Correction of Defective Chemotaxis With Thiamine in Shwachman-Diamond Syndrome

Szüts, P; Katona, Zoltan; Ilyés, M.; Szabó, Imre; Csató, M.

doi:10.1016/s0140-6736(84)91476-4

Cited by 8 publications

(5 citation statements)

References 13 publications

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“…In contrast to the earlier report [31], excessive thiamine supplementation did not correct the aberrant neutrophil function in patients with the Shwachman syndrome. Firstly, the failure of the therapy trial may be due to the different route of administration of thiamine; Szt~ts et al [31] used parenteral administration, whereas we used oral administration.…”

Section: Discussioncontrasting

confidence: 99%

“…Firstly, the failure of the therapy trial may be due to the different route of administration of thiamine; Szt~ts et al [31] used parenteral administration, whereas we used oral administration. Possibly the concentrations of the antioxidants attained by oral administration were not sufficiently high.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that thiamine (vitamin B1) therapy corrects the chemotactic defect of neutrophils in patients with the Shwachman syndrome [31]. ct-Tocopherol increases chemotactic responses of neutrophils in vitro [7] and decreases hydrogen peroxide production by neutrophils [5].…”

Section: Offprint Requests To: M Ristolamentioning

confidence: 99%

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Increased whole blood chemiluminescence in patients with Shwachman syndrome: therapy trial with thiamine and α-tocopherol

et al. 1991

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Neutrophils purified from peripheral blood of patients with the Shwachman syndrome show enhanced chemiluminescence (CL) and depressed chemotaxis. Here we present data showing that the increased CL response can be demonstrated by using a whole blood CL assay. This assay is well-suited for studies in infants, because the blood sample volumes needed are small. Increase in CL was most distinct in the initial (1 min) activation induced by N-formyl-methionyl-leucyl-phenylalanine. The 1-min response is considered to derive from extracellular production of oxygen radicals. Such an extracellular oxygen radical production may render the patients susceptible to undue oxidant stress. We therefore treated the patients with two antioxidants, thiamine and alpha-tocopherol, for 3 months. This supplementation, however, failed to exert any significant effect on either whole blood CL or migration of the patients' neutrophils under agarose.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Increased whole blood chemiluminescence in patients with Shwachman syndrome: therapy trial with thiamine and α-tocopherol

et al. 1991

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“…8,12,13 Most SDS patients have mutations in the SBDS gene located at chromosome 7, which is currently the only known affected gene in SDS. 14 The earliest studies on chemotaxis defects in SDS patients were published in the late 1970s 11,15 and were confirmed in later studies. [7][8][9] At the cellular and molecular level, Stepanovic et al showed that directed, but not random movement of SDS neutrophils is impaired and Wessels et al showed in Dictyostelium Discoideum that GFP-SBDS was localized in the pseudopod during chemotaxis.…”

Section: Introductionmentioning

confidence: 91%

Shwachman-Diamond syndrome neutrophils have altered chemoattractant-induced F-actin polymerization and polarization characteristics

Orelio

Kuijpers

2009

Haematologica

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delayed in SDS neutrophils. This is the first study revealing a molecular defect, namely defective F-actin cytoskeletal remodeling, which may contribute to impaired chemotaxis in SDS patients. Design and Methods Neutrophil isolation and cell cultureBlood was obtained after informed consent of healthy volunteers (26-43 years) and SDS patients (2-29 years; all with mutations 183-184 A>CT [K62X]/IVS2 258+2T>C [C84fs]). The study was approved by the Medical Ethics Committees of the AMC Hospital and the institutional review board and was in accordance with the Declaration of Helsinki. Neutrophils were isolated as described. 8 PLB-985 and GFP-Rac2 PLB-985 17 cells were cultured in RPMI/10% FCS/penicillin (200 µg/mL)/streptomycin (200 µg/mL)/ L-glutamine (4 mM). PLB-985 cells were differentiated with 0.5% dimethylformamide (DMF; Sigma-Aldrich) for 5-7 days. Cellular spreading and immunofluorescenceNeutrophils or PLB-985 cells in Hepes medium (132 mM NaCl, 20 mM Hepes, 6mM KCL, 1 mM MgSO4, 1.2 mM K2HPO4, 1 mM CaCl2, 5 mM Glucose, 2.5% human albumin (Cealb; Sanquin reagents)) were seeded on fibronectin-coated coverslips and allowed to adhere for 30 min. Cells were stimulated with 20nM fMLP, fixed with 4% paraformaldehyde/PBS and processed for immunofluorescence staining as described. 18 Antibodies used: SBDS (rabbit polyclonal), Phalloidin-Alexa488 or BODIPY conjugated. Pictures were taken with a Zeiss LSM510 microscope with a Zeiss 65x oil lens and processed with LSM 510 software. Neutrophils (2×10 6 /mL) in Hepes medium were stimulated with 100nM fMLP or 40nM C5a. At indicated time points 2×10 5 cells were harvested and fixed with buffer 1 (Intraprep Permeabilization Reagent Kit; Immunotech), permeabilized with buffer 2 and stained with Phalloidin-Alexa488 (Molecular Probes, Invitrogen). Cells were analyzed on LSRII (BD Biosciences) flow cytometer for F-actin content. F-actin polymerization and cellular polarizationTo determine F-actin polarization, neutrophils were embedded with Mowiol 4-88 and analyzed by confocal microscopy. For each experiment at least 50 cells per time-point were analyzed in a blind fashion. Results and Discussion SBDS co-localizes with F-actin and Rac2 in human neutrophilsTo investigate a possible link between SBDS and the actin cytoskeleton, we performed immunofluorescence stainings in neutrophils and PLB-985 cells, with an anti-SBDS antibody that we have generated and which specifically recognized SBDS (Online Supplementary Figure S1A/B). In resting human neutrophils we observed that SBDS is localized prominently to the nucleus and to a lesser extent to the cytoplasm (Online Supplementary Figure 1C). However, in these resting cells there is not much polymerized F-actin cytoskeleton detectable (data not shown) and therefore we set out to investigate SBDS in relation to the F-actin cytoskeleton in activated neutrophilic cells. Human peripheral blood neutrophils were allowed to adhere to fibronectin and were subsequently stimulated with fMLP. These activated cells displayed Factin enriched c...

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“…The improvement in PMN motility was ob tained using lithium concentrations which usually do not induce side effects. To date, as far as we are aware, only one paper dealing with a pharmacologi cal attempt to improve PMN chemotaxis in SDS has been published [20], The use of lithium could be very interesting because the drug is able not only to modu late PMN functions, but also to induce leukocytosis [21]. Our data allow us to suggest a therapeutic use of lithium in SDS, since the drug could modulate the cytoskeletons of the various structures involved in the syndrome and ameliorate the degree of neutropenia.…”

Section: Discussionmentioning

confidence: 99%

In vivo Effectiveness of Lithium on Impaired Neutrophil Chemotaxis in Shwachman-Diamond Syndrome

Azzarà

Carulli²,

Ceccarelli³

et al. 1991

Acta Haematol

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The effect of lithium treatment on the impaired neutrophil chemotactic function of a patient affected by Shwachman-Diamond syndrome is reported. We found that (1) a cytoskeletal cellular defect seems to be involved in the impairment of neutrophil function (and perhaps of cellular secretion and chondrocyte function) in the syndrome; (2) intermittent neutropenia is always present in the syndrome, and (3) lithium seems capable, in addition to its capacity of inducing leukocytosis, of modulating leukocyte functions by modulating the microtubular system. The drug, at usual therapeutic dosage, was able to normalize neutrophil functions without side effects. As no therapy is available in this syndrome to date, our data suggest the therapeutic use of lithium in order to improve these cytoskeleton-mediated functions and the degree of neutropenia.

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Correction of Defective Chemotaxis With Thiamine in Shwachman-Diamond Syndrome

Cited by 8 publications

References 13 publications

Increased whole blood chemiluminescence in patients with Shwachman syndrome: therapy trial with thiamine and α-tocopherol

Increased whole blood chemiluminescence in patients with Shwachman syndrome: therapy trial with thiamine and α-tocopherol

Shwachman-Diamond syndrome neutrophils have altered chemoattractant-induced F-actin polymerization and polarization characteristics

In vivo Effectiveness of Lithium on Impaired Neutrophil Chemotaxis in Shwachman-Diamond Syndrome

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