bluuebunny/crossref_metadata_2025_split huggingface dataset:
Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl‐lysophospholipid ET‐18‐OCH3
Authors: Wierenga Pieter K. , Setroikromo Rita , Vellenga Edo , Kampinga Harm H. 
Published: July 2010

Hyperthermia has been shown to be a potential purging modality in autologous stem cell transplantation settings owing to its selective toxicity towards leukaemic cells. We describe two approaches to further increase the therapeutic index of the hyperthermic purging modality by using normal murine bone marrow cells and a murine model for acute myeloid leukaemia. First, the tetrapeptide AcSDKP was used to protect the normal haematopoietic progenitor cells against hyperthermic damage. Pretreatment for 8 h at 37°C with 1 × 10−9 mol/l AcSDKP resulted in a decrease in hyperthermic sensitivity of only normal haematopoietic progenitor cells. This combined treatment protocol revealed a therapeutic index (ratio of surviving fractions of normal vs. leukaemic cells) of > 500, which was considered to be sufficient for purging. This was confirmed in vivo by the survival of lethally irradiated recipients transplanted with purged simulated remission bone marrow (1 × 106 normal bone marrow cells and 5 × 104 leukaemic cells). A further increase of the therapeutic index cells was achieved by the alkyl‐lysophospholipid ET‐18‐OCH3. An incubation for 4 h at 37°C with 25 μg/ml in the presence of 5% fetal calf serum preferentially enhanced the cytotoxic effect towards the leukaemic stem cell. The combination of AcSDKP and ET‐18‐OCH3 with hyperthermia resulted in a therapeutic index of > 5000. This enabled a reduction of the hyperthermic treatment and will further minimize the toxicity to normal haematopoietic stem cell subsets, while a therapeutic index far above the required value is achieved. This tripartite purging treatment therefore offers a safe and fast purging protocol for the elimination of residual leukaemic cells in autografts.
Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres
Authors: Kuter David J. , Bain Barbara , Mufti Ghulam , Bagg Adam , Hasserjian Robert P. 
Published: July 2010

SummaryIn bone marrow biopsies, stromal structural fibres are detected by reticulin and trichrome stains, routine stains performed on bone marrow biopsy specimens in diagnostic laboratories. Increased reticulin staining (reticulin fibrosis) is associated with many benign and malignant conditions while increased trichrome staining (collagen fibrosis) is particularly prominent in late stages of severe myeloproliferative diseases or following tumour metastasis to the bone marrow. Recent evidence has shown that the amount of bone marrow reticulin staining often exhibits no correlation to disease severity, while the presence of type 1 collagen, as detected by trichrome staining, is often associated with more severe disease and a poorer prognosis. It was originally thought that increases in bone marrow stromal fibres themselves contributed to the haematopoietic abnormalities seen in certain diseases, but recent studies suggest that these increases are a result of underlying cellular abnormalities rather than a cause. A growing body of evidence suggests that increased deposition of bone marrow stromal fibres is mediated by transforming growth factor‐β and other factors elaborated by megakaryocytes, but it is likely that other cells, cytokines and growth factors are also involved. This suggests new avenues for investigation into the pathogenesis of various disorders associated with increased bone marrow stromal fibres.
Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease
Authors: Oyajobi Babatunde O. , Garrett I. Ross , Gupta Anjana , Flores Alda , Esparza Javier , Muñoz Steve , Zhao Ming , Mundy Gregory R. 
Published: July 2010

SummaryImpaired bone formation contributes to the lack of bone healing in multiple myeloma and there is a need for agents with bone anabolic properties to reverse the bone deficit in patients. Bortezomib, a proteasome inhibitor with antitumour efficacy in myeloma patients, enhanced new bone formation in mouse calvarial cultures; this effect was blocked by dickkopf 1(Dkk1), an antagonist of Wnt signalling implicated in myeloma bone disease. Bortezomib inhibited Dkk1 expression in calvariae and bone marrow‐derived stromal cells, suggesting a novel mechanism by which bortezomib exerts its effects in bone. Clinical trials in patients with myeloma bone disease are needed to validate these results.
Polymorphisms in von Willebrand factor gene promoter influence the glucocorticoid‐induced increase in von Willebrand factor: the lesson learned from Cushing syndrome
Authors: Casonato Alessandra , Daidone Viviana , Sartorello Francesca , Albiger Nora , Romualdi Chiara , Mantero Franco , Pagnan Antonio , Scaroni Carla 
Published: July 2010

SummaryCushing syndrome (CS) features high‐glucocorticoid secretion and an associated hypercoagulable state often involving an increase in von Willebrand factor (VWF). To identify any influence of VWF promoter on glucocorticoid haemostatic effects, four polymorphic positions (‐3267, ‐2708, ‐2659 and ‐2525) segregating as haplotypes 1 (GCAG) or 2 (CTGA) were analysed in 50 CS patients with high VWF (group I) and normal VWF (group II) levels, divided by ABO group. Genotype distribution differed significantly between the two groups: in group I, 25·8% had genotype 1/1, 22·6% had 2/2 and 38·7% had 1/2; in group II, 0% had genotype 1/1, 57·9% had 2/2 and 31·6% had 1/2 (P = 0·03). Patients’ genotypes also differed from those of controls (P = 0·003 for group I, P = 0·03 for group II). Haplotype 1 was prevalent in group I, haplotype 2 in group II (P = 0·002), both with frequencies differing from controls (P < 0·001 and P = 0·009). By odds ratio analysis, genotype 1/1 carried a 12 times greater risk of high‐VWF levels than genotype 2/2, and haplotype 1 carried a five times greater risk than haplotype 2. Our findings suggest that VWF promoter haplotypes influence the corticosteroid‐mediated increase in VWF.
Influences on parental evaluation of the content of early intervention following early identification of deafness: a study about parents' preferences and satisfaction
Authors: Gascon‐Ramos M. , Campbell M. , Bamford J. , Young A. 
Published: July 2010

AbstractBackground  Following early identification of deafness attention has now turned to early intervention of deaf children and their families. Improved outcomes associated with early identification and quality early intervention have been long predicated. However, the effectiveness of early intervention is mediated by parents' values, beliefs and preferences. How these mediate the nature of intervention is key to understand how early intervention impacts on outcomes.Methods  Eighty‐two parents of early identified deaf children participated in a longitudinal study (UK). Data from parents were collected through postal questionnaires. Parents provided repeated data on My Views on Services questionnaire (at 6‐month interval). They also filled in once the Trait Emotional Intelligence questionnaire and a socio‐demographic questionnaire. Statistical analyses were carried out to investigate parents' preferences and satisfaction with content of early intervention.Results  Families had contact with a median of five professionals and 45 h of early intervention (on a 6‐month basis). Parents view all content of early intervention as important. Content that supported parents to support their child was a priority for them. Length of involvement in early intervention and mothers' personal disposition did not have an effect on ratings of importance. However, mothers' educational background did influence ratings on the Supporting Parents subscale (F= 3.41; d.f. = 3 and 66; P= 0.023). Parents' satisfaction scores with content of early intervention were neutral (mean: 0.2; SD 0.8). Parents were more satisfied with contents that supported them to support their deaf child, than with those aimed to support themselves. Parents' satisfaction with content that supported themselves did increase with length of involvement in early intervention (t=−3.435; P= 0.004). Significant correlations (r= 0.221; r= 0.230; r= 0.252) between mothers' well‐being and satisfaction scores were identified.Conclusion  These findings underscore the importance of understanding how parents' beliefs, values and perceived need impact on their experience of early intervention.
HLA-DR, DQ and T cell antigen receptor constant beta genes in Japanese patients with ulcerative colitis
Authors: KOBAYASHI K , ATOH M , KONOEDA Y , YAGITA A , INOKO H , SEKIGUCHI S 
Published: July 2010

SUMMARY
We studied the T cell antigen receptor (TcR) constant beta chain genes on HLA typed Japanese patients with ulcerative colitis (UC). A TcR constant beta EcoRI 6.0-kb fragment was present in all Japanese UC patients (n= 17) but completely absent in the controls (n= 35) (x2= 47.6, P&lt;0.001). The frequency of HLA-DR2 antigen was significantly higher in UC patients (85%versus 28% in controls, P&lt;0.001). Furthermore, HLA-DQwl antigen was also increased in UC patients (96%versus 60% in controls, P&lt;0.001). However, HLA-DR4 antigen was significantly decreased in UC patients (12%versus 37%, P=0.02). HLA-DR1 antigen was not found in UC patients and was present in only 15% of the controls. These results suggest that TcR beta chain and HLA-DQwl antigen may be important in the pathogenesis of Japanese UC.
Identification and characterization of IgA andVicia villosa-binding T cell subsets in rheumatoid arthritis
Authors: FORTUNE F , KINGSTON J , BARNES C S , LEHNER T 
Published: July 2010

SUMMARYAutoimmunity may be due to augmentation of immune responses by human CD8 cells which bind the lectin Vicia villosa (VV). We have investigated T cells in rheumatoid arthritis (RA) by double immunofluorescence flow cytometry, in order to assess VV-binding CD8 and CD4 cells from the peripheral blood and synovial fluid. A significant increase in CD8+ VV adherent (P&lt;0.0001) and CD4+ VV adherent cells (P &lt;0.001) was found in synovial fluid, as compared with peripheral blood from patients with RA. A significant increase in VV-binding CD8+ or CD4+ cells was, however, not found in the blood of patients with RA, as compared with controls. We suggest that the lack of VV-binding T cells separated from blood, in contrast to those from synovial fluid, may be due to an inhibiting agent expressing N-acetyl d-galactosamine. Indeed, IgA1 is rich in N-acetyl d-galactosamine, it inhibits VV binding to T cells and is significantly bound to CD8 cells (P&lt;0.001). The IgA1 was then characterized and in about half the patients J chains and secretory component was found, suggesting that the IgA1 is of the polymeric and secretory variety. IgA bound to the T cells engaged the Fcα receptors and a significant decrease in the Fcα receptors was found in CD8 cells (P&lt;0.000l) and CD4 cells (P&lt;0.0l). Desorption studies were then carried out on CD8 and CD4 cells which showed that a loss of cell-bound IgA1 was associated with an increase in VV binding. Conversely, adsorption of IgA to T cells was associated with a loss in VV binding. The results suggest that the failure of VV binding to CD8+ andCD4+ cells from peripheral blood of patients with RA can be ascribed to cell-bound IgA 1. Cytophilic IgA1 may inhibit the function of CD8+ VV binding cells, thereby preventing augmentation of the systemic immune response, consistent with the lack of extra-articular disease in these patients with RA.
Prostaglandin E1 suppresses macrophage infiltration and ameliorates injury in an experimental model of macrophage-dependent glomerulonephritis
Authors: CATTELL V , SMITH J , COOK H T 
Published: July 2010

SUMMARYProstaglandin E1 (PGE1) suppresses macrophage infiltration and ameliorates injury in an experimental model of macrophage dependent glomerulonephritis. Macrophages are mediators of glomerular injury in models of proliferative glomerulonephritis. We have recently shown that macrophages in glomerulonephritis have low prostaglandin E2 (PGE) generation, and other evidence implicates eicosanoids as regulators of macrophage activation. Here we have studied in rats the effect of 15(S)-15-methyl PGE1 (M-PGE1) on accelerated nephrotoxic nephritis, a model of acute macrophage-dependent glomerular injury. M-PGE1 ameliorated proteinuria (day 4; 61 ± 13 mg/24 h, n=9; vehicle treated, 164.17 mg/24 h, n=11; P&lt;0.002) and glomerular hypercellularity; quantification of infiltrating macrophages by isolating glomerular cells showed reduction in the numbers of macrophages (44.9/glomerulus; vehicle treated, 119.15/glomerulus; P &lt;0.02) with inhibition of Ia antigen expression on infiltrating macrophages (8.5%; vehicle treated 25.4%P &lt; 0.05). Glomerular binding of nephrotoxic globulin and levels of autologous antibodies were not affected by M-PGE1. Thus the mechanism of suppression involves inhibition of macrophage accumulation and activation. M-PGE1 administered to normal rats did not affect numbers of resident leucocytes (12.6±1.5/glomerulus; vehicle treated, 13.2±1.3/glomerulus) or alter Ia antigen expression (4.1±0.2 Ia + cells/glomerulus; vehicle treated, 3.9±0.6/glomerulus). This study suggests a therapeutic role for PGE1 in this type of glomerulonephritis, and has implications for the pathophysiology of macrophage-mediated inflammation.
An increase in polymorphonuclear leucocyte chemotaxis accompanied by a change in the membrane fluidity with age during childhood
Authors: YASUI K , MASUDA M , TSUNO T , MATSUOKA T , KOMIYAMA A , AKABANE T , MURATA K 
Published: July 2010

SUMMARY
Leucocyte membrane fluidity affects cell deformability as well as the accessibility of receptors and the degree of their exposure on the membrane. These effects modulate the subsequent cellular responsiveness. We have assayed membrane fluidity of polymorphonuclear leucocytes of children, using an excimer-forming lipid technique in flow cytometry. and evaluated its relation to their chemotaxis to a formyl peptide. We report that membrane fluidity and chemotaxis of polymorpho nuclear leucocytes are increased with age. These findings may have important implications for the physiological processes in polymorphonuclear leucocyte motility during childhood.
Natural thymocytotoxic autoantibodies in non-obese diabetic (NOD) mice: characterization and fine specificity
Authors: LEHUEN A , ALTMAN J , BACH J-F , CARNAUD C 
Published: July 2010

SUMMARYThe NOD mouse is a model of human juvenile type I diabetes mellitus. As in humans and in the BB rat model, the development of diabetes in NOD mice is accompanied by evident manifestations of cell-mediated and humoral autoimmunity. Beside autoantibodies directed at putative islet cell antigens, NOD sera contain antibodies with specificity for lymphocyte cell-surface determinants. Here we demonstrate that these anti-lymphocyte antibodies have the same characteristics of target cell specificity, of isotype, and of temperature reactivity, as do natural thymocytotoxic autoantibodies (NTA) from lupic NZB mice, or from mice undergoing polyclonal B cell activation. We also demonstrate that the thymocytotoxic activity of NOD sera is not due to cross-reactive anti-insulin antibodies. Biochemical characterization of the determinants recognized by these anti-lymphocyte antibodies reveals two membrane-associated proteins of 28 and 33 kD, partially similar to the two peptides recognized by NTA from NZB mice (30 and 33 kD). Altogether, these results suggest that NOD mice develop manifestations of polyclonal B cell activation similar to those observed in lupus-prone mice. The relationship of these anomalies with the organ-specific pancreatic disease remains to be properly evaluated.
In vitroproduction of B cell growth factor and B cell differentiation factor by peripheral blood mononuclear cells and bronchoalveolar lavage T lymphocytes from patients with idiopathic pulmonary fibrosis
Authors: EMURA M , NAGAI S , TAKEUCHI M , KITAICHI M , IZUMI T 
Published: July 2010

SUMMARYThe activation of B lymphocytes and formation of immune complexes have been suggested to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To investigate the mechanisms of activation of B lymphocytes, we studied the production of B cell growth factor (BCGF) and B cell differentiation factor (BCDF) in patients with IPF and those with interstitial pneumonia associated with collagen vascular diseases (IP-CVD), in comparison with healthy controls. Culture supernatants of peripheral blood mononuclear cells from patients with IPF induced more IgM and IgA production by B lymphocytes than those from healthy controls, indicating a higher production of BCDF in the patients. Culture supernatants of T lymphocytes obtained from bronchoalveolar lavage fluids (BALF) of patients with IPF induced higher proliferation of B lymphocytes than those from healthy controls, indicating a higher production of BCGF. An increase in production of BCGF and BCDF was not observed in patients with IP-CVD. In the light of these results, it was suggested that there may be an imbalance in T lymphocyte subsets that release lymphokines like BCGF and BCDF in patients with IPF, and that the subsets may differ between blood and BALF. It remains to be elucidated whether the activation of B lymphocytes depending on T lymphocytes determines the development of disease in IPF.
Prolonged circulation of immune complexes due to various altered immune functions contributes to nephritis in MKL/lprmice
Authors: GRANHOLM N A , CAVALLO T 
Published: July 2010

SUMMARYTo gain some insight into the pathogenesis of protiferativc lupus nephritis in MRL/Ipr mice we investigated the kinetics of removal of immune complexes from the circulation, the carrier stale of blood cells, the uptake of complexes by the mononuclear phagocyte system, and the localization of complexes in kidneys. In nephritic MRL/lpr mice challenged with a subsaturating dose of radiolabelled complexes (2.5 mg bovine serum albumin-anti-bovine serum albumin) liver uptake was profoundly decreased, removal of circulating complexes was delayed, and 12-h kidney localization of complexes was enhanced 7.3-fold, in comparison to control mice. The findings were not encumbered by differences in complement concentration and most likely are attributable to various altered immune functions: spontaneous polyclonal activation of Bcells, enhanced production of endogenous immune complexes, delayed removal of complexes from the circulation, and decreased uptake of complexes by the mononuclear phagocyte system. In concert, such altered functions contribute to prolonged circulation of complexes to result in their enhanced deposition in the microcirculation.
Influence of FK506 and cyclosporin A on alloantibody production and lymphocyte activation following blood transfusion
Authors: WOO J , PROPPER D J , MACLEOD A M , THOMSON A W 
Published: July 2010

SummaryThe effect of administration of cyclosporin A (CyA) or the novel macrolide FK506 was investigated in AO rats given DA blood transfusions. CyA (10 mg/kg, orally) or FK506 (1 mg/kg, intramuscularly) administered for 14 days from the time of transfusion effectively inhibited primary anti-MHC class I alloantibody production. This profound inhibitory effect persisted throughout the 2-month investigation period, with little increase in ‘secondary’ alloantibody production following a challenge injection 28 days after drug withdrawal. Flow cytometrie analysis revealed no significant differences in the absolute numbers of W3/25+ (CD4+), OX-8+ (CD8+) or OX-12+ (B lymphocytes), in either the spleen or peripheral blood of transfused compared with normal, untreated animals. However, a small but significant increase in the numbers of splenocytes expressing the activation marker OX-40 (activated CD4+ cells) was observed in transfused animals. Either CyA or FK506 significantly reduced the number of cells expressing OX-39 (interleukin-2 receptors) and OX-40. Treatment of transfused animals with CyA, but not FK506 for 14 days resulted in minor, transient reduction in peripheral blood OX-19+ and W3/25+ cells, while ‘sparing’ the OX-8+ cells; these changes were not observed in spleens. In contrast, the absolute spleen cell numbers of OX-19+, W3/25+ and OX-8+ cells were significantly reduced in transfused animals given 14 days of FK506 treatment, while the corresponding blood cells were unaffected. Induction of splenic lymphoproliferative responses by the T cell mitogen concanavalin A remained normal in animals receiving transfusion alone or with CyA. In contrast, profound inhibition of mitogenic responses was observed in FK506-treated animals and this inhibitory effect declined gradually following drug withdrawal. No non-specific suppressor cell activity was detected in the spleens of rats given transfusion alone or in CyA or FK506-treated transfused animals.
Experimental murine thyroiditis induced by porcine thyroid peroxidase and its transfer by the antigen-specific T cell line
Authors: KOTANI T , UMEKI K , HIRAI K , OHTAKI S 
Published: July 2010

SUMMARYThyroid peroxidase purified from porcine thyroid (pTPO) was found to induce an experimental murine thyroiditis with genetic restriction which was very different from that induced by mouse thyroglobulin (mTg). C57BL/6 and C57BL/10 (both H-2b) were good responders for thyroiditis, whereas A/J (H.2a), BALB/c (H-2d), DBA/2 (H-2d), CBA (H-2k), C3H/He (H-2k), and SJL/J (H-2s) were poor responders. Genetic analyses using congenic or recombinant strains revealed the following results: The H-2-linked gene (probably the I-A subregion) had a weak association with the induction of thyroiditis, and at least one non-H-2-linked gene controlled the development of thyroid lesions; antibody production to pTPO, porcine thyroglobulin (pTg) and mTg did not correlate with the incidence of thyroiditis in any strain. None of the murine thyroid microsome-specific antibodies tested by the indirect immunofluorescent technique was detected. The T cell line specific for pTPO was successfully transferred to produce thyroid lesions in C57BL/6 mice. Thyroiditis appeared 3 days after the transfer of T cell blasts, and a low concentration of anti-pTPO antibodies was detected concurrently. Thyroid lesions remained up to 48 days with almost the same extent of thyroiditis, but anti-pTPO antibodies gradually increased. In the vaccination experiments using either 0–645 C/kg (2500 rad)-irradiated or 0.3% glutaraldehyde-fixed T cell blasts, the induction of thyroid lesions by transfer was strongly suppressed. Glutaraldehyde fixation was more effective than X-irradiation in preventing thyroiditis after the transfer of T cell blasts. Vaccination also suppressed significantly the development of thyroid lesions after pTPO administration.