bluuebunny/crossref_metadata_2025 huggingface dataset:
Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials
Authors: Stanworth S. J. , Brunskill S. J. , Hyde C. J. , McClelland D. B. L. , Murphy M. F.
Published: June 2004

Randomized controlled trials of good quality are a recognized means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomized trials involving fresh frozen plasma (FFP) has been undertaken in parallel to the drafting of the updated British Committee for Standards in Haematology guidelines on the use of FFP. A total of 57 trials met the criteria for inclusion in the review. Most clinical uses of FFP, currently recommended by practice guidelines, are not supported by evidence from randomized trials. In particular, there is little evidence for the effectiveness of the prophylactic use of FFP. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias. No studies have taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. There is a need to consider how best to develop new trials to determine the efficacy of FFP in different clinical scenarios to provide the evidence base to support national guidelines for transfusion practice. Trials of modified FFP (e.g. pathogen inactivated) are of questionable value when there is little evidence that the standard product is an effective treatment.
Haemostatic and inflammatory biomarkers in advanced chronic heart failure: role of oral anticoagulants and successful heart transplantation
Authors: Cugno Massimo , Mari Daniela , Meroni Pier Luigi , Gronda Edoardo , Vicari Francesco , Frigerio Maria , Coppola Raffaella , Bottasso Bianca , Borghi Maria Orietta , Gregorini Luisa
Published: June 2004

Advanced chronic heart failure (CHF) is associated with abnormal haemostasis and inflammation, but it is not known how these abnormalities are related, whether they are modified by oral anticoagulants (OAT), or if they persist after successful heart transplantation. We studied 25 patients with CHF (New York Heart Association class IV, 10 of whom underwent heart transplantation) and 25 age‐ and sex‐matched healthy controls by measuring their plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin (TAT) complexes, tissue plasminogen activator (t‐PA), plasminogen activator inhibitor‐1 (PAI‐1), D‐dimer, factor VII (FVII), fibrinogen, von Willebrand factor (VWF), tumour necrosis factor (TNF), soluble TNF receptor II (sTNFRII), interleukin 6 (IL‐6), soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), endothelial‐selectin (E‐selectin) and thrombomodulin. CHF patients had higher plasma levels of TAT, D‐dimer, t‐PA, fibrinogen, VWF, TNF, IL‐6, sTNFRII, sVCAM‐1 (P = 0·0001), sICAM‐1 (P = 0·003) and thrombomodulin (P = 0·007) than controls. There were significant correlations (r = 0·414–0·595) between coagulation, fibrinolysis, endothelial dysfunction and inflammation parameters, which were lower in those patients treated with OATs. Heart transplantation led to reductions in fibrinogen (P = 0·001), VWF (P = 0·05), D‐dimer (P = 0·05) and IL‐6 levels (P = 0·05), but all the parameters remained significantly higher (P = 0·01–0·0001) than in the controls. Advanced CHF is associated with coagulation activation, endothelial dysfunction and increased proinflammatory cytokine levels. Most of these abnormalities parallel each other, tend to normalize in patients treated with OATs and, although reduced, persist in patients undergoing successful heart transplantation, despite the absence of clinical signs of CHF.
Analysis of IgVH gene mutations in B cell chronic lymphocytic leukaemia according to antigen‐driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery
Authors: Degan Massimo , Bomben Riccardo , Bo Michele Dal , Zucchetto Antonella , Nanni Paola , Rupolo Maurizio , Steffan Agostino , Attadia Vincenza , Ballerini Pier Ferruccio , Damiani Daniela , Pucillo Carlo , Poeta Giovanni Del , Colombatti Alfonso , Gattei Valter
Published: June 2004

Cases of B‐cell chronic lymphocytic leukaemia (B‐CLL) with mutated (M) IgVH genes have a better prognosis than unmutated (UM) cases. We analysed the IgVH mutational status of B‐CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B‐CLLs, 124 cases were examined for IgVH gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity‐determining regions as evidence of antigen‐driven selection; this identified three B‐CLL subsets: significantly mutated (sM), with evidence of antigen‐driven selection, not significantly mutated (nsM) and UM, without such evidence and IgVH gene per cent mutations above or below the 2% cut‐off. sM B‐CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgVH genes. sM, nsM and UM B‐CLL were also characterized for the biased usage of IgVH families, intraclonal IgVH gene diversification, preference of mutations to target‐specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase ζ and η and activation‐induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B‐CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B‐CLL.
Leukaemia – a developmental perspective
Authors: Izraeli Shai
Published: June 2004

Leukaemia is characterized by the accumulation of malignant haematopoietic precursors. Recent studies have revealed that acquired alterations in genes that regulate normal haematopoiesis are frequently detected in leukaemia. The progression to leukaemia depends on additional mutations that promote the survival of developmentally arrested cells. This review describes three examples of this general paradigm of leukaemogenesis: RUNX1 abnormalities in acute leukaemias, GATA1 mutations in the leukaemias of Down syndrome, and SCL and LMO2 ectopic expression in T cell acute lymphoblastic leukaemia.
Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia
Authors: Briggs Carol , Kunka Stefan , Hart Dan , Oguni Shinichiro , Machin Samuel J.
Published: June 2004

A new automated method to reliably quantify reticulated platelets, expressed as the immature platelet fraction (IPF), has been developed utilizing the XE‐2100 blood cell counter with upgraded software (Sysmex, Kobe, Japan). The IPF is identified by flow cytometry techniques and the use of a nucleic acid specific dye in the reticulocyte/optical platelet channel. The clinical utility of this parameter was established in the laboratory diagnosis of thrombocytopenia due to increased peripheral platelet destruction, particularly autoimmune thrombocytopenic purpura (AITP) and thrombotic thrombocytopenic purpura (TTP). Reproducibility and stability results over 48 h were good. An IPF reference range in healthy individuals was established as 1·1–6·1%, with a mean of 3·4%. Patients in whom platelet destruction might be abnormal, were studied and two of these patients followed serially during the course of treatment. The IPF was raised in several disease states. The most significant increases in IPF values were found in patients with AITP (mean 22·3%, range 9·2–33·1%) and acute TTP (mean 17·2%, range 11·2–30·9%). Following patients during treatment demonstrated that as the platelet count recovered the IPF% fell. These results show that a rapid, inexpensive automated method for measuring the IPF% is feasible and should become a standard parameter in evaluating the thrombocytopenic patient.
Response to desmopressin of factors XI, X and V in patients with factor VIII deficiency and von Willebrand disease
Authors: White B. , Lawler P. , Riddell A. , Nitu‐Whalley I. C. , Hermans C. , Lee C. A. , Brown S. A.
Published: June 2004

Desmopressin [1‐deamino‐8‐d‐arginine vasopressin (DDAVP)] has been successfully used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and may represent an effective treatment for mild FXI deficiency. We assessed the DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33 individuals with VWD or MHA. DDAVP did not produce a clinically significant increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean ± SD FXI:C pre‐DDAVP (time 0) and at 1 h post‐DDAVP was 90·7 (±22·9) U/dl and 92·1 (±20·9) U/dl, respectively. The mean (±SD) FXI:Ag at time 0 and 1 h was 92·2 (±20·1) U/dl and 89·9 (±21·3) U/dl, respectively. There was a small reduction at 1 h post‐DDAVP in both FV:C, from 101·8 (±20·9) U/dl to 97·2 (±21·4) U/dl (P < 0·001), and FX:C from 103 (±19·5) U/dl to 98·8 (±18·7) U/dl (P < 0·001). No significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post‐DDAVP. This study failed to demonstrate a clinically significant increase in the levels of FXI, FX or FV following administration of DDAVP.
Blood dendritic cells in patients with acute lymphoblastic leukaemia
Authors: Mami Naira Ben , Mohty Mohamad , Chambost Hervé , Gaugler Béatrice , Olive Daniel
Published: June 2004

Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play a key role in the initiation of immune responses. In this study, we show a severe reduction of MDCs and PDCs in patients with B lineage acute lymphoblastic leukaemia (B‐ALL; P = 0·01 vs. controls). DCs from patients with T lineage ALL (T‐ALL) were quantitatively and functionally comparable to healthy donors, as demonstrated by secretion of interleukin (IL)‐12p70 and interferon‐α. In vitro, the circulating CD34+ fraction of B‐ALL cases did not generate either CD1a+ MDCs or PDCs, suggesting that DC development is probably affected in B‐ALL, but not in T‐ALL.
Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays
Authors: Moyo Victor M. , Mukhina Galina L. , Garrett Elizabeth S. , Brodsky Robert A.
Published: June 2004

Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, acquired disorder of blood cells caused by mutation of the phosphatidylinositol glycan class A (PIG‐A) gene. The disease often manifests with haemoglobinuria, peripheral blood cytopenias, and venous thrombosis. The natural history of PNH has been documented in retrospective series; but there has only been one study that correlated the more sensitive and specific flow cytometric assays that have become available in the last decade with severe symptoms associated with PNH. In a retrospective analysis of 49 consecutive patients with PNH evaluated at Johns Hopkins, large PNH clones were associated with an increased risk for thrombosis as well as haemoglobinuria, abdominal pain, oesophageal spasm, and impotence. Of the 14 (29%) patients that developed thrombosis, nine died; six of these from complications related to thromboses. According to logistic regression modelling, for a 10% change in PNH clone size, the odds ratio for risk of thrombosis was estimated to be 1·64. No patient with <61% PNH granulocytes developed a thrombosis, whereas 12 of 22 patients (54·5%) with ≥61% PNH granulocytes manifested with thrombosis. These data not only confirm that the size of the PNH clone correlates with the risk for thrombosis, but they also suggest a correlation of PNH clone size to more symptomatic PNH.
Most cases of primary salivary mucosa‐associated lymphoid tissue lymphoma are associated either with Sjoegren syndrome or hepatitis C virus infection
Authors: Ambrosetti Achille , Zanotti Roberta , Pattaro Cristian , Lenzi Lorenza , Chilosi Marco , Caramaschi Paola , Arcaini Luca , Pasini Felice , Biasi Domenico , Orlandi Ester , D'Adda Mariella , Lucioni Marco , Pizzolo Giovanni
Published: June 2004

Salivary gland mucosa‐associated lymphoid tissue (MALT) lymphomas (SGML) are rare, as are data concerning their behaviour. We analysed clinical features at presentation, particularly the association with Sjoegren syndrome (SS) and hepatitis C virus (HCV) infection, and outcome in 33 cases of SGML diagnosed between March 1985 and April 2003. There were five males and 28 females, with a median age of 61 years. At presentation, 12/33 (36%) had multiple salivary glands or mucosal involvement and four had bone marrow infiltration. Ann Arbor stage was IE in 15 (46%), IIE in four (12%) and IV in 14 patients (42%). Fifteen patients had a history of SS (46%), two of other autoimmune diseases, seven of HCV infection. No case had both SS and HCV. Of the 29 treated patients, 17 received surgery or local radiotherapy; 69% achieved complete remission. Histological transformation occurred in four (12%). Five patients died (three of lymphoma, two of unrelated causes). The 5 year‐overall survival (OS), cause‐specific survival and progression‐free survival was 85 ± 8%, 94 ± 6% and 65 ± 10% respectively. Overall, the disease course was indolent, despite the advanced stage at diagnosis, and local therapy often appeared to be adequate. The only prognostic factors influencing OS were histological transformation and age. The close association of SGML with either autoimmune diseases or HCV infection in our series (73%) confirms their possible role in the pathogenesis of these lymphomas.
Improved extension of platelet storage in a polyolefin container with higher oxygen permeability
Authors: Yuasa Takeshi , Ohto Hitoshi , Yasunaga Reiko , Kai Takanori , Shirahama Noriaki , Ogata Takashi
Published: June 2004

This study evaluated a newly developed polyolefin bag, which has a 50%/m2 higher oxygen permeability to extend the shelf‐life of platelets. Single‐donor aphaeresis platelets were pooled, separated equally into two bags, PO‐80 (0·8 l capacity) and KBP‐PO (1 l capacity) for control, and stored in plasma for up to 7 d. Platelet biochemical and functional parameters were monitored in bags containing high (4·2 × 1011/250 ml/bag, n = 9) and low (2·0 × 1011/200 ml/bag, n = 3) concentrations of platelets over the storage period. After 7 d of storage, the PO‐80 bags containing high concentrations of platelets had a better pH (mean pH 6·74) than those stored in KBP‐PO (pH 6·32, P < 0·01); none of the nine PO‐80 bags with a high platelet concentration had a pH below 6·2, compared with four of nine controls (P < 0·05). Similarly, lactate values were 20·19 mmol/l and 28·09 mmol/l respectively (P < 0·05). Aerobic metabolism was maintained better with greater O2 consumption and less lactate generation in high‐platelet concentration PO‐80 bags than in the control bags. A significant difference was also found in pH, pCO2 and lactate levels between the two bags containing low concentrations of platelets during the 7‐d period. The in vitro characteristics of platelets declined less over 7 d when stored in a higher oxygen permeable container than in a marketed bag.
A mouse model to study organ homing behaviour of haemopoietic progenitor cells reveals high selectivity but low efficiency of multipotent progenitors to home into haemopoietic organs
Authors: Henschler R. , Fehervizyova Z. , Bistrian R. , Seifried E.
Published: June 2004

To study the homing behaviour of an enriched multipotent primitive haemopoietic progenitor cell (HPC) population in mice, undifferentiated murine factor‐dependent multipotent HPCs (FDCP‐mix), stably transfected with the green fluorescence protein gene, were intravenously injected into congenic mice. After 2 or 24 h, cell suspensions were prepared from bone marrow, spleen, lung, liver, muscle, colon, kidney, brain or blood of the mice and analysed by flow cytometry. Using direct quantifiable determination of total HPC numbers homed per organ and a method to estimate the degree of organ contamination by HPC that were present in blood vessels within the organs before preparation, the highest absolute numbers of HPC were detected in the liver and lungs at 2 h but this was sharply decreased at 24 h, whereas HPC selectively accumulated in the bone marrow and spleen at 24 h after transplantation. Only a few HPC were detected in other organs. The seeding efficiency of homed FDCP‐mix HPC to the bone marrow and spleen was approximately 1·5% and ranged between that of primary whole bone marrow cells and lineage‐depleted freshly isolated bone marrow cells. Pretreatment of HPC with inhibitors of signal transduction indicated that short‐term homing of multipotent HPC into haemopoietic organs is an active process requiring co‐ordinated intracellular signalling through Rho family small GTPases and protein kinases. Thus, short‐term homing of FDCP‐mix HPC into haemopoietic organs is of low efficiency but high selectivity, and provides a system to analyse the mechanisms and manipulation of primitive HPC which saves large numbers of donor animals.
Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16·3;q32) in multiple myeloma
Authors: Stewart James Peter , Thompson Alexander , Santra Madhumita , Barlogie Bart , Lappin Terence R. J. , Shaughnessy John
Published: June 2004

The t(4;14)(p16;q32) translocation seen in c. 18% of newly diagnosed multiple myeloma (MM) cases, results in FGFR3 activation and creation of an IGH/MMSET fusion transcript. We have recently shown that FGFR3 is activated in only 75% of t(4;14)+ cases, suggesting that alternative genes near the breakpoint may be involved in the transforming event. The gene, TACC3, located just 50 kb telomeric of FGFR3, with transforming capacity, therefore represented a candidate gene. Using a real‐time quantitative polymerase chain reaction‐based approach on a cohort of 54 patients, we found a statistically significant, twofold increase in TACC3 expression in t(4;14)+ cases. TACC3, MMSET and p21 values were positively correlated in all cases and, of particular interest, six patient samples [three t(4;14)−, three t(4;14)+] samples showed a joint up‐regulation of TACC3, MMSET and p21. Although a poor prognosis is linked with elevated MMSET expression, an extended follow‐up period will be required to evaluate the significance of elevated TACC3 and p21 expression in this subgroup of MM.
Two novel mutations in severe factor VII deficiency
Authors: Gomez Keith , Laffan Michael A. , Kemball‐Cook Geoffrey , Pasi John , Layton Mark , Singer Jack D. , Tuddenham Edward G. D. , McVey John H.
Published: June 2004

We have characterized the molecular defect in two families with severe factor VII (FVII) deficiency. In family I, the proband was found to be homozygous for a novel 18 bp deletion in exon  8 (g.10896‐10913del) resulting in the in‐frame deletion of six amino acids in the serine protease domain. Molecular modelling suggests the deletion is likely to disrupt folding of the FVII molecule. The reduced FVII antigen (21 U/dl) and negligible activity (0·4 U/dl) in the patient's plasma indicated that the deletion affected both the secretion/stability and function of the mutant protein. In family II, the proband was found to be a compound heterozygote for a novel missense mutation (g.7884G>A; FVII G117R) in exon  5 encoding the EGF2 domain of FVII and a nonsense mutation (g.8960C>T; FVII R152X) in exon  6. Extensive sequence comparison in a wide evolutionary context suggested that the Gly117 residue is critical for structure of FVII. The grossly reduced FVII antigen (1·1 U/dl) and activity (0·4 U/dl) plasma values indicate the mutation primarily affected the folding/secretion or stability of the protein.
Renin–angiotensin system expression in rat bone marrow haematopoietic and stromal cells
Authors: Strawn William B. , Richmond Renee S. , Ann Tallant E. , Gallagher Patricia E. , Ferrario Carlos M.
Published: June 2004

The existence of a bone marrow renin–angiotensin system (RAS) is evidenced by the association of renin, angiotensin converting enzyme (ACE), and angiotensin (Ang) II and its AT1 and AT2 receptors with both normal and disturbed haematopoiesis. The expression of RAS components by rat unfractionated bone marrow cells (BMC), haematopoietic‐lineage BMC and cultured marrow stromal cells (MSC) was investigated to determine which specific cell types may contribute to a local bone marrow RAS. The mRNAs for angiotensinogen, renin, ACE, and AT1a and AT2 receptors were present in BMC and in cultured MSC; ACE2 mRNA was detected only in BMC. Two‐colour flow fluorocytometry analysis showed immunodetectable angiotensinogen, ACE, AT1 and AT2 receptors, and Ang  II, as well as binding of Ang  II to AT1 and AT2 receptors, in CD4+, CD11b/c+, CD45R+ and CD90+ BMC and cultured MSC; renin was found in all cell types with the exception of CD4+ BMC. Furthermore, Ang  II was detected by radioimmunoassay in MSC homogenates as well as conditioned culture medium. The presence of Ang  II receptors in both haematopoietic‐lineage BMC and MSC, and the de novo synthesis of Ang  II by MSC suggest a potential autocrine–paracrine mechanism for local RAS‐mediated regulation of haematopoiesis.
Expression of FoxP3, a key molecule in CD4+CD25+ regulatory T cells, in adult T‐cell leukaemia/lymphoma cells
Authors: Karube Kennosuke , Ohshima Koichi , Tsuchiya Takeshi , Yamaguchi Takahiro , Kawano Riko , Suzumiya Junji , Utsunomiya Atae , Harada Mine , Kikuchi Masahiro
Published: June 2004

Adult T‐cell leukaemia/lymphoma (ATLL) is an aggressive neoplastic disease that usually exhibits a CD4+CD25+ phenotype. Regulatory T cells (Treg), which suppress T‐cell effector function, are characterized by the co‐expression of CD4 and CD25. We analysed the expression of forkhead/winged helix transcription factor (FoxP3), a specific marker that is important for the function of Treg, on ATLL cells from 17 patients (peripheral blood, n = 8; lymph node, n = 9). Real‐time polymerase chain reaction and immunostaining detected FoxP3 expression in 10 ATLL cases, but was relatively down‐regulated compared with Treg from normal subjects. These results indicate the association of ATLL and Treg.
Mutational analysis of the IκBα gene in activated B cell‐like diffuse large B‐cell lymphoma
Authors: Thomas Roman K. , Wickenhauser Claudia , Tawadros Samir , Diehl Volker , Küppers Ralf , Wolf Jürgen , Schmitz Roland
Published: June 2004

The lymphoma cells of the activated B cell‐like (ABC‐) subtype of diffuse large B‐cell lymphoma (DLBCL) show constitutive activity of the transcription factor, nuclear factor κB (NFκB). We sought to determine whether mutations in the IκBα gene – the predominant inhibitor of NFκB – might play a role in the pathogenesis of ABC‐DLBCL. All exons of the IκBα gene were directly sequenced from 10 cases of immunohistochemically classified ABC‐DLBCL and from six non‐ABC‐DLBCL cases. Two novel polymorphisms were identified, based on their presence in tumour as well as non‐tumour DNA of the respective patients: a duplication near the transcriptional start and a single nucleotide exchange in exon  1. A somatic missense mutation was identified in exon  3, in addition to a wild‐type sequence in only one ABC‐DLBCL case. Thus, also in this case no clonal biallelic inactivating mutation was present in the IκBα gene. We conclude that mutations in the IκBα gene do not play a dominant role in the pathogenesis of ABC‐DLBCL.
Characteristic expansion of CD45RA+ CD27− CD28− CCR7− lymphocytes with stable natural killer (NK) receptor expression in NK‐ and T‐cell type lymphoproliferative disease of granular lymphocytes
Authors: Mitsui Takeki , Maekawa Izuru , Yamane Arito , Ishikawa Tomomi , Koiso Hiromi , Yokohama Akihiko , Handa Hiroshi , Matsushima Takafumi , Tsukamoto Norifumi , Murakami Hirokazu , Nojima Yoshihisa , Karasawa Masamitsu
Published: June 2004

We analysed the cell surface expression of chemokine receptors and natural killer receptors (NKRs) in addition to conventional T‐ and natural killer (NK)‐cell markers in patients with lymphoproliferative disease of granular lymphocytes (LDGL), and compared results between NK‐ and T‐LDGL subgroups. The subjects of this study were 15 LDGL patients: four NK‐LDGL and 11 T‐LDGL [six CD8+ T‐cell receptor (TCR) αβ+, four CD4+ TCRαβ+ and one CD8+ TCRγδ+] cases. Flow cytometric analysis showed that the expanding cells had a common phenotype, CD45RA+ CD27− CD28− CCR7−, in NK‐ and T‐LDGL patients irrespective of differences in TCR status. There were no marked differences in the expression patterns of chemokine receptors between NK‐ and T‐LDGL patients. Although restricted NKR subsets were expressed on both NK‐ and T‐large granular lymphocytes (LGLs), CD94 was the most widely expressed marker. These findings may be unique to cells of LDGL cases, because normal CD56dim NK cells frequently express killer cell immunoglobulin‐like receptors. Furthermore, analysis of NKR expression was repeated over an interval of more than 6 months, and fluctuations of NKR repertoire in the LGL clones were minimal.
Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t‐AML/MDS
Authors: Fern Lorna , Pallis Monica , Ian Carter G. , Seedhouse Claire , Russell Nigel , Byrne Jennifer
Published: June 2004

The molecular pathogenesis of therapy‐related acute myeloid leukaemia/myelodysplastic syndrome (t‐AML/MDS) remains uncertain. However, clonal haemopoiesis may develop following stem cell transplantation and precede the development of t‐AML/MDS. Moreover, accelerated telomere shortening may be induced by replicative stress or oxidative damage, leading to genomic instability, and inactivating polymorphisms of the gene encoding NADPH‐quinone oxidoreductase (NQO1) are more frequently observed in patients with t‐AML. We studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients receiving conventional chemotherapy for non‐myeloid malignancies. Clonal haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was reduced in patients following chemotherapy (n = 52) compared with controls (n = 42) (P < 0·001), particularly in those with clonal haemopoiesis (P < 0·002). Whilst there was a trend towards telomere shortening in control subjects polymorphic for NQO1‐187Ser (n = 12), chemotherapy‐exposed patients polymorphic for the NQO1‐187Ser allele (n = 29) had significantly shorter telomeres (P < 0·001). Furthermore, chemotherapy‐treated patients with the NQO1‐187Ser, polymorphism were more likely to develop clonal haemopoiesis than patients with wild type NQO1 (odds ratio = 7; 1·16–42·6). We conclude that a switch to clonal haemopoiesis may occur after conventional chemotherapy and lead to accelerated telomere shortening. Patients with the NQO1‐187Ser polymorphism have an increased risk of developing both clonal haemopoiesis and telomere shortening, which may partly explain the predisposition to t‐AML in NQO1‐187Ser null individuals.
Efficacy and safety of two different rG‐CSF preparations in the treatment of patients with severe congenital neutropenia*
Authors: Carlsson Göran , Åhlin Anders , Dahllöf Göran , Elinder Göran , Henter Jan‐Inge , Palmblad Jan
Published: June 2004

In patients with severe congenital neutropenia (SCN), the absolute neutrophil count (ANC) is raised during treatment with granulocyte colony‐stimulating factor (G‐CSF), resulting in a marked reduction of bacterial infection. Some patients, however, still have recurrent but less severe bacterial infections and severe periodontal infections. As it has been suggested that the biological activity of glycosylated recombinant human G‐CSF (rHuG‐CSF, i.e. lenograstim) is higher than the non‐glycosylated form (i.e. filgrastim), we compared the two given in equimolar doses. Seven SCN patients participated in an open, randomized, double crossover study comprising 60 weeks, with four 12‐week periods when the two drugs alternated after a 12‐week run‐in‐period. The mean ANC values, sampled every second week, were 5·1 × 109/l during filgrastim treatment and 4·2 × 109/l during lenograstim treatment (P = 0·042). The ANC levels were also significantly higher during filgrastim treatment, when comparing each complementary pair of ANC measurements (P = 0·011) as well as the mean ANC values during each 12‐week treatment period (P = 0·033). There were no differences regarding the frequency of infection, antibiotic treatment, gingival bleeding and the number of hospital admissions between the groups. We conclude that filgrastim and lenograstim displayed equal clinical efficacy, but that ANC levels were higher during filgrastim treatment, when administered in equimolar doses.
Treatment with intranasal fluticasone propionate significantly improves ocular symptoms in patients with seasonal allergic rhinitis
Authors: Bernstein D.I. , Levy A.L. , Hampel F.C. , Baidoo C.A. , Cook C.K. , Philpot E.E. , Rickard K.A.
Published: June 2004

Background
If monotherapy with an intranasal corticosteroid can alleviate both nasal and ocular symptoms of allergic rhinitis, treatment may be simplified and costs may be reduced.

Objective
The purpose of this study was to evaluate the efficacy of once‐daily fluticasone propionate (FP) aqueous nasal spray 200 μg compared with vehicle placebo and oral loratadine (LOR) 10 mg in reducing ocular symptoms associated with seasonal allergic rhinitis.

Methods
A total of 471 patients received vehicle placebo, LOR, or FP in this multi‐centre, double‐blind, double‐dummy, randomized study. Patients were12 years old with a history of seasonal allergic rhinitis and a positive skin test for a relevant allergen. During the baseline and treatment periods, patients rated the severity of eye itching, tearing, and redness via visual analogue scales that ranged from 0 (no symptoms) to 100 (most severe symptoms). The three ocular ratings were added to derive the total ocular symptom score (TOSS). Patients with a TOSS120 on at least 4 of the 7 days before the randomization visit were enrolled. The primary outcome was the difference between FP and vehicle placebo in the mean change from baseline in the reflective TOSS overall (averaged over the 28‐day treatment period). A difference between FP and vehicle placebo of 25.5 was considered clinically significant.

Results
The overall mean change from baseline in the TOSS was significantly greater in the FP group compared with vehicle placebo (clinically significant difference of 28.8; P<0.001) and compared with LOR (difference of 16.2; P=0.028). Overall mean (SEM) changes were −59.9 (5.4) for the placebo group, −72.5 (5.4) for the LOR group, and −88.7 (5.3) for the FP group. The FP treatment group also showed significantly greater overall mean changes in ocular itching, tearing, and redness compared with vehicle placebo (P<0.001) and compared with LOR (P0.045).

Conclusion
Patients treated with intranasal FP had clinically and statistically significant decreases in ocular symptom scores compared with vehicle placebo. Data also suggest that FP reduced ocular symptoms more than or comparable with oral LOR. Patients experiencing ocular symptoms associated with allergic rhinitis may benefit from monotherapy with intranasal FP.
Allergen‐specific T cells from birch‐pollen‐allergic patients and healthy controls differ in T helper 2 cytokine and in interleukin‐10 production
Authors: Bullens D. M. A. , Van den Keybus C. , Dilissen E. , Kasran A. , Ceuppens J. L.
Published: June 2004

Background
T helper (Th)2 cells play an important role in the development of IgE‐mediated diseases, with local overproduction of Th2 cytokines (IL‐4, IL‐5 and IL‐13) at the site of allergic inflammation. Furthermore, IL‐10 has been suggested to play a modulatory role in the induction and maintenance of allergen‐specific tolerance in human atopic diseases.

Aim
We studied whether circulating allergen‐specific Th2 cells persist outside the season of exposure in patients mono‐sensitized to birch pollen and whether healthy control individuals also have allergen‐specific Th2 cells. We also studied whether IL‐10‐producing allergen‐specific T cells can be found in circulation either in healthy controls or in allergic patients.

Methods
Blood was drawn outside the birch‐pollen season from 15 birch‐pollen‐allergic patients, with seasonal respiratory symptoms and with (n=12) or without (n=3) oral allergy syndrome, and from 10 matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with recombinant Bet v 1 allergen, control antigen tetanus toxoid (TT) and anti‐CD3/CD80. In part of the cultures, rIL‐4 was added in order to reinforce the allergen‐specific Th2 cell responses.

Results
In the presence of rBet v 1, T cells from allergic patients, but not from healthy controls, produced IL‐4, IL‐5 and IL‐13. IL‐5 production by patients' T cells was further enhanced by adding more IL‐4. In contrast, rBet v 1 together with IL‐4‐induced significant IL‐10 production in control subjects but not in patients. Both Th1 and Th2 cytokines were equally induced by polyclonal stimulation in allergic patients and controls, but in the presence of IL‐4, polyclonally induced IL‐10 production was lower in the patient group.

Conclusion
rBet v 1‐specific Th2 cells circulate outside the season of exposure in the blood of birch‐pollen‐allergic subjects but not in healthy controls. Allergen‐specific T cells were also demonstrated in controls but these cells produce IL‐10 when stimulated with rBet v 1 in the presence of IL‐4. Our data reveal a different allergen‐induced cytokine profile in birch‐pollen‐allergic patients vs. controls, and suggest that a regulatory mechanism involving IL‐4‐induced allergen‐specific IL‐10 production might be defective in allergic subjects.
Risk factors for atopy among school children in a rural area of Latin America
Authors: Cooper P. J. , Chico M. E. , Rodrigues L. C. , Strachan D. P. , Anderson H. R. , Rodriguez E. A. , Gaus D. P. , Griffin G. E.
Published: June 2004

Background
Infection with common childhood infectious diseases including geohelminth infections may provide protection against the development of atopy and allergic disease. Few studies have investigated risk factors for atopy among children living in rural areas of Latin America.

Objective
To identify risk factors associated with atopy among school‐age children in a rural area of Latin America.

Methods
Analytic cross‐sectional study of school‐age children conducted in seven rural schools in Pichincha Province in Ecuador. Detailed risk factor information was obtained by questionnaire, stool samples were collected for identification of geohelminth parasites, and Mantoux testing was performed to determine tuberculin sensitization.

Results
A total of 1002 children from seven rural schools were recruited. The prevalence of geohelminth infections was high (70.1% were infected with at least one geohelminth parasite) and the prevalence of allergic sensitization was high (20.0% had evidence of aeroallergen sensitization). Factors associated with significant protection against atopy in multivariate analyses were the presence of overcrowding in the child's home, low socio‐economic level, and infection with geohelminth parasites, and the protective effects of the three factors were statistically independent.

Conclusion
Low socio‐economic level, overcrowding and geohelminth infection, are independently protective against atopy among school‐age children living in a rural area of Latin America.
Does maternal immunoglobulin E decrease with increasing order of live offspring? Investigation into maternal immune tolerance
Authors: Karmaus W. , Arshad S. H. , Sadeghnejad A. , Twiselton R.
Published: June 2004

Background
Identifying the protective effect of a higher number of siblings is a significant finding in understanding the aetiology of allergic sensitization, asthma, eczema, and hayfever. Knowledge about causes behind the sibling effect may allow us to prevent atopic manifestations.

Objective
We tested the hypothesis that rising order of live offspring increases maternal immune tolerance (immune non‐reactivity) against allergens. To this end, we investigated whether maternal IgE levels are associated with the number of live offspring.

Methods
In a cohort of 1456 newborns recruited between January 1989 and February 1990 on the Isle of Wight, UK, we determined maternal and cord serum IgE, and the order of live offspring. The data were analysed by means of linear and path analysis.

Results
Maternal and cord serum IgE were available in 820 mother–infant pairs with birth order information. We found that the number of live offspring significantly reduces maternal IgE. The decline was more prominent in mothers with atopy (n=268). The geometric means of IgE after the first, second, and third or higher delivery were 74.4, 66.6, and 43.0 kU/L, respectively. Findings of path analysis suggest a significant direct effect of birth order on maternal IgE, but no direct effect of birth order on cord serum IgE.

Conclusion
The findings support that maternal immune tolerance against allergens may increase with increasing order of live offspring and thus pass on a lower risk of developing atopy in children of higher birth order.
Levocetirizine improves nasal obstruction and modulates cytokine pattern in patients with seasonal allergic rhinitis: a pilot study
Authors: Ciprandi G. , Cirillo I. , Vizzaccaro A. , Tosca M. A.
Published: June 2004

Background
Allergic rhinitis is characterized by an IgE‐dependent inflammation. Nasal obstruction is related to allergic inflammation. Some antihistamines have been demonstrated to be capable of improving this nasal symptom.

Objective
The aim of this pilot study was to evaluate nasal symptoms, nasal airflow, inflammatory cells, and cytokine pattern in patients with seasonal allergic rhinitis (SAR), before and after treatment with levocetirizine, desloratadine, or placebo.

Methods
Thirty patients with SAR were evaluated, 27 males and three females (mean age 26.9±5.4 years). All of them received levocetirizine (5 mg/day), desloratadine (5 mg/day), or placebo for 2 weeks. The study was double‐blind, parallel‐group, placebo‐controlled, and randomized. Total symptom score (TSS) (including: rhinorrhea, nasal itching, sneezing, and nasal obstruction) was assessed before and after treatment. Rhinomanometry, nasal lavage, and nasal scraping were performed in all subjects before and after treatment. Inflammatory cells were counted by conventional staining; IL‐4 and IL‐8 were measured by immunoassay on fluids recovered from nasal lavage.

Results
Levocetirizine treatment induced significant symptom relief (P=0.0009) and improved nasal airflow (P=0.038). Desloratadine also relieved TSS (P=0.01), but did not affect nasal airflow. Levocetirizine significantly reduced eosinophils (P=0.029), neutrophils (P=0.005), IL‐4 (P=0.041), and IL‐8 (P=0.02), whereas desloratadine diminished IL‐4 only (P=0.044). Placebo treatment did not significantly affect any evaluated parameters.

Conclusions
This pilot study demonstrates the effectiveness of levocetirizine in: (i) relieving nasal symptoms, (ii) improving nasal airflow, (iii) reducing leucocyte infiltration, and (iv) diminishing cytokine levels. These findings are the first evidence of the effectiveness of levocetirizine in SAR.
Inhaled cornstarch glove powder increases latex‐induced airway hyper‐sensitivity in guinea‐pigs
Authors: Barbara J. , Santais M.‐C. , Levy D. A. , Ruff F. , Leynadier F.
Published: June 2004

Background
Breathing is one of the most important modes of sensitization to natural rubber latex (NRL) for health‐care workers, a group most at risk. Cornstarch powder (CSp) from medical powdered NRL gloves is known to be an allergen carrier, and sensitization to NRL can occur by inhaling airborne particles from such gloves.

Objective
The aim of this study was to demonstrate, using an experimental model, which CSp may act as an adjuvant in NRL‐induced airway hyper‐responsiveness.

Methods
Guinea‐pigs were exposed to aerosolized NRL‐contaminated CSp or to NRL in saline solution for 1 h every day for 2 weeks. The control groups were exposed either to CSp or to saline alone. An additional group of guinea‐pigs was exposed to aerosolized ovalbumin (OVA) in saline. Three weeks after the last exposure, specific bronchial challenges were performed. In addition, Specific IgG and IgG1 in sera and thromboxane (Tx) B2 levels in bronchoalveolar lavage fluid (BALF) were measured.

Results
The NRL challenge caused significant bronchospasm in the animals that had been exposed to NRL compared with those in the control groups (P<0.02). Guinea‐pigs exposed to OVA also demonstrated a significant bronchospasm after OVA challenge (P<0.001). The guinea‐pigs that had inhaled NRL‐contaminated CSp had a significantly higher bronchoconstriction level than those that had inhaled NRL alone (P<0.02). Specific IgG and IgG1 were undetectable in sera from all groups, whereas significant amounts of TxB2 (P<0.001) were found in the lungs of the guinea‐pigs exposed to NRL or OVA.

Conclusion
Inhaling CSp increases the airway response to NRL. The fact that specific IgG and IgG1 were not detected might be the result of an immune response limited to the airways. This finding is supported by a significant increase of TxB2 level in the BALF of sensitized guinea‐pigs.
Effect of glucocorticosteroids on tumour necrosis factor‐α‐induced intercellular adhesion molecule‐1 expression in cultured primary human nasal epithelial cells
Authors: Shirasaki H. , Watanabe K. , Kanaizumi E. , Sato J. , Konno N. , Narita S. , Himi T.
Published: June 2004

Objective
In order to confirm the direct effect of glucocorticosteroids on epithelial intercellular adhesion molecule‐1 (ICAM‐1) expression, we examined ICAM‐1 expression on primary cultured human nasal epithelial cells (HNECs) at both protein and mRNA levels.

Material and methods
HNECs were stimulated with recombinant human TNF‐α (20 pg/mL–20 ng/mL) for specified time periods (0, 12, 24, and 48 h) and ICAM‐1 mRNA and the soluble ICAM‐1 (sICAM‐1) concentrations were measured by quantitative RT‐PCR and ELISA, respectively. We also evaluated surface expression of ICAM‐1 by flow cytometry 48 h after stimulation and determined the effect of dexamethasone (DEX) on TNF‐α‐induced ICAM‐1 expression.

Results
Significant increases in ICAM‐1 gene expression in HNECs were initially detected at 24 h, peaking at 48 h after the stimulation. The TNF‐mediated‐ICAM‐1 mRNA and ICAM‐1 surface expression at 48 h was significantly inhibited by co‐incubation with human recombinant soluble TNF receptor I. Similarly, TNF‐α‐induced release sICAM‐1 occurred in a time‐ and concentration‐dependent manner. DEX 10−6 m attenuated the TNF‐α‐induced ICAM‐1 expression at mRNA and protein levels.

Conclusions
Our finding suggests a potential role for topical steroids in allergic rhinitis in suppressing inflammatory reactions in the nasal mucosa by regulating ICAM‐1 expression on nasal epithelium.
Urinary 3‐bromotyrosine and 3‐chlorotyrosine concentrations in asthmatic patients: lack of increase in 3‐bromotyrosine concentration in urine and plasma proteins in aspirin‐induced asthma after intravenous aspirin challenge
Authors: Mita H. , Higashi N. , Taniguchi M. , Higashi A. , Kawagishi Y. , Akiyama K.
Published: June 2004

Background
Eosinophil peroxidase and myeloperoxidase halogenate tyrosine residues in plasma proteins and generate 3‐bromotyrosine (BY) and 3‐chlorotyrosine (CY), respectively.

Objectives
(1) To estimate urinary concentrations of BY and CY in asthmatic patients. (2) To investigate BY concentration in relation to urinary leukotriene E4 (LTE4) concentration in order to evaluate the activation of eosinophils in patients with aspirin‐induced asthma (AIA).

Methods
BY and CY were quantified with a gas chromatograph‐mass spectrometer using 13C‐labelled compounds as internal standards.

Results
(1) Activation of eosinophils and neutrophils by immobilized IgG1 induced preferential formation of BY and CY, respectively. (2) A significantly higher concentration of BY was observed in the urine from asthmatic patients than in that from healthy control subjects (45±21.7 vs. 22.6±10.8 ng/mg‐creatinine, P<0.01). CY concentration was also elevated in the urine from asthmatic patients (4.4±3.2 vs. 1.5±1.0 ng/mg‐creatinine, P<0.01). (3) After intravenous aspirin challenge of aspirin‐induced asthmatic patients, the concentration of BY in urine did not significantly change. No significant change was also observed in the ratio of BY concentration to total tyrosine concentration in plasma proteins. In contrast, the concentration of urinary LTE4 significantly increased after the intravenous aspirin challenge.

Conclusion
Determination of BY and CY concentrations may be useful for monitoring the activation of eosinophils and neutrophils in asthmatic patients, respectively. After aspirin challenge of AIA patients, the increased concentration of urinary LTE4 did not accompany changes in BY concentration in both urine and plasma proteins. These results may preclude the activation of eosinophils after aspirin challenge in patients with AIA.
Characteristics of patients with seasonal allergic rhinitis and concomitant asthma
Authors: Bousquet J. , Boushey H. A. , Busse W. W. , Canonica G. W. , Durham S. R. , Irvin C. G. , Karpel J. P. , Van Cauwenberge P. , Chen R. , Iezzoni D. G. , Harris A. G.
Published: June 2004

Background
Allergic rhinitis and asthma often co‐exist and appear to produce a continuum of airway disease, but whether the clinical characteristics of asthma in patients with seasonal rhinitis differ from those of persistent asthma has not been examined.

Objective
The aim of this retrospective study was to characterize the clinical features of patients with seasonal allergic rhinitis with concomitant asthma and to compare them with those in patients with persistent asthma.

Methods
The patient populations for this study were derived from nine prospective, placebo‐controlled planned clinical trials of similar design. Six studies (958 patients) enrolled patients with seasonal allergic rhinitis and concomitant asthma; three (607 patients) involved patients with persistent asthma. In all studies, patients were excluded from oral corticosteroid therapy in the preceding 3 months, and from inhaled corticosteroids in the preceding month.

Results
Patients with seasonal rhinitis and asthma had a significantly (P<0.001) higher total asthma symptom score than those with persistent asthma. In particular, cough was three times more severe. The need for β2‐agonist as a rescue medication and the ratio of forced expiratory volume in 1 s/forced vital capacity (FVC) were similar in the two groups whereas forced expiratory fraction 25–75%/FVC was significantly (P<0.02) reduced in the persistent asthmatics. Asthma and nasal symptom severity scores were correlated in patients with seasonal rhinitis and asthma (P<0.0001).

Conclusions
Patients with seasonal allergic rhinitis and concomitant asthma appear to differ from those with persistent asthma. A prospective study should be designed to discover whether patients with seasonal rhinitis and asthma may represent a distinct nosological entity, ‘allergic airway disease’.