bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

SummaryThe 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

SummaryWe 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

SummaryThe 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

SummaryAdult 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

SummaryThe 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

SummaryWe 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

SummaryThe 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

SummaryIn 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

SummaryBackground
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

SummaryBackground
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

SummaryBackground
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

SummaryBackground
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

SummaryBackground
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.