Tam Metin - Marmara Medical Journal

Transkript

Marmara Medical Journal
Marmara Üniversitesi Tıp Fakültesi Dergisi
Editör
Prof. Dr. Mithat Erenus
Koordinatörler
Seza Arbay, MA
Dr. Vera Bulgurlu
Editörler Kurulu
Prof. Dr. Mehmet Ağırbaşlı
Prof. Dr. Serpil Bilsel
Prof. Dr. Safiye Çavdar
Prof. Dr. Tolga Dağlı
Prof. Dr. Haner Direskeneli
Prof. Dr. Kaya Emerk
Prof. Dr. Mithat Erenus
Prof. Dr. Zeynep Eti
Prof. Dr. RainerVV. Guillery
Prof. Dr. Oya Gürbüz
Prof. Dr. Hande Harmancı
Prof. Dr. Hızır Kurtel
Prof. Dr. Ayşe Özer
Prof. Dr. Tülin Tanrıdağ
Prof. Dr. Tufan Tarcan
Prof. Dr. Cihangir Tetik
Prof. Dr. Ferruh Şimşek
Prof. Dr. Dr. Ayşegül Yağcı
Prof. Dr. Berrak Yeğen
Doç. Dr. İpek Akman
Doç. Dr. Gül Başaran
Doç. Dr. Hasan Batırel
Doç. Dr. Nural Bekiroğlu
Doç. Dr. Şule Çetinel
Doç. Dr. Mustafa Çetiner
Doç. Dr. Arzu Denizbaşı
Doç. Dr. Gazanfer Ekinci
Doç. Dr. Dilek Gogas
Doç. Dr. Sibel Kalaça
Doç. Dr. Atila Karaalp
Doç. Dr. Bülent Karadağ
Doç. Dr. Handan Kaya
Doç. Dr. Gürsu Kıyan
Doç. Dr. Şule Yavuz
Asist. Dr. Asım Cingi
Asist. Dr. Arzu Uzuner
Marmara Üniversitesi T p Fakültesi Dergisi
DERGİ HAKKINDA
Marmara Medical Journal, Marmara Üniversitesi Tıp Fakültesi tarafından
yayımlanan multidisipliner ulusal ve uluslararası tüm tıbbi kurum ve personele
ulaşmayı hedefleyen bilimsel bir dergidir. Marmara Üniversitesi Tıp Fakültesi
Dergisi, tıbbın her alanını içeren özgün klinik ve deneysel çalışmaları, ilginç olgu
bildirimlerini, derlemeleri,
davet edilmiş derlemeleri, Editöre mektupları,
toplantı, haber ve duyuruları, klinik haberleri ve ilginç araştırmaların özetlerini ,
ayırıcı tanı, tanınız nedir başlıklı olgu sunumlarını, , ilginç, fotoğraflı soru-cevap
yazıları (photo-quiz) ,toplantı, haber ve duyuruları, klinik haberleri ve tıp
gündemini belirleyen güncel konuları yayınlar.
Periyodu: Marmara Medical Journal -Marmara Üniversitesi Tıp Fakültesi Dergisi
yılda 3 sayı olarak OCAK,MAYIS VE EKİM AYLARINDA yayınlanmaktadır.
Yayına başlama tarihi:1988
2004 Yılından itibaren yanlızca elektronik olarak
yayınlanmaktadır
Yayın Dili: Türkçe, İngilizce
eISSN: 1309-9469
Temel Hedef Kitlesi: Tıp alanında tüm branşlardaki hekimler, uzman ve öğretim
üyeleri, tıp öğrencileri
İndekslendiği dizinler: EMBASE - Excerpta Medica ,TUBITAK - Türkiye Bilimsel
ve Teknik Araştırma Kurumu , Türk Sağlık Bilimleri İndeksi, Turk Medline,Türkiye
Makaleler Bibliyografyası ,DOAJ (Directory of Open Access Journals)
Makalelerin ortalama değerlendirme süresi: 8 haftadır
Makale takibi -iletişim
Seza Arbay
Marmara Medical Journal (Marmara Üniversitesi Tıp Fakültesi Dergisi)
Marmara Üniversitesi Tıp Fakültesi Dekanlığı,
Tıbbiye cad No:.49 Haydarpaşa 34668, İSTANBUL
Tel: +90 0 216 4144734
Faks: +90 O 216 4144731
e-posta: [email protected]
Yayıncı
Plexus BilişimTeknolojileri A.Ş.
Tahran Caddesi. No:6/8, Kavaklıdere, Ankara
Tel: +90 0 312 4272608
Faks: +90 0312 4272602
Yayın Hakları: Marmara Medical Journal ‘in basılı ve web ortamında yayınlanan yazı, resim,
şekil, tablo ve uygulamalar yazılı izin alınmadan kısmen veya tamamen herhangi bir vasıtayla
basılamaz. Bilimsel amaçlarla kaynak göstermek kaydıyla özetleme ve alıntı yapılabilir.
www.marmaramedicaljournal.org
Marmara Üniversitesi Tıp Fakültesi Dergisi
YAZARLARA BİLGİ
Marmara Medical Journal – Marmara
Üniversitesi Tıp Fakültesi Dergisine ilginize
teşekkür ederiz.
Derginin elektronik ortamdaki yayınına
erişim www.marmaramedicaljournal.org
adresinden serbesttir.
Marmara Medical Journal tıbbın
klinik
ve
deneysel
alanlarında
özgün
araştırmalar, olgu sunumları, derlemeler,
davet edilmiş derlemeler, mektuplar, ilginç,
fotoğraflı soru-cevap yazıları (photo-quiz),
editöre mektup , toplantı, haber ve
duyuruları,
klinik
haberleri
ve
ilginç
araştırmaların özetlerini yayınlamaktadır.
Yılda 3 sayı olarak Ocak, Mayıs ve Ekim
aylarında
yayınlanan
Marmara
Medical
Journal
hakemli
ve
multidisipliner
bir
dergidir.Gönderilen
yazılar
Türkçe
veya
İngilizce olabilir.
Değerlendirme süreci
Dergiye gönderilen yazılar, ilk olarak
dergi standartları açısından incelenir. Derginin
istediği forma uymayan yazılar, daha ileri bir
incelemeye gerek görülmeksizin yazarlarına
iade edilir. Zaman ve emek kaybına yol
açılmaması için, yazarlar
dergi kurallarını
dikkatli incelemeleri önerilir.
Dergi kurallarına uygunluğuna karar
verilen yazılar Editörler Kurulu tarafından
incelenir ve en az biri başka kurumdan olmak
üzere iki ya da daha fazla hakeme gönderilir.
Editör, Kurulu yazıyı reddetme ya da
yazara(lara) ek değişiklikler için gönderme
veya
yazarları
bilgilendirerek
kısaltma
yapmak hakkına sahiptir.
Yazarlardan
istenen değişiklik ve düzeltmeler yapılana
kadar,
yazılar
yayın
programına
alınmamaktadır.
Marmara Medical Journal gönderilen
yazıları
sadece
online
olarak
http://marmaramedicaljournal.org/submit.
adresinden kabul etmektedir.
Yazıların bilimsel sorumluluğu yazarlara
aittir. Marmara Medical Journal yazıların
bilimsel sorumluluğunu kabul etmez. Makale
yayına kabul edildiği takdirde Yayın Hakkı
Devir Formu imzalanıp dergiye iletilmelidir.
Gönderilen yazıların dergide yayınlanabilmesi
için daha önce başka bir bilimsel yayın
organında yayınlanmamış olması gerekir.
Daha önce sözlü ya da poster olarak
sunulmuş
çalışmalar,
yazının
başlık
sayfasında
tarihi
ve
yeri
ile
birlikte
belirtilmelidir. Yayınlanması için başvuruda
bulunulan makalelerin, adı geçen tüm
yazarlar tarafından onaylanmış olması ve
çalışmanın başka bir yerde yayınlanmamış
olması
da
yayınlanmak
üzere
ya
değerlendirmede olmaması gerekmektedir.
Yazının son halinin bütün yazarlar tarafından
onaylandığı ve çalışmanın yürtüldüğü kurum
sorumluları
tarafından
onaylandığı
belirtilmelidir.Yazarlar tarafından imzalanarak
onaylanan üst yazıda ayrıca tüm yazarların
makale
ile
ilgili
bilimsel
katkı
ve
sorumlulukları yer almalı, çalışma ile ilgili
herhangi bir mali ya da diğer çıkar çatışması
var ise bildirilmelidir.( * )
( * ) Orijinal araştırma makalesi veya vaka
sunumu ile başvuran yazarlar için üst yazı
örneği:
"Marmara Medical Journal'de yayımlanmak
üzere sunduğum (sunduğumuz) "…-" başlıklı
makale,
çalışmanın
yapıldığı
laboratuvar/kurum
yetkilileri
tarafından
onaylanmıştır. Bu çalışma daha önce başka
bir dergide yayımlanmamıştır (400 sözcük –
ya da daha az – özet şekli hariç) veya
yayınlanmak
üzere
başka
bir
dergide
değerlendirmede bulunmamaktadır.
Yazıların hazırlanması
Derginin
yayın
dili
İngilizce
veya
Türkçe’dir. Türkçe yazılarda Türk Dil Kurumu
Türkçe
Sözlüğü
(http://tdk.org.tr) esas
alınmalıdır. Anatomik terimlerin ve diğer tıp
terimlerinin
adları
Latince
olmalıdır.
Gönderilen yazılar, yazım kuralları açısından
Uluslararası Tıp Editörleri Komitesi tarafından
hazırlanan “Biomedikal Dergilere Gönderilen
Makalelerde Bulunması Gereken Standartlar “
a ( Uniform Requirements For Manuscripts
Submittted to Biomedical Journals ) uygun
olarak hazırlanmalıdır.
(http://www. ulakbim.gov.tr /cabim/vt)
Makale içinde kullanılan kısaltmalar
Uluslararası kabul edilen şeklide olmalıdır
(http..//www.journals.tubitak.gov.tr/kitap/ma
knasyaz/)
kaynağına
başvurulabilir.
Birimler, Ağırlıklar ve Ölçüler 11. Genel
Konferansı'nda
kabul
edildiği
şekilde
Uluslararası Sistem (SI) ile uyumlu olmalıdır.
Makaleler
Word,
WordPerfect,
EPS,
LaTeX, text, Postscript veya RTF formatında
hazırlanmalı, şekil ve fotoğraflar ayrı dosyalar
halinde TIFF, GIF, JPG, BMP, Postscript, veya
EPS formatında kabul edilmektedir.
Yazı kategorileri
Yazının gönderildiği metin dosyasının
içinde sırasıyla, Türkçe başlık, özet, anahtar
sözcükler, İngilizce başlık, özet,
İngilizce
anahtar
sözcükler,
makalenin
metini,
kaynaklar, her sayfaya bir tablo olmak üzere
tablolar ve son sayfada şekillerin (varsa) alt
yazıları şeklinde olmalıdır. Metin dosyanızın
içinde, yazar isimleri ve kurumlara ait bilgi,
makalede
kullanılan
şekil
ve
resimler
olmamalıdır.
Özgün Araştırma Makaleleri
Türkçe ve İngilizce özetler yazı başlığı
ile birlikte verilmelidir.
(i)özetler: Amaç (Objectives), Gereç ve
Yöntem
(Materials and Methods) ya da
Hastalar
ve
Yöntemler
(Patients
and
Methods), Bulgular (Results) ve Sonuç
(Conclusion) bölümlerine ayrılmalı ve 200
sözcüğü geçmemelidir.
(ii) Anahtar Sözcükler Index Medicus
Medical Subject Headings (MeSH) ‘e uygun
seçilmelidir.
Yazının diğer bölümleri, (iii) Giriş, (iv)
Gereç
ve
Yöntem
/
Hastalar
ve
Yöntemler, (v) Bulgular, (vi) Tartışma ve
(vii) Kaynaklar'dır. Başlık sayfası dışında
yazının hiçbir bölümünün ayrı sayfalarda
başlatılması zorunluluğu yoktur.
Maddi kaynak , çalışmayı destekleyen
burslar, kuruluşlar, fonlar, metnin sonunda
teşekkürler kısmında belirtilmelidir.
Olgu sunumları
İngilizce ve Türkçe özetleri kısa ve tek
paragraflık olmalıdır. Olgu sunumu özetleri
ağırlıklı olarak mutlaka olgu hakkında bilgileri
içermektedir. Anahtar sözcüklerinden sonra
giriş, olgu(lar) tartışma ve kaynaklar şeklinde
düzenlenmelidir.
Derleme yazıları
İngilizce ve Türkçe başlık, İngilizce ve
Türkçe özet ve İngilizce ve Türkçe anahtar
kelimeler yer almalıdır. Kaynak sayısı 50 ile
sınırlanması önerilmektedir.
Kaynaklar
Kaynaklar yazıda kullanılış sırasına göre
numaralanmalıdır.
Kaynaklarda
verilen
makale yazarlarının sayısı 6 dan fazla ise ilk
3 yazar belirtilmeli ve İngilizce kaynaklarda
ilk 3 yazar isminden sonra “ et al.”, Türkçe
kaynaklarda ise ilk 3 yazar isminden sonra “
ve ark. “ ibaresi kullanılmalıdır.
Noktalamalara birden çok yazarlı bir
çalışmayı tek yazar adıyla kısaltmamaya ve
kaynak sayfalarının başlangıç ve bitimlerinin
belirtilmesine dikkat edilmelidir. Kaynaklarda
verilen dergi isimleri
Index Medicus'a
(http://www.ncbi.nim.nih.gov/sites/entrez/qu
ery.fcgi?db=nlmcatalog) veya Ulakbim/Türk
Tıp Dizini’ne uygun olarak kısaltılmalıdır.
Makale: Tuna H, Avcı Ş, Tükenmez Ö,
Kokino
S.
İnmeli
olguların
sublukse
omuzlarında kas-sinir elektrik uyarımının
etkinliği.
Trakya
Univ
Tıp
Fak
Derg
2005;22:70-5.
Kitap: Norman IJ, Redfern SJ, (editors).
Mental health care for elderly people. New
York: Churchill Livingstone, 1996.
Kitaptan Bölüm: Phillips SJ, Whisnant JP
Hypertension and stroke. In: Laragh JH,
Brenner
BM,
editors.
Hypertension:
Pathophysiology,
Diagnosis,
and
Management. 2nd ed. New York: Raven Pres,
1995:465-78.
Kaynak web sitesi ise:
Kaynak
makalerdeki gibi istenilen bilgiler verildikten
sonra erişim olarak web sitesi adresi ve
erişim tarihi bildirilmelidir.
Kaynak internet ortamında basılan
bir dergi ise:
Kaynak makaledeki gibi
istenilen bilgiler verildikten sonra erişim
olarak URL adresi ve erişim tarihi verilmelidir.
Kongre
Bildirileri:
Bengtsson
S,
Solheim BG. Enforcement of data protection,
privacy and security in medical informatics.
In: Lun KC, Degoulet P, Piemme TE, Rienhoff
O, editors. MEDINFO 92. Proceedings of the
7th World Congress on Medical Informatics;
1992 Sep 6-10; Geneva, Switzerland.
Amsterdam: North-Holland; 1992:1561-5.
Tablo, şekil, grafik ve fotoğraf
Tablo, şekil grafik ve fotoğraflar yazının
içine yerleştirilmiş halde gönderilmemeli.
Tablolar, her sayfaya bir tablo olmak üzere
yazının gönderildiği dosya içinde olmalı ancak
yazıya ait şekil, grafik ve fotografların her biri
ayrı bir imaj dosyası (jpeg yada gif) olarak
gönderilmelidir.
Tablo başlıkları ve şekil altyazıları eksik
bırakılmamalıdır. Şekillere ait açıklamalar
yazının gönderildiği dosyanın en sonuna
yazılmalıdır. Tablo, şekil ve grafiklerin
numaralanarak
yazı
içinde
yerleri
belirtilmelidir. Tablolar yazı içindeki bilginin
tekrarı olmamalıdır.
Makale yazarlarının, makalede eğer daha
önce yayınlanmış alıntı yazı, tablo, şekil,
grafik, resim vb var ise yayın hakkı sahibi ve
yazarlardan yazılı izin almaları ve makale üst
yazısına ekleyerek dergiye ulaştırmaları
gerekmektedir.
Tablolar Metin içinde atıfta bulunulan
sıraya
göre
romen
rakkamı
ile
numaralanmalıdır. Her tablo ayrı bir sayfaya
ve tablonun üst kısmına kısa ancak anlaşılır
bir başlık verilerek hazırlanmalıdır. Başlık ve
dipnot açıklayıcı olmalıdır.
Sütun başlıkları kısa ve ölçüm değerleri
parantez
içinde
verilmelidir.
Bütün
kısaltmalar
ve
semboller
dipnotta
açıklanmalıdır. Dipnotlarda şu semboller:
(†‡¶§) ve P değerleri için ise *, **, ***
kullanılmalıdır.
SD veya SEM gibi istatistiksel değerler
tablo veya şekildin altında not olarak
belirtilmelidir.
Grafik, fotoğraf ve çizimler ŞEKİL olarak
adlandırılmalı, makalede geçtiği sıraya gore
numaralanmalı ve açıklamaları şekil altına
yazılmalıdır Şekil alt yazıları, ayrıca metinin
son sayfasına da eklenmelidir. Büyütmeler,
şekilde uzunluk birimi (bar çubuğu içinde) ile
belirtilmelidir.
Mikroskopik
resimlerde
büyütme
oranı
ve
boyama
tekniği
açıklanmalıdır.
Etik
Marmara Medical Journal’a yayınlanması
amacı
ile
gönderilen
yazılar
Helsinki
Bildirgesi, İyi Klinik Uygulamalar Kılavuzu,İyi
Laboratuar Uygulamaları Kılavuzu esaslarına
uymalıdır. Gerek insanlar gerekse hayvanlar
açısından etik koşullara uygun olmayan
yazılar yayınlanmak üzere kabul edilemez.
Marmara Medical Journal, insanlar üzerinde
yapılan araştırmaların önceden Araştırma Etik
Kurulu tarafından onayının alınması şartını
arar. Yazarlardan, yazının detaylarını ve
tarihini bildirecek şekilde imzalı bir beyan ile
başvurmaları istenir.
Çalışmalar deney hayvanı kullanımını
içeriyorsa, hayvan bakımı ve kullanımında
yapılan
işlemler
yazı
içinde
kısaca
tanımlanmalıdır. Deney hayvanlarında özel
derişimlerde ilaç kullanıldıysa, yazar bu
derişimin kullanılma mantığını belirtmelidir.
İnsanlar
üzerinde
yapılan
deneysel
çalışmaların sonuçlarını bildiren yazılarda,
Kurumsal Etik Kurul onayı alındığını ve bu
çalışmanın yapıldığı gönüllü ya da hastalara
uygulanacak prosedürlerin özelliği tümüyle
kendilerine anlatıldıktan sonra, onaylarının
alındığını gösterir cümleler yer almalıdır.
Yazarlar, bu tür bir çalışma söz konusu
olduğunda, uluslararası alanda kabul edilen
kılavuzlara ve TC. Sağlık Bakanlığı tarafından
getirilen ve 28 Aralık 2008 tarih ve 27089
sayılı Resmi Gazete'de yayınlanan "Klinik
araştırmaları Hakkında Yönetmelik" ve daha
sonra yayınlanan 11 Mart 2010 tarihli resmi
gazete ve 25518 sayılı “Klinik Araştırmalar
Hakkında Yönetmelikte Değişiklik Yapıldığına
Dair Yönetmelik” hükümlerine uyulduğunu
belirtmeli ve kurumdan aldıkları Etik Komitesi
onayını göndermelidir. Hayvanlar üzerinde
yapılan çalışmalar için de gereken izin
alınmalı; yazıda deneklere ağrı, acı ve
rahatsızlık verilmemesi için neler yapıldığı
açık bir şekilde belirtilmelidir.
Hasta
kimliğini
tanıtacak
fotoğraf
kullanıldığında,
hastanın
yazılı
onayı
gönderilmelidir.
Yazı takip ve sorularınız için iletişim:
Seza Arbay
Marmara Universitesi Tıp Fakültesi
Dekanlığı,
Tıbbiye Caddesi, No: 49, Haydarpaşa
34668, İstanbul
Tel:+90 0 216 4144734
Faks:+90 0 216 4144731
e-posta: [email protected]
İÇİNDEKİLER
Orjinal Araştırma
THE INCIDENCE OF LOW BIRTH WEIGHT IN 5000 LIVEBORN INFANTS AND THE
ETIOLOGY OF FETAL RISK FACTORS
Emel Altuncu, Sultan Kavuncuoğlu, Pınar Özdemir Gökmirza, Zeynel Albayrak, Ayfer Arduç…….…46
THE ROLE OF VAGINAL MATURATION VALUE ASSESSMENT IN PREDICTION OF
VAGINAL PH, SERUM FSH AND E2 LEVELS
Pınar Yörük, Meltem Uygur, Mithat Erenus, Funda Eren……………………………………..…………...52
RELATIONSHIP BETWEEN ELEVATED SERUM CRP LEVEL AND DIABETES
MELLITUS IN ACUTE MYOCARDIAL INFARCTION
Kenan Topal, Sunay Sandıkçı, Hakan Demirhindi, Ersin Akpınar, Esra Saatçı………………………....58
SOCIAL ISOLATION STRESS IN THE EARLY LIFE REDUCES THE SEVERITY OF
COLONIC INFLAMMATION
Sevgin Özlem İşeri, Fatma Tavsu, Beyhan Sağlam, Feriha Ercan, Nursal Gedik, Berrak C. Yeğen.....65
Olgu Sunumu
LAPAROSCOPIC APPROACH FOR EPIPHRENIC ESOPHAGEAL DIVERTICULA
Osman Kurukahvecioğlu, Ekmel Tezel, Bahadır Ege, Hande Köksal, Emin Ersoy……………..….……73
NEONATAL MIXED SEX-CORD STROMAL TUMOR OF THE TESTIS: A CASE REPORT
Asıf Yıldırım, Erem Başok, Adnan Başaran, Ebru Zemheri, Reşit Tokuç…….…………………………...77
SECONDARY MALIGNANCIES AFTER LYMPHOMA TREATED BY RADIOTHERAPYCASE REPORT
Alper Çelik, Suat Kutun, Turgay Fen, Gülay Bilir, Akın Önder, Abdullah Çetin…………....…………..80
TWO NEW KABUKI CASES OF KABUKI MAKE-UP SYNDROME
Ahmet Sert, Mehmet Emre Atabek, Özgür Pirgon……………………………………………………...........86
Derleme
IS THERE A “HIDDEN HIV/AIDS EPIDEMIC” IN TURKEY?: THE GAP BETWEEN THE
NUMBERS AND THE FACTS
Pınar Ay, Selma Karabey………………………………………………………………………...……………...90
MAGNETIC RESONANCE IMAGING AND ANESTHESIA
Berrin Işık……………………………………………………………………………………………………….…98
ORIGINAL RESEARCH
THE INCIDENCE OF LOW BIRTH WEIGHT IN 5000 LIVEBORN INFANTS AND THE
ETIOLOGY OF FETAL RISK FACTORS
Emel Altuncu, Sultan Kavuncuoğlu, Pınar Özdemir Gökmirza, Zeynel Albayrak, Ayfer Arduç
Ministry of Health,Istanbul Bakırköy Maternity and Children Teaching Hospital, Department of Pediatrics,
Istanbul, Türkiye.
ABSTRACT
Objective: To identify the low birth weight (LBW) incidence in 5000 live born babies in the Bakirkoy
Maternity and Children Teaching Hospital.
Material and Methods: LBW was defined as infant weight below 2500g and these infants constituted the
study group. Babies with normal birth weight (NBW) chosen randomly in equal numbers from 5000 live
born babies formed the control group. Presentation, route of delivery, congenital anomaly, multiple births
and the sex of the infants were also recorded.
Results: In the 5000 live born babies, incidence of LBW was 9.14%. The incidence of preterm and full term
was 5.7% and 3.4%, respectively. Of the LBW infants, 62.8% were preterm, 37.2% were full term. The rate
of multiple gestations was found to be 13.9% in LBW infants and 0.8% in NBW infants. Excluding multiple
gestations, 46.4% of the babies in the LBW group were female, and 53.6% were male. In the NBW group,
the rates were 46.3% and 53.7% respectively. Abdominal delivery was seen in 32.3% of the LBW infants
and 21.6% in the NBW infants. The rate of breech presentation was higher in the LBW (5.1%) than in the
NBW infants (1.3%). The incidence of congenital anomaly was 6.2% in the LBW group and 3.3% in the
NBW group.
Conclusion: The sex of the infant did not have any influence on the birth weight; however, multiple
gestation and congenital anomaly were important factors. Additionally, abdominal delivery and non-vertex
presentations were observed more frequently in the LBW infants.
Keywords: Low birth weight, Incidence, Aetiology
5000 CANLI DOĞUMDA DÜŞÜK DOĞUM AĞIRLIKLI BEBEK ORANI VE
ETYOLOJİDEKİ FETAL RİSK FAKTÖRLERİ
ÖZET
Amaç: Hastanemizde gerçekleşen 5000 canlı doğumdaki düşük doğum ağırlıklı (DDA) bebek oranını
belirlemek amaçlandı.
Gereç ve Yöntem: Doğum ağırlığı 2500g altında olan bebekler düşük doğum ağırlıklı olarak tanımlandı ve
çalışma grubunu oluşturdu. 5000 canlı doğum içinden basit rastgele yöntemle seçilen, DDA bebeklerle aynı
sayıda normal doğum ağırlıklı (NDA) bebek alınarak kontrol grubu oluşturuldu. Tüm bebekler için cinsiyet,
doğum şekli, çoğul gebelikler ve konjenital anomali varlığı öğrenildi.
Bulgular: Beşbin canlı doğumda DDA sıklığı %9.14, term ve preterm DDA bebeklerin sıklığı ise sırasıyla
%5.7 ve %3.4 idi. DDA bebeklerin %62.8'i preterm, %37.2'si term bulundu. Çoğul gebelik sıklığının DDA
bebeklerde %13.9 ve NDA bebeklerde %0.8 olduğu görüldü. Çoğul gebelikler dışlandıktan sonra iki grup
karşılaştırıldı. DDA bebeklerin %46.4'i kız, %53.6'si erkek, NDA bebeklerin %46.3'ü kız ve %53.7'sı
erkekti. Sezeryanla doğum DDA bebeklerde (%32.3), NDA bebeklerden (%21.6) daha fazlaydı. Benzer
şekilde, makat doğum DDA bebeklerde daha sık görüldü (sırasıyla %5.1 ve %1.3). Konjenital anomali
sıklığı DDA bebeklerde %6.2 iken, bu oran NDA bebeklere %3.3 olarak bulundu.
Sonuç: Bebeğin cinsiyetinin doğum ağırlığına etkisi görülmezken, çoğul gebelik ve konjenital anomali
varlığı doğum ağırlığını etkilemekteydi. Ayrıca, DDA bebeklerde sezeryanla doğum ve baş geliş dışındaki
prezentasyonlar daha sık görülmekteydi.
Anahtar Kelimeler: Düşük doğum ağırlığı, Sıklık, Etyoloji
İletişim Bilgileri:
Emel Altuncu
e-mail: [email protected]
SB. Istanbul Bakırköy Maternity and Children Teaching
Hospital,Department of Pediatrics, Istanbul, Turkey
Marmara Medical Journal 2006;19(2);46-51
46
Emel Altuncu, et al.
The incidence of low birth weight in 5000 liveborn infants and the etiology of fetal risk factors
before 37 completed gestational weeks were
defined as preterm. The neonates were
examined
and
all
anthropometric
measurements were obtained at the same
time. A baby was classified as SGA if the
birth weight fell below the 10th percentile for
gestational age, based on Lubchencho curves.
The sex of the infants, presentation, route of
delivery, congenital anomaly and multiple
births were recorded on prepared forms. A
history of congenital anomaly in the family
was also obtained. Babies with normal birth
weight (NBW) (≥2500g) chosen randomly in
equal numbers from 5000 live born babies
formed the control group and the same
parameters were evaluated for this group.
INTRODUCTION
Low birth weight (LBW) is responsible for 60%
of the infant mortality in the first year of life and
it carries a 40-fold increase in the risk of neonatal
mortality during the first month 1-4. Since birth
weight has a strong correlation with infant
survival, attentions have been given to strategies
that will reduce the proportion of infants with
LBW. With recent advances in modern obstetric
and neonatal care and technological development,
high risk neonates have a greater chance of
survival in the newly formed intensive care units.
This also causes an increase in the rate of LBW
infants, and subsequently an increased rate of
long-term neurological sequelae.
The World Health Organization has estimated that
annually 24 million LBW infants are born in
developing countries. As the prevalence of LBW
infants is around 5% in many industrialized
countries, it changes between 5-30% in
underdeveloped or developing countries 3,5-12. If
we take into account that, millions of LBW
infants are born annually in the World, we need
to begin researching the health of neonates
starting with birth weight. In this prospective
study, we aimed to identify the LBW incidence in
5000 live born babies in our hospital and the
associated risk factors of LBW related to the
infant. We also aimed to evaluate the rate of
infants who were small for gestational age
(SGA), rate of preterm delivery, their sex
distribution, route of delivery, presentation,
incidence of multiple gestations and congenital
anomalies.
We used Chi Square and Mantel-Haenszel
tests for statistical analysis. Statistical
significance in this study was defined as
p<0,05.
RESULTS
Of the 5000 live born babies, 457 were LBW
infants. The overall incidence of the LBW was
9.14% and 62.8% of the LBW infants were
preterm, 37.2% were full term. The incidence of
preterm delivery and full term SGA was 5.7%
and 3.4%, respectively. The preterm SGA
incidence was 1.1%. NBW infants chosen
randomly in equal numbers were 457 in number
and incidence of preterm delivery was 2.4%. The
mean gestational age and birth weight of the
infants in two groups were shown in Table I. The
birth weight of 3.3% of the LBW infants was less
than 1000g, 10.7% weighed between 1001-1500g,
22.3% weighed between 1501-2000g and 63.7%
were between 2001-2500g.
METHODS
In this prospective cross-sectional study, 5000 live
born babies were evaluated randomly between
October 2000-May 2001 in the Bakirköy
Maternity and Children’s Hospital in Istanbul.
Aborted babies and stillbirths were excluded
because of difficulties in accurately defining
gestational age. The infants were weighed on an
electronic metric scale in the delivery room
immediately after birth.
There were 410 mothers in the LBW group and
456 mothers in the NBW group. The rate of
multiple gestations was found to be 13.9% in the
LBW infants and 0.8% in the NBW infants (Table
I). There was a statistically significant difference
between the two groups (x2=52.01, p=0.000).
Multiple gestations were found to be an important
risk factor in the aetiology of LBW.
LBW was defined as infant weight below
2500g and these infants constituted the study
group. Since the accurate date of the last
menstrual period was not known in about one
third of the mother and due to failing routines
in the maternity ward, the gestational age was
estimated by Ballard scoring performed in the
first 24 hours after delivery. Babies born
To evaluate the other risk factors related to
the birthweight, we excluded the multiple
gestations.Excluding multiple gestations,
there were 353 infants in the LBW group and
453 infants in the NBW group.
In the LBW group, 46.4% were female, 53.6%
were male and in the NBW group 46.3% were
female, 53.7% were male (Table I). No
47
difference was statistically significant (x2=11.63,
p=0.001). The indications for abdominal delivery
are in Table II. Elective abdominal deliveries were
more frequent in the NBW infants but the
preference for caeserean section was based more
commonly on perinatal problems among the LBW
births.
statistically significant difference was found when
comparing the sex of the babies in the two groups
(x2=0.01, p=0.97).
Mode of delivery was compared between the two
groups. Delivery by way of caesarean section was
seen in 32.3% of the LBW group and this rate was
21.6% in the NBW group (Table I). The
Table I: Characteristics of LBW and NBW infants
LBW
NBW
The mean gestational age (w)
35.8 ±2.5
38.1 ± 0.6
The mean birth weight (g)
2037.7 ± 430.6
3352.1 ± 401.8
Multiple gestation (%)
13.9
0.8
Female (%)
46.4
46.3
Male (%)
53.6
53.7
Caesarean section (%)
32.3
21.6
Non-vertex presentation (%)
6.5
1.3
Congenital anomalies (%)
6.2
3.3
Table II: The indications for abdominal delivery in LBW and NBW infants
Indications
Fetal distress
LBW
n:353
31
%
8
NBW
n:453
%
31
7
Elective C/S
28
8
47
10
IUGR/LGA
12
3
4
1
Preeclampsia
11
3
2
0.4
Abruptio placenta
7
2
4
1
Oligohydroamniosis
9
2
-
-
Non-vertex presentation
6
2
2
2
Placenta previa
2
1
4
1
Premature rupture of membranes
5
1
1
0.2
Cord presentation
1
0.3
2
0.4
Fetal anomaly
2
0.5
1
0.2
Maternal hyperthyroidism
-
-
1
0.2
48
preterm infants with congenital anomalies were
preterm SGA babies. 72% of the LBW infants
with congenital anomalies were full term or
preterm SGA. A family history of congenital
anomalies was seen in 2.8% of the LBW infants
and in 2.4% of the NBW babies. There was no
important difference statistically (x2=0.12,
p=0.72). Also, the effect of consanguinity
between parents on birth weight was evaluated.
7.5% of the cases had first-degree consanguinity
between the mother and father in the LBW group
and this rate was 7.8% in the NBW group. Second
or higher degrees of consanguinity rates were 7%
and 5%, respectively in both groups. This result
did not create a statistically significant importance
(x2=0.05, p=0.81). and consanguinity between
parents was not found to be a risk factor in the
aetiology of LBW.
The rate of breech presentation was higher in the
LBW (5.1%) than in the NBW infants (1.3%).
1.4% of the
LBW infants were born by
incomplete breech presentation, but there were no
babies born by incomplete breech presentation
among the NBW infants (Table I). LBW was
associated with increased rate of non-vertex
presentations (x2=16.46, p=0.000).
In this study, congenital anomalies of the study
and the control groups were evaluated (Table III).
The incidence was 6.2% in the LBW group and
3.3% in the NBW group (Table I). The difference
between the two groups was important (x2=3.86,
p=0.04). Among the LBW newborns having
isolated or multiple congenital malformations,
2.5% were SGA and 3.7% were premature. The
incidence of congenital malformations in all SGA
babies was 5.8%. In our preterm population, the
malformation incidence was 6.5%, but 54% of the
Table III: Congenital anomalies of LBW and NBW infants
LBW
Isolated defects
Congenital hip dislocation
(+ Pes equinovarus)
Sacral sinus
Myeloschisis
Hypospadias
Cryptorchidism
Inguinal hernia
Ambiguous genitale
Anal atresia/small intestine stenosis
Cleft lip and palate
Extremity anomalies
Others (diastasis recti, hypotelorism,
cleft uvula, penile mass)
Multiple anomalies
Down’s Syndrome
Ambiguous genitalia, hydrocephaly, vaginal
atresia, anal atresia
Myelomeningocele, hydrocephaly, extremity
anomaly
Atypical face, cyanotic congenital heart
disease, limb anomaly
Cleft lip and palate, microcephaly, atypical face,
syndactylism
49
NBW
6
3
2
1
3
1
2
1
2
3
1
2
4
1
1
1
1
4
-
1
1
-
1
-
1
-
1
-
cord passes the cervix before the head, so the
umbilical cord is entrapped in between the cervix
and head. After the beginning of compression,
delay in labour increases hypoxia. With a LBW
infant, the size of the head is even greater in
relation to that of the buttocks and the chance of
entrapment is markedly increased. This condition
results in increased hypoxia and because it needs
traction, it can cause trauma to the spinal cord and
skeletal system. Goldenberg and Nelson found
that, during labour, the premature fetus in breech
presentation was 16 times more likely to die than
the premature fetus in vertex presentation 18. For
these reasons, in LBW neonatesthe most rational
method of delivery is caesarean section 19. In view
of this information it may
be said that,
identification of high-risk pregnancies and choice
of appropriate method of delivery have been
successfully achieved in our hospital parallel to
the literature.
Intrauterine growth retardation (IUGR) is a
frequently reported outcome among infants with
congenital malformations. The presence of IUGR
may indicate an underlying structural abnormality
or aetiologically it may predispose to defects
rather than vice versa 20. The rate of congenital
malformations was 6.2% in the LBW group, 3.3%
in the NBW group indicating a strong association
between LBW and malformations. Among the
LBW neonates with isolated or multiple
congenital malformations, 2.5% were SGA and
3.7% were premature. However, the incidence of
congenital malformations in all SGA babies, was
5.8%. In our preterm population, malformation
incidence was 6.5%, but 54% of the preterm
infants with congenital anomalies were preterm
SGA babies. If we take full term and preterm
SGA infants into consideration together, 72% of
LBW infants with congenital anomalies were
SGA. In a study reported in our hospital in 1999,
congenital malformations was the fourth leading
cause of death (11.4%) in perinatal mortality
cases4. The significant role of congenital
malformation in the aetiology of the LBW,
especially for IUGR, causing an increase from
3.3% to 8% in the risk of LBW indicates a need to
check for malformations by performing antenatal
ultrasonography more strictly in IUGR
fetuses.Furthermore, it emphasızes the need for a
higher number of more developed genetic
laboratories.
There was a limitation in this study. Because our
study was performed in a maternity ward, if there
were no symptoms or sings reflecting congenital
infections, we did not check for congenital
DISCUSSION
In this study, incidence of LBW infants was
9.14% and this was similar to the literature 13.
Previous studies have reported similar results, for
example, the LBW rates in two different studies in
Turkey were 8.7% and 10%, respectively 14,15. In
many developed countries, LBW rates are around
5% 12. The rate of LBW in our study was similar
to rates reported in developed countries. The
similarity to developed countries can be based
upon the contribution of only live born neonates.
The perinatal mortality (34.9‰) is very high in
our country and a great number of LBW and very
LBW infants are lost during parturition 4. So this
leads to misinterpretation of the outcome.
Although multiple gestations represented only
2.09% of the live births, they account for a
disproportionately large share of adverse
pregnancy outcomes. With the development of
obstetrical approaches, the incidence of multiple
gestations began to increase. The risk of giving
birth to a LBW infant increased significantly in
multiple gestations in our study and 80% of
multiple gestations resulted in preterm birth.
Studies dealing with the aetiology of LBW have
shown us that, female sex is an important risk
factor and this is attributed to the predisposition of
the female sex to the other risk factors 6,16,17. In
our study, the rate of male and female sex among
LBW infants was similar and this led us to
conclude that the sex of the infant did not affect
the weight of the baby.
Other important results were the significant
differences in the method of delivery and the
presentations of neonates between the LBW and
NBW groups. The rate of caesarean section was
much higher in the LBW births (32.3%) than in
the NBW births (21.6%). Delivery by way of
caesarean section was seen more frequently in
LBW infants and this indicated once more that
LBW infants were more prone to morbidity and
mortality.
The rate of cephalic presentation was 93.5% in the
LBW group, but 98.7% in the NBW group. When
compared with cephalic presentation, breech
births were associated with an increased rate of
LBW. Whereas, the overall incidence of breech
presentation in deliveries is only 3% to 4%, for
infants weighing less than 2500g at birth, the
incidence may be 30% or greater. As compared
with the NBW infants, birth trauma and umbilical
cord prolapsus are seen more commonly in LBW
and/or breech births. During labour, the umbilical
50
8.
infections because of high cost. So we did not
include the incidence of congenital infections in
the aetiology of LBW.
9.
In summary, improving the community health
should start with improving baby health, and
developing new strategies to decrease the
incidence of LBW infants should be the one of
our first goals. A history of a LBW infant should
be an indication to seek recurrent cases of low
birth weight and to ensure that close monitoring of
fetal growth is implemented in subsequent
pregnancies.
10.
11.
12.
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ORIGINAL RESEARCH
THE ROLE OF VAGINAL MATURATION VALUE ASSESSMENT IN PREDICTION OF
VAGINAL PH, SERUM FSH AND E2 LEVELS
1
Pınar Yörük1, Meltem Uygur1, Mithat Erenus1, Funda Eren2
Marmara University, Obstetrics and Gynecology, İstanbul, Türkiye 2Marmara University, Pathology,
İstanbul, Türkiye
ABSTRACT
Introduction: The objective of this study is to detect the correlation between vaginal maturation value (MV)
and vaginal pH measurement, serum FSH and E2 levels in women without vaginal infection.
Materials And Methods: Fifty women with vasomotor symptoms were enrolled at the present study. All
women underwent vaginal pH assessment, measurement of serum FSH and E2 levels and vaginal MV
measurement in addition to routine follow-up. For determination of vaginal MV, pap smear from lateral
vaginal wall was obtained and evaluated.
Results: In women with atrophic symptoms, the age and vaginal pH levels were significantly higher than
women without these symptoms. Highly significant correlation between vaginal pH, vaginal MV and serum
FSH was detected. Similarly highly significant inverse correlation was present between vaginal pH levels
and vaginal MV.
Discussion: In summary, this study confirms that vaginal pH and MV are similar to FSH in the identification
of patients who have low estrogen levels or who are menopausal. Methods of deriving vaginal pH and MV
are simple, practical, quick and economic. As a conclusion, the present study demonstrated that vaginal pH
measurement and vaginal MV assessment is similar in diagnosis and monitoring of estrogen deficiency in
women with urogenital atrophic symptoms.
Keywords: vaginal maturation value, pH, menopause
VAJİNAL PH, SERUM FSH VE E2 SEVİYELERİNİ ÖN GÖRMEDE VAJİNAL
MATURASYON İNDEKSİNİN DEĞERİ
ÖZET
Giriş: Bu çalışmanın amacı vajinal enfeksiyonu olmayan kadınlarda vajinal maturasyon değeri (MV) ile
vajinal pH, serum FSH ve E2 değerleri arasındaki korelasyonu saptamaktır.
Materyal ve Metotlar: Vasomotor semptomları olan 50 kadın çalışmaya dahil edildi. Kadınlara rutin takibe
ek olarak vajinal pH, vajinal MV, serum FSH ve E2 ölçümleri uygulandı.
Sonuçlar: Atrofik semptomları olan kadınlarda yaş ve vajinal pH değerleri semptomu olmayan kadınlara
oranla anlamlı olarak daha yüksek bulundu. Vajinal pH, vajinal MV ve serum FSH arasında kuvvetli bir
korelasyon tespit edildi. Benzer şekilde, vajinal pH değerleriyle vajinal MV arasında da kuvvetli ters
korelasyon gözlendi.
Tartışma: Bu çalışmanın sonuçları menopozda olan veya düşük serum östrojeni olan kadınların ayırımında
vajinal pH ve vajinal MV değerlerinin serum FSH ile benzer olduğunu doğrulamaktadır. Vajinal pH ve MV
ölçümü basit, pratik,hızlı ve ekonomiktir. Vajinal pH ve vajinal MV ölçümünün ürogenital atrofik şikayetleri
olan kadınlarda östrogen eksikliğinin tanısında ve takibinde benzer olduğu gösterilmiştir.
Anahtar Kelimeler: vajinal maturasyon değeri, pH, menopoz
Pınar Yörük
Marmara University, Obstetrics and Gynecology, İstanbul, Türkiye
52
Pınar Yörük, et al.
The role of vaginal maturatıon value assessment in prediction of vaginal ph, serum fsh and E2 levels
wrapped test (contains nitrazine yellow for pH test
and bromocresol green for amines test), and sterile
amine controlled cotton swabs. Cotton swabs are
applied to the lateral vaginal wall, then rubbed
over the entire surface of the tests. Results are
interpreted by formation of blue “plus” or
“minus” sign on each test. Afterwards, nitrazine
paper is contacted to the vagina for 5 seconds, and
the color of the paper is compared with a
colorimetric scale on an enclosed card, and the pH
value is determined.
INTRODUCTION
Menopause has great impacts on life-quality of all
women and is defined as cessation of menstrual
bleeding for at least 12 months, serum FSH value
≥ 40 mIU/ml, and serum E2 level < 20 pg/ml. It
has been known for decades that without vaginal
infections, vaginal pH is ≤ 4.5 during the
reproductive years and > 4.5 before menarche and
after menopause 1. Only methods of deriving
vaginal pH were not practical, and had low
sensitivity and specificity due to contamination
with cervical mucus, blood, or semen 2. Vaginal
maturation value (MV) of Meisels 3 calculated
from the ratios of superficial, intermediate and
parabasal cells in vaginal smears has been used to
detect vaginal atrophy and estrogen deficiency in
postmenopausal symptomatic women. MV is a
useful marker to examine vaginal maturation and
reveal vaginal estrogen deficiency regardless of
the presence of inflammation4. After the
introduction of vaginal pH device, it has been
proposed that determination of vaginal pH in the
absence of vaginitis in an outpatient setting might
be a diagnostic feature of menopause. In this
study we aimed to detect the correlation of vaginal
MV with vaginal pH measurement, serum FSH
and E2 levels in women with climacteric
symptoms.
Vaginal MV assessment: Cytological evaluation
was performed by vaginal smears collected from
the mid-third of the vaginal lateral wall and
evaluated in our Pathology Department . In a total
of 100 exfoliation cells, parabasal cells (P),
intermediary cells (I), and superficial cells (S)
were counted and results were expressed as the
maturation value (MV) of Meisels 3. Superficial
cells were assigned a point value of 1.0,
intermediate cells were assigned a point value of
0.5, and parabasal cells were assigned a point
value of 0. The number of cells in each category
was multiplied by the point value, and the 3
results were added to arrive at a maturation value.
A value of 0 to 49 indicated low estrogen effect, a
value of 50 to 64 indicated moderate estrogen
effect, and a value of 65 to 100 indicated high
estrogen effect. All examinations were interpreted
by the same cytopathologist without prior
knowledge of the subjects’ data.
METHODS
Study population: Fifty peri-postmenopausal
otherwise healthy women attending to our
menopause outpatient clinic with climacteric
symptoms for the first time were enrolled at the
present study. Demograpic characteristics
including age, gravidy, parity and body mass
index (BMI) and urogenital atrophic symptoms
were questioned by the presence of vaginal
dryness, dyspareunia, pruritus and dysuri. All
women underwent vaginal pH assessment,
measurement of serum FSH and E2 levels and
vaginal MV measurement in addition to routine
follow-up. Amine test was carried out
simultaneously with vaginal pH assessment in
order to rule out vaginal infections and exclude
false positive pH values. Women who have
surgical menopause, systemic diseases, positive
amine test, previous vaginal surgery involving
more than 1/3 of the vagina, and women with
history of current or past therapy of estrogenprogesteron replacement are excluded.
Statistical analysis: In women with negative
amine test, chi-square test, Pearson correlation test
and logistic regression test were used where
appropiate to assess vaginal pH levels and vaginal
MV with menopausal status and urogenital
atrophic symptoms. For statistical analysis SPSS
11.5 (SPSS, Inc, Chicago, IL, U.S.A.) was used.
RESULTS
Out of 50 women enrolled, 2 had positive amine
test and remaining 48 women were included into
the statistical analysis. The mean age was 54,7
years (range 47-70 years), mean body mass index
was 25,5. Of the 48 women 18 (37,5%) had serum
FSH levels < 40mIU/ml. The mean FSH value, E2
value, and MV were 53,3 mIu/ml; 17,4 pg/ml and
49,1 respectively. The percentage of women with
pruritus was 18,7% (n=9); dysuri was 27%
(n=13), vaginal dryness was 64,6% (n=31) and
dyspareunia was 70,8% (n=34). All of the women
with urogenital atrophic symptoms had vaginal
pH values >5.2 (mean value 6,5±0,48), MV< 65
(mean value 34,7±16,2), serum FSH levels > 40
mIU/ml and E2 levels < 20 pg/ml. The
Vaginal pH measurement: Vaginal pH levels are
measured by Quickvue® Advance pH and Amines
Test, developed by Quidel® Corporation (San
Diego, USA). This device is composed of a foil
53
E2 levels, and vaginal MV (p<0,001; p<0,01
respectively) (Figure 1). However, serum FSH
levels were statistically similar between groups
probably due to high standart deviation values.
There was no significant difference between
groups according to gravidy, parity and body mass
index.
demographic and hormonal characteristics of the
women according to the presence of any of the
questioned urogenital atrophic symptoms are
listed in Table 1.
In women with atrophic symptoms, the age and
vaginal pH levels were significantly higher than
women without these symptoms (p<0,003;
p<0,001 respectively). In addition, women with
atrophic symptoms had significantly lower serum
Table 1: The demographic and hormonal characteristics of the women according to the presence of vaginal atrophic
symptoms
General Features
Age (yrs)
Gravidy
Parity
BMI
Hormonal Features
Serum FSH (mIU/ml)
E2 (pg/ml)
Vaginal
Maturation Value
Parabasal
Intermediate
Superficial
pH
(+)
(-)
n=34 (70,8%)
n=14 (29,2%)
Mean ± SD
Mean ± SD
56,4
3,3
1,8
25,1
±
±
±
±
5,1 ¹
2,5
1,2
3,4
50,1
4,1
2,2
26,4
Mean ± SD
12,6 ± 3,7
4
32,2 ± 15,5
Mean ± SD
±
±
±
±
±
4,8¹
2,2
0,8
3,7
Mean ± SD
70,1 ± 23,2
4
11,2 ± 5,4
34,7
19,7
75,6
4,7
6,5
±
±
±
±
Mean ± SD
16,2 ³
27,7
26,9
9,4
0,48 ²
83,8
4,6
32,8
62,5
4,6
±
±
±
±
±
9,4³
7,4
35,3
34,1
0,31²
4
¹ = p<0,003; ² = p<0,001; ³ = p<0,01; = p<0,001
Figure 1: A-B) Different examples of atrophic vaginal smear (Pap stain x 100)
54
n=48 (100%)
Mean ± SD
54,7
3,5
1,1
25,5
±
±
±
±
5,5
2,4
3,5
3,5
Mean ± SD
53,3 ± 32,8
17,4 ± 13,4
Mean ± SD
49,1
15,3
63,1
21,5
5,9
±
±
±
±
±
26,7
24,5
35,2
33
0,95
decrease in MV only moderately correlated with
decreasing circulating E2 values. Lineer regression
analysis was performed and showed significant
increase of vaginal pH and significant decrease of
MV with rising serum FSH levels. In the present
study the positive and negative predictive values
for vaginal MV < 65 to predict serum FSH levels
≥ 40mIU/ml was calculated as 100% and 83%
respectively.
DISCUSSION
In the present study vaginal MV assessment and
vaginal pH measurement correlates with serum
FSH and E2 levels. Accordingly estrogen
deficiency in women can be detected by simply
determining MV in vaginal smear specimens as
well as measuring vaginal pH performed during
routine gynecologic follow-up. The menopausal
transition period lead to the development of
certain signs and symptoms adversely affecting
the life-quality of most women due to systemic
estrogen deficiency. Most prominent of these
symptoms are vasomotor hot flushes, insomnia,
urogenital atrophy and problems in sexual
function 5. In spite of the fact that vaginal dryness
due to atrophic vaginitis is known to be present in
up to 40% of postmenopausal women 6, the real
incidence might be even higher since women,
especially in advanced ages, regard these
symptoms as age specific. Capewell et al,
proposed that some clinical characteristics can
predict the atrophy degree 7. In their study of 120
postmenopausal women, they found a correlation,
among the atrophy degree at the vaginal cytology
and the vaginal dryness at physical examination,
low parity and physical thinness 7. However,
Davila et al demonstrated weak correlations
between symptoms scores and objective measures
of genital atrophy 8. They concluded that vaginal
pH is the solid predictor of maturation value and
may be the most reliable indicator of urogenital
atrophy 8. In the present study, the strong inverse
correlation between vaginal pH and MV confirms
the previous findings. According to the results of
the present study, MV measurement can aid the
clinicians to predict serum FSH levels and vaginal
pH values. MV assessment alone could be a guide
for the diagnosis and management of a woman
with urogenital atrophy regardless of the presence
of atrophic symptoms.
Figure 2: The inverse correlation between serum FSH
levels and vaginal MV. (r=-0,868; p<0,01)
Figure 3: The inverse correlation between vaginal pH and
vaginal MV (r=-0,903; p<0,01)
Pearson correlation analysis showed highly
significant inverse correlation between vaginal
MV and serum FSH (r=-0,87; p<0.01) (Figure 2).
Similarly highly significant inverse correlation
was present between vaginal pH levels and
vaginal MV (r=-0,9; p<0,01) (Figure 3).
Calculated correlation was moderate between
vaginal MV and serum E2 levels (r=0,55; p<0,01).
MV significantly decreased concomitant with
increasing serum FSH levels and increasing
vaginal pH values. On the other hand, the
The positive correlation between vaginal pH and
serum FSH has been demonstrated previously in
the meta-analysis of 16 reports by Roy et al 9. In
their study they confirmed that vaginal pH reflects
circulating estradiol levels 9. Therefore, with the
55
use of vaginal pH values, it is possible to monitor
the introduction dose, change the continuation
dose and route of therapy in women receiving
estrogen replacement therapy (ET). In women
with urogenital atrophic symptoms, who receive
ERT, elevated vaginal pH decrease to lower levels
resulting in partially or completely relief of the
symptoms 9. In a postmenopausal woman who is
on ET, vaginal pH value of > 4,5 indicates low
circulating estradiol levels, which suggests the
need for an adjustment of dose or route of
hormone therapy 10. However in the present study
decreasing serum E2 levels were only moderately
correlated with increasing vaginal pH values and
decreasing MV. It has been demonstrated
previously that in some women although serum E2
levels are sufficient, vaginal atrophy may persist
11
. For them, augmenting oral therapy with topical
vaginal estrogen may be necessary 12. In the
present study the demonstrated inverse correlation
between vaginal pH and MV point out that MV <
65, similarly, suggests vaginal estrogen deficiency
although sufficient circulating E2 levels might be
detected, and administration of ET or adjustments
in dose or route of ET would be necessary.
In women with vaginitis, vaginal pH measurement
has increased false positive results due to
overgrowth of facultatively and obligately
anaerobic bacteria 13, and is useful only for
monitoring antimicrobial therapy. Therefore,
amine test is preferably performed simultaneously
with the vaginal pH measurement to rule out
vaginal inflammation even in asymptomatic
women. Conversely, MV is not adversely affected
and can be safely used to document estrogen
deficiency in women with vaginal inflammation.
classified according to urogenital atrophic
symptoms might not be generalized for older
women who regard these symptoms as age
specific.
In the present study we concluded that vaginal
MV is similar to vaginal pH in the identification
of patients who have low estrogen levels or who
are menopausal. In postmenopausal women
receiving ET, vaginal MV calculation would aid
the clinicians, in the same manner as vaginal pH,
to monitor the therapy, change the dose or route of
administration, or augment the therapy with a
topical vaginal estrogen. Methods of deriving
vaginal MV and pH are simple, practical, quick
and economic. Moreover, MV can be obtained
simultaneously with Pap smear test, which is a
part of routine follow-up, does not require
additional intervention, and easily interpreted at
office setting. As a conclusion the present study
demonstrated that vaginal maturation value
assessment, unlike serum E2 levels, is similar to
vaginal pH values in diagnosis and management
of estrogen deficiency in perimenopausal and
early postmenopausal women with urogenital
atrophic symptoms regardless of receiving past or
current estrogen replacement therapy.
REFERENCES
1.
2.
From previous studies it is known that body mass
index can influence serum E2 values and
consecutively vaginal pH 9. In the present study
body mass index of women without vaginal
atrophic symptoms was similar to women with
vaginal atrophy. Therefore body mass index was
not a confounding factor in the present study.
3.
4.
The positive and negative predictive values should
be calculated by epidemiologic population-based
studies. The power of this study is not obviously
enough to calculate a solid predictive value of
vaginal pH or MV for menopausal status. On the
other hand, percentages mentioned reflect the
population referring to our clinic and might aid
the clinicians in diagnosis and follow-up. It should
also be noted that the population included into the
present study was perimenopausal and early
postmenopausal women; therefore results
5.
6.
7.
8.
56
Cruickshank, R., Sharman A. The biology of the
vagina in human subjects: I, glycogen in the
vaginal epithelium and its relation to ovarian
activity; II, the bacterial flora and secretion of the
vagina at various age-periods and their relation to
glycogen in the vaginal epithelium; III, vaginal
discharge of non-infective origin. J Obstet
Gynaecol Br Empire, 1934(41): 190-207, 208-26,
369-84.
Rein, M.F., Muller, M. Trichomonas vaginalis and
trichomonias, in Sexually transmitted diseases,
K.K. Holmes, et al., Editors. 1990, McGraw-Hill:
New York. 481-92.
Meisels, A. The maturation value. Acta Cytol,
1967. 11(4): 249.
Chiechi, L.M., Putignano, G., Guerra, V.,
Schiavelli, M.P., Cisternino, A.M., Carriero, C. The
effect of a soy rich diet on the vaginal epithelium in
postmenopause: a randomized double blind trial.
Maturitas, 2003. 45(4): 241-6.
Zapantis, G., Santoro, N. The menopausal
transition: characteristics and management. Best
Pract Res Clin Endocrinol Metab, 2003. 17(1): 3352.
Bachmann, G.A., Nevadunsky N.S. Diagnosis and
treatment of atrophic vaginitis. Am Fam Physician,
2000. 61(10): 3090-6.
Capewell, A.E., McIntyre M.A, Elton R.A. Postmenopausal atrophy in elderly women: is a vaginal
smear necessary for diagnosis? Age Ageing, 1992.
21(2): 117-20.
Davila, G.W., Singh, A., Karapanagiotou, I.,
Woodhouse, S., Huber, K., Zimberg, S., et al. Are
women with urogenital atrophy symptomatic? Am
J Obstet Gynecol, 2003. 188(2): 382-8.
9. Roy, S., Caillouette, J.C., Roy, T., Faden, J.S.
Vaginal pH is similar to follicle-stimulating
hormone for menopause diagnosis. Am J Obstet
Gynecol, 2004. 190(5): 1272-7.
10. Caillouette, J.C., Sharp, C.F. Jr., Zimmerman, G.J.,
Roy, S. Vaginal pH as a marker for bacterial
pathogens and menopausal status. Am J Obstet
Gynecol, 1997. 176(6): 1270-5; discussion 1275-7.
11. Benjamin, F., Deutsch, S. Immunoreactive plasma
estrogens and vaginal hormone cytology in
postmenopausal women. Int J Gynaecol Obstet,
1980. 17(6): 546-50.
12. Notelovitz, M. Estrogen therapy in the management
of problems associated with urogenital ageing: a
simple diagnostic test and the effect of the route of
hormone administration. Maturitas, 1995. 22 Suppl:
S31-3.
13. Cauci, S., Driussi, S., De Santo, D., Penacchioni,
P., Iannicelli, T., Lanzafarne, P. et al. Prevalence of
bacterial vaginosis and vaginal flora changes in
peri- and postmenopausal women. J Clin
Microbiol, 2002. 40(6): 2147-52.
57
ORIGINAL RESEARCH
AKUT MYOKARD ENFARKTÜSÜNDE YÜKSELMİŞ SERUM CRP DÜZEYİ VE
DİABETES MELLİTUS İLE İLİŞKİSİ
Kenan Topal1, Sunay Sandıkçı1, Hakan Demirhindi2, Ersin Akpınar3, Esra Saatçı3
Adana Numune Eğitim ve Araştırma Hastanesi , Aile Hekimliği, Adana, Türkiye 2Çukurova Üniversitesi Tıp
Fakültesi , Halk Sağlığı Anabilim Dalı, Adana, Türkiye 3Çukurova Üniversitesi Tıp Fakültesi, Aile Hekimliği
Anabilim Dalı, Adana, Türkiye
1
ÖZET
Amaç: Günümüzde aterosklerozun enflamatuar bir hastalık olduğu ve serum CRP düzeyinin, aterosklerozun
şiddeti ve genişliği ile korele şekilde yükseldiği kabul edilmektedir. Bu çalışmada, Ocak 2000 ile Temmuz
2000 tarihleri arasında, Adana Numune Eğitim ve Araştırma Hastanesi Koroner Yoğun Bakım Ünitesi’ne
(KYBÜ) AMİ tanısıyla yatırılıp trombolitik tedavi uygulanan 55 hastada infarkt tipi ve genişliği ile serum
CRP düzeyleri arasındaki ilişki incelendi.
Gereç ve Yöntem: Göğüs ağrısının başlangıcından itibaren 12. saatte serum CRP, kardiak troponin İ, CKMB, LDH, AST, beyaz küre, sedimantasyon düzeyleri incelendi.
Bulgular: Serum CRP düzeyi ortalama 24.5 mg/L, beyaz küre sayısı ortalama 14.2 X103/ml olup belirgin
olarak yüksekti. Serum CRP düzeyi ile infarkt tipi ve genişliği arasında ilişki yoktu. Ayrıca CRP yüksekliği
ile diabetes mellitus varlığı arasında pozitif yönde bir ilişki olduğu görüldü (r: 0.479, p<0.01).
Sonuç: AMİ’nde serum CRP düzeyinin yükselmesi, akut koroner sendromlarda enflamasyonun rolünü
göstermesi açısından önemlidir.
Anahtar Kelimeler: Ateroskleroz, enflamasyon, CRP, akut myokard enfarktüsü
RELATIONSHIP BETWEEN ELEVATED SERUM CRP LEVEL AND DIABETES
MELLITUS IN ACUTE MYOCARDIAL INFARCTION
ABSTRACT
Aim: Today, atherosclerosis is accepted as an inflammatory disease and serum CRP levels increase in
correlation with the severity and extensiveness of atherosclerosis. The aim of this study is to investigate the
relationship between infarct type and extensiveness and serum CRP levels in 55 patients hospitalized in
Intensive Care Unit of Adana Numune Hospital for acute myocardial infarction (AMI) between January-July
2000.
Methods: Serum CRP, cardiac troponin I, CK-MB, LDH, AST, WBC, ESR levels were performed within 12
hours after the onset of chest pain.
Results: Serum CRP and WBC were significantly high with 24.5 mg/L and 14.2 X103/ml, respectively.
There was no relationship between serum CRP level and infarct type and extensiveness. There was positive
correlation between CRP and diabetes mellitus (r: 0.479, p<0.01).
Conclusion: Elevated serum CRP levels in AMI shows the role of inflammation in acute coronary
syndromes.
Keywords: Atherosclerosis, inflammation, CRP, acute myocardial infarction
Esra Saatçı
Çukurova Üniversitesi Tıp Fakültesi, Aile Hekimliği Anabilim Dalı, Adana, Türkiye
58
Kenan Topal ve ark.
Akut myokard enfarktüsünde yükselmiş serum CRP düzeyi ve diabetes mellitus ile ilişkisi
Akut Yaygın Anterior Mİ: DI-AVL, V1-V6’da ST
yükselmesi varsa
- Akut İnferior Mİ: DII-DIII-AVF’de ST
yükselmesi, V5-V6’da ise ST çökmesi varsa
GİRİŞ
-
Son yıllarda aterosklerozun etiyopatogenezine
yönelik çalışmalar aterosklerozun enflamatuar bir
hastalık olduğunu, her evresinde enflamasyonun
rol aldığını, enflamasyonun aterom plağı
gelişimini hızlandırdığını ve akut olayların
oluşumunu çabuklaştırdığını göstermektedir1-5.
Koroner arter hastalıklarında ‘akut faz reaktanları’
olan C-reaktif protein (CRP), serum amiloid-A
(SAA) ve fibrinojen düzeylerinin yükseldiği
gösterilmiştir. Miyokard nekrozunun olmadığı
kardiyovasküler hastalıklarda, serum CRP düzeyi
aterosklerozun şiddeti ve genişliğiyle korelasyon
göstermektedir6-9.Diğer yandan akut myokard
infarktüsünde
(AMİ),
dolaşımdaki
CRP
düzeylerinin infarktın genişliği ile korele olduğu
saptanmıştır10,11. Tamamen sağlıklı görünen
bireylerde
ise
hs-CRP
yüksekliğinin
kardiyovasküler olaylar açısından, gelecekteki
artmış riski belirleyen ölçütlerden biri olduğu
gösterilmiştir12-14.
Hatta
CRP’nin
LDL
kolesterolden daha kuvvetli bir kardiyovasküler
risk faktörü olduğu ileri sürülmektedir15.
Tüm hastalara trombolitik tedavi (Streptokinaz 1.5
MÜ, 45 dakikada intravenöz infüzyon şeklinde)
uygulandı. Göğüs ağrısının başlangıcından 12 saat
sonra, alınan kan örneğinde CK-MB, kardiak
troponin İ, AST, ALT, LDH, beyaz küre,
sedimentasyon ve CRP düzeylerine bakıldı.
Kardiyak troponin İ için alınan kan 3000 rpm’de 3
dakika döndürülerek plazması ayrıldı ve
Çukurova Üniversitesi Tıp Fakültesi Balcalı
Hastanesi Merkez Laboratuarı’na gönderildi.
Ölçümler Microparticle Enzyme Immun Assay
yöntemiyle (MEIA), Abbott (Troponin I List no.
3C29) kiti kullanılarak yapıldı ve AMİ için
diagnostik kesme değeri >2.0 ng/mL idi.
Diğer tüm hematolojik ve biyokimyasal
parametreler Adana Numune Eğitim ve Araştırma
Hastanesi Laboratuarı’nda yapıldı. Serum CRP
düzeyi, immunotürbidimetrik yöntemle tayin
edildi ve ölçüm için Cobas Integra otoanalizörü
kullanıldı.
Daha önce yapılan çalışmalarda, AMİ’nde beyaz
küre sayısının yüksekliğinin epikardiyal kan
akımında
azalma,
myokardial
perfüzyon
bozukluğu, dirençli trombüsler ve kötü klinik
sonuçlarla birlikte olduğu gösterilmiştir16.
Hastaların hepsi sigara içimi, hipertansiyon,
diabetes mellitus, hiperlipidemi, koroner kalp
hastalığı yönünden aile öyküsü gibi kardiyak risk
faktörleri ve kullandığı ilaçlar yönünden
sorgulandı.
Bu çalışmada, AMİ’lü hastalarda infarkt tipi ile
serum CRP düzeyi ve beyaz küre sayısı arasındaki
ilişkiyi araştırdık. Koroner Yoğun Bakım
Ünitesi’ne (KYBÜ), AMİ tanısıyla yatırılıp
trombolitik tedavi uygulanan hastalarda göğüs
ağrısının başlangıcından 12 saat sonra serum CRP
ve CK-MB, kardiak troponin İ düzeyleri ile beyaz
küre sayısını tayin ettik17,18.
İstatistik analizler
Başlangıçta tüm değişkenlere normal dağılıma
uygunluk testi yapılarak parametrik test
kriterlerine uyum değerlendirildi. Buna göre
verilerimiz iki gruba ayrıldı: Birinci grupta,
hastaların yaşı, beyaz küre sayısı ve alanin
aminotransferaz (ALT) değerleri yer alıyordu ve
parametrik yöntemlerle analizleri yapıldı. Diğer
grup ise sedimentasyon, aspartat amino transferaz
(AST), laktik dehidrogenaz (LDH), CK-MB, CRP
ve kardiyak troponin İ’den oluşuyordu ve nonparametrik yöntemler uygulanarak analizleri
yapıldı. Non-parametrik yöntem olarak Kindependent samples = Kruskal Wallis varyans
analizi ve parametrik yöntem olarak tek yönlü
varyans analizi = One way ANOVA (Bonferrari
karşılaştırmalı) kullanıldı. Yine veriler arasındaki
korelasyonlar için non-parametrik verilerde
Spearman sıra korelasyon ve parametrik verilerde
Pearson korelasyon yöntemleri kullanıldı.
Ortalama karşılaştırmalarında non-parametrik
veriler için Mann-Whitney testi, parametrik
veriler için Student’s t testi kullanıldı.
MATERYAL VE METOT
Bu çalışma, Adana Numune Eğitim ve Araştırma
Hastanesi KYBÜ’ne 01.01.2000-01.07.2000
tarihleri arasında AMİ tanısıyla yatırılan 55 hasta
ile yürütüldü. Hastaların hepsi şiddetli göğüs
ağrısı ile Acil Servis’e başvurmuşlardı. Yapılan
muayene ve tetkikler sonucunda AMİ tanısı
kesinleşen ve ağrı başladıktan sonraki ilk 6 saat
içinde hastaneye başvuran hastalar çalışma
kapsamına alındı. Hastaların başvuru sırasındaki
EKG bulgularına göre AMİ tiplendirilmesi
aşağıdaki şekilde yapıldı:
- Akut Anterior Duvar Mİ: DI-AVL, V3-V4’de ST
yükselmesi varsa
- Akut Anteroseptal Mİ: DI-AVL, V1-V3’de ST
yükselmesi varsa
59
Kenan Topal ve ark.
BULGULAR
Hematolojik ve Biyokimyasal Analizler
Demografik veriler
Çalışmaya alınan olgu sayısı toplam 55 olup
bunların 44’ü erkek (%80) ve 11’i kadın (%20)
idi. Olguların yaş ortalaması 55.5±13.3 olup, en
küçük yaş 29, en büyük yaş ise 80 idi. Kadınların
yaş ortalaması 64±13.2 iken erkeklerde yaş
ortalaması 53.3±13.2 idi.
Ortalama serum AST, LDH, CK-MB ve troponin
İ, beyaz küre sayıları ve enflamatuar yanıtı
gösteren CRP düzeyleri normalin üzerinde
bulundu. Ortalama serum CRP değeri 24.5mg/L,
ortalama beyaz küre sayısı 14.2 X109/L ve
ortalama serum kardiak troponin İ düzeyi
859.8ng/ml idi. Bu verilerin normal dağılıma uyup
uymadıklarını anlamak için Kolmogorov-Smirnov
normalite testleri uygulandı. Normal dağılıma
uyan veriler yaş, beyaz küre iken; uymayan veriler
sedimentasyon, AST, LDH, CKMB, CRP ve
troponin İ idi. Normal dağılıma uyan verilerin
analizleri parametrik yöntemlerle yapılırken,
uymayan verilerin analizleri non-parametrik
yöntemlerle yapıldı. Hastaların CRP ve troponin İ
normal dağılım grafikleri Şekil 1’de verilmiştir.
Hastaların %34.5’i (19 kişi) hiç sigara içmemiş,
%16.4’ü (9 kişi) geçmişte sigara içmiş ve %49.1’i
ise halen sigara içiyordu. Hastaların %29.1’inde
hipertansiyon, %16.4’ünde diabetes mellitus ve
%14.5’inde dislipidemi öyküsü vardı. Yine
hastaların %25.5’i kardiyovasküler hastalık
açısından pozitif aile öyküsüne sahipti (Tablo 1).
Tablo 1: Çalışmaya alınan hastaların koroner risk faktörleri açısından durumları
Cinsiyet
Sigara içme durumu
HT
DM
Dislipidemi
Aile Öyküsü
Erkek
Kadın
Hiç içmemiş
Bırakmış
İçiyor
yok
var
yok
var
yok
var
yok
var
n
44
11
19
9
27
39
16
46
9
47
8
41
14
%
80.0
20.0
34.5
16.4
49.1
70.9
29.1
83.6
16.4
85.5
14.5
74.5
25.5
HT: Hipertansiyon, DM: Diabetes Mellitus.
Sekil 1:
60
Kenan Topal ve ark.
Hematolojik ve Biyokimyasal Verilerin Diğer
Faktörlere Göre Dağılımı
Hastalarda bulunan CRP değerlerinin korelasyon
analizleri
Hastaların
hematolojik
ve
biyokimyasal
değerlerinin sigara içme durumuna göre dağılımı
Tablo 2, ve diabetes mellitus olup olmadığına
göre dağılımı Tablo 3’de verilmiştir.
Bu çalışmada yapılan parametrik ve nonparametrik
korelasyon
analizlerinde
CRP
değerleri ile diğer risk faktörleri ve AMİ tipi
karşılaştırıldı. CRP yüksekliği ile miyokard
enfarktüsü tipi arasında anlamlı bir ilişki
bulunamadı (p>0.05). Halen sigara içen hastalarda
CRP yüksekliği ile ters yönde bir ilişki bulundu
(r:-0.710, p<0.01). Diğer taraftan CRP ile diabetes
mellitus varlığı arasında pozitif yönde bir ilişki
olduğu görüldü (r:0.479 ve p<0.01). CRP ile LDH
değerleri arasında pozitif bir ilişki bulundu
(r:0.330 ve p<0.05).
Serum CRP düzeyi ortalama 24.5mg/L olup akut
myokard enfarktüsü için CRP’nin kesme değeri
olan 20mg/L’nin altında kalan olguların sayısı 34
(%61.8) ve 20mg/L üstünde olan olguların sayısı
21 (%38.2) idi. CRP yüksekliği ile miyokard
enfarktüsü tipi arasında anlamlı bir ilişki
bulunamadı (p>0.05). Halen sigara içen hastalarla
CRP yüksekliği arasında ters yönde, orta düzeyde
güçlü bir korelasyon vardı. Diabetes mellitus
varlığı ile CRP yüksekliği arasında anlamlı, orta
düzeyde güçlü, pozitif bir ilişki olduğu görüldü
(p<0.05).
CRP değerleri ile hipertansiyon, diabetes mellitus,
dislipidemi, aile öyküsü, sigara ve AMİ tipleri
arasındaki korelasyon katsayıları Tablo 4’de
verilmiştir. CRP değerleri ile diğer hematolojik ve
biyokimyasal
parametrelerin
korelasyon
katsayıları Tablo 5’de verilmiştir.
Tablo 2: Hastaların hematolojik ve biyokimyasal değerlerinin sigara içme durumuna göre dağılımı
Sigara içme
Beyaz
ESH
AST
LDH
CKMB
CRP
Troponin
durumu
Küre
1
U/L
U/L
U/L
mg/L
İ
X109/L
saat
Ort.
13.1
14.6
220.6
1382.1
202.9
34.0*
991.1
SD
5.7
14.4
189.4
940.2
210.0
37.1
736.4
n
19
19
19
19
19
13
19
Ort.
14.4
13.0
135.7
877.2
111.7
15.4
521.4
SD
3.2
12.2
91.8
459.0
84.4
6.6
694.8
N
9
9
9
9
9
6
9
Ort.
14.9
7.7
286.8
1604.5
290.0
21.6*
880.2
SD
3.4
10.8
171.0
763.0
201.6
17.6
675.2
N
27
27
27
27
27
24
27
Hiç
ng/mL
içmemiş
Geçmişte
içmiş
İçiyor
*Spearman korelasyonu anlamlı, p<0.01
61
Kenan Topal ve ark.
Tablo 3: Hastaların hematolojik ve biyokimyasal değerlerinin diabetes mellitus olup olmadığına göre dağılımı
Diabetes
Beyaz
ESH
AST
LDH
CKMB
CRP
Troponin
Mellitus
Küre
1
U/L
U/L
U/L
mg/L
İ
X109/L
saat
Ort.
14.7
7.3
257.6
1440.3
254.2
19.4*
870.3
SD
4.4
7.1
175.7
841.6
207.6
20.0
719.8
n
46
46
46
46
46
37
46
Ort.
11.5
29.3
145.2
1246.6
111.0
55.9*
805.8
SD
3.2
18.3
138.5
721.7
79.9
29.9
661.6
N
9
9
9
9
9
6
9
yok
var
ng/mL
Tablo 4: CRP değerleri ile diğer risk faktörleri arasındaki ilişki
CRP
Sigara
Hipertansiyon
Diabet
Dislipidemi
Aile öykü
AMİ tipi
1.000
-0.710*
-0.117
0.479**
0.099
0.099
0.105
*Bir yönlü ve iki yönlü Spearman korelasyon analizine göre p<0.01 düzeyinde anlamlıdır.
**Bir yönlü ve iki yönlü Spearman korelasyon analizine göre p<0.01 düzeyinde anlamlıdır.
Tablo 5: CRP ile diğer hematolojik ve biyokimyasal parametreler arasındaki ilişki
CRP
Sed 1
AST
LDH
CKMB
Trop. I
1.000
0.143
0.110
0.330*
0.126
0.246
*İki yönlü Spearmen korelasyon p<0.05 düzeyinde anlamlıdır
ölüm arasında anlamlı bir korelasyon olduğu
görülmüştür8,13,14,19-21.
TARTIŞMA
Son çalışmalar aterosklerozun enflamatuar bir
hastalık olduğunu ve akut koroner sendromlarda
CRP düzeyinin yükseldiğini göstermektedir.
Kararsız anjina pektorisli hastalarda, serum CRP
düzeyinin 3mg/L’nin üstünde olmasının anlamlı
olarak
kötü
prognozla
birlikte
olduğu
görülmüştür1-7. Akut myokard enfarktüsünde,
CRP düzeyinin infarkt alanının genişliği ile
korelasyon gösterdiği ileri sürülmüştür. European
Concerted Action on Thrombosis and Disabilities
(ECAT) çalışmasında, CRP düzeyleri ile iki yıllık
süre içinde ortaya çıkan AMİ ve ani kardiyak
De Beer 1982 yılında AMİ geçiren 33 hastada
CRP yüksekliğinin infarkt alanı ile korelasyon
gösterdiğini ve devam eden yüksek CRP
düzeylerinin yeni koroner olaylarla birlikte
olduğunu bulmuştur10. Pietila 1987 yılında, ilk kez
AMİ geçiren ve bir grubuna da streptokinaz
tedavisi uygulanan 23 hastada, AMİ sonrası CRP
yüksekliğinin infarkt alanı ile korelasyon
gösterdiğini ve reperfüzyonun infarkta bağlı CRP
yanıtını azalttığını göstermiştir20. Pietila 1991
yılında ise, AMİ’lü 30 hastada, MI sonrası CRP
62
Kenan Topal ve ark.
yüksekliğinin, kalp yetmezliği ile korelasyon
gösterdiği fakat infarkt alanı ile korelasyon
göstermediğini bulmuştur22. Pietila 1996 yılında
ise AMİ geçiren 188 hastada yaptığı araştırmada
AMİ sonrasında ilk 6 ayda ölen hastaların
enfarktüs sonrası CRP düzeylerinin yüksek
olduğunu, CRP düzeyleri ile infarkt alanı arasında
korelasyon olmadığını göstermiştir11.
enflamatuar belirteçlerin, tedavinin izlenmesine
yönelik olarak kullanılmasını ise gelecekte
yapılacak yeni çalışmalar belirleyecektir.
KAYNAKLAR
1.
2.
Çalışmamızda, ortalama serum CRP düzeyi
24.5mg/L olup normal değerlerin ve kesme değeri
olan 20mg/L’nin üzerindeydi. Ancak CRP
yüksekliği ile miyokard enfarktüsü tipi arasında
anlamlı bir ilişki yoktu. Bu sonuçlar, Pietila’nın
çalışmalarındaki sonuçlar ile uyumludur. Serum
CRP düzeyleri olguların 34’ünde (%61.8)
20mg/L’nin altında, 21’inde (%38.2) ise
20mg/L’nin üstündeydi. Pietella’nın da bulduğu
gibi trombolitik tedavi ile sağlanan başarılı
reperfüzyon sonucu CRP değerlerinin çok fazla
yükselmediğini düşünüyoruz.
3.
4.
5.
6.
Diğer yandan çalışmamızdaki CRP değerleri,
diabeti olanlarda anlamlı olarak (p<0.01) daha
yüksekti ve CRP ile diabetes mellitus varlığı
arasında anlamlı, orta düzeyde güçlü bir
korelasyon
vardı
(r:0.479).
Zira
AMI
geçirenlerden diabetik olanlarda ortalama CRP
değeri 55.9mg/dL iken diabetik olmayanlarda
19.4mg/dL idi ve aradaki fark anlamlıydı
(p<0.01). Onat ve arkadaşlarının TEKHARF
kohortunun 10.yıl taramasında da diabetik
bireylerde CRP değerleri ortalamasının glukoz
toleransı normal olan kişilerden anlamlı olarak
daha yüksek olduğu bulunmuştur23.
7.
8.
9.
Sigara içimi ile CRP düzeyi arasında ters yönde
bir ilişki bulundu (r:-0.710, p<0.01). Halen sigara
içen hastalarda serum CRP düzeyi, içmeyenlere
göre anlamlı olarak daha düşüktü. Hoekstra ve
arkadaşları CRP ile erkeklerde sigara kullanma
yılı arasında anlamlı bir ilişki bulmalarına rağmen
gerek Onat ve ark. gerek Mendall ve ark.
çalışmalarında sigara kullanımı ile CRP arasında
bir ilişki bulamamıştır23-25.
10.
11.
SONUÇ
Akut myokard enfarktüsünde serum CRP
düzeyinin yükselmesi, akut koroner sendromlarda
enflamasyonun rolünü göstermesi açısından
önemlidir.
Koroner
kalp
hastalıklarında
enflamasyonun varlığını ve rolünü belirlemek,
tüm dünyada olduğu gibi ülkemizde de en önemli
ölüm nedeni olan bu hastalığa karşı yeni ve etkin
korunma ve tedavi yöntemlerinin geliştirilmesine
yardımcı olacaktır. Kardiyovasküler hastalıklar
için risk belirlenmesinde kullanılması önerilen
12.
13.
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64
ORIGINAL RESEARCH
SOCIAL ISOLATION STRESS IN THE EARLY LIFE REDUCES THE SEVERITY OF
COLONIC INFLAMMATION
1
Sevgin Özlem İşeri1, Fatma Tavsu1, Beyhan Sağlam2, Feriha Ercan2, Nursal Gedik3, Berrak C.Yeğen1
Marmara University, School of Medicine, Physiology, Istanbul, Türkiye2Marmara University, School of
Medicine, Histology and Embryology, Istanbul, Türkiye3Kasımpaşa Military Hospital , Biochemistry ,
Istanbul, Türkiye
ABSTRACT
Objective: To investigate whether the early-life stress interact with a brief stress exposure and acute colonic
inflammation in adulthood.
Methods: Female Sprague–Dawley rats on the postnatal 21st day were exposed to isolation stress until they
reach 250 g. On the last 3 days with or without isolation, water-avoidance-stress (WAS) for 30 min/day or
acetic acid(5 %) colitis were performed. After the last WAS or on the 4th day of colitis, rats were decapitated
to collect serum for TNF-alpha levels, colonic tissues for histological analysis, myeloperoxidase activity
(MPO), evidence of neutrophil infiltration, and glutathione (GSH) levels, a key antioxidant.
Results: In the non-isolated and isolated groups, WAS and colitis both elevated the TNF-alpha, MDA levels
and MPO activity compared to control (p<0.05-p<0.001). GSH levels were reduced in the non-isolated WAS or -colitis groups and in the isolated-WAS group (p<0.01-0.001), while GSH level of the isolatedcolitis group was not different than control. In the isolated-colitis group, MPO activity and microscopic
scores were lower compared to non-isolated group (p<005-0.001). TNF-alpha levels were not different
between non-isolated and isolated colitis groups.
Conclusion: Post-weaning isolation stress has a protective effect on colonic inflammation and does not
exacerbate the colonic response to acute stressors.
Keywords: myeloperoxidase, colitis, psychological stress, water avoidance stress (WAS), social isolation
HAYATIN ERKEN DÖNEMİNDE KARŞILAŞILAN SOSYAL İZOLASYON STRESİ,
KOLON İNFLAMASYONUNUN ŞİDDETİNİ AZALTIR
ÖZET
Amaç: Hayatın erken dönemindeki stresin, ileri yaştaki akut barsak inflamasyonu ve strese maruz kalma
üzerine etkilerini araştırmak.
Material Metod: Dişi Sprague–Dawley sıçanlara, doğum sonrası 21. günde, sosyal izolasyon stresi
uygulandı. 250 g. ağırlığa ulaşılana dek beklendi. 60 günlük protokolün son 3 gününde, izole edilen,
edilmeyen gruplara sudan kaçınma stresi (WAS) 30 dak./gün uygulandı. Sıçanların kalan yarısında ise izole
olan, olmayan gruplara, kolona %5'lik asetik asit verilerek kolit oluşturuldu. Son WAS uygulamasından
hemen sonra ya da kolit indüksiyonunun 4. gününde sıçanlar dekapite edilerek, TNF-alpha seviyelerinin
ölçümü için kan, histolojik değerlendirme, doku myeloperoksidaz (MPO) aktivitesi, nötrofil infiltrasyonunun
göstergesi, ölçümü ve glutatyon (GSH) seviyelerinin, antioksidan, ölçümü için kolon dokusu alındı.
Bulgular: İzole olan, olmayan guruplarda, WAS ve kolit indüksiyonu serum TNF-alpha, doku MDA
seviyelerini, MPO aktivitelerini kontrole göre anlamlı arttırmıştır (p<0.05-p<0.001). GSH seviyeleri izole
olmayan grupta WAS ya da kolit indüksiyonu ile azalmış, fakat GSH izole grupta WAS sonrası azalırken
(p<0.01-0.001), kolit sonrası kontrole göre değişiklik olmamıştır. Kolitli izole grupta, MPO aktivitesi ve
mikroskobik hasar skorları, izole olmayan grupla karşılaştırıldığında anlamlı azalmıştır (p<005-0.001). TNFalpha seviyeleri izole olan veya olmayan kolit gruplarında farklılık göstermemiştir.
Sonuç: Sütten kesilme sonrasındaki sosyal izolasyon stresi kolit hasarından koruyucu etkili ve kolon
inflamasyonunun stresle artışına yol açmaz.
Anahtar Kelimeler: myeloperoksidaz, kolit, psikolojik stres, sudan kaçınma stresi, sosyal izolasyon
Sevgin Özlem İşeri
Marmara University, School of Medicine, Physiology, Istanbul, Türkiye
65
Sevgin Özlem İşeri, et al.
Social isolation stress in the early lifee reduces the severity of colonic inflammation
Repeated maternal deprivation during this
neonatal period yields to a more tentative
behavior and decreased gain of body weight 9,
exacerbates the severity of trinitrobenzene
sulfonic acid (TNBS)-induced colitis 10 and
increases gastric ulcer susceptibility in the adult
11
. On the other hand, brief maternal separation
has a protective effect on adult stress exposure,
protecting the animals from dextran sodium
sulphate (DSS)- induced colitis, while the nonhandling condition sensitizes mucosa to DSS
exposure 12. Social isolation stress during the postweaning period also leads to behavioural and
neurochemical sequelae in rats 13. However, the
effect of post-weaning social isolation stress on
secondary stress exposures during the later phases
of life, whether it will alleviate or exacerbate the
inflammatory responses, is not clarified yet.
INTRODUCTION
Stress of various types during daily life, and
adequate responses to these stressors are
necessary for survival. If the severity or the
chronicity of the stressful experience exceeds the
adaptive capacity, the individual will be
predisposed to illness and disease in multiple
organ systems 1. Stress can induce inflammatory
responses in various organs and when stress is
chronic it may induce or aggravate chronic
inflammatory diseases. Although the influence of
psychological stress on the symptoms and clinical
course of intestinal inflammatory processes has
long been recognized, it has recently received the
attention of the researchers 2. Recent data suggest
that stress induced alterations in gastrointestinal
inflammation may be mediated through changes
in hypothalamic-pituitary-adrenal (HPA) axis
function and alterations in bacterial-mucosal
interactions, and via mucosal mast cells and
mediators such as corticotrophin releasing factor
(CRF)3.
Based on the current knowledge about the impact
of stress on the course of inflammatory bowel
diseases, the present study was designed to
investigate whether the early-life stress at the
post-weaning period might interact with a brief
stress exposure and acute colonic inflammation in
adulthood.
Psychological stress in adulthood has long been
reported to increase disease activity in
inflammatory bowel disease (IBD), and recent
well-designed studies have confirmed that chronic
stress and depression increase the likelihood of
relapse in patients with quiescent IBD 3. Although
long-term perceived stress in patients with
ulcerative colitis increases the risk of exacerbation
over a period of months to years, it was shown
that short-term stress does not trigger exacerbation
4
. Similarly, it has been shown that different stress
models in animals may have varying effects on
colonic inflammation induced by different
methods. Partial restraint stress applied during 4
consecutive days causes exacerbation of 2,4,6trinitrobenzenesulfonic
acid
(TNB)-induced
colitis in adult rats 5. In contrary, we have
previously shown that acute stress exposure
applied as water avoidance stress (WAS) 6 or
electric shock 7 reduces the severity of colitis
induced by acetic acid or TNBS, respectively.
METHODS
Animals
Adult female Sprague–Dawley rats (250–300 g)
were kept in a light- and temperature-controlled
room with 12:12 h- light-dark cycle, where the
temperature (22 ± 0.5 ºC) and relative humidity
(65–70 %) were kept constant. The animals were
fed a standard pellet and food was withdrawn
overnight before colitis induction. Access to water
was allowed ad libitum. Experiments were
approved by the Marmara University School of
Medicine Animal Care and Use Committee.
Social isolation stress
Dams and their litters were assigned to the nonisolation (n=18) protocol or to social isolation
stress (n=18) protocol. To induce post-weaning
social isolation stress, rats were removed from
their cages and dams on the postnatal 21st day and
were placed in individual plastic cages to be kept
in another room. Before the experiments, pups
were allowed to reach at least to 250 g body
weight for 60 days. The growth of the animals
was followed only by inspection and the rats were
not handled following the separation. The animals
were transferred to clean cages with new chip
bedding at weekly intervals without handling.
A large number of studies have also shown that
early-life trauma can affect the development and
clinical course of intestinal disorders and
reactivate inflammation in experimental colitis 2,5.
The neonatal period, roughly extending in rats
from birth to day 14, is often referred to as a stress
hyporesponsive period characterized by a
diminished adrenocorticotropin and corticosterone
response to most stressors8.
66
duplicates using the commercial kit (Biosource
Europe S.A., Nivelles, Belgium). The activity of
radioactive assays was measured by a gamma
counter (LKB WALLAC 1270 RACK, Canada)
and the values were expressed as ng/ml.
Water avoidance stress (WAS)
At the end of the 60-days protocol with or without
isolation, when the required weight was reached,
water avoidance stress (WAS) was performed as
previously described 14. Rats were individually
placed onto a plastic platform (6 cm × 6 cm × 8
cm) located in the middle of a plastic cylinder
container (50 cm × 56 cm) filled with warm water
(25 ºC) up to 1 cm below the height of the
platform. Stress sessions, which lasted for 30 min,
were performed for 3 consecutive days between
16:00 and 16:30 p.m. to minimize any diurnal
variation in the responses. Rats were then put
back to their home cages with free access to water
and food.
Myeloperoxidase (MPO) activity
Tissue-associated
myeloperoxidase
(MPO)
activity was determined in the colonic samples as
an indication of accumulation of neutrophils. All
reagents for MPO assay were obtained from
Sigma. The tissue samples (0.2–0.3 g) were
homogenized in 10 volumes of ice-cold potassium
phosphate buffer (50 mM K2HPO4, pH 6.0)
containing
hexadecyltrimethylammonium
bromide (HETAB; 0.5%, w/v). The homogenate
was centrifuged at 12,000 rpm for 10 min at 4 ºC,
and the supernatant was discarded. The pellet was
then rehomogenized with an equivalent volume of
50 mM K2HPO4 containing 0.5% (w/v)
hexadecyltrimethylammonium bromide and 10
mM ethylenediaminetetraacetic acid (EDTA,
Sigma). MPO activity was assessed by measuring
the
H2O2-dependent
oxidation
of
odianizidine·2HCl. One unit (U) of enzyme activity
was defined as the amount of the MPO present per
gram of tissue weight that caused a change in
absorbance of 1.0 min−1 at 460 nm and 37 ºC16.
Induction of colitis
Ath end of 60–days follow-up period, another
group of rats (n=12; isolated and non-isolated)
were fasted for 18 h before the induction of
colitis. Colitis was induced by a modification of
the method introduced by MacPherson and
Pfeiffer 15. Under light ether anesthesia, a
polyethylene catheter (PE-60) was inserted into
the colon with its tip positioned 8 cm from the
anus. To induce colitis, a single solution of 1 ml
of 5 % (v/v) acetic acid diluted in saline (pH 2.3)
was instilled.
Determination of glutathione level
Experimental protocol
Tissue samples were homogenized in 10 ml vol.
of ice-cold 10% trichloroacetic acid, in an Ultra
Turrax tissue homogenizer. Homogenized tissue
samples were centrifuged at 3000 rpm for 15 min
at 4 ºC. The supernatant was removed and
recentrifuged at 15,000 rpm for 8 min.
Glutathione measurements were performed using
a modification of the Ellman procedure17.
On the 4th day, immediately after the last WAS
exposure or on the 4th day of colitis induction,
rats were decapitated. The rats in the control
group (n=12) were handled at the same time
points as in the WAS-applied group, but were not
placed on the platform and isotonic saline was
instilled intracolonically instead of acetic acid.
Control rats were decapitated on the 4th day of
intracolonic saline application. Trunk blood was
collected for the assessment of TNF-α levels. The
distal 8 cm of the colon were opened down their
mesenteric borders and cleansed of luminal
contents. Colonic tissue was obtained from each
animal and stored at −80 ºC until the
determination of tissue myeloperoxidase activity
(MPO), as an indirect evidence of neutrophil
infiltration, and the level of glutathione (GSH), a
key antioxidant. For the histological analysis, a 1
square cm sample at 8 cm from anus was obtained
from each animal to be fixed in formaldehyde.
Histological assessment of colonic injury
For light microscopic investigations samples from
the colon were fixed with 10% formaldehyde,
dehydrated in graded alcohol series, cleared with
toluen and embeded in paraffin. Tissue sections (5
µm) were stained with hematoxylin and eosin
(H&E) for general morphology and examined
under a Olympus BX51 photomicroscope (Tokyo,
Japan). All tissue sections were examined
microscopically
for
characterization
of
histopathological changes by an experienced
histologist (F.E.) who was unaware of the
treatment conditions. Assessment of the colonic
injury was performed using the previously
described criteria: Damage/necrosis (0: None, 1:
Localised, 2: Moderate, 3: Severe); Submucosal
edema (0:None, 1: Mild, 2: Moderate, 3: Severe);
Measurement of serum TNF-α level
Serum TNF-α level was evaluated by a RIA–
IRMA (radioimmunoassay–immunoradiometric
assay) method. All samples were assayed in
67
Inflammatory cell infiltration (0: None, 1: Mild, 2:
Moderate, 3: Severe); Vasculitis (0: None, 1:
Mild, 2: Moderate, 3: Severe); Perforation (0:
Absent, 1: Present); with a maximum score of 1339
The microscopic damage scores of the two control
groups with or without isolation stress were found
to be similar (Fig. 2a), indicating that chronic
isolation stress alone did not cause any significant
changes in the histological appearance of the
colon. Exposure to acute water avoidance stress
and acetic acid instillation resulted in significant
microscopic damage in the non- isolated groups
(p<0.05 and p<0.001). The score given in the
chemically-induced colitis was nearly 3-folds
higher than the acute stressed group. In the postweaning isolated group, the microscopic damage
scores in both WAS and colitis groups were found
to be less with respect to corresponding nonisolated groups (p<0.05 and p<0.001). As seen in
the non-isolated groups, the damage score reached
by acetic acid in the group with a previous
isolation stress was clearly higher than the group
exposed to the secondary stress.
Statistics
The results are expressed as means ± SEM.
Following the assurance of normal distribution of
data, one-way analysis of variance (ANOVA) was
used for multiple comparisons and Student's t-test
was used to evaluate the level of statistical
significance between pairs (GraphPad Software,
San Diego, CA, USA). Differences were
considered statistically significant if P<0.05.
RESULTS
In the non-isolated groups, exposure to WAS and
induction of colitis both elevated the serum levels
of TNF-α significantly, as compared to the control
group that had neither colitis nor stress exposure
(p<0.001; Fig. 1). However, isolation for two
months per se in the control group, resulted in
elevated serum TNF-a (p<0.01). WAS enhanced
the isolation-induced increase in TNF-α level
when compared to animals without acute stress.
On the other hand, colitis induction had no further
effect on the cytokine level that was already
elevated by chronic isolation stress.
The histological analysis in the non-isolated
control group showed regular colonic morphology
(Fig. 3A). Colonic tissues of both non-isoloted
and isolated WAS groups (Fig. 3B and E) and
isolated control group (Fig. 3D) demonstrated
only mild inflammatory cell infiltration. In the
non-isolated colitis group (Fig. 3C), severe
damage of mucosa with epithelial and glandular
degeneration,
severe
inflammatory
cell
infiltration, vasculitis and submucosal edema were
evident. However, in the isolated colitis group
(Fig. 3F), mild mucosal degeneration with
localized epithelial and glandular degeneration,
moderate submucosal edema, vasculitis and
inflammatory cell infiltration were observed.
Social isolation for two months did not alter the
colonic GSH content (Fig. 2b). However,
exposure to acute WAS depleted the GSH content
in both the non-isolated and isolated groups
(p<0.001). Similarly, colonic GSH levels of the
rats with acetic acid colitis were also reduced in
the non-isolated group (p<0.01), but the reduction
was relatively less than the WAS group.
Figure 1: TNF-α levels, in colonic tissues of non-isolated
and isolated groups of control, WAS-exposure and colitisinduced groups. ***p<0.001 compared to control group,
++p<0.01 compared to corresponding group in non-isolated
group.
Figure 2: A)Microscopic score B) Glutathione (GSH) levels C) Myeloperoxidase (MPO) activity in colonic tissues of non-isolated
and isolated groups of control, WAS-exposure and colitis-induced groups. *p<0.05, **p<0.01, ***p<0.001 compared to control
group, +p<0.05, +++p<0.001 compared to corresponding group in non-isolated group.
68
DISCUSSION
In the present study, the data show that rats
exposed to prolonged isolation stress in the early
life immediately after the weaning period, develop
a resistance to colonic inflammation occuring later
in life. Social isolation that was experienced
before the adult life reduced the colonic
microscopic damage, prevented the depletion of
colonic glutathione and reduced the neutrophil
accumulation to colonic tissue, making the rats
less vulnerable to experimentally induced colonic
inflammation. Interestingly, having a history of
early-life stress does not change the colonic
response to acute psychological stress introduced
in the adult life, but still alleviates the severity of
histological damage.
Physical and emotional stress-related disturbances
of homeostasis and induction of the pathogenesis
of various diseases are well established. Maternal
separation of pups from dams is often used as an
early life stressor that causes profound
neurochemical and behavioral changes in the pups
that persist into adulthood. The neonatal period,
roughly extending in rats from birth to day 14, is
often referred to as a stress hyporesponsive period
characterized by a blunted activation of HPA
responses to a variety of environmental stressor,
and circulating levels of adrenocorticotropin and
corticosterone are low18. If newborn rats are
subjected to chronic or prolonged maternal
separation, a hyperresponsiveness to stress is
observed along with increased release of
corticotropin-releasing hormone (CRH) and
altered
expression
of
glucocorticoid
receptors,19,20,21. Early life events in humans were
also found to be associated with a long-term
enhancement in stress-responsiveness and CRH
secretion in adults22,23,24. Alterations in the HPA
axis are related with numerous long-term
disorders, such as anxiety, depression, feeding
behaviour abnormalities and increased gastric
ulcer susceptibility in the adult11,25. It has been
shown that prolonged neonatal maternal
deprivation may alter the mucosal immunity and
predispose
adult
animals
to
increased
vulnerability to pathogenic bacteria and to colonic
barrier dysfunction in response to mild stress26,27.
On the other hand, brief maternal separation
during the critical phase of development has been
shown to lower the CRH and ACTH response12
and decrease the acute stress-induced anxious
behavior
and
HPA
activation
during
adulthood28,29. It is postulated that these brief
separations are normal for development30. Our
results show that isolation-induced stress in the
Figure 3: Micrographs illustrating the histological
appearances of colonic tissues in different experimental
groups. Non-isolated control group (A), regular colon
morphology; non-isolated WAS group (B), mild
inflammatory cell infiltration; non-isolated colitis group (C),
severe damage of mucosa with epithelial degeneration,
severe submucosal edema, vasculitis and inflammatory cell
infiltration; isolated control group (D), mild inflammatory
cell infiltration; isolated WAS group (E) mild inflammatory
cell infiltration; isolated colitis group (F) mild damage of
mucosa with localized epithelial degeneration, moderate
submucosal edema, vasculitis and inflammatory cell
infiltration. H&E staining, original magnifications, ×100.
Epithelial degeneration (→), submucosal edema (s) and
inflammatory cell infiltration (*).
On the other hand, colonic GSH in the rats with
colitis that were previously isolated was found to
be similar to that of the control levels, showing
that the depletion of colonic GSH by colitis does
not occur in chronically stressed animals. In
contrary, the pre-existing isolation stress did not
alter the reduction in the colonic GSH induced by
the acute WAS.
MPO activity, indicating tissue neutrophil
infiltration, was elevated in the colonic tissues of
both the isolated and non-isolated rats that were
exposed to acute WAS (p<0.01; Fig. 2c). A
similar elevation in the colonic MPO activity was
observed in the colitis groups with or without
isolation stress (p<0.001). However, colitisinduced increase in colonic MPO activity was
found to be less in the rats that had isolation stress
before, as compared to non-isolated colitis group
(p<0.05).
69
increase the damage35. In the present study,
colitis-induced increase in MPO activity was
relatively less when the rats were exposed to
isolation stress previously, suggesting that the
protective effect of the early stressor on colonic
inflammation may involve the inhibition of
neutrophil recruitment, which then inhibits the
adhesion and aggrevation of neutrophil
leukocytes36. On the other hand, it seems that
isolation stress during post-weaning period
protected the colonic tissue against WAS
exposure by a mechanism independent of
neutrophil accumulation. However, the TNF-α
level was already increased in the rats that were
exposed to isolation stress, suggesting that the
cytokine response was enhanced by the early life
stressor. Nevertheless, the important function of
antibodies in recognizing and neutralizing some of
the damaging cytokines like TNF-a may be
changed by alterations in the HPA axis12. The
present data demonstrates that hypersensitivity to
inflammation, via increased synthesis or release of
proinflammatory mediators, is not further
enhanced by new stressors of chemical or
psychological origin.
early life, but clearly beyond the vulnerable
period, yields to a reduction in the inflammatory
response to colitis induction, which may suggest a
decrease in the HPA activation. As the other mild
stressors, post-weaning isolation may induce an
adaptive response to protect the individual to
subsequent pathological conditions. Thus, adult
rats exposed to isolation stress during their postweaning period are protected from chemically
induced colitis.
Experimental and clinical studies have shown that
any harmful tissue event is perceived by
macrophages and monocytes, which in turn
secrete cytokines. Cytokines then activate
inflammatory
cells
(neutrophils,
macrophages/monocytes, platelets, mastocytes)
releasing large amounts of toxic oxygen and
nitrogen species, which cause cellular injury via
several mechanisms. Glutathione is an important
constituent of intracellular protective mechanisms
against various noxious stimuli including
oxidative stress. However, reduced glutathione as
the main component of endogenous non-protein
sulfhydryl pool, is known to be a major low
molecular weight scavenger of free radicals in the
cytoplasm31,32. In accordance with the previous
reports, our results support the notion that
depletion of tissue GSH, as observed in the acetic
acid- and WAS-induced colonic injury, is one of
the major factors that permit tissue damage. Since
exposure to isolation stress previously has reduced
the colonic GSH depletion, it appears that the
protective effect of the early life stressor may
involve the maintenance of antioxidant capacity in
protecting the colonic tissue against oxidative
stress. However, the presence of isolation stress in
the early life period has not altered the WASinduced GSH depletion. Interestingly, the
previous stress has not exacerbated the destruction
of antioxidant capacity induced by an acute
stressor.
The newborn is totally dependent on maternal
care. Feeding and maintaining optimal body
temperature depend on parental sensitivity to the
offspring's signals, and tactile stimulation appears
to be crucial for the infant's biological and
behavioral responses37. Therefore, repeated
maternal separation delays the gain in body
weight28. Since neonatal stress consisted of early
weaning, milk deprivation has been proposed as a
major factor involved in numerous long-term
disorders,
such
as
increased
ulcer
susceptibility11,38. However, in our study, the rats
were isolated after the weaning period and the
weight gain was found to be similar in both the
isolated and non-isolated rats. Since the separated
animals were capable of self-care, isolation did
not directly affect the feeding behavior. Along
with the behavioral symptoms, the current data
show that post-weaning isolation has a protective
effect
on
chemically
induced
colonic
inflammation. Furthermore, isolation following
weaning does not exacerbate colonic response to
subsequent acute stressors. In conclusion, our
results show that stress exposure does not always
contribute to the exacerbation of the inflammatory
bowel disease. Stress, depending on intensity,
duration and the time of exposure, may elicit
adaptive or maladaptive physiological changes,
providing advantageous or deleterious effects on
psychosomatic vulnerability.
The tissue-associated MPO, which is known as
the index of neutrophil infiltration, plays a
fundamental role in oxidant production by
neutrophils33. In our observation, elevated MPO
levels in the colonic tissues indicate that
neutrophil accumulation contributes to the colitisand WAS-induced oxidative injury. As shared by
other inflammatory disorders in the gut, active
lesions in the ulcerative colitis involve the
migration
of
activated
neutrophils
and
macrophages34. A growing body of evidence
suggests that neutrophils release chemotactic
substances, which further promote neutrophil
migration to the tissue, activate neutrophils, and
70
14. Kresse AE, Million M, Saperas E and Tache Y.
Colitis induces CRF expression in hypothalamic
magnocellular neurons and blunts CRF gene
response to stress in rats. Am. J. Physiol. 2001;
281: pp. G1203–G1213.
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72
CASE REPORTS
LAPAROSCOPIC APPROACH FOR EPIPHRENIC ESOPHAGEAL DIVERTICULA
Osman Kurukahvecioğlu, Ekmel Tezel, Bahadır Ege, Hande Köksal, Emin Ersoy
Gazi Üniversitesi Tıp Fakültesi, Genel Cerrahi Anabilim Dalı, Ankara, Türkiye
ABSTRACT
Epiphrenic diverticula of the esophagus are rare disorders frequently associated with esophageal dismotility
that is thought to be the cause of the diverticulum and some of the symptoms. Treatment is surgery and only
indicated to the symptomatic patients. The operation can be performed successfully by laparoscopy, which
offers good access to the distal esophagus and the inferior mediastinum. A 68 year-old woman presented
with symptoms of heartburn, regurgitation and vomiting. Two diverticula located in distal esophagus were
detected with barium esophagography and endoscopy. The biggest diverticulum was resected by the
endoscopy assisted laparoscopic approach.
Laparoscopic approach to epiphrenic diverticula seems to be feasible and safe provided when surgeons
trained in minimally invasive procedures of the gastroesophageal junction perform it.
Keywords: Esophageal diverticula, minimal invasive surgery, laparoscopy
EPİFRENİK ÖZAFAGUS DİVERTİKÜLLERİNE LAPAROSKOPİK YAKLAŞIM
ÖZET
Epifrenik özafagus divertikülleri nadir rastlanan bir hastalık olup sıklıkla divertiküllerin ve semptomların
nedeni olduğu düşünülen özafagus motor bozukluklarıyla birliktelik gösterir. Tedavisi cerrahi olup sadece
semptomatik hastalara uygulanmaktadır. Ameliyat alt özafagus ve mediastende iyi görüş sağlayan
laparoskopik yöntemle başarılı bir şekilde yapılabilir. Yazımızda göğüste yanma ve kusma şikayeti ile
başvuran 68 yaşındaki bir kadın hasta sunulmaktadır. Baryumlu özafagografi ve endoskopisinde alt
özafagusta yerleşmiş iki adet divertikül saptanan hasta intraoperatif endoskopi yardımıyla laparoskopik
olarak ameliyat edildi. Epifrenik divertiküllere laparoskopik yaklaşım,gastroözafageal bölge konusunda
deneyimli cerrahlar tarafından güvenle uygulanabilmektedir.
Anahtar Kelimeler: Özafagus divertikülleri, minimal invaziv cerrahi, laparoskopi
maximal diameter of the pouch, diameter of the
diverticular neck, the appearance of the
gastroesophageal junction and the presence of
tertiary contractions. By the help of the endoscopy
findings of esophagitis or those suggestive of a
motility disorder can be recorded also 1.
INTRODUCTION
Esophageal diverticula are rare diseases mostly
classified by location and etiology. The exact
prevalence of this condition is not known because
asymptomatic cases are usually not discovered.
Symptoms are variable. Some patients have only
mild dysphagia however other patients have
worsening and incapacitating symptoms like
severe dysphagia, regurgitation with recurrent
episodes of pneumonia due to aspiration,
heartburn, cardiac arrhythmias, obstruction,
weight loss, chronic cough and halitosis 1.
The treatment of these diverticula is surgical. The
decision must be made with regarding the
patient’s symptoms, operative risk and
complication and the surgical expertise locally
available, considering the rarity of the disease.
With the introduction of minimally invasive
surgical techniques esophageal diseases have been
successfully treated by laparoscopic approach.
Laparoscopy offers good access to the distal
esophagus and the inferior mediastinum therefore
it should be considered as an alternative to the
Diagnosis is radiological. All patients with
suspicion of having epiphrenic diverticulum
should undergo barium study in order to
document the location of the diverticulum,
Hande Köksal
Gazi Üniversitesi Tıp Fakültesi, Genel Cerrahi Anabilim Dalı, Ankara, Türkiye
73
Osman Kurukahvecioğlu, et al
Laparoscopic approach for epiphrenic esophageal diverticula
traditional transthoracic approach and may
eventually become the standard technique 1,2.
Trendelenburg. The surgeon was standing
between the legs. Pneumoperitoneum was
established and five operating ports were placed
as usual from the abdomen. A 30º-angled scope
was used. After dividing phreno-esophageal
membrane, the diaphragmatic crura were exposed.
The esophagus was isolated and completely
encircled with a rubber tape for traction. Blunt
dissection was carried out in the mediastinum
until 8-10 cm above the diaphragmatic crura
staying close to the esophageal surface. At the
same time the larger diverticular pouch was
identified by endoscopy and isolated up to the
superior margin of its neck and then resected with
a linear endoscopic stapler with the nasogastric
tube inside the esophageal lumen. Intraoperative
endoscopy was used in order to avoid the
narrowing of the lumen by the stapler and to
detect an incomplete resection, also to check the
stapled suture line for any leak. Endoscopically
there was no evidence of leak at the suture line
therefore suture of the esophageal musculature
was not performed (figure 2). The smaller
diverticulum was not resected because of being
asymptomatic. A Toupet fundoplication was
chosen for the repair of the hiatal hernia. The
procedure was finished after 95 minutes. The
postoperative course was uneventful. She had
check-up swallow radiography with water-soluble
contrast medium on the 6th postoperative day and
no leakage was shown. She resumed oral intake
on the same day and discharged on day 8. She has
been totally asymptomatic during a 10 months
follow-up period.
Here we report a case of lower esophageal
diverticulum
treated
successfully
with
laparoscopic approach.
CASE PRESENTATION
A 68 year-old woman presented at our clinic with
symptoms of heartburn, regurgitation and
vomiting. The duration of symptoms was six
months. The diagnostic work-up consisted of
barium esophagography and endoscopy. She did
not have any signs during the endoscopy
suspecting a gastro-esophageal reflux so we did
not perform pH monitoring. Barium study showed
two diverticula located in the distal third of the
esophagus. The average sizes of the pouches were
4 cm and 2 cm (figure 1). The diverticula were
located 6-7 cm above the cardia measured by
endoscopy and a hiatal hernia was also diagnosed.
No findings suggestive of primary esophageal
motility disorder like dilatation of the esophagus,
retained food, and resistance at the level of
gastroesophageal junction or tertiary contractions
were recorded during endoscopy so the symptoms
of the patient were thought to be related with the
compression of the larger diverticulum to the
distal esophagus. Following a complete
preoperative evaluation, the patient was scheduled
for laparoscopic operation. The position of the
patient, surgeon and the trocar sites were the same
as for the laparoscopic treatment of functional
diseases of the esophagogastric junction.
The patient was placed on the operating table in
the lithotomy position with a 30º reverse
Figure 1: Barium study images showed the diverticula
located in the distal third of the esophagus.
Figure 2: Endoscopically there was no evidence of leak at
the suture line
74
Osman Kurukahvecioğlu, et al.
Laparoscopıc approach for epiphrenic esophageal diverticula
location of the diverticulum is correlated with
symptoms 2. The traditional surgical treatment for
an epiphrenic diverticulum consists of an
esophageal myotomy, diverticulectomy or
diverticulopexy and an anti-reflux procedure
usually
through
a
thoracotomy.
Using
conventional techniques diverticula in the lower
portion of the esophagus can be operated with
morbidity and mortality rates of 33% and 9%
respectively 2. With the introduction of minimally
invasive surgical techniques, esophageal diseases
have been successfully treated by laparoscopic
approach. Because thoracoscopic surgery can
have some troubles especially in dissection and
placing the stapler, laparoscopic route is chosen to
minimize the risk of incomplete resection and
narrowing of the passage by the stapled suture
line. Simultaneous endoluminal visualization can
be used in order to accelerate the procedure, to
allow proper placement of the stapler and finally
giving opportunity to check the suture line for any
leak. All pathophysiologic problems of this
disorder can be solved by laparoscopy: the
removal of the diverticulum, the treatment of the
motor disorder and the reflux. But the procedure
is still a matter of discussion while it has been
stated that diverticulectomy alone is enough if no
motor abnormality is detected 7,8. If there is motor
disturbance in esophagus then myotomy should be
added 9. Also the relationship between the motility
abnormality and the development of the
diverticulum is described to be more likely around
60% by Streitz et all 7. In our patient no motor
abnormality was recognized so myotomy was not
performed. We do recommend the use of a partial
wrap of fundus if the patient has reflux on
preoperative workup, because total fundoplication
can create an obstacle for the esophageal flow and
this may result in leakage from the suture line or
recurrence of a diverticulum.
DISCUSSION
Esophageal diverticula are rare. The true
incidence is unknown. The etiology, symptoms
and therapeutic requirements suggest a
categorization in three forms: pharyngoesophageal (Zenker diverticula), parabronchial
and epiphrenic diverticula.
Epiphrenic diverticula arise within the distal 10
cm of the thoracic esophagus. The exact
prevalence of this condition is not known because
asymptomatic cases are usually not discovered. It
seems to occur less frequently than Zenker’s
diverticula with a ratio of 1:5 2. Most of these are
found in middle aged- elderly patients and male
gender has a slight predominance.
Pathophysiology of the epiphrenic diverticulum is
still unclear. The herniation of the mucosa and
submucosa through a defect in the muscular layer
is probably caused by a longstanding impairment
of the esophageal motor activity. However the
associated motor disorder is not always
recognized and diagnosed.
Symptoms are variable. Many patients do not
have any symptoms and some have only mild
dysphagia. In these patients diverticulum is an
incidental finding on barium swallow done for
unrelated reasons. However other patients have
worsening and incapacitating symptoms like
severe dysphagia, regurgitation with recurrent
aspiration and pneumonia, heartburn, cardiac
arrhythmias, obstruction, weight loss, chronic
cough and halitosis 1. Bleeding, spontaneous
perforation and also carcinoma have been noted 3.
Diagnosis is radiological. All patients with
suspected epiphrenic diverticulum should undergo
barium study. Exact identification of the
diverticulum is of crucial importance for a
successful procedure. Therefore endoscopysupported visualization of the diverticulum has
been recommended 4. Manometry is mandatory to
define associated motility disorders. If gastroesophageal reflux is suspected, a 24-hour pH
study can also be performed.
In conclusion, laparoscopic approach to
epiphrenic diverticula seems to be feasible and
safe provided when surgeons trained in minimally
invasive procedures of the gastroesophageal
junction perform it.
The treatment of these diverticula is surgical.
However, the presence of a diverticulum is not an
indication for surgery. There is almost a
consensus that surgery should be preserved for
symptomatic patients 5. The desicion must be
balanced between the patient’s symptoms, the
complication and operative risk. Patients with
minimal symptoms should be managed
conservatively 5,6. If symptoms are incapacitating
an operation should be advised. Neither size nor
REFERENCES
1.
2.
75
Costantini M, Zaninotto G, Rizzetto C, Narne S,
Ancona E. Oesophageal diverticula. Best Pract Res
Clin gastroenterol 2004; 18: 3-17.
Benacci JC, Deschamps C, Trastek VF, Allen MS,
Daly RC, Pairolero PC. Epiphrenic diverticulum:
Results of surgical treatment. Ann Thorac Surg
1993; 55: 1109-1113.
Osman Kurukahvecioğlu, et al.
Laparoscopıc approach for epiphrenic esophageal diverticula
3.
4.
5.
Schultz SC, Byrne DM, De Cunzo P, Byrne WB.
Carcinoma arising within epiphrenic diverticula. A
report of two cases and review of the literature. J
Cardiovasc Surg 1996; 37: 649-651.
Rosati R, Fumagalli U, Bona S, Bonavina L,
Peracchia A. Diverticulectomy, myotomy and
fundoplication through a laparoscopy: A new
option to treat epiphrenic esophageal diverticula?
Ann Surg 1998; 227: 174-178.
Evander A, Little AG, Ferguson MK, Skinner DB.
Diverticula of the mid and lower esophagus:
Pathogenesis and surgical management. World J
Surg 1986; 10: 820-828.
6.
7.
8.
9.
76
Fernando HC, Luketich JD, Samphire J, et al.
Minimally invasive operation for esophageal
diverticula. Ann Thorac Surg. 2005; 80: 20762080.
Streitz JM, Glick ME, Ellis H. Selective use of
myotomy for treatment of epiphrenic diverticula:
Manometric and clinical analysis. Arch Surg 1992;
127: 585-588.
Gockel I, Eckardt VF, Junginger T. Epiphrenic
diverticulum: Possible causes and surgical therapy.
Chirurg 2005; 76: 777-782.
Abe T, Tangoku A, Oka M. Esophageal diverticula.
Nippon Geka Gakkai Zasshi. 2003; 104: 601-605.
CASE REPORTS
NEONATAL MIXED SEX-CORD STROMAL TUMOR OF THE TESTIS: A CASE
REPORT
1
Asıf Yıldırım1, Erem Başok1, Adnan Başaran1, Ebru Zemheri2, Reşit Tokuç1
SB İstanbul Göztepe Eğitim ve Araştırma Hastanesi, Üroloji, İstanbul, Türkiye 2SB İstanbul Göztepe Eğitim
ve Araştırma Hastanesi, Patoloji, İstanbul, Türkiye
ABSTRACT
Sex cord-stromal tumors of the testis are rare. We report a mixed type sex-cord stromal tumor in neonate.
According to published reports, sex-cord stromal testis tumors exhibit benign behavior in prepubertal
patients. However, undifferentiated stromal tumor with a large number of mitotic figures may exhibit
metastatic behavior.
Keywords: testis, sex cord-stromal tumor, neonate
NEONATAL TESTİS MİKST SEKS-KORD STROMAL TÜMÖR: OLGU SUNUMU
ÖZET
Testisin seks-kord stromal tümörü nadir olarak görülmektedir. Bu yazıda, neonatal testisin mikst tipte sekskord stromal tümör olgusu sunuldu. Literatüre bakıldığında, prepübertal dönemde testisin seks-kord stromal
tümörleri benign seyir göstermektedir. Buna karşın, çok sayıda mitotik aktivite ile diferansiye-olmayan
stromal tümör malign davranış gösterebilir.
Anahtar Kelimeler: testis, seks kord-stromal tümör, neonatal
microcalcification, which had entirely replaced
the normal testicular parenchyma (Figure 2).
Serum AFP was 13.927 ng/ml (normal range 0.616.387). Inguinal exploration and right radical
orchiectomy were performed. The gross
appearance was primarily of tan-yellow nodular
lesions containing multiple thin-walled cysts with
hemorrhagic fluid (Figure 3). Pathological
examination revealed small nests, narrow cords
and thick trabeculae, tubular structure enveloped
by fine connective tissue and a mixed sex-cord
stromal (sertoli cell and juvenile granulosa cell)
tumor that had completely replaced the testis.
(Figure 4). Immunohistochemical study of the
tumor showed a strong positivity for vimentin,
inhibin-alfa and a negative staining for alphafetoprotein (AFP), Carcinoembryogenic antigen
(CEA), placental-like alkaline phosphatase
(PLAP), cytokeratin, epithelial membrane antigen
(EMA) and desmin (Figure 5). The patient did
well postoperatively and at 16 months follow-up
AFP was normal.
INTRODUCTION
Testis tumors in the neonate are extremely rare
and with the exception of the previous reports of
the Tumor Registry data, few cases have been
documented in the literature.1 Sex-cord stromal
testis tumors represent only 5% of all testicular
neoplasms, and include Leydig cell, Sertoli cell,
juvenile granulosa cell, thecal cell tumors, mixed
cell types and undifferentiated tumors.2 We report
a case of neonatal mixed sex-cord stromal tumor
and discuss its diagnosis and treatment. To our
knowledge no such cases have been reported in
the literature.
CASE PRESENTATION
An otherwise healthy full-term male infant was
referred for a markedly enlarged and firm right
testis. On physical examination both testes were
descended, and the right testis was enlarged and
non-tender (Figure 1). Color Doppler ultrasound
showed
a
solid
cystic
mass
with
Asıf Yıldırım
SB İstanbul Göztepe Eğitim ve Araştırma Hastanesi, Üroloji, İstanbul, Türkiye
77
Asıf Yıldırım, et al
Neonatal mixed sex-cord stromal tumor of the testis: a case report
Figure 1: Enlarged right testis
Figure 3: Gross appearance of testis
Figure 2: Color Doppler Ultrasonography of the right testis
Figure 4: Small nests (arrow) enveloped by fine connective
tissue (H&E, reduced from X 20)
Figure 5: A. Strong positive staining for inhibin alfa. B. Positive staining for vimentin in stroma and negative staining
for vimentin in tubular structure. (H&E, reduced from X40)
78
Asıf Yıldırım, et al
Neonatal mixed sex-cord stromal tumor of the testis: a case report
marker of testicular sex cord-stromal tumors.7
Similar to previous studies, the tumor exhibited
strong positive staining for inhibin and vimentin
in the present case.8
DISCUSSION
On microscopic examination granulosa cell
tumors contain granulose-like cells that line a
cystic space, which is intermixed with solid
nodular areas. These tumors can be reliably
differentiated from yolk sac tumors because they
demonstrate positive immunostaining with inhibin
and negative immunostaining with AFP.1,3,4
Microscopically, sertoli cell tumors consist of an
interlacing network of loose fibrous stroma with a
cellular parenchyma composed of moderately
small cells with irregular hyperchromatic nuclei.2,3
Management of sex cord-stromal testis tumors is
still debated, since the rarity of such tumors
makes it difficult to develop a consensus on a
standardized approach.
CONCLUSION
Stromal testis tumors are rare. Data from the
Prepubertal Testis Tumor Registry confirm the
benign behavior of most of these tumors. Periodic
follow-up of the remaining testicle through
puberty and self-examination thereafter seem
reasonable.
According to a recent report from the Prepubertal
Testis Tumor Registry (1980-2001), of the 43
registered cases of stromal tumors, 8 were mixed
or undifferentiated stromal tumor.3 Interpretation
of tumor markers in neonates and infants is
difficult. In a recent report average AFP for a fullterm newborn was 48.406 ng/ml. This value
decreases to less than 8.5 ng/ml by age 8 months4.
REFERENCES
1.
2.
The data in the registry confirm that the vast
majority of stromal tumors are benign. No patient
with leydig cell, juvenile granulosa cell or sertoli
cell tumor had metastatic disease during an
average 24.6 months of followup.3 However, in
the literature at least 4 malignant sertoli cell
tumors have been reported in prepubertal
patients.3 Juvenile granulosa cell tumor (JGCT) is
a distinct variety of gonadal sex-cord stromal
tumor that has most often reported in the ovaries
of premenarchal girls, rarely in adults, and only
recently in the infantile testis.5 The first case of
JGCT of the infantile testis was reported by
Crump in 1983.6 Subsequently, Lawrence et al
described 14 cases and established this tumor as a
distinct
clinicopathologic
entity.4
The
immunohistochemical profile of ovarian sex cordstromal tumors has been well characterized, but
few studies have detailed the immunophenotype
of the corresponding testicular neoplasms.7
Inhibin is a peptide hormone that is produced by
ovarian granulosa cells and testicular sertoli cells8.
McCluggage et al found inhibin to be a good
3.
4.
5.
6.
7.
8.
79
Uehling DT, Smith JE, Logan R and Hafez GR.
Newborn granulosa cell tumor of the testis. J Urol.
1987; 138: 385-386.
Emanuele C, Sara SM, Nicola F, Cristian F, Paola
B, Dario F. Undifferentiated sex cord-stromal testis
tumor. J Urol. 2004; 171 (6): 2375.
Thomas JC, Ross JH and Kay R. Stromal testis
tumors in children: e report from the Prepubertal
Testis Tumor Registry. J Urol. 2001; 166: 23382340.
Lawrence WD, Young RH and Scully RE. Juvenile
granulosa cell tumor of the infant testis. A report of
14 cases. Am J Surg Pathol. 1985; 9: 87-94.
Antonio PA, Nancy J, Howard M. Juvenile
Granulosa Cell Tumor of the Infantile Testis:
Evidence of a dual epithelial-smooth muscle
differentiation. Am J Surg Pathol. 1996; 20 (1): 7279.
Crump WD. Juvenile granulosa cell (sex cordstromal) tumor of fetal testis. J Urol. 1983; 129:
1057-1058.
McCluggage WG, Shanks J, Whiteside C, Maxwell
P, Benerjee S, Biggart JD. Immunohistochemical
study of testicular sex cord-stromal tumors,
including staining with anti-inhibin antibody. Am J
of Surg Pathol. 1998; 22 (5): 615-619.
Merchenthaler I, Culler MD, Petrusz P, NegroViler A. Immunohistochemical localization of
inhibin in rat and human reproductive tissues. Mol
Cell Endocrinol. 1988; 54: 239-243.
CASE REPORTS
LENFOMA NEDENİYLE UYGULANAN RADYOTERAPİ SONRASI SEKONDER
MALİGNİTELER-OLGU SUNUMU
Alper Çelik1, Suat Kutun2, Turgay Fen3, Gülay Bilir4, Akın Önder5, Abdullah Çetin6
1
Gaziosmanpaşa Üniversitesi Tıp Fakültesi, Genel Cerrahi Anabilim Dalı, Tokat, Türkiye 2Ankara Onkoloji
Hastanesi, 1. Genel Cerrahi Kliniği , Ankara, Türkiye 3Ankara Onkoloji Hastanesi, Hematoloji Kliniği,
Ankara, Türkiye 4Ankara Onkoloji Hastanesi, Patoloji Kliniği, Ankara , Türkiye 5Ankara Onkoloji Hastanesi
, 1. Genel Cerrahi Kliniği , Ankara, Türkiye 6Ankara Onkoloji Hastanesi , 1. Genel Cerrahi Kliniği , Ankara,
Türkiye
ÖZET
Bu olgu sunumunda Hodgkin lenfoma tanısıyla baş-boyun bölgesine radyoterapi uygulanmasını takiben
ortaya çıkan akciğer ve çoklu cilt kanserleri tespit edilen bir olgu sunulmuştur. Elli yaşında, Evre IA
Hodgkin lenfoma nedeniyle mantle alanına radyoterapi verilen erkek hastada, 6 yıl sonra burun üzerinde
bazal hücreli karsinom, sağ kulak üzerinde invaziv epidermoid karsinom ve sol infraorbital bölgede in-situ
epidermoid karsinom tespit edildi. Cerrahi tedavi sonrası sağ aurikuler alana ve sol infraorbital sahaya lateral
cerrahi sınırın yakın olması ve hastanın re-eksizyonu kabul etmemesi nedeniyle radyoterapi verilen olgu bir
yıl sonra nefes darlığı şikayeti ile başvurdu. Sağ akciğer üst ve orta zonları tutan kitle tespit edilen olgunun
bronkoskobik biyopsi sonucu Epidermoid karsinom olarak rapor edildi. Vena cava superior sendromu tespit
edilen hastaya tekrar radyoterapi ve medikal tedavi uygulandı. Genel durumu giderek bozulan hasta 15 gün
sonra öldü.
Anahtar Kelimeler: Hodgkin lenfoma, radyoterapi, ikincil kanser
SECONDARY MALIGNANCIES AFTER LYMPHOMA TREATED BY
RADIOTHERAPY-CASE REPORT
ABSTRACT
We hereby describe a case of Hodgkin lymphoma treated with radiotherapy to head and neck region, who
further developed lung and multiple skin cancers. A 50-year-old male patient with stage IA Hodgkin
lymphoma was treated with radiotherapy to mantle zone. Six years later we detected basal cell carcinoma on
his nose, invasive epidermoid carcinoma on his right ear, and in-situ epidermoid carcinoma on left
infraorbital area. After surgical removal, radiotherapy was applied to right auricular area and left infraorbital
area due to close lateral margin and the patient’s refusal for re-excision. One year later he admitted with
dyspnea. We detected a mass involving the upper and middle zones of his right lung, and bronchoscopic
biopsy revealed epidermoid carcinoma. Vena cava superior syndrome was established, and he was re-treated
with radiotherapy and medical treatment. His medical condition deteriorated, and 15 days later he died.
Keywords: Hodgkin lymphoma, radiotherapy, secondary cancer
GİRİŞ
1) Her iki tümörün de histolojik olarak malign
olduğu ispat edilmelidir.
İkinci primer maligniteler indeks karsinomla aynı
anda tanı alırlarsa simültane, indeks tümör
tanısından sonraki 6 aylık dönemde ortaya
çıkarlarsa senkron ve 6 aydan sonra da metakron
karsinom olarak isimlendirilirler 1. Bir malignite
olgusunun ikinci primer tanısı alabilmesi için
Warren ve Gates kriterleri2 geliştirilmiştir:
2) İki tümör arasında minimum 2 cm sağlıklı doku
olmalıdır. Aynı lokalizasyonda olan tümörlerde
birbirlerinden 5 yıl süre farkı olmalıdır.
3) Metastatik hastalık ekarte edilmelidir.
Alper Çelik
Gaziosmanpaşa Üniversitesi Tıp Fakültesi, Genel Cerrahi Anabilim Dalı, Tokat
80
Alper Çelik ve ark.
Lenfoma nedeniyle uygulanan radyoterapi sonrası sekonder maligniteler-olgu sunumu
poliklinik takibine alınan hasta 1 yıl sonra nefes
darlığı nedeniyle başvurdu. Fizik muayenesinde
ortopne saptanan hastanın sağ akciğer üst ve orta
zonlarda solunum sesleri alınamadı. Göğüs
bölgesinde Vena cava superior sendromu ile
uyumlu kollateraller ve pletorik görünüm
saptandı. Akciğer grafisinde sağ akciğer üst ve
orta zonlarda konsolidasyon alanları ve bilateral
plevral efüzyon saptanan hastanın akciğer
tomografisinde sağ hilusta ana bronşu ve segment
bronşlarını çevreleyerek daraltan düzensiz sınırlı
kraniokaudal boyutu yaklaşık 6 cm, vena kava
superior ve pulmoner arterden sınırları net ayırt
edilemeyen kitle saptandı (Resim 5). Fiberoptik
bronkoskopi’de sağ ana bronş girişinden itibaren
başlayıp üst lob girişini tama yakın kapatan, üst
lob-orta lob ayrım karinasını obstrükte eden
infiltratif lezyon saptandı. Bronkoskopik biyopsi
sonucu epidermoid karsinom olarak rapor edilen
hastanın, bronkoskopik biyopsi materyalinin
yüzey epitel ile ilişkisi olmaması nedeniyle primer
veya metastatik tümör ayrımı yapılamadı. Acil
radyoterapi endikasyonu konulan hastanın daha
önce mediasten ışınlaması ve medulla spinalis
dozları da dikkate alınarak 15 MV foton ile, ilk
gün şiddetli dispnesi olması sebebiyle 400
cGy’den kitle ve mediastene yönelik olarak, daha
sonraki tedavisi oblik alanlardan planlanan
hastaya iki gün daha 300 cGy/gün olmak üzere
toplam 1000 cGy (Biyolojik eşdeğer doz = 1200
cGy) palyatif radyoterapi verildi. Sonraki
takiplerinde plevral efüzyonu artan hastaya
torasentez, diüretik ve kortikosteroid tedavisi de
uygulandı. Ancak, hasta 15 gün sonra respiratuvar
arrest nedeniyle vefat etti.
Bu olgu sunumu ile primer radyoterapi sonrası
multipl kanserler nedeniyle takip ve tedavisi
yapılan bir olguya ait tecrübemizi sizlerle
paylaşmayı amaçladık. Olgu sunumu için
hastadan sözel ve yazılı olarak izin alınmıştır.
OLGU SUNUSU
Boyun sol tarafında şişlik nedeniyle hastanemize
başvuran 50 yaşında erkek hastanın yapılan fizik
muayenesinde sol servikal zincirde lenfadenopati
tespit edildi. Çiftçilik yapan hastanın diğer sistem
muayeneleri normal idi. Tanısal amaçlı sol
servikal lenf nodu eksizyonu uygulanan hastanın
patoloji raporu miks selüler tip Hodgkin lenfoma
olarak rapor edildi. Hastanemizde yapılan
laboratuar
incelemelerinde;
hemogram,
biyokimya, akciğer ve batın tomografileri normal
idi. Özgeçmişinde sigara bağımlılığı (30 yıl süre
ile günde yaklaşık 40 sigara) dışında önemli
özellik yoktu. Sistemik semptomları olmayan
hastanın kemik iliği aspirasyon ve biyopsisi
normal olarak değerlendirildi. Evre IA kabul
edilerek kemoterapi endikasyonu konmayan
hastanın baş-boyun ve supradiyafragmatik
bölgelere Mantle tekniği ile 6 MV foton ile 200
cGy/ gün mediasten, supraklaviküler, aksilla ve
boyun ışınlaması (boyun 4200 cGy, mediasten
3800 cGy) ve bir ay sonra paraaortik ve splenik
sahalara 15 MV foton ile 3600 cGy proflaktik
radyoterapi uygulandı. Ondört ay boyunca
takipleri sorunsuz seyreden hastanın bu
dönemdeki kontrolünde yaklaşık 6 ay önce
başlayan sağ kulak üzerinde, sol infraorbital
bölgede ve burun sırtında üzeri skuamlı,
hiperpigmente, makülopapüler lezyonlar tespit
edildi. Burun üzerindeki ve sol infraorbital
sahadaki lezyonlarına eksizyonel, sağ kulak
üzerindeki lezyonlarına insizyonel biyopsi
uygulanan hastanın burun üzerindeki lezyon Bazal
Hücreli Karsinom, sağ aurikula üzerindeki lezyon
invaziv Epidermoid Karsinom ve sol infraorbital
bölgedeki lezyon ise in-situ Epidermoid Karsinom
olarak rapor edildi (Resim 1-2-3). Burun
üzerindeki ve sol infraorbital sahadaki
lezyonlarının cerrahi sınırları negatif olarak
bildirilen hastaya sağ aurikula üzerindeki lezyon
nedeniyle, hastanın da onayı alınarak sağ
auriküler parsiyel eksizyon uygulandı (Resim 4).
Adjuvan kemoterapi endikasyonu konmayan
hastanın sol infraorbital sahadaki lezyonuna
yönelik lateral cerrahi sınıra yakın (1 mm) olması
ve hastanın re-eksizyonu kabul etmemesi
sebepleriyle 6 MeV elektronla 300 cGy/gün x 17
fraksiyonda toplam 5100 cGy radyoterapi
uygulandı. Akciğer tomografisi radyoterapiye
bağlı değişiklikler dışında normal olan ve
Resim 1: Bazal hücreli karsinom. Periferal palizatlanmanın
eşlik ettiği tipik nodüler görünüm
81
Resim 2: Belirgin nükleollü, geniş yuvarlak nükleuslu atipik
epitelyal hücrelerin oluşturduğu iyi diferansiye epidermoid
karsinom.
Resim 4: Parsiyel aurikuler eksizyon sonrası görünüm.
Resim 3: Tüm epitel katlarını tutan atipi, parakeratozis,
anormal mitotik aktivite ve bozulmuş maturasyon paterni
gösteren in-situ epidermoid karsinom.
Resim 5: Sağ akciğerdeki kitlenin tomografik görünümü.
TARTIŞMA
iliği transplantı sonrası tüm vücut ışınlaması
sonrası sekonder kanserlerin gelişebildiği ifade
edilmiştir. Radyoterapi sonrası ortaya çıkan
sekonder
tümörler
iki
ayrı
grupta
incelenmelidirler. Birinci grup özellikle yüksek
doz radyoterapiye maruz kalan sahalarda ortaya
çıkan sarkomlar veya sarkomatoid tümörlerdir.
İkinci grubu ise primer radyoterapi alanından uzak
organ veya dokularda ortaya çıkan tümörler
oluştururlar. Radyoterapi sonrası ikincil kanser
gelişimi ilgili en geniş iki araştırma serviks ve
prostat kanserli hastalar üzerinde yapılmıştır.
Malignite hastalarında uygulanan multimodaliter
tedavilerin sağkalımı artırmasına paralel olarak
hastaların küçümsenmeyecek bir bölümünde
ikincil kanserler ortaya çıkmaktadır. Radyoterapi
ve kemoterapinin mutajen ve karsinojenleri
tetikleyerek ikincil karsinomların patogenezinde
rol oynayabildikleri gösterilmiştir3.
Özellikle çocukluk çağı maligniteleri, serviks
kanseri, Hodgkin lenfoma ve meme kanseri
nedeniyle radyoterapi uygulaması, ayrıca kemik
82
dışında geliştiğini bildirmişlerdir 15. Sachs ve
Brenner’in çalışmasında 3 Gy ve daha düşük
dozlarda radyoterapiye bağlı ortaya çıkan ikincil
kanserlerin özellikle atom bombası sonrası
Japonya kaynaklı araştırmalar sebebiyle iyi
bilindiği, ancak yüksek doz radyoterapiye bağlı
ikincil kanserlerin daha yeni bir konu olduğu
vurgulanmıştır. Önceden yüksek doz RT alan
hastalarda bu bölgede ciddi bir hücre ölümü
meydana geldiği ve bu sahalardan kanser
gelişemeyeceği düşüncesi hâkim idi. Ancak adı
geçen çalışmayla gösterilmiştir ki, hücre ölümü
gerçekleşen sahalara radyasyondan etkilenen
organdaki kök hücreler migrate olmaktadırlar.
Kök hücrelere ait bu migrasyon ve proliferasyona
repopülasyon adı verilmiştir. Nekrotik saha ve
periferindeki hücre repopülasyonu bu sahalarda
gelişen
ikincil
malignitelerden
sorumlu
tutulmuştur. Re-popülasyon adı verilen hücre
kinetiği yüksek doz RT uygulanan sahalardaki
ikincil kanser olasılığını matematiksel olarak
belirleyebilme olanağını da sağlar16.
Serviks
kanserli
hastalarda
radyoterapi
uygulanmayan
hastalarla
karşılaştırıldığında
özellikle lösemi riskinde küçük bir artış olduğu
ifade edilmiş, bunun yanı sıra rektum, mesane,
vajen ve kemik tümörlerinin sıklığında artış
olduğu, daha da önemlisi radyoterapi alanından
uzak olan mide malignitelerinin de özellikle 1 Gy
ve
üzerinde
dozlarda
sıklığının
arttığı
belirtilmiştir4. Diğer çalışmada prostat kanseri
nedeniyle radyoterapi alan hastalar sadece cerrahi
tedavi uygulanan hastalarla karşılaştırılmış ve
mesane, rektum tümörlerinin yanı sıra özellikle
sarkom sıklığında artış olduğu bildirilmiştir 5.
İkincil karsinom sıklığı baş ve boyunda lokalize
yassı epitel hücreli kanserlerde % 5-36 arasında
değişmektedir 6. Farklı nedenlerle radyoterapi
uygulanan saha ve çevresinde osteosarkom 7,
anjiosarkom 8 ve bazal hücreli karsinomların 9
gelişebildiği bildirilmiştir.
Hodgkin lenfoma nedeniyle alkilleyici ajan
kullanımı lösemi riskini artırmaktadır. Alkilleyici
ajanların yanı sıra radyoterapi uygulanması lösemi
riskinde ilave bir artışa neden olmamakla birlikte
meme, akciğer, kemik, tiroid, mide ve cilt
tümörlerinin görülme riskini artırmaktadır. Meme
ve tiroid kanserleri için genellikle 15 yıllık bir
latent period gerekli olmakla beraber akciğer
kanserlerinin tedaviden sonraki 5 yıllık dönemde
dahi ortaya çıkabileceği iddia edilmiştir 3,10,11.
Melanom Dışı Cilt Kanserleri (MDCK) için hem
UV hem de ionizan radyasyon risk faktörüdür 17.
Radyasyonun en önemli özelliği lokal olarak
biyolojik
önemi
olan
kimyasal
bağları
parçalayabilecek güçte büyük miktarlarda enerji
açığa çıkarmasıdır. Karsinogenezde önemli olan
iyonize radyasyon, başlıca elektromanyetik xışınları, gama ışınları ve elektron, proton, alfa
partiküller ve ağır iyonlar gibi yüklü olanlar ve
nötronlar gibi yüksüz olan partiküllü ışınlardır.
Pek çok merkez tarafından MDCK hem sık
görüldüklerinden hem de sağkalım özellikle erken
evrelerde iyi olduğundan veritabanı kaydı
tutulmamaktadır. Bu yaklaşım konu hakkındaki
edinimlerimizin genellikle kişisel veya kurumsal
tecrübe ve bilgi birikimi ile sınırlı kalmasına yol
açmaktadır. Perkins’in çalışması çok merkezli bir
çalışma olması sebebiyle bu konuda üzerinde
durulması gereken bir çalışmadır. Çocukluk
çağında malignite nedeniyle %90’ı RT almış
13132 hasta üzerinde yapılan çalışmada 213
olguda MDCK tespit edilmiş olup, bu olguların
yaklaşık %10’luk bölümünde ortaya çıkan cilt
kanserlerinin RT alanının dışında olduğu ve
radyasyon tedavisi almış olmanın MDCK riskini
normal popülasyona göre 6.3 kat arttırdığı
bildirilmiştir 17. Bir diğer araştırmada daha önce
MDCK dışı hastalıklar nedeniyle RT almış
hastalarda Bazal Hücreli Karsinom (BHK)
sıklığında anlamlı artış saptanmış, Yassı Hücreli
Karsinom (YHK) sıklığında da artış saptanmış
ancak
bu
artış
istatistiksel
anlamlılığa
ulaşmamıştır18.
Lorigan ve ark. çalışmasında Hodgkin lenfoma
tedavisi almış hastalarda akciğer kanseri gelişme
için 2.6-7 kat artmış relatif risk olduğu, bu riskin
tedaviden sonra geçen süre ile anlamlı artış
gösterdiği ve 45 yaşın üzerinde tedavi gören hasta
grubunda anlamlı artış olduğu belirtilmiştir. Bir
diğer önemli nokta ise kemoterapi ile
radyoterapinin additif etki gösterdiği ve sigara
kullanımının bu riski daha da artırdığı gerçeğidir
12
. İonizan radyasyon-akciğer kanseri ilişkisi pek
çok çalışmada vurgulanmıştır. Hatta ionizan
radyasyon dozuna göre sekonder akciğer kanseri
gelişme riskinin belirlenebileceği dahi iddia
edilmiştir 13. Bir diğer araştırmada ionizan
radyasyon tedavisi alan hastalarda 40 Gy ve
üzerinde radyoterapi dozlarında sekonder akciğer
kanseri riskinde anlamlı artış olduğu, daha düşük
dozlarda da artış olmakla beraber istatistiki
anlamlılık olmadığı ve sekonder akciğer kanseri
gelişme riskinde her Gy başına %0.15 artış olduğu
bildirilmiştir 14. Gilbert ve ark. çalışmasında da
ikincil
akciğer
kanserlerinin
%79.5’inin
radyoterapi tedavi alanı içinde olduğu,
%19.2’sinin daha düşük dozlarda radyoterapi alan
sahalarda ve hatta %17.3’ünün tedavi sahası
83
3.
Ultraviole radyasyon tipinin cilt kanseri sıklığı
üzerine olan etkisinin araştırıldığı bir çalışmada
psöriazis nedeniyle Psöralen + Ultraviole A (UVA) tedavisi gören hastalarda özellikle YHK
sıklığında anlamlı artış saptanmıştır. Ancak, bu
hastalarda zaten cilt duyarlılığı ve cilt yapısı
nedeniyle YHK’a yatkınlık olduğu göz önünde
bulundurulmalıdır 19. Bizim hastamızda da benzer
bir cilt duyarlılığı söz konusu olmasına rağmen
sol infraorbital sahadaki lezyona lateral cerrahi
sınırın yakın olması ve hastanın re-eksizyonu
kabul etmemesi sebebiyle adjuvan radyoterapi
uygulandı.
4.
5.
6.
Sunduğumuz olguda ikincil akciğer kanseri
Hodgkin lenfoma tanısından 7 yıl sonra ortaya
çıktı. Ancak hastamızın kemoterapi almamış
olması ve sigara bağımlısı olması akciğer
kanserinin radyoterapiye sekonder olmaması
ihtimalini kuvvetlendirmektedir. Hastamızın çiftçi
olması ve uzun süre güneşe maruz kalmış olması
da tek başına önemli bir risk faktörüdür. Ayrıca,
cilt kanseri ile akciğer kanserinin aynı histolojik
tipte olması ve bronkoskobik materyalde yüzey
epitel ile ilişkinin gösterilememiş olması da
akciğer kanserinin orijininin belirlenmesini
güçleştirmektedir. Eğer, akciğer kanseri ile cilt
kanserinin farklı Grade’e sahip oldukları veya
akciğer kanserinde in-situ komponent varlığı
gösterilebilmiş olsaydı primer akciğer kanseri
tanısı konulabilirdi 20. Hastamızda genetik
predispozisyon varlığı araştırılmadı. Ancak
akciğerde lokalize malignitelerde, primer veya
metastatik tümör ayrımında immünhistokimyasal
yöntemlerden, özellikle sitokeratin boyalarından
yararlanılarak, hastamızın tedavisinde farklı yollar
izlenilebilirdi. Bu bağlamda ikincil tümör şüphesi
olan olgularda İnce İğne Aspirasyon Biyopsisi
(İİAB) gibi tanısal yöntemlerden ziyade dokunun
yüzey epitel veya sağlam doku ile ilişkisi
gösterilerek, indeks tümörle ikincil tümör arasında
Grade farklılığı veya ikincil tümörde in-situ
komponent
varlığının
ortaya
konmasının
metastazın ekarte edilerek, ikincil tümör tanısının
konmasında en önemli yaklaşım olduğunu
düşünmekteyiz.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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85
CASE REPORTS
TWO NEW KABUKI CASES OF KABUKI MAKE-UP SYNDROME
Ahmet Sert, Mehmet Emre Atabek, Özgür Pirgon
Selçuk Üniversitesi Meram Tıp Fakültesi, Pediatrik Endokrinoloji, Konya, Türkiye
ABSTRACT
Kabuki syndrome (Kabuki make-up syndrome, Niikawa–Kuroki syndrome) is a multiple congenital
anomaly/mental retardation syndrome. We report on an 11-month-old girl with Kabuki make-up syndrome
who has premature telarche, premature pubarche and epilepsy, and a 4-month-old boy with Kabuki make-up
syndrome who had been operated due to diaphragmatic hernia and had mesocardia confirmed by
echocardiography. In the study, we emphasize that careful phenotypic examination of children should be
performed in every patient presenting with mental retardation and epilepsy to diagnose Kabuki syndrome
and the patients diagnosed as Kabuki syndrome should be followed for precocius puberty. We suggest that
mesocardia, which has not been reported in the literature yet, may be considered as one of the cardiological
findings of Kabuki syndrome and all Kabuki patients should be evaluated for life-threatening complications
of congenital diaphragmatic hernia.
Keywords: Diaphragmatic hernia, epilepsy, Kabuki syndrome, premature telarche
KABUKİ MAKE-UP SENDROMUNUN İKİ YENİ VAKASI
ÖZET
Kabuki sendromu (Kabuki make-up sendromu, Niikawa-Kuroki sendromu) çoklu doğumsal anomali/mental
gerilik sendromudur. Epilepsi, prematür telarş ve prematür pubarşı olan Kabuki make-up sendromlu 11 aylık
kız ve ekokardiyografi ile mezokardisi doğrulanan ve diyafragma hernisi nedeniyle opere edilen Kabuki
make-up sendromlu 4 aylık erkek çocuğu sunuyoruz. Mental gerilik ve epilepsi ile prezente olan her hastada
dikkatli fenotipik inceleme yapılması gerektiğini ve Kabuki sendromu teşhisi konulan hastaların erken
puberte için takip edilmesi gerektiğini vurguluyoruz. Bunun yanında, henüz literatürde bildirilmeyen
mezokardinin Kabuki sendromunun kardiyolojik bulgularından birisi olarak dikkate alınabileceğini ve
Kabuki sendromlu bütün hastaların doğumsal diyafragma hernisinin yaşamı tehdit eden komplikasyonları
için değerlendirilmesi gerektiğini öneriyoruz.
Anahtar Kelimeler: Diafragma hernisi, epilepsi, Kabuki sendromu, prematür telarş
association with Kabuki make up syndrome have
been rarely reported in the literature4.
Diaphragmatic defect is an uncommon finding in
Kabuki syndrome, reported in only two female
patients with a diaphragmatic eventration5 and in
an aborted fetus with a diaphragmatic hernia6.
Mesocardia accompanied by Kabuki syndrome in
the literature has not been reported yet. We report
on an 11-month-old girl with Kabuki make up
syndrome who has premature telarche, premature
pubarche and epilepsy, and a 4-month-old boy
with Kabuki make up syndrome who has
mesocardia and diaphragmatic hernia.
INTRODUCTION
Kabuki syndrome (Kabuki make-up syndrome,
Niikawa–Kuroki syndrome) is a multiple
congenital anomaly/mental retardation syndrome
that was first described simultaneously by two
groups in Japan, Niikawa et al.1 and Kuroki et al.2.
The prevalence of Kabuki syndrome in the
Japanese population has been estimated to be
1/32,0003. The designation Kabuki make-up refers
to the resemblance of the facial features with the
characteristic make-up used by actors of Kabuki, a
traditional Japanese theatrical form1. Premature
telarche, premature pubarche and epilepsy
Ahmet Sert
Selçuk Üniversitesi Meram Tıp Fakültesi, Pediatrik Endokrinoloji, Konya, Türkiye
86
Ahmet Sert, et al
Two new kabuki cases of kabuki make-up syndrome
CASE PRESENTATION
Case 1
An 11-month-old girl was referred to emergency
clinics for diarrhea and vomiting. She was born by
cesarean section due to breech presentation after a
term gestation to a primigravida mother. The
parents were healthy first-degree cousins. She had
psychomotor developmental delay and seizures at
ten months of age. However, the breast
development was tanner stage 2 at 4 months of
age. The pubic hair was tanner stage 2 at 9 months
of age. Her height was 69 cm (50-75 p), weight
7.3 kg (3-10 p) and head circumference 40 cm (<
3 percentile). She had facial dysmorphism with
high arched eyebrows sparse laterally, long
palpebral fissures with everted lower eyelids, long
eyelashes accompanying microcephaly. Her nose
was broad with depressed tip, and ears were
prominent and protruding (Fig. 1). On oral
examination she had high arched palate. She had a
generalized hypotonia. She had both premature
telarche and premature pubarche. The other
system findings were normal. During one hour
follow up, generalized afebrile tonic-clonic
seizures, lasting longer than 30 min were
observed. The status epilepticus was well
controlled by an appropriate treatment. On
admission biochemical investigations, including
serum electrolytes, liver function tests, lipid
profiles, and coagulation tests were all within
normal limits except for presence of leukocytosis
(28.1X109/L) in the complete blood count. The
electroencephalography and magnetic resonance
imaging of the brain and pituitary region were
normal as well as abdomen and pelvic
ultrasonography,
and
echocardiographic
examination.
Ophthalmologic
examination
revealed normal findings. Bone age was at six
months girl. Gonadotrophin releasing hormone
test was performed to rule out the presence of
precocious puberty revealed an exaggerated
follicle stimulating hormone response and
prepubertal level of luteinizing hormone response.
She was diagnosed as Kabuki syndrome due to
her clinical findings. Testing of three consecutive
stool specimens showed Entamoeba histolytica as
the causative agent for the diarrhea and vomiting.
Stool cultures were negative for other
enteropathogens. The patient was treated
successfully by metronidazole. She improved
clinically during her stay at the hospital, and was
discharged in 10 days.
Figure 1: An 11 months old girl showing facial dysmorphism
typical for Kabuki syndrome with long palpebral fissures,
arched eyebrows sparse laterally, epicanthic folds, and
premature telarche.
Case 2
A 4-month-old boy was referred to pediatric
endocrinology division to be evaluated for facial
dysmorphism. He was born to a normal pregnancy
by vaginal delivery. His birth weight was 2700 g.
His
parents
were
healthy
and
nonconsanguineous. There was no family history for
mentally retarded persons nor individuals with
congenital anomalies. Immediately after birth, he
had been diagnosed as having diaphragmatic
hernia and was intubated by endotracheal tube. At
3 days of age, a surgical operation for an anterior
diaphragmatic hernia through the foramen of
Morgagni was performed. He had been followed
by mechanic ventilation for 25 days in the
newborn intensive care unite, and antibiotic
therapy was administered for sepsis during
follow-up. At 4 months of age, physical
examination revealed his height as 64.5 cm (50 p),
weight 4500 g (3 p) and head circumference 37.6
cm (< 3 p). He was noted to have facial
dysmorphic features—long palpebral fissures with
eversion of the lower lateral eyelids, arched
eyebrows with lateral sparseness, depressed nasal
tip, large, prominent and cupped ears (Fig. 2).
87
Ahmet Sert, et al
patterns) in 93% of their patients, mild to
moderate mental retardation in 92% of their
patients, and postnatal growth deficiency in 83%
of their patients. There have also been a number
of less frequent findings reported in Kabuki
syndrome, including visceral abnormalities,
premature breast development in females, and
susceptibility to frequent infections 3,7. Tutar et al.
reported the first non-Japanese Asian case with
Kabuki make up syndrome who had premature
thelarche from Turkey 8. In our study, the female
patient had premature telarche and serious
infection was established in the boy. The
dysmorphic features of our patients are in
accordance with detailed clinical findings
observed in Kabuki patients.
In addition to the distinct facial features, he also
had high arched palate, persistent fetal finger
pads, arachnodactyly, bilateral simian line and
umblical hernia. Cardiac examination revealed no
significant murmurs. The other system findings
were normal. Laboratory examinations were
within normal limits. Chest radiography showed
no cardiac enlargement. Echocardiography
demonstrated mesocardia with no other associated
cardiac anomalies. He was diagnosed as Kabuki
make up syndrome due to clinical findings.
Although diagnosis relies on dysmorphic features,
neurological symptoms are the most invalidating
manifestations in the Kabuki syndrome clinical
spectrum, often presenting as the first complaint;
nevertheless, Kabuki syndrome is still a rare
diagnoses at neurology clinics 4. Neurological and
endocrinological anomalies that are reported to
include neonatal hypotonia, feeding problems,
seizures, West syndrome, microcephaly, brain
atrophy, growth hormone deficiency, precocious
puberty,
hypoglycemia,
delayed
sexual
development, and diabetes insipidus. Other
neurological
abnormalities
observed
are
subatrophy of the optic nerves, subarachnoid cyst,
cerebellar and brainstem atrophy, and epilepsy
2,9,10
. In accordance with the literature, the female
patient presented with developmental delay and
seizures. On the other hand she also had
microcephaly. Schrander-Stumpel et al. reported
29 Caucasian patients and reviewed 60 Japanese
and 29 non-Japanese patients, noting that nonJapanese patients with this syndrome had more
marked neurological symptoms. In over 80% of
non-Japanese patients, neurological symptoms
were a major clinical problem 11. Precocious
puberty is an occasional finding in the syndrome.
Early breast development was noted in 7 of 31
female Japanese patients. Endocrine studies in 5
cases demonstrated markedly elevated plasma
follicle-stimulating hormone and moderately high
prolactin levels 3. Bereket et al. reported that the
diagnosis of Kabuki syndrome should be
considered in patients with hypoglycemia or
premature thelarche when associated with
developmental delay and a peculiar facies 10. The
girl patient did not have precocious puberty but
had markedly elevated plasma follicle-stimulating
hormone levels which is consistent with literature
data.
Figure 2: Male patient showing facial dysmorphic features
suggestive for Kabuki make-up syndrome.
DISCUSSION
Kabuki make-up syndrome was established with
clinical findings in both patients. Currently, there
is no consensus on the diagnostic criteria for
Kabuki syndrome and there is no clinically
available genetic test to confirm the diagnosis. In
1988, Niikawa et al. reported on the clinical
findings in 62 patients diagnosed with Kabuki
syndrome. Based on the findings in these patients,
five cardinal manifestations were defined. These
included a ‘peculiar face’ (eversion of the lower
lateral eyelid, arched eyebrows with the lateral
one-third dispersed or sparse, depressed nasal tip,
and prominent ears) in 100% of their patients,
skeletal anomalies (deformed spinal column with
or without sagittal cleft vertebrae, and
brachydactyly V) in 92% of their patients,
dermatoglyphic abnormalities (fingertip pads,
absence of digital triradius c and/or d, and
increased digital ulnar loop and hypothenar loop
88
Ahmet Sert, et al
Diaphragmatic defects have been reported
previously in only five patients with Kabuki
syndrome. Bilateral eventration of the diaphragm
was reported in two Kabuki syndrome patients 5.
Diaphragmatic defects were prenatally diagnosed
in a fetus of a mother with minor facial anomalies
of Kabuki syndrome and a previous child with
Kabuki syndrome 6. A partial defect of the right
diaphragm with herniation of the liver into the
thorax was present in a fourth patient 12. Recently,
a fifth patient with diaphragmatic hernia was
reported 13. The male patient supports the previous
suggestion that Kabuki syndrome should be added
to the list of syndromes rarely associated with
diaphragm defects.
2.
3.
4.
5.
6.
In recent studies, it has been reported that
congenital heart defect is present in 58% of
patients with Kabuki syndrome 14. The most
common finding appears to be juxtaductal
coarctation of the aorta, a relatively rare heart
defect, followed by VSD and ASD 15. To the best
of our knowledge, a patient with mesocardia in
Kabuki make up syndrome hasn’t been reported
yet and our patient will be the first ever reported.
7.
8.
9.
In
conclusion,
careful
dysmorphological
examination should be performed in all patients
presenting with mental retardation and epilepsy to
diagnose Kabuki syndrome. The patients
diagnosed as Kabuki syndrome should be
followed for premature telarche and precocious
puberty. Furthermore, we suggest that mesocardia
should be kept in mind as a cardiological finding
of Kabuki syndrome, and all cases should be
evaluated for life-threatening anomalies such as
congenital diaphragmatic hernia and its
complications.
10.
11.
12.
13.
14.
REFERENCES
1.
Niikawa N, Matsuura N. Kabuki make-up
syndrome: a syndrome of mental retardation,
unusual facies, large and protruding ears, and
15.
89
postnatal growth deficiency. J Pediatr 1981;
99:565–569.
Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A
new malformation syndrome of long palpebral
fissures, large ears, depressed nasal tip, and skeletal
anomalies associated with postnatal dwarfism and
mental retardation. J Pediatr 1981; 99:570–573.
Niikawa N, Kuroki Y, Kajii T, et al. Kabuki makeup (Niikawa–Kuroki) syndrome: a study of 62
patients. Am J Med Genet 1988; 31:565–589.
Di Gennaro G, Condoluci C, Casali C, Ciccarelli O,
Albertini G. Epilepsy and polymicrogyria in
Kabuki make-up (Niikawa-Kuroki) syndrome.
Pediatr Neurol 1999; 21:566-568.
Silengo M, Lerone M, Seri M, Romeo G.
Inheritance of Niikawa- Kuroki (Kabuki make-up)
syndrome. Am J Med Genet 1996; 66:368.
Philip N, Meinecke P, David A, et al. Kabuki
make-up (Niikawa- Kuroki) syndrome: a study of
16 non-Japanese cases. Clin Dysmorph 1992; 1:63–
77.
Kawame H, Hannibal C, Hudgins L, Pagon RA.
Phenotypic spectrum and management issues in
Kabuki syndrome. J Pediatr 1999; 134: 480–485.
Tutar HE, Ocal G, Ince E, Cin S. Premature
thelarche in Kabuki make-up syndrome. Acta
Paediatr Jpn 1994; 36(1):104-106.
Kasuya H, Shimizu T, Nakamura S, Takakura K.
Kabuki make-up syndrome and report of a case
with hydrocephalus. Child’s Nerv Syst 1998;
14:230–235.
Bereket A, Turan S, Alper G, Comu S, Alpay H,
Akalin F. Two patients with Kabuki syndrome
presenting with endocrine problems. J Pediatr
Endocrinol Metab 2001; 14(2):215-20.
Schrander-Stumpel C, Meinecke P, Wilson G, et al.
The Kabuki (Niikawa-Kuroki) syndrome: further
delineation of the phenotype in 29 non-Japanese
patients. Eur J Pediatr 1994; 153:438–445.
Tsukahara M, Kuroki Y, Imaizumi K, Miyazawa Y,
Matsuo K. Dominant inheritance of Kabuki makeup syndrome. Am J Med Genet 1997; 73:19–23.
Donadio A, Garavelli L, Banchini G, Neri G.
Kabuki syndrome and diaphragmatic defects: a
frequent association in non-Asian patients? Am J
Med Genet 2000; 91:164-165.
Digilio MC, Marino B, Toscano A, Giannotti A,
Dallapiccola B. Congenital heart defects in Kabuki
syndrome. Am J Med Genet 2001; 100:269-274.
Hughes HE, Davies SJ. Coarctation of the aorta in
Kabuki syndrome. Arch Dis Child 1994; 70:512–
514.
REVIEW
IS THERE A “HIDDEN HIV/AIDS EPIDEMIC” IN TURKEY?: THE GAP BETWEEN
THE NUMBERS AND THE FACTS
1
Pınar Ay1, Selma Karabey2
Marmara Üniversitesi Tıp Fakültesi, Halk Sağlığı Anabilim Dalı, İstanbul, Türkiye 2İstanbul Üniversitesi
İstanbul Tıp Fakültesi, Halk Sağlığı Anabilim Dalı, İstanbul, Türkiye
ABSTRACT
Since the number of persons living with HIV/AIDS was relatively low compared to the hard-hit countries,
HIV/AIDS was not considered as an emerging health problem in Turkey. However Turkey carries a number
of factors which enable the spread of HIV/AIDS and the reported rates are accepted to be an underestimation
due to the drawbacks of the present surveillance system. This paper discusses the epidemiology of
HIV/AIDS in Turkey, factors influencing risk and prevention and the need concerning prevention and
control activities in order to address future challenges to combat the epidemic.
Keywords: HIV/AIDS, Turkey, epidemiology, prevention, control
TÜRKİYE’DE GİZLİ SEYREDEN BİR HIV/AIDS SALGINI MI VAR?: SAYILAR VE
GERÇEKLER ARASINDAKİ FARKLILIKLAR
ÖZET
Türkiye’de HIV/AIDS’in öncelikli sağlık sorunları arasında sayılmaması, olgu sayılarının bu hastalık
tarafından vurulan diğer pek çok ülkeye kıyasla göreceli olarak düşük olmasından kaynaklanmaktadır. Ancak
Türkiye’nin HIV/AIDS’in yayılımını kolaylaştıran pek çok risk faktörünü barındırdığı ve bildirilen olgu
sayılarındaki düşüklüğün sürveyans sistemindeki yetersizliklere bağlı olduğu kabul edilmektedir. Bu
makalede, HIV/AIDS epidemisi ile mücadele ederken yapılması gerekenleri ortaya koymak amacıyla
Türkiye’deki hastalık epidemiyolojisi, riski etkileyen faktörler, önleme ve kontrol etkinlikleriyle ilgili
gereksinimler tartışılmaktadır.
Anahtar Kelimeler: HIV/AIDS, Türkiye, epidemiyoloji, önleme, kontrol
number of PLHA in Turkey from 1985 through
the end of 2004.
INTRODUCTION
HIV/AIDS is considered as one of the most
devastating disease of the recent decade due to its
high morbidity, mortality and economic impact.
As for December 2004, it is estimated that a total
of 39.4 million people worldwide carry the HIV
virus1. The epidemic has been growing and there
is no region unaffected.
Since the reported prevalence was relatively low
compared to the hard-hit countries, policy- makers
as well as the community did not consider
HIV/AIDS as an emerging health problem in
Turkey. However, the figures mentioned above
are accepted to be an underestimation due to the
drawbacks of the present surveillance system.
Moreover, Turkey has a number of risk factors
that enable the spread of HIV/AIDS3. So the aim
of this paper is to discuss the epidemiology of
HIV/AIDS in Turkey, factors influencing risk and
prevention and the need concerning prevention
and control activities in order to address future
challenges to combat the epidemic.
Today, HIV/AIDS should be considered as an
emerging disease for Turkey, too. According to
the statistics of the Turkish Ministry of Health, a
total of 1922 persons living with HIV/AIDS
(PLHA) were notified from 1985 to December
2004 in a population of more than 70 million. In
the year 2004, 163 HIV and 47 AIDS cases were
newly identified2. Figure 1 shows the reported
Pınar Ay
Marmara Üniversitesi Tıp Fakültesi, Halk Sağlığı Anabilim Dalı, İstanbul, Türkiye
90
Pınar Ay, Selma Karabey
Is there a “Hidden HIV/AIDS epidemic” in Turkey?: the gap between the numbers and the facts
among the persons under high-risk4. There is no
surveillance system targeting unregistered sex
workers, men who have sex with men (MSM) or
intravenous drug users (IUD). Although tests are
performed in the public hospitals during antenatal
examinations, this practice is also not
implemented systematically.
In this paper, initially the present surveillance
system for HIV/AIDS and its limitations will be
discussed. Subsequently, the authors will present
the epidemiological pattern of HIV/AIDS, the
factors which influence the risk of the country and
the prevention-control activities which are carried
by both the governmental and the non
governmental organizations. Lastly, taking into
consideration the epidemiological pattern and the
limitations of the present prevention- control
programs, the authors will communicate the
strategies to tackle the problem.
In this paper, primarily the statistics obtained from
the Turkish Ministry of Health as well as the
reports of UNAIDS are utilized. The authors
retrieved all the articles cited in Pubmed through
using the key words of “HIV/AIDS” and
“Turkey”. The authors also made an effort to
cover the nationally published articles relevant to
HIV/AIDS.
The present surveillance system and the
drawbacks of the morbidity data
Also the number of reported cases can not be
accepted as a sufficient indicator by itself.
Particularly in regions with low prevalence,
surveillance programs that evaluate behavioral
change among vulnerable groups are needed5. The
rate of condom use in commercial or casual sex or
needle exchange should be evaluated. Yet in
Turkey, this information is currently lacking.
Turkish Ministry of Health reported that in the
year 2003 nearly 2.5 million HIV tests were
performed. Interestingly, only %0.5 of the tests
was performed on sex workers. Commercial sex
work is considered as the major driver of the
epidemic in Turkey6. But sex workers who were
tested for HIV are the registered ones and do not
represent the parent population. In Turkey, there
are approximately 2000 registered sex workers,
but the estimated number for unregistered sex
workers is 15 000 only for Istanbul7. Moreover
after the fall of the Eastern Block, some women
from the former Soviet Union and the East
Europe, who come by tourist visas, work as
commercial sex workers in Turkey. Yet the data
about the unregistered sex workers, who might be
at an increased risk and have decreased access to
health services, is limited to those arrested by the
police and to some small-scaled studies.
Since 1987, serologic tests had been compulsory
for blood and organ donors, registered sex
workers and Turkish men who reside in foreign
countries, but come to Turkey for their military
services. From the year 2002 onwards, HIV
testing was also required for couples before
getting married. Public as well as the private
sector, both of which are within the HIV
surveillance system, perform HIV tests and report
to the Ministry of Health. However sentinel sites
do not exist within the present system.
The major problem concerning the morbidity data
is that testing is limited and is not systematic
Figure 1: Reported HIV Positive and AIDS Cases in Turkey (1985-2004)2
91
Private sector, which has been flourishing for the
last two decades, is becoming an important health
service provider in Turkey. Persons suffering
from sexually transmitted infections (STIs) prefer
the private sector since they do not want to
disclose their diseases in a conservative
community8. Another important problem with the
morbidity data is that notification from the private
sector is under the actual figures.
The epidemiological pattern of HIV/AIDS in
Turkey is similar to the African pattern, where
heterosexual transmission is the main route of
spread8. Homo-bisexual route is the second most
common route among male. But since
homosexuality is still a taboo in Turkey, MSM are
probably underreported. Although Turkey’s
geographic location is close to the countries of
Eastern Europe, it still shows a different pattern
from them8 because IDU is not as prevalent as the
Eastern European countries. The dominant
heterosexual route and the increasing prevalence
among women can be expected to increase the
vertical transmission throughout the years in
Turkey, where antenatal HIV testing is limited
and not systematic.
Although a systematic and a comprehensive
surveillance system for HIV/AIDS is not present
in Turkey yet, there are constructive efforts in this
direction. Recently, a project was started within
the context of the Reproductive Health Program
of the European Union, which aims to implement
a sentinel surveillance system designed for STIs
and HIV/AIDS9. Also in 2005, the Turkish
Ministry of Health received a grant from the
“Global Fund to Fight HIV/AIDS, Tuberculosis
and Malaria” for the HIV/AIDS Prevention and
Support Project. Within this project, a behavioral
study targeting the vulnerable groups will be
carried out which consequently will provide an
important database for planning the prevention
activities.
The epidemiological pattern of HIV/AIDS in
Turkey
Figure 3: Reported modes of transmission among men10
The factors influencing risk and prevention
Turkey deserves special attention since it carries
several risk factors for the spread of HIV/AIDS.
Geographic location of the country and high
mobility, low social and economic status as well
as the wide gaps, gender inequalities and
demographic structure are evaluated as important
risk factors for HIV/AIDS3,4,7. Moreover, there are
other risk factors which are mentioned by
UNAIDS, that are important in countries of low
prevalence5. Both the public and the governments
do not view HIV/AIDS as a priority due to the
underreporting which leads to low number of
cases. Therefore insufficient funds are allocated to
this issue among the limited public health
resources. Opinions such as “HIV can not infect
me” or “HIV is others’ disease” are very common.
These attitudes prevent the discussion on risky
behavior and thus preclude the prevention
measures building an environment enabling the
spread of HIV.
Figure 2: Reported modes of transmission among women10
In Turkey, HIV positive cases show male
dominance. Among all reported cases, the malefemale ratio is approximately 2.210
This ratio showed a decreasing trend and women
showed an increasing proportion throughout the
years. Nearly 70% of the reported HIV/AIDS
cases belong to the 15-39 year age group. The
major mode of transmission is the heterosexual
relationship for both sexes10
• Geographic location and mobility:
Turkey is closely located to the countries that
have an increased prevalence of HIV/AIDS. The
Figure 2 and 3 summarizes the possible routes of
transmission for both genders.
92
women who were exposed to abuse had physical
violence. Abused women had a lower level of
education and were more likely to have unplanned
pregnancies14. Also nearly 40% of women
considered the violence used by their husband as a
legitimatized act11. This finding is important in
showing the internalization of the socially
subordinate role of women.
high prevalence and the accelerated epidemic in
Eastern Europe will have a significant impact on
Turkey, too. The movement of commercial sex
workers from these countries to Turkey is an
important mode in transmission. From 1996 to
2002, 23 500 foreigners were deported from being
involved in illegal sex work6. Also trading
activities with the neighboring countries, the
travel of businessmen and tourism increases the
risk3.
•Cultural context - beliefs and attitudes:
Turkey was considered a traditional and mostly a
patriarchal society. But within the recent decades,
industrialization, urbanization, advances in
education have caused variations within the social
and the cultural context. Social norms started to
change, thus the number of sex partners are
expected to increase3. This change was quite rapid
and yet uneven through the society. Although still
mostly traditional, now Turkey represents a
complex cultural structure with diverse social
norms. In some parts of the community discussing
sexuality is a taboo while in others it is discussed
indirectly or sometimes openly. The approach to
sexuality influences the knowledge concerning
HIV/AIDS. In a study conducted among high
school students in Turkey, one of the most
important factors influencing the level of
knowledge was the attitude of the family about
sexuality. The students who discussed sexuality
comfortably within the family had the highest
knowledge scores. The scores were less among
the ones who discussed sexuality indirectly and
the least who among the ones whose families
considered sexuality as a taboo15.
From 1985 to 2003, 22.6% of the HIV positive
cases that were reported had a foreign nationality.
When we look at the countries of the origin,
nearly 30% of the cases were from the former
Soviet Union, about 20% are from the East
European, 20% percent are from the African and
more than 10% percent are from the West
European countries10. Sometimes this fact is
falsely interpreted by the community and HIV is
perceived as if it is a disease of foreigners.
• Social and economic inequalities:
Socio-economic deprivation and wide inequalities
also increase the risk of HIV/AIDS in Turkey.
Turkey has a GNP per capita of approximately
3300 US Dollars. But more importantly, there are
deep inequalities within the country. Almost all
health and educational indices vary highly from
west to east. The knowledge and attitudes towards
HIV/AIDS is consistent with this fact. Turkish
Demographic and Health Survey (TDHS) which
was conducted in 2003, determined that the
percentage of married women who had heard of
AIDS in the west and east region of the country
was 92.3% and 69.1%, respectively. In the west
region 71.2% of the women believed that
HIV/AIDS was preventable. However in the east
only 43.3% considered this disease as preventable.
When education status was taken into account, the
married women who were illiterate was the most
susceptible group11. Again according to TDHS
2003, overall 21.9% of the married women stated
condom as one of the preventive measures.
However among illiterate women only 5.5%
pronounced condom as a measure11.
•Gender power inequalities:
A qualitative study, which was published in 1995,
evaluated the beliefs and attitudes of Turkish
women and men4. This study points out that
women consider “cleanness” as the important
factor in HIV prevention. The main belief is that
by keeping clean i.e. vaginal douche women can
prevent HIV infections. This belief is not
unexpected since the association of personal
hygiene was promoted for the prevention of many
infectious diseases during the previous years.
Differently from women, men considered
themselves as “strong” and thus having a
“biological resistance” for the disease. These two
important concepts and the belief models should
be further evaluated in order to plan effective
intervention strategies, which aim behavior
change.
Research has shown that gender power
inequalities and violence against women is
associated with inconsistent condom use and
unplanned pregnancies12,13. Domestic violence is
not rare in Turkey. In a survey, which is carried
out among pregnant women in a province in the
east of Turkey, the prevalence of physical or
psychological abuse during pregnancy was
determined as 33.3%. More than half of the
Although it is the second most common route of
transmission, the presence of MSM has been
denied. The stigmatization and discrimination
prevent these men to accept their behavior leading
93
to the internalization of homophobia. These
people show high-risk behavior and can not
access the already limited preventive services.
Due to social pressure most MSM also have
heterosexual relations and so do not consider
themselves as homosexual16.
that uncircumcised men had more than a two fold
increased risk per sex act compared to
circumcised men22. In Turkey, the risk of
transmission could be less than the expected since
the main mode of transmission is the heterosexual
relationship and most men are circumcised before
they become sexually active in Turkey.
• Attitudes of health care workers
Traditional family life, the migration of workers
together with their families and the prohibition of
sexual relationships before marriage in the rural
areas might also serve as preventive factors.
Since HIV/AIDS is integrated into the medical
curriculum recently and the prevalence is
relatively low, many health practitioners lack
experience on diagnosis, treatment and
counselling skills8. So among the health care
workers, the bulk of the knowledge about
HIV/AIDS is gained from the media just like the
other members of the society, which resulted in
the formation of stigmatization and discrimination
towards PLHA. A research carried out among
surgeons in one of the leading teaching hospitals
in the capital of Turkey revealed that doctors
overestimated the risk for acquiring the HIV.
Moreover they had negative attitudes as anger and
worry towards PLHA. Doctors were less willing
to interact with AIDS patients and they did not
want to work with professionals who had AIDS in
the same environment17.
Current prevention and control activities
In Turkey, although there were important steps
taken in the first years of the epidemic by the
Ministry of Health, national policy was not in
action as recommended by the UN’s Declaration
of Commitment. In 1985, when the first case was
notified HIV/AIDS was included in the list of
infectious diseases that should be notified. In
1987, compulsory serologic test was applied for
some of the vulnerable groups. But since the
reported number of cases was relatively small,
HIV/AIDS was not considered as one of the
priorities of the country. On the other hand,
despite the efforts of NGOs, the business
community was not involved and did not provide
the support, which it did for other health projects,
due to the stigma attached to HIV/AIDS.
• Demographic structure
15-24 year old persons account for nearly the half
of all new HIV cases worldwide18. Turkey has a
young population and nearly 27% of the
population is between the ages of 15-2911. In a
study carried out in a university in Turkey, it was
determined that more than one third of the
students had had sexual experience, most of them
at the ages of 15-1919. Research evaluating the
knowledge of young people about HIV/AIDS
indicated that their knowledge concerning STIs
was inadequate15,19,20. The study carried out by
Ungan determined that there was also relatively
low level of condom use among both genders20.
In 1996 National AIDS Commission was
established which was the principal decision
authority at the national level. National AIDS
Commission consists of representatives from
different ministries, NGOs and occupational
organizations, which work related to HIV/AIDS.
The main aim of the Commission was to develop
and recommend strategies for the prevention of
HIV/AIDS by intersectoral collaboration. But the
Commission was not able to function as required
due to the rapid turnover of the ministers23. In
2002 national objectives and strategies were
formulated and an Action Plan was developed.
But since it lacked the leadership and the financial
support, the plan was not implemented24.
In Turkey, the funds released from the
international NGOs, particularly from the United
Nations System, was inadequate to carry out the
required activities. Recently, United Nations
Global Fund provided funds in order to support
the National Action Plan25. Lately 55 million
EURO was donated by the European Union for
the Reproductive Health Program to Turkey.
Hence with this fund, the aim of improving the
sexual and reproductive health status of the
Turkish population especially women and youth
•Male circumcision:
Today the role of male circumcision, which is a
very frequent practice among the Turkish
population, is being discussed for the prevention
of HIV/AIDS in the medical literature. Although
male circumcision does not prevent HIV
transmission entirely, some studies indicate that it
reduces the risk. Yet these observational studies
are criticized since their results could be
confounded by behavioral practices21. However,
recently an observational study took into account
ethnic, religious differences and controlled for the
sexual behavior of men. This study determined
94
card” which enables them to get the services and
treatment free of charge.
will be achievable through the projects
implemented by NGOs in collaboration with the
Ministry of Health9
Recently, it was demonstrated that treatment
programs that are not combined with effective
prevention activities will have only a small impact
on the incidence of HIV over the next 15 years.
The research underlines that only if effective
prevention is practices treatment will be
affordable in the long run. This result focuses on
the need of an integrated approach consisting of
prevention and tratment as the most cost effective
way30.
Also, the Ministry of Health adopts a strategy,
which aims to combine the reproductive health
services to the routine services in order to
encompass the persons who do not have
accessibility to the services and who do not get
comprehensive care. Until 2015 this strategy will
be implemented in all health care institutions and
predominantly in primary health care centers. One
of the main subjects of this program is to increase
the demand and supply of services26.
Future challenges
NGOs
•Economic development, larger investment in
health and education sectors, maintaining equity is
important not just for the prevention and control
of HIV/AIDS, but for the well being of our
society.
After attending the International Population and
Development Conference in 1994 in Cairo, both
the Ministry of Health and the NGOs changed
their services taking into consideration a
comprehensive reproductive health approach.
New NGOs focusing on STIs and HIV/AIDS
were founded. Through the last 20-30 years,
NGOs implemented programs and adopted
strategies focusing on new service models,
training and communication, needs assessment,
services to disadvantaged groups, which increased
the demand and the accessibility for the services27.
•Political
commitment
by
the
Turkish
Government is a prerequisite for developing and
maintaining effective prevention-control activities
as well as raising and allocating funds to this
issue. Political determination will improve the
decision making process, the implementation,
monitoring and evaluation of activities carried out
by the National AIDS Commission. Also political
support will accelerate the activities of various
NGOs that have been working in this area with
limited resources.
There are various NGOs which function in the
field of HIV/AIDS in Turkey. Differently from
the official organizations, the decision making
process is faster and not as bureaucratic. Since
NGOs function more flexible and rapid, and are
aware of the needs of the community they operate
as an efficient resources27 NGOs both participate
in the prevention-control activities and also
together with the international organizations in
motivating the government to take action8. Their
activities
mostly
focus
on
training,
communication, advocacy, some of which target
groups under high risk as sex workers, IDUs,
MSM and the street children8.
•A comprehensive and a reliable surveillance
system which also includes the indicators
concerning high-risk behavior should be adopted
for STIs and HIV/AIDS3.
•Adopting and evaluating programs that target
behavior change are necessary for young people
and the vulnerable populations. The believes,
values, attitudes ,behaviors and risk perceptions of
the Turkish society regarding STIs and HIV/AIDS
should be studied and better understood in order
to develop effective prevention programs. Gender
power inequalities, the low rate of condom use
should be dealt with.
Care and treatment of the people living with
HIV/AIDS
WHO estimates the percentage of adults covered
among those in need of antiretroviral treatment as
60% for Turkey28. In Turkey nearly 65% of the
population is covered with health insurance29.
Although there are some problems in the
implementation, HIV/AIDS treatment expenses
are covered by these insurance systems. In 1994 a
new procedure was utilized for persons most
deprived and not covered by the insurance.
Persons who do not have any insurance and are
below a certain economic level could get “green
•Sexual health education including STIs and
HIV/AIDS should be covered within the
curriculum and awareness should be raised during
the early school years. The trainers providing
sexual health education should be trained and
empowered31.
•Counseling and voluntary testing (VCT) services
for STI and HIV/AIDS should be provided
widely, particularly to the vulnerable groups. Each
health care organization should by law encompass
95
a trained health care worker for the counseling
services.
5.
•In order to maintain prevention, early diagnosis
and treatment of STI, the services should be
integrated to the primary care level. The personnel
working in the primary care should be adequate
and qualified to provide these services effectively.
6.
•NGOs can strengthen their capacity by providing
technical assistance and financial support from
United Nations, European Union or other
international organizations. It is important to use
the scarce sources in a most effective way without
duplicating the activities. The National AIDS
commission should provide the synergistic
function of NGOs and maintain intersectoral
cooperation.
7.
8.
9.
10.
CONCLUSION
The present studies, although small-scaled,
indicate that high risk behavior particularly not
using condoms in commercial sex is prevalent32-34.
The low number of cases can be explained by the
inadequacy of VCT services and so the low
number of cases getting HIV tests. Yet, the highly
accelerating epidemic in the former Eastern Block
countries and the high mobility in the region
suggest a potential HIV/AIDS epidemic. Although
there are important deficiencies in the prevention
program, important steps are taken in order to put
into action some of the above-mentioned
recommendations.
Hopefuly,
the
Turkish
Reproductive Health Program and the HIV/AIDS
Prevention and Support Project will be important
in achieving the goals by both the Ministry of
Health and the NGOs working in this field.
11.
12.
13.
14.
15.
16.
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REVIEW
MANYETİK REZONANS GÖRÜNTÜLEME VE ANESTEZİ
Berrin Işık
Gazi Üniversitesi Tıp Fakültesi, Anesteziyoloji ve Reanimasyon Anabilim Dalı, Ankara, Türkiye
ÖZET
Manyetik rezonans görüntüleme (MRG) ünitesi anestezist için ortamdan, hastadan, işlemden kaynaklanan
farklı özellikleri taşıyan ve giderek daha fazla talebin olduğu bir uygulama sahasıdır. Manyetik rezonans
görüntüleme ünitesinin ve burada anestezi uygulanan hasta grubunun özelliklerinin bilinmesi hasta ve
çalışanların güvenliği yanında verimliliği de artıracaktır. Bu yazıda MRG ünitesinde sürdürülen anestezi
uygulamalarının derlenerek bildirilmesi hedeflenmiştir.
Anahtar Kelimeler: Manyetik Rezonans, Görüntüleme, Anestezi
MAGNETIC RESONANCE IMAGING AND ANESTHESIA
ABSTRACT
The magnetic resonance imaging (MRI) unit is a challenging environment for the anesthesiologist, and
carries inherent risks. Several factors account for this, including the remote location, the unique features of
the magnetic resonance imaging scanner, and patient-related factors. Understanding the implications of the
magnetic resonance imaging environment will facilitate ensuring the safety of the patient and personnel. In
this rewiev we aim to give information about anesthetic applications in the MRI unit as compiled.
Keywords: Magnetic Resonance, Imaging, Anesthesia
ile literatür bilgileri ışığında alternatif anestezi
uygulamalarının bildirilmesi hedeflenmiştir.
GİRİŞ
Yüksek görüntü kalitesi ve bilinen bir zararının
olmaması nedeniyle günümüzde manyetik
rezonans görüntüleme (MRG)'ye olan talep
giderek artmaktadır. Ancak şiddetli gürültü
varlığı, görüntü sağlanabilmesi için bu işlem
sırasında tam hareketsizliğin gerekmesi ve dar
tubuler bir alana girme zorunluluğu özellikle 8 yaş
altı çocuklarda ve hareketsiz kalamayan, zihinsel
özürlü ya da kapalı alan korkusu olan erişkinlerde
sedasyon veya genel anestezi uygulamasını
gerekli kılmaktadır 1-6. Takip ve tedavisi gereken
kritik hastalarda ise monitorize hasta bakımı için
anestezistin bulunması zorunlu olmaktadır.
MANYETİK
GÖRÜNTÜLEME NEDİR?
REZONANS
Manyetik rezonans görüntüleme; statik ve
gradient manyetik sahada dokuya gönderilen
radyo dalgalarının uyardığı hücrelerdeki hidrojen
atomlarının ürettiği enerjinin, özel ara birimler
(koil) sayesinde bilgisayar ortamına aktarılarak
görüntüye dönüştürüldüğü, noninvaziv bir
görüntüleme yöntemidir. Alınan sinyallerin
yoğunluğunun doku tipine göre değişmesi ise
görüntülemenin esasını oluşturmaktadır. Manyetik
rezonans görüntüleme sırasında en sık hidrojen
kullanılmasının nedeni, tek proton içermesi ve
insan dokularında en fazla bulunan elementlerden
olmasıdır. Radyo dalgaları varlığında hidrojen
atomları manyetizmanın etkisiyle düzgün şekilde
sıralanırlar. Bu dizilim sırasında elde edilen
yoğunluğa göre bilgisayar ortamında görüntü
Görüntülemenin kuvvetli manyetik alanda
yapılması özel donanımı ve yine hasta grubunun
özellikleri dikkatli bir değerlendirme, hazırlık ve
deneyimi gerektirmektedir 5,6.
Bu
yazıda
MRG
sırasında
anestezi
uygulamalarında dikkat edilmesi gereken konular
Berrin Işık
Gazi Üniversitesi Týp Fakültesi, Anesteziyoloji ve Reanimasyon
Anabilim Dalý, Ankara, Türkiye
98
Berrin Işık
Manyetik rezonans görüntüleme ve anestezi
Manyetik rezonans görüntüleme sırasında hasta
izleminde ve anestezi uygulamasında kullanılacak
olan monitör ve cihazlar da ferromanyetik parça
içermeyen, MR uyumlu cihazlar olmalıdır.
oluşturulur. Diğer radyolojik görüntüleme
yöntemleri ile karşılaştırıldığında iyonizan
radyasyon içermemesi en önemli avantajıdır6,7. İki
- dört Tesla (T) gücündeki manyetik sahanın insan
hücreleri üzerine zararlı etkisi gözlenmemiş,
Amerikan Food and Drug Administration (FDA)
derneği risk açısından MRG cihazlarını sınıf II
olarak tanımlamıştır8. MRG sırasında yaşanan
komplikasyonlar
genellikle
ferromanyetik
objelerle ilgilidir7-11.
MONİTÖR
GEREÇLER
VE
DİĞER
ARAÇ
Hasta güvenliği için MRG ünitesinde de
Amerikan Anesteziyologlar Derneği (ASA)
Operasyon Odası Dışı Anestezi Uygulamaları
Standardında 15 belirtilen donanım desteği ve
anestezi uygulaması yapabilmek için gerekli olan
16,17
asgari
monitorizasyon
şartları
oluşturulmalıdır. Manyetik rezonans uyumlu
monitörlerde bile görüntüleme sırasında EKG'nin
sağlıklı değerlendirilemeyebileceği 18 ve iskemik
kalp hastalığı olan hastalarda takip güçlüğü
yaşanabileceği bilinmelidir.
MANYETİK
REZONANS
GÖRÜNTÜLEME
VE
FERROMANYETİK CİSİMLER
Manyetik sahanın gücü genellikle 0.15 ile 2 T
arasında (1 T = 10,000 gauss) olup, bu değer yerin
normal manyetik çekim gücü olan 0.5 gauss ile
karşılaştırıldığında çok yüksektir. Görüntüleme
için zorunlu olan bu kuvvetli manyetik alan
ferromanyetik cisimlerin kuvvetle çekilmesine
neden olur. Metal oksijen tüpleri, cerrahi
pansuman aletleri manyetik alanda hızla hareket
ederek zarar verebilir 9-11. Klemp, pens, makas,
steteskop, non-lityum piller, standart medikal gaz
silindirleri ferromanyetik cisimlerdir. Çelik
(stainless steel), nikel, titanyum ve plastik ise
manyetik rezonans (MR) uyumlu materyallerdir.
Manyetik alanda standart EKG monitörü
kullanılması elektrot telleri anten görevi yaparak
görüntüyü bozacağından ya da teller ısınarak
hastanın yanmasına neden olabileceğinden uygun
olmayıp, ısınmayan karbon yapıda elektrod
kabloları
olan
MR
uyumlu
monitörler
kullanılmalıdır. Periferik oksijen satürasyonunu
ölçmede ferromanyetik olmayan, fiberoptik
kablolu sensor tercih edilmelidir. Ancak bu da
yanıkları önleyemeyebilir. Noninvaziv kan basıncı
ölçümünde ise en uygunu osilometrik metoddur.
Solunum fonksiyonunu değerlendirmede periferik
oksijen satürasyonu yanı sıra, soluk sonu
karbondioksit basıncı (EtCO2) ölçümünün
yapılması güvenli olacaktır 4. Yeni MR uyumlu
fizyolojik monitorizasyon sistemleri; invaziv kan
basıncı, santral venöz basınç ölçümleri yanında
fiberoptik yüzey sensörleri aracılığı ile ısı
monitorizasyonu da yapabilmektedir.
Hasta ya da çalışanların vücudunda ferromanyetik
cisimlerin varlığı dikkat edilmediğinde bir
faciayla sonuçlanabilir. Bu nedenle pace-maker,
prostetik kalp kapakçıkları, kemik implantları,
retina ya da beyin damarlarında bulunan metalik
klipsler, implante infüzyon pompaları, koklear
implant, saçma parçacıkları olup olmadığı
dikkatle sorgulanmalıdır. Manyetik alan pacemaker ile ilgili olarak elektromanyetik etkileşim,
programda bozulma, silinme, asenkron moda
geçiş, kapanma ve ısınmaya bağlı sorunlara neden
olarak yaşamı tehdit eder 4,7-11.
Manyetik rezonans görüntüleme ünitesinde
anestezi cihazı MR uyumlu olmalıdır. Bu amaçla
üretilmiş MR uyumlu anestezi cihazları oldukça
pahalı olmakla birlikte medikal marketlerde
bulunmaktadır.
Son yıllarda kullanılan implante materyallerin
çoğu MR uyumlu olduğundan özellikle eski tarihli
implantlarda dikkatli olunmalı, yerleştirilmiş olan
metalik implantların MR uyumlu olup olmadığı
değerlendirilmeli, güncellenerek yayınlanan MR
uyumlu implantların listesi MRG ünitelerinde
bulundurulmalıdır 7,8.
Ferromanyetik medikal gaz silindirleri manyetik
ortamda hızla hareket ederek hasta ve cihazlara
zarar
verebileceğinden
gaz
silindirleri
alüminyumdan yapılmış olmalıdır 4,7,9,11.
Dövme ve kalıcı makyajda ferromanyetik
maddeler kullanıldığından MRG sırasında lokal
cilt hasarı yaratabilmektedir 12-14.
MANYETİK
REZONANS
GÖRÜNTÜLEME SIRASINDA HASTA
BAKIMI VE KONFORU
Floopy disketler, USP, telefon kartları, manyetik
yaka kartları, bankamatik kartları, saat pilleri de
kuvvetli manyetik alan etkisi ile bozularak
işlemez
hale
geleceğinden
ortamda
bulundurulmamalıdır.
Manyetik rezonans görüntüleme sırasında
anestezistin hastadan uzakta olması ve hastayı
yakından izleyememesi en önemli sorundur. Bazı
servislerde kapalı sistem video ile hasta
99
Berrin Işık
24-27
. Murphy ve ark 28, kontrast madde olarak
gadolinyum verilen toplam 21000 hastanın
kayıtlarını değerlendirdiklerinde 36 hastada
(15'inde bulantı kusma, 12'sinde yaygın eritem
veya cilt irritasyonu, 7'sinde solunum yakınmaları,
2'sinde solunum sıkıntısı ve periorbital ödem
şeklinde) alerjik reaksiyon görüldüğünü, yalnızca
5'inde tedavi gerektiğini bildirmiştir. Yüz beş
merkeze ait bilgilerin değerlendirildiği bir diğer
çalışmada ise 687,255 gadopentetate dimeglumine
uygulaması sonrası 314 (% 0.046) olguda nonalerjik reaksiyon, 107 (% 0.016) olguda hafif, 28
(% 0.004) olguda orta ve 5 (% 0.001) olguda ciddi
alerjik reaksiyon olduğu bildirilmiştir 29. Alerjik
reaksiyonlar seyrek görülmekle birlikte fatal
reaksiyonlar da gelişebildiğinden gerekli ilaç ve
malzemeler hazır tutulmalıdır 30.
görüntüleri
izlenmekte
ise
de,
sıklıkla
monitorizasyon ile elde edilen vital parametrelerin
değerlendirilmesi ile hasta takibi yapılmaktadır.
Manyetik rezonans uyumlu anestezi cihazının ve
monitörlerinin olmadığı merkezlerde ise anestezist
MRG odasında bulunarak hastayı izlemekte, fakat
şiddetli gürültü nedeni ile özellikle uzun süreli
işlemlerde
çalışanlar
açısından
sakıncalar
yaratmakta ve hastanın vital parametreleri de
sağlıklı olarak takip edilememektedir.
Kapalı alan fobisi olan erişkinlerde herhangi bir
sedasyon veya anestezi uygulanmadığında,
şiddetli kaygı nedeniyle hareketsiz kalamadıkları
için görüntüleme mümkün olamamaktadır. Murpy
ve Brunberg19, üniversite hastanesinde rastgele
seçilen bir 7 haftalık periyotta MRG yapılan 18
yaş ve üzeri toplam 939 hastanın 134'ünde
(%14.3) oral sedasyon, İV sedasyon veya genel
anestezi gerektiğini, sedasyon uygulananların;
%64.1'inin kadın, %35.8'inin erkek olduğunu,
%66.4'ünün beyin görüntülemesinin yapıldığını,
daha önce MRG deneyimi olması ortalamasının
ise 1.56 olduğunu bildirmişlerdir.
MANYETİK
REZONANS
GÖRÜNTÜLEME
SIRASINDA
ANESTEZİ UYGULAMALARI
Manyetik rezonans görüntüleme sırasında anestezi
uygulaması yakın zamana kadar, yalnızca
hareketsizliğin sağlanması için gerekmekteyken,
günümüzde; santral sinir sistemine ait girişimler
sırasında da MRG yapıldığı bildirilmektedir 31,32.
Anestezi tekniği ve ajanlarının seçimi hastanın ve
işlemin
özelliklerine
göre
yapılmalı,
görüntülemenin süresi, cerrahi girişim yapılıp
yapılmayacağı da göz önünde bulundurulmalıdır.
Manyetik rezonans görüntüleme sırasında gürültü
de hasta konforunu ve işitme fonksiyonunu
etkileyen bir faktördür. Radyofrekans dalgaları
sırasında tellerin vibrasyonu sonucunda 1.5 T
gücündeki MR'da şiddeti 95 dB'e varan gürültü
ortaya çıkar. Kulak tıkaçları kullanılması işitme
hasarını önlemede ya da azaltmada etkili ve pratik
bir çözümdür 20.
Santral sinir sistemine ait girişimler sırasında
yapılan MRG için uygulanacak anestezi
yönteminde; cerrahi ağrı, kan kaybı ve beyinin
homeostazisini etkileyen diğer faktörleri de göz
önünde bulundurmak gerekmektedir. Schmitz ve
ark. 32, intraoperatif MRG'nin uygulandığı beyin
ameliyatlarında; propofol, remifentanil ve cisatraküryumun sürekli infüzyonunu başarı ile
kullandıklarını bildirmektedirler.
Manyetik rezonans ortamında bir diğer risk ise
yanık tehlikesidir 4,14,21,22. Monitorizasyonda
kullanılan tellerle olan yanıkların yanı sıra hasta
vücuduna tedavi amaçlı yapıştırılan yama (patch)
ile de yanıklar bildirilmiştir 23.
Hastada göz makyajı veya dövme varlığında
görüntüleme sırasında lokal cilt irritasyonu
gözlenebilir 12-14. Anestezi altındaki bir hastada
görüntüleme sırasında herhangi bir yakınma
olmayacağından anestezistin bu konuda gerekli
uyarıyı işlem öncesi yapması uygun olacaktır.
Yalnızca görüntüleme amacıyla yapılan anestezi
uygulamalarında; bilinçli sedasyon, derin
sedasyon, rejyonal anestezi, total intravenöz
anestezi (TİVA) veya inhalasyon anestezisi
uygulanabilir.
Cerrahisiz
MRG
yapılan
erişkinlerin % 14 ila % 20'sinin aşırı kaygı ya da
klostrofobi nedeniyle anestezi desteğine ihtiyaç
duyduğu gösterilmiştir. Hastaların çoğunda oral
ya da IV yolla verilen benzodiyazepinler yeterli
olmaktadır.
Sedasyonun
yeterli
olmadığı
olgularda uygun monitorizasyon şartları varlığında
başta propofol ile TİVA olmak üzere hemen tüm
anestezi
yöntemleri
kullanılabilir4,19,33-34.
Sevofluranın
O2/N2O
içinde
düşük
konsantrasyonlarda maske ile uygulanması ile
Manyetik rezonans görüntüleme sırasında görüntü
kalitesini artırmak amacıyla kontrast madde
seçiminde sıklıkla düşük ozmolar iyonik madde
olan Gadopentetate dimeglumine (Gadolinium)
tercih edilmektedir. Bunun eliminasyon yarılanma
ömrü 1.3-1.6 saat olup asıl atılım yolu
böbreklerdir. Yenidoğan ve küçük çocuklarda
klirensi erişkine kıyasla daha düşüktür. Bulantı
kusma, başağrısı, tromboflebit şeklinde yan
etkileri bildirilmiştir. Yaşamı tehdit eden alerjik
reaksiyon sıklığı diğer iyodinize ajanlardan azdır
100
Berrin Işık
bilinçli sedasyon yapılan olgular da vardır 35.
Obez hastalarda sedasyon yöntemleri kullanılırken
havayolu
problemleri
ile
daha
sık
karşılaşılabileceği akılda tutulmalıdır.
97,9 olguda optimal başarıyı sağladıklarını
bildirmektedir. Genel anestezi ve sedasyon
uygulamalarına bir alternatif olarak Gozal D ve
Gozal Y40, ciddi spastik paraparezisi olan
hastalarda
spinal
anesteziyi
güvenle
uyguladıklarını bildirmektedir.
Çocuk hasta grubunda ise; oral 75-100 mg.kg-1
kloral hidrat, rektal 20-30 mg.kg-1 metoheksital,
IV yol bulunamayan hastalarda IM 5 mg.kg-1
ketamin, oral rektal veya IV 4-5 mg.kg-1
pentobarbital, IV 2-3 mg.kg-1 yükleme dozundan
sonra 100 µg.kg-1.dk-1 propofol infüzyonu, oral
0.25-0.75 mg-1.kg-1 ya da IV 0.05-0.15 mg.kg-1
midazolam önerilebilir. Kloral hidrat metabolitleri
de aktif olduğundan çocuklarda özellikle
yenidoğan
döneminde
derlenmenin
çok
uzayabileceği
bilinmelidir.
Ketamin,
sekresyonlarda
artışa
yol
açacağından,
antisiyalogog bir ajanla birlikte verilebilir.
Midazolam ile sedasyon yeterli olmadığında
istemsiz hareketler daha sık görüldüğünden çok
seçilen bir alternatif değildir. Sedasyon uygulanan
çocuklarda; adenotonsiler hipertrofi, obsrüktif
uyku apnesi, üst solunum yoluna ait patoloji
varlığında solunumun baskılanarak hipoksemiye
neden olabileceği bilinmelidir 4,36.
Klinik uygulamalarımızda özellikle çocuk
grubunda sıklıkla %50/50 O2/N2O içinde %7-8
sevofluran ile inhalasyon indüksiyonunun
ardından laringeal maske yerleştirerek %50/50
O2/N2O içinde % 1-1.5 konsantrasyonda
sevofluran inhalasyonunu başarılı buluyoruz.
Aşırı korkan çocuklara 0.5 mg.kg-1 (maksimum 15
mg) oral midazolam, kaygılı erişkin hastalara
0.02-0.05 mg.kg-1 tek doz IV midazolam
premedikasyonu, ağrı nedeniyle duramayan
hastalara 1-2 µg.kg-1 IV fentanil, kapalı alan fobisi
nedeniyle uyum gösteremeyen erişkinlere de 100200 µg.kg-1.dk-1 IV propofol ya da 1µg.kg-1 10
dakika içinde yükleme dozundan sonra
0.2/0.7µg.kg-1.saat-1 deksmedetomidin infüzyonu
ile
sedasyonu,
inhalasyon
anestezisinin
kontrendike olmadığı kritik hastalarda ise %100
O2 ya da %50/50 O2/N2O içinde düşük
konsantrasyonda sevofluran ile inhalasyon
anestezisini tercih ediyoruz.
Malviya ve ark. 37, çocuklarda MRG veya
kompütorize tomografi sırasında sedasyon
uygulandığında
hareket
nedeniyle
görüntüleyememe ve hipoksemi riskinin daha
yüksek olduğunu, görüntülemenin tekrar edilmesi
ya da işlemin iptal edilmesinin; zaman, para ve
emek kaybına yol açarak maliyeti önemli ölçüde
artırdığını, bu nedenle genel anestezinin daha
başarılı olduğunu bildirmiştir. Sedasyonda
başarısızlık merkezlere göre değişmekle birlikte
%5 ile %16 arasında değişen oranlardadır 2,5.
Keengwe ve ark. 38, 90 mg.kg-1 (maksimum 2g)
kloral hidrat ile sedasyon uygulanan 5 yaş altı 727
hastanın % 6,9'unda sedasyonun başarısız
olduğunu bildirmiştir. Çocukların uyumsuz kişilik
özellikleri de sedasyon yetersizliklerinde etkili bir
faktördür 2.
Bazı merkezlerde MRG sırasında sedasyon veya
anestezi uygulamasını eğitimli hemşireler
yürütmekteyse de anestezist olmayanların
uygulamalarının anestezistlerin uygulamaları ile
karşılaştırıldığında hipoksemi ve başarısız işlem
oranının daha yüksek olduğu bildirilmiştir. Aynı
şekilde derlenmede uzama, motor dengesizlik,
ajitasyon, gastrointestinal yan etkiler ve taburcu
sonrası
huzursuzluk
da
daha
fazla
bildirilmektedir41-42.
Hastaların
özelliklerine
uygun net protokoller geliştiren anestezistlerin
görev aldığı kliniklerde başarı oranı çok
yükselmektedir.
MANYETİK
REZONANS
GÖRÜNTÜLEMEDE
HASTA
GRUBUNUN ÖZELLİKLERİ
Usher ve ark. 34, 100 çocuk olguda MRG
nedeniyle maskeyle oksijen desteği ile spontan
solunum korunurken, ortalama 3.9 mg.kg-1
indüksiyonunun ardından 193 µg.kg-1.dak-1
infüzyon
şeklinde
sürdürdükleri
propofol
anestezisi ile havayolu güvenliğinin ve hızlı
derlenmenin
sağlandığını
ve
güvenle
kullanılabileceğini bildirmiştir. Bir diğer anestezi
yöntemi de rektal midazolam ve S(+) ketamin ile
endotrakeal
entübasyon
gerektirmeksizin
sedasyon/genel anestezi sağlanmasıdır 5. De
Sanctis Briggs39, yaşları 1 gün-12 ay arası değişen
640 olguda maske ile sevofluran uygulaması ile %
Anestezi uygulanması planlanan tüm hastalarda
olduğu gibi MRG öncesi de hastalar sistemik
muayene
ve
uygun
tetkikler
yapılarak
değerlendirilmiş olmalıdır. İntrakranyal kitle ön
tanısıyla MRG istenilen olgularda, kafaiçi
basıncını artıracak uygulamalardan kaçınılmalıdır.
Henüz tanı konulmamış araştırma aşamasındaki
olgularda, özellikle sendrom düşünülen bebek ve
çocuklarda muayene ile elde edilen klinik veriler
dikkatle
değerlendirilmeli
ve
olası
komplikasyonlar için önlemler alınmış olmalıdır43.
Görüntüleme sırasında EKG ile iskemi takibi
101
Berrin Işık
yeterince
yapılamayacağından
myokardiyal
iskemi riski olan hastalar, kan basıncı labil olan ya
da inotrop ajan desteği gereken hastalarda
hemodinamik stabilizasyonu sürdürmek ve
izlemek zor olacağından, bu hastalarda MRG
sırasında doğabilecek sorunlar klinisyenlerle
açıkça konuşularak risk belirlenmeli ve ortak
karara varılmalıdır.
ANESTEZİ SONRASI SORUNLAR
Manyetik rezonans görüntüleme için uygulanan
anestezi sonrası yan etkilerin değerlendirildiği
çalışmalarda
en
sık
bulantı/kusma
bildirilmektedir. Sandner-Kiesling ve ark.44,
kraniyal MRG nedeniyle genel anestezi uygulanan
168 çocuk olguyu 72 saat izleyerek yan etkileri
değerlendirdikleri çalışmalarında 14 farklı yan
etki gözlendiğini, yan etkilerin en çok ilk 1 saatte
görüldüğünü, nörolojik yan etkilerin 5 yaş
üzerinde ve intrakranyal lezyonu olanlarda daha
çok görüldüğünü, en sık görülen yan etkilerin; baş
ağrısı, ajitasyon, güçsüzlük, baş dönmesi ve
hıçkırık olduğunu bildirmiştir. Malviya ve ark. 42
ise nöro-görüntüleme için kloral hidrat kullanılan
çocukların %5'inden fazlasında 6 saatten uzun
süre huzursuzluk ve ajitasyon görüldüğünü,
bunların normal aktivitelerine dönmelerinin
işlemden sonra 2 günü aldığını bildirmektedir.
Cravero ve ark. 45, Görüntüleme nedeniyle
sevofluran anestezisi verilen 18 ay-10 yaş arası
çocuklarda kontrol grubunda %56 oranında
derlenme ajitasyonu gözlenirken, 1 µg.kg-1
fentanil verilenlerde %12'ye düştüğünü ve küçük
doz fentanilin cerrahisiz postanestezik derlenme
ajitasyonunu
azaltmada
etkili
olduğunu
bildirmiştir. Manyetik rezonans görüntüleme
sırasında sevofluran anestezisi uygulanan çocuklar
üzerinde gerçekleştirdiğimiz çalışmalarda anestezi
indüksiyonu ardından verilen 1 µg.kg-1
deksmedetomidinin ve anestezi indüksiyonunda
veya sevofluran sonlandırılmadan önce IV yolla
verilen 1 µg.kg-1 fentanilin derlenme ajitasyonu
görülme sıklığını azalttığını saptadık 46,47. Çocuk
olgulardaki sedasyon uygulamalarında mortalite
gibi ciddi komplikasyonların oranını tam olarak
bilmek elde yeterli veri olmadığından mümkün
değildir.
derlenmesinin sağlanmasıdır. Uyanmada sorun
olabileceği
öngörülen
olguların
derlenme
dönemini, deneyimli ekip ve donanımın
bulunduğu ameliyathaneye ait postanestezik
derlenme ünitesinde geçirmesi uygun olacaktır.
Bu amaçla monitorizasyon ve oksijen desteğinin
sürdürülebileceği
transport
imkânları
hazırlanmalıdır. Transport sırasında anestezi
sürdürülebileceği gibi uyandırmayı takiben hızla
nakil de düşünülebilir.
Sonuç olarak; MRG nedeniyle anestezi
uygulamasına giderek daha fazla talep olmaktadır.
Bu
ortamın,
donanımın
ve
anestezi
uygulamalarının özelliklerinin iyi bilinmesi hasta
konforunu ve iş başarısını artırırken çalışanın da
güvenliğini artıracaktır.
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103

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