bodily pain were
37 Table 2. Comparison of several variables according to the fertility status of the participants.
Infertility Factor - P value* Covariate - P value** No (n=38) Yes (n=52) p Employment Education Age WPI (median [IQR]) 3.0 [2.0 - 5.0] 3.0 [0.0 - 8.5] 0.669 - - - SSS (median [IQR]) 6.0 [4.0 - 8.0] 4.0 [1.0 - 6.0] 0.007 FM (%) - - - No 29 (76.3) 41 (78.8) 0.977 - - - Yes 9 (23.7) 11 (21.2) - - - Physical Function (median [IQR]) 87.5 [55.0 - 100.0] 100.0 [88.8 - 100.0] 0.009 0.426 0.763 0.052 Role Physical (median [IQR]) 62.5 [0.0 - 100.0] 100.0 [50.0 - 100.0] 0.025 0.999 0.999 0.193 Role Emotional (median [IQR]) 67.0 [0.0 - 100.0] 100.0 [0.0 - 100.0] 0.179 - - - Viability (median [IQR]) 40.0 [31.2 - 58.8] 55.0 [50.0 - 66.2] 0.001 0.407 0.931 0.065 Mental Health 52.0 [44.0, 67.0] 68.0 [60.0, 76.0] <0.001 0.999 0.700 0.001 Social Functioning (median [IQR]) 63.0 [38.0 -100.0] 81.5 [63.0 - 100.0] 0.022 0.460 0.277 0.124 Bodily Pain (median [IQR]) 68.0 [45.0 - 80.0] 90.0 [68.0 - 100.0] 0.001 0.785 0.675 0.006 General Health Perception 58.3 ± 22.4 61.2 ± 15.5 0.500 - - - FIQ (median [IQR]) 55.0 [43.0 - 57.0] 50.6 [44.9 - 54.0] 0.239 - - - 1 – Subjective sleep quality (median [IQR]) 1.0 [1.0 - 2.0] 1.0 [1.0 - 1.0] 0.148 - - - 2 – Sleep latency (median [IQR]) 1.0 [0.0 - 2.0] 1.0 [1.0 - 2.0] 0.759 - - - 3 – Sleep duration (median [IQR]) 1.0 [0.0 - 1.0] 0.0 [0.0 - 1.0] 0.036 0.999 0.999 0.439 4 – Habitual sleep efficiency (median [IQR]) 0.0 [0.0 - 0.0] 0.0 [0.0 - 0.0] 0.368 - - - 5 – Sleep disturbance (median [IQR]) 1.0 [1.0 - 2.0] 1.0 [1.0 - 1.0] 0.181 - - - 6 – Sleep medications (median [IQR]) 0.0 [0.0 - 0.0] 0.0 [0.0 - 0.0] NaN - - - 7 – Daytime sleep dysfunction (median [IQR]) 0.5 [0.0 - 1.8] 0.0 [0.0 - 1.0] 0.189 - - - PSQI (median [IQR]) 5.0 [3.0 - 8.0] 5.0 [3.0 - 6.0] 0.351 - - -
IQR, Interquartile Range; FM, fibromyalgia; WPI, widespread pain index; SSS, symptom severity scale; BMI, Body Mass Index; FIQ, fibromyalgia impact ques- tionnaire; PSQI, Pittsburgh Sleep Quality Index. Descriptive statistics for normally distributed variables were given as mean ± SD and Independent Samples t test was used for comparison. Descriptive statistics for variables that didn’t have normal distribution were given as median [IQR] and Mann Whitney U test was used for comparison. Descriptive statistics for categorical variables were given as number (%). P values in bold were accepted to be statistically significant (p<0.05). *: An R software package “Rfit” (Rank Estimation for Linear Models), “raov” function was used. **: An R software package “sm” (Smoothing Methods for Nonparametric Regression and Density Estimation),” sm.ancova” function was used (r=0.288) (Table 4). endometriosis. Thus, this may have obscured a possible
DISCUSSION significant relationship. Raphael and Marbach et al. examined In this study we evaluated the relationships between infertility, fecundity in 162 women with myofacial pain syndrome some fibromyalgia, reproductive hormones, quality of life, and sleep of which also had fibromyalgia 8. The authors found that only quality. The results of this present study did not show any women with fibromyalgia had decreased rates of fecundity and difference in FM frequency between infertile women and they discussed HPA axis malfunction as a possible explanation control subjects. for the association between infertility and chronic pain Sinaii et al. demonstrated increased prevalence of FM syndromes. In our study, small sample size might have in patients with endometriosis which is one of the main causes decreased the chance to find a relationship between FM and of infertility 9. On the other hand, Nunes et al. couldn’t find a infertility. difference in the prevalence of fibromyalgia between women In our study, infertile women had higher quality of life with and without endometriosis 21. Some factors may account scores than women who had children. This may be surprising at for the lack of a positive relationship in our study results first but there are several factors that may explain such a between FM and infertility. Our study didn’t include a relationship. Lau et al. evaluated 192 infertile couples in China diagnostic interview and examination of patients, instead it and showed that lower income and lower education status were relied on self-report forms completed by the patients which among the causes of lower quality of life 22. Bien et al. may have augmented the prevalence rate. Moreover, our study investigated quality of life of women who are childless by sample included women with infertility with reasons other than choice and found that financial status and education were sig-
38 Table 3. Comparison of several variables according to the presence of fibromyalgia.
FM Hayır (n=41) Evet (n=11) p Age (median [IQR]) 28.0 [26.0 - 31.0] 31.0 [28.5 - 35.0] 0.056** Weight(median [IQR]) 66.0 [58.0 - 70.0] 72.0 [65.5 - 77.0] 0.071** Height (median [IQR]) 160.0 [155.0 - 165.0] 163.0 [160.0 - 166.5] 0.357** BMI (median [IQR]) 24.8 [21.8 - 28.0] 28.6 [25.6 - 29.3] 0.097** Education level (%) Secondary school 24 (58.5) 3 (27.3) High school 11 (26.8) 4 (36.4) 0.107* University 6 (14.6) 4 (36.4) Employment status (%) Unemployed 35 (85.4) 7 (63.6) 0.190* Employed 6 (14.6) 4 (36.4) TSH (median [IQR]) 2.0 [1.4 - 2.9] 3.2 [2.0 - 3.3] 0.139** Prolactin (median [IQR]) 18.0 [14.0 - 25.5] 22.0 [17.0 - 25.1] 0.560** FSH (median [IQR]) 7.2 [5.6 - 8.2] 6.0 [5.4 - 6.8] 0.235** LH (median [IQR]) 6.2 [4.9 - 8.1] 4.8 [4.3 - 7.2] 0.319** AMH (median [IQR]) 3.3 [1.4 - 5.5] 1.8 [0.7 - 4.0] 0.180** Physical functioning (median [IQR]) 100.0 [95.0 - 100.0] 80.0 [75.0 - 90.0] 0.002** Role physical (median [IQR]) 100.0 [75.0 - 100.0] 25.0 [0.0 - 87.5] 0.002** Role emotional (median [IQR]) 100.0 [33.0 - 100.0] 0.0 [0.0 - 100.0] 0.056** Vitality (median [IQR]) 55.0 [50.0 - 70.0] 50.0 [40.0 - 62.5] 0.138** Mental health (median [IQR]) 68.0 [60.0 - 76.0] 68.0 [60.0 - 76.0] 0.937** Social functioning (median [IQR]) 88.0 [63.0 - 100.0] 63.0 [63.0 - 81.5] 0.060** Bodily pain (median [IQR]) 90.0 [88.0 - 100.0] 58.0 [53.0 - 69.0] <0.001** General Health Perception (median [IQR]) 60.0 [50.0 - 80.0] 50.0 [47.5 - 60.0] 0.060** PSQI (median [IQR]) 4.0 [3.0 - 5.2] 6.0 [4.5 - 7.5] 0.040** 1 – Subjective sleep quality (median [IQR]) 1.0 [1.0 - 1.0] 1.0 [1.0 - 2.0] 0.046** 2 – Sleep latency (median [IQR]) 1.0 [0.0 - 2.0] 1.0 [1.0 - 1.5] 0.792** 3 – Sleep duration (median [IQR]) 0.0 [0.0 - 1.0] 0.0 [0.0 - 1.5] 0.140** 4 – Habitual sleep efficiency (median [IQR]) 0.0 [0.0 - 0.0] 0.0 [0.0 - 0.0] 0.176** 5 – Sleep disturbance (median [IQR]) 1.0 [1.0 - 1.0] 2.0 [1.0 - 2.0] 0.005** 6 – Sleep medications (median [IQR]) 0.0 [0.0 - 0.0] 0.0 [0.0 - 0.0] NaN** 7 – Daytime sleep dysfunction (median [IQR]) 0.0 [0.0 - 1.0] 1.0 [0.0 - 1.0] 0.434**
IQR, Interquartile Range; FM, fibromyalgia; BMI: Body Mass Index, PSQI: Pittsburgh Sleep Quality Index; TSH, thyroid stimulating hormone; FSH, follicule stimualting hormone; LH, luteinizing hormone; AMH, anti-Mullerian hormone, NaN: Not-a-Number Descriptive statistics for normally distributed variables were given as mean ± SD verilip and Independent Samples t test was used for comparison. Descriptive statistics for variables that didn’t have normal distribution were given as median [IQR] and Mann Whitney U test was used for comparison. Descriptive statis- tics for categorical variables were given as number (%). P values in bold were accepted to be statistically significant (p<0.05). *: Pearson Chi-square test was used. **: Mann Whitney U test was used. nificant factors and a high education level and a good financial Table 4. Correlations between several clinical parameters and hormone levels in infertile patients.
TSH Prolactin FSH LH AMH WPI 0.182 0.137 -0.064 -0.122 -0.177 SSS 0.182 0.044 -0.147 -0.063 -0.210 Physical Functioning -0.003 -0.145 -0.014 0.276 0.291 Role physical -0.118 -0.165 -0.155 0.306 0.384 Role emotional -0.190 0.039 -0.069 0.235 0.314* Vitality -0.059 -0.052 0.019 0.260 0.234 Mental health -0.048 -0.042 -0.092 0.124 0.266 Social functioning -0.100 0.128 -0.113 0.135 0.261 Bodily pain -0.174 -0.126 -0.176 0.288* 0.278* General health questionnaire -0.093 0.104 0.122 0.051 -0.015 PSQI, total 0.246 0.009 0.098 -0.077 0.167 Subjective sleep quality 0.202 -0.138 0.006 -0.174 0.145 Sleep latency 0.255 -0.021 0.043 -0.022 0.158 Sleep duration 0.357* -0.009 -0.083 -0.153 -0.013 Habitual sleep efficiency 0.227 0.157 -0.098 0.019 0.407* Sleep disturbance -0.004 0.024 0.153 -0.080 0.110 Sleep medication NaN NaN NaN NaN NaN Daytime dysfunction 0.133 0.072 0.195 0.007 0.077
WPI, widespread pain index; SSS, symptom severity index; Correlation coefficients in bold were accepted to be statistically significant (*p<0.05). Spearman’s Rho correlation coefficient was used. NaN: Not-a-Number
39 had less than 7 hours of sleep per day and 43.3% had PSQI standing predicted better quality of life 23. In a study score more than 5 indicating poor sleep quality 29. They also performed in American population, it was found that childless found high anxiety levels in infertile women which may be the individuals earned more and accumulated more wealth than cause of sleep difficulties experienced by these women. those who had children 24. In our study, infertile women had a The results of our study showed an association higher education status and a higher employment rate which between AMH levels and habitual sleep efficiency component may have caused higher quality of life scores than women who of PSQI. To the best of our knowledge, no previous study has had children. To investigate the effects of age, education level reported findings about such a relationship. Pal et al. asked ‘do and employment status, we controlled these covariates with you experience disturbed sleep?’ to infertile women and found statistical methods and we found that working status, and a significant relationship between diminished ovarian reserve education did not affect any of the significant parameters. Age and sleep disturbance 10. The authors proposed that decreased affected only mental health and bodily pain components. These testosterone and estrogen levels may underlie this relationship. results suggested that having children imposes adverse effects They also suggested that low fertility potential may have on quality of life independent from working status and increased the anxiety level of these subjects and led to sleep education. disturbance. Quality of life in FM is a frequently investigated topic We also found a significant relationship between TSH and we found consistent findings with previous studies. level and sleep duration component of SF-36. A previous study Verbunt et al. evaluated 54 visitors of a rehabilitation found that TSH levels surged under acute sleep deprivation 30. department and found lower quality of life scores in physical Our finding also suggest that TSH levels increase in patients functioning (37.8), role limitations because of physical health with decreased sleep duration. (8.3), bodily pain (30.8), vitality (34.6), and general health Small sample size is the main limitation of this study. (38.5) domains of SF-36 25. Martinez et al. studied FM patients In addition, sleep quality was measured with a subjective tool from a rheumatology outpatient clinic and demonstrated lower and the subjects were not grouped according to the causes of scores in all 8 domains of SF-36 26. We also found significantly infertility. Yet, this study provides important clues regarding lower scores in physical functioning, role physical, and bodily the relations among infertility, fibromyalgia, sleep quality, and pain dimensions of SF-36 scales which suggest that pain and quality of life. physical limitations due to disease impair the quality of life in FM patients. We found significant positive correlations CONCLUSION between AMH level and Role Emotional and Bodily Pain Infertility is a common problem which causes stress and components of SF-36 in infertile women. One possible expla- impairs quality of life of infertile women. However caring for nation for the association of AMH with bodily pain and role small children imposes a high burden on mothers with emotional dimensions of PCOS is through polycystic ovarian accompanying sleep disturbances and financial hardships syndrome (PCOS). PCOS is a treatable cause of infertility and which may cause stress levels equal to or even higher than the AMH levels consistently rise in this disorder. Studies in former group. Many factors including economic, social, and women with PCOS consistently demonstrated poor quality of gender role related ones should be assessed when evaluating life in all domains of SF-36. Jones et al. found that role the effects of infertility, and motherhood on quality of life and emotional had the greatest negative impact on HRQoL in sleep quality of women at childbearing age. women with PCOS 27. Our results showed worse sleep duration Conflict of interest component of PSQI in infertile women compared with the The authors have no conflicts of interest to declare. control group. This finding is in accordance with Goldstein et al.’s study which showed sleep disorders in 57% of women REFERENCES receiving IVF treatment during the pretreatment period 28. 1. Practice Committee of the American Society for Reproductive Huang et al. also demonstrated that 56.2% of infertile women Medicine. Definitions of infertility and recurrent pregnancy loss.
40 Fertil Steril. 2008;89(6):1603. 15. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health 2. Ashraf DM, Ali D, Azadeh DM. Effect of infertility on the quality survey (SF-36). I. Conceptual framework and item selection. Med of life, a cross- sectional study. J Clin Diagn Res. 2014;8(10):13- Care. 1992;30(6):473-483. 15. 16. Koçyigit H, Aydemir O, Olmez N, Memis A. [Reliability and validi- 3. Aarts JW, Huppelschoten AG, van Empel IW, Boivin J, Verhaak ty of SF-36 for Turkish]SF-36'nin Turkce icin guvenilirligi ve CM, Kremer JA, et al. How patient-centred care relates to gecerliligi. Ege Fiz Ted Reh Derg. 1999;12:102-106. patients' quality of life and distress: a study in 427 women 17. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. experiencing infertility. Hum Reprod. 2012;27(2):488-495. The Pittsburgh Sleep Quality Index: a new instrument for 4. Yusuf L. Depression, anxiety and stress among female patients of psychiatric practice and research. Psychiatry Res. 1989;28(2):193 infertility; A case control study. Pak J Med Sci. 2016;32(6):1340- -213. 1343. 18. Ağargün M, Kara H, Anlar Ö. [Validity and reliability of Pittsburgh 5. Hauser W, Ablin J, Fitzcharles MA, Littlejohn G, Luciano JV, Usui sleep quality index] Pittsburgh uyku kalitesi İndeksi'nin geçerliliği C, et al. Fibromyalgia. Nat Rev Dis Primers. 201513;1:15022:1- ve güvenirliliği. Turkish Journal of Psychiatry. . 1996;7(2):107- 16. 115. 6. Jahan F, Nanji K, Qidwai W, Qasim R. Fibromyalgia syndrome: an 19. Burckhardt CS, Clark SR, Bennett RM. The fibromyalgia impact overview of pathophysiology, diagnosis and management. Oman questionnaire: development and validation. J Rheumatol. Med J. 2012;27(3):192-195. 1991;18(5):728-733. 7. Tanriverdi F, Karaca Z, Unluhizarci K, Kelestimur F. The 20. Sarmer S, Ergin S, Yavuzer G. The validity and reliability of the hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome Turkish version of the Fibromyalgia Impact Questionnaire. and fibromyalgia syndrome. Stress. 2007;10(1):13-25. Rheumatol Int. 2000;20(1):9-12. 8. Raphael KG, Marbach JJ. Comorbid fibromyalgia accounts for 21. Nunes FR, Ferreira JM, Bahamondes L. Prevalence of reduced fecundity in women with myofascial face pain. Clin J fibromyalgia and quality of life in women with and without Pain. 2000;16(1):29-36. endometriosis. Gynecol Endocrinol. 2014;30(4):307-310. 9. Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High 22. Lau JT, Wang Q, Cheng Y, Kim JH, Yang X, Tsui HY. rates of autoimmune and endocrine disorders, fibromyalgia, Infertility-related perceptions and responses and their associa- chronic fatigue syndrome and atopic diseases among women tions with quality of life among rural chinese infertile couples. J with endometriosis: a survey analysis. Hum Reprod. 2002;17 Sex Marital Ther. 2008;34(3):248-67. (10):2715-2724. 23. Bien A, Rzonca E, Iwanowicz-Palus G, Lecyk U, Bojar I. The 10. Pal L, Bevilacqua K, Zeitlian G, Shu J, Santoro N. Implications of quality of life and satisfaction with life of women who are diminished ovarian reserve (DOR) extend well beyond childless by choice. Ann Agric Environ Med. 2017;24(2):250-253. reproductive concerns. Menopause. 2008;15(6):1086-1094. 24. Plotnick RD. Childlessness and the economic well-being of older 11. Lin JL, Lin YH, Chueh KH. Somatic symptoms, psychological Americans. J Gerontol B Psychol Sci Soc Sci. 2009;64(6):767-776. distress and sleep disturbance among infertile women with 25. Verbunt JA, Pernot DH, Smeets RJ. Disability and quality of life in intrauterine insemination treatment. J Clin Nurs. 2014;23(11- patients with fibromyalgia. Health Qual Life Outcomes. 2008; 12):1677-1684. 22;6:8:1-8. 12. Hoffman DL, Dukes EM. The health status burden of people with 26. Martinez JE, Barauna Filho IS, Kubokawa K, Pedreira IS, Machado fibromyalgia: a review of studies that assessed health status LA, Cevasco G. Evaluation of the quality of life in Brazilian with the SF-36 or the SF-12. Int J Clin Pract. 2008;62(1):115-126. women with fibromyalgia, through the medical outcome survey 13. Hansen KR, Hodnett GM, Knowlton N, Craig LB. Correlation of 36 item short-form study. Disabil Rehabil. 2001;20;23(2):64-68. ovarian reserve tests with histologically determined primordial 27. Jones GL, Benes K, Clark TL, Denham R, Holder MG, Haynes TJ, et follicle number. Fertil Steril. 2011;95(1):170-175. al. The Polycystic Ovary Syndrome Health-Related Quality of Life 14. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Questionnaire (PCOSQ): a validation. Hum Reprod. 2004;19 Mease P, et al. The American College of Rheumatology prelimi- (2):371-377. nary diagnostic criteria for fibromyalgia and measurement of 28. Goldstein CA, Lanham MS, Smith YR, O'Brien LM. Sleep in symptom severity. Arthritis Care Res (Hoboken). 2010;62(5):600- women undergoing in vitro fertilization: a pilot study. Sleep 610. Med. 2017;32:105-113.
41 29. Huang LH, Kuo CP, Lu YC, Lee MS, Lee SH. Association of emotional distress and quality of sleep among women receiving in-vitro fertilization treatment. Taiwan J Obstet Gynecol. 2019;58(1):168-172. 30. Van Cauter E, Tasali E. Endocrine physiology in relation to sleep and sleep disturbances. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. Elsevier; 2017. p. 202- 219.
42 Int J Acad Med Pharm, 2021; 3 (1); 43-46
International of Academic Medicine and Pharmacy
Hip Pain associated with High Risk of Metastasis in Elderly Population
Hüseyin Sina Coşkun 1, Hikmet Çinka 2*, Nevzat Dabak 3, Ferhat Say 4, Hasan Göçer 5
1,2,3,4,5 Department of Orthopedics and Traumatology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
ORCID; 0000-0003-2965-3112, 0000-0002-9423-1728, 0000-0002-4591-7897, 0000-0002-8021-0942, 0000-0002-7660-8165
Article info Research article
Received :27.08.2020 Abstract; The study aimed to determine the sociodemographic distribution, metastatic foci, and localizations of Received in revised form :26.11.2020 metastatic cases evaluated at a regional bone and soft tissue tumor center and emphasize the importance of the hip region Accepted :02.11.2020 in the aspect of metastatic bone disease. A total of 356 cases of the metastatic bone disease were detected in the local Available online :05.01.2021 database which contains 2586 patients who applied to the center due to bone and soft tissue tumor at Ondokuz Mayıs University Faculty of Medicine between 2004-2018 (13.76% of all bone and soft tissue tumors cases). These patients were included in the study by determining the age, gender, localization, and primer foci. While the youngest age was seen at 6 years of age, the oldest age of metastatic bone disease was 89 (mean 59.36). There were 205 male patients and 151 female Keywords patients. 67 of the 356 metastatic cases were present with pathologic fracture (18.82%). Metastases were observed in the range of 60-69 years (26.68%), followed by 50-59 and 70-79 age ranges respectively (25.84% and 19.54%). The most Metastasis common site of metastasis was the hip (149 cases, 41.85%). There were localizations following thigh (44 cases) and Hip shoulder (29 cases) (12.35% and 8.14% respectively). The mean age of patients with the metastatic disease around hip was Bone sarcoma 63.3 and the most common primary foci were lung, followed by breast and kidney. Primary foci were not detected in 60 Elderly patients. When metastatic patients evaluated at our center were examined, the metastatic bone disease was more frequently Pathologic fracture observed in male patients aged 60-69 years who presented with pain in the hip region. Metastatic bone disease is a condition that should be considered in this patient group.
INTRODUCTION metastatic bone disease, especially in the hip region, may be Hip pain is one of the most common symptoms in orthopedics overlooked for another reason in orthopedics and traumatology and traumatology outpatient clinics. The etiology of hip pain outpatient clinic. varies by age. While diseases affecting epiphysis, trauma, and infectious conditions should be considered primarily in the MATERIAL and METHODS early years of life, trauma and metastatic bone disease should be kept in mind, especially at the age of 65 and over. In the Ethical approval elderly patient group, hip pain due to metastatic bone disease This study was found ethically appropriate by the Ondokuz can sometimes mimic the findings of osteoarthritis, so the Mayıs University Clinical Research Ethics Committee on treatment of metastatic bone disease may delay. It should be 20.07.2017 with the decision number OMUKAEK 2017/259. kept in mind that a common pathology such as trochanteric No budget was used for the study. bursitis can confuse with metastatic bone disease. A clue about the metastatic bone disease can be obtained when a brief Study design systematic examination is performed in elderly patients with The data of BSTTC, operating under the Department of hip pain. Orthopedics and Traumatology, Ondokuz Mayıs University In this study, we examined the distribution of patients Faculty of Medicine, between years 2004-2017, were analyzed with metastatic bone disease who applied to the Bone and Soft retrospectively. Working parameters based on tumor council Tissue Tumor Council (BSTTC) operating under the form; The name of the patient includes the surname, protocol Department of Orthopedics and Traumatology, Ondokuz Mayıs number, age, gender, briefly complaint, pre-diagnosis, final University. It was our secondary goal to point out that diagnosis, and council decision.
*Corresponding author: Hikmet Çinka, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.45994
43 Statistical analyses The research data was uploaded and evaluated on the computer via Microsoft Excel program via “SPSS for Windows 21.0 (SPSS Inc, Chicago, IL)”. Descriptive statistics were presented as mean (±) standard deviation, median (minimum-maximum), frequency distribution, and percentage.
RESULTS The metastatic bone disease was detected in a total of 356 cases in 1230 patients who were examined with a pre-diagnosis of metastatic bone disease in BSTTC (28.94%). The youngest age Figure 3. Localization distribution of 356 metastatic bone cases was 6 years, while the oldest was 89 (Average 59.36). In contrast to 205 male patients, 151 female patients were available in the study. 37 of 356 cases of metastatic bone disease presented with pathological fractures (10.39%). Metastasis cases were observed mostly in the 60-69 age range (26.68%), followed by the 50-59 and 70-79 age ran- ge (25.84% and 19.54% respectively). The area with the most common metastasis was the hip (149 cases, 41.85%). There were localizations following thigh (44 cases) and shoulders (29 cases) and hips (12.35% and 8.14%, respectively). Figure 4. Distribution of metastatic bone patients by foci Distribution of metastasis cases according to age, gender, localization, and primary foci are given in figures 1,2, 3, and 4, respectively. DISCUSSION Metastatic bone disease has now become a common discomfort. Especially given the prolonged life expectancy and increasing life expectancy, proper diagnosis of the disease and its treatment are important. Also, new classes of drugs and new interventions give these patients a better quality of life and increase life expectancy. Bone metastases are characterized by severe pain, movement disorder, pathological fractures, spinal cord syndrome, bone marrow aplasia, and hypercalcemia, and cause important morbidity 1. Bone tissue is a common site of Figure 1. Distribution of 356 metastatic bone cases with age metastasic disease. Once bone metastasis develops, the characteristics prognosis in cancer patients starts to worsen. Most skeletal metastases are due to breast and prostate cancer. Bone metastasis is much more common than primary bone cancers, especially in adults 2. Even the advanced modalities are widely used in hospitals, the diagnosis is based on signs, symptoms, and imaging. Although the metastatic bone disease is sometimes apparently presented, it can sometimes hide behind other symptoms and be easily overlooked. Patients often use the media to research the symptoms Figure 2. Gender distribution
44 and diseases. Pazarcı et al. 3 studied to evaluate the evaluated, the female-male ratio was 1.5, the average age was representation of orthopaedic oncology in the media . Early 59.2, and the most common localization was proximal femur, diagnosis and correct imformation is very important for and the most common foci of metastasis was lung. A primary orthopaedic oncology patients. According to their study, a very tumor could not be detected in 25% of these cases 9. In our small number of news items about bone cancer symptoms and series, the number of metastasis cases with no primary focus is bone metastasis were seen in the media 3. It would be better to 60 and proportionally corresponds to 16.85% of all metastasis improve media visibility for orthopaedic oncology, so patients cases. Primary site detection is often not possible in the can access correct information. And so they may get early presence of multiple metastases. In 490 metastasis cases diagnosis. detected in the series of Yücetürk et al., the lung was most In our clinic, patients who applied to BSTTC and had frequently detected as a focus (27%) 10. Our data on the a pre-diagnosed metastatic bone disease constituted 35% of all primary foci of metastatic bone disease is compatible with the bone tumors. While the incidence rate was 57.6% in men, this literature. rate was 43% in women. The vast majority of cases were Hip pain is a common and disabling condition that observed between the ages of 50-70 (52.5%). When we affects patients of all ages. The differential diagnosis of hip compare our data with the literature, it is seen that metastatic pain is broad, presenting a diagnostic challenge 11.There may bone tumors are generally observed in the 5th and 6th decades be many causes of hip pain. Especially in advanced ages, 4, 5, 6. osteoarthritis of the hip joint, and changes in the surrounding When the foci of metastasis cases were examined, the soft tissues are the main causes of hip pain. Therefore, lung was the most common site (37.64%), followed by breast diagnosis of metastatic bone disease can easily be referred to as cancer (21.34%). In an autopsy study, at least 70% of autopsy other problems in patients presenting with hip pain. If a careful patients, breast and prostate ranked first with a rate of 84% 7. physical examination and systematic evaluation are not Although metastases occur at later stages of life, it should be performed, tumors located in the hip area may be overlooked. kept in mind that breast and thyroid cancers can occur with Especially in the presence of nocturnal pain, metastasis in the 4th and even 3rd decade. In a study in which activity-independent pain and swelling, the presence of a tumor 9505 metastatic bone disease was examined, the most common around the hip should be suspected. White et al. 12 presented a primary site was detected as breast (n = 1798), and the second case of a 55-year-old woman with a six-month history of pain most common primary site was prostate (n = 1862) 4. Although over the lateral aspect of her left hip in the trochanteric region. the primary sites vary, lung, breast, kidney, prostate, and She had a history of hip pain for six months. On examination, thyroid tissue are the primary foci that should be considered she had a marked antalgic gait. A radiograph of the pelvis primarily in the presence of metastatic bone disease 8. revealed the lytic area over the greater trochanter, and the However, it should be kept in mind that there are cancer types primary foci were scanned and she has been diagnosed with that can cause metastatic bone disease outside these sites. metastatic breast cancer 12. The number of metastases in the Rizzoli archive, Up to the study of Ashford et al. 13, even in an adult which is one of the largest series in the literature was 4431. The young patient with progressive pain or night pain should be most common age range was 60-69 years old, and the most referred for urgent radiographic assessment to rule out a common localization was vertebra. The localization following primary malignant bone tumor. Early diagnosis is essential in the vertebra was the proximal femur and iliac wing, these patients as the disease can be rapidly progressive 13. respectively. The most common localization in our study was In our study, the diagnosis time of metastatic bone the proximal femur and hip region. The low rate of vertebral disease around the hip after their first referral to the orthopedic metastasis in our series can be explained by the fact that clinic is unknown. We noticed that there are patients who have vertebral metastases are examined by spinal surgeons in our metastatic bone disease in their hip area during their treatment hospital and therefore these data are not reflected in our for another reason concerning the hip. However, we could not statistics. detect this statistically. This was one of the limitations of our In a study in which 28 metastatic bone tumors were study.
45 A 69-year-old male patient applied to the orthopedic CONCLUSION outpatient clinic. He had pain in his right hip for the last 3-4 In conclusion, the most common localization of bone and soft months. A lytic area was observed in the right femoral tissue tumors was determined as hip. Musculoskeletal tumors subtrochanteric area on direct radiography. In the MRI and metastatic bone disease should be considered in the diffe- sections, it was observed that the medullae were infiltrated. The rential diagnosis especially in patients over 60 years old who patient was then reconstructed with modular tumor prosthesis present with hip pain. following proximal femur resection (Figure 5). Conflict of interest The author declares that there is no conflict of interest.
Figure 5. Preoperative and postoperative images of a 69-year-old male patient with right hip pain
REFERENCES 7. Picci P, Manfrini M, Fabbri N, Gambarotti M, Vanel D. Atlas of 1. Cecchini M G, Wetterwald A, Van Der Pluijm G, Thalmann G N. musculoskeletal tumors and tumorlike lesions: the Rizzoli case Molecular and biological mechanisms of bone metastasis. EAU archive. Springer Science & Business Media. 2014 Update Series. 2005; 3(4), 214-226 8. Budczies J, von Winterfeld M, Klauschen F, Bockmayr M, Lennerz 2. Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L ve ark. J K, Denkert C ve ark. The landscape of metastatic progression Bone metastases: an overview. Oncol Reviews. 2005; 11 (1): 321. patterns across major human cancers. Oncotarget. 2015; 6(1), 3. Pazarcı Ö, Tülüce İ, Şirin E, Sağlam F, Sofulu Ö, Erol B.The Repre- 570. sentation of Orthopaedic Oncology in the Media in Turkey. 9. Dabak N, Tomak Y, Karaismailoğlu T, Tilki K, Tepe S. Approach to International Journal of Academic Medicine and Pharmacy in Extremity and Pelvic Region Localized Metastatic Bone Tu- 2020;2:123-129 mors. Journal of Experimental and Clinical Medicine. 2010; 15 4. Li S, Peng Y, Weinhandl E D, Blaes A H, Cetin K, Chia V M ve ark. (1). Estimated number of prevalent cases of metastatic bone disease 10. Yücetürk G, Sabah D, Kececi B, Kara A D, Yalcinkaya S. Prevalence in the US adult population. Clinical Epidemiology, 2012; 4, 87. of bone and soft tissue tumors. Acta Orthopaedica et 5. Singh V A, Haseeb A, Alkubaisi A A H A. Incidence and outcome Traumatologica Turcica. 2011; 45(3), 135-43. of bone metastatic disease at University Malaya Medical Centre. 11. Wilson J J, Furukawa M. Evaluation of the patient with hip pain. Singapore Medical Journal. 2014; 55(10), 539. American Family Physician. 2014;89(1):27-34. 6. Wisanuyotin T, Sirichativapee W, Sumnanoont C, Paholpak P, 12. White H, Barrett M, Gooding C. Chronic hip pain. BMJ. 2018; Laupattarakasem P, Sukhonthamarn K ve ark. Prognostic and risk 360. factors in patients with metastatic bone disease of an upper 13. Ashford R U, Eastley N C. Hip pain in young adults: consider pri- extremity. Journal of Bone Oncology. 2018; 13, 71-75. mary bone sarcoma. BMJ. 2018; 362.
46 Int J Acad Med Pharm, 2021; 3 (1); 47-51
International of Academic Medicine and Pharmacy
Obsesif-Kompulsif Bozukluk Tanısı Almış Yetişkin Bireylerde Benlik Saygısı ile Anksiyete arasındaki İlişkinin İncelenmesi The Relationship Between Self-Esteem and Anxiety in Adults with Obsessive Compulsive Disorder
Ahmet Aytaş 1, Habib Erensoy 2* 1 Üsküdar Üniversitesi Sosyal Bilimler Enstitüsü, Psikoloji Bölümü, İstanbul, Türkiye 2 Üsküdar Üniversitesi Tıp Fakültesi, Psikiyatri Anabilim Dalı, İstanbul, Türkiye
ORCID; 0000-0002-6441-0447, 0000-0002-4278-2739
Makale bilgisi Araştırma makalesi
Alındı :01.08.2020 Özet; Bu çalışmada obsesif kompulsif bozukluk (OKB) tanısı almış hastaların anksiyete ve benlik saygıları Revize makale alındı :- incelenmiştir. İlk olarak OKB’li 75 hasta, hem durumluk-sürekli anksiyete hem de benlik saygıları bakımından çeşitli Kabul :02.11.2020 sosyo-demografik özelliklerine göre karşılaştırılmıştır. Bu karşılaştırmalarda hem parametrik testlerden (t-test ve Online yayım :05.01.2021 ANOVA) hem de parametrik olmayan testlerden (Mann Whitney U ve Kruskal-Wallis H) yararlanılmıştır. Durumluk ve sürekli kaygı verileri Durumluk-Sürekli Kaygı Envanteri, benlik saygısı verileri ise Rosenberg’in Benlik Saygısı Envanteri kullanılarak toplanmıştır. Çalışmada hastaların benlik saygıları, OKB tedavi sürelerine ve eğitim durumlarına Anahtar kelimeler göre anlamlı bir şekilde farklılık göstermiştir. Fakat yaş, cinsiyet, gelir, medeni durum ve iş durumlarına göre anlamlı bir farklılaşma tespit edilmemiştir. Bunların yanı sıra OKB hastalarının sürekli kaygı seviyeleri cinsiyete göre farklılık Benlik saygısı göstermektedir. Kadın hastaların sürekli kaygı düzeyleri erkek hastalardan daha yüksektir. Çalışmada ayrıca kontrol grubu Anksiyete da kullanılmıştır ve toplam 75 gönüllü birey bu gruba katılmıştır. Kontrol grubuyla yapılan karşılaştırmalarda ise OKB’li OKB hastaların diğer insanlara göre daha yüksek durumluk-sürekli kaygı ve daha düşük benlik saygısına sahip oldukları Durumluk-sürekli kaygı envanteri bulunmuştur. Bunun yanı sıra durumluk-sürekli kaygı ile benlik saygısı arasında güçlü ve negatif yönlü bir ilişki mevcuttur.
Article info Research article
Received :01.08.2020 Abstract;In this study, anxiety and self-esteem of patients with obsessive compulsive disorder (OCD) were examined. Received in revised form :- First, 75 patients with OCD were compared according to their state-trait anxiety and self-esteem. In these comparisons, Accepted :02.11.2020 both parametric tests (t-test and ANOVA) and non-parametric tests (Mann Whitney U and Kruskal-Wallis H) were used. Available online :05.01.2021 State and trait anxiety data were collected by State-Trait Anxiety Inventory and self-esteem data were collected by Rosenberg's Self-Esteem Inventory. In the study, self-esteem of the patients differed significantly according to OCD treatment duration and patients’ educational levels. However, no significant difference was found by age, gender, income, Keywords marital status and job status. In addition, trait anxiety levels of OCD patients differ according to gender. Trait anxiety levels of female patients are higher than male patients.The control group was also used in the study and a total of 75 Self-esteem volunteer individuals were included in this group. It was concluded that OCD patients had higher state-trait anxiety and Anxiety lower self-esteem than others. Besides, there is a strong and negative relationship between state-trait anxiety and OCD self-esteem. State-trait anxiety inventory
GİRİŞ (örneğin, tekrarlayan el yıkama, sipariş verme veya sürekli Obsesif kompulsif bozukluk, obsesyonların, zorlayıcı kontrol etme) ya da zihinsel eylemler (örneğin, tekrarlayan dua ritüellerin veya en yaygın olarak her ikisinin de ortaya etme, sayma veya kötü düşünceleri geri almak ya da çıkmasıyla karakterize edilir. Obsesyonlar genel olarak tekrar- değiştirmek için iyi düşünceler düşünmek) olup, etkilenen layıcı ve sürekli düşünceler, dürtüler veya müdahaleci olarak birey, takıntı ya da katı kurallara göre (örneğin, tam olarak beş deneyimlenen ve büyük kaygıya yol açan imgelerden oluşur 1. kez açılıp kapatılarak bir cihazın kapanıp kapanmadığının Etkilenen birey, bunları başka bir düşünce ya da eylemle kontrol edilmesi) hareket eder 2. Kompulsiyonların amacı, görmezden gelmeye, bastırmaya ya da etkisiz hale getirmeye sıkıntıların önlenmesi veya azaltılması ya da bazı korkulan çalışır. Bunun yanında kişi, bu düşüncelerin aklının bir ürünü olayların engellenmesidir 3. OKB ile ilgili olarak, düşük benlik olduğunu kabul eder. Kompulsiyonlar, tekrarlayan davranışlar saygısının bozukluğun birtakım olası prodromal
*Corresponding author: Habib Erensoy, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.45548
47 semptomlarından biri olduğunu, düşük benlik saygısının belki Bu araştırma 2018 yılı sonu ve 2019 yılı başlangıcı itibariyle de genel bir savunmasızlık faktörü olarak hareket edebileceğini Üsküdar Üniversitesi’ne bağlı kliniklerde tedavi gören OKB belirtmektedir 4,5.OKB'li hastaların genelleştirilmiş benlik tanısı almış hastaların anksiyete ve benlik saygısı düzeylerini saygısı değerlendirmelerinde klinik olmayan kontrollerden incelemektedir. OKB tanısı almış hastalara uygulanan önemli ölçüde farklı olduğunu ve benlik saygısı ve OKB'nin anketler çeşitli karşılaştırma testleriyle incelenmiştir. Bunun duygudurumun etkisinden bağımsız bir Bu bulgular OKB'nin yanı sıra, OKB’li hastalar kontrol grubuyla da karşılaştırılmış mevcut bilişsel kuramları ile ilişkili olarak, obsesyon ve bu iki grubun anksiyete ve benlik saygısı düzeylerinin ne düşüncelerinin yanlış yorumlanmasına yönelik duyguların derecede farklılaştığı araştırılmıştır. Bu bilgiler ışığında geliştirilmesine atıfta bulunan ve bilişsel müdahalelerin çalışmada OKB tanısı alan yetişkin bireylerin, benlik saygıları yönetilmesinde etkisiz stratejilere yol açan durumlara dikkat ile kaygı düzeyleri arasındaki ilişki incelenecektir. çekmektedir 6. OKB'si olan bireylerin benlik saygısı algılarını bozabilecekleri ileri sürülmüştür ve müdahaleci düşüncelerin Evren ve örneklem önemine dair bu konudaki önemine dair çalışmalar mevcuttur Çalışma üniversite kliniklerinde tedavi gören 75 OKB’li hasta bağlantıya sahip olduğunu bildiren neticeler elde etmişlerdir 7. ve 75 kişiden oluşan kontrol grubu içermektedir. Hastaların Yüksek gelirli ülkelerde yapılan araştırmalar OKB'nin özellikle tedavi süreleri çeşitlilik göstermekle beraber bir kısmı sürekli anksiyete ve duygudurum bozuklukları olmak üzere yüksek bir kısmı da aralıklı olarak tedavilere devam etmişlerdir. düzeyde psikiyatrik komorbidite ile ilişkili olduğunu OKB’li hastalar grubunda yer alan bireylerin dahil edilme göstermiştir 8. Bu güçlü ilişki göz önüne alındığında, OKB ve kriterleri şunlardır: düşük benlik saygısı arasındaki ilişkiyi ele almak oldukça Birincil tanısının OKB olması makuldür. Bazı çalışmalar, birçok psikiyatrik hastalıkta benlik Yetişkin olması (18 yaşından büyük) 9 saygısının önemli bir etken olduğunu göstermiştir . Yüksek OKB’den dolayı tedavi görüyor olması gelir düzeyindeki ülkelerde OKB çalışmalarında açıkça önemli Dışlama kriterleri ise şu şekildedir: ilerlemeler olmasına rağmen, düşük gelirli nüfuslardan klinik OKB tanısı almamış olmak özellikleri ve fenomenolojisi ile ilgili çok az veri bulunmakta- OKB tanısı almış olsa bile çalışma esnasında tedavi dır. Bu, çapraz-kültürel epidemiyolojik çalışmaların, OKB'nin görmüyor olmak hem Batı hem de Batı dışı kültürlerdeki yaygınlık ve klinik Birincil tanının OKB olmaması özellikler bakımından genellikle benzer olduğunu göstermesine 18 yaşından küçük olmak rağmen kültürlerarası farklılıklar halen literatürde önemli bir Kontrol grubunun dahil edilme kriterleri ise geçmişte boşluktur. Özellikle OKB'ye ilişkin benlik saygısı OKB tanısı almamış ve yetişkin bir birey olmak şeklindedir. meselelerinin daha kapsamlı bir araştırmasının, hastalığın OKB ya da farklı bozukluklar nedeniyle tedavi görme ya da anlaşılmasını ve sonuçta hedefe yönelik müdahalelerin 18 yaşın altında olma ise kontrol grubunun dışlanma etkinliğini artırabileceği açıktır. Ancak, bildiğimiz kadarıyla, kriterleridir. bugüne kadar ülkemizde OKB ve benlik saygısı arasındaki ilişkiyi araştıran özellikle klinik bir çalışma yoktur. Bu Veri toplama araçları çalışmada bu yönüyle literatüre önemli katkı sağlamaktadır. Çalışmada verilerin toplanması iki önemli envantere dayan-
maktadır: Durumluk-Sürekli Kaygı Envanteri (DSKE) ve GEREÇ ve YÖNTEMLER Rosenberg (1965)’in Benlik Saygısı Ölçeği (BSÖ)
kullanılmıştır. Araştırmanın etik yönü
Araştırmaya başlamadan önce araştırmanın yapılacağı yer BULGULAR olan Üsküdar Üniversitesi girişimsel olmayan araştırmalar
Etik Kurul başkanlığın’dan B. 08. 6. YÖK. 2. ÜS.0.05.0.06 / Betimleyici istatistikler 2018/812 sayı ve 25.09.2018 tarihli etik kurul izni alındı. Çalışmaya katılan 75 OKB’li hastadan 37’si kadın ve 38’i Hastalardan yazılı onam alındı. erkektir. Bu yönüyle dağılımın neredeyse eşit olduğu
48 görülmektedir. Kontrol grubunun ise %48’i kadın, %52’si Yaş arttıkça genel itibariyle ölçeklere ait puanlar erkeklerden oluşmaktadır. azalmıştır fakat bu değişimler anlamlı değildir. Şekil 1, OKB tanısı alan hastaların tedavi süreleri ile Benlik saygısında ise çalışmayanların daha düşük bir ilgili dağılımı göstermektedir. Bu değişken tedavi süresinin ortalamaya sahip oldukları fakat çalışmayanlarla aralarındaki hastaların benlik saygısı ve durumluk-sürekli kaygı farkın istatistiksel olarak anlamlı olmadığı görülmektedir. seviyelerine etki edip etmediğinin incelenmesi adına OKB’li hastaların durumluk-kaygı düzeyleri ve benlik kaygısı eklenmiştir. seviyeleri medeni durumlarına , çocuk sayılarına ve eğitim durumlarına göre farklılık göstermemektedir. Şekil 2, Şekil 3 ve Şekil 4, Görüldüğü gibi tedavi süresiyle kaygı seviyeleri arasında negatif; benlik saygısıyla ise pozitif yönlü bir ilişki mevcuttur. Bu farklılıklar istatistiksel olarak anlamlı görülmektedir.
Şekil 1. Tedavi süresi değişkeni dağılımı
Ölçeklerin OKB’li hastalarda sosyo-demografik özelliklere göre karşılaştırılması OKB’li hastalardan alınan veriler, cinsiyet, yaş, medeni durum, iş durumu, tedavi süresi, eğitim durumu ve gelir gibi Şekil 2. Tedavi süresi ve dur umluk kaygı sosyo-demografik özelliklere göre karşılaştırılmıştır. Karşılaştırmalarda parametrik testler olan bağımsız örneklem t-testinden ve ANOVA’dan yararlanılmıştır. Yalnızca bir karşılaştırma (tedavi süresine göre farklılaşmaların incelenmesi) Levene testi varyans eşitliği şartı sağlanamadığı için hem ANOVA hem de parametik olmayan bir test olan Kruskal-Wallis ile analiz edilmiştir. Tablo1,durumluk-sürekli kaygı ve benlik saygısı ölçeklerinin cinsiyete göre farklılaşıp farklılaşmadığını göstermektedir. Hastalarn sürekli kaygı seviyeleri ise cinsiyete göre istatistiksel olarak anlamlı bir Şekil 3. Tedavi süresi ve sürekli kaygı şekilde farklılaşmıştır (p<0,05).
Tablo 1. Cinsiyete göre farklılaşmalar
Std. Levene Ölçek Cinsiyet N Ort. t sd p Sapma p
Kadın 37 47,41 11,172 Durumluk 1,043 73 0,300 0,114 Kaygı Erkek 38 44,50 12,863
Kadın 37 54,76 7,780 Sürekli 6,296 73 0,000 0,028 Kaygı Erkek 38 40,84 11,034
Kadın 37 15,14 7,111 Benlik -1,078 73 0,285 0,980 Saygısı Erkek 38 16,87 6,815 Şekil 4. Tedavi süresi ve benlik saygısı
49 OKB’li hastaların kontrol grubuyla karşılaştırılması alan kişilerin durumluk-sürekli kaygı seviyeleri ve benlik 75 kişiden oluşan OKB’li hastalar, 75 kişilik kontrol grubuyla saygıları arasında anlamlı bir farklılık bulunmaktadır. durumluk-sürekli kaygı ve benlik saygısı puanları yönünden Tablo 2 ’te yer alan ortalama değerler de bu sonucu haliyle karşılaştırılmışlardır. OKB’li hastalar ile kontrol grubunda yer desteklemektedir.
Tablo 2. OKB'li hastaların kontr ol gr ubuyla karşılaştırılması
Std. Levene Grup N Ort. t sd p Mann-Whitney U Mann-Whitney p Sapma p
OKB li hastalar 75 45,93 12,066 Durumluk Kaygı 10,120 150 0,000 0,000 -7,327 0,000 Kontrol grubu 75 31,02 3,460 OKB li hastalar 75 47,71 11,806 Sürekli Kaygı 8,219 150 0,000 0,000 -6,190 0,000 Kontrol grubu 75 36,09 2,693 OKB li hastalar 75 16,01 6,970 Benlik Saygısı -2,623 150 0,020 0,008 -3,176 0,000 Kontrol grubu 75 19,77 9,671
TARTIŞMA OKB’li kadın hastaların sürekli kaygı seviyeleri erkek Bu çalışma, klinik bir örneklemde OKB tanısı almış ve bunun hastalara göre daha yüksektir. için tedavi gören hastaların benlik saygısı ve kaygı düzeylerini OKB’li hastaların durumluk-sürekli kaygıları ve benlik karşılaştırmış, çeşitli demografik verilere göre bu iki ölçeğin saygıları yaşa göre anlamlı bir şekilde farklılık farklılaşıp farklılaşmadığını tespit etmiştir. Literatürdeki göstermemektedir. geçmiş araştırmalar benlik saygısını obsesif kompulsif OKB’li hastaların durumluk-sürekli kaygıları ve benlik 10 bozukluğun önemli bir bileşeni olarak tanımlamışlardır . saygıları çalışma durumlarına göre farklılık OKB, genellikle sıkıntıları önlemek ya da azaltmak amacıyla göstermemektedir. zihinde beliren düşünceler ya da davranışlar tarafından takip OKB’li hastaların durumluk-sürekli kaygıları ve benlik edilen müdahaleci, kaygı uyandıran fikirlerin (obsesyonlar) saygıları gelir durumlarına göre farklılık göstermemekte- 11 oluşması ile karakterizedir . OKB'nin erken dönem bilişsel dir. kavramsallaştırmaları, obsesyonların doğası ve kökenine OKB’li hastaların durumluk-sürekli kaygıları ve benlik odaklanmış, bu durum, müdahaleci düşüncelerin ortaya saygıları medeni durumlarına göre farklılık göstermemek- çıkmasının, bu hastalığın en ayırt edici faktörü olduğunu tedir. 12 göstermiştir . OKB’li hastaların durumluk-sürekli kaygıları ve benlik Bhar ve Kyrios, OKB ve hassas benlik saygısı saygıları çocuk sayısına göre farklılık göstermemektedir. arasındaki bağlantıyı araştıran ilk çalışmalardan birini OKB’li hastaların durumluk kaygıları ve benlik saygıları yapmışlardır. OKB'si olan bireylerin, özellikle ahlak ve sosyal eğitim durumlarına göre anlamlı bir şekilde farklılık gös- kabul alanlarında, öz-değer konusunda kararsız oldukları terirken sürekli kaygı seviyeleri göre farklılaşma görül- hipotezini test etmişlerdir 13. OKB’si olan bireylerin, klinik memiştir. Eğitim seviyesi yüksek olan hastaların benlik olmayan kontrollerle karşılaştırıldıklarında, kendi kendine saygıları da yüksektir. kararsızlık indekslerinin anlamlı olarak daha yüksek olduğu OKB şikâyet süresinin hastaların benlik saygısı ve du- tespit edilmekle birlikte, bu sonuç diğer anksiyete rumluk-sürekli kaygıları üzerinde anlamlı bir etkisinin bozuklukları olan bireylerden çok da farklı değildir. Daha olmadığı görülmektedir. Bu durumun sebeplerinden birisi önemlisi, benlik saygısı, depresyon ve anksiyete düzeyi her hastanın OKB şikayetleri başladığı anda tedaviye kontrol edilse bile, OKB ile öz-kararsızlık olumlu yönde ulaşamamış ya da yönelmemiş olması olabilir. ilişkili bulunmuştur 13. OKB’li hastaların tedavi süreleri, hem durumluk-sürekli Yukarıda özetlenen çalışmalarla paralel olarak bu kaygıları hem de benlik saygıları üzerinden anlamlı bir çalışmada ulaşılan ana sonuçlar şunlardır: etkiye sahiptir. Uzun süredir tedavi gören hastaların du- OKB’li hastaların durumluk kaygıları ve benlik saygıları rumluk-sürekli kaygı seviyelerinde bariz iyileşmeler gö- cinsiyete göre farklılık göstermezken, sürekli kaygı rülmüş, bunun yanı sıra benlik saygılarının da anlamlı bir seviyeleri cinsiyete göre anlamlı bir şekilde şekilde arttığı tespit edilmiştir. farklılaşmaktadır.
50 Bu çalışmanın ana temalarından birisi de OKB’li 4. McKeon J, Roa B, Mann A. Life events and personality traits in hastaların durumluk-sürekli kaygı seviyeleri ile benlik saygı- obsessive-compulsive neurosis. The British Journal of larını bir kontrol grubuyla karşılaştırmak ve literatürde işaret Psychiatry. 1984; 144: 185–189. edilen bulguların doğruluğunu ya da geçerliliğini sınamaktır. 5. Ehntholt, K. A., Salkovskis, P. M., Rimes, K. A. Kontrol grubuyla yapılan karşılaştırmalar göstermiştir ki Obsessive–compulsive disorder, anxiety disorders, and self- OKB’li hastaların durumluk ve sürekli kaygıları, kontrol esteem: An exploratory study. Behaviour Research and The- grubunda yer alanlara göre bariz bir şekilde yüksektir. Bu rapy.1999; 37(8):771-781. 6. Doron, G., Moulding, R., Kyrios, M., Nedeljkovic, M. Sensitivity farklar istatistiksel olarak anlamlıdır ve literatürde yer alan, of self-beliefs in obsessive compulsive disorder. Depression and OKB’nin yüksek kaygıyla paralel olduğunu belirten Anxiety. 2008; 25(10), 874-884. çalışmalarla uyumludur. Buna ilave olarak OKB’li hastaların 7. Rachman, S. A cognitive theory of obsessions: Elaborations. benlik saygısının kontrol grubu ortalamasından anlamlı bir Behaviour Research and Therapy. 1998; 36(4), 385-401. şekilde düşük olduğu gözlemlenmiştir. Bir başka ifadeyle 8. Cummings, J. A., Hayes, A. M., Cardaciotto, L., Newman, C. F. OKB, düşük benlik saygısıyla sonuçlanmaktadır. Bu yönüyle The dynamics of self-esteem in cognitive therapy for avoidant çalışmada elde edilen bulgular Bhar ve Kyrios ile oldukça and obsessive-compulsive personality disorders: An adaptive uyumludur 13. role of self-esteem variability? Cognitive Therapy and Research. 2012; 36(4), 272-281. Çıkar çatışması 9. Silverstone PH, Salsali M., Low self-esteem and psychiatric pati- Tüm yazarlar bu makalede bildirilen çalışmayı etkileyebilecek ents: Part I - The relationship between low self-esteem and hiçbir mali çıkar veya kişisel çatışmalarının olmadığını beyan psychiatric diagnosis. Annals of General Psychiatry. 2003 Feb. ederler. 11; 2(1):2. 10. Ehntholt, K. A., Salkovskis, P. M., Rimes, K. A. Obsessive– KAYNAKLAR compulsive disorder, anxiety disorders, and self-esteem: An 1. Ghamari G, Imani B, Sadeghi M. The Investigation of emotional exploratory study. Behaviour Research and Therapy.1999; 37 inhibition and recognition in patients with (8), 771 - 781. obsessive-compulsive (Persian). Journal of Clinical Psychology. 11. Abramowitz, J. S., Taylor, S., McKay, D. Obsessive-compulsive 2012; 4(2):9–18. disorder. The Lancet.2009; 374, 491-499. 2. Zeigler-Hill, V.The connections between self-esteem and psyc- 12. Salkovskis, P. M. Obsessional-compulsive problems: A cogniti- hopathology. Journal of Contemporary Psychotherapy.2011;41: ve-behavioural analysis. Behaviour Research and The- 157-164. rapy.1985; 23(5), 571-583. 3. American Psychiatric Association: Practice guideline for the 13. Bhar, S. S., Kyrios, M. An investigation of self-ambivalence in treatment of patients with major depressive disorder. obsessive compulsive disorder. Behaviour Research and American Journal of Psychiatry. 2010 ;( October suppl) 1-152 Therapy.2007; 45(8), 1845-1857. [G].
51 Int J Acad Med Pharm, 2021; 3 (1); 52-57
International of Academic Medicine and Pharmacy
Antioxidant Activity of Apocynin against Intestinal Ischemia-Reperfusion Induced Oxidative Damage in Lung and Intestinal Tissues
Derya Güzel Erdoğan 1, Ayhan Tanyeli 2*, Ersen Eraslan 3, Mustafa Can Güler 4
1 Department of Physiology, Faculty of Medicine, Sakarya University, Sakarya, Turkey. 2,4 Department of Physiology, Faculty of Medicine, Atatürk University, Erzurum, Turkey. 3 Department of Physiology, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey.
ORCID; 0000-0002-7618-5043, 0000-0002-0095-0917, 0000-0003-2424-2269, 0000-0001-8588-1035
Article info Research article
Received :04.09.2020 Abstract; Potential effects of Apocynin against intestinal ischemia reperfusion-related oxidative damage was Received in revised form :05.11.2020 investigated in intestinal and lung tissues. Intestinal ischemia-reperfusion model was established. The superior mesenteric Accepted :02.11.2020 artery was occluded via an atraumatic clamp for 1 hour. Following ischemia, reperfusion was allowed for 2 hours. After Available online :05.01.2021 the experimental processes, the animals were immolated, intestinal and lung tissue samples were removed. MPO activity and TOS, MDA, OSI, TNF-α, IL-1β levels raised in the ischemia-reperfusion group while TAS level and SOD activity Keywords diminished. TAS value and SOD activity elevated while MPO activity, OSI, TOS, TNF-α, IL-1β, and MDA levels decreased in low and high doses of Apocynin (20 mg/kg and 50 mg/kg) groups. Different doses of Apocynin Ischemia-reperfusion administration demonstrated beneficial effects against intestinal ischemia reperfusion-induced oxidative damage in Apocynin intestinal and lung tissues. Intestinal Lung Rat Oxidative damage
INTRODUCTION (NADPH) oxidase (NOX) is considered as the main source of Intestinal ischemia-reperfusion (I/R) mostly occurs due to a ROS formation in ALI 16. Apocynin (Apoc) (4-hydroxy-3- decrease in blood flow and perfusion 1. It can be observed methoxy-acetophenone) is a catechol that inhibits NOX. It is during trauma, major abdominal and vascular interventions, the primary enzyme responsible for generating the initial ROS and sepsis 2. A collapse in systemic circulation may lead to I/R molecule superoxide in activated leukocytes 17. Apoc has been injury 3. Intestinal I/R injuries are related to intestinal reported to be a powerful antioxidant, and anti-inflammatory obstruction, necrotizing colitis, and similar health conditions 4, molecule in studies conducted to date 18, 19. Apoc alleviates 5. Intestinal I/R is detrimental to the intestine and other tissues cerebral infarction through declining superoxide formation 20. It 6. Intestinal I/R may lead to organ injuries, including liver, also eases brain injury via diminishing inflammation 21. In kidneys, heart, and lungs 7. Acute lung injury (ALI) is an another study, Apoc demonstrated therapeutic effects against intestinal I/R complication which may induce acute respiratory severe acute pancreatitis-induced lung injury 22. Here, Apoc distress syndrome (ARDS) 8. Reactive oxygen species (ROS) was examined against intestinal and lung injuries induced by have essential roles in ALI formation 9, 10. Intestinal I/R may intestinal I/R in rats. also damage remote organs through cytokines, ROS, and inflammatory cells. Excessive ROS levels and low antioxidant MATERIAL and METHODS system activity may result in an I/R injury. The lung is a sensitive organ against ROS 11. ROS injure the endothelial and Ethical approval and drugs epithelial parts of lung tissues by inducing proinflammatory Permission for the current study was obtained from our cytokines 12. It has been mentioned I/R-induced intestinal University Experimental Animals Local Ethics Committee damage through ROS in previous studies 13-15. (protocol no:30.03.2018/63), and the experimental steps were Nicotinamide adenine dinucleotide phosphate carried out at our University Experimental Animals Research
*Corresponding author: Ayhan Tanyeli, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.46157
52 and Application Center, where also the animals were procured. tissues were centrifuged at 9000g at +4 ° C for 10 minutes, and Standard laboratory conditions were provided, including their supernatants were obtained. After the homogenization of appropriate temperature, moisture, and light/night cycle. tissues, all biochemical analyses were performed via Xylazine (Alfazyne %2 Injectable, Ege Vet. supernatants. Malondialdehyde (MDA) value was gauged with Hayvancılık San. ve Tic. Ltd. Şti. İzmir, Turkey) and Ketamine the method by Ohkawa et al. 27. Superoxide dismutase (SOD) 28 (Ketalar 500 Mg Injectable Flacon, Pfizer İlaçları Ltd. Şti. and Myeloperoxidase (MPO) 29 activities were evaluated. The İstanbul, Turkey) were preferred for anesthesia. Apoc was measurements of total oxidant status (TOS) (Rel Assay purchased from Sigma Aldrich USA. Apoc doses and the Diagnostics, Gaziantep, Turkey) and total antioxidant status method of administration used in the study were made (TAS) (Rel Assay Diagnostics, Gaziantep, Turkey) were according to previous studies 23, 24. carried out with applicable kits. Oxidative stress index (OSI) is the rate of TOS to TAS. TNF-α and IL-1β values were Experimental design, drugs, and groups examined with appropriate Elisa kits (Elabscience, Wuhan, Thirty-two healthy Wistar Albino female rats were weighed China). (250-300 gr) and randomized to 4 groups (n=8). All rats were fixed on board in the supine position. Surgical areas were Statistical analysis shaved firstly. Then, the area was disinfected with 10% All data were shown as mean±SD and determined by One-way povidone-iodine. Anesthesia (ketamine/xylazine 60/10 mg/kg, ANOVA. Tukey test was used for pairwise comparisons of the intraperitoneally, i.p.) was applied during all experimental groups. The differences were approved significantly in case of steps. p<0.05. Sham group: Following the animals’ preparation, abdominal midlines were incised for 2 cm and sutured with 3/0 RESULTS silk suture. SOD and TAS levels declined while MPO, TOS, OSI, and I/R group: After incision, the superior mesenteric MDA values elevated in the I/R group compared to the sham artery was exposed to microvascular clip occlusion for 1 hour group in intestinal tissues,. When Apoc 20 mg/kg group and I/ to create ischemia for each rat. Then, the clips were released, R group were compared, all parameters (except SOD) demon- incision fields were sutured, and intestinal reperfusion was strated a statistically significant change, and oxidative markers allowed for 2 hours as described in previous studies (25, 26). decreased while the TAS level increased. All values changed Apoc 20 mg/kg group: All steps were performed as significantly in Apoc 50 mg/kg group compared to the I/R the same with I/R group. However, 20 mg/kg of Apoc was group (table 1). administered i.p. just before the reperfusion phase. Remote tissue damage was evaluated for the lung tis- Apoc 50 mg/kg group: All steps were the same as sues. When the I/R group was compared to the sham group, Apoc 20 mg/kg group. But 50 mg/kg Apoc was administered SOD and TAS values declined, but TOS, MDA, OSI, and MPO i.p. just before the reperfusion phase. levels elevated. When Apoc 20 mg/kg and I/R groups were In the end, rats were immolated by high-dose compared, TOS, MDA, MPO, and OSI levels diminished sig- anesthesia. Intestinal and lung tissue samples were collected. nificantly, but the increase in TAS and SOD values was not significant. When the Apo 50 mg/kg group is compared to the Biochemical Analysis of Intestinal and Lung Tissues I/R group, TOS, MDA, MPO, and OSI values declined while Intestinal and lung tissues were homogenized using 1 ml cold SOD and TAS values were raised statistically significantly phosphate buffer per 100 mg of tissue. The homogenized (table 2).
Table 1 The effects of Apoc treatment in I/R-induced intestinal injury Experimental Groups TAS (mmol/L) TOS (µmol/L) OSI SOD MPO MDA (n=8) (U/mg protein) (U/g protein) (µmol/g tissue) Sham 1,50±0,24 4,31±0,41 0,29±0,02 309,26±85,91 343583,30±188185,50 61,85±8,89 I/R 0,52±0,06a 6,86±1,34a 1,34±0,34a 183,09±31,67c 585283,71±99139,59a 99,35±21,57a Apoc 20 mg/kg 0,98±0,08b 4,87±0,56b 0,49±0,03b 277,02±86,11 416053,60±80234,94d 71,73±11,45b Apoc 50 mg/kg 1,43±0,22b 4,55±0,54b 0,31±0,05b 284,31±41,70d 352168,94±76521,13b 64,58±8,90b ap<0.001 and cp<0.05 compared to sham group. bp<0.001 and dp<0.05 compared to I/R group 53 When IL-1β and TNF-α values of intestinal and lung treatment, IL-1β and TNF-α values declined significantly in tissues were evaluated, there was an increase in both tissues in both tissue samples of Apoc 20 mg/kg and Apoc 50 mg/kg the I/R group compared to the sham group. With Apoc groups (figure 1 and figure 2).
Table 2. Effects of Apoc treatment in I/R-induced lung injury Experimental Groups TAS TOS OSI SOD MPO MDA (n=8) (mmol/L) (µmol/L) (U/mg protein) (U/g protein) (µmol/g tissue) Sham 1,16±0,21 8,56±1,28 0,76±0,22 180,66±31,56 326543,26±37695,22 69,27±2,71 I/R 0,79±0,07a 12,10±1,62a 1,51±0,18a 125,88±32,84a 475788,7±62770,03a 108,46±30,99a Apoc 20 mg/kg 0,99±0,16 9,30±0,85b 0,96±0,20b 163,09±27,16 335486,44±23297,06b 77,81±12,37b Apoc 50 mg/kg 1,19±0,21b 8,70±0,65b 0,74±0,08b 176,52±54,17b 331418,75±68529,04b 75,26±8,90b ap<0.001 compared to sham group. bp<0.001 compared to I/R group
Figure 1. The results of (a) TNF-α and (b) IL-1β levels in I/R-induced Figure 2. The results of (a) TNF-α and (b) IL-1β levels in I/R-induced intestinal injury. lung injury.
DISCUSSION powerful antioxidant enzymes such as SOD perform cellular Intestinal tissues are highly vulnerable to I/R 30. Various defense 49. Oxidant molecules such as MDA occur during I/R conditions, including acute mesenteric ischemia, sepsis may and increase the formation of free radicals that cause damage in lead to intestinal I/R 31. Interruption of blood supply is the main cell membranes 50. NOX is an enzyme whose physiological reason for intestinal ischemia 32. During surgical interventions, function is to generate ROS. Possible NOX-derived ROS reperfusion, which follows elongated ischemia, leads to cellular sources occur during I/R in the lung including oxidative stress 3, 33, 34. Intestinal I/R causes primary (intestinal leukocytes, endothelial cells, epithelial cells, and dendritic cells tissues) and secondary (remote organ tissues) organ damage 51. Apoc has been shown to stimulate the synthesis of some such as lungs, which are exposed to ALI and ARDS 35, 36. antioxidant enzymes and inhibition of ROS formation through Intestinal I/R may result in ALI and ARDS, which increase NOX inhibition and eliminate various molecules that cause endothelial leakage and accumulation of inflammatory cells 37. oxidation of proteins such as MDA 23, 52-54. Our results show Inflammation and oxidative stress induce proinflammatory that high dose Apoc administration contributed significantly to response activation and play a role in I/R pathogenesis 38. ROS increased antioxidant enzyme levels, and both Apoc doses also play a part in I/R injury pathogenesis 39-42. Oxidative administration decreased oxidant molecule level. stress, which plays a significant role in the formation of I/R MPO is a specific oxidase in polymorphonuclear damage, continues a process leading to lipid peroxidation, leukocytes (PMNL). It is used to predict MPO activity, PMNL oxidation of cell proteins, DNA helix damage, and death 3, 41, 43. chemotaxis, and infiltration in tissues 29. PMNL infiltration The prolongation of the reperfusion period initiates an during the reperfusion period can result in the generation and inflammatory cascade that causes irreversible tissue damage 44. release of oxidants that aggravate this harmful cascade 55. Apoc Several therapies have been tried to reverse cellular acts on both MPO and NOX 56. The importance of Apoc in the injury after I/R. Studies about antioxidant agents about this MPO inhibition process has been reported 57. In our study, the health condition have been increasing recently 45, 46. TAS and MPO level increased in the I/R group while approaching sham TOS are preferred in I/R injury-related studies for the group’s value in Apoc applied groups. MPO level decreased biochemical analysis to evaluate oxidative balance 47. OSI, significantly in the Apoc 50 mg/kg group, particularly. Our TOS, and TAS ratio plays a role in the follow-up of therapy results are compatible with various I/R models in the literature besides reflecting the oxidant and antioxidant status 48. Besides, 23, 58. 54 I/R damage is associated with the coordinated activation of 8. Carden DL, Granger DN. Pathophysiology of several cytokines and adhesion molecules. Apoc has been ischaemia-reperfusion injury. J Pathol. 2000;190(3):255-66. reported to cause NF-κB inhibition in various diseases 58. 9. Kim K, Li Y, Jin G, Chong W, Liu B, Lu J, ve ark. Effect of valproic NF-κB inhibition suppresses levels of proinflammatory acid on acute lung injury in a rodent model of intestinal ischemia cytokines such as TNF-α and IL-1β. This study measured reperfusion. Resuscitation. 2012;83(2):243-8. serum TNF-α and IL-1β levels to evaluate intestinal and lung 10. Liu KX, Wu WK, He W, Liu CL. Ginkgo biloba extract (EGb 761) inflammation activity by the ELISA method. We found that attenuates lung injury induced by intestinal ischemia/ reperfusion in rats: roles of oxidative stress and nitric oxide. Apoc therapy inhibits the I/R induced inflammatory response. World J Gastroenterol. 2007;13(2):299-305. Following the literature, we have again shown that Apoc is a 11. Shen L, Zhang J. Ginsenoside Rg1 increases ischemia-induced cell potent anti-inflammatory molecule. proliferation and survival in the dentate gyrus of adult gerbils.
Neurosci Lett. 2003;344(1):1-4. CONCLUSION 12. Zu G, Guo J, Che N, Zhou T, Zhang X. Protective effects of Apoc administration demonstrated protective effects on ginsenoside Rg1 on intestinal ischemia/reperfusion alleviating I/R injury triggered by intestinal I/R in intestinal injury-induced oxidative stress and apoptosis via activation of and lung tissues. Current data may be new hope for intestinal the Wnt/beta-catenin pathway. Sci Rep. 2016;6:38480. and even other I/R injuries in further studies. 13. Güzel Erdoğan D, Tanyeli A. Inhibition of NADPH oxidase attenuates sepsis induced acute lung oxidative damage in rats. Conflict of interest JCNOS. 2018;10(2). The authors declare that they have no conflict of interest 14. Tanyeli Ayhan, Güzel Erdoğan D. Investigation into the Biochemical Effects of Barbaloin on Renal Tissue in Cecal Ligation REFERENCES and Puncture-Induced Polymicrobial Sepsis Model in Rats. SCIE
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57 Int J Acad Med Pharm, 2021; 3 (1); 58-63
International of Academic Medicine and Pharmacy
Tweak Levels in Rheumatic Inflammatory Diseases
Demet Yalcin Kehribar 1*
1 19 Mayis University Medical Faculty Department of Internal Medicine, Samsun, Turkey . ORCID; 0000-0002-1852-7981
Article info Research article
Received :24.09.2020 Abstract; The objective of this study is to investigate and compare serum levels of tumor necrosis factor-like weak Received in revised form :- inducer of apoptosis (TWEAK) in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Behçet's disease. Accepted :02.11.2020 Patients with a diagnosis of RA (n = 20), SLE (n = 20) and Behçet's disease (n = 20) and a healthy control group (n = 19) Available online :05.01.2021 were included in our study. Disease activity indexes, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were recorded in the patient groups. Serum TWEAK levels were measured with available commercial enzyme linked immunosorbent assay kits. The serum TWEAK levels were significantly higher in all patient groups compared to the control group. However, no significant difference was found in paired comparisons among patient groups. When the Keywords patients with high disease activity scores were compared to patients with low disease activity scores in RA, SLE and Behçet’s disease subgroups, there was no significant difference in terms of TWEAK levels. Hypertension, atherosclerosis, TWEAK diabetes mellitus and smoking had no effect on serum TWEAK levels. In correlation analysis, although serum TWEAK Rheumatoid arthritis levels showed a significant negative correlation with age (r = -0.361, p = 0.005), there was no significant correlation with Systemic lupus erythematosus body mass index (BMI), ESR, and CRP levels. In RA, SLE and Behçet's disease, although different inflammatory Behçet’s disease pathways and different cytokine release patterns play a role in their pathogenesis, the similar increase in serum TWEAK levels and the absence of a relationship with the disease activity scores reflecting the last stage of inflammation may indicate that the TWEAK / Fn14 pathway plays a role in earlier stages where the inflammatory pathways have not differentiated yet.
INTRODUCTION The immune system plays a leading role in the pathogenesis of stimulates the release of cytokines such as TNF- α, IL-1, IL-6, rheumatological diseases. Rheumatologic diseases manifest granulocyte-colony stimulating factor (G-CSF), and itself within the framework of a specific inflammatory interferon -γ monocyte chemoattractant protein-1 (MCP-1), response, different cytokine patterns and consequently different macrophage inflammatory protein-1 alpha (MIP-1α), intercel- clinics. Rheumatoid arthritis (RA) and systemic lupus lular adhesion molecule-1 (ICAM-1), vascular cell adhesion erythematosus (SLE) are autoimmune diseases in which molecule -1 (VCAM-1)9, 10. The main source of soluble acquired immune response is essential in their TWEAK in inflammatory tissue is macrophages / monocytes11. pathophysiology. While there is a T-helper-1 type cytokine These data show that the TWEAK / Fn14 pathway makes release pattern in RA, there is a T-helper-2 type cytokine pat- significant contributions to inflammation in tissues and tern in SLE1, 2. On the other hand, Behçet's disease is generally indicates that excessive or persistent upregulation of this accepted as an autoinflammatory disease because the natural pathway contributes significantly to the pathogenesis of some immune response is more prominent in its pathophysiology3. inflammatory diseases such as SLE and RA12-15. Tumor necrosis factor-like weak inducer of apoptosis In this study, it was aimed to investigate and compare (TWEAK) is a member of the TNF ligand family and is first serum TWEAK levels in RA, SLE and Behçet's disease. synthesized as a 249 amino acid transmembrane protein4. Although it was initially defined as an apoptosis stimulant5, it MATERIALS and METHODS was shown in later studies that it participated in many inflam- matory and immunological processes6, 7. TWEAK binds to its Ethical approval only known receptor, fibroblast growth factor-inducible 14 This study protocol was approved by local ethic committee (Fn14)8, and increased TWEAK levels due to inflammation (OMU-KAEK, approval no. 2020-024).
*Corresponding author: Demet Yalcin Kehribar, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.46563
58 Healthy and patient volunteers data. The results were expressed using the mean ± standard Patients with a diagnosis of RA (n = 20), SLE (n = 20), deviation (SD). One-way analysis of variance (ANOVA) fol- Behçet's disease (n = 20) and a healthy control group (n = 19) lowed by Tukey's post hoc test were used to determine the sta- who admitted to our rheumatology outpatient clinic between tistical differences among the groups. The categorical variables May 1-31, 2020 were included in our study. The study protocol were compared with the chi-square test. The Pearson correla- was approved by the local ethics committee. The diagnosis of tion coefficient was used for correlation analysis. Analysis of RA was made according to the 2010 ACR/EULAR RA classifi- covariance (ANCOVA) was also used in order to modify the cation criteria16, the diagnosis of SLE was made using the 2019 variables for age, gender, and BMI. Values of p<0.05 were -EULAR/ACR Classification Criteria for Systemic Lupus Ery- considered statistically significant. thematosus diagnostic criteria17 and the diagnosis of Behçet's disease was made according to the International Criteria for RESULTS Behçet's Disease (ICBD)18. In evaluating disease activities, BD The demographic and laboratory data of the patients and current activity form (BDCAF)19 for Behçet's disease, Disease healthy volunteers included in the study are summarized in Activity Score 28-joint (DAS28)20 for RA and SLE Disease Table 1. The DAS28 was 5.31 ± 1.8 in the RA group, the Activity Index 2000 (SLEDAI-2 K)21 for SLE were used. The SLEDAI was 7.8 ± 6.2 in the SLE group, and the BDCAF gender and age of the patients, medical history, physical exami- score was 4.7 ± 2.9 in the Behçet's disease group. There was a nation findings and laboratory data, additional diseases, and significant difference among all groups in terms of age with the smoking status were recorded. The patients with active infec- ANOVA Test (Table 1). In post-hoc statistical analysis, there tion, a diagnosis of malignancy, chronic lung, kidney or liver was no significant difference in age between the healthy con- disease, and heart failure were excluded from the study. trol group and the Behcet's disease group (p> 0.05), but there was a significant difference in age in all other paired compari- Laboratory analysis sons among the groups (p <0.05). Serums obtained by centrifuging blood samples (Shimadzu There was no significant difference between the pa- UV160A, S.No: 28006648, Japan) at 3000 rpm for 10 minutes tient groups in terms of BMI, hypertension, atherosclerosis, stored at -800C. On the day of analysis, samples were dissolved diabetes mellitus and smoking, although a significant differ- at room temperature. All analysis was done according to the ence was found in terms of gender (Table 1). manufacturer’s instructions. Samples showing high concentra- ESR and CRP levels were higher in all patient groups tion were diluted and measured twice. compared to the healthy control group. While there was no TWEAK concentrations in serum were measured using difference between the patient groups in terms of CRP level in the commercially available TWEAK enzyme linked immuno- paired comparisons, the sedimentation level was higher in the sorbent assay (ELISA) (Human Tumour Necrosis Factor Relat- RA group than in the Behçet's disease group (p=0.045). ed Weak Inducer of Apoptosis, Cat. No. E1820Hu, Bioassay Serum TWEAK levels were significantly higher in all Technology Laboratory, Shangai, China). Enzymatic reactions patient groups compared to the control group (Figure 1). How- were measured in an automatic microplate photometer. ever, no significant difference was found in paired comparisons TWEAK levels were determined by comparing the optical den- among patient groups. When patients with high and low dis- sity of the samples with the standard curve. The mean within- ease activity scores were compared, there was no significant test and within-test percentage coefficients of variation for difference in terms of TWEAK levels. Hypertension, athero- TWEAK were <10% and <8%, respectively. All experiments sclerosis, diabetes mellitus and smoking had no effect on serum were carried out in accordance with the manufacturer's instruc- TWEAK levels. tions. The expected values of the test were 10-4000 mg / L. Although serum TWEAK levels showed a significant negative correlation with age Statistical analysis (r=-0.361, p=0.005) in correlation analysis, there was The Statistical Package for the Social Sciences (SPSS 11.0, no significant correlation with BMI, ESR and CRP levels. Chicago, IL, USA) was used for the statistical analysis of all
59 Table 1. Demographics and laborator y data in the study groups.
Healthy Controls Rheumatoid Arthritis SLE Behcet’s Disease P (n:19) (n:20) (n:20) (n:20) Age (years) 39.5 ± 10.7 54.9 ± 12.5 48.4 ± 14.2 38.7 ± 10.6 <0.001 Gender (F/M) 10/9 14/6 18/2 10/10 0.022 BMI (kg/m2) 25.1±5.1 23.4 ±4.9 24.7±5.2 0.923 Smoking - 5 5 6 0.918 Hypertension - 6 8 3 0.210 Atherosclerosis - 2 2 3 0.851 Diabetes Mellitus - 2 2 2 1.000 ESR (mm/h) 3.38 ± 1.01 46 ± 27.3 35.6 ± 18.3 29.8 ± 17.7 <0.001 CRP (mg/l) 1.42 ± 0.5 19.8 ± 47.1 6.4 ± 7.7 5.6 ± 7.5 0.001 TWEAK (ng/ml) 55 ± 52 1201 ± 872 1187 ± 839 1171 ± 734 <0.001 SLE: Systemic lupus erythematosus, BMI: Body mass index, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, TWEAK: Tumor necrosis factor-like weak inducer of apoptosis
performed in SLE nephritis. On the other hand, Balajkova et ** al.23 investigated the role of TWEAK in neuropsychiatric SLE
) 4000 **
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r e S 0 ANCA-associated vasculitis with active renal involvement and HC RA SLE BD stated that TWEAK was not a specific biomarker for SLE and Figure 1. Serum TWEAK levels in the study gr oups SLE nephritis. In our study, the increase in the serum TWEAK level in all three patient groups supports the view that TWEAK DISCUSSION level is not a specific biomarker for SLE. In this study, the serum TWEAK levels of RA, SLE and There are limited number of studies investigating the Behçet’s disease patients, in which different immune mecha- role of TWEAK in Behçet's disease. Lopalco et al.25 showed nisms play a role in the etiopathogenesis and consequently that serum TWEAK levels were increased compared to healthy present with different clinical findings, were compared with controls in their study published in 2017. They also reported healthy volunteers. Although there are different cytokine that serum TWEAK levels were upregulated both in active and release patterns, previous studies have claimed that the inactive Behçet’s disease patients. On the other hand, Icli et TWEAK pathway also plays a role in the pathophysiology of al.26 found that serum TWEAK level was increased in Behçet's these three diseases. The serum TWEAK levels were disease patients and demonstrated that serum TWEAK level significantly higher in patients with RA, SLE, and Behçet’s correlated with disease activity. In our study, serum TWEAK disease when compared with healthy volunteers. However, levels were increased in Behçet's disease, but were not when these three rheumatic inflammatory diseases were associated with disease activity similar to the study by Lopalco compared with each other, there was no significant difference et al.25 in terms of serum TWEAK levels. In addition, in the patient In studies conducted to investigate the possible role of groups, no significant difference was found in the serum the TWEAK / Fn14 pathway in the physiopathology of RA, it TWEAK levels of the patients with low and high disease was found that TWEAK levels increased in the synovial tissue, activity. The serum TWEAK levels showed a negative synovial fluid and serum of RA patients27. In animal models of correlation only with the age, but not with the ESR and CRP RA, anti-tweak monoclonal antibodies were observed to pro- levels. vide significant reductions in disease inflammation, joint in- El-Shehaby et al.22 found that urinary TWEAK level flammation, angiogenesis, cartilage, and bone loss28. In the was higher in patients with renal involvement compared to Phase I study conducted in RA, it was found that there was a those without renal involvement in a case-control study significant decrease in TWEAK levels and inflammatory
60 markers at the end of the 1st month due to anti-TWEAK Conflict of interest monoclonal antibodies29. In our study, high TWEAK levels in The authors declare that they have no conflict of interest RA patients compared to the healthy control group indicate that the TWEAK / Fn14 pathway plays a role in the inflammation Acknowledgement in RA development. The Author thanks Metin Ozgen and Bahattin Avci for TWEAK is a pluripotent and multifunctional cytokine technical support. that belongs to the TNF superfamily. It has been shown to have active roles in many processes such as cellular proliferation, REFERENCES differentiation, migration, survival, apoptosis, angiogenesis and 1. Ozgen M, Koca SS, Aksoy K, Dagli N, Ustundag B, Isik A. Visfatin inflammation30-32. Apart from RA, SLE, and Behcet's disease, levels and intima-media thicknesses in rheumatic diseases. Clin there are results suggesting that the TWEAK / Fn14 pathway Rheumatol. 2011;30:757-763. plays a role in diseases such as multiple sclerosis and 2. Lit LCW, Wong CK, Li EKM, Tam LS, Lam CWK, Lo YMD. Elevated inflammatory bowel disease33, 34. Although there are different gene expression of Th1/Th2 associated transcription factors is cytokine patterns and different inflammatory pathways in the correlated with disease activity in patients with systemic lupus pathogenesis of each of these diseases, they all have high erythematosus. J Rheumatol. 2007;34:89-96. 3. Eksioglu Demiralp E, Direskeneli H, Kibaroglu A, Yavuz S, Ergun T, TWEAK levels. In our study, while TWEAK levels were found Akoglu T. Neutrophil activation in Behçet's disease. Clin Exp to be significantly higher in patients with RA, SLE and Rheumatol. 2001;19:19-24. Behçet's disease, a significant increase in ESR and CRP levels 4. Roos C, Wicovsky A, Müller N, Salzmann S, Rosenthal T, Kalthoff occurred in patients with active disease compared with those in H, et al. Soluble and transmembrane TNF-like weak inducer of remission whereas there was no significant difference in terms apoptosis differentially activate the classical and noncanonical of TWEAK levels. These results suggest that the TWEAK / NF-kappa B pathway. J Immun 2010;3:1593-1695. Fn14 pathway may be involved in a more common and 5. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, preliminary stage in which inflammatory cascades have not et al. TWEAK, a new secreted ligand in the tumor necrosis factor differentiated from each other yet. family that weakly induces apoptosis. J Biol Chem. The main limitations of this study are its 1997;272:32401 -32410. cross-sectional design and small sample size. Failure to find a 6. Xia Y, Herlitz LC, Gindea S, Wen J , Pawar RD, Misharin A, et al. relationship between TWEAK levels and disease activities in Deficiency of fibroblast growth factor-inducible 14 (Fn14) patient groups may be due to the small number of patient preserves the filtration barrier and ameliorates lupus nephritis. J groups. Also, investigating for other inflammatory cytokines Am Soc Nephrol. 2015;5:1053-1070. together would be good to demonstrate their association with 7. Xia WY, Stock A, Michaelson JS, Burkly LC, Gulinello M, different cytokine release patterns. Moreover, we believe that it Putterman C, et al. Neuropsychiatric disease in murine lupus is is also important to measure and compare TWEAK levels in dependent on the TWEAK/Fn14 pathway. J Autoimmun. these rheumatic inflammatory diseases known to have different 2013;43:44-54. cytokine release patterns. 8. Winkles JA. The TWEAK-Fn14 cytokine-receptor axis: discovery, In conclusion, the increase in serum TWEAK levels biology and therapeutic targeting. Nat Rev Drug Discov. in RA, SLE and Behçet's disease, which are rheumatic 2008;7:411-425. inflammatory diseases, suggests that it plays a role in the 9. Zimmermann M, Koreck A, Meyer N, Basinski T, Meiler F, Simone B, et al. TNF-like weak inducer of apoptosis (TWEAK) and pathophysiology of these diseases. The similar increase in TNF-α cooperate in the induction of keratinocyte TWEAK levels in these diseases of different nature and the apoptosis. J Allergy Clin Immunol. 2011; 1: 200-207. absence of a relationship with CRP and disease activity 10. Burkly LC, Michaelson JS, Hahm K, Jakubowski A, Zheng TS. indexes, which mostly suggests the last stages of inflammation, TWEAKing tissue remodeling by a multifunctional cytokine: role indicate that the TWEAK/Fn14 pathway plays a role in earlier of TWEAK/Fn14 pathway in health and disease. Cytokine. stages where the inflammatory pathways have not 2007;40:1-16. differentiated yet. ……………………………………………………………………………..
61 11. Madrigal-Matute J, Fernandez-Laso V, Sastre C, Llamas-Granda monocyte chemoattractant protein-1 (MCP-1), and IL-8 with P, Egido J, Ventura MJL, et al. TWEAK/Fn14 interaction promotes lupus nephritis. J Clin Immunol. 2011;31:848-856. oxidative stress through NADPH oxidase activation in macro- 23. V Balajkova 1, M Olejarova, R Moravcova, P Kozelek, M phages. Cardiovasc Res. 2015;1:139-147. Posmurova, H Hulejova, L Senolt. Is serum TWEAK a useful 12. Wisniacki N, Amaravadi L, Galluppi GR, Zheng TS, Zhang R, Kong biomarker of neuropsychiatric systemic lupus erythematosus? J, Burkly LC. Safety, tolerability, pharmacokinetics, and Physiol Res. 2020;69:339-346. pharmacodynamics of anti-TWEAK monoclonal antibody in pa- 24. Mirioglu S, Cinar S, Yazici H, Ozluk Y, Kilicaslan I, A Gul, et al. tients with rheumatoid arthritis. Clin Ther. 2013;35:1137-1149. Serum and urine TNF-like weak inducer of apoptosis, monocyte 13. Sun F, Teng J, Yu P, Li W, Chang J, Xu H. Involvement chemoattractant protein-1 and neutrophil gelatinase-associated of TWEAK and the NF-κB signaling pathway in lupus nephritis. lipocalin as biomarkers of disease activity in patients with Exp Ther Med. 2018;15:2611-2619. systemic lupus erythematosus. Lupus. 2020;29:379-388. 14. Panezai J, Ali A, Ghaffar A, Benchimol D, Altamash M, Klinge B, et 25. Lopalco G, Lucherini OM, Lopalco A, Venerito V, Fabiani C, al. Upregulation of circulating inflammatory biomarkers under Frediani B, et al. Cytokine Signatures in Mucocutaneous and the influence of periodontal disease in rheumatoid arthritis Ocular Behçet's Disease. Front Immunol. 2017;8:200. patients. Cytokine 2020;131:155117. 26. Icli A, Cure MC, Cure E, Arslan S, Unal M, Sakiz D, et al. Soluble 15. Chen J, Jia F, Ren K, Luo M, Min X, Wang P, et al. Inhibition of Tumor Necrosis Factor (TNF)-Like Weak Inducer of Apoptosis suppressor of cytokine signaling 1 mediates the profibrotic effect (Tweak) Independently Predicts Subclinical Atherosclerosis of TWEAK/Fn14 signaling on kidney cells. Cell Signal in Behcet's Disease. Acta Medica (Hradec Kralove) 2018;61:86- 2020;71:109615. 92. 16. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 27. Van Kuijk AW, Wijbrandts CA, Vinkenoog M , Zheng TS, CO, et al. 2010 Rheumatoid arthritis classification criteria: an Reedquist KA, Tak PP. TWEAK and its receptor Fn14 in the American College of Rheumatology/European League Against synovium of patients with rheumatoid arthritis compared to Rheumatism collaborative initiative. Arthritis Rheum. psoriatic arthritis and its response to TNF blockade. Ann Rheum 2010;62:2569-2581. Dis. 2009;69:301-4. 17. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, 28. Kamata K, Kmaijo S, Nakajima A, Koyanagi A, Kurosawa H, Yagita Ramsey-Goldman R, et al. 2019 European League Against H, et al. Involvementof TNF-like WEAK inducer of apoptosis in Rheumatism/American College of Rheumatology Classification thepathogenesisof collagen-inducedarthritis. J Immunol. Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. 2006;177:6433-6439. 2019;71:1400-1412. 29. Nicolas Wisniacki 1, Lakshmi Amaravadi, Gerald R Galluppi, 18. International Study Group for Behcet’s Disease. Disease ISGfBs. Timothy S Zheng, Ray Zhang, Jessica Kong, Linda C Burkly. Criteria for diagnosis of Behcet’s disease. Lancet. 1990; 335:1078 Safety, tolerability, pharmacokinetics, and pharmacodynamics -1080. of anti-TWEAK monoclonal antibody in patients with 19. Lawton G, Bhakta BB, Chamberlain MA, Tennant A. The Behcet’s rheumatoid arthritis. Clin Ther .2013;35:1137-1149. disease activity index. Rheumatology (Oxford). 2004;43:73-78. 30. Choe JY, Kim SK. Serum TWEAK as a biomarker for disease 20. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de activity of systemic lupus erythematosus. Inflamm Res. 2016; Putte LB, van Riel PL. Modified disease activity scores that 65: 479-88. include twenty-eight-joint counts. Development and validation 31. Reyes-Martinez F, Pérez-Navarro M, Rodriguez-Matias in a prospective longitudinal study of patients with rheumatoid A, Virgilia Soto-Abraham V, Gutierrez-Reyes G, Medina-Avila Z, arthritis. Arthritis Rheumol 1995;38:44–48. et al. Assessment of urinary TWEAK levels in Mexican patients 21. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus with untreated lupus nephritis: an exploratory study. erythematosus disease activity index 2000. J Rheumatol. Nefrologia. 2018; 38:152-160. 2002;29:288–291. 32. Schwartz N, Michaelson JS, Putterman C. Lipocalin-2, TWEAK, 22. El-Shehaby A, Darweesh H, El-Khatib M, Momtaz M, Marzouk S, and other cytokines as urinary biomarkers for lupus nephritis. El-Shaarawy N, et al. Correlations of urinary biomarkers, TNF-like Ann N Y Acad Sci. 2007;1109:265-274. weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), ……………………………………………….
62 33. Grimstad T, Skoie IM, Doerner J, Isaksen K, Karlsen L, Aabakken L, et al. TWEAK is not elevated in patients with newly diagnosed inflammatory bowel disease. J Gastroenterol. 2017;52:420-4. 34. Maarouf A, Stephan D, Ranjeva MP, Ranjeva JP, Pelletier J, Audoin B, et al. High levels of serum soluble TWEAK are associated with neuroinflammation during multiple sclerosis. J Transl Med. 2019;17:51.
63 Int J Acad Med Pharm, 2021; 3 (1); 64-69
International of Academic Medicine and Pharmacy
Neuroimaging Manifestations of Behcet’s Disease: A Retrospective Study from the Eastern Mediterranean Region of Turkey**
Gülen Burakgazi ˡ* , Fatma Duman 2
1 Recep Tayyip Erdoğan University, Faculty of Medicine, Department of Radiology, Rize, Turkey 2 Hatay Mustafa Kemal University, Faculty of Medicine, Department of Anatomy, Hatay, Turkey . ORCID; 0000-0003-4913-4838, 0000-0001-5747-9989
Article info Research article
Received :22.08.2020 Abstract; In this article, we aimed to emphasize the importance of neuroimaging together with neurological Received in revised form :07.11.2020 examination in the early diagnosis and treatment of cerebrovascular pathologies in Behçet's disease (BD), in terms of Accepted :02.11.2020 diagnosis, differential diagnosis and prevention of complications. A retrospective evaluation was made of cases diagnosed Available online :05.01.2021 with BD disease who presented at our hospital with neurological findings between 2010 and 2017. Multi-slice computed tomography and magnetic resonance images obtained from these patients were retrospectively evaluated. Retrospective evaluation was made of a total of 121 patients (63 males, 58 females) with neurological symptoms who underwent Keywords neuroimaging. The most common symptom was headache and the most common finding (89%) determined was in the brain parenchyma. Of the vascular origin pathologies, thrombus in the superior sagittal sinus was most often determined Headache (15%). Early diagnosis of neurological findings in BD is important in respect of preventing cerebrovascular complications. Neuro-Behçet’s disease Magnetic resonance imaging
INTRODUCTION addition to clinical findings plays an important role in both Behçet’s disease (BD) is a systemic disease characterized by diagnosis and in the evaluation of complications 6. recurrent oral and genital ulcers, uveitis, arthritis, arterial Neuroimaging is typically applied for headache that is aneurysms, venous thrombosis, skin lesions and suggestive of intercranial (intracranial?)pathology. Previous gastrointestinal lesions. In this chronic vasculitis disease, the studies have shown that imaging of headache in the absence of etiology of which is not known, neurological symptoms are neurological symptoms in BD or atypical characteristics does seen in 4%-49% of patients. These can include, meningitis, not reveal a visible abnormality. The widely accepted view for meningoencephalitis, cranial nerve paralysis, and psychiatric neuroimaging in cases with headache, is that of red flag symptoms 1,2. symptoms and findings, the presence of focal neurological Neurological involvement is seen in approximately findings despite appropriate treatment, and sudden onset and 11% of BD patients and this involvement is one of the most progressive neurological findings during the course of systemic destructive findings of BD 3. BD may emerge first with disease 7. neurological symptoms and findings. The first finding of Neuro The aim of this study is to present the neuroimaging -Behçet’s disease (NBD) in BD patients is usually headache of findings of BD patients with neurological symptoms in the a benign nature. Although headache types have been defined light of the literature. for NBD, careful neurological examination must be made of BD patients with headache and neuroimaging should be MATERIALS and METHODS applied. In the differential diagnosis of NBD, intracranial tumor, aseptic meningitis and multiple sclerosis should be Ethical approval considered. This condition in BD can mask the potentially fatal Approval was obtained from the relevant university clinical complication of NBD findings 4,5. In most cases, diagnosis with research ethics committee (Ethics No: 2018/156). The study clinical examination alone is difficult. Neuroimaging in was also carried out in accordance with the Helsinki
*Corresponding author: Gülen Burakgazi, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.47105 ** The manuscript has been oral presented in 26th international symposium on morphological sciences, 05/07/2018, Prag. 64
Declaration of Principles. 5.78% on MRA, 40.50% on MRV, 13.22% on diffusion MRI and 4.96% on MSCT. The presence of pathology was Patients and study design determined most on conventional brain MRI. The most A retrospective evaluation was made of 121 patients (63 males, common finding on MRI was non-specific ischemic focus in 58 females), with neuroimaging and without systemic disease 71.90% (Figure 1). On the MRV examination, sinus thrombus from 197 patients, diagnosed with BD who presented at our (Figure 2) and hypoplasia were determined. In the transverse hospital with neurological symptoms between 2010 and 2017. sinus of one patient, widespread collaterals were observed to Cases diagnosed by a senior neurologist or internal medicine have developed secondary to chronic thrombus (Figure 3). physician were selected from the archive. Since it is a Table 2. Classification of MRI findings according to location retrospective study, there is no information about their N % treatment. Parenchymal finding 37 30.6 The multi-slice computed tomography (MSCT) and Vascular finding 10 8.3 magnetic resonance images (MRI) acquired from these patients Parenchymal and vascular finding 9 7.4 Normal 63 52.1 were evaluated retrospectively. The MSCT images were No conventional MRI 2 1.7 obtained using a 64-detector Toshiba device, and the MRI using a 1,5 Tesla Philips Achieva device. The images were TOTAL 121 100.0 evaluated on a workstation by a specialist radiologist. The brain arterial and venous vascular structures were evaluated on 3-dimensional reformatted images obtained from MR angiography (MRA) and MR venography (MRV).
RESULTS Retrospective evaluation was made of 121 patients comprising 63 (52.1%) males and 58 (47.9%) females with a mean age of 36±1.17 years (range, 18-77 years). When the clinical symptoms were examined, 89.26% of patients were seen to have presented at hospital with complaints of headache (Table 1). Other symptoms were neck pain, dizziness, fainting, loss of balance and speech impairment. Figure 1. Axial FLAIR sequence; there are hyperintense non-specific foci in the bilateral periventricular area
Table 1. Associated clinical symptoms
N % Headache 108 89.26 Neck pain 3 2.48 Dizziness 25 20.66 Position dizziness 1 0.83 Fainting 1 0.83 Loss of balance 2 1.65 Speech disorder 2 1.65 On the brain MRI, parenchymal involvement was observed in 30.6% of cases, vascular involvement in 8.3%, and both vascular and parenchymal involvement in 7.4% (Table 2). The brain MRI, MRA, MRV, diffusion MRI and MSCT findings of all the patients were examined in detail (Table 3).
From the findings observed on the images obtained from the Figure 2. In the patient with Behçet's disease, the absence of flow indi- cases, pathology was determined at the rate of 56.20% on MRI, cating the presence of thrombus in the left transverse sinus is observed in MRV images.
65 Table 3. Findings of different imaging methods of the cases.
MRI MRA MRV DİF-MRI MDCT
N % N % N % N % N %
Normal 68 56.20 7 5.78 49 40.50 16 13.22 6 4.96 Intensity increase in brainstem and cerebellum 1 0.83 ------Nonspesific focus 87 71.90 - - - - - 1 0.83 Atrophy Cerebral 8 6.61 ------3 2.49 Cerebellar 1 0.83 ------Brainstem 2 1.65 - - - - - Diffuse 1 0.83 ------Thalamus 2 1.65 ------Capsula interna infarction ------1 0.83 Thrombus Transverse sinus - - - - 15 12.40 - - - -
Sigmoid sinus 1 0.83 ------Hypoplasia (Transverse sinus) - - - - 4 3. 31 - - - -
and laboratory findings of the cases. In addition, there were findings such as collateral circulation developing secondary to thrombus and presence of reanalyzed flow in the control MRV examinations of the cases. When the formation of thrombus or findings of parenchymal or vascular involvement were examined, no statistically significant difference was determined between the genders (p>0.05) (Table 5).
Table 4. Location of nonspecific ischemic foci in MRI examination
Bilateral Unilateral Left Right N % N % N % Frontal 2 2.30 2 2.30 - - Figure 3. In patients with Behçet's disease, absence of current in the Parietal - - 1 1.15 - - bilateral transverse sinus secondary to chronic thrombosis and widespread Occipital - - 2 2.30 - - collateral flow are observed in MRV images. Periventricular 24 27.59 2 2.30 1 1.15 Sentrum semiovale 15 17.24 Brainstem 1 1.15 On the brain MRI analysis, non-specific ischemic Subkortical white matter 1 1.15 TOTAL 79 90.81 7 8.05 1 1.15 focus were seen most at the rate of 27.59% with periventricular localization (Table 4). In the MSCT taken first because of Table 5. Gender distribution of findings neurological symptoms in one case, other than chronic Female Male N % N % X2 P ischemic changes, no pathological finding was determined Thrombus 6 10.3 10 15.9 0.804 0.370 radiologically. Parenchymal involvement 14 24.1 23 36.5 2.305 0.129 Vasculer involvement 4 6.9 6 9.5 0.307 0.580 In 10 (8.26%) patients, pathology was determined on
conventional brain MRI, and the MRV examinations of the same patients were observed to be normal. In 12 (9.92%) DISCUSSION The most important findings of this study were; parenchymal patients, pathology was determined on MRV, and the involvement was observed in the majority of cases, cerebral conventional MRI examinations were evaluated as normal. atrophy observed more common, non-specific foci were seen While diagnosing of cerebral venous thrombosis (CVT), we high percentage and specially in the periventricular area, the evaluated MRV with conventional MRI examinations, clinical
66 most widespread symptom was headache, thrombus mostly parenchymal brain lesions 12. In the MSCT evaluations of the seen in transverse sinus and there was no significant difference current study cases, capsule interna infarct was observed in one in findings between gender (p>0.05). patient and cerebral atrophy in eight. Although cerebral atrophy Neuro-Behçet’s disease (NBD) generally emerges in could be a finding of chronic BD and it is known that it could two forms as parenchymal or non-parenchymal (vascular) accompany several neurological diseases, it is a non-diagnostic involvement. There may also be a mixed type of parenchymal finding. In 6.6% of the current study patients, findings and non-parenchymal involvement together 8. Although consistent with atrophy were observed, usually in the cerebrum. parenchymal involvement was observed in the majority of the The average age of the patients with atrophy was 51.7 year (the current study patients, there were also recorded cases of range of 27-77 year). In the youngest case, cerebral, cerebellar vascular and mixed-type involvement. Parenchymal disease and brainstem atrophy was observed. All cases were in the primarily affects the brain stem, cerebral hemisphere and the chronic stage and in some of them, there was concomitant spinal cord 9. atrophy in the cerebellum and brain stem 13,14. The most common form of NBD (80%) is an Brain MRI is the most frequently used imaging inflammatory perivasculitis in the form of subacute method in patients with suspected NBD. In the acute disease meningoencephalitis usually involving the brain stem. course, lesions are seen in the basal ganglion or the brain stem, Involvement in this form is typically in the unilateral thalamus extending to the diencephalic structures, and in some, an and basal ganglions. Thalamus involvement was determined in increase in central contrast is seen with the mass effect. MRI 2 cases in the current study, which was consistent with findings T2-weighted and FLAIR (fluid-attenuated inversion recovery) in literature of parenchymal involvement (Figure 4). sequences are used for the determination of ischemic or gliotic changes and ischemic white matter lesions. On T2-weighted images, the MRI findings are usually high signals from areas of the cerebral central structures with scattered localization affecting the cerebral peduncle and pons 10,13,14. In the MRI examinations of the current cases, non-specific foci were generally seen. These were most often in the periventricular area and were observed bilaterally at a high rate. Hyperintense foci can be seen at a high rate in T2A in MRI examination in the normal population 15. Therefore, this finding in present study cannot be associated primarily with Neuro-Behçet disease. In the diffusion MRI and MRA examinations obtained from the cases with acute neurological findings, no Figure 4. A patient with Behçet's disease has a hyperintense pathological findings were determined. In cases with appearance in the axial T2W sequence secondary to involvement in the right thalamus. neurological findings on diffusion MRI and MRA, advanced Recent studies have shown that there is inflammatory cellular imaging methods should be applied. infiltration around the peripheral small venules and arterioles of Although no consensus has been reached on NBD, parenchymal lesions in NBD, and the consequent diagnosis is generally made from the presence of lesions con- demyelinisation leads to edema 10,11. In vascular involvement, sistent with neuroimaging in BD patients with neurological cerebral venous thrombus is often seen (20%), and thrombus symptoms or headache. A relationship has been found between can cause increased intracranial pressure. In the current study, NBD and the frequently seen symptom of headache in 10%- although pathological findings of the parenchyma were 15% of BD patients, and even if there is no central nervous determined most, there were also vascular findings at a system involvement, it has been emphasized in literature that noteworthy rate. headache can be seen as a widespread symptom 8,14,16-18. In the MSCT has been reported to be non-diagnostic in majority of the current study patients (89%), headache was
67 seen to be the first symptom on presentation at the polyclinic. BD, and when the severity of headache increases, NBD should Headache is important in parenchymal involvement and in be considered without examination for the presence of vascular involvement. The most typical feature of headache in neurological findings, and neuroimaging should be performed. our cases is sudden onset, and was not in a typical localization. Neuroimaging is extremely important in diagnosis, differential Headache has been reported to be the most common diagnosis, early initiation of treatment, and in the prevention of and the most important symptom in 80% of cases with cerebral complications. As NBD can be seen secondary to parenchymal venous thrombosis. Generally in BD, it is the first, and and/or vascular involvement, advanced imaging methods and sometimes the only finding, which is severe, general, and MRV should be added to conventional MRI. progressive and increases with the Valsalva maneuver. Furthermore, in 2% of patients with venous thrombosis an Conflict of interest association has been found with NBD 19,20. In the current study, No conflict of interest was declared by the authors. it was noticeable that headache was the most frequent symptom in the cases determined with cerebral venous thrombosis. In Financial disclosure addition to headache, other complaints of the cases were The authors declared that this study hasn’t received no recorded as neck pain, dizziness, fainting, loss of balance and financial support. speech impairments. CVT may be seen at the rate of 3.6% in BD and it may REFERENCES be the first finding before diagnosis or it may emerge in the 1. Hegde AN, Mohan S, Lath N et-al. Differential diagnosis for course of the disease. CVT is seen in the superior sagittal bilateral abnormalities of the basal ganglia and thalamus. sinus, transverse sinus, sigmoid sinus and the straight sinus Radiographics. 2011; 31(1):5-30. 8,21,22 . In the present study, CVT was seen most often in the 2. Tunc R, Saip S, Siva A: Cerebral venous thrombosis is associated transverse sinus and thrombus was observed in the sigmoid with major vessel disease in Behcet’s syndrome. Ann Rheum Dis. sinus in only one patient. 2004; 63:1693-1694. In neuroimaging using MRI and MRV together, dural 3. Davatchi F, Chams-Davatchi C, Shams H et al. Adult Behcet's sinus thrombosis and parenchymal lesions can be easily disease in Iran: Analysis of 6075 patients, Int. J. Rheum Dis. determined 23,24. When the MRI and MRV tests were evaluated, 2016; 19(1):95-103. the findings were determined to show a difference. In cases 4. Topcuoglu OM, Topcuoglu ED, Altay CM, Genc S. Imaging pearls determined with pathological signal intensity increase at the of pediatric Behçet's disease. Eur J Radiol. 2017; 94:115-124. rate of 8.26% on MRI, the MRV examination was normal, and 5. Fountain EM, Dhurandhar A. Neuro-Behçet's disease: an unusual in cases with pathological change determined on MRV at 9.6%, cause of headache. J Gen Intern Med. 2014; 29(6):956-960. the MRI tests were normal. Therefore, for NBD diagnosis in 6. Mehdipoor G, Davatchi F, Ghoreishian H, Arjmand Shabestari A. BD patients, MRI and MRV must be evaluated together. This Imaging manifestations of Behcet's disease: Key considerations and major features. Eur J Radiol. 2018; 98:214-225. evaluation can be considered useful for both early diagnosis 7. Tsushima Y, Endo K. MR Imaging in the evaluation of chronic or and differential diagnosis. recurrent headache. Radiology. 2005; 235(2):575–579.
8. Al-Araji A, Kidd DP. Neuro-Behçet’s disease: epidemiology, CONCLUSION clinical characteristics, and management. Lancet Neurol. 2009; 8 In BD, the symptom of headache is an important symptom (2):192–204. showing intracranial pathologies. Several studies have shown 9. Kabukcu T, Edemci S, Ucan H, Celik C, Gunes HN, Yoldas T, Whole that in the absence of neurological symptoms or atypical thoracal spinal cord involvement in case of neuro-Behcet's clinical characteristics, imaging methods in cases with disease. Rheumatol. Int. 2009; 29(6):707–709. headache have revealed findings of the rarely seen 10. Akman -Demir G, Serdaroglu P, Tasçi B. Clinical patterns of Neuro-Behçet’s disease. Therefore, in BD cases with headache neurological involvement in Behçet’s disease: evaluation of 200 and no accompanying neurological symptoms, neuroimaging patients. Brain. 1999;122(11):2171–2182. should be performed. When there is new onset of headache in ………………………………...
68 11. Haghighi AB, Sharifzad HR, Matin S, Rezaee S. The 19. Ferro J.M, Canhao P. Cerebral venous sinus thrombosis: update pathologicalpresentations of neuro-Behcet disease: a case on diagnosis and management, Curr. Cardiol. Rep. 2014; 16 report and reviewof the literature. Neurologist. 2007;13:209- (9):523. 214. 20. Souirti Z, Messouak O, Belahsen F. Cerebral venous thrombosis: 12. Banna M, El-Ramahl K. Neurologic involvement in Behcet a Moroccan retrospective study of 30 cases. Pan Afr Med J. disease: imaging findings in 16 patients, AJNR Am. J. Neurora- 2014;14;17:281. diol. 1991; 12 (4):791–796. 21. Rottenstreıch A, Machol K, Eısensteın EM et al. Behçet’s disease 13. Abdel Razek AA, Alvarez H, Bagg S, Refaat S, Castillo M. Imaging and cerebral sinus vein thrombosis in children: a case study and spectrum of CNS vasculitis. Radiographics. 2014; 34(4):873-894. review of the literature. Clin Exp Rheumatol. 2015;33 (Suppl. 14. Al Kawi MZ, Bohlega S, Banna M. MRI findings in neuro-Behcet's 94): S163-8. disease. Neurology. 1991; 41(3):405–408. 22. Aguiar de Sousa D, Mestre T, Ferro J.M. Cerebral venous 15. Figatowska MB. T2-hyperintense Foci on Brain MR Imaging. thrombosis in Behcet's disease: a systematic review, J. Neurol. Med Sci Monit. 2004 ;10 Suppl 3:80-87. 2011; 258(5): 719–727. 16. Siva A, Kantarci OH, Saip S, et al. Behçet’s disease: diagnostic 23. Bonneville F. Imaging of cerebral venous thrombosis, Diagn. and prognostic aspects of neurological involvement. J Neurol. Interv. Imaging. 2014; 95(12):1145–1150. 2001; 248(2):95–103. 24. Kocer N, Islak C, Siva A et al. CNS involvement in neuro-Behçet 17. Farahangiz S, Sarhadi S, Safari A, Borhani-Haghighi A. Magnetic syndrome: an MR study. AJNR Am J Neuroradiol. 1999; 20:1015- resonance imaging findings and outcome of neuro-Behçet's 24. disease: the predictive factors. Int J Rheum Dis. 2012;15(6): e142 -149. 18. Ndıaye M, Sow AS, Valıollah A et al.: Behçet’s disease in black skin. A retrospective study of 50 cases in Dakar. J Dermatol Case Rep. 2015; 9:98-102.
69 Int J Acad Med Pharm, 2021; 3 (1); 70-75
International of Academic Medicine and Pharmacy
Evaluation of the Relationship Between Epicardial Fat Tissue Area and Coronary Atherosclerosis
İnan Korkmaz 1*, Ali Balcı 2, Sinem Karazincir 3, Hanifi Bayaroğulları 4
1,3,4 Hatay Mustafa Kemal University, Faculty of Medicine, Department of Radiology, Hatay, Turkey 2 9 Eylül University, Faculty of Medicine, Department of Radiology, Izmir, Turkey . ORCID; 0000-0001-6820-8199, 0000-0002-5781-2910, 0000-0003-3269-0483, 0000-0001-6147-5876
Article info Research article
Received :02.09.2020 Abstract; In our study, it was aimed to investigating the correlation between the quantity of epicardial adipose tissue Received in revised form :26.11.2020 with the development of coronary atherosclerosis and coronary artery disease. In this retrospective research we used Accepted :02.11.2020 Cardiac CT Angiography images of 40 patients (age range 23-80, 30 males, 10 females). The area of epicardial adipose Available online :05.01.2021 tissue and total calcium score values were measured. All the patients were examined for obstructive coronary artery disease. Epicardial adipose tissue areas were measured in the level of the left main coronary artery. The data obtained were analyzed with SPSS program. 13 patients were found positive for Ca score and coronary stenosis was dedected in 18 patients. There is independent correlation between the area of epicardial adipose tissue and; age and total calcium score Keywords (age: p=0.003, total calcium score: p=0.020). Based on results and statiscal analysis, the area of epicardial adipose tissue was found statistically significant among the patients, who have positive Ca score (p=0.017) and coronary artery stenosis Epicardial fat area (p=0.019). As result, based on the outcomes of this study, it can be concluded that the increase of epicardial adipose tissue Coronary artery disease has significant impact on occurence of coronary artery stenosis and calcific-atherosclerotic changes. Also, for the Coroner Ca score calculation of epicardial adipose tissue quantity, the measurement of cross section area from left main coronary artery Cardiac CT angiography surface is a good alternative to have an easiness of measurement as well as total volume of epicardial adipose tissue.
INTRODUCTION layers of large and medium-sized muscular arteries of varying Cardiovascular diseases play an increasingly important role size from the aorta to the epicardial coronary arteries 8. In worldwide as the major cause of mortality and morbidity. human anatomy, epicardial adipose tissue is observed more Studies conducted before the 2000s show that the mortality rate prominently in different parts of the heart. Most watched places from cardiovascular diseases worldwide will increase from are; the right ventricular free wall, the left ventricular free wall, 28.9% to 36.3% between 1990 and 2020 1. In recent studies, it the periphery of the atria and adventitia of the coronary artery has been reported that the absolute number of deaths related to branches. cardiovascular disease (CVD) increased globally and in most During embryogenesis, epicardial and intraabdominal regions between 1990 and 2017. In the same period, the adipose tissues develop from brown adipose tissue 9. The fully absolute number of CVD deaths among males rose from 5.9 differentiated white adipose tissue is found in the million to 9.3 million (54% increase) and from 6 million to 8.4 interventricular and atrioventricular grooves in the adult heart million (40% increase) for women 2. and it extends to the apex. As the epicardial adipose tissue Coronary artery calcification, which is one of the increases, it fills the space between the ventricles and covers known factors of coronary atherosclerosis, arises as a result of the entire epicardial surface. A small amount of adipose tissue severe inflammation and proliferative changes in the vascular extends from the epicardial surface to the myocardium by wall 3-6. following the adventitia of the coronary artery branches. In Atherosclerosis is a disease that can be stopped or summary, there appears to be a functional and anatomical regressed if its causes are identified and treated, and affects not relationship between the fat and muscle content of the heart 10. only coronary vessels but all arterial structures 7. It is a chronic Atherosclerotic intimal lesions were observed more in inflammatory disease with a fibroproliferative character that the parts of the coronary arteries covered with epicardial primarily involves the intima and then the media and adventitia adipose tissue compared to the parts surrounded by the
*Corresponding author: İnan Korkmaz, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.47303
70 myocardium11. Epicardial adipose tissue was measured thicker Cardiac CT Angiography examination: Cardiac in patients with coronary artery disease and with unstable CT Angiography examinations of all patients were performed angina pectoris than in patients without coronary artery disease on the Toshiba Aquilion 64-slice CT device in our hospital and in patients with stable angina pectoris 12. (120 kV, 500 mA, 1000 mAs, 400 ms rotation time). CT Today, it is accepted that adipose tissue, which is seen angiography was performed in patients with a heart rate as an energy store, is an important endocrine organ of the body. between 60 and 70. 70-90 ml 400mg iodine / ml contrast agent Adipose tissue has biological activities related to energy was administered to the patients intravenously. ECG correlated metabolism, neuroendocrine function and immune functions. tube flow model was used for image creation and images were Both the deficiency and the excess of adipose tissue have reconstructed at the level of 75% of the cardiac cycle in the important metabolic and endocrinological consequences. mid-diastolic phase. In this study, we aimed to investigate the relationship The obtained images were transferred to the between the amount of epicardial adipose tissue and coronary multi-slice CT device's workstation and then examined by an calcium score value and the development of obstructive experienced radiologist in 3 dimensions with curved referance coronary artery disease in 40 patients who are in our archive and MIP formats on the cross-sectional images. Patients with and underwent Cardiac Computed Tomography (CT) coronary calcium plaques were examined in terms of whether Angiography. calcium plaques caused stenosis in the lumen together with the assessment of the calcium score. All patients were examined in MATERIALS and METHODS MIP and curved reference imaging formats for non-calcific (soft) plaque that could cause filling defect (stenosis) in the Etical approval lumen. The data in this study was obtained retrospectively from the Epicardial fat measurement: Epicardial fat is hospital automation system and because of that no ethical located between the myocardium and the visceral leaf of the approval was taken. pericardium. For the measurement of epicardial fat, were used images with 3 mm slice thickness which used for calcium score Patients measurement. Fat measurements were made at the level of the The study protocol conforms to the ethical guidelines of the origin of the left main coronary artery from a single-slice view 1975 Declaration of Helsinki as reflected in a prior approval by on the CT device console. Density threshold value was taken as the institution's human research committee. In our study, a total (-30) - (-230) for fat voxel calculation.The amount of fat was of 40 patients who underwent cardiac CT Angiography at the calculated in mm² of area in the threshold density range Radiology Clinic of Mustafa Kemal University from May 2009 (Figure 2). to September 2011 were evaluated. Of the 40 patients included in the study, 10 were female, and 30 were male. Statistical analysis Continuous variables were given as mean ± standard deviation Imaging methods (SD) and Categorical variables as %. Whether the data showed Coronary calcium scoring: Coronary calcium (Ca) scoring normal distribution was evaluated with the test was performed on Toshiba Aquilon 64-slice CT device Kolmogorov-Smirnov test. Total calcium score did not show (120 kV, 300 mA, 75 mAs, 250 ms rotation time). Images were normal distribution (p <0.05). Other variables (epicardial fatty created at a slice thickness of 3 mm and were evaluated after area, age, gender and presence of stenosis) showed normal transfer to the workstation. The Agatston Scoring Method was distribution (p> 0.05). Subgroup analysis was performed used for calcium scoring (Figure 1). After the coronary arteries using Student's t test according to calcium score positivity and of all patients were examined one by one at the workstation, the presence of stenosis. Independent relationship between existing calcium plaques were marked using the software epicardial fatty area and other variables was evaluated by program and the total calcium scores were calculated. multiple linear regression test (Stepwise model).
71 area in pa-
A B Figure 1. A and B, Cor onar y calcium scoring, the agatson scoring method. Figure 2. Epicardial adipose tissue measurement.
RESULTS tients with positive Ca scores was statistically significantly Data of a total of 40 patients were used in the study. There higher (p = 0.017) than those without Ca score positivity were 30 male and 10 female in the group. The average age of (Figure 3). the cases was 49.52 ± 13.4 years; the age range was 23-80 The mean epicardial adipose tissue area was 1171mm² years. 595.79 ±in 22 patients (55%) without coronary artery stenosis, In the study, positivity of Ca score, total Ca score, and 1781mm² ± 965.81 in 18 patients (45%) with coronary amount of epicardial fat from the left main coronary artery artery stenosis. Epicardial adipose tissue area of patients with level and presence of stenotic coronary artery disease were coronary artery stenosis was found to be statistically examined. significantly higher (p = 0.019) than those without coronary Ca score positivity was detected in 13 patients artery stenosis (Figure 4). (32.5%). The mean calcium score these patients were found to In multiple regression analysis, an independent rela- be 341.92 ±.524.06 tionship was found between epicardial adipose tissue area and Stenosis was detected in 18 patients (45%). The age and total calcium score (age: p = 0.003, total Ca score: p = number of vessels with stenosis left main coronary (LM) 0.020). artery, left anterior descending (LAD) artery, circumflex (Cx) Table 1. Epicardial adipose tissue area of patients artery, right coronary artery (RCA) was examined. Stenotic Patients N Mean SD P changes were observed in 1 vessel in 13 patients, in 2 vessels in Ca score 3 patients; and in 3 vessels in 2 patients. negative 27 (67,5%) 1173 mm2 526,27 2 The mean epicardial adipose tissue (EAT) area was pozitive 13 (32,5%) 2012 mm 1064,79 0,017 Stenosis found 1173mm² 526.27 ±in 27 patients (67.5%) without Ca negative 22 (55%) 1171 mm2 595,79 score positivity and 2012mm² 1064.79 ±in 13 patients (32.5%) pozitive 18 (45%) 1781 mm2 965,81 0,019 with positive Ca scores (Table 1). Epicardial adipose tissue
A B
Figure 3. A, Multiple calcium plaques in LAD. B, Increased epicardial adipose tissue area of the same patient.
72
A B
C D
Figure 4. Patient with cor onar y ar tery stenosis and calcium score positivity. A, Calcific plaque formation causing lu-
men stenosis in LAD, B. Calcific plaque in Cx that does not cause significant stenosis in the lumen, C. Calcific plaque for- mation on LAD is seen in 3D image of the same patient, D. High amount of epicardial fat in the same patient.
DISCUSSION alters hemostasis. As a result, it causes atherosclerosis and the Atherosclerosis is a systemic disease that causes progressive formation of atherosclerotic plaque 15. arterial stenosis and occlusion due to intimal plaques In the light of the information obtained, a positive containing lipids, fibroblasts, macrophages, smooth muscle correlation was found between epicardial adipose tissue cells and extracellular substances in different proportions, thickness and coronary artery disease and metabolic syndrome affecting not only coronary vessels but all arterial structures 7. 10. Atherosclerosis begins early in life and progresses In studies using MDCT, atherosclerotic plaque throughout life. The most important complications are development and coronary stenosis were investigated using myocardial infarction and sudden cardiac death. In addition to parameters such as epicardial adipose tissue volume, epicardial the known causes of atherosclerosis, epicardial adipose tissue adipose tissue thickness, and pericoronary fat amount. In the has also been reported in recent years to cause atherosclerosis literature, volumetric measurements have been used in most of and coronary artery disease. Today, it has been proven that the examinations made for the amount of epicardial adipose pericardial adipose tissue secretes more inflammatory tissue. However, a software program is required for the cytokines than subcutaneous adipose tissue, and inflammation calculation of total adipose tissue volume and the calculation caused by these cytokines is one of the causes of coronary takes a long time. artery disease 13. In a study by Oyama et al., single-section epicardial Epicardial adipose tissue has protective functions such fat area measurement and epicardial fat volume were as providing free fatty acids in the myocardium, protecting the examined, and fat area measurements taken from the levels of myocardium against toxic levels of fatty acids, secretion of the right pulmonary artery, left main coronary artery, right cor- cardioprotective adipokine and preventing the torsion of onary artery and coronary sinus were compared with the total coronary arteries during cardiac contraction 14. However, when epicardial fat volume. In this study, it was reported that the the amount of epicardial fat increases, it becomes hypoxic and level that showed the most correlation with epicardial fat dysfunctional due to increased lipolysis and inflammation and
73 volume in relation to coronary artery disease (CAD) was the In our study, the epicardial adipose tissue area of left main coronary artery level 16. In our study, we used the area patients with Ca score positivity and coronary artery stenosis measurement over a single section at the level of the left main was found to be statistically significantly higher. The findings coronary artery in epicardial adipose tissue examinations. we have obtained by measuring the epicardial adipose tissue Many studies have reported high epicardial adipose area and the results of the studies conducted by measuring the tissue volume in patients with calcium plaque formation. In the total adipose tissue volume are consistent. Our findings support study conducted by Nakanishi et al., It was thought that an that the increase in epicardial adipose tissue increases the increase of 15% or more in epicardial adipose tissue volume development of calcium plaque in coronary arteries and caused an increase in coronary calcium score 17. In another coronary artery disease, as in the literature. study conducted with 515 patients, it was found that the calcific There are several limitations in our study. Routine plaque formation was significantly increased in patients with clinical follow-up of our cases was not performed and their epicardial adipose tissue volume above 100 ml compared to relationships with traditional atherosclerotic risk factors such as those below 100 ml. In addition, in this study, it was reported diabetes and HT and anthropometric parameters such as BMI that epicardial adipose tissue volume increased in patients with were not evaluated. The presence of these risk factors and coronary stenosis over 50% and calcium score above 400 18. parameters may have affected the cardiovascular risk profile Also, although there are different studies 19, 20 and the amount of epicardial adipose tissue. In our study, only reporting a significant positive relationship between coronary CT findings were evaluated. calcium score and epicardial adipose tissue volume and epicardial adipose tissue thickness in the literature, in another CONCLUSION study Aslanabadi et al. measured epicardial fat volume, As a result, an independent relationship was found between the pericardial fat volume and epicardial fat thickness and they amount of epicardial adipose tissue and coronary calcium score found a significant linear relationship between coronary positivity. Epicardial adipose tissue area was found to be calcium score and pericardial fat volüme. However, it has been significantly higher in patients with coronary artery stenosis reported that there is no significant correlation between and positive coronary calcium score. In the light of these epicardial fat volume and coronary calcium score 21. findings, it can be concluded that epicardial adipose tissue In our study, epicardial adipose tissue area was increase is effective in the development of coronary artery significantly increased in patients with positive coronary stenosis and calcific-atherosclerotic changes in coronary calcium scores. arteries. In many studies in the literature using epicardial fat In addition, it is thought that the measurement of a volume, pericardial fat volume and epicardial adipose tissue single cross-sectional area from the left main coronary artery thickness, a strong positive correlation was found between level in calculating the amount of epicardial adipose tissue may coronary artery stenosis and ischemic lesions and the amount be a good alternative to total epicardial adipose tissue volume of adipose tissue 13,15,19,21. In the study conducted by Du et al., calculations due to easier measurement. pericardial fat volume was found to be higher in patients with significant stenosis and ischemic lesions compared to those Conflict of interest without 22. 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75 Int J Acad Med Pharm, 2021; 3 (1); 76-81
International of Academic Medicine and Pharmacy
Student Opinions About Anatomy Education From Past to Future
Erengül Boduç 1*
1 Department of Anatomy, Faculty of Medicine, Kafkas University, Kars, Turkey
ORCID; 0000-0001-8872-1993
Article info Research article
Received :05.10.2020 Abstract; The aim of this study is to analyze the effect of student views on the situations in the history of anatomy Received in revised form :- education that should be transferred to the future education and the structures that should be supported. 155 students Accepted :25.11.2020 participated in the study. The questions asked were created with a 5-point Likert test, and the students answered the Available online :05.01.2021 questions via mail. Answers were analyzed on the system and then statistically analyzed. According to the statistics of the chi-square test of first and second-grade answers, there is a significant difference only in the first (p=0.010) and eleventh Keywords (p=0.006) questions (p<0.05). Supporting the study with student views has been very beneficial in terms of how to proceed in education. Analysis of student views can bring an effective and contemporary structuring to anatomy Anatomy education education, which is the main course of medical education. Likert test Cadaver Digital software
INTRODUCTION The indispensable element of anatomy education since history paved the way for the need for renewal and development 10. has been cadavers 1. For many years, the place and importance In recent years, different tools have started to take of cadavers and dissection have always been discussed 2, 3. In place in anatomy education 11. One of them is recent years, especially in our country, cadaveric anatomy three -dimensional models and software. The development of education actually requires an enormous infrastructure. technology has enabled the transition to the digital world in the Preservation (coolant-tank-solution), acquisition (high-cost field of anatomy 12, 13. In particular, digital three-dimensional purchase when the donation is not available), and dissection of atlases and three-dimensional cadaver software are of interest cadavers require both laboratory and qualified instructor to students 14, 15. In addition, the digital system has become infrastructure 4, 5. In order to have vast dissection knowledge, almost indispensable for clinical and surgical branches within dissection in a large number of cadavers and being skilled like radiological anatomy and laparoscopic anatomy. While this is a surgeon are two important factors. In addition to these, the the case, the integration of cadavers and three-dimensional necessity to overcome cadaver anxiety and to have a digital systems has become necessary for anatomy education 16, three-dimensional depth perception can be added to these 17 . elements 6, 7. In this study, students' opinions were taken to guide Surgical cadaver courses held in recent years have education about the present and future of anatomy education. increased the importance of both anatomy instructors and The student views obtained in the study can guide and benefit cadaver education 8, 9. Another significant effect of this is the instructors in preparing an ideal and effective training model. development of cadaver embalming solutions used in anatomy The aim of the study is to present the idea of an ideal integrated laboratories. Fresh-looking cadavers and cadaveric embalming education model to the literature by benefiting from student solutions, which are especially desired in the courses, have also views.
*Corresponding author: Erengül Boduç, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.47389
76 MATERIALS and METHODS proportions in other options are close to each other. The answer to the fourth question is quite different between first year and Ethical approval second year students. First year students give the answer “I The study was approved by the ethics committee of Medicine absolutely do not agree with the question” at a high rate Faculty of Kafkas University (Approval number: 2019/12). The (34.7%), while second year students give a high rate of study was performed following the aid of the ethical standards “disagree” (38.7%) and indecisive attitude is also high (27.5%). down in the 1964 Declaration of Helsinki and its later While the first graders gave the answer “strongly disagree” (5th amendments. -6th questions 33.3%) (to the opinions of 5th and 6th questions, the second graders marked the “I do not agree” (5th question, Study design 36.3%; 6th question, 31.3%) option a little more softening. The The study was carried out on the first and second-year medical second graders marked the answer, “I do not agree” with the students of Medicine Faculty of Kafkas University in the 2019– opinion of the 7th question at a higher rate than the first graders 2020 academic year. The data collection forms used in the (second class 45%, first-class 32%). While the first graders study were prepared on the web and sent to the students by e- gave a high rate of “disagree” (28%) to the opinion of the 8th mail. One hundred fifty-five students (75 from the first class, question, the second graders interestingly showed a high rate of 80 from the second class) answered the questions in the data indecision (40%). To the opinion of the 9th question, the first collection form. Data collection questions were prepared with a graders answered 'I strongly agree' at a high rate (56%), while five-point Likert scale (totally agree, agree, undecided, disa- the second graders answered 'I agree' at a high rate (40%). The gree, totally disagree) 18. The answers given by the students number of indecisive and disagreeing with the opinion of the were automatically analyzed through the web system and the 10th question in the first year is both the same and high results were obtained through the software. The answer options (30.7%). The second grade, on the other hand, answered the given were calculated automatically on the system with the opinion of the 10th question with a high rate of disagree with calculation of frequency and percentage. The answers are given the first grade (31.3%). While the first grade answered the by the first year and second-year students to the questions were answer “strongly do not agree with the opinion of the 11th statistically compared with the chi-square test 19. question” (30.7%), the second class answered “I do not agree” with a high rate (33.8%). Both the first and second-year RESULTS students highly disagree with the opinion of the 12th question. The first and second years were compared according to the All the answer rates given by the first and second graders answers given by the students. Statistical analysis was carried regarding the questions are given in tables 1 and 2. According out using SPSS 22.0 version software program for Windows. to the statistics of the chi-square test of first and second-grade Descriptive statistics for categorical variables are expressed as answers, there is a significant difference only in the first frequency and percentage values. A Chi-square test was used in (p=0.010) and eleventh (p=0.006) questions (p<0.05). Other ‘p’ the analysis of categorical data. The results were evaluated at a values are given in table 3. 95% confidence interval, and a p-value of <0.05 was considered significant. First-year students agreed with the first DISCUSSION question opinion more than the second year students (62.7%, The basis of anatomy education is cadaver 20. However, 38.8%). In the second grade, there is a high rate of indecision technological developments in recent years have brought a lot (26.3%). While first-year students marked “I definitely agree” of innovation, especially in the field of three-dimensional with the second question opinion (44%), second-year students anatomy. Thanks to three-dimensional software, the most marked “I agree” with a higher rate (53.7%). In the third extreme points or cross-sectional anatomy that could not be question, the answers of both the first and the second year dissected in the cadaver were able to be examined very well. students were quite divided. In fact, both classes marked the This situation made it necessary for cadavers and technology to answer “I do not agree” at a high rate (25.3%, 43.8%). But the interact with each other 13, 21, 22.
77 Table 1. Percentage of frequency (f) that first-year students gave to the questions
First Year students of the medicine faculty n:75 Totally Agree Agree Undecided Totally Disagree Disagree (%) (%) (%) (%) (%)
1-"The only element that should remain unchanged from the past to the 62,7 18,7 10,7 1,3 6,7 present and the future in anatomy education is the cadaver." 2-'Three-dimensional software tools describing digital subjects used in 44 45,3 5,3 2,7 2,7 anatomy education today are effective in learning the lessons' 3-'Education can be done without cadavers with digital software containing 12 22,7 18,7 21,3 25,3 transparent cadaver images that replace cadavers in the future' 4-'Anatomy education should be explained through fully digital 9,3 9,3 14,7 34,7 32 three-dimensional software programs today and in the future' 5-'Digital three-dimensional software can even reflect depth perception 0 18,7 21,3 33,3 26,7 perceived by touch learning (even without touching)' 6-'In anatomy education, cadaver can be replaced by digital 5,3 20 13,3 33,3 28 three-dimensional software' 7-‘Cadaver is viewed with the eyes of the first patient in medical education. 6,7 20 12 29,3 32 The first patient can also be provided with digital three-dimensional software. A digital cadaver can replace a real cadaver. ' 8-‘In the past, by touching the cadaver and based on cadaver dissection, 8 17,3 25,3 21,3 28 anatomy education can create a virtual three-dimensional dissection environ- ment on the digital cadaver today and in the future. This is a very scientific education that does not match the old education. ' 9-'The foundation of anatomy education was dissection in the past and it 56 26,7 12 1,3 4 should be today. Cadavers are essential for education.' 10-'In anatomy education, mock-up and digital images are extremely suffi- 6,7 14,7 30,7 17,3 30,7 cient in providing perception of reality. In the future, lessons should be taught on these two materials.' 11-‘Variational situations that occur in cadavers can also be created with 9,3 20 14,7 30,7 25,3 digital three-dimensional software programs. Thus, there will be no need for cadavers in the future.’ 12-'Even if there is no perception of reality in anatomy education, anatomy 4 17,3 9,3 33,3 36 will be learned with digital three-dimensional software or models, and in the future, a real patient will be touched and the perception of reality will be understood.’
Table 2. Percentage of frequency (f) that second year students gave to the questions
Second year students of the medicine faculty n:80 Totally Agree Agree Undecided Totally Disagree Disagree (%) (%) (%) (%) (%)
1-"The only element that should remain unchanged from the past to the 38,8 30 26,3 2,5 2,5 present and the future in anatomy education is the cadaver." 2-'Three-dimensional software tools describing digital subjects used in 33,8 53,7 8,8 3,7 anatomy education today are effective in learning the lessons' 3-'Education can be done without cadavers with digital software containing 10 16,2 16,3 13,8 43,8 transparent cadaver images that replace cadavers in the future' 4-'Anatomy education should be explained through fully digital 3,8 10 27,5 20 38,7 three-dimensional software programs today and in the future' 5-'Digital three-dimensional software can even reflect depth perception 6,3 23,7 16,3 17,5 36,3 perceived by touch learning (even without touching)' 6-'In anatomy education, cadaver can be replaced by digital three-dimensional 3,8 23,8 20 21,3 31,3 software' 7-‘Cadaver is viewed with the eyes of the first patient in medical education. 5 15 15 20 45 The first patient can also be provided with digital three-dimensional software. A digital cadaver can replace a real cadaver. ' 8-‘In the past, by touching the cadaver and based on cadaver dissection, 5 21,3 40 8,8 25 anatomy education can create a virtual three-dimensional dissection environ- ment on the digital cadaver today and in the future. This is a very scientific education that does not match the old education. ' 9-'The foundation of anatomy education was dissection in the past and it 32,5 40 13,8 2,5 11,3 should be today. Cadavers are essential for education.' 10-'In anatomy education, mock-up and digital images are extremely sufficient 2,5 26,3 26,3 13,8 31,3 in providing perception of reality. In the future, lessons should be taught on these two materials.' 11-‘Variational situations that occur in cadavers can also be created with 2,5 26,3 26,3 11,3 33,8 digital three-dimensional software programs. Thus, there will be no need for cadavers in the future.’ 12-'Even if there is no perception of reality in anatomy education, anatomy 2,5 15 21,2 23,8 37,5 will be learned with digital three-dimensional software or models, and in the future, a real patient will be touched and the perception of reality will be understood.’
78 Table 3. ‘p’ values of first and second year students' answers to each question with chi-square test
Questiones p
1-"The only element that should remain unchanged from the past to the present and the future in anatomy education is the cadaver." 0.010
2-'Three-dimensional software tools describing digital subjects used in anatomy education today are effective in learning the lessons' 0.341
3-'Education can be done without cadavers with digital software containing transparent cadaver images that replace cadavers in the future' 0.189
4-'Anatomy education should be explained through fully digital three-dimensional software programs today and in the future' 0.076
5-'Digital three-dimensional software can even reflect depth perception perceived by touch learning (even without touching)' 0.030
6-'In anatomy education, cadaver can be replaced by digital three-dimensional software' 0.446
7-‘Cadaver is viewed with the eyes of the first patient in medical education. The first patient can also be provided with digital three-dimensional 0.398 software. A digital cadaver can replace a real cadaver. ' 8-‘In the past, by touching the cadaver and based on cadaver dissection, anatomy education can create a virtual three-dimensional dissection 0.106 environment on the digital cadaver today and in the future. This is a very scientific education that does not match the old education. ' 9-'The foundation of anatomy education was dissection in the past and it should be today. Cadavers are essential for education.' 0.042
10-'In anatomy education, mock-up and digital images are extremely sufficient in providing perception of reality. In the future, lessons should be 0.331 taught on these two materials.' 11-‘Variational situations that occur in cadavers can also be created with digital three-dimensional software programs. Thus, there will be no 0.006 need for cadavers in the future.’ 12-'Even if there is no perception of reality in anatomy education, anatomy will be learned with digital three-dimensional software or models, 0.265 and in the future, a real patient will be touched and the perception of reality will be understood.’ p: Chi-square test of 1st and 2nd grade students ‘p’ values
In this study, how the future of anatomy education In both first and second grades, almost very few agree with the should be was presented to students' opinions. Both first and view that 'Cadaver is viewed with the eyes of the first patient in second-year students highly agree with the view that cadavers medical education. The first patient can also be provided with should be the only element that should remain unchanged from three-dimensional digital software. A digital cadaver can past to present and future in anatomy education. Both first and replace a real cadaver '. In this question, sensory perception is second graders adopt the view that three-dimensional software wanted to be further reinforced. The students are presented tools that describe digital subjects used in anatomy education with a slightly different version of the 6th question. Thus, the are effective in learning lessons. Although both first and second desired perception situation was achieved, and the high rate of graders strongly disagree with the sentence 'With digital rejection of the students achieved the desired perceptual goal. software containing transparent cadaver images that replace One of the most contradictory questions asked to cadavers in the future', both first and second graders are students is that ‘In anatomy education, which is based on undecided and there are also those who agree with this view. cadaver dissection and touching the cadaver in the past, a However both first year and second-year students do not favor virtual dissection environment can be created in three the subject of teaching anatomy education today and in the dimensions on the digital cadaver today and in the future. This future through completely digital three-dimensional software is a very scientific education that does not match the old programs. education. 'is the opinion. Those who do not agree with this It demonstrated a fairly high non-adoption of digital interpretation and the first graders and undecided are almost anatomy without the first class sense of touch. Although there proportionally close to each other. In the second grade, the is a high rate of participation in this situation in the second indecisive attitude is quite high. After all, the concept of virtual year, the indecisive attitude is also quite high in this class. cadaver may have come to students as an interesting and When we move on to this question, which is asked for the intriguing object. finalization of the views such as 'cadaver in anatomy education 'The foundation of anatomy education was dissection can leave its place to three-dimensional digital software', there in the past and should be today. Cadavers are essential for is a high rate of disagreement with the opinion in both the first education.' Participation to the opinion is quite high both in the and second grade, but there is also a low rate of agreement. first and second grades. As fantastic as digital education may From here, it can be said that there is a student population that seem, cadaver education still maintains its mystery and appeal. wants a completely digital world and ignores sensory learning. ‘Variational situations that occur in cadavers can also be
79 created with digital three-dimensional software programs. 2. Granger NA. Dissection laboratory is vital to medical gross Thus, there will be no need for cadavers in the future. 'Both anatomy education. Anat Rec B New Anat. 2004; 281(1):6-8. first and second-grade students highly disagree with the 3. Rizzolo LJ, Stewart WB. Should we continue teaching anatomy by opinion. Besides, the opinion that touching a cadaver that can dissection when? Anat Rec B New Anat. 2006; 289(6):215-218. be created with three-dimensional software can be equivalent to 4. McLachlan JC, Bligh J, Bradley P, Searle J. Teaching anatomy the perception of reality is quite low. without cadavers. Med Educ. 2004; 38(4):418-424. As a result, the foundation of anatomy education was 5. Singh R, Shane Tubbs R, Gupta K, Singh M, Jones DG, Kumar R. Is the decline of human anatomy hazardous to medical education/ dissection in the past and today, students have demonstrated a profession?--A review. Surg Radiol Anat. 2015; 37(10):1257- high rate of acceptance of the view that cadavers should be 1265. essential for education. Digital three-dimensional software is 6. Anyanwu EG. Background music in the dissection laboratory: interesting and very positive about the fantasy world. In impact on stress associated with the dissection experience. Adv addition, it has a wide range of uses in some difficult areas and Physiol Educ. 2015; 39(2):96-101. cross-sectional anatomy. Therefore, three-dimensional digital 7. Estai M, Bunt S. Best teaching practices in anatomy education: A software can be useful tools to support anatomy education. The critical review. Ann Anat. 2016; 208:151-157. integration of cadaveric education with digital tools can be a 8. Are C, Stoddard HA, Northam LC, Thompson JS, Todd GL. An very useful and up-to-date education model for both students experience in surgical anatomy to provide first-year medical and teachers. Based on the data of the study, it is predicted that students with an early exposure to general surgery: a pilot study. the education model that students actually want can be like this. J Surg Educ. 2009; 66(4):186-189. 9. Ozcan S, Huri E, Tatar I, Sargon M, Karakan T, Yagli OF, Bagcioglu CONCLUSION M, Larre S. Impact of cadaveric surgical anatomy training on In this study, support was obtained from student views about urology residents knowledge: a preliminary study. Turk J Urol. the future state of anatomy education. In this direction, it is 2015; 41(2):83-87. aimed to investigate the form of anatomy education that can be 10. Porzionato A, Polese L, Lezoche E, Macchi V, Lezoche G, Da Dalt the most effective and efficient for students. Cadaver is G, Stecco C, Norberto L, Merigliano S, De Caro R. On the essential for anatomy education, but as long as it is integrated suitability of Thiel cadavers for natural orifice transluminal into technological innovations. Neither cadaver education nor endoscopic surgery (NOTES): surgical training, feasibility studies, digital technology education alone is enough. It must be and anatomical education. Surg Endosc. 2015; 29(3):737-746 integrated with each other. 11. Biasutto SN, Caussa LI, Criado delRio LE. Teaching anatomy: cadavers vs. computers? Ann Anat. 2006; 188(2):187-190. 12. Gunderman RB, Wilson PK. Viewpoint: exploring the human Conflict of interest interior: the roles of cadaver dissection and radiologic imaging in No conflict of interest was declared by the author. teaching anatomy. Acad Med. 2005; 80(8):745-749.
13. Hoyek N, Collet C, Di Rienzo F, De Almeida M, Guillot A. Financial disclosure Effectiveness of three-dimensional digital animation in teaching The authors declared that this study hasn’t received any finan- human anatomy in an authentic classroom context. Anat Sci cial support. Educ. 2014; 7(6):430-437.
14. Kotze SH, Mole CG, Greyling LM. The translucent cadaver: an Acknowledgments evaluation of the use of full body digital X-ray images and Thanks to Sercan Kenan Başar and Bisher Tahhan students of drawings in surface anatomy education. Anat Sci Educ. 2012; 5 the Kafkas University, Medicine Faculty, who helped carry out (5):287-294. this study. 15. Lewis TL, Burnett B, Tunstall RG, Abrahams PH. Complementing anatomy education using three-dimensional anatomy mobile REFERENCES software applications on tablet computers. Clin Anat. 2014; 27 1. Sugand K, Abrahams P, Khurana A. The anatomy of anatomy: a (3):313-320. review for its modernization. Anat Sci Educ. 2010; 3(2):83-93. ………………………………………………………………………………….
80 16. Fitzpatrick CM, Kolesari GL, Brasel KJ. Teaching anatomy with 20. Parker LM. Anatomical dissection: why are we cutting it out? surgeons' tools: use of the laparoscope in clinical anatomy. Clin Dissection in undergraduate teaching. ANZ J Surg. 2002; 72 Anat. 2001; 14(5):349-353. (12):910-912. 17. Murgitroyd E, Madurska M, Gonzalez J, Watson A. 3D digital 21. McLachlan JC. New path for teaching anatomy: living anatomy anatomy modelling - Practical or pretty? Surgeon. 2015; 13 and medical imaging vs. dissection. Anat Rec B New Anat. 2004; (3):177-180. 281(1):4-5. 18. Gözil R, Özkan S, Bahçelioğlu M, Kadıoğlu D, Çalgüner E, Öktem 22. Older J. Anatomy: a must for teaching the next generation. H, Şenol E, Mutlu M, Kürkçüoğlu A, Yücel D. Gazi University Surgeon. 2004; 2(2):79-90. Faculty of Medicine 2nd Year Students' Evaluation of Anatomy Education. Tıp Eğitimi Dünyası. 2006; 23(23):27-32. 19. Bahsi I, Topal Z, Cetkin M, Orhan M, Kervancioglu P, Odabasioglu ME, Cihan OF. Evaluation of attitudes and opinions of medical faculty students against the use of cadaver in anatomy education and investigation of the factors affecting their emotional responses related thereto. Surg Radiol Anat. 2020. doi: 10.1007/s00276-020-02567-8.
81 Int J Acad Med Pharm, 2021; 3 (1); 82-87
International of Academic Medicine and Pharmacy
The Relationship Between Systemic Immune-Inflammation Index and TNM Stage in Patients Underwent Pancreatic Cancer Surgery
Mer ç Emre Bostancı 1* , Kürşat Karadayı 2
1,2 S vas Cumhur yet Un vers ty, Faculty of Med c ne, Department of Surg cal Oncology, S vas, Turkey
ORCID; 0000-0002-0429-9834, 0000-0002-1459-8432
Article info Research article
Received :21.08.2020 Abstract; The purpose of this study is to investigate the prognostic value of the systemic immune inflammation index Received in revised form :25.10.2020 (SII) by comparing it with postoperative TNM stages and other clinical-pathological data in patients undergoing curative Accepted :02.11.2020 surgery for pancreatic cancer. Pathological and clinical data of 44 patients who were operated for pancreatic cancer be- Available online :05.01.2021 tween January 2012 and January 2020 were retrospectively analyzed. Neutrophil, platelet and lymphocyte counts taken from preoperative complete blood samples were recorded and SII was calculated. The formula used in the calculation of the index is SII = Platelet x Neutrophil / Lymphocyte count. A comparison of the pathological stage and other clinical Keywords pathological findings was made for the two groups, which were formed with a cut-off value of 600 for SII. Twenty (45.4%) of the patients were female and 24 (54.5%) were male. Mean patient age was 65.4 ± 5.3 (21-86). In general, as the Pancreatic cancer pathological stages of the patients increased, SII was also observed to increase creating a statistically significant difference Systemic immune inflammation index (p <0.001). The cut-off value for SII was taken as 600, forming two different groups. The difference in pathological stage TNM distribution of these two groups was found to be statistically significant (p <0.001). The difference between the groups according to differentiation degree, CA 19-9 level, presence of pancreatitis, pT, tumor diameter was statistically significant (respectively p = 0.026, p = 0.009, p = 0.046, p = 0.047, p = 0.017). It shows that preoperative SII significantly correlates with well-established prognostic factors in pancreatic cancer patients undergoing pancreatic surgery (resection). SII measurement is both low cost and easily applicable. SII can be used in conjunction with and supporting well- established prognostic factors.
INTRODUCTION edition, 2017) is summarized in Table 1 8. Regarding cancer-related mortality, pancreatic cancer (PC) is in the fourth place, whereas it is fifth among the most common cancers in the world 1. Pancreatic Cancer has gained attention Table 1. Pancreatic cancer TNM staging among gastrointestinal cancers with its increasing frequency in recent years and it is followed by gastric and colon cancer in Prognostic Staging Groups our country in deaths related to gastrointestinal cancer 2. PC is T N M Stage one of the 2 most deadly cancer types among all cancer types 3. Tis N0 M0 0 T1 N0 M0 IA The 5-year survival rate of pancreatic cancer, which is among T1 N1 M0 IIB the most lethal cancer types due to its few symptoms, early T1 N2 M0 III T2 N0 M0 IB detection an d lack of effective treatment options, is less than T2 N1 M0 IIB 5% and 50% of patients die within the first 6 months 4. At the T2 N2 M0 III T3 N0 M0 IIA diagnosis, the vast majority of patients have already lost the T3 N1 M0 IIB chance of curative resection 5. Only 20% of them have surgical T3 N2 M0 III T4 Any N M0 III 6 resection chance . It has been reported that many factors Any T Any N M1 IV related to the patient affect survival in PC. The size, location, stage, and lymph node relationship of the tumor have been In patients with pancreatic cancer resected according associated with clinical results 7. The preferred staging system to prognostic stage groupings in the eighth edition, survival for all pancreatic cancers (exocrine and neuroendocrine) is the curves were obtained from a Surveillance, Epidemiology and American Cancer Combination Committee (AJCC) / Union for End Results database analysis, and the analysis were based on International Cancer Control (UICC) tumor, lymph node, the data of 8960 patients. According to this analysis, the medi- metastasis (TNM) system. The current staging system (eighth an survival times for Stage IA, IB, IIA, IIB and III patients
*Correspond ng author: Mer ç Emre Bostancı, E-ma l; drmer cemrebostanc @gma l.com, http://dx.do .org/10.29228/jamp.45887
82 were 38, 24, 18, 17 and 14 months, respectively 9. were collected from the medical records. Acute infection, One of the factors that play a crucial role in the diabetes, congestive heart failure, any autoimmune, progression of cancer and survival of patients is the interaction hematological diseases and obese patients were excluded from between systemic inflammation and local immune response 10 . our study. Preoperative data were collected before the surgery. Regarding tumor-associated inflammation, systemic Neutrophil, lymphocyte and platelet counts were recorded from inflammatory response (SIR) has been shown to diminish the the whole blood count samples and SSI was calculated. SII is outcome and to be of major prognostic importance in various based on the counts of neutrophil (N), platelet (P), and cancers 11,12 . Platelet-lymphocyte ratio (PLR), neutrophil lymphocyte (L) and computed using the formula: SII = P*N/L lymphocyte ratio (NLR), and systemic immune-inflammation 23 . Average SIIs were calculated according to pathological index (SII) are inflammation-based scores and their utility is stages. Pathological stage comparison was made for the two based on the markers that are available before surgery. Hu et groups formed by taking the cut-off value 600 for SII. al. have first described SII 13 . Elevated SII was found to be associated with clinicopathological parameters; it was proven RESULTS to be an independent prognostic factor in a number of Twenty of the patients (45.4%) are women and twenty-four malignancies, including PK 14,15,16 . In the study of Mohammad (54.5%) were male. Patients’ average age was 65.4 ± 5.3 et al., SII was reported to be an independent predictor of both (21-86). Pathology results of the patients were 36 ductal cancer-specific survival and recurrence in pancreatic cancer adenocarcinoma, 5 neuroendocrine tumors, and 3 intra-ductal that can be resected 17 . There are many studies in the literature papillary mucinous neoplasia. Pancreaticoduodenectomy was investigating potentially prognostic and promising histologic performed in 27 patients (61.3%) and distal pancreatectomy in and immunologic biomarkers in PK 18,19 . But their evaluation is 17 patients (38.6%). In 12 (27.2%) of the cases, the tumor was usually time-consuming and expensive. Metastatic lymph node found to be good, 25 (56.8%) of them were moderate, and 7 ratio, tumor differentiation and resection margin can be named (15.9%) of them were badly differentiated. The mean tumor as the histological prognostic factors that are the predictors of diameter of the patients was 4.9 ± 2.3 cm. While 26 of the survival in PK patients who can be resected 20,21 . The problem patients had a history of pancreatitis, 18 of them had no history is that these well-established histological predictors are of pancreatitis. While CA19-9 was normal in 19 of the patients, available for assessment only after the surgery. it was observed that there was a high detection rate in 25 of Thus, it is crucial to investigate tumor-driving them. The distribution of clinical-pathological characteristics inflammation-based components, in addition focusing on the belonging to two different groups created by taking the SII path of inflammatory response may be a cornerstone of cancer cut-off value of 600 is given in Table 2. The two groups were treatment 22 . Defining easily accessible markers can help found to be differentiate significantly in terms of CA 19-9 identify individual treatment approaches. This study attempted level, the presence of pancreatitis, and pT (p= 0.026, p= 0.009, to investigate the prognostic value of SII by comparing it with p= 0.046, p= 0.047, respectively) postoperative pathological TNM stages and other Mean SII in Stage 1A was calculated as 280.5 ± 30.4, clinical-pathological data in patients undergoing curative mean SII 423.4 ± 44.3 in Stage 1b, mean SII 584 ±82.3 in surgery due to pancreatic cancer. Stage 2A, mean SII 791.9 ± 119.6 in Stage 2B, mean SII 1010 ± 162.6 in Stage 3. In general, as the pathological stages of the MATERIAL and METHOD patients increased, an increase was observed in SII, which was found to be statistically significant at p <0.001 (Table 3). The Ethical approval comparison of the groups among themselves showed that the No need for ethical approval difference between stage 1A and 1B (p = 0.271), and between stage 2B and 3 (p = 0.104) were not statistically significant Patients and study design (Figure 1). Clinical and pathological data of 44 pancreatic cancer patients Two different groups were formed by taking the who underwent curative surgery between January 2012 and cut-off value for SII as 600. There were a total of 19 patients in January 2020 were analyzed retrospectively. the group below SII 600, including 2 (10.5%) in Stage IA, 10 Clinicopathological data of the patients, such as, age, gender, (52.6%) in Stage IB, 4 (21.1%) in Stage IIA, and 3 (15.8%) in tumor site, histopathological tumor grading, preoperative Stage IIB. There was a total of 25 patients in the group with SII lymphocyte, neutrophil, and platelet counts, and staging (TNM) above 600, including 2 (8%) in Stage 2A, 16 (64%) in Stage
83 2B, and 7 (28%) in Stage 3. A statistically significant difference was observed in the pathological stage distribution of these two groups (p <0.001) (Table 4) (Figure 2). Two different groups, which were formed with a cut-off value of 600 for SII, were compared according to pathological tumor size. The mean tumor diameter was found to be 3.16 cm in the group below SII 600, and 6.0 cm in the group above SII 600 (Table 5). A statistically significant differ- ence was observed in tumor diameter of these two groups (p = 0.017).
Table 2 . Distribution of clinical-pathological features of the cases according to SII. SII SII p Factors All <600 >600 N 44 19 25 Sex Male 24 8 16 0,149 Woman 20 11 9 pT 1 6 5 1 2 14 9 5 0,047 3 20 6 14 Figure 1. Average SII values according to the pathological stage 4 4 1 3 pN 0 16 10 6 1 20 7 13 0,132 2 8 2 6 Grade 1 12 9 3 2 25 10 15 0,026 3 7 1 6 CA19-9 U/ml <37 19 12 7 0,009 >37 25 6 19 Pancreatitis yes 26 8 18 0,046 no 18 11 7 Surgical procedure F gure 2. D str but on of patholog cal stages between groups. Whipple 27 12 15 0,583 Distal pancreatectomy 17 9 8
Table 3. Average SII values according to the pathological stage
SYSTEMIC IMMUNE INFLAMMATION INDEX Standard Minimum Maximum Mean Deviation Percentile 25 Percentile 75 Median IQR p Stage 1A 259,00 302,00 280,50 30,41 259,00 302,00 280,50 43,00 1B 339,00 466,00 423,40 44,31 396,00 447,00 442,50 51,00 2A 476,00 729,00 584,00 82,34 554,00 591,00 577,00 37,00 < 0,001 2B 520,00 934,00 791,95 119,63 767,00 876,00 829,00 109,00 3 798,00 1256,00 1010,00 162,64 818,00 1112,00 1002,00 294,00 Table 4. Pathological stage distribution between groups
Stage 1A 1B 2A 2B 3 Total Total SII <600 n 2 10 4 3 0 19 % 10,5 52,6 21,1 15,8 0,0 100,0 <0,001 SII SII >600 n 0 0 2 16 7 25 % 0,0 0,0 8,0 64,0 28,0 100,0
Table 5. Tumor diameters by groups TUMOR DIAMETER Minimum Maximum Mean Standard Deviation Percentile 25 Percentile 75 Median IQR P SII <600 1,00 7,00 3,16 1,89 2,00 4,00 3,00 2,00 0,017 SII >600 2,00 13,00 6,00 4,00 3,00 9,00 4,00 6,00 84 DISCUSSION patients having high SII may be worse due to the The relationship between cancer and chronic inflammation micrometastases. For instance, the adhesion of tumor cells to started with Rudolf Virchow's definition of leukocytes in tumor microvascular endothelium is supported by the platelets in tissue about a hundred years ago 24,25 . Since then, many studies pancreatic cancer 39 . Platelets in the circulation may built a have been conducted to show that chronic inflammation, which defensive barrier around tumor cells, which allows tumorous occurs as a host response in tumor tissue, is effective in tumor cells to escape from the host’s immune system surveillance 40 . development, metastasis, prognosis, and response to treatment. High SII values, corresponding to high platelet and neutrophil In recent studies, the relationship between the degree of counts, and low number of lymphocytes, indicate an systemic inflammation and cancer has been demonstrated by inflammation activity caused by metastases and enhanced evaluating parameters such as systemic inflammation markers tumor invasion, which can be associated to poor survival. NLR, PLO, and SII 26,27 . Tumor microenvironment is regulated Regarding the studies on the prognostic capacity of SII, PLR, by inflammatory cells. Neutrophils and platelets, tumor cells and NLR, our findings are consistent with the results of Chawla block apoptosis, angiogenesis, DNA damage, proliferation and et al., who showed that in patients with resectable PC, metastasis of tumor cells to prevent metastasis and proliferation preoperative SII is an independent prognostic factor for OS, of lymphocytes directly contributing to the secretion of rather than NLR and PLR. Haldar and Ben-Eliyahu have protective and inflammatory factors 28 . Lymphocytopenia in the recently addressed the effect of COX2 inhibition and tumor tissue also causes the interruption of the immune perioperative β-adrenergic blockade on cancer outcomes 41 . response that the host should give. Systemically, NLR, PLR Accordingly, patients, who have a resectable PDAC and with and SII will be higher due to the increase in neutrophil-platelet high preoperative SII, might benefit from anti-inflammatory count and decrease in lymphocyte count. Based on these and/or anti-immunotherapy before and after surgery. results, various inflammation-based scores were used in cancer There is no consensus on the cutoff value of patients as prognostic indicators. In this study, the relationship inflammation indices. The cutoff level is usually specified of SII, one of the inflammatory biomarkers, with the individually according to their relevance and significance in a well-established prognostic clinical-pathological markers in patient cohort and in a way that they allow the survival rate of patients resected for pancreatic cancer was revealed. the group to be predicted significantly. Hence, the cut-off Inflammation-based biomarkers and scores have values for these indices vary in a wide range. We specified the recently been shown to play a significant prognostic role in a cut-off value as 600 in accordance with the general belief. number of malignant diseases 29,30 . SII, which is based on CA19-9, which is a sialylated Lewis A blood group neutrophils, platelets, and lymphocytes count, is one of these antigen, is commonly expressed and shed in many new prognostic scores. SII, which reflects patient’s malignancies, including pancreatic and hepatobiliary disease. inflammatory status, has been confirmed as a prognostic factor The increase of CA 19-9 is also observed in benign conditions first in hepatocellular carcinoma, and then in small cell lung such as bile cholangitis, duct obstruction, acute or chronic cancer 14,31 . Elevated preoperative SII has a key role in pancreatitis, inflammatory bowel disease, thyroid diseases, prognosis estimation in several malignancies, including PC cystic fibrosis, and liver cirrhosis 42 . The body does not 15,16,32,33,34 . produce CA 19-9 in 5% of the population 43 . Healthy In our study, we observed this as the pathological individuals may have high levels as well 43 . In our study, SII stage progressed, SII increased and there were only stage 2 and was found to be higher in patients with high CA19-9. This 3 patients in the group with SII over 600. This relationship may suggests that SII can be an alternative in benign and be due to different reasons. Thrombocythemia, lymphopenia, physiological conditions where CA 19-9, an important and neutrophilia causes high SII, which may be due to the prognostic marker in pancreatic cancer, is elevated. combination of impairment of the adaptive immune system and Chronic pancreatitis, which is known as a risk factor nonspecific inflammation 35,36 . Pancreatic cancer is particularly for PC, makes contribution to PC development through the associated with nonspecific inflammation, which is often formation of pancreatic intraepithelial lesions 44,45 . In our study, ineffective against the cancer itself 37 . The recent data showed 26 patients had a history of pancreatitis, and SII of 18 of these that the relation between cancer-associated thrombocytosis and patients were over 600. Eighteen patients did not have a history the diminishing of the host immunity is due to the suppression of pancreatitis and 11 of these patients had SII below 600. In of T-cell responses against tumors 38 . The survival of the our study, we evaluated that SII increased with the presence of
85 pancreatitis. Our study has limitations such as being Inflamma on Outcome Study. BJC . 2011;104(4):726–34. retrospective, single centered, relatively low number of 12. Jomrich G, Hollenstein M, John M, Baierl A, Paireder M, Kristo I patients, and absence of a control group including healthy et al. The modified glasgow prognos c score is an independent individuals. prognos c indicator in neoadjuvantly treated adenocarcinoma of the esophagogastric junc_on. Oncotarget . 2018;9(6):6968–76. CONCLUSION 13. Hu B, Yang XR, Xu Y, et al. Systemic immune-inflamma on index In short, this study shows that in PDAC patients who predicts prognosis of pa ents resec on for hepatocellular underwent pancreatic resection, preoperative SII is an carcinoma. CCRJ . 2014; 20:6212–6222. independent predictor of OS. Measurement of SII is both low 14. Hong X, Cui B, Wang M, Yang Z, Wang L, Xu Q. Systemic cost and easily applicable. Anti-inflammatory and/or immuneinflamma on index, based on platelet counts and anti-immunotherapy may be beneficial for the patients who neutrophil– lymphocyte ra o, is useful for predic ng prognosis have high preoperative SII. in small cell lung cancer. TJEM . 2015;236(4):297–304.
15. Feng JF, Chen S, Yang X. Systemic immune-inflamma on index Conflict of interest (SII) is a useful prognos c indicator for pa ents with squamous The authors declare that they have no conflict of interest. cell carcinoma of the esophagus. MBJ. 2017;96 (4): e5886.
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87 Int J Acad Med Pharm, 2021; 3 (1); 88-91
International of Academic Medicine and Pharmacy
Preventive Nutritional Style for New Type 2019 Coronavirus SARS-CoV-2 (COVID-19) Pandemic
Hasan Basri Savaş 1*, Mehmet Enes Sözen 2
1 Medical Faculty Department of Biochemistry, Alanya Alaaddin Keykubat University, Antalya, Turkey 2 Medical Faculty Department of Histology and Embryology, Alanya Alaaddin Keykubat University, Antalya, Turkey
ORCID; 0000-0001-87594507, 0000-0002-5007-6631
Article info Review article
Received :19.09.2020 Received in revised form :16.11.2020 Abstract; The COVID-19 infection, which emerged at the beginning of 2019 and spread all over the world, led to the Accepted :19.11.2020 global pandemic. The destructive effects of the pandemic are tried to be stopped all over the world. In this process, scien- Available online :05.01.2021 tific methods should be applied to combat the pandemic. Personal precautions are personal hygiene, apply social isolation and strengthen the immune system, support a natural, balanced, healthy diet, support nutrition with exercise and have a healthy lifestyle. Strong individual immunity is the main factor in avoiding virus infection or the severity of the infection. Social isolation advice has changed the lifestyle of some individuals and brought with a sedentary lifestyle and an irregular Keywords diet. As an expected result of this condition, the immune system has been weakened. Therefore, switching to a natural and balanced diet that will create a strong immune system will protect against the destructive effects of the new type of corona COVID-19 virus pandemic. It is very important to supplement food containing vitamins, minerals, prebiotics and probiotics naturally Coronavirus with adequate water intake. Vitamin C, probiotics, prebiotics, thymoquinone, selenium and zinc supplements will Pandemic strengthen the immune system, increase body resistance, thereby activating possible protective effects mechanisms for Preventive COVID-19 infection. Nutrition
INTRODUCTION supplement food containing vitamins, minerals, prebiotics and Coronavirus pandemic has spread to the whole world, starting probiotics naturally with adequate water intake1-8 . We aimed to from the Far East countries at the end of 2019. Covid-19 give information about preventive nutritional style against infection effects the cytokines and chemokines levels. High coronavirus cytokines and chemokines levels enhance the inflammation and cause organ and tissue failure. With a very rapid spread and Probiotics and prebiotics destructive effect, the pandemic has been struggled against by The origin of the word probiotic is in Latin and it means life. many countries which have been affected by it. In this process, Probiotics can be found more often in traditional and scientific methods should be applied to combat the pandemic. complementary medical advice. It is recommended to consume Personal precautions are personal hygiene, apply social probiotics and prebiotics a lot for health. Fermented milk isolation and strengthen the immune system, support a natural, products are the most common way of consuming probiotics. balanced, healthy diet, support nutrition with exercise and have There are some good bacteria in probiotic foods that are a healthy lifestyle. Strong individual immunity is the main beneficial for digestion. Probiotics also have properties that factor in avoiding virus infection or the severity of the reduce weight gain and prevent obesity. Food and drinks such infection. Social isolation advice has changed the lifestyle of as yoghurt, buttermilk, kefir, cheese, pickle, vinegar, boza, some individuals and brought with a sedentary lifestyle and an turnip produced by fermentation are very rich sources of irregular diet. As an expected result of this condition, the probiotics. Probiotics are very valuable to keep the microbiota immune system has been weakened. Therefore, switching to a healthy and thus to have a strong immunity. However, in order natural and balanced diet that will create a strong immune to benefit from probiotics, prebiotics should be taken in system will protect against the destructive effects of the new nutrition. Strong prebiotic foods can be listed as onion, garlic, type of corona virus pandemic. It is very important to Jerusalem artichoke, leek, banana, apple, barley, oats, flaxseed
*Corresponding author: Hasan Basri Savaş, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.47018
88 and cocoa. To summarize, fruits, vegetables and cereals are health. Recommended daily zinc intake for adult men and powerful prebiotic foods. They are helpful in digestion thanks women respectively; is 8 and 11 mg19 . to their fibrous structure. Prebiotics that support probiotics and microbiota should be taken daily. In several studies, the Selenium efficacy of probiotics in viral infection treatments has been Selenium is a trace element necessary for making important tried and proved. Probiotics reduce the severity of the disease antioxidant enzymes such as glutathione peroxidase. They also in various viral infections, shorten the duration and help the play an important role in the regulation and balance of the symptoms improve quickly. Probiotic supplementation in antioxidant system. Selenium helps to prevent free radical cell creases interferon, T lymphocyte and B lymphocyte levels in damage with its antioxidant feature. Trace elements including individuals who have an infection, thereby strengthening selenium, can modulate cell membrane permeability, regulate immunity9-12 . Probiotics fight with pathogens for food and gene expression, participate in electron transport, and stops their proliferation and interaction with the intestines. participate in the synthesis of hormones and vitamins20-23 . Probiotics induce intestinal epithelial cells by interacting to Selenium deficiency is known to increase the severity and secrete Il-6. Furthermore probiotics improve IgA secretion in development of viral infections such as influenza, HIV, intestines and the other organs. In tis way probiotics induce Coxsackie virüs24 . Selenium supplementation has been shown immune stimulation13 . to increase neutrophil function, antibody production, T and B lymphocyte proliferation, Natural Killer-mediated cell Zinc destruction, and lymphokine production25 . The decrease in Zinc is the second most common trace element in the human cellular immunity due to aging can be reduced with Se body, after iron, which is considered essential, must be taken support26 . Due to all these features, sufficient selenium should daily with nutrition for a healthy life. Zinc, which participates be taken within nutrition. In this way, it will be possible to in the structure of many large molecules such as enzymes, strengthen the immune system. Recommended daily selenium hormones, proteins, etc., performs important functions. Zinc is intake for adults is 55 mikrogram19 . involved in more than three hundred enzymatic reactions. Zinc has been shown to play a role in the immune-boosting and Thymoquinone supportive system. Unhealthy nutrition plays an important role Thymoquinone is the most important bioactive component in zinc deficiency. Which nutrients contain what level of zinc found in black seed (Nigella sativa) essential oil in the ratio of has been determined by previous studies. In developing 18.4 -24%. For this reason, thymokinone can be considered as countries, zinc deficiency has been observed as a result of a the main active ingredient of the black seed plant. Nigella high phytate protein based diet14-16 . Zinc is very important for sativa and isolated from black cumin seeds, thymoquinone has cell proliferation and effects congenital immunity and acquired many beneficial effects such as being an antioxidant, immunity. In addition to taking part in cytosolic defense antihyperlipidemic, antidiabetic, anti-inflammatory, against oxidative stress, it takes part in the regulation of gastroprotective and hepatoprotective. Researches on animals cytokine release and contributes to the continuation of mucosal reveal that Thymoquinone has hypoglycemic, hypolipidemic membran integrity17 . Zinc has multiple antiviral effects in a lot and hypocholesterolemic effects27-29 . Thymoquinone has been of viral speciesincluding nidoviruses which coronavirus shown to regulate the production of antibodies. Thymoquinone belongs too. This antiviral effects include effecting the immun- has also been shown to support the cytotoxic activities of NK ity, cell membrane integrity which inhibits the entry of the cells. Thymoquinone generates its immunomodulatory effects virus and inhibiting RNA synthesizing activity of nidovirusus via the NF-KB pathway. Thymoquinone has immune (including coronavirus) by altering RNA-dependent RNA modulating functions in cellular and humoral immunity30 . polymerase activity. Zinc also effects protein translation and Thanks to all these effects, consumption of thymoquinone is protein processing18 . Therefore, adequate zinc intake with very important in strengthening immunity and protecting nutrition is very important to strengthen immunity and support against infections
89 Vitamin C selenium and zinc components can all be taken with foods by Ascorbate is an antioxidant with no obvious toxic effects. naturally with a proper, balanced and healthy diet. If there are Infectious diseases are often accompanied by oxidation, and problems and deficiencies in this way, supplementation may be infected individuals have a large amounts of free radicals. For recommended with the indication to be placed by the this reason, ascorbate can both neutralize the abundant free physician. Thanks to the correct application of nutritional radicals and reduce the tissue to the redox state of the patients. biochemistry information, preventive and protective effects can Vitamin C is very effective in reducing the redox environment be achieved for various infections, including COVID-19. due to the organism's strong response to oxidative stress, injury or damage during infection. A redox condition caused by Conflict of interest vitamin C alters cellular signals caused by free radicals. Thanks The authors have no conflicts of interest to declare. to vitamin C, the immune response of the body is regulated correctly by preventing the shock situation that may occur due REFERENCES to infection and reducing the formation of inflammation. 1. Cakir Z, Savas HB. A mathematical modelling for the COVID- Previous studies have reported that high doses of vitamin C are 19 pandemic in Iran. Ortadogu Tıp Derg. 2020;12(2):206-210. effective against viral diseases. The antiviral capacity of https://doi.org/10.21601/ortadogutipdergisi.715612 2. Savas HB, Gultekin F. Effects Of Nutrition Style On vitamin C was thought to be proportional to the concentration Metabolism. J Ann Eu Med. 2017;5(2):50-2. and duration of treatment. Along with antiviral drug therapy, 3. Savas HB. [Weight Loss and Healthy Living Secrets]. Kilo high doses of vitamin C have been reported to activate the Verme ve Sağlıklı Yaşam Sırları. 1. Edition. Orion Publishing. body's immune and infection defense mechanisms. In other Ankara. 2018. studies, inadequate vitamin C intake with foods has been 4. Savas HB. [Evidence-Based Approach in Clinical Biochemistry]. shown to increase the mortality rate from infectious diseases. Klinik Biyokimyada Kanıta Dayalı Yaklaşım. 1. Edition. Akade- For all these reasons, it has been suggested to use vitamin C as misyen Publishing. Ankara. 2019. an adjunct in treatment against a wide range of viral and 5. Savas HB. [Medical Biochemistry Laboratory]. Tıbbi Biyokimya bacterial diseases. High doses of vitamin C were recommended Laboratuvarı. Akademisyen Publishing. 1. Edition. Ankara. 2019. 6. Savaş HB, et al. Effects of food based yeast supplementation on for many years, especially in all infectious diseases. Many oxidative stress in rats fed by high cholesterol diet. Cell scientific studies have shown that vitamin C has antiviral Membranes and Free Radical Research. 2013; 5:3 252-255. activity. This activity is directly proportional to the dose31-38 . 7. Şanlidere Aloğlu H, Demir Özer E, Öner Z, Savaş HB, Uz E. Vitamin C decreases necrosis/NETosis by increasing apoptosis Investigation of a Probiotic Yeast as a Cholesterol Lowering 32 therefore it protects tissues against enhanced tissue damage . Agent on Rats Fed on a High Cholesterol Enriched Diet. Kafkas Vitamin C provides resistance to infection with its high Univ Vet Fak Derg. 2015;21:(5):685-689. doi: 10.9775/ antioxidant and tissue integrity protective effects. There is a lot kvfd.2015.13143. of data to think that vitamin C is protective and preventive for 8. Yüksel Ö, Yüksel F, İlhan İ, Savaş HB, Karatas D, Uz E. Serum COVID-19 infection. Zinc Levels in Patients Suffering From Reccurent Aphthous Stomatitis. Int J Health Nutr. 2013;4(2):9-13.
9. Gultekin F, Oner ME, Savas HB, Dogan B. Food additives and CONCLUSIONS microbiota. North Clin Istanb. 2020;17;7(2):192-200. doi: As a result, it can be thought that, considering our past 10.14744/nci.2019.92499. researches and literature, vitamin C, probiotics, prebiotics, 10. Isolauri E, Sutas Y, Kankaanpaa P, Arvilommi H, Salminen S. thymoquinone, selenium and zinc supplements will strengthen Probiotics: effect on immunity. Am J Clin Nutr. 2001;2:444-50. the immune system, increase body resistance, thereby 11. Lykova EA, Vorobev AA, Bokovoi AG, Murashova AO. activating possible protective effects mechanisms for Impaired interferon status in children with acute respiratory COVID-19 infection. Evidence-based benefits should be infection and its correction with bifidum bacterin forte. Microbiol demonstrated by testing the ideal mix ratio and scientific Epidemiol Immünobiol. 2001;2:65-7. 12. Cross ML. Immunoregulation by probitic lactobacilli: pro-Th1 efficacy of the recommended food supplement for possible signals and their relevance to human health. Clin Appl Immunol protective effect for COVID-19 infection with new projects Reviews. 2002;24:37-43. and research. Vitamin C, probiotics, prebiotics, thymoquinone, 90 13. Shaterzadeh-Yazdi H, Noorbakhsh MF, Hayati F, Samarghandian 27. Abdel-Fattah AFM, Matsumoto K, Watanabe H. Antinociceptive S, Farkhondeh T. Immunomodulatory and Anti-inflammatory effects of Nigella sativa oil and its major component, Effects of Thymoquinone. Cardiovasc Hematol Disord Drug thymoquinone in mice. Eur J Pharmacol. 2000;400:89-97. Targets. 2018;18(1):52-60. 28. Cüce G, Sözen ME, Çetinkaya S, Canbaz HT, Seflek H, Kalkan 14. Aras NK, Mauerhofer E. Trace elements in diets of Turkish S. Effects of Nigella sativa L. seed oil on intima–media Children Determined by INAA. Trans Am Nuc Soc. 1992;65:7. thickness and Bax and Caspase 3 expression in diabetic rat aorta. 15. Arcasoy A. [Zinc and Zinc Deficiency]. Çinko ve Çinko Eksikli- Anatol J Cardiol. 2016;16(7):460–466. ği. Öğütler Publishing. 2. Edition. İstanbul. Türkiye. 2002. 29. Seflek HN, Kalkan S, Cuce G, Kılınc I, Sozen ME. Effects of 16. Rink L, Gabriel P. Zinc and the immune system. Proc Nutr Soc. Nigella sativa oil on ovarian volume, oxidant systems, XIAP and 2000;59(4):541-52 NF-kB expression in an experimental model of diabetes. Biotech 17. Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected Histochem. 2019;94(5):325-333. vitamins and trace elements support immune function by 30. Majdalawieh AF, Fayyad MW. Immunomodulatory and strengthening epithelial barriers and cellular and humoral anti-inflammatory action of Nigella sativa and thymoquinone: A immune responses. Br J Nutr. 2007;98:1:29-35. comprehensive review. Int Immunopharmacol. 2015;28(1):295- 18. Kumar A, Kubota Y, Chernov M, Kasuya H. Potential role of 304. zinc supplementation in prophylaxis and treatment of COVID-19. 31. Cakir Z, Savas HB. A Mathematical Modelling Approach in the Medical Hypotheses. 2020;25;144:109848. doi: 10.1016/ Spread of the Novel 2019 Coronavirus SARS-CoV-2 (COVID- j.mehy.2020.109848. 19) Pandemic. Electron J Gen Med. 2020;17(4):em205. https:// 19. Gombart AF, Pierre A, Maggini S. A Review of Micronutrients doi.org/10.29333/ejgm/7861. and the Immune System-Working in Harmony to Reduce the 32. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. Risk of Infection. Nutrients. 2020;16;12(1):236. doi: 10.3390/ 2017;3;9(11):1211. doi: 10.3390/nu9111211. nu12010236. 33. Kim H, Jang M, Kim Y, Choi J, Jeon J, Kim J, Hwang YI, Kang 20. Feng JF, Lu L, Zeng P, Yang YH, Luo J, Yang YW, Wang D. JS, Lee WJ. Red ginseng and vitamin C increase immune cell Serum total oxidant/antioxidant status and trace element levels in activity and decrease lung inflammation induced by influenza A breast cancer patients. Int J Clin Oncol. 2012;17(6):575–583. virus/H1N1 infection. J Pharm Pharmacol. 2016;68(3):406-20. 21. Christophersen OA, Haug A. Animal products, diseases and doi: 10.1111/jphp.12529. drugs, a plea for better integration between agricultural sciences, 34. Klenner F. Significance of High Daily Intake of Ascorbic Acid in human nutrition and human pharmacology. Lipids Health Dis. Preventive Medicine. Journal of the International Academy of 2011;10:16. doi: 10.1186/1476-511X-10-16 Preventive Medicine. 1974;1:1:45-69. 22. Cuce G, Canbaz HT, Sozen ME, Yerlikaya FH, Kalkan S. 35. Cathcart RF 3rd. Vitamin C in the treatment of acquired immune Vitamin E and selenium treatment of monocrotaline induced deficiency syndrome (AIDS). Med Hypotheses. 1984;14(4):423- hepatotoxicity in rats. Biotechnic & Histochemistry. 33. doi: 10.1016/0306-9877(84)90149-x. 2017;92:1:59-67 36. Maggini S, Beveridge S, Suter M. A combination of high-dose 23. Sadeghian S, Kojouri GA, Mohebbi A. Nanoparticles of vitamin C plus zinc for the common cold. J Int Med Res. 2012;40 Selenium as Species with stronger physiological effects in sheep (1):28-42. doi: 10.1177/147323001204000104. in comparison with sodium selenite. Biol Trace Elem Res. 37. Padayatty SJ, Levine M. Vitamin C: the known and the unknown 2012;146(3):302–308. and Goldilocks. Oral Dis. 2016;22(6):463-93. 24. Gill H, Walker G. Selenium, immune function and resistance to 38. Spoelstra-de Man AME, Elbers PWG, Oudemans-Van Straaten viral infections. Nutrition & Dietetics. 2008; 65(3):41-47. HM. Vitamin C: should we supplement? Curr Opin Crit Care. 25. Kiremidjian-Schumacher, L, Stotzky G. Selenium and immune 2018;24(4):248-255. doi: 10.1097/MCC.0000000000000510. responses. Environ Res. 1987;42(2):277-303. 26. McKenzie RC, Rafferty TS, Beckett GJ. Selenium: an essential element for immune function. Immunol Today. 1998;19(8):342- 5.
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Association of Communicating Extralobar Bronchopulmonary Sequestration with Intralobar Sequestration in a Patient Who had Anal Atresia**
İbrahim Karaman1*, Selma Uysal Ramadan2, Ayşegül Zenciroğlu3, Özlem Balcı4, Ayşe Karaman5
1,4,5; University of Health Sciences Turkey, Ankara Dr Sami Ulus Maternity and Children Health and Research Application Center, Departments of Pediatric Surgery, Ankara, Turkey 2; University of Health Sciences Turkey, Ankara Keçiören Training and Research Hospital, Department of Radiology, Ankara, Turkey 3; University of Health Sciences Turkey, Ankara Dr Sami Ulus Maternity and Children Health and Research Application Center, Departments of Neonatology, Ankara, Turkey
ORCID; 0000-0001-7490-4158, 0000-0002-3653-7892, 0000-0002-3488-4962, 0000-0002-4926-5451, 0000-0001-6860-1222
Article info Case report
Received :16.06.2020 Abstract;Bronchopulmonary sequestration is an uncommon anomaly in children. It is characterized by nonfunctioning Received in revised form :- pulmonary tissue that is not connected to the normal tracheobronchial tree, and its blood supply derived from a systemic Accepted :10.09.2020 arterial source. A 2900-gram male term baby was referred to our clinic with the diagnosis of anal atresia. A diverting Available online :05.01.2021 sigmoidostomy was performed. He was started to oral feeding on the second postoperative day, but patient’s general condition was impaired and right lower lobe pneumonia was documented on chest X-ray. A thoracic CT scan demonstrated multiple cysts and pneumonic consolidation, which indicated abscess at right lower lobe. The thoracic CT scan also showed bronchus like structure, which was entering to the esophagus. An esophagogram showed a fistula from distal esophagus to the right lower lobe of the lung. At thoracotomy, a connection between the right lower lobe of the lung Keywords and distal of the esophagus by its bronchus was noted. An anomalous artery was found, originating from thoracic aorta.
Pulmonary sequestration The fistula was divided from esophagus and right lower lobectomy was performed. Also basal region of the right middle Anal atresia lobe were not inflated with ventilation and congested with a clear demarcation from normal appearing lung. This situation was evaluated as an intralobar sequestration and resection was performed. We present here association of communicating Bronchopulmonary foregut malformation extralobar sequestration with intralobar sequestration in a patient who had anal atresia. To the best of our knowledge this Newborn combination has never been reported before.
INTRODUCTION Case report Bronchopulmonary sequestration (BPS) is an uncommon A 2900-gram male term baby, born through spontaneous anomaly in children. It is characterized by nonfunctioning vaginal delivery to a mother of 22 years of age in the first pulmonary tissue that is not connected to the normal pregnancy was referred to our clinic with the diagnosis of anal tracheobronchial tree, and its blood supply derived from a atresia. Anal atresia and right nonpalpable testis were detected systemic arterial source 1. on physical examination. Meconium was observed at external Bronchopulmonary sequestrations are subdivided into urinary meatus and invertogram showed high type anorectal extralobar (eBPS) and intralobar (iBPS) types. eBPS is malformation. The abdominal ultrasound and echocardiogram completely separate from the normal lung and invested by its were normal. own visceral pleura. eBPS is more common on the left side and A diverting colostomy was performed. In the follow most of them are found in the left costophrenic angle. iBPS is up period of the patient, oral feeding related recurrent incorporated within the normal surrounding lung and there isn’t pulmonary infections was developed. A chest radiograph any anatomic plane of clevage between the sequestered and the showed necrotizing pneumonia on the right lower lobe. A normal pulmonary parenchyma and most of them are found at thoracic CT scan demonstrated multiple cysts and pneumonic the posterior basal segments of the lower lobes 1,2,3. consolidation, which indicated abscess at right lower lobe. The The coexistence of eBPS and iBPS is extremely rare 2. thoracic CT scan also showed bronchus like structure, which We present here association of communicating eBPS with was entering to the eosophagus. An eosophagogram showed a iBPS in a patient who had anal atresia. To our knowledge this fistula from distal eosophagus to the right lower lobe of the combination has never been reported before. lung (Figure 1).
*Corresponding author: Ibrahim Karaman, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.44262 **; Presented at the XIIth Balkan Congress of Radiology, October 16-19, 2014, İstanbul, Turkey 92 the lobe, as seen in the thorax CT. An anomalous artery was found, originating from thoracic aorta. The fistula was divided from esophagus and right lower lobectomy was performed. Microscopic examination of the eBPS revealed that pulmonary parenchyma was normal except the multiple spaces, which were filled by purulent material. Also basal region of the right middle lobe were not inflated with ventilation and congested with a clear demarcation from normal appearing lung
Figure 1: (a) An upper gastr ointestinal contrast study showing an (Figure 2). A large vessel feeding to the mass was detected but esophageal bronchus, (b) A thoracic CT scan demonstrated multiple cysts its origin could not be identified. This situation was evaluated and pneumonic consolidation, which suggested that abscess. The thoracic CT scan also showed bronchus like structure was entering the esophagus. as an iBPS and resection was performed. In the pathologic examination, normal pulmonary parenchyma, which had no He was operated when he was 27 days old. At thoracotomy, the communication with tracheobronchial tree, was demonstrated. right lower lobe of lung was sequestrated and connected to the The patient died on postoperative seventh day due to Klebsiella distal esophagus by its bronchus. Esophageal bronchus of the sepsis. sequestrated right lower lobe was divided into two branches in
Figure 2: (a) Basal region of the right middle lobe were congested with a clear demarcation from normal appearing lung. (b) Intraoperative view of esophageal bronchus (suspended with silk suture), which provides the link between bronchopulmonary sequestration and esophagus (*).
DISCUSSION normal lung and becomes a pulmonary sequestration and this eBPS occur on the left costophrenic sulcus from 80 to 90 % of accessory lung bud keeps its systemic blood supply derived the patients and eighty per cent of affected patients are boys 3. from the surrounding thoracic mesenchymal tissue. If The sequestrated lung tissue can also present at sequestrated lung bud forms before the development of pleura, intradiaphragmatic or subdiaphragmatic location 4. A large it becomes an iBPS. If the accessory bud forms after the number of anomalies associated with eBPS have been reported. development of pleura, it becomes invested by its own pleura Additional anomalies such as diaphragmatic hernia, pectus and an eBPS is occur 5. excavatum, congenital heart disease, esophageal atresia, But, there are some theories about iBPS, which foregut duplications and vertebral anomalies were reported indicates that iBPS is an acquired one. According to this from 15 to 60 % of patients 1,3. Most iBPS are found within the theory, bronchial obstruction caused by aspiration or basal segments of lower lobe, with two third occur at the left inflammation is leads to formation of iBPS. It was claimed that side. Associated anomalies are rarely reported with iBPS 1. chronic infection occluding the pulmonary artery and this There are several theories about the development of situation is leading to neovascularization from the systemic the sequestration. The most widely accepted theory is that an circulation. However, as in our case, neonatal cases suggest accessory lung bud arises from foregut is separate from the congenital origin 6.
93 Both iBPS and eBPS may communicate with the 2. Shibli M, Connery C, Shapiro JM. Intralobar and extralobar eosophagus or the stomach and this situation is called by bronchopulmonary sequestration complicated by Nocardia communicating bronchopulmonary foregut malformation 4. asteroides infection. South Med J. 2003; 96(1):78-80. This communication may lead infection of the sequestrated 3. Schulman MH. Cyst and cystlike lesions of the lung. Radiol Clin lung, which causes symptoms early period as our patient. North Am 1993; 31(3): 631-649. The association of iBPS with eBPS is extremely rare. 4. Bratu I, Flageole H, Chen MF, Di Lorenzo M, Yazbeck Laberge We presented here association of communicating eBPS with JM. The multiple facets of pulmonary sequestration. J Pediatr Surg 2001; 36:784-790. iBPS and anal atresia. To the best of our knowledge this 5. Devine PC, Malone FD. Noncardiac thoracic anomalies. Clin combination has never been reported. Perinatol 2000; 27(4):865-899.
6. Serrano A, Santonja C, Calderon JA, Ruiz-Lopez MJ, Minguez A. Conflict of interest Intralobar pulmonary squestration as the cause of neonatal There is no conflict of interest among the authors of the article. respiratory distress. Arch Bronconeumol 1996; 32(6):310-312.
REFERENCES 1. Laje P, Flake AW. Congenital bronchopulmonary malformations. In: Holcomb III GW, Murphy JP, St. Peter SD, editors. Holcomb and Ashcraft’s Pediatric Surgery. Philadelphia: Elsevier, p. 348- 360; 2020.
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Development of Acute Generalized Exanthematous Pustulosis due to Hydroxychloroquine Use for COVID-19 Treatment
Mustafa Tosun 1*
1,4,5; Sivas Cumhuriyet University, Faculty of Medicine, Department of Dermatology, Sivas, Turkey
ORCID; 0000-0002-6189-8016
Article info Case report
Received :15.08.2020 Abstract;Acute generalized exanthematous pustulosis (AGEP) is a cutaneous drug eruption, which is characterized by Received in revised form :02.11.2020 nonfollicular, sterile pustules, rapidly and severely progresses on an erythematous base. Although antibiotics have been Accepted :10.11.2020 considered to be responsible for most of the development of AGEP, many drugs, such as hydroxychloroquine (HCQ), may Available online :05.01.2021 also cause it. Recently, HCQ is frequently used in the prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection along with antiviral drugs. In our study, we have presented an AGEP reaction case that has been developed in one patient who is being treated for coronavirus disease-19 (COVID-19) and using the HCQ. Keywords
Hidroksiklorokin AGEP COVID
INTRODUCTION administered. He did not have any psoriasis history, another Acute generalized exanthematous pustulosis (AGEP) is a drug use, or any disease. In the physical examination of the cutaneous drug eruption, which is characterized by patient, there were pustular lesions and desquamation on the nonfollicular, sterile pustules and rapidly and severely erythematous base in the lower and upper extremities of the progresses on an erythematous base. Although antibiotics have body (Figure 1). There was no mucosal involvement. The ex- been considered to be responsible for most of the development aminations of the other systems were normal. of AGEP, many drugs, such as hydroxychloroquine (HCQ), a b may also cause it1. HCQ is an antimalarial treatment agent. It has safely been used in the treatment of Systemic Lupus Erythematosus, Rheumatoid Arthritis and Malaria for more than 50 years2. Recently, HCQ is frequently used in the prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection along with antiviral drugs3. In our study, we have presented an AGEP reaction case that has been developed in one patient who is being treated for coronavirus disease-19 (COVID-19) and using the HCQ.
Case report Figure 1. a) Pustular lesions and b) desquamation on the erythematous A 47-year-old male patient who is being followed in the base in the upper extremities of the body COVID-19 service was consulted to dermatology clinic due to rashes developed on his body. Widespread rashes were found In laboratory analysis, Leukocytosis (WBC 10.96 / mm3) and to be developed on his body on the 3rd day of the patient’s neutrophilia (NEU 9.3 / mm3) were found. The patient was treatment to whom hydroxychloroquine (400 mg) started to be diagnosed with acute generalized exanthematous pustulosis
*Corresponding author: Mustafa Tosun, E-mail; [email protected], http://dx.doi.org/10.29228/jamp.46449
95 (AGEP) with these histopathological and clinical findings. Hy- Conflict of interest droxychloroquine treatment was stopped. Local steroid, mois- There is no conflict of interest among the authors of the article. turizing and antihistamine treatment were initiated. During the follow-up of the patient, his lesions were observed to be REFERENCES regressed. 1. Bhat YJ, Akhtar S, Ahmad M, Hassan I, Wani R. Etiopathologi- cal and clinical study of acute generalized exanthematous pustu- DISCUSSION losis: Experience from a tertiary care hospital in North India. Indian Dermatology Online Journal. 2020; 11(3):391. AGEP is a disease typically characterized by erythematous 2. Kuraitis D, Murina A. Facts, not fear: Safety of sterile pustules that rapidly develops within 48 hours after drug hydroxychloroquine. The American Journal of the Medical exposure4. The most common treatment agents that cause Sciences. 2020. AGEP are aminopenicillins, macrolides, sulfonamides, 3. Robustelli Test E, Vezzoli P, Carugno A, Raponi F, Gianatti A, 5 terbinafine, diltizem and antimalarials as in our case . Rongioletti F, Sena P. Acute generalized exanthematous COVID-19, severe acute respiratory syndrome, is a highly pustulosis with erythema multiforme-like lesions in a contagious respiratory disease, which is caused by coronavirus COVID-19 woman. Journal of the European Academy of 2 (SARS-Cov-2), was defined in Wuhan, China for the first Dermatology and Venereology. 2020. time on 11th December, 2019 and has been declared as a 4. Szatkowski J, Schwartz RA. Acute generalized exanthematous pustulosis (AGEP): a review and update. Journal of the American pandemic by the World Health Organization (WHO) on 11th Academy of Dermatology. 2015;73(5):843-848. March 2020. Millions of people have been infected until today. 5. Munshi M, Junge A, Gadaldi K, Yawalkar N, Heidemeyer K. Many skin manifestations, such as urticarial, maculopapular, Ixekizumab for treatment of refractory acute generalized purpuric, livedoid, and thrombocytemic similar to chickenpox exanthematous pustulosis caused by hydroxychloroquine. JAAD 6 are seen in COVID-19 infection . In our case, skin rashes due Case Reports. 2020; 6(7):634-636. to hydroxychloroquine, which is widely used in COVID-19 6. Elmas ÖF, Demirbaş A, Özyurt K, Atasoy M, Türsen Ü. infection, was seen. As there may be skin rashes due to the Cutaneous manifestations of COVID‐19: A review of the pub- disease itself, skin rashes may also develop depending on the lished literature. Dermatologic Therapy. 2020. drugs used in the treatment (especially hydroxychloroquine). This should be taken into account in terms of differential diagnosis. This case is presented to emphasize the importance of this.
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