Para compra cialis puede ser visto como un desafío. Aumenta Smomenta, y todos los que se poco a poco abrumado, como es lógico, cada vez más hombres están diagnosticados con disfunción eréctil.

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Brief report
Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligandsand rise of leukocyte counts Kerstin Lu¨hn, Thorsten Marquardt, Erik Harms, and Dietmar Vestweber Leukocyte adhesion deficiency type II
administration of oral fucose. Parallel to
to the decrease of selectin ligands. Selec-
(LADII) is a rare inherited disorder of
this treatment the lack of E- and P-
tin ligands reappeared promptly after re-
fucose metabolism. Patients with LADII
selectin ligands on neutrophils was cor-
sumption of the fucose therapy, demon-
lack fucosylated glycoconjugates, includ-
rected, and high peripheral neutrophil
strating a causal relationship between
ing the carbohydrate ligands of the selec-
counts were reduced to normal levels.
fucose treatment and selectin ligand ex-
tins, leading to an immunodeficiency
This study reports that discontinuation of
pression
peripheral
neutrophil
caused by the lack of selectin-mediated
this therapy leads to the complete loss of
counts. (Blood. 2001;97:330-332)
leukocyte-endothelial
interactions.
E-selectin ligands within 3 days and of
simple and effective therapy has recently
P-selectin ligands within 7 days. Periph-
been described for LADII, based on the
eral neutrophil counts increased parallel
2001 by The American Society of Hematology
Introduction
Selectins initiate the contact formation between leukocytes and addressed by discontinuing therapy for 9 days, during which time endothelial cells and thereby the extravasation of leukocytes.1 They leukocyte counts, expression of selectin ligands on the patient’s form a family of 3 cell adhesion molecules of which 2 are inducible neutrophils, and other parameters were closely followed.
on the surface of endothelial cells (E- and P-selectin), and one isconstitutively expressed on most leukocytes (L-selectin). Althoughthe precise carbohydrate structure of selectin ligands has not yetbeen determined definitively, ample evidence suggests that theyresemble or are derivatives of the tetrasaccharide sialyl Lewis X(sLex) (NeuAc␣2,3-Gal␤1,4[Fuc␣1,3] GlcNAc). Fucose is anessential structural element of all known selectin ligands as hasbeen demonstrated in mice deficient for the gene for fucosyltrans-ferase VII.2 Thus, a defect in fucose metabolism would be expectedto severely hamper leukocyte entry into tissue.
Leukocyte adhesion deficiency type II (LADII) is a still-undefined genetic defect that results in the lack of fucosylated glycoconjugates,including sialyl Lewis X. Patients suffer from recurrent episodes ofinfections, persistent leukocytosis, and severe mental and growthretardation.3-5 Leukocyte rolling in postcapillary venules of such pa-tients is markedly reduced, and selectin ligands on leukocytes aremissing.6,7 The genetic defect seems to affect intracellular GDP-fucose supply because culturing of fibroblasts of different LADIIpatients in the presence of fucose can rescue the expression offucosylated glycoconjugates.8,9 We have recently described a newcase of LADII10 and have established a successful therapy based onthe administration of oral fucose.9 Since the onset of therapy,neutrophil counts were reduced to normal levels, no episodes offever were observed, and nearly normal expression levels of first P-and later of E-selectin ligands were reached while fucose doseswere gradually increased. However, we could not demonstrate Figure 1. Peripheral neutrophil counts and other therapy parameters during
discontinuation and resumption of fucose therapy.
Peripheral neutrophil counts,
whether fucose treatment did indeed cause the changes or whether fucose doses, serum fucose levels, body temperature, and C reactive protein (CRP) they merely occurred coincidentally. This question was now were recorded for each time point as indicated.
From the Institute of Cell Biology, ZMBE, University of Mu¨nster; Max-Planck- Reprints: Dietmar Vestweber, Institute of Cell Biology, ZMBE, University of
Institute for Physiological and Clinical Research, Mu¨nster, Germany; and Klinik Mu¨nster, Von-Esmarch-Str. 56, 48149 Mu¨nster, Germany; e-mail: vestweb und Poliklinik fu¨r Kinderheilkunde, Mu¨nster, Germany.
Submitted June 23, 2000; accepted September 13, 2000.
The publication costs of this article were defrayed in part by page charge Supported in part by the Deutsche Forschungsgemeinschaft, SFB 293 (K.L.
payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
K.L. and T.M. contributed equally to this report.
2001 by The American Society of Hematology BLOOD, 1 JANUARY 2001 ⅐ VOLUME 97, NUMBER 1 EFFECTS OF FUCOSE IN LADII ARE REVERSIBLE served. Serum fucose concentrations determined 60 to 90 minutes Study design
after fucose ingestion were in the range of 150 to 250 ␮M.
Following these 470 days of therapy, treatment with fucose was A detailed description of the patient has been given elsewhere.10 Fucose discontinued for 9 days. Serum fucose concentration levels dropped therapy on the boy was started at 14 months of age and conducted for 16 below detection limit (Յ 5 ␮M) as was determined on day 3, 5, 7, months before it was interrupted for 9 days. Permission for the trial on this and 9 after onset of discontinuation of therapy (Figure 1).
patient was obtained from the Human Subject Committee of the University Expression of E- and P-selectin ligands on neutrophils was Clinic of Mu¨nster, Germany. Body weight at this time was 7900 g (3rd determined by FACS analysis, using selectin-IgG fusion proteins as percentile, 10 400 g) and body length 76 cm (3rd percentile, 84 cm).
Isolation and fluorescence-activated cell sorter (FACS) analysis of periph- probes that were detected by fluorescence-labeled secondary eral blood leukocytes as well as determination of serum fucose concentra- antibodies (Figure 2). At the third day without fucose, E-selectin tions were performed as described.9 The selectin-immunoglobulin G (IgG) ligands were already undetectable, sLex levels were strongly chimeras (used at 25 ␮g/mL) contained the lectin, epidermal growth factor, reduced, whereas expression levels of P-selectin ligands were and first 2 consensus repeats of mouse E- or P-selectin, respectively, fused partially reduced (Figure 2, row II). P-selectin ligands and sLex to the Fc-part of human IgG1.11 Fc-receptors were blocked as described.10 were almost undetectable on day 7 after onset of discontinuation offucose therapy (Figure 2, row III). We conclude that fucose in thepatient’s diet was necessary for the generation of selectin ligands.
Results and discussion
Peripheral neutrophil counts were determined on day 1, 3, 5, 7, and 9 after discontinuing therapy. As shown in Figure 1, neutrophil The first 280 days of fucose therapy have been documented.9 Since counts increased 11-fold at day 5. At the same time, C reactive then, the therapy has been continued for another 190 days with 5 protein (CRP) was elevated from undetectable levels to 5.5 mg/dL, daily doses of 400 mg fucose/kg (15 g per day). During the whole and body temperature increased to 38.8°C. Cefixime was adminis- period of 470 days, neutrophil counts stayed in the normal range tered, resulting in normal body temperature and 2-fold reduction of [Ͻ8.5 ϫ 109/L (Ͻ8500/␮L)], and no fever episodes were ob- CRP levels. Neutrophil counts were partially reduced but stayed at Figure 2. Expression of selectin ligands and sLex
during discontinuation and resumption of fucose
therapy.
Neutrophils were isolated at the time points
before (row I) and during discontinuation (rows II and III)
and during resumption of therapy (rows IV and V) as
indicated on the left. Expression levels were analyzed by
flow cytometry, using the following reagents: (A and B)
E-selectin–IgG (E-Sel–IgG) or P-selectin–IgG (P-Sel–
IgG) in the presence of Caϩϩ (red, bold line), or in the
presence of EDTA (green, thin line), VE-cadherin–IgG
(blue, dashed line); (C) anti-sLex monoclonal antibody
CSLEX-1 (red, bold line). In each case the fluorescence-
labeled secondary antibody alone (negative control) was
depicted in black (dotted line).
BLOOD, 1 JANUARY 2001 ⅐ VOLUME 97, NUMBER 1 elevated levels during the course of fucose therapy discontinuation.
this context it is interesting that the analysis of mice with multiple Our results establish that interruption of fucose substitution therapy targeted deficiencies in selectin genes revealed a predominant role for only a few days led to the loss of selectin ligands, accompanied for P-selectin in regulating leukocyte behavior in mice.15 by leukocytosis and elevated body temperature.
A major concern from the onset of therapy had been that the Fucose therapy was resumed after 9 days of discontinuation, H-antigen, the ␣1,2-fucosylated core structure of the blood group starting with 5 daily doses of 100 mg/kg for the first 16 days, antigens, could be expressed on fucose therapy, possibly causing followed by 200 mg/kg doses for the next 10 days and a further problems with autoimmune antibodies. Surprisingly, this structure has increase to 290 mg/kg later. At 16 days after restarting therapy, not yet appeared during more then 1.5 years of therapy. It is possible P-selectin ligand expression levels had been partially reconstituted, that higher levels of fucose are necessary for the expression of the whereas sLex was almost and E-selectin ligands were still com- H-antigen than for the expression of selectin ligands. Alternatively, pletely undetectable (Figure 2, row IV). At 33 days after restarting erythrocyte progenitors might have a quantitatively insignificant or therapy, E-selectin ligands were reexpressed, whereas P-selectin inefficient salvage pathway for GDP-fucose synthesis.
ligands and sLex had reached near normal levels. Thus, similar to The genetic defect that leads to LADII has not yet been the original start of therapy, our results demonstrate that higher identified. For one of the first patients a possible defect indirectly fucose levels are necessary for the expression of E-selectin ligands affecting the activity of GDP-D-mannose-4,6-dehydratase was than for the expression of P-selectin ligands. This might indicate reported.16 An attempt to treat the patient with low doses of fucose that P-selectin ligands require lower levels of fucosylation for did not yield a positive therapeutic response. This could either be selectin-binding than E-selectin ligands. Indeed, a study on mouse- based on defects in a different gene or on defects of different parts activated T cells indirectly suggested that lower activation and of the same gene, resulting in different sensitivity to the rescue by fucosylation levels were necessary for the binding to P-selectin externally added fucose.17 Cell extracts of our patient displayed than for the binding to E-selectin.12 PSGL-1, the major ligand of normal activity levels of the dehydratase and the FX protein.18 P-selectin, has only very few fucosylated glycan side chains, and Instead, decreased import of GDP-fucose into the Golgi of these only one side chain can be sufficient for high affinity binding to cells was observed, indicating that the basis for LADII might be a defect in the transport rather than the synthesis of GDP-fucose.19 Parallel to the reexpression of selectin ligands, peripheral neutrophil counts dropped to normal levels when therapy wasresumed (Figure 1). Our results establish a causal relationshipbetween fucose treatment and selectin ligand expression. Further- Acknowledgment
more, restoration of P-selectin ligands alone was already sufficientto restore normal neutrophil counts, whereas E-selectin ligands, as K. Holtmann is gratefully acknowledged for help with the detectable by FACS analysis, were not required for this effect. In References
1. Vestweber D, Blanks JE. Mechanisms that regu- sion deficiency type II. Blood. 1994;84:1635- ligand-1 from HL-60 cells. J Biol Chem. 1996; late the function of the selectins and their ligands.
8. Karsan A, Cornejo CJ, Winn RK, et al. Leukocyte 14. Leppa¨nen A, Mehta P, Ouyang YB, et al. A novel 2. Maly P, Thall AD, Petryniak B, et al. The ␣-(1,3)fu- adhesion deficiency type II is a generalized de- glycosulfopeptide binds to P-selectin and inhibits cosyltransferase Fuc-TVII controls leukocyte traf- fect of de novo GDP-fucose biosynthesis: endo- leukocyte adhesion to P-selectin. J Biol Chem.
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5. Becker DJ, Lowe JB. Leukocyte adhesion defi- Vestweber D. Five TNF-inducible cell adhesion ciency type II. Biochim Biophys Acta. 1999;1455: mechanisms on the surface of mouse endothe- 18. Ko¨rner C, Linnebank M, Koch HG, Harms E, von lioma cells mediate the binding of leukocytes.
Figura K, Marquardt T. Decreased availability of 6. von Andrian UH, Berger EM, Ramezani L, et al. In GDP-L-fucose in a patient with LAD II with normal vivo behavior of neutrophils from two patients 12. Borges E, Pendl G, Eytner R, Steegmaier M, with distinct inherited leukocyte adhesion defi- Zo¨llner O, Vestweber D. The binding of T cell- activities. J Leukoc Biol. 1999;66:95-98.
ciency syndromes. J Clin Invest. 1993;91:2893- expressed P-selectin glycoprotein ligand-1 to E- 19. Lu¨bke T, Marquardt T, von Figura K, Korner C. A and P-selectin is differentially regulated. J Biol new type of carbohydrate-deficient glycoprotein 7. Price TH, Ochs HD, Gershoni Baruch R, Harlan syndrome due to a decreased import of GDP- JM, Etzioni A. In vivo neutrophil and lymphocyte 13. Wilkins PP, McEver RP, Cummings RD. Struc- fucose into the golgi. J Biol Chem. 1999;274: function studies in a patient with leukocyte adhe- tures of the O-glycans on P-selectin glycoprotein

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