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    Children with breakthrough varicella infection requiring hospitalization in Turkey (VARICOMP Study 2008-2013)
    (Elsevier Ltd, 2015) Dinleyici E.C.; Kurugol Z.; Kara A.; Tezer H.; Tas M.A.; Guler E.; Yasa O.; Devrim I.; Ciftci E.; Ozdemir H.; Somer A.; Ozen M.; Sensoy G.; Dalgic N.; Alhan E.; Kuzdan C.; Bayram S.N.; Uygur-Kulcu N.; Sag C.; Nuhoglu C.; Metin O.; Kondolot M.; Tapisiz A.; Celebi S.; Hacimustafaoglu M.; Akarsu S.; Aygun D.; Akin F.; Elevli M.; Velipasalioglu S.; Oncel S.; Emiroglu M.; Karbuz A.; Turel O.; Kuyucu N.; Ceyhan M.; Yilmaz-Ciftdogan D.; Hatipoglu N.; Kilic O.; Siraneci R.; Kara A.; Apa H.; Gulhan B.; Parlakay A.; Kocabas E.; Say A.; Belet N.; Baktir A.; Karli A.; Tanir G.; Ince E.; Bal B.; Akaslan A.; Goksugur Y.; Arisoy E.S.; Hatipoglu S.; VARICOMP Study Group
    Introduction: Varicella in previously immunized individuals, known as "breakthrough varicella". While the majority of breakthrough cases are mild, some may be severe, requiring hospitalization in previously healthy children or children with an underlying condition. Methods: This report, as a part of the prospective national pediatric varicella hospitalizations study (including 29 centers, represent 50% of pediatric population) in Turkey, is aimed to evaluate breakthrough varicella infection requiring hospitalization before the routine use of single-dose live varicella vaccine in national program from 2008 to 2013 (<10% of the pediatric age group received a single-dose vaccine). Results: In the time period, 1939 children were hospitalized due to varicella infection in Turkey; 36 children (20 boys, 16 girls, mean age 68.0 + 37.6 months, all received single dose live varicella vaccine) with breakthrough varicella infection. Breakthrough varicella infection might be severe in previously healthy children (61.1%) and children with immune-compromising conditions (38.9%). The time elapsed between vaccination and hospitalization was approximately 5 years, and neurological complications, mainly encephalitis and meningitis, were the most common reason for hospitalization in previously healthy children. Conclusion: Pediatric breakthrough varicella requiring hospitalization have been seen in Turkey, is mainly observed in previously healthy children at 5 years after a single-dose varicella vaccine. The varicella vaccine has been implemented as part of the National Immunization Program in Turkey in 2013 (a single dose at age 12 months). Further surveillance in the same settings could evaluate the effectiveness of national immunization with single-dose varicella vaccine at 12 months of age and potential need for second dose of vaccine. © 2015 Elsevier Ltd.
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    Clinical features of candidiasis in patients with inherited interleukin 12 receptor ß1 deficiency
    (2014) Ouederni M.; Sanal O.; Ikinciogullari A.; Tezcan I.; Dogu F.; Sologuren I.; Pedraza-Sánchez S.; Keser M.; Tanir G.; Nieuwhof C.; Colino E.; Kumararatne D.; Levy J.; Kutukculer N.; Aytekin C.; Herrera-Ramos E.; Bhatti M.; Karaca N.; Barbouche R.; Broides A.; Goudouris E.; Franco J.L.; Parvaneh N.; Reisli I.; Strickler A.; Shcherbina A.; Somer A.; Segal A.; Angel-Moreno A.; Lezana-Fernandez J.L.; Bejaoui M.; Bobadilla-Del Valle M.; Kachboura S.; Sentongo T.; Ben-Mustapha I.; Bustamante J.; Picard C.; Puel A.; Boisson-Dupuis S.; Abel L.; Casanova J.-L.; Rodríguez-Gallego C.
    Background. Interleukin 12Rß1 (IL-12Rß1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rß1 deficiency.Results. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin.Conclusions. Patients who are deficient in IL-12Rß1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients. © The Author 2013.
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    Comparison of two different regimens of combined interferon-?2a and lamivudine therapy in children with chronic hepatitis B infection
    (2006) Kansu A.; Doganci T.; Akman S.A.; Artan R.; Kuyucu N.; Kalayci A.G.; Dikici B.; Dalgiç B.; Selimoglu A.; Kasirga E.; Özkan T.B.; Kuloglu Z.; Aydogdu S.; Boşnak M.; Ertekin V.; Tanir G.; Haspolat K.; Girgin N.; Yagci R.V.
    Aim: To evaluate the efficacy of two regimens of combined interferon-?2a (IFN-?2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. Methods: A total of 177 patients received IFN-?2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7±3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-?2a, in group II (65 patients, 9.6±3.8 years) 3TC was started 2 months prior to IFN-?2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in non-responders. Results: Baseline alanine aminotransferase (ALT) was 134.2±34.1 and 147.0±45.3; histological activity index (HAI) was 7.4±2.7 and 7.1±2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively (P>0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively (P<0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I (P<0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively (P>0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9±4.6 and 14.1±5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively (P>0.05, P>0.05, P>0.05). Responders had higher HAI (HAI>6) and higher pre-treatment ALT than non-responders. Conclusion: Simultaneous 3TC+IFN-?2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies. © 2006 International Medical Press.
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    Il-12rß1 deficiency in two of fifty children with severe tuberculosis from IRN, MAR, and TUR
    (2011) Boisson-Dupuis S.; Baghdadi J.E; Parvaneh N.; Bousfiha A.; Bustamante J.; Feinberg J.; Samarina A.; Grant A.V.; Janniere L.; Hafidi N.; Hassani A.; Nolan D.; Najib J.; Camcioglu Y.; Hatipoglu N.; Aydogmus C.; Tanir G.; Aytekin C.; Keser M.; Somer A.; Aksu G.; Kutukculer N.; Mansouri D.; Mahdaviani A.; Mamishi S.; Alcais A.; Abel L.; Casanova J.-L.
    Background and Objectives: In the last decade, autosomal recessive IL-12Rß1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from MAR, Spain, and TUR, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rß1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. Methods and Principal Findings: We searched for IL12RB1 mutations in a series of 50 children from IRN, MAR, and TUR. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from IRN and another from MAR, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rß1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rß1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. Significance: This finding may have important medical implications, as recombinant IFN-? is an effective treatment for mycobacterial infections in IL-12Rß1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity. © 2011 Boisson-Dupuis et al.
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    Revisiting human IL-12Rß1 deficiency: A survey of 141 patients from 30 countries
    (2010) De Beaucoudrey L.; Samarina A.; Bustamante J.; Cobat A.; Boisson-Dupuis S.; Feinberg J.; Al-Muhsen S.; Jannière L.; Rose Y.; De Suremain M.; Kong X.-F.; Filipe-Santos O.; Chapgier A.; Picard C.; Fischer A.; Dogu F.; Ikinciogullari A.; Tanir G.; Al-Hajjar S.; Al-Jumaah S.; Frayha H.H.; Alsum Z.; Al-Ajaji S.; Alangari A.; Al-Ghonaium A.; Adimi P.; Mansouri D.; Ben-Mustapha I.; Yancoski J.; Garty B.-Z.; Rodriguez-Gallego C.; Caragol I.; Kutukculer N.; Kumararatne D.S.; Patel S.; Doffinger R.; Exley A.; Jeppsson O.; Reichenbach J.; Nadal D.; Boyko Y.; Pietrucha B.; Anderson S.; Levin M.; Schandené L.; Schepers K.; Efira A.; Mascart F.; Matsuoka M.; Sakai T.; Siegrist C.-A.; Frecerova K.; Blüetters-Sawatzki R.; Bernhöft J.; Freihorst J.; Baumann U.; Richter D.; Haerynck F.; De Baets F.; Novelli V.; Lammas D.; Vermylen C.; Tuerlinckx D.; Nieuwhof C.; Pac M.; Haas W.H.; Müller-Fleckenstein I.; Fleckenstein B.; Levy J.; Raj R.; Cohen A.C.; Lewis D.B.; Holland S.M.; Yang K.D.; Wang X.; Wang X.; Jiang L.; Yang X.; Zhu C.; Xie Y.; Lee P.P.W.; Chan K.W.; Chen T.-X.; Castro G.; Natera I.; Codoceo A.; King A.; Bezrodnik L.; Di Giovani D.; Gaillard M.I.; De Moraes-Vasconcelos D.; Grumach A.S.; Da Silva Duarte A.J.; Aldana R.; Espinosa-Rosales F.J.; Bejaoui M.; Bousfiha A.A.; Baghdadi J.E.; Özbek N.; Aksu G.; Keser M.; Somer A.; Hatipoglu N.; Aydogmus C.; Asilsoy S.; Camcioglu Y.; Gülle S.; Ozgur T.T.; Ozen M.; Oleastro M.; Bernasconi A.; Mamishi S.; Parvaneh N.; Rosenzweig S.; Barbouche R.; Pedraza S.; Lau Y.L.; Ehlayel M.S.; Fieschi C.; Abel L.; Sanal O.; Casanova J.-L.
    Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought. © 2010 Lippincott Williams & Wilkins.