Agammaglobulinemia: causative mutations and their implications for novel therapies

References

• Bousfiha AA, Jeddane L, Ailal F et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J. Clin. Immunol. 33(6), 1078–1087 (2013).
   PubMed Web of Science ®Google Scholar
• Conley ME, Broides A, Hernandez-Trujillo V et al. Genetic analysis of patients with defects in early B-cell development. Immunol. Rev. 203, 216–34 (2005).
   PubMed Web of Science ®Google Scholar
• Primary immunodeficiency diseases: a molecular & cellular approach. (3rd Edition). Ochs H, Smith C, Puck J ( Eds). Oxford University Press, New York, USA.
   Google Scholar
• Winkelstein JA, Marino MC, Lederman HM et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine 85(4), 193–202 (2006).
   PubMed Web of Science ®Google Scholar
• Conley ME, Dobbs AK, Farmer DM et al. Primary B cell immunodeficiencies: comparisons and contrasts. Ann. Rev. Immunol. 27, 199–227 (2009).
   PubMed Web of Science ®Google Scholar
• Vetrie D, Vorechovský I, Sideras P et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361(6409), 226–233 (1993).
   PubMed Web of Science ®Google Scholar
• Tsukada S, Saffran DC, Rawlings DJ et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72(2), 279–290 (1993).
   PubMed Web of Science ®Google Scholar
• Lindvall JM, Blomberg KEM, Väliaho J et al. Bruton’s tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol. Rev. 203, 200–215 (2005).
   PubMed Web of Science ®Google Scholar
• Noordzij JG, de Bruin-Versteeg S, Hartwig NG et al. XLA patients with BTK splice-site mutations produce low levels of wild-type BTK transcripts. J. Clin. Immunol. 22(5), 306–318 (2002).
   PubMedGoogle Scholar
• Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME. Mutations in the human λ5/14.1 gene result in B cell deficiency and agammaglobulinemia. J. Exp. Med. 187(1), 71–77 (1998).
   PubMed Web of Science ®Google Scholar
• Yel L, Minegishi Y, Coustan-Smith E et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N. Engl. J. Med. 335(20), 1486–1493 (1996).
   PubMed Web of Science ®Google Scholar
• Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME. Mutations in Igα(CD79a) result in a complete block in B-cell development. J. Clin. Invest. 104(8), 1115–1121 (1999).
   PubMed Web of Science ®Google Scholar
• Ferrari S, Lougaris V, Caraffi S et al. Mutations of the Igβ gene cause agammaglobulinemia in man. J. Exp. Med. 204(9), 2047–2051 (2007).
   PubMed Web of Science ®Google Scholar
• Dobbs AK, Yang T, Farmer D, Kager L, Parolini O, Conley ME. Cutting edge: a hypomorphic mutation in Igβ (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J. Immunol. 179(4), 2055–2059 (2007).
   PubMed Web of Science ®Google Scholar
• Minegishi Y, Rohrer J, Coustan-Smith E et al. An essential role for BLNK in human B cell development. Science 286(5446), 1954–1957 (1999).
   PubMed Web of Science ®Google Scholar
• Conley ME, Dobbs AK, Quintana AM et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J. Exp. Med. 209(3), 463–70 (2012).
   PubMed Web of Science ®Google Scholar
• Dobbs AK, Bosompem A, Coustan-Smith E, Tyerman G, Saulsbury FT, Conley ME. Agammaglobulinemia associated with BCR-B cells and enhanced expression of CD19. Blood 118(7), 1828–1837 (2011).
   PubMedGoogle Scholar
• Van Zelm MC, Reisli I, van der Burg M et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354(18), 1901–1912 (2006).
   PubMed Web of Science ®Google Scholar
• Van Zelm MC, Geertsema C, Nieuwenhuis N et al. Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. Am. J. Hum. Genet. 82(2), 320–332 (2008).
   PubMedGoogle Scholar
• Rickert RC, Roes J, Rajewsky K. B lymphocyte-specific, Cre-mediated mutagenesis in mice. Nucleic Acids Res. 25(6), 1317–1318 (1997).
   PubMed Web of Science ®Google Scholar
• Nodland SE, Berkowska MA, Bajer AA et al. IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells. Blood 118(8), 2116–2127 (2011).
   PubMedGoogle Scholar
• Conley ME, Rohrer J, Rapalus L, Boylin EC, Minegishi Y. Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol. Rev. 178, 75–90 (2000).
   PubMed Web of Science ®Google Scholar
• Khan WN, Alt FW, Gerstein RM et al. Defective B cell development and function in Btk-deficient mice. Immunity 3(3), 283–299 (1995).
   PubMed Web of Science ®Google Scholar
• Berglöf A, Sandstedt K, Feinstein R, Bölske G, Smith CIE. B cell-deficient muMT mice as an experimental model for Mycoplasma infections in X-linked agammaglobulinemia. Eur. J. Immunol. 27(8), 2118–2121 (1997).
   PubMedGoogle Scholar
• Ellmeier W, Jung S, Sunshine MJ et al. Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk. J. Exp. Med. 192(11), 1611–1624 (2000).
   PubMed Web of Science ®Google Scholar
• Kitamura D, Rajewsky K. Targeted disruption of µ chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356(6365), 154–156 (1992).
   PubMedGoogle Scholar
• Pelanda R, Braun U, Hobeika E, Nussenzweig MC, Reth M. B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-α and Ig-β. J. Immunol. 169(2), 865–872 (2002).
   PubMedGoogle Scholar
• Gong S, Nussenzweig MC. Regulation of an early developmental checkpoint in the B cell pathway by Igβ. Science 272(5260), 411–414 (1996).
   PubMedGoogle Scholar
• Kitamura D, Kudo A, Schaal S, Müller W, Melchers F, Rajewsky K. A critical role of λ5 protein in B cell development. Cell 69(5), 823–831 (1992).
   PubMedGoogle Scholar
• Yablonski D, Weiss A. Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. Adv. Immunol. 79, 93–128 (2001).
   PubMedGoogle Scholar
• Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3(1), 39–50 (1995).
   PubMed Web of Science ®Google Scholar
• Maas A, Dingjan GM, Grosveld F, Hendriks RW. Early arrest in B cell development in transgenic mice that express the E41K Bruton’s tyrosine kinase mutant under the control of the CD19 promoter region. J. Immunol. 162(11), 6526–6533 (1999).
   PubMedGoogle Scholar
• Satterthwaite AB, Cheroutre H, Khan WN, Sideras P, Witte ON. Btk dosage determines sensitivity to B cell antigen receptor cross-linking. Proc. Natl Acad. Sci. USA. 94(24), 13152–13157 (1997).
   PubMedGoogle Scholar
• Drabek D, Raguz S, De Wit TP et al. Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region. Proc. Natl Acad. Sci. USA 94(2), 610–615 (1997).
   PubMedGoogle Scholar
• Maas A, Dingjan GM, Savelkoul HF, Kinnon C, Grosveld F, Hendriks RW. The X-linked immunodeficiency defect in the mouse is corrected by expression of human Bruton’s tyrosine kinase from a yeast artificial chromosome transgene. Eur. J. Immunol. 27(9), 2180–2187 (1997).
   PubMedGoogle Scholar
• Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270(5237), 794–797 (1995).
   PubMedGoogle Scholar
• Fruman DA, Satterthwaite AB, Witte ON. Xid-like phenotypes: a B cell signalosome takes shape. Immunity 13(1), 1–3 (2000).
   PubMed Web of Science ®Google Scholar
• Yamazaki T, Takeda K, Gotoh K, Takeshima H, Akira S, Kurosaki T. Essential immunoregulatory role for BCAP in B cell development and function. J. Exp. Med. 195(5), 535–545 (2002).
   PubMedGoogle Scholar
• Ombrello MJ, Remmers EF, Sun G et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366(4), 330–338 (2012).
   PubMed Web of Science ®Google Scholar
• Hendriks RW, Middendorp S. The pre-BCR checkpoint as a cell-autonomous proliferation switch. Trends Immunol. 25(5), 249–56 (2004).
   PubMedGoogle Scholar
• Kurosaki T. Regulation of BCR signaling. Mol. Immunol. 48(11), 1287–1291 (2011).
   PubMedGoogle Scholar
• Cunningham-Rundles C. Key aspects for successful immunoglobulin therapy of primary immunodeficiencies. Clin. Exp. Neuroimmunol. 164(Suppl.) 16–19 (2011).
   Google Scholar
• Howard V, Myers LA, Williams DA, et al. Stem cell transplants for patients with X-linked agammaglobulinemia. Clin. Immunol. 107(2), 98–102 (2003).
   PubMedGoogle Scholar
• Segal DJ, Meckler JF. Genome Engineering at the Dawn of the Golden Age. Annu. Rev. Genomics Hum Genet. 14, 135–158 (2013).
   PubMedGoogle Scholar
• Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. 20 years of gene therapy for SCID. Nat. Immunol. 11(6), 457–460 (2010).
   PubMed Web of Science ®Google Scholar
• Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012 – an update. J. Gene Med. 15(2), 65–77 (2013).
   PubMed Web of Science ®Google Scholar
• Moreau T, Barlogis V, Bardin F et al. Development of an enhanced B-specific lentiviral vector expressing BTK: a tool for gene therapy of XLA. Gene Ther. 15(12), 942–952 (2008).
   PubMedGoogle Scholar
• Yu PW, Tabuchi RS, Kato RM et al. Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer. Blood 104(5), 1281–1290 (2004).
   PubMedGoogle Scholar
• Kerns HM, Ryu BY, Stirling B V et al. B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. Blood 115(11), 2146–2155 (2010).
   PubMedGoogle Scholar
• Ng YY, Baert MR, Pike-Overzet K et al. Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK. Leukemia 24(9), 1617–1630 (2010).
   PubMedGoogle Scholar
• Li L, Krymskaya L, Wang J et al. Genomic Editing of the HIV-1 Coreceptor CCR5 in Adult Hematopoietic Stem and Progenitor Cells Using Zinc Finger Nucleases. Mol. Ther. 21(6), 1259–1269 (2013).
   PubMed Web of Science ®Google Scholar
• Ellis BL, Hirsch ML, Porter SN, Samulski RJ, Porteus MH. Zinc-finger nuclease-mediated gene correction using single AAV vector transduction and enhancement by Food and Drug Administration-approved drugs. Gene Ther. 20(1), 35–42 (2013).
   PubMed Web of Science ®Google Scholar
• Lombardo A, Cesana D, Genovese P et al. Site-specific integration and tailoring of cassette design for sustainable gene transfer. Nat. Methods 8(10), 861–869 (2011).
   PubMed Web of Science ®Google Scholar
• Wood AJ, Lo TW, Zeitler B et al. Targeted genome editing across species using ZFNs and TALENs. Science 333(6040), 307 (2011).
   PubMedGoogle Scholar
• Hockemeyer D, Wang H, Kiani S et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat. Biotechnol. 29(8), 731–734 (2011).
   PubMed Web of Science ®Google Scholar
• Li H, Haurigot V, Doyon Y et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475(7355), 217–221 (2011).
   PubMed Web of Science ®Google Scholar
• Mali P, Yang L, Esvelt KM et al. RNA-guided human genome engineering via Cas9. Science 339(6121), 823–826 (2013).
   PubMed Web of Science ®Google Scholar
• Cong L, Ran FA, Cox D et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121), 819–823 (2013).
   PubMed Web of Science ®Google Scholar
• Kim E, Kim S, Kim DH, Choi B-S, Choi I-Y, Kim J-S. Precision genome engineering with programmable DNA-nicking enzymes. Genome Res. 22(7), 1327–1333 (2012).
   PubMed Web of Science ®Google Scholar
• Havens MA, Duelli DM, Hastings ML. Targeting RNA splicing for disease therapy. Wiley Interdiscip Rev. RNA 4(3), 247–266 (2013).
   PubMed Web of Science ®Google Scholar
• Lopez-Herrera G, Berron-Ruiz L, Mogica-Martinez D, Espinosa-Rosales F, Santos-Argumedo L. Characterization of Bruton’s tyrosine kinase mutations in Mexican patients with X-linked agammaglobulinemia. Mol. Immunol. 45(4), 1094–1098 (2008).
   PubMedGoogle Scholar
• Kralovicova J, Hwang G, Asplund AC, Churbanov A, Smith CIE, Vorechovsky I. Compensatory signals associated with the activation of human GC 5’ splice sites. Nucleic Acids Res. 39(16), 7077–7091 (2011).
   PubMedGoogle Scholar
• Cirak S, Arechavala-Gomeza V, Guglieri M et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378(9791), 595–605 (2011).
   PubMed Web of Science ®Google Scholar
• Goemans NM, Tulinius M, van den Akker JT et al. Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N. Engl. J. Med. 364(16), 1513–1522 (2011).
   PubMed Web of Science ®Google Scholar
• Douglas AGL, Wood MJA. Splicing therapy for neuromuscular disease. Mol. Cell Neurosci. 56C, 169–185 (2013).
   Google Scholar
• Pinotti M, Balestra D, Rizzotto L, Maestri I, Pagani F, Bernardi F. Rescue of coagulation factor VII function by the U1+5A snRNA. Blood 113(25), 6461–6464 (2009).
   PubMedGoogle Scholar
• Fernandez Alanis E, Pinotti M, Dal Mas A et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum. Mol. Genet. 21(11), 2389–2398 (2012).
   PubMed Web of Science ®Google Scholar
• Owen N, Zhou H, Malygin AA et al. Design principles for bifunctional targeted oligonucleotide enhancers of splicing. Nucleic Acids Res. 39(16), 7194–7208 (2011).
   PubMedGoogle Scholar
• Chao H, Mansfield SG, Bartel RC et al. Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nat. Med. 9(8), 1015–1019 (2003).
   PubMed Web of Science ®Google Scholar
• Cooray S, Howe SJ, Thrasher AJ. Retrovirus and lentivirus vector design and methods of cell conditioning. Methods Enzymol. 507, 29–57 (2012).
   PubMed Web of Science ®Google Scholar
• Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. Gene therapy of primary T cell immunodeficiencies. Gene (2013).
   PubMedGoogle Scholar
• Sather BD, Ryu BY, Stirling B V et al. Development of B-lineage predominant lentiviral vectors for use in genetic therapies for B cell disorders. Mol. Ther. 19(3), 515–525 (2011).
   PubMedGoogle Scholar
• Suerth JD, Maetzig T, Brugman MH et al. Alpharetroviral self-inactivating vectors: long-term transgene expression in murine hematopoietic cells and low genotoxicity. Mol. Ther. 20(5), 1022–1032 (2012).
   PubMed Web of Science ®Google Scholar
• Nienhuis AW. Development of gene therapy for blood disorders: an update. Blood 122(9), 1556–1564 (2013).
   PubMed Web of Science ®Google Scholar
• Di Matteo M, Belay E, Chuah MK, VandenDriessche T. Recent developments in transposon-mediated gene therapy. Expert Opin. Biol. Ther. 12(7), 841–858 (2012).
   PubMed Web of Science ®Google Scholar
• Hackett PB, Largaespada DA, Switzer KC, Cooper LJN. Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. Transl. Res. 161(4), 265–283 (2013).
   PubMed Web of Science ®Google Scholar
• Lopez Granados E, Porpiglia AS, Hogan MB, et al. Clinical and molecular analysis of patients with defects in μ heavy chain gene. J. Clin. Invest. 110(7), 1029–1035 (2002).
   Google Scholar
• Väliaho J, Smith CIE, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum. Mutat. 27(12), 1209–1217 (2006).
   PubMedGoogle Scholar
• Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature 481(7381), 295–305 (2012).
   PubMed Web of Science ®Google Scholar
• Hanna J, Wernig M, Markoulaki S et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318(5858), 1920–1923 (2007).
   PubMed Web of Science ®Google Scholar
• Panopoulos AD, Belmonte JC. Induced pluripotent stem cells in clinical hematology: potentials, progress, and remaining obstacles. Curr. Opin. Hematol. 19(4), 256–260 (2012).
   PubMedGoogle Scholar
• Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature 474(7350), 212–215 (2011).
   PubMed Web of Science ®Google Scholar
• Mayshar Y, Ben-David U, Lavon N et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell. 7(4), 521–531 (2010).
   PubMed Web of Science ®Google Scholar
• Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 9(1), 17–23 (2011).
   PubMed Web of Science ®Google Scholar
• Abad M, Mosteiro L, Pantoja C et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature doi:10.1038/nature12586 (2013) (Epub ahead of print).
   Google Scholar
• Rais Y, Zviran A, Geula S et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature doi:10.1038/nature 12587 (2013) (Epub ahead of print).
   Google Scholar
• Limon JJ, Fruman DA. Akt and mTOR in B Cell Activation and Differentiation. Front Immunol. 3, 228 (2012).
   PubMed Web of Science ®Google Scholar
• Schuman J, Chen Y, Podd A et al. A critical role of TAK1 in B-cell receptor-mediated nuclear factor κB activation. Blood 113(19), 4566–4574 (2009).
   PubMedGoogle Scholar
• Samuelson EM, Laird RM, Maue AC, Rochford R, Hayes SM. Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunol. Cell Biol. 90(6), 620–629 (2012).
   PubMedGoogle Scholar
• Pappu BP, Lin X. Potential role of CARMA1 in CD40-induced splenic B cell proliferation and marginal zone B cell maturation. Eur. J. Immunol. 36(11), 3033–3043 (2006).
   PubMedGoogle Scholar
• Winslow MM, Gallo EM, Neilson JR, Crabtree GR. The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24(2), 141–152 (2006).
   PubMed Web of Science ®Google Scholar
• Yasuda T, Sanjo H, Pagès G et al. Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity 28(4), 499–508 (2008).
   PubMedGoogle Scholar
• Dengler HS, Baracho G V, Omori SA et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat. Immunol. 9(12), 1388–1398 (2008).
   PubMed Web of Science ®Google Scholar
• Hinman RM, Nichols WA, Diaz TM, Gallardo TD, Castrillon DH, Satterthwaite AB. Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution. Int. Immunol. 21(7), 831–842 (2009).
   PubMedGoogle Scholar
• Chaimowitz NS, Falanga YT, Ryan JJ, Conrad DH. Fyn kinase is required for optimal humoral responses. PloS ONE 8(4), e60640 (2013).
   PubMedGoogle Scholar
• Hibbs ML, Tarlinton DM, Armes J et al. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83(2), 301–311 (1995).
   PubMed Web of Science ®Google Scholar
• Saijo K, Schmedt C, Su I-H et al. Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development. Nat. Immunol. 4(3), 274–279 (2003).
   PubMed Web of Science ®Google Scholar
• Coughlin JJ, Stang SL, Dower NA, Stone JC. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. J. Immunol. 175(11), 7179–7184 (2005).
   PubMed Web of Science ®Google Scholar
• Turner M, Gulbranson-Judge A, Quinn ME, Walters AE, MacLennan IC, Tybulewicz VL. Syk tyrosine kinase is required for the positive selection of immature B cells into the recirculating B cell pool. J. Exp. Med. 186(12), 2013–2021 (1997).
   PubMedGoogle Scholar
• Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T. Syk tyrosine kinase required for mouse viability and B-cell development. Nature 378(6554), 303–306 (1995).
   PubMed Web of Science ®Google Scholar
• Tedford K, Nitschke L, Girkontaite I et al. Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Nat. Immunol. 2(6), 548–55 (2001).
   PubMed Web of Science ®Google Scholar
• Mundt C, Licence S, Shimizu T, Melchers F, Mårtensson IL. Loss of precursor B cell expansion but not allelic exclusion in VpreB1/VpreB2 double-deficient mice. J. Exp. Med. 193(4), 435–445 (2001).
   PubMedGoogle Scholar