Download PDF
Eur J Pediatr Surg 2005; 15(4): 229-235
DOI: 10.1055/s-2005-865766
Original Article

Georg Thieme Verlag KG Stuttgart, New York · Masson Editeur Paris

The Basic Biology of Apoptosis and its Implications for Pediatric Surgery

I. Sukhotnik1 , A. Bernshteyn1 , J. G. Mogilner1
  • 1Department of Pediatric Surgery, Rappaport Faculty of Medicine, Technion, Bnai Zion Medical Center, Haifa, Israel
Further Information

Publication History

Received: July 15, 2004

Accepted after Revision: July 23, 2004

Publication Date:
14 September 2005 (online)

Also available at
    Permissions and Reprints

Abstract

Apoptosis, or programmed cell death, is an evolutionarily conserved and highly regulated process of nonfunctional cell death. Through this process, the body disposes of unwanted cells by self-destruction: it is our final defense against damaged cells. In the last decades, many of the essential pathways that control this phenomenon have been elucidated. Apoptosis plays an important role in developmental processes, as well as in cellular homeostasis. This process is known to be accelerated or diminished in many pathologic states. Therefore the understanding of apoptotic regulation has significant clinical ramifications. This article reviews the basic understanding of programmed cell death with respect to areas of interest to pediatric surgeons, including: Hirschsprung disease, intestinal atresias, testicular disorders, short bowel syndrome, ischemia-reperfusion injury and pediatric oncology. Pro or antiapoptotic interventions may become a future target for cell and organ protection in patients suffering from these diseases.

Résumé

Buts: L'apoptose ou la mort cellulaire programmée est un processus très important et précisément régulé de la mort des cellules non fonctionnelles. Par ce processus, le corps dispose de moyens d'autodestruction des cellules non désirées et c'est notre plus grande défense contre les cellules endommagées. Dans les dernières décades, nombre des mécanismes qui contrôlent ce phénomène ont été expliqués. L'apoptose jour un rôle important dans les processus de développement comme dans l'homéostasie cellulaire. Ce processus est connu pour être accéléré ou diminué dans de nombreux états pathologiques. Néanmoins, la compréhension de la régulation de l'apoptose a de multiples ramifications. Cet article revoit la compréhension basique de la mort cellulaire programmée avec des points particuliers d'intérêt pour le chirurgien-pédiatre incluant la Maladie de Hirschsprung, l'atrésie intestinale, les désordres testiculaires, le grêle court, le traumatisme de l'ischémie reperfusion et l'oncologie pédiatrique. Le traitement pour ou anti apoptose peuvent devenir les futures cibles pour protéger les cellules et l'organe chez les patients souffrant de ces maladies.

Resumen

La apoptosis o muerte celular programada es un proceso conservado evolutivamente y altamente regulado de muerte de células no funcionales. Así elimina el cuerpo por autodestrucción células indeseadas siendo el mejor mecanismo de defensa contra las células dañadas. En las últimas décadas han sido elucidadas muchas de las vías que controlan este fenómeno. La apoptosis juega un papel importante en procesos de desarrollo así como en homeostasis celular. Se sabe que está aumentada o disminuida en muchas condiciones patológicas. Por lo tanto la comprensión de la regulación de la apoptosis tiene repercusiones clínicas significativas. Este artículo revisa el conocimiento básico de la muerte celular programada con respecto a áreas de interés para cirujanos pediatras que incluyen la enfermedad de Hirschsprung, las atresias intestinales, trastornos testiculares, intestino corto, isquemia-reperfusión y oncología. Intervenciones pro o anti-apoptóticas pueden constituir objetivos futuros para la protección de células y órganos en pacientes que sufren estas enfermedades.

Zusammenfassung

Die Apoptosis oder der programmierte Zelltod ist ein evolutionärer, erhaltender und hoch regulierter Prozess des nicht funktionellen Zelltods. Durch diesen Prozess stößt der Körper unerwünschte Zellen durch Selbstzerstörung ab. Die Apoptosis ist somit eine der wichtigsten Abwehrmaßnahmen gegen Zellschäden. In den letzten Jahrzehnten wurden viele der wichtigsten Verfahrensweisen dieses Phänomens aufgeklärt. Dabei zeigte es sich, dass die Apoptose eine zentrale Rolle bei Entwicklungsprozessen und der zellulären Homeostase spielt. Es ist bekannt, dass der Prozess viele pathologische Stadien beschleunigen oder verlangsamen kann. Deshalb hat das Verständnis der apoptotischen Regulationsmechanismen eine entscheidende klinische Bedeutung. In der vorliegenden Arbeit werden die Grundlagen des programmierten Zelltodes im Hinblick auf kinderchirurgische Aspekte dargelegt. Insbesondere die Hirschsprungsche Erkrankung, intestinale Atresien, Hodenerkrankungen, das Kurzdarmsyndrom, der Ischämie-Reperfusionsschaden und die pädiatrische Onkologie werden angesprochen. Pro- oder antiapoptotische Maßnahmen werden in Zukunft das Ziel sein, um organschützend bei Patienten, die an diesen Erkrankungen leiden, vorgehen zu können.

Key words

Apoptosis - cell death - diseases - pediatric surgery

Mots-clés

Apoptose - mort cellulaire - maladies - chirurgie pédiatrique

Palabras clave

Apoptosis - muerte celular - enfermedades - cirugía pediátrica

Schlüsselwörter

Apoptosis - Zelltod - Kinderchirurgie - Regulationsmechanismen

References

  • 1 Baccetti B, Collodel G, Piomboni P. Apoptosis in human ejaculated sperm cells (notulae seminologicae 9).  Submicrosc Cytol Pathol. 1996;  28 587-596
    PubMedGoogle Scholar
  • 2 Bardeesy N, Beckwith J B, Pelletier J. Clonal expansion and attenuated apoptosis in Wilms' tumors are associated with p53 gene mutations.  Cancer Res. 1995;  55 215-219
    PubMedGoogle Scholar
  • 3 Bates M D, Deutsch G H. Molecular insights into congenital disorders of the digestive system.  Pediatr Dev Pathol. 2003;  6 284-298
    PubMedGoogle Scholar
  • 4 Bessis M C. Death of a Cell, 16-mm film. New York; Swift Motion Picture Laboratories 1958
    Google Scholar
  • 5 Beierle E A, Dai W, Langham Jr M R, Chen M K. Neuroblastoma, apoptosis, and growth factors.  Am Surg. 2003;  69 28-31
    PubMedGoogle Scholar
  • 6 Beierle E A, Dai W, Iyengar R, Langham Jr M R, Copeland 3rd E M. Differential expression of bcl-2 and bax may enhance neuroblastoma survival.  J Pediatr Surg. 2003;  38 486-491
    CrossrefPubMedGoogle Scholar
  • 7 Berensztein E B, Sciara M I, Rivarola M A, Belgorosky A. Apoptosis and proliferation of human testicular somatic and germ cells during prepuberty: high rate of testicular growth in newborns mediated by decreased apoptosis.  J Clin Endocrinol Metab. 2002;  87 5113-5118
    CrossrefPubMedGoogle Scholar
  • 8 Boise L H, Gottschalk A R, Quintans J, Thompson C B. Bcl-2 and bcl-2-related proteins in apoptosis regulation.  Curr Top Microbiol Immunol. 1995;  200 107-121
    PubMedGoogle Scholar
  • 9 Bordeaux M C, Forcet C, Granger L, Corset V, Bidaud C, Billaud M, Bredesen D E, Edery P, Mehlen P. The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.  EMBOJ. 2000;  19 4056-4063
    PubMedGoogle Scholar
  • 10 Cheng W, Tam P K. Apoptosis in murine duodenum during embryonic development.  Pediatr Surg Int. 2000;  16 485-487
    CrossrefPubMedGoogle Scholar
  • 11 Delatte S J, Hazen-Martin D J, Re G G, Kelly J R, Sutphin A, Tagge E P. Restoration of p53 function in anaplastic Wilms' tumor.  J Pediatr Surg. 2001;  36 43-50
    CrossrefPubMedGoogle Scholar
  • 12 Di Bartolomeo S, Di Sano F, Piacentini M, Spinedi A. Apoptosis induced by doxorubicin in neurotumor cells is divorced from drug effects on ceramide accumulation and may involve cell cycle-dependent caspase activation.  Neurochem. 2000;  75 532-539
    PubMedGoogle Scholar
  • 13 Dijkstra C D. Nobel Prize for Physiology or Medicine 2002 is awarded for research into the genetic regulation of organ development and programmed cell death.  Ned Tijdschr Geneeskd. 2002;  146 2525-2527
    PubMedGoogle Scholar
  • 14 Englert C, Maheswaran S, Garvin A J, Kreidberg J, Haber D A. Induction of p21 by the Wilms' tumor suppressor gene WT1.  Cancer Res. 1997;  57 1429-1434
    PubMedGoogle Scholar
  • 15 Erkkila K, Suomalainen L, Wikstrom M, Parvinen M, Dunkel L. Chemical anoxia delays germ cell apoptosis in the human testis.  Biol Reprod. 2003;  69 617-626
    CrossrefPubMedGoogle Scholar
  • 16 Flemming W. Historical paper. Contributions to the knowledge of the cell and its vital processes.  J Cell Biol. 1965;  25 1-69
    PubMedGoogle Scholar
  • 17 Foley J G, Bard J B. Apoptosis in the cortex of the developing mouse kidney.  J Anat. 2002;  201 477-484
    CrossrefPubMedGoogle Scholar
  • 18 Fujisawa M, Hiramine C, Tanaka H, Okada H, Arakawa S, Kamidono S. Decrease in apoptosis of germ cells in the testes of infertile men with varicocele.  World J Urol. 1999;  17 296-300
    CrossrefPubMedGoogle Scholar
  • 19 Gallo G, Giarnieri E, Bosco S, Cappelli C, Alderisio M, Giovagnoli M R, Giordano A, Vecchione A. Aberrant bcl-2 and bax protein expression related to chemotherapy response in neuroblastoma.  Anticancer Res. 2003;  23 777-784
    PubMedGoogle Scholar
  • 20 Garaventa A, Luksch R, Piccolo M S, Cavadini E, Montaldo P G, Pizzitola M R, Boni L, Ponzoni M, Decensi A, Bernardi B D, Bellani F F, Formelli F. Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma.  Clin Cancer Res. 2003;  9 2032-2039
    PubMedGoogle Scholar
  • 21 Garcia-Gil M, Pesi R, Perna S, Allegrini S, Giannecchini M, Camici M, Tozzi M G. 5′-aminoimidazole-4-carboxamide riboside induces apoptosis in human neuroblastoma cells.  Neuroscience. 2003;  117 811-820
    CrossrefPubMedGoogle Scholar
  • 22 Hewitt S M, Hamada S, McDonnell T J, Rauscher 3rd F J. Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1.  Cancer Res. 1995;  55 5386-5389
    PubMedGoogle Scholar
  • 23 Hikim A P, Lue Y, Yamamoto C M, Vera Y, Rodriguez S, Yen P H, Soeng K, Wang C, Swerdloff R S. Key apoptotic pathways for heat-induced programmed germ cell death in the testis.  Endocrinology. 2003;  144 3167-3175
    CrossrefPubMedGoogle Scholar
  • 24 Horton W A. Skeletal development: insights from targeting the mouse genome.  Lancet. 2003;  362 560-569
    CrossrefPubMedGoogle Scholar
  • 25 Igarashi P. Transcription factors and apoptosis in kidney development.  Curr Opin Nephrol Hypertens. 1994;  3 308-317
    PubMedGoogle Scholar
  • 26 Kapur R P. Early death of neural crest cells is responsible for total enteric aganglionosis in Sox10(Dom)/Sox10(Dom) mouse embryos.  Pediatr Dev Pathol. 1999;  2 559-569
    CrossrefPubMedGoogle Scholar
  • 27 Kerr J F. Shrinkage necrosis: a distinct mode of cellular death.  J Pathol. 1971;  105 13-20
    PubMedGoogle Scholar
  • 28 Kerr J F, Wyllie A H, Currie A R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.  Br J Cancer. 1972;  26 239-257
    CrossrefPubMedGoogle Scholar
  • 29 Khloponin P A, Patiuchenko O LU. Cardiomyogenesis in the embryonic period of human development.  Morfologiia. 2003;  123 50-54
    PubMedGoogle Scholar
  • 30 Kimura M, Itoh N, Takagi S, Sasao T, Takahashi A, Masumori N, Tsukamoto T. Balance of apoptosis and proliferation of germ cells related to spermatogenesis in aged men.  J Androl. 2003;  24 185-191
    PubMedGoogle Scholar
  • 31 Kubota Y, Shimotake T, Yanagihara J, Iwai N. Development of anorectal malformations using etretinate.  J Pediatr Surg. 1998;  33 127-129
    CrossrefPubMedGoogle Scholar
  • 32 Lau L, Tai D, Weitzman S, Grant R, Baruchel S, Malkin D. Factors influencing survival in children with recurrent neuroblastoma.  J Pediatr Hematol Oncol. 2004;  26 227-232
    PubMedGoogle Scholar
  • 33 Levy Y S, Streifler J Y, Panet H, Melamed E, Offen D. Hemin-induced apoptosis in PC12 and neuroblastoma cells: implications for local neuronal death associated with intracerebral hemorrhage.  Neurotox Res. 2002;  4 609-616
    CrossrefPubMedGoogle Scholar
  • 34 Lo W D, Akhmametyeva E M, Zhu L, Friesen P D, Chang L S. Induction of apoptosis by the p53-related p73 and partial inhibition by the baculovirus-encoded p35 in neuronal cells.  Brain Res Mol Brain Res. 2003;  113 1-12
    PubMedGoogle Scholar
  • 35 Lovat P E, Ranalli M, Corazzari M, Raffaghello L, Pearson A D, Ponzoni M, Piacentini M, Melino G, Redfern C P. Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma.  J Cell Biochem. 2003;  89 698-708
    CrossrefPubMedGoogle Scholar
  • 36 Lysiak J J, Nguyen Q A, Kirby J L, Turner T T. Ischemia-reperfusion of the murine testis stimulates the expression of proinflammatory cytokines and activation of C-Jun N-terminal kinase in a pathway to E-selectin expression.  Biol Reprod. 2003;  69 202-210
    CrossrefPubMedGoogle Scholar
  • 37 Maheswaran S, Englert C, Bennett P, Heinrich G, Haber D A. The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis.  Genes Dev. 1995;  9 2143-2156
    PubMedGoogle Scholar
  • 38 Majno G, Joris I. Apoptosis, oncosis and necrosis. An overview of cell death.  Am J Pathol. 1995;  146 3-15
    PubMedGoogle Scholar
  • 39 Manie S, Santoro M, Fusco A, Billaud M. The RET receptor: function in development and dysfunction in congenital malformation.  Trends Genet. 2001;  17 580-589
    CrossrefPubMedGoogle Scholar
  • 40 Marmar J L. The pathophysiology of varicoceles in the light of current molecular and genetic information.  Hum Reprod Update. 2001;  7 461-472
    CrossrefPubMedGoogle Scholar
  • 41 Mayhew T M, Myklebust R, Whybrow A, Jenkins R. Epithelial integrity, cell death and cell loss in mammalian small intestine.  Histol Histopathol. 1999;  14 257-267
    PubMedGoogle Scholar
  • 42 Milani D, Zauli G, Rimondi E, Celeghini C, Marmiroli S, Narducci P, Capitani S, Secchiero P. Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathways in SK-N-MC neuronal cells.  J Neurochem. 2003;  86 126-135
    CrossrefPubMedGoogle Scholar
  • 43 Modi D N, Sane S, Bhartiya D. Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads.  Mol Hum Reprod. 2003;  9 219-225
    CrossrefPubMedGoogle Scholar
  • 44 Mograbi B, Bocciardi R, Bourget I, Juhel T, Farahi-Far D, Romeo G, Ceccherini I, Rossi B. The sensitivity of activated Cys Ret mutants to glial cell line-derived neurotrophic factor is mandatory to rescue neuroectodermic cells from apoptosis.  Mol Cell Biol. 2001;  21 6719-6730
    CrossrefPubMedGoogle Scholar
  • 45 Nahreini P, Andreatta C, Hanson A, Prasad K N. Concomitant differentiation and partial proteasome inhibition trigger apoptosis in neuroblastoma cells.  J Neurooncol. 2003;  63 15-23
    CrossrefPubMedGoogle Scholar
  • 46 Nakamuta N, Kobayashi S. Expression of p63 in the testis of mouse embryos.  J Vet Med Sci. 2003;  65 853-856
    CrossrefPubMedGoogle Scholar
  • 47 Natzker S, Heinemann T, Figueroa-Perez S, Schnieders B, Schmidt R R, Sandhoff K, van Echten-Deckert G. Cis-4-methylsphingosine phosphate induces apoptosis in neuroblastoma cells by opposite effects on p38 and ERK mitogen-activated protein kinases.  Biol Chem. 2002;  383 1885-1894
    CrossrefPubMedGoogle Scholar
  • 48 Nicholson D W, Ali A, Thornberry N A, Vaillancourt J P, Ding C K, Gallant M, Gareau Y, Griffin P R, Labelle M, Lazebnik Y A. et al . Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.  Nature. 1995;  376 37-43
    CrossrefPubMedGoogle Scholar
  • 49 Orford J, Manglick P, Cass D T, Tam P P. Mechanisms for the development of esophageal atresia.  J Pediatr Surg. 2001;  36 985-994
    CrossrefPubMedGoogle Scholar
  • 50 Pignatelli M, Luna-Medina R, Perez-Rendon A, Santos A, Perez-Castillo A. The transcription factor EGR-1 promotes apoptosis of neuroblastoma cells.  Biochem J. 2003;  373 739-746
    CrossrefPubMedGoogle Scholar
  • 51 Qi M, Ikematsu S, Ichihara-Tanaka K, Sakuma S, Muramatsu T, Kadomatsu K. Midkine rescues Wilms' tumor cells from cisplatin-induced apoptosis: regulation of bcl-2 expression by Midkine.  J Biochem (Tokyo). 2000;  127 269-277
    PubMedGoogle Scholar
  • 52 Puri P, Darton D, O'Donnell B. Prepubertal testicular torsion: subsequent fertility.  J Pediatr Surg. 1985;  20 598-601
    PubMedGoogle Scholar
  • 53 Re G G, Hazen-Martin D J, El Bahtimi R, Brownlee N A, Willingham M C, Garvin A J. Prognostic significance of Bcl-2 in Wilms' tumor and oncogenic potential of Bcl-X(L) in rare tumor cases.  Int J Cancer. 1999;  84 192-200
    CrossrefPubMedGoogle Scholar
  • 54 Seguier-Lipszyc E, El-Ghoneimi A, Brinon C, Florentin A, Simonneau M, Aigrain Y, Peuchmaur M. GDNF expression in Wilms' tumor.  Urol. 2001;  165 2269-2273
    PubMedGoogle Scholar
  • 55 Shiraishi K, Yoshida K, Naito K. Activation of endothelial nitric oxide synthase in contralateral testis during unilateral testicular torsion in rats.  Arch Androl. 2003;  49 179-190
    PubMedGoogle Scholar
  • 56 Simsek F, Turkeri L, Cevik I, Bircan K, Akdas A. Role of apoptosis in testicular tissue damage caused by varicocele.  Arch Esp Urol. 1998;  51 947-950
    PubMedGoogle Scholar
  • 57 Sun F, Akazawa S, Sugahara K, Kamihira S, Kawasaki E, Eguchi K, Koji T. Apoptosis in normal rat embryo tissues during early organogenesis: the possible involvement of bax and bcl-2.  Arch Histol Cytol. 2002;  65 145-157
    PubMedGoogle Scholar
  • 58 Takamizawa S, Scott D, Wen J, Grundy P, Bishop W, Kimura K, Sandler A. The survivin:fas ratio in pediatric renal tumors.  J Pediatr Surg. 2001;  36 37-42
    CrossrefPubMedGoogle Scholar
  • 59 Tanaka H, Fujisawa M, Tanaka H, Okada H, Kamidono S. Apoptosis-related proteins in the testes of infertile men with varicocele.  BJU Int. 2002;  89 905-909
    CrossrefPubMedGoogle Scholar
  • 60 Tanaka K, Granata C, Wang Y, O'Briain D S, Puri P. Apoptosis and bcl-2 oncogene expression in Wilms' tumor.  Pediatr Surg Int. 1999;  15 243-247
    CrossrefPubMedGoogle Scholar
  • 61 Thompson C B. Apoptosis in the pathogenesis and treatment of disease.  Science. 1995;  267 1456-1462
    CrossrefPubMedGoogle Scholar
  • 62 Thompson H J, Strange R, Schedin P J. Apoptosis in the genesis and prevention of cancer.  Cancer Epidemiol Biomarkers Prev. 1992;  1 597-602
    PubMedGoogle Scholar
  • 63 Toder V, Carp H, Fein A, Torchinsky A. The role of pro- and anti-apoptotic molecular interactions in embryonic maldevelopment.  Am J Reprod Immunol. 2002;  48 235-244
    CrossrefPubMedGoogle Scholar
  • 64 Tomomasa H, Adachi Y, Oshio S, Umeda T, Irie H, Ishikawa H. Germ cell apoptosis in undescended testis: the origin of its impaired spermatogenesis in the TS inbred rat.  Urol. 2002;  168 343-347
    PubMedGoogle Scholar
  • 65 Turner T T, Tung K S, Tomomasa H, Wilson L W. Acute testicular ischemia results in germ cell-specific apoptosis in the rat.  Biol Reprod. 1997;  57 1267-1274
    CrossrefPubMedGoogle Scholar
  • 66 van Golen C M, Soules M E, Grauman A R, Feldman E L. N-Myc overexpression leads to decreased beta1 integrin expression and increased apoptosis in human neuroblastoma cells.  Oncogene. 2003;  22 2664-2673
    CrossrefPubMedGoogle Scholar
  • 67 Voigt A, Zintl F. Effects of retinoic acid on proliferation, apoptosis, cytotoxicity, migration, and invasion of neuroblastoma cells.  Med Pediatr Oncol. 2003;  40 205-213
    CrossrefPubMedGoogle Scholar
  • 68 Wang C C, Wu C H, Shieh J Y, Wen C Y. Microglial distribution and apoptosis in fetal rat brain.  Brain Res Dev Brain Res. 2002;  139 337-342
    PubMedGoogle Scholar
  • 69 Wang X, Zalcenstein A, Oren M. Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation.  Cell Death Differ. 2003;  10 468-476
    CrossrefPubMedGoogle Scholar
  • 70 Wang Z Q, Todani T, Watanabe Y, Toki A, Ogura K, Miyamoto O, Toyoshima T, Itano T. Germ-cell degeneration in experimental unilateral cryptorchidism: role of apoptosis.  Pediatr Surg Int. 1998;  14 9-13
    CrossrefPubMedGoogle Scholar
  • 71 Wester T, Olsson Y, Olsen L. Expression of bcl-2 in enteric neurons in normal human bowel and Hirschsprung disease.  Arch Pathol Lab Med. 1999;  123 1264-1268
    PubMedGoogle Scholar
  • 72 Wiedemeyer R, Westermann F, Wittke I, Nowock J, Schwab M. Ataxin-2 promotes apoptosis of human neuroblastoma cells.  Oncogene. 2003;  22 401-411
    CrossrefPubMedGoogle Scholar
  • 73 Yan Y, Frisen J, Lee M H, Massague J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development.  Genes Dev. 1997;  11 973-983
    PubMedGoogle Scholar
  • 74 Yang X, Merchant M S, Romero M E, Tsokos M, Wexler L H, Kontny U, Mackall C L, Thiele C J. Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB.  Cancer Res. 2003;  63 1122-1129
    PubMedGoogle Scholar
  • 75 Zini A, Abitbol J, Girardi S K, Schulsinger D, Goldstein M, Schlegel P N. Germ cell apoptosis and endothelial nitric oxide synthase (eNOS) expression following ischemia-reperfusion injury to testis.  Arch Androl. 1998;  41 57-65
    PubMedGoogle Scholar

M.D. Igor Sukhotnik

Department of Pediatric Surgery B
Bnai Zion Medical Center

47 Golomb St.

P.O.B. 4940

Haifa 31048

Israel

Email: igor-dr@internet-zahav.net