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1Volume 75 Number 3-4 July-December 2012Volume 75 Number 3-4 July-December 2012
75 3-4 I- 2012 75 3-4 I- 2012
www.e-child.grwww.e-child.gr
2 e-mail: [email protected]
:http://e-child.gr/publications/instructions-to-authors
IE E 15,15451, . T.: 2107771140e-mail: [email protected]
E : 40E, : 20
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75 3-4 I- 2012
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3Trimonthly publication of the Greek Paediatric Society
PaediatrikiVolume 75 Number 3-4 July-December 2012
PresidentA. Constantopoulos
Editorial boardDirectorG. S. Varlamis
MembersS. AndronikouE. GalanakisA. EvangeliouL. ThomaidouM. KanariouA. KapogiannisS. Kitsiou-TzeliE. MantadakisP. Panagiotopoulou-GartaganiA. PapadopoulouV. PapaevagelouA. PapathanassiouA. Siamopoulou-MavridouA. Syrigou-Papavasiliou
Manuscript submissione-mail: [email protected]
Instructions to authors:http://e-child.gr/publications/instructions-to-authors
OwnerGreek Paediatric Society15, Mpakopoulou st.GR - 15451, . PsychikoT.: +302107771140,e-mail: [email protected]
Annual subscriptionAll foreign countries: US$50
CONTENTS
06
12
22
32
44
60
74
90
108
EDITORIALG.S.Varlamis
SPECIAL ARTICLEGreek Neonatal Society: Guidelines for management of hyperbilirubinemia in in-fants gestational age 35 weeks or moreD. Konstantinou, A. Varvarigou, A. Daskalaki, E. Diamanti
REVIEW ARTICLESFood allergy in infancy and childhood: diagnosis, management and future ap-proachesA. Mavroudi, I. Xinias
Food protein induced enterocolitis syndrome: an unusual type of food allergy Evangelia Stefanaki, Stavroula Giavi, Savvas Savvatianos, Nikolaos Douladiris, Emman-ouel Manousakis, Nicolaos Papadopoulos
Attention deficit hyperactivity disorder: a review of the essential factsAggeliki Skardoutsou
Genetics in Diabetes Mellitus type 1Panagiota Triantafyllou, Charikleia Chatzisevastou
ORIGINAL ARTICLESDysmetabolic syndrome manifestation is not related with therapy stages in acute lymphoblastic leukemia of childhoodE. Koultouki, G. Trimis, G. Lambrou, M. Tsotra, N. Tourkantoni, K. Karamolegou, M. Ad-amaki, J. Papassotiriou, G. Chrousos, F. Tzortzatou-Stathopoulou, M. Moschovi
Evaluation of potential benefit of universal rotavirus vaccination program in GreeceV. Syriopoulou, D. Kafetzis, M. Theodoridou, G. Syrogiannopoulos, St. Mantagos, M. Ma-vrikou, G. Trimis, A. Konstantopoulos
CASE REPORTSMolecular study in jacobsen syndrome with array cghelen Leze, Maria Tzetis, Konstantina Kosma, Areti Syrmou, Krinio Giannikou, Vasilis Oikonomakis, Elisabeth Kouvidis, Aggeliki Nika, Ioannis Kapetanakis, Emmanuel Ka-navakis, Sofia Kitsiou-Tzeli
4 E E
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M. . . . . . . K-. . -. . . . -. -
116
122
e-mail: [email protected]
:http://e-child.gr/publications/instructions-to-authors
IE E 15,15451, . T.: 2107771140e-mail: [email protected]
E : 40E, : 20
130
138
140
75 3-4 I- 2012
Plasmodium vivax : 20 , , , , , , .
Candida parapsilosis : - , , K, , , , .
: , , , , , .
, .
5Trimonthly publication of the Greek Paediatric Society
PaediatrikiPresidentA. Constantopoulos
Editorial boardDirectorG. S. Varlamis
MembersS. AndronikouE. GalanakisA. EvangeliouL. ThomaidouM. KanariouA. KapogiannisS. Kitsiou-TzeliE. MantadakisP. Panagiotopoulou-GartaganiA. PapadopoulouV. PapaevagelouA. PapathanassiouA. Siamopoulou-MavridouA. Syrigou-Papavasiliou
CONTENTS
116
122
Manuscript submissione-mail: [email protected]
Instructions to authors:http://e-child.gr/publications/instructions-to-authors
OwnerGreek Paediatric Society15, Mpakopoulou st.GR - 15451, . PsychikoT.: +302107771140,e-mail: [email protected]
Annual subscriptionAll foreign countries: US$50
130
138
140
Volume 75 Number 3-4 July-December 2012
Autochthonous malaria by Plasmodium vivax in two children from Thiva: First re-ported paediatric cases 20 years after the eradication of the disease in Greece. Polymerou, P. Korovessi, G. Amountza, G. Kampouropoulou, E. Antonopoulou, A. Peg-kou, I. Papadea
Childhood Cystic Nephroma: diagnosis and treatment (Case Presentation)V. Papadakis, A. Papanikolaou, K. Stefanaki, J. Alexandrou, M. Zeis, Sp. Antypas
Candida parapsilosis endocarditis in a premature neonate. Successful outcome with combined antifungal and surgical treatmentK. Papadopoulou-Legbelou, G. Kalavrouziotis, C. Reveliotis, K. Karachristou, M. Lithoxo-poulou, G. Varlamis, N. Nikolaidis
BOOK REVIEW The children invite us to have a dialogue.oukou M., Georgouli A.
ACKNOWLEDGMENT
6 75
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SPECIAL ARTICLE
D. Konstantinou 1
NICU, IASO Maternity Hospital, Athens, Greece
A. Varvarigou 2
Neonatal Dpt University Hospital of Patras, Patras, Greece
A. Daskalaki 3
Neonatal Dpt Attikon Hospital, Athens, Greece
E. Diamanti 4
1st Neonatal Dpt Aristotle University of Thessaloniki, Thes-saloniki, Greece
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Greek Neonatal Society: Guidelines for management of hyperbilirubinemia in infants gestational age 35 weeks or more
D. Konstantinou 1, A. Varvarigou 2, A. Daskalaki 3, E. Diamanti 4
Hyperbilirubinemia is the most common neonatal problem which requires medical intervention in order to avoid neonatal encephalopathy and/or kernicterus, both rarely seen. Since the management of hyperbilirubinemia is not evidence based, guidelines for its management differ between countries. A lack of guidelines in Greece resulted in un-necessary treatment of jaundiced babies without justification, fearing bilirubin increase and the wrong aspect that prophylactic phototherapy can improve the final outcome. In order to establish a common and logical management program for neonatal jaundice in our country, a working team of neonatologists appointed by the Greek Neonatal Soci-ety established these guidelines, based on management protocols from other countries. Thus, we expect the same management of neonatal jaundice from all pediatricians, using common guidelines and minimizing or eliminating unnecessary medical interventions. In addition we will strive to avoid the unnecessary interruption of breast feeding of jaun-diced infants.
Key words: Neonatal Jaundice, Hyperbilirubinemia, Guidelines
13
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,. 37-39, 15123 , e-mail: [email protected]
CorrespodenceDimitris KonstantinouNICU IASO Maternity Hospital, Kifissias Av 37-39, 15123 Maroussi, Athens, Greecee-mail: [email protected]
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14
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1. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Ges-tation, Subcommitee on Hyperbilirubinemia, Pediatrics 2004;114:297-316.
2. Barrington KJ, Sankaran K. Canadian pediatric society. Guidelines for detection, man-agement and prevention of hyperbilirubinemia in term and late preterm newborn in-fants, Paediatr Child Health 2007;12(Supl B): 1B-12B.
3. Kaplan M, Merlob P and Regev R. Israel guidelines for the management of neonatal hyperbilirubinemia and prevention of kernicterus. J Perinatol 2008;28:389-387.
4. National Collaborating Centre for Womens and Childrens Health, Neonatal Jaundice, National Institute for Health and Clinical Excellence, Clinical Guidelines for the NHS by NICE, May 2010.
5. Bratlid D, Nakstad B, Hansen TW. National guidelines for treatment of jaundice in the newborn. Acta Paediatr. 2011;100(4):499-505.
6. aisels MJ, Kring E. Transcutaneous bilirubinometry decreases the need for serum bilirubin measurements and saves money. Pediatrics 1997 Apr;99(4):599-601.
7. Roubatelli FF, Gourley GR LoskampN et al, Transcutaneous bilirubin measurement: a multicenter evaluation of a new device. Pediatrics 2001 Jun;107(6):1264-71.
8. , , , . ()
21
BiliCheck. 37o 28-30 1999, .
9. Maisels J and McDonagh AF, Phototherapy fon Neonatal Jaundice, N Engl J Med 2008;358:920-8.
10. Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark A, Watchko JF. Hyperbilirubine-mia in the Newborn Infant 35 Weeks Gestation: An Update with Clarifications. Pediat-rics 2009;124:1193-1198.
11. Newman TB, Liljestrand P, Jeremy RJ, Ferriero D, Wu Y, Hudes E et al, Outcomes among Newborns with Total Serum Bilirubin Levels of 25 mg per Deciliter or More, N Engl J Med 2006;354:1889-1949.
12. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for Subsequent significant hyperbilirubinemia in healthy term and near-term newborns, Pediatrics 1999 ;103 : 6-14.
13. Varvarigou A, Fouzas S, Skylogianni E, Mantagou L, Bougioukou D, Mantagos S. Trans-cutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia. Pediatrics 2009; 124: 1052-59.
14. Maisels J, Ostrea E, Touch S, Clune S, Cepeda E, Kring E et al, Evaluation of a new Transcutaneous Bilirubinometer. Pediatrics 2004; 113; 1628.
15. aisels M J. Screening and early postnatal management strategies to prevent haz-ardous hyperbilirubinemia in newborns of 35 or more weeks of gestation. Seminars in fetal & neonatal medicine 2010;15:129-135.
16. ABM Clinical protocol 22: Guidelines for management of jaundice in the breastfed-ing infant equal to or greater than 35 weeks gestation. The Academy of breastfeeding medicine protocol committee. Breastfeeding medicine 2010;5(2):87-93.
17. Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts in bilirubin encephalopa-thy. Eur J Clin Invest Review 2003 Nov;33(11):988-97.
18. Shapiro SM. Definition of the clinical spectrum of kernicterus and bilirubin induced neurologic dysfunction (BIND). J Perinatol 2005 Jan;25(1):54-59.
19. Gourley GR, Kreamer B, Cohnen M, Kosorok MR. Neonatal jauntice and diet. Arch Pediatr Adolesc Med. 1999 Feb;153(2):184-8.
20. Hulzebos CV, van Imhoff DE, Bos AF, Ahlfors CE, Verkade HJ, Dijk PH. Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity in premature in-fants. Arch Dis Child Fetal Neonatal Ed. 2008 Sep;93(5):F384-F388.
21. Ahlfors CE, Amin SB, Parker AE. Unbound bilirubin predicts abnormal automated audi-tory brainstem response in a diverse newborn population. J Perinatol 2009 Apr;29(4):305-309. Epub 2009 Feb 26.
22. Gottstein R and Cooke RWI. Systematic review of iv immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003;88:F6-F10.
22
Abstract
. . (..) -
A. MavroudiI. Xinias3rd Pediatric Department, Aris-totle University of Thessaloniki, Ippokratio-General Hospital of Thessaloniki
REVIEW ARTICLES
: ,
. , .
, 8% 3 . , , IgE, -IgE . , . . , . . IgE , anti-IgE , . .
: , , , , .
Food allergy in infancy and childhood: diagnosis, man-agement and future approaches
A. Mavroudi, I. Xinias
Food allergy is common in childhood affecting up to 8% of children less than 3 years of age. Food induced allergic reactions are responsible for a variety of symptoms involv-ing the skin, the gastrointestinal and the respiratory tract, caused by IgE-mediated or/and non-IgE-mediated mechanisms. Allergic eosinophilic gastroenteritis is characterized by eosinophilic infiltration of the gastrointestinal tract, and most patients have multi-ple food allergies.In case of multiple sensitivities a period of strict elimination followed by careful reintroduction of foods, one after the other can help to establish foods that are to be avoided.Oral food challenges are invaluable in the appropriate diagnosis and management of patients with food allergy. Once the diagnosis of food hypersensitiv-ity is established, the only proven therapy is strict elimination of the offending allergen. Injectable epinephrine and oral antihistamines should be readily availible at all times to treat patients, who are at risk of acute severe food induced anaphylaxis. Several novel immunoterapeutic strategies are being examined as treatment modalities for IgE-medi-ated food allergy, such as humanized anti-IgE monoclonal antibody therapy, engineered allergen protein immunotherapy, peptide immunotherapy. Currently, the treatment of
23
66, 543 52, , : 2310909632 Fax: 2310992981 : 6976718209 e-mail: [email protected]
CorrespodenceAntigoni MavroudiSpirou Loui 66 St., 543 52, Pilea, Thes-salonikiTel: +302310909632Fax: +302310992981Mob: +30 6976718209e-mail: [email protected]
food allergy is directed to the complete avoidance of the offending food allergens and its success is depended on the correct identification of the allergens and their complete exclusion from the diet.
Key words: Food allergy, eosinophilic gastroenteritis, food challenges, anaphylaxis, children.
, . IgE IgE . - .1
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24
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25
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26
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28
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29
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30
1. Mary V. Lasley. Adverse reactions to foods. Nelson Essentials of Pediatrics, 5th ed. Phil-adelphia. Elsevier Saunders Co; 2006. p 419-421.
2. M. Thirumala Krishna, George Mavroleon, Stephen Tholgate. Food Allergy. Essentials of Allergy, United Kingdom: Martin Dunitz Ltd ;2001 p107-127.
3. S. Allan Bock, Hugh A. Sampson. Evaluation of Food Allergy. Pediatric Allergy: Principles and Practice. USA: Elseviers Health Sciences ;2003 p 478-487.
4. Ronina A. Covar, Joseph D. Spahn, Stanley J. Szefler. Special Considerations for Infants and Young Children. Pediatric Allergy: Principles and Practice. USA Elseviers Health Sci-ences; 2003 p 379-391.
5. Sampson HA, Anderson JA: Summary and recommendations: classification of gastro-intestinal manifestations due to immunologic reactions to foods in infants and young children.J Pediatr Gastroenterol Nutr 2000 ;30(Suppl): S87-S94.
6. Kelly KJ: Eosinophilic gastroenteritis. J Pediatr Gastroenterol Nutr 2000;30 (Suppl): S28-S35.
7. Takafuji S, Bischoff SC, De Weck AL, Dahinden CA. IL-3 and IL-5 prime normal human eo-sinophils to produce leukotriene C4 in response to soluble agonists. J Immunol 1991;147: 3855-3861.
8. Burks AW, James JM, Hiegel A, Wilson G, Wheeler JG Jones SM, et al. Atopic dermatitis and food hypersensitivity. J Pediatr 1998;132: 132-136.
9. Sporik R, Hill DJ, Hosking CS: Specificity of allergen skin testing in predicting prositive open food challenges to milk egg and peanut in children. Clin Exp Allergy 2000;30: 1540-1546.
10. Hill DJ, Hosking CS, Reyes-Benito MLV: Reducing the need for food allergen challeng-es in young children: comparison of in vitro with in vivo tests. Clin Exp Allergy 2001;31: 1031-1035.
11. Rance F, Juchet A, Bremont F, et al. Correlations between skin prick tests using com-mercial extracts and fresh foods, specific IgE and food challenges. Allergy 1997;52: 1031-1035.
12. Lockey RF: Adverse reactions associated with skin testing and immunotherapy. Al-lergy Proc 1995; 16:293-296.
13. Sampson HA: Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107: 891-896.
14. Arvola T, Holmberg-Marttila D: Benefits and risks of elimination diets. Ann Med 1999; 31: 293-298.
15. Liu T, Howard RM, Mancini AJ, Weston WL, Paller AS, Drolet BA,et al. Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance. Arch Dermatol .2001;137: 630-636.
16. Liacouras CA, Markowitz JE: Eosinophilic esophagitis: A subset of eosinophilic gastro-enteritis. Curr Gastroenterol Rep . 1991;1: 253-258.
31
17. Bock SA, Munoz-Furlogn A, Sampson HA: Fatalities caused by anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107: 191-192.
18. AAAAI Board of Directors. Anaphylaxis in schools and other child-care settings. J Al-lergy Clin Immunol.1998;102: 173-176.
19. Beyer K, Eckermann O, Hompes S, Grabenhenrich L& Worm M. Anaphylaxis in an emergency setting-elicitors, therapy and incidence of severe allergic reactions. Allergy 2012; 67: 1451-1456.
20. Sampson HA: Immunological approaches to the treatment of food allergy, Pediatr Allergy Immunol.2001;12: 91-96.
21. Nowak-Wegrzyn A, Sampson H. Future Therapies for food Allergies. J Allergy Clin Im-munol 2011; 127: 558-573.
32
Abstract
1
, 2
2
2
2
2
, , .& .
Evangelia Stefanaki1 2nd Pediatric Department, Venizelion General Hospital, HeraklionStavroula Giavi2
Savvas Savvatianos2
Nikolaos Douladiris2
Emmanouel Manousakis2
Nicolaos Papadopoulos2
Allergy Department, 2nd Pediatric Clinic, University of Athens, Childrens Hospital P & A Kyriakou
REVIEW ARTICLES
: -
1, 2, 2, 2, 2, 2
(food protein induced enterocolitis syn-drome-FPIES) - . , . . , FPIES. TNF- TGF- FPIES. FPIES . .
-: , , , ,
Food protein induced enterocolitis syndrome: an unusu-al type of food allergy
Evangelia Stefanaki1, Stavroula Giavi2, Savvas Savvatianos2, Nikolaos Douladi-ris2, Emmanouel Manousakis2, Nicolaos Papadopoulos2
Food protein induced enterocolitis syndrome-FPIES-is an unusual T-cell mediated gas-trointestinal food hypersensitivity reaction. It begins in the first months of life either pro-gressively with emesis, diarrhea and failure to thrive or with acute emesis with or with-out diarrhea after first ingestion of food. Symptoms resolve after the causal protein is removed from the diet but recur with a characteristic way on re-exposure. Milk, soya and rice are the most common causes of FPIES. Imbalance in expression TNF- TGF- may be important in the pathophysiology of FPIES. Natural history of FPIES differs according to the population. Increased index of suspicion will lead to early diagnosis and treatment.
Key-words: Food allergy, enterocolitis, milk, soya, rice
33
22,71409 , : 2810210140e-mail: [email protected]
CorrespodenceStefanaki Evangelia22, Kariotaki St.,71409 Heraklion, CreteTel: +302810210140e-mail: [email protected]
FPIES = Food protein induced entero-colitis syndrome-
SPT = Skin Prick Test-
APT = Atopy Patch Test-
TNF- = Tumor Necrosis Factor-
TGF- = Transforming Growth Factor -
IgE,IgA, IgG = , ,G
. IgE (.. ) - gE , (4-48 ) (.. ). IgE - . - 40% 1. 6-8%, 2 . 2,5% 2. (. , Europrevall).
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34
2: FPIES
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FPIES / FPIES / 12 . 3,4. FPIES IgA . FPIES 12. FPIES 10,13. . 42-60% FPIES , 5,7,10. (2009) 16 Mehr . , 3 7 2 12
35
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36
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37
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FPIES FPIES . 18-24 30. 27 FPIES 64% 10 92% 31. FPIES 12 6 8 . FPIES 4. 0,06-0,6gr/kg , 6,32. , 3-6 gr 10-20 gr ( 100 ml ). 3 45 33. 2-3 , . 30. H FPIES 6. 20ml/kg/ . , - . . Hwang 34. 15 16 >10/ , 3 , 2 . ,
38
, . , FPIES 60% , ( )5,6,30. 3-10 . 20% 35,36. . ..., FPIES / FPIES 6 5,10. Mehr 83% FPIES . ()14. , , . ... FPIES 80% . ( ) 50% . ,
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4: FPIES
39
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FPIES , . , , . ( , , ) 30.
. 60% 25%, , 3 (...). FPIES 3 , 40% , 66% 67% (). ... FPIES , 6,10. 3 83% 80% 10 , 64% 92% 31. FPIES 1 . ... FPIES . FPIES10,30. FPIES IgE , IgE 6. IgE . FPIES. FPIES10,14. , .
. FPIES37. FPIES in vitro (p
40
40. TNF-a . Chung TGF- (Transforming Growth Factor-) 28 FPIES 41. TGF- . 1 TGF- (p
41
11. Levy Y, Danon YL. Food protein-induced enterocolitis syndrome not only due to cows milk and soy. Pediatr Allergy Immunol 2003;14:3259.
12. Monti G, Castagno E, Liguori SA, Lupica MM, Tarasco V, Viola S, et al. Food proteininduced enterocolitis syndrome by cows milk proteins passed through breast milk. J Al-lergy Clin Immun 2011 Article in press.
13. Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastroenterol Nutr 2000;30: 5860.
14. Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics 2009; 123:459464.
15. Faber MR, Rieu P, Semmekrot BA, Van Krieken JH, Tolboom JJ, Draaisma JM. Allergic colitis presenting within the first hours of premature life. Acta Paediatr 2005; 94:15141515.
16. Eggertsen SC, Pereira PK. Necrotizing enterocolitis and milk protein intolerance:causes of rectal bleeding in a term infant. J Fam Pract 1989; 28:219223.
17. Masumoto K, Takahashi Y, Nakatsuji T, Arima T, Kukita J. Radiological findings in two patients with cows milk allergic enterocolitis. Asian J Surg 2004; 27:238240.
18. Jayasooriya S, Fox AT, Murch SH. Do not laparotomize food-protein-induced entero-colitis syndrome. Pediatr Emerg Care 2007; 23:173175.
19. Murray K, Christie D. Dietary protein intolerance in infants with transient methemo-globinemia and diarrhea. J Pediatr;122:902.
20. Anand RK, Appachi E. Case report of methemoglobinemia in two patients with food protein-induced enterocolitis. Clin Pediatr (Phila) 2006; 45:679682.
21. Zapatero RL, Alonso LE, Martin FE, Martinez Molero MI. Food-protein-inducedentero-colitis syndrome caused by fish. Allergol Immunopathol (Madr) 2005;33:312316.
22. Hojsak I, Kljaic-Turkalj M, Misak Z, Kolacek S. Rice protein-induced enterocolitis syn-drome. Clin Nutr 2006; 25:533536.
23. Gray HC, Foy TM, Becker BA, Knutsen AP. Rice-induced enterocolitis in an infant. TH1/TH2 cellular hypersensitivity and absent IgE reactivity. Ann Allergy Asthma Immunol 2004; 93:601605.
24. F. Bruni, D. G. Peroni, G. L. Piacentini, G. De Luca,A. L. Boner. Fruit proteins: another cause of food protein-induced enterocolitis syndrome Allergy 2008: 63: 16401646.
25. Sampson HA, Anderson JA. Summary and recommendations: classification of gas-trointestinal manifestations due to immunologic reactions to foods in infants and young children. J Pediatr Gastroenterol Nutr 2000; 30:S87S94.
26. Hwang JB, Lee SH, Kang YN, Kim SP, Suh SI, Kam S. Indexes of suspicion of typical cows milk protein-induced enterocolitis. J Korean Med Sci 2007; 22:993997.
27. Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol 2006; 17:351355.
28. Richards DG, Somers S, Issenman RM, Stevenson GW. Cows milk protein/soy protein allergy: gastrointestinal imaging. Radiology 1988; 167:721723.
29. McIlhenny J, Sutphen JL, Block CA. Food allergy presenting as obstruction in an in-fant. AJR Am J Roentgenol 1988; 150:373375.
42
30. Sicherer SH. Food protein-induced entercolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol 2005; 115:149156.
31. Hwang JB, Sohn SM, Kim AS. Prospective follow up-oral food challenge in food pro-tein-induced enterocolitis syndrome. Arch Dis Child 2009; 94:425428.
32. Powell GK. Food protein-induced enterocolitis of infancy: differential diagnosis and management. Comp Ther 1986; 12:2837.
33. A health professionals guide to food challenges. Mofidi S, Bock SA, editors. Fairfax, Virginia, USA: The Food Allergy and Anaphylaxis Network; 2004.
34. Hwang JB, Song JY, Kang YN, Kim SP, Suh SI, Kam S, et al. The significance of gastric juice analysis for a positive challenge by a standard oral challenge test in typical cows milk protein-induced enterocolitis. J Korean Med Sci 2008; 23:251255.
35. Vanderhoof JA, Murray ND, Kaufman SS, Mack DR, Antonson DL, Corkins MR et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastro-intestinal symptoms in infants. J Pediatr 1997; 131:741744.
36. Kelso JM, Sampson HA. Food protein-induced enterocolitis to casein hydrolysate for-mulas. J Allergy Clin Immunol 1993; 92:909910.
37. Powell GK, McDonald PJ, VanSickle GJ, Goldblum RM. Absorption of food protein antigen in infants with food protein-induced enterocolitis. Dig Dis Sci 1989; 34:781788.
38. VanSickle GJ, Powell GK, McDonald PJ, Goldblum RM. Milk and soy protein induced entercolitis: evidence for lymphocyte sensitization to specific food proteins. Gastroenter-ology 1985; 88:19151921.
39. Rodriguez P, Heyman M, Candalh C, Blaton MA, Bouchaud C. Tumour necrosis fac-tor-alpha induces morphological and functional alterations of intestinal HT29 cl.19A cell monolayers. Cytokine 1995; 7:441448.
40. Benlounes N, Candalh C, Matarazzo P,Dupont C, Heyman M. The time-course of milk antigen induced TNF-alpha secretion differs according to the clinical symptoms in chil-dren with cows milk allergy. J Allergy Clin Immunol 1999; 104:863869.
41. Chung HL, Hwang JB, Park JJ, Kim SG. Expression of transforming growth factor beta1, transforming growth factor type I and II receptors, and TNF-alpha in the mucosa of the small intestine in infants with food protein-induced enterocolitis syndrome. J Al-lergy Clin Immunol 2002; 109:150154.
42. McDonald PJ, Goldblum RM, VanSickle GJ, Powell GK. Food protein-induced entero-colitis: altered antibody response to ingested antigen. Pediatr Res 1984;18:751755.
43. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determination of food spe-cific IgE levels over time can predict the development of tolerance in cows milk and hens egg allergy. J Allergy Clin Immunol 2004; 114:387391.
43
44
Abstract
. , ,
Aggeliki Skardoutsou2nd Department of Pediatrics, University of Athens, Aglaia Kyri-akou Childrens Hospital, Athens, Greece
REVIEW ARTICLES
- .
.
- () , . , , , , . . , , . .
: , , , , , .
Attention deficit hyperactivity disorder: a review of the essential facts
Aggeliki Skardoutsou
Attention deficit hyperactivity disorder (ADHD) is a complex disability: both genetic and environmental influences make a substantial contribution to the risk for the disor-der. Comorbidity with learning disabilities, oppositional defiant and conduct disorders and mood and anxiety disorders is common in children and adults with this disorder and are associated with adversive academic and vocational outcomes and tremendous stress to families. Medication with dopaminergic and noradrenergic activity seems to reduce ADHD symptoms by blocking dopamine and norepinephrine reuptake. The aim of this review is to provide clinicians with a brief synopsis of the current under-standing about the etiology of ADHD, co-morbidity and associated problems, develop-mental course and intervention options. Parents understanding about the current data increases their consent to intervention, and the adherence to psychosocial and pharma-cological treatment.
Key words: Attention deficit - hyperactivity disorder, co-existing problems methyl-phenidate, atomoxetine, children.
45
, , , 115 27, . e-mail: [email protected]
CorrespodenceAggeliki Skardoutsou2nd Department of Pediatrics, University of Athens, P& A Kyriakou Childrens Hospital, Goudi, 115 27, Athens, Greecee-mail: [email protected]
- () 21 . 20 , . 21 . .
H 8-12% , , . (1). () . Diagnostic and Statistical Manual of the American Psychiatric Association (4th edition;DSM-IV) , , ( 1). . (2). (Hyperkinetic Disorder - HKD) (10 ) - International Classification of Diseases (10th edition; ICN -10) (3). DSM-IV (HKD) DSM-IV (4). D .
46
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47
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. (11). - (-) (12). . . , . , (12). .
48
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) H . 25% 50% (21). . . 4 7 (DRD4-7) in vitro
49
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(22). 5 (DRD5) ( (DRD5 148bp ) (23) (DAT-10 3 ) (24). 1 (DRD1), 5- (5-HT (1B), ( Taq 1) (SNAP-25) (22). , . (16). (25).
) , , , , , , , (26,27,28). , , . (29). 70 , , , . (30). . ( DAT-10 ( ) (7). , , . . (, , ) . . . (22).
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50
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51
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52
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, (42). . , , , 75 % (42,43,44). 2-3 (42-43) (48). , . 30 3-4 2-3 (42,43,44). 1.5 . , . 2.5 mg . . . , . 22% 78% 12 (43). 18mg 5 mg o 3 . H 54 mg 72 mg . . , , , ( ), () .
53
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- (Ritalin)
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54
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. . 2-3 , . . . 6-12 (49-50). (50). , , , , . . . . . Tourette. , , . . , . . (44). . . ( ) (4-48-51-53). . (4-47-48-51-53). - , (4). . . , (51-52). , , , , -, (42).
55
. , . . . . . . .
1. ADORE Study group Preus Ul, Ralston S, Baldursson G. et al. Study design, baseline patient characteristics and intervention in a cross-cultural framework; results from the ADORE study. Eur Child Adolesc Psychiatry (Suppl 1) 2006;15 :1/4 -1/13.
2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disor-ders, 4th ed.Washington, DC, American Psychiatric Association.1994.
3. World Health Organisation. International Classification of Diseases, ed. Geneva WHO, 1978.
4. Taylor E. European clinical guidelines for hyperkinetic disorder-first upgrade. Eur Child Adoles. Psychiatry 2004; (Suppl 1) Vol 13:1/7 -1/30.
5. Taylor E, Similarities and Differences In DSM -1V and ICD -10 Diagnostic Criteria. Child and Adolescent Psychiatric Clinics of North America.1994;V3:2, 209-225.
6. A. -, . , . . . . ADHD Rating Scale-IV. 2005.
7. Biederman J, Faraone S. Attention-deficit-hyperactivity disorder. The Lancet 2005; 16:238-247.
8. Kytja K.S. Voeller, MD; Attention-Deficit Hyperactivity Disorder (ADHD) J Child Neurol 2004;19:798-814.
9. Sonuga -Barker EJ, Dalen E Daley D, Reminghton B. Are planning, working memory, and inhibition associated with individual differences in preschool ADHD symptoms? Dev Neuropsychol 2002;21:255-72.
10. Dreyer B. The diagnosis and Management of Attention -Deficit /Hyperactivity Disor-ders in Preschool Children: The state of Our Knowledge and Practice. Curr Prob Pediatr Adolesc Health Care. 2006;36: 6-30.
11. Vies JS, Feron FG, Hendriksen J, Van Kroonenburgh MJ,Weber W. Methylphenidate down regulates the dopamine receptor and transporter system in children with atten-tion defitit hyperactivity disorder. Neuropediatrics 2003;34:77-80.
12. Powell K, Voeller K, J Prefrontal Executive Function Syndromes in children. J Child Neurol 2004;19:785-797.
56
-
13. Johansen E, Aase H, Meyer A. Attention deficit/Hyperactivity disorder (ADHD) behav-ior explained by dysfunction reinforcement and extinction processes. Behav Brain. Res 2002;130:37-45.
14. Sonuga-Barke E.J. The dual pathway model of AD/HD; an elaboration of neurodevel-opmental characteristics. Neurosci Biobehav Rev. 2003;27:593-604.
15. Seargent J. The cognitive -energetic model; an empirical approach to attention -defi-cit hyperactivity disorder. Neurosci Biobehav Rev. 2000;24:7-12.
16. Sonuga- Barke EJ; Casual models of Attention -deficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways. Biol Psychiatry 2005;57:1231-38.
17. Castellanos FX, Lee PP, Sharp W et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention deficit /hyperactivity disorder. JAMA 2002;288:1740-48.
18. Showell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS. Corti-cal abnormalities in children and adolescents with attention deficit/hyperactivity disor-der. Lancet 2003;362:1699-707.
19. Seidman LJ,Valera E, Bush G, Brain function and structure in adults with attention deficit /hyperactivity disorders. In Spencer T et al. Psychiatric Clinics of North America. Philadelphia PA Saunders Press, 2004;323-47.
20. Durston S, Tottenham NT, Thomas KM, Differential patterns of striatal activation in young children with and without ADHD, Biol Psychiaty, 2003;53:871-7.
21. Faraone SV, Doyle AE. The nature and heredability of attention deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin.North Am.2001;10:299-316.
22. Faraone SV, Perlis RH, Doyle AE et al, Molecular genetics of attention deficit hyperac-tivity disorder. Biol Psychiatry 2005;57:1313-23.
23. Lowe N, Kirley A, Hawi Z et al. Joint analysis of DRD 5 marker concludes association with ADHD confirmed to the predominantly inattentive and combined types. Am J Hum Genet. 2004;74:348-56.
24. Dougherty DD, Bonab AA, Spencer T, Rauch SL, Madras BK, Fishman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 1999;354:2132-33.
25. Smalley SL, Kustanivich V, Genetic linkage of attention deficit hyperactivity disorder on chromosome 16p 13, in a region implicated in autism. Am J Hum Gen.2002;71:59-963.
26. Mick E, Biederman J, Prince J, Fisher MJ, Faraone SV. Impact of low birth weight on attention deficit hyperactivity disorder. J Dev Behav Pediatrics. 2002;23:16-22.
27. Autti -Ramo I.Twelve-year follow up of children exposed to alcohol in utero. Dev Med Child Neurology. 2000;42: 406-11.
28. Bastra L, Hadders -Algra M, Neelman J. Effect of antenatal exposure to maternal smoking on behavioral problems and academic achievement in childhood ; prospective evidence from a Dutch birth cohort. Early Hum Dev.2003;75:21 -33.
29. He Y. Yang X. Xu F. Application of Conners Rating Scales in the study of lead exposure and behavioral effects in children. Zhonghua Yu Fang Yi Xue Za Zhi 2000;34:290-93.
30. Eigenmann P, Haenggeli C. Food colourings and preservatives-allergy and hyperactiv-ity. The Lancet 2004;364:823-824.
57
31. Biederman J, Newcorn J, Spritch S. Commorbidity of attention deficit hyperactivity disorder with conduct, depressive anxiety and other disorders. Am J Psychiatry 1999;148 :564-577.
32. Biederman J, Mick E, Faraone S. Age dependent decline of symptoms of attention deficit hyperactivity disorder; impact of remission definition and symptom type. Am J Psychiatry 2000;157:816-8.
33. Wasserstein J. Diagnostic issues for adolescents and adults with ADHD. J Clin Psychia-try 2005;61:535-47.
34. Goodman D. The consequences of Attention Deficit Hyperactivity disorder in adults. Jour Practical Psychiatry and Behavior 2007;13:318-327.
35. Barbaresi W, Katusic S, Coligan R, Weaver A, Jacobsen S. Long term school outcome for children with attention deficit hyperactivity disorder; a population based perspec-tives. J Dev Behav Pediatr 2007;28:265-73.
36. Biederman J, Faraone S. The effect of attention-deficit /hyperactivity disorder on employment and household income. Med Gen 2006;8-12.
37. Babinski L, Hartsough C, Lambert N. Childhood conduct problems, hyperactivity im-pulsivity and inattention as predictors of adult criminal activity. J Child Psychol Psyciatry 1999;40:347-55.
38. Barkley R. Driving impairments in teens and adults with attention deficit/hyperactiv-ity disorder. Psychiatr Clin North Am 2004;27:233-60.
39. Wilens T. Attention deficit hyperactivity disorder and the substance use disorders. The nature of the relationship, subtypes at risk and treatment issues. Psychiatr Clin North Amer; 2004;27:283-301.
40. Biederman J, Montreau MC, Mick E, et al Is cigarette smoking a getaway to alcohol and illicit drug use disorder. A study of youths with and without attention deficit hyperac-tivity disorder. Biol Psychiatry 2006;59:258-264.
41. Wilens T, Faraone S, Biederman J, et al. Does stimulation therapy of attention deficit hyperactivity disorder beget later substance abuse? A meta-analytic review of the litera-ture. Pediatrics 2003;111:179-85.
42. Elia J. Ambrosius M, Rapaport J. Treatment of attention deficit hyperactivity disorder. New Engl Jour Med 1999;340:10:780-788.
43. Lopez J.ADHD. New pharmacological Treatments on the horizon. Jour of Develop and Behav Pediatr. 2006;27 (5) 410-416.
44. Newcorn, MD. Ivanov LL, Psychopharmacologic Treatment of attention-Deficit/hy-peractivity Disorder and disruptive Behavior Disorders. Pediatric Annals 2007;36-9.
45. Spencer T, Biederman J, Coffey B et al: The 4-year course of tick disorders in boys with attention deficit /hyperactivity disorder. Arch Gen Psychiatry 1999;56:842-47.
46. Wilens T, Faraone SV, Biederman J, Gunawardens S, Does stimulant therapy of atten-tion deficit hyperactivity disorder beget later substance abuse? Pediatrics 2003;1111:179-85.
47. MTA Cooperative Group. National Institute of Mental Health. Multimodal Treatment Study of ADHD follow-up changes in effectiveness and growth after the end of treat-ment. Pediatrics 2004;113(4)762-9.
48. Jensen PS, Arnold LE, Swanson JM et al, 3year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007 Aug ;46(8)989-1002.
58
-
49. elsey DK, Summer CR, Casat CD et al. Once daily atomoxetine treatment for children with attention deficit hyperactivity disorder, including an assessment of evening and morning behavior; a double blind, placebo-controlled trial. Pediatrics 2004;114:(1)1-8.
50. Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD,Ruff DD,et al. Atomoxetine and osmot-ically released methylphenidate for the treatment of attention deficit hyperactivity dis-order: acute comparison and differential response. Am J Psychiatry. 2008;165:(6)721-30.
51. Van der Oord S, Prins PG, Oosterlaan J, Emmelkamp PM. Efficacy of methylpheni-date, psychosocial treatments and their combination in school-aged children with ADHD: a meta-analysis. Clin Psychol Rev 2008,28(5)783-800.
52. Advokat C. What are the cognitive effects of stimulant medications? Emphasis on adults with attention -deficit / hyperactivity disorder (ADHD). Neurosci Biobehav Rev.2010 Jul;34(8) 1256 -66.
53. Klein R, Abikoff H, Hechtman L, et all. Design and rationale of controlled study of long- term methylphenidate and multimodal psychosocial treatment in children with ADHD. J Am Acad Child Adolesc Psychiatry 2004;43,792-801.
59
60
Abstract
X ,
Panagiota TriantafyllouCharikleia Chatzisevastou1st Department of Pediatrics, Aristotle University of Thes-saloniki, Hippokratio Hospital, Thessaloniki
REVIEW ARTICLES
1
, X
, 1. (genome-wide asso-ciation studies) . . HLA , -HLA . -. , 1.
: 1, ,
Genetics in Diabetes Mellitus type 1
Panagiota Triantafyllou, Charikleia Chatzisevastou
During the last years there has been dramatic progress in understanding the genetics, the autoimmune mechanisms and natural history of diabetes mellitus type 1. Genome-wide association studies have shown that there are at least four major and few minor genetic loci associated with the risk of diabetes type 1. Genes within HLA region seems to play the most important role, whereas, genes outside the HLA region may also con-tribute to the risk but their role is much less important. The majority of these loci appear to affect the immune system and the activation of T-cells, in particular. Elucidating the actual way that the products of these loci function could contribute in the understanding of how they affect the risk of diabetes type 1. Furthermore, these findings may improve our ability to predict and prevent diabetes type 1 through clinical applications.
Key-words: diabetes mellitus type 1, autoantibodies, genetic analysis
1 (-1). , , , -1(1-2). , . -1 - . : 1, -
61
. 16, .. 53351, : 2310440100e-mail: [email protected]
CorrespodencePanagiota Triantafyllou16 Ethn. Antistaseos str, GR 53351, Thessaloniki, GreeceTel: +302310440100e-mail: [email protected]
1
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-1 ( ) D (non-obese diabetic) -DP (Bio-Breed diabetes-prone) . 80% -1 . (9,15) 0,4% , 3% -1 5% -1. 8% (20 ). O -1. , -1 100% 25% 50%(3,16). 44 183 -1 , 22.650 , 27% 3,8% (17). 134 53 38%, 24 6% 24 (18) (.
62
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63
D - -(13). D natural killers T-. . (linkage studies) - ( ) (as-sociation studies) - (1-3,16). (genome-wide assotiation studies) (1-3,10,13,16,22-24,25-31) (. 2). HLA 6p21, 50% -1 , 11p15, PTPN22 1p13 CTLA4 2q33. , 60 -1 (. 2)(24).
HLA 6 6p21.3 -1(3,10,13,21-24,27). HLA (Human Leukocyte Antigens) . HLA ( , )(27). -1 DR DQ(16,23-27). LA (): DR4-DQ8 DR3-DQ2, 90% -1(16,25-27). DR15-DQ6 1% -1 20% -1(16,25,30-32). DR-DQ -1. . , , -1 (22-23). CD8+ - (16,10,13,22,26). HLA-DR HLA-DQ -1 (33-37). , DR3 / DQ2 -. HLA-DR4 DQ8 . HLA . . - OD -1.
64
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-1 (INS) 11p15.5(16,23,38). DNA (DNA sequencing) (upstream) (VNTR: variable number of tandem repeat). INS VNTR (39). 3 (39). -1 (28-44 ), (138-159 ) (40). , (16). - . INS VNTR, , -1. INS VNTR . ( -), , -1 (10,16,26,32,41-42).
To -1 - (10,13,15,16,21,23-24,26). PTPN22, o 1p13 , Lyp. Lyp - -. Bottini . (43) 1858C/T -1, (44-48). 30,6% -1 21,3% . -1, . , , (49). , PTPN22 . -1 1858C/T - (10).
65
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(linkage studies) -1, NOD CTLA4 (cytotoxic T-lymphocyte-associated antigen 4) 2q33 -1(50). CTLA4 -, -. CTLA4 - -1(10,16,21,23-24,26).
HLA-DR HLA-DQ, , (7-9,15-16,21,51-58). (DR3-DQ2 DR4-DQ8) 1 20 -1 15 (59). / -1 55% (9,15-16,61). 2,3% . DAISY(51), -1 Denver 50% 5 . HLA , HLA. . , ( HLA) (3,23-24). , . , DAISY(51) . , 40% , 1 30 . . , -1, . -1. -. screening test .
66
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HLA -1. -HLA . -. , -1.
1. Baker PR 2nd, Steck AK. The past, present, and future of genetic associations in type 1 diabetes. Curr Diab Rep 2011; 11(5):445-53.
2. Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem 2011; 57(2):176-85.
3. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. The New England jour-nal of medicine 2009; 360: 1646-1654.
4. Eisenbarth GS, Jeffrey J. The natural history of type 1A diabetes. Arquivos brasileiros de endocrinologia e metabologia 2008; 52: 146-155.
5. Nagamine K, Peterson P, Scott HS et al. Positional cloning of the APECED gene. Nature genetics 1997; 17: 393-398.
6. Bennett CL, Ochs HD. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenom-ena. Current opinion in pediatrics 2001; 13: 533-538.
7. Stadinski B, Kappler J, Eisenbarth GS. Molecular targeting of islet autoantigens. Immu-nity 2010; 32: 446-456.
8. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010; 464: 1293-1300.
9. Bonifacio E, Ziegler AG. Advances in the prediction and natural history of type 1 diabe-tes. Endocrinology and metabolism clinics of North America 2010; 39: 513-525.
10. Mehers KL, Gillespie KM. The genetic basis for type 1 diabetes. British medical bulletin 2008; 88: 115-129.
11. Wenzlau JM, Juhl K, Yu L et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 17040-17045.
12. Zhang Y, Bandala-Sanchez E, Harrison LC. Revisiting regulatory T cells in type 1 diabe-tes. Curr Opin Endocrinol Diabetes Obes 2012; 19(4):271-8.
13. Ounissi-Benkalha H, Polychronakos C. The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends in molecular medicine 2008; 14: 268-275.
14. Santamaria P. The long and winding road to understanding and conquering type 1 diabetes. Immunity 2010; 32: 437-445.
15. Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity 2010; 32: 468-478.
16. Polychronakos C, Li Quan. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Gen 2011;12: 781-792.
67
17. Hyttinen V, Kaprio J, Kinnunen L et al. Genetic liability of type 1 diabetes and the on-set age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes 2003; 52: 1052-1055.
18. Redondo MJ, Fain PR, Eisenbarth GS. Genetics of type 1A diabetes. Recent progress in hormone research 2001; 56: 69-89.
19. Gale EA. The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002; 51: 3353-3361.
20. Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of Type I diabetes--the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395-1403.
21. Todd JA. Etiology of type 1 diabetes. Immunity 2010; 32: 457-467.
22. Noble JA, Valdes AM. Genetics of the HLA Region in the Prediction of Type 1 Diabe-tes. Curr Diab Rep 2011;11:533-542.
23. Noble JA, Erlich HA Genetics of type 1 diabetes. Cold Spring Harb Perspect Med 2012;2:a007732.
24. Morahan G. Insights into type 1 diabetes provided by genetic analyses. Curr Opin En-docrinol Diabetes Obes 2012;19: 263-270.
25. Bartsocas CS, Gerasimidi-Vazeou A. Genetics of type 1 diabetes mellitus. Pediatric en-docrinology reviews : PER 2006; 3 Suppl 3: 508-513.
26. Kim MS, Polychronakos C. Immunogenetics of type 1 diabetes. Hormone research 2005; 64: 180-188.
27. Polychronakos C. Animal models of spontaneous autoimmune diabetes: notes on their relevance to the human disease. Current diabetes reports 2004; 4: 151-154.
28. Grant SF, Hakonarson H. Genome-wide association studies in type 1 diabetes. Current diabetes reports 2009; 9: 157-163.
29. Bergholdt R. Understanding type 1 diabetes genetics - approaches for identification of susceptibility genes in multi-factorial diseases. Danish medical bulletin 2009; 56: 1-39.
30. Rubio-Cabezas O, Argente J. Current insights into the genetic basis of diabetes mel-litus in children and adolescents. Journal of pediatric endocrinology & metabolism : JPEM 2008; 21: 917-940.
31. Aribi M. Candidate genes implicated in type 1 diabetes susceptibility. Current diabe-tes reviews 2008; 4: 110-121.
32. Pugliese A, Zeller M, Fernandez A, Jr. et al. The insulin gene is transcribed in the hu-man thymus and transcription levels correlated with allelic variation at the INS VNTR-ID-DM2 susceptibility locus for type 1 diabetes. Nature genetics 1997; 15: 293-297.
33. Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. An-nual review of immunology 2005; 23: 447-485.
34. Nishimoto H, Kikutani H, Yamamura K, Kishimoto T. Prevention of autoimmune insuli-tis by expression of I-E molecules in NOD mice. Nature 1987; 328: 432-434.
35. Lund T, OReilly L, Hutchings P et al. Prevention of insulin-dependent diabetes melli-tus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature 1990; 345: 727-729.
36. Wherrett DK, Singer SM, McDevitt HO. Reduction in diabetes incidence in an I-Ag7 transgenic nonobese diabetic mouse line. Diabetes 1997; 46: 1970-1974.
68
1
37. Uehira M, Uno M, Kurner T et al. Development of autoimmune insulitis is prevented in E alpha d but not in A beta k NOD transgenic mice. International immunology 1989; 1: 209-213.
38. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associ-ated with insulin-dependent diabetes mellitus. Diabetes 1984; 33: 176-183.
39. Bennett ST, Lucassen AM, Gough SC et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature genetics 1995; 9: 284-292.
40. Chung HR, Yang SW, Shin SH, Park KS, Lee YA, Kim JH et al. The association of vari-able number of tandem repeats of the insulin gene with susceptibility to type 1 diabetes among Korean subjects. Diab Metab Res Rev 2010;26:474-480.
41. Vafiadis P, Bennett ST, Todd JA et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature genetics 1997; 15: 289-292.
42. Polychronakos C. Zeroing in on the target. Pediatric diabetes 2010; 11: 2-3.
43. Bottini N, Musumeci L, Alonso A et al. A functional variant of lymphoid tyrosine phos-phatase is associated with type I diabetes. Nature genetics 2004; 36: 337-338.
44. Qu H, Tessier MC, Hudson TJ, Polychronakos C. Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. Journal of medical genetics 2005; 42: 266-270.
45. Smyth D, Cooper JD, Collins JE et al. Replication of an association between the lym-phoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020-3023.
46. Onengut-Gumuscu S, Ewens KG, Spielman RS, Concannon P. A functional polymor-phism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in mul-tiplex families. Genes and immunity 2004; 5: 678-680.
47. Ladner MB, Bottini N, Valdes AM, Noble JA. Association of the single nucleotide poly-morphism C1858T of the PTPN22 gene with type 1 diabetes. Human immunology 2005; 66: 60-64.
48. Hill RJ, Zozulya S, Lu YL et al. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Experimental hematology 2002; 30: 237-244.
49. Bottini N, Vang T, Cucca F, Mustelin T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Seminars in immunology 2006; 18: 207-213.
50. Nistico L, Buzzetti R, Pritchard LE et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Human mo-lecular genetics 1996; 5: 1075-1080.
51. Barker JM, Barriga KJ, Yu L et al. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). The Journal of clinical endocrinology and metabolism 2004; 89: 3896-3902.
52. Eisenbarth GS. Prediction of type 1 diabetes: the natural history of the prediabetic period. Advances in experimental medicine and biology 2004; 552: 268-290.
53. Bagley J, Paez-Cortez J, Tian C, Iacomini J. Gene therapy in type 1 diabetes. Critical reviews in immunology 2008; 28: 301-324.
54. Baschal EE, Eisenbarth GS. Extreme genetic risk for type 1A diabetes in the post-ge-nome era. Journal of autoimmunity 2008; 31: 1-6.
69
55. McDevitt HO, Unanue ER. Autoimmune diabetes mellitus--much progress, but many challenges. Advances in immunology 2008; 100: 1-12.
56. Sherr J, Sosenko J, Skyler JS, Herold KC. Prevention of type 1 diabetes: the time has come. Na-ture clinical practice. Endocrinology & metabolism 2008; 4: 334-343.
57. Pugliese A, Gianani R, Moromisato R et al. HLA-DQB1*0602 is associated with dominant protec-tion from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diabetes 1995; 44: 608-613.
58. Luo X, Herold KC, Miller SD. Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity 2010; 32: 488-499.
59. Aly TA, Ide A, Humphrey K et al. Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes. Jour-nal of autoimmunity 2005; 25 Suppl: 40-45.
60. Aly TA, Ide A, Jahromi MM et al. Extreme genetic risk for type 1A diabetes. Proceedings of the National Academy of Sciences of the United States of America 2006; 103: 14074-14079.
2: -1(24).
PGM1
PTPN22 1
RGS1
IL10
, IL18RAP
Intergenic
IFIH1
CTLA4
HLA
BACH2
C6orf173
SKAP2
COBL
GLIS3
IL2RA
PRKCQ
/ (Mb) (SNP)
1
1
1
1
2
2
2
2
4
6
6
6
7
7
9
10
10
63.9
114.2
190.8
205
12.6
24.5
162.9
204.4
25.7
32.7
91
126.7
26.9
51
4.3
6.1
6.4
rs2269241
rs2476601
rs2816316
rs3024505
rs1534422
rs2165738
rs3747517
rs231727
rs10517086
rs9272346
rs11755527
rs9388489
rs7804356
rs4948088
rs7020673
rs12251307
rs947474
70
1
/ (Mb) (SNP)
RNLS
INS
CD69
12q13
SH2B3
ZFP36L1
CTSH
CLEC16A
ORF; PRM3; TNP2
UMOD
IL27
CTRB2
DNAH2
GSDMB, ORMDL3
SMARCE1
PTPN2
PRKD2
SIRPG
Ubash3a
LOC729980
C1QTNF6
GAB3
EFR3B
AFF3
SLC11A1
10
11
12
12
12
14
14
15
16
16
16
16
16
17
17
17
18
19
20
21
22
22
X
2
2
2
90
2.1
9.8
54.8
111
68.3
97.6
77
11.1
11.3
20.3
28.4
73.8
7.6
35.3
36
12.8
51.9
1.6
42.7
28.9
35.9
153.6
25.3
100.2
2219.3
rs10509540
rs689
rs4763879
rs2292239; rs1701704
rs17696736
rs1465788
rs4900384
rs3825932
rs12708716
rs416603
rs12444268
rs4788084
rs7202877
rs16956936
rs2290400
rs7221109
rs2542151
rs425105
rs2281808
rs876498
rs5753037
rs229541
rs2664170
rs478222
rs9653442
rs3731865
71
/ (Mb) (SNP)
CCR5
IL2
CAPSL
LOC729653
HLA
AGER
TNFAIP3
TAGAP
6q27
IKZF1
CUX2
LMO7
DLK1
RASGRP1
CCR7
Trp53
FHOD3
CD226 18
PRKD2
FUT2
3
4
5
6
6
6
6
6
6
7
12
13
14
15
17
17
18
18
19
19
3 46.3
123.3
35.9
29.5
31.3
32.1
138
159.4
170.4
50.5
111.4
76
100.4
36.7
38.8
7.6
34.2
67.5
47.2
49.2
rs11711054
rs2069763
rs6897932
rs1592410
rs3094663
rs9469089
rs10499194
rs1738074
rs924043
rs10272724
rs1265564
rs539514
rs941576
rs17574546
rs7221109
n/a
rs2644261
rs763361
rs425105
rs601338
72
1
1: -1(4).
2: -1(53)
-
;
C-
C-
1973/4
1983/4
1988
1994
1998
2003
2004/5
2007/8
HLA
INS
HLA
CTLA-4
PTPN22
HLA
7
73
74
. 1, . 1, . 1, . 1, . 1, . 1, . 1, . 2, . 3, . -1, . 1
: (). () . : 48 (33 , 68,75%) 3,88 ( 0,37-13,97). (9 3 ).: (, , , HDL-- ) . , () ( ) HDL- ( 6 ), .: , , , - , , . , .
: , , .
Dysmetabolic syndrome manifestation is not related with therapy stages in acute lymphoblastic leukemia of childhood
E. Koultouki1, G. Trimis1, G. Lambrou1, M. Tsotra1, N. Tourkantoni1, K. Karamo-legou1, M. Adamaki1, J. Papassotiriou2, G. Chrousos3, F. Tzortzatou-Stathopou-lou1, M. Moschovi1
Background: Survivors of childhood cancer have an increased probability to present dys-metabolic syndrome (DS). Purpose of this study was to investigate the presence of DS in patients who undergo treatment for acute lymphoblastic leukemia (ALL) of childhood.
ORIGINAL ARTICLES
. 1
. 1
. 1
. 1
. 1
. 1
. 1
. -1
. 1
-, ,
. 2
,
. 3
, , ,
Abstract
75
& , 115 27, .. 2107467604, 6947193193Fax: 2107759167e-mail: [email protected] E. Koultouki MD PhDThivon & Livadias, 115 27, AthensTel. 2107467604, 6947193193Fax: 2107759167e-mail: [email protected]
E. Koultouki1
G. Trimis1
G. Lambrou1
M. Tsotra1
N. Tourkantoni1
K. Karamolegou1
M. Adamaki1
F. Tzortzatou-Stathopoulou1
M. Moschovi1
Haematology-Oncology Unit, 1st Department of Pediatrics, University of Athens, Aghia Sophia Childrens Hospital
J. Papassotiriou2
Department of Biochemistry, Aghia Sophia Childrens Hospital
G. Chrousos3
Endocrinology, Metabolism and Diabetes Units, First Department of Pediatrics, University of Athens, Aghia Sophia Childrens Hospital
Patients and Methods: The study included 48 patients with ALL (33 males, 68.7%) with a median age of 3.88 years (range 0.37-13.97). Measurements were done at diagnosis and in time intervals up to the end of therapy (9 measurements in 3 years).Results: During chemotherapy, no DS criteria (obesity, hypertriglyceridemia, hyperinsu-linemia, reduced HDL-cholesterol and hypertension) were detected in any patient. Values of these parameters were not correlated with treatment stages; however there was an increasing trend of body mass index (BMI) during therapy (till the end of follow-up) and a temporal increase of triglycerides together with a temporal decrease of HDL-cholesterol after the first cycle of therapy (up to 6 months), without overcoming the statistical sig-nificance.Conclusions: Young survivors of childhood ALL are at risk for obesity, insulin resistance, dyslipidemia, hypertension and, finally, full DS installation, several years after the comple-tion of therapy, without being evident during therapy, up to its completion (3 years). DS development soon after the end of chemotherapy and trends of increase or decrease of these markers during therapy indicate the need of individual approach and treatment of children with ALL, in order to prevent DS development.
Key words: children, leukemia treatment, dysmetabolic syndrome.
, , (1-3). , . , (GH), , , , , (4-6). 9.6 . , . , 45 . (7-10). , 6 (11). . , . , , -. . ,
=
=
=
=
=
76
-
3 (2006-2009), 62 - . , 6 , , 5 . , 48 (33 , 68,7%). 3,88 ( 0.37-13.97) 4,97 . : ( 0, CI 95%, 00.13), ~28 (CI 95%, 281.79), ~60 (CI 95%, 603.94), ~6 (180 , CI 95%, 1806.77), ~1 (365 , CI 95%, 3656.45), 1,5 (547 , CI 95%, 54710.52), ~2 (730 , CI 95%, 73034.95), 2,5 (912 , CI 95%, 91272) ~3 (1095 , CI 95%, 1095107.6). HOPDA (Haematology/Oncology Paediatric Department of Athens University) (HOPDA97) (2,12). ( 1). 28 . , , . . , , , . .
, , () . . 10-14 , . -700 C . 0,5 0,5 . . (kg/m2) () , (13). >97 , >75
77
Lipid Research Clinics Programme. , (15,16). . , C- (CRP) A (SAA), latex BN ProSpec (Dade Behring, Liederbach, ). (T4 TSH) Bayer ACS180 (Bayer Corporation, Tarry-town, NY, USA). IGF-1 chemi-luminescences (Nichols Institute Diagnostics, CA, USA). HbA1c HPLC (HA8121 HPLC system, Arkray Inc, Kyoto, Japan). (homeostasis model assessment, HOMA), ( x ) 22.5, U/ml mmol/L (17).
, . . , (National Choles-terol Education Programs Adult Treatment ) , (18). , . HOMA , (17). 1.
1: * .
HDL-C
>97
>95
95 (>18.7 U/ml 5-25 )
>95 ,
* : HDL-C: HDL-: , :
78
( ) ( ). Fisher (Fishers exact test) . t-test . O Pearson, Kendalls Tau Pearson. Cox . p
79
2. - (BMI) (A), (B), (C), HDL LDL (D) LDH ALP (E). LDH , .
(. -). . , , ( 1). . . ( 2) . ( 2). ~28 , ( 256.36, CI 95% 72.52, 78.51, CI 95% 78.51), . . ( 2C), , . HDL LDL ( 2D). LDH ( 2E). , . , . LDH . LDH ALP ( 2E).
80
Females
15
1
4
5
2
2
1
Total
48
3
13
13
9
2
7
% (overall)
31.25%
2.08%
8.33%
10.42%
4.17%
4.17%
2.08%
Median
3.88
0.72
2.45
3.83
5.78
7.63
12.82
%(within Group)
31.25%
33.33%
30.77%
38.46%
22.22%
100.00%
14.29%
StDev
3.42
0.20
0.39
0.46
0.56
0.28
1.74
Median
3.83
0.72
2.52
3.83
5.96
7.63
10.14
CI 95%
0.97
0.23
0.21
0.25
0.37
0.39
1.29
StDev
2.48
0.00
0.29
0.60
0.71
0.28
0.00
CI 95%
1.25
0.28
0.52
0.98
0.39
TABLE 2
2: . . .
Age at Diagnosis
Totals
Age
81
Total
48
3
13
13
9
2
average
4.97
0.64
2.45
3.69
5.87
7.63
StDev
3.42
0.20
0.39
0.46
0.56
0.28
CI 95%
0.97
0.23
0.21
0.25
0.37
0.39
Females
15
1
4
5
2
2
% (overall)
31.25%
2.08%
8.33%
10.42%
4.17%
4.17%
%(within Group)
31.25%
33.33%
30.77%
38.46%
22.22%
100.00%
Median
4.46
0.72
2.50
3.77
5.96
7.63
StDev
2.48
0.00
0.29
0.60
0.71
0.28
CI 95%
1.25
0.28
0.52
0.98
0.39
Age at Diagnosis
Totals
Age
82
, , . ( 3A), , . , ( 3B-3D). . SGOT GT
3. /.
3. /.
, SGPT . . LDH ( 3E). , ( 3F, 3G).
83
- . IGF1 . , , Pearson. , . , IGF1 ALP . GT . GT, LDH . , , , IGF1 ( 5). IGF1 GT, , . LDH. ( 5B). , .
4. (A), (B, C) LDH (D).
5. , IGF1 GT, , , LDL.
. , . . . , ( 4). ~28 , ( 4B, 4C). 3 5 . LDH 1-3 9 ( 4D). , , , .
84
6. (A). (B) LDL (C) ALP (D) .
. , . . 6 , ( 6), ( 6B) HDL LDL ( 6C) ALP LDH ( 6D). (R2=0.7), HDL (R2=0.81) ALP (R2=0.901). , , . .
() . , , HDL-,