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Absence of skin rash in Goodpasture’s syndrome: The hyaluronan effect
Medical Hypotheses 83 (2014) 769–771
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Absence of skin rash in Goodpasture’s syndrome: The hyaluronan effect A. Stern a,⇑, R. Stern b a b
Division of Nephrology, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, 79-01 Broadway, Elmhurst, NY 11373, United States Department of Basic Biomedical Sciences, Touro/Harlem College of Osteopathic Medicine, 230 West-125th Street, New York, NY 10027, United States
a r t i c l e
i n f o
Article history: Received 30 July 2014 Accepted 13 October 2014
a b s t r a c t Goodpasture’s syndrome is a rare disease that involves rapidly progressive kidney failure as well as hemorrhagic lung disease. It is a form of autoimmune disorder with unusual features; marked male preponderance, in contrast with other autoimmune disease in which females are at far greater risk. The autoantibodies are directed again the carboxy-extension non-collagenous (NC1) portion of one of the basement membrane-specific collagen IV alpha 3 chains. Basal laminas throughout the body share this structure, including those in kidney, lung and skin. But curiously, skin is rarely involved in Goodpasture’s syndrome. Hyaluronan is a large extracellular matrix carbohydrate polymer. Half of total body hyaluronan occurs in skin. High molecular weight hyaluronan, a potent immunosuppressive polymer, might be functioning as an immune shield for skin in Goodpasture’s syndrome, and be the basis for the anomaly. A summary of this putative effect is described, including possible molecular mechanisms involved, and suggestions for testing this hypothesis. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction
Basal lamina
Goodpasture’s syndrome is an unusual human disease characterized by rapidly progressive renal failure and hemoptysis. It is thought to be an autoimmune disorder, but unlike most other such immune disorders, there is a marked male preponderance. The autoantibodies involved are directed again carboxy-extension globular portion of a basement membrane-specific alpha chain of collagen IV [1]. Basement membranes throughout the body share this structure, including those in kidney, lung and skin. However skin is rarely involved in Goodpasture’s syndrome. HA (hyaluronan, hyaluronic acid) is a large extracellular matrix carbohydrate polymer, and the most prominent component of that matrix. Half of total body HA occurs in skin. HMW-HA (high molecular weight-HA), a potent immunosuppressive polymer, might be functioning as an immune shield for skin in Goodpasture’s syndrome, and be the basis for the anomaly. A summary of this putative effect is described, including possible molecular mechanisms involved, and suggestions for testing this hypothesis.
Basement membranes are resilient structures that form a mechanical barrier between epithelium and underlying stromal connective tissues. The exception is the basal laminas associated with muscle and endothelial cells. These can be perceived as highly specialized forms of stromal cells. The basement membranes of glomeruli are derived in part by the endothelium of renal capillaries. HA is an extracellular matrix straight chain carbohydrate polymer. More than 50% of the body’s HA occurs in skin [2], and much of that is within the basal lamina that lies between epidermis and dermis. Skin dermis and epidermis also contain HA [3]. The HA occurs in the mammalian body in a number of sizes. The HMW-HA forms are anti-inflammatory, anti-angiogenic and immune-suppressive, a reflection of normal healthy tissues. The immune-protective effect of such HMW-HA is well documented [4–9]. By contrast, fragmented forms of HA are associated with highly inflammatory, very angiogenic and immune-stimulatory processes, reflecting tissues under stress. This range of functions for a simple unadorned sugar polymer suggests that it is an information–rich system dependent only on polymer size [10]. These size-dependent changes in function are probably a result of the dynamic variations in shape associated with the polymers, and the volumes of water that surround them.
Abbreviations: HA, hyaluronan, hyaluronic acid; HMW-HA, high molecular weight-HA. ⇑ Corresponding author. E-mail address: [email protected] (A. Stern). http://dx.doi.org/10.1016/j.mehy.2014.10.007 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
770
A. Stern, R. Stern / Medical Hypotheses 83 (2014) 769–771
Basal lamina HA The nature of HA within the basal lamina remains an enigma. Its presence is well documented, but it has not been well characterized. The electric eel Electrophorus electricus has a well-developed basal lamina associated with the electric organ, which facilitates such studies [11]. The glycosaminoglycan content of the eel’s electric organ basal lamina is more than 50% HA [12].
hemoptysis. Circulating IgG antibodies were demonstrated that reacted with skin basement membranes. Six years later, this patient developed acute renal failure due to Goodpasture’s syndrome [17]. A further clinical curiosity is a patient that presented with atypical cutaneous vasculitis with features of Churg–Strauss syndrome associated with anti-glomerular basement membrane antibodies [18]. Conclusions
Basal lamina collagens Collagens have a universal motif of three polypeptide chains, referred to as alpha chains that form a triple-helical structure. Collagen IV is a major structural protein of basement membranes, and is chemically and genetically distinct from the major stromal collagens I and III, and cartilage collagen II. There are six genes associated with human collagen IV (formerly Type IV collagen), referred to as COL-IV A1, 2, 3, 4, 5, and 6. The collagens are synthesized as soluble precursors with noncollagenous globular extensions that occur at both amino and carboxy-termini. It is these non-collagenous extension peptides that confer solubility. The collagens become insoluble matrix proteins by enzymatic removal of the extension peptides. Unlike the other collagens however, the carboxy termini of the collagen IV proteins are not removed as part of post-translational processing, but remain attached to the collagenous portion of the molecule. In addition, the fibers are attached head-to-head, rather than in parallel, as occurs with other collagens. Most collagens contain glycine-x-y repeats throughout the triple helical portion of the molecule, providing the tightly coiled triple helical structure. The glycine moieties are sites at which the ‘‘twist’’ occur, being the only amino acid sufficiently small to permit the three strands to interact with each other, Collagen IV does not contain the strict glycine in every third position, facilitating the formation of the sheet-like structure found in basal laminas. It is the retained globular carboxy-terminal alpha 3 subunit (COL-IV A3) that is the antigen implicated in Goodpasture’s syndrome [13].
We postulate that HMW-HA in skin is protective and is the basis of the absence of skin manifestations in Goodpasture’s syndrome A direct test of this hypothesis is possible. Frozen sections of skin biopsies from Goodpasture’s syndrome patients can be incubated with a bacterial hyaluronidase, Streptomyces hyalurolyticus, available commercially, that removes all the HA. Incubation of such sections with anti-basement membrane collagen IV alpha 3 antibodies, or antibodies collected from the sera of patients with Goodpasture’s syndrome should now react with the tissue sections. Controls of sections without preliminary hyaluronidase incubation should not be reactive. The prediction is that removal of HA exposes the covert underlying epitopes, permitting the immune reaction to now occur. Another conclusion that could be reached from such experiments is that basal laminas throughout the body differ widely in structure and constitution. The basement membranes of lung epithelium, and of the renal glomerular apparatus may contain far less HMW-HA and its associated immunosuppressive effects. In conclusion, the protective effect of HA may be the basis for the lack of skin manifestations in Goodpasture’s syndrome. Enzymatic removal of the HA in tissue sections of skin from such patients are predicted to make the Goodpasture’s syndrome epitopes available to the immune reaction that underlies the disease in lungs and kidneys. Source of support None.
Goodpasture’s syndrome Conflict of interest Goodpasture’s syndrome is a rare disorder that presents with rapidly progressive glomerulonephritis and hemoptysis. The immune system is thought to attack the basement membranes of renal glomeruli and pulmonary alveoli. Antigenic sites on the carboxy-terminal collagen IV alpha 3 chains become exposed or unraveled because of some unknown injury, possibly environmental. The resulting circulating IgG antibodies can be seen in renal biopsies as linear deposits along the basement membrane. Unlike other autoimmune disorders, men are far more likely to develop Goodpasture’s syndrome than women, with a ratio of 8:1. The basis of the male preponderance is unknown. Curiously, mutations in the genes encoding the COL-IV alpha 3 and alpha 4 chains are responsible for other renal disorders, including Alport syndrome [14,15]. The conundrum in the disorder is that the same carboxy termini of the alpha 3 chains of collagen IV occur in the basal lamina of skin. Deposits therein would likely be associated with a rash, or some other dermatologic manifestation, as observed in other immune disorders involving skin. The testable hypothesis is that the HMW-HA of skin protects or occludes exposure of the alpha 3 chain carboxy epitope. Goodpasture’s syndrome with skin involvement, however, can occur on rare occasions. A case is reported in which a woman with Goodpasture’s syndrome presented with a skin rash [16]. In another patient, atypical bullous lesions occurred together with
The authors report no conflict of interest. References [1] Dammacco F, Battaglia S, Gesualdo L, Racanelli V. Goodpasture’s disease: a report of ten cases and a review of the literature. Autoimmun Rev 2013;12(11):1101–8. [2] Reed RK, Lilja K, Laurent TC. Hyaluronan in the rat with special reference to the skin. Acta Physiol Scand 1988;134(3):405–11. [3] Lin W, Shuster S, Maibach HI, Stern R. Patterns of hyaluronan staining are modified by fixation techniques. J Histochem Cytochem 1997;45(8):1157–63. [4] Delmage JM, Powars DR, Jaynes PK, Allerton SE. The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci 1986;16(4):303–10. [5] McBride WH, Bard JB. Hyaluronidase-sensitive halos around adherent cells. Their role in blocking lymphocyte-mediated cytolysis. J Exp Med 1979;149(2):507–15. [6] Muto J, Yamasaki K, Taylor KR, Gallo RL. Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS. Mol Immunol 2009;47(2–3):449–56. [7] Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol Rev 2011;91(1):221–64. [8] Bollyky PL, Lord JD, Masewicz SA, Evanko SP, Buckner JH, Wight TN, et al. Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells. J Immunol 2007;179(2):744–7. [9] Bollyky PL, Falk BA, Wu RP, Buckner JH, Wight TN, Nepom GT. Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells. J Leukoc Biol 2009;86(3):567–72. [10] Stern R, Asari AR, Sugahara KN. Size- specific fragments of hyaluronan: an information-rich system. Eur J Cell Biol 2006;85(8):699–715.
A. Stern, R. Stern / Medical Hypotheses 83 (2014) 769–771 [11] Granafei A, Hassón-Voloch A. Studies on hyaluronic acid from the electric organ of Electrophorus electricus (L.). An Acad Bras Cienc 1980;52(1): 171–7. [12] Inestrosa NC, Nader HB, Garrido J, Sampaio LO, Brandan E, Dietrich CP. Glycosaminoglycan composition of electric organ basement membranes. J Neurosci Res 1987;17(3):256–64. [13] Khoshnoodi J, Pedchenko V, Hudson BG. Mammalian collagen IV. Microsc Res Tech 2008;71(5):357–70. [14] Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 2001;12(1):97–106.
771
[15] Pescucci C, Longo I, Bruttini M, Mari F, Renieri A. Type-IV collagen related diseases. J Nephrol 2003;16(2):314–6. [16] Ross JB, Cohen AD, Ghose T. Goodpasture’s syndrome associated with skin involvement. Arch Dermatol 1985;121(11):1442–4. [17] Davenport A, Verbov JL, Goldsmith HJ. Circulating anti-skin basement membrane zone antibodies in a patient with Goodpasture’s syndrome. Br J Dermatol 1987;117(1):125–7. [18] Gleeson CM, Levy JB, Cook HT, Francis ND, Robson A, Pope FM. An atypical cutaneous presentation of vasculitis with features of Churg–Strauss syndrome, associated with anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane antibodies. Clin Exp Dermatol 2009;34(8):577–80.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Absence of skin rash in Goodpasture’s syndrome: The hyaluronan effect A. Stern a,⇑, R. Stern b a b
Division of Nephrology, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, 79-01 Broadway, Elmhurst, NY 11373, United States Department of Basic Biomedical Sciences, Touro/Harlem College of Osteopathic Medicine, 230 West-125th Street, New York, NY 10027, United States
a r t i c l e
i n f o
Article history: Received 30 July 2014 Accepted 13 October 2014
a b s t r a c t Goodpasture’s syndrome is a rare disease that involves rapidly progressive kidney failure as well as hemorrhagic lung disease. It is a form of autoimmune disorder with unusual features; marked male preponderance, in contrast with other autoimmune disease in which females are at far greater risk. The autoantibodies are directed again the carboxy-extension non-collagenous (NC1) portion of one of the basement membrane-specific collagen IV alpha 3 chains. Basal laminas throughout the body share this structure, including those in kidney, lung and skin. But curiously, skin is rarely involved in Goodpasture’s syndrome. Hyaluronan is a large extracellular matrix carbohydrate polymer. Half of total body hyaluronan occurs in skin. High molecular weight hyaluronan, a potent immunosuppressive polymer, might be functioning as an immune shield for skin in Goodpasture’s syndrome, and be the basis for the anomaly. A summary of this putative effect is described, including possible molecular mechanisms involved, and suggestions for testing this hypothesis. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction
Basal lamina
Goodpasture’s syndrome is an unusual human disease characterized by rapidly progressive renal failure and hemoptysis. It is thought to be an autoimmune disorder, but unlike most other such immune disorders, there is a marked male preponderance. The autoantibodies involved are directed again carboxy-extension globular portion of a basement membrane-specific alpha chain of collagen IV [1]. Basement membranes throughout the body share this structure, including those in kidney, lung and skin. However skin is rarely involved in Goodpasture’s syndrome. HA (hyaluronan, hyaluronic acid) is a large extracellular matrix carbohydrate polymer, and the most prominent component of that matrix. Half of total body HA occurs in skin. HMW-HA (high molecular weight-HA), a potent immunosuppressive polymer, might be functioning as an immune shield for skin in Goodpasture’s syndrome, and be the basis for the anomaly. A summary of this putative effect is described, including possible molecular mechanisms involved, and suggestions for testing this hypothesis.
Basement membranes are resilient structures that form a mechanical barrier between epithelium and underlying stromal connective tissues. The exception is the basal laminas associated with muscle and endothelial cells. These can be perceived as highly specialized forms of stromal cells. The basement membranes of glomeruli are derived in part by the endothelium of renal capillaries. HA is an extracellular matrix straight chain carbohydrate polymer. More than 50% of the body’s HA occurs in skin [2], and much of that is within the basal lamina that lies between epidermis and dermis. Skin dermis and epidermis also contain HA [3]. The HA occurs in the mammalian body in a number of sizes. The HMW-HA forms are anti-inflammatory, anti-angiogenic and immune-suppressive, a reflection of normal healthy tissues. The immune-protective effect of such HMW-HA is well documented [4–9]. By contrast, fragmented forms of HA are associated with highly inflammatory, very angiogenic and immune-stimulatory processes, reflecting tissues under stress. This range of functions for a simple unadorned sugar polymer suggests that it is an information–rich system dependent only on polymer size [10]. These size-dependent changes in function are probably a result of the dynamic variations in shape associated with the polymers, and the volumes of water that surround them.
Abbreviations: HA, hyaluronan, hyaluronic acid; HMW-HA, high molecular weight-HA. ⇑ Corresponding author. E-mail address: [email protected] (A. Stern). http://dx.doi.org/10.1016/j.mehy.2014.10.007 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
770
A. Stern, R. Stern / Medical Hypotheses 83 (2014) 769–771
Basal lamina HA The nature of HA within the basal lamina remains an enigma. Its presence is well documented, but it has not been well characterized. The electric eel Electrophorus electricus has a well-developed basal lamina associated with the electric organ, which facilitates such studies [11]. The glycosaminoglycan content of the eel’s electric organ basal lamina is more than 50% HA [12].
hemoptysis. Circulating IgG antibodies were demonstrated that reacted with skin basement membranes. Six years later, this patient developed acute renal failure due to Goodpasture’s syndrome [17]. A further clinical curiosity is a patient that presented with atypical cutaneous vasculitis with features of Churg–Strauss syndrome associated with anti-glomerular basement membrane antibodies [18]. Conclusions
Basal lamina collagens Collagens have a universal motif of three polypeptide chains, referred to as alpha chains that form a triple-helical structure. Collagen IV is a major structural protein of basement membranes, and is chemically and genetically distinct from the major stromal collagens I and III, and cartilage collagen II. There are six genes associated with human collagen IV (formerly Type IV collagen), referred to as COL-IV A1, 2, 3, 4, 5, and 6. The collagens are synthesized as soluble precursors with noncollagenous globular extensions that occur at both amino and carboxy-termini. It is these non-collagenous extension peptides that confer solubility. The collagens become insoluble matrix proteins by enzymatic removal of the extension peptides. Unlike the other collagens however, the carboxy termini of the collagen IV proteins are not removed as part of post-translational processing, but remain attached to the collagenous portion of the molecule. In addition, the fibers are attached head-to-head, rather than in parallel, as occurs with other collagens. Most collagens contain glycine-x-y repeats throughout the triple helical portion of the molecule, providing the tightly coiled triple helical structure. The glycine moieties are sites at which the ‘‘twist’’ occur, being the only amino acid sufficiently small to permit the three strands to interact with each other, Collagen IV does not contain the strict glycine in every third position, facilitating the formation of the sheet-like structure found in basal laminas. It is the retained globular carboxy-terminal alpha 3 subunit (COL-IV A3) that is the antigen implicated in Goodpasture’s syndrome [13].
We postulate that HMW-HA in skin is protective and is the basis of the absence of skin manifestations in Goodpasture’s syndrome A direct test of this hypothesis is possible. Frozen sections of skin biopsies from Goodpasture’s syndrome patients can be incubated with a bacterial hyaluronidase, Streptomyces hyalurolyticus, available commercially, that removes all the HA. Incubation of such sections with anti-basement membrane collagen IV alpha 3 antibodies, or antibodies collected from the sera of patients with Goodpasture’s syndrome should now react with the tissue sections. Controls of sections without preliminary hyaluronidase incubation should not be reactive. The prediction is that removal of HA exposes the covert underlying epitopes, permitting the immune reaction to now occur. Another conclusion that could be reached from such experiments is that basal laminas throughout the body differ widely in structure and constitution. The basement membranes of lung epithelium, and of the renal glomerular apparatus may contain far less HMW-HA and its associated immunosuppressive effects. In conclusion, the protective effect of HA may be the basis for the lack of skin manifestations in Goodpasture’s syndrome. Enzymatic removal of the HA in tissue sections of skin from such patients are predicted to make the Goodpasture’s syndrome epitopes available to the immune reaction that underlies the disease in lungs and kidneys. Source of support None.
Goodpasture’s syndrome Conflict of interest Goodpasture’s syndrome is a rare disorder that presents with rapidly progressive glomerulonephritis and hemoptysis. The immune system is thought to attack the basement membranes of renal glomeruli and pulmonary alveoli. Antigenic sites on the carboxy-terminal collagen IV alpha 3 chains become exposed or unraveled because of some unknown injury, possibly environmental. The resulting circulating IgG antibodies can be seen in renal biopsies as linear deposits along the basement membrane. Unlike other autoimmune disorders, men are far more likely to develop Goodpasture’s syndrome than women, with a ratio of 8:1. The basis of the male preponderance is unknown. Curiously, mutations in the genes encoding the COL-IV alpha 3 and alpha 4 chains are responsible for other renal disorders, including Alport syndrome [14,15]. The conundrum in the disorder is that the same carboxy termini of the alpha 3 chains of collagen IV occur in the basal lamina of skin. Deposits therein would likely be associated with a rash, or some other dermatologic manifestation, as observed in other immune disorders involving skin. The testable hypothesis is that the HMW-HA of skin protects or occludes exposure of the alpha 3 chain carboxy epitope. Goodpasture’s syndrome with skin involvement, however, can occur on rare occasions. A case is reported in which a woman with Goodpasture’s syndrome presented with a skin rash [16]. In another patient, atypical bullous lesions occurred together with
The authors report no conflict of interest. References [1] Dammacco F, Battaglia S, Gesualdo L, Racanelli V. Goodpasture’s disease: a report of ten cases and a review of the literature. Autoimmun Rev 2013;12(11):1101–8. [2] Reed RK, Lilja K, Laurent TC. Hyaluronan in the rat with special reference to the skin. Acta Physiol Scand 1988;134(3):405–11. [3] Lin W, Shuster S, Maibach HI, Stern R. Patterns of hyaluronan staining are modified by fixation techniques. J Histochem Cytochem 1997;45(8):1157–63. [4] Delmage JM, Powars DR, Jaynes PK, Allerton SE. The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci 1986;16(4):303–10. [5] McBride WH, Bard JB. Hyaluronidase-sensitive halos around adherent cells. Their role in blocking lymphocyte-mediated cytolysis. J Exp Med 1979;149(2):507–15. [6] Muto J, Yamasaki K, Taylor KR, Gallo RL. Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS. Mol Immunol 2009;47(2–3):449–56. [7] Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol Rev 2011;91(1):221–64. [8] Bollyky PL, Lord JD, Masewicz SA, Evanko SP, Buckner JH, Wight TN, et al. Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells. J Immunol 2007;179(2):744–7. [9] Bollyky PL, Falk BA, Wu RP, Buckner JH, Wight TN, Nepom GT. Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells. J Leukoc Biol 2009;86(3):567–72. [10] Stern R, Asari AR, Sugahara KN. Size- specific fragments of hyaluronan: an information-rich system. Eur J Cell Biol 2006;85(8):699–715.
A. Stern, R. Stern / Medical Hypotheses 83 (2014) 769–771 [11] Granafei A, Hassón-Voloch A. Studies on hyaluronic acid from the electric organ of Electrophorus electricus (L.). An Acad Bras Cienc 1980;52(1): 171–7. [12] Inestrosa NC, Nader HB, Garrido J, Sampaio LO, Brandan E, Dietrich CP. Glycosaminoglycan composition of electric organ basement membranes. J Neurosci Res 1987;17(3):256–64. [13] Khoshnoodi J, Pedchenko V, Hudson BG. Mammalian collagen IV. Microsc Res Tech 2008;71(5):357–70. [14] Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 2001;12(1):97–106.
771
[15] Pescucci C, Longo I, Bruttini M, Mari F, Renieri A. Type-IV collagen related diseases. J Nephrol 2003;16(2):314–6. [16] Ross JB, Cohen AD, Ghose T. Goodpasture’s syndrome associated with skin involvement. Arch Dermatol 1985;121(11):1442–4. [17] Davenport A, Verbov JL, Goldsmith HJ. Circulating anti-skin basement membrane zone antibodies in a patient with Goodpasture’s syndrome. Br J Dermatol 1987;117(1):125–7. [18] Gleeson CM, Levy JB, Cook HT, Francis ND, Robson A, Pope FM. An atypical cutaneous presentation of vasculitis with features of Churg–Strauss syndrome, associated with anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane antibodies. Clin Exp Dermatol 2009;34(8):577–80.