bluuebunny/crossref_metadata_2025_split huggingface dataset:
t(11;18)(q21;q21) of mucosa‐associated lymphoid tissue lymphoma results from illegitimate non‐homologous end joining following double strand breaks
Authors: Liu Hongxiang , Hamoudi Rifat A. , Ye Hongtao , Ruskone‐Fourmestraux Agnes , Dogan Ahmet , Isaacson Peter G. , Du Ming‐Qing 
Published: December 2004

Summaryt(11;18)(q21;q21) is the most frequent chromosomal aberration specifically associated with mucosa‐associated lymphoid tissue (MALT) lymphoma. The translocation fuses the API2 gene to the MALT1 gene and generates a functional API2‐MALT1 transcript. The breakpoint of the fusion gene is well characterized at the transcript level but poorly understood at the genomic level and the mechanism underlying the translocation is unknown. We identified the genomic breakpoint in 19 t(11;18)‐positive MALT lymphoma cases by polymerase chain reaction and sequencing and analysed the junctional sequences. The breakpoints were scattered in intron 7 and exon 8 of the API2 gene, and introns 4, 6, 7 and 8 of the MALT1 gene. Comparative sequence analysis between the API2‐MALT1 fusion on der(11) and the MALT1‐API2 fusion on der(18) showed extensive alterations including deletions, duplications and non‐template‐based insertions at the fusion junctions in all cases examined. An extensive sequence search failed to reveal any known sequence motifs that might be associated with chromosomal recombination or any novel consensus sequences at or near the breakpoints on both der(11) and der(18) except in one case, in which Alu repeats spanned the breakpoint of the MALT1‐API2 fusion. Our results suggest that t(11;18) may result from illegitimate non‐homologous end joining following double strand breaks.
Frequent HPRT mutations in paroxysmal nocturnal haemoglobinuria reflect T cell clonal expansion, not genomic instability
Authors: Chen Guibin , Zeng Weihua , Green Spencer , Young Neal S. 
Published: December 2004

SummaryParoxysmal nocturnal haemoglobinuria (PNH) results from acquired mutations in the PIG‐A gene of an haematopoietic stem cell, leading to defective biosynthesis of glycosylphosphatidylinositol (GPI) anchors and deficient expression of GPI‐anchored proteins on the surface of the cell's progeny. Some laboratory and clinical findings have suggested genomic instability to be intrinsic in PNH; this possibility has been supported by mutation analysis of hypoxanthine‐guanine phosphoribosyltransferase (HPRT) gene abnormalities. However, the HPRT assay examines lymphocytes in peripheral blood (PB), and T cells may be related to the pathophysiology of PNH. We analysed the molecular and functional features of HPRT mutants in PB mononuclear cells from eleven PNH patients. CD8 T cells predominated in these samples; approximately half of the CD8 cells lacked GPI‐anchored protein expression, while only a small proportion of CD4 cells appeared to derive from the PNH clone. The HPRT mutant frequency (Mf) in T lymphocytes from PNH patients was significantly higher than in healthy controls. The majority of the mutant T lymphocyte clones were of CD4 phenotype, and they had phenotypically normal GPI‐anchored protein expression. In PNH patients, the majority of HPRT mutant clones were contained within the Vβ2 T cell receptor (TCR) subfamily, which was oligoclonal by complementarity‐determining region three (CDR3) size analysis. Our results are more consistent with detection of uniform populations of expanded T cell clones, which presumably acquired HPRT mutations during antigen‐driven cell proliferation, and not due to an increased Mf in PNH. HPRT mutant analysis does not support underlying genomic instability in PNH.
Aspergillus fumigatus antigens activate innate immune cells via toll‐like receptors 2 and 4
Authors: Braedel Sibylla , Radsak Markus , Einsele Hermann , Latgé Jean‐Paul , Michan Andreas , Loeffler Juergen , Haddad Ziad , Grigoleit Ulrich , Schild Hansjoerg , Hebart Holger 
Published: December 2004

SummaryInvasive aspergillosis (IA) is a leading cause of mortality in haematological patients. Appropriate activation of the innate immune system is crucial for the successful clearance of IA. Therefore, we studied the Aspergillus fumigatus‐mediated activation of human granulocytes and monocyte‐derived immature dendritic cells (DCs), as well as murine bone marrow‐derived DCs (BMDCs) from wild type, toll‐like receptor (TLR)4‐deficient, TLR2 knockout, and TLR2/TLR4 double deficient mice. Aspergillus fumigatus antigens induced the activation and maturation of immature DCs as characterized by CD83 expression, upregulation of major histocompatibility complex and co‐stimulatory molecules. Moreover, fungal antigens enhanced the phagocytosis and production of interleukin (IL)‐8 in granulocytes. The release of IL‐12 by BMDCs in response to A. fumigatus antigens was dependent on the expression of TLR2, whereas the release of IL‐6 was dependent on the expression of functional TLR4 molecules. The protein precipitate of A. fumigatus supernatant provided strong stimulation of DCs and granulocytes, indicating that a factor secreted by A. fumigatus might activate innate immune cells. In conclusion, A. fumigatus antigens induced the activation of DCs and granulocytes. Our results indicated that this activation was mediated via TLR2 and TLR4. Future studies are needed to assess the clinical impact of these findings in patients at high risk for IA.
New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia
Authors: Voskaridou Ersi , Terpos Evangelos 
Published: December 2004

SummaryOsteoporosis represents an important cause of morbidity in adult patients with thalassaemia major (TM). The pathogenesis of osteoporosis in TM is multifactorial, and includes bone marrow expansion, endocrine dysfunction and iron overload. Additional genetic factors, such as the COLIA 1 gene polymorphism, seem to play an important role in the development of low bone mass in these patients. However, the mechanisms through which these factors lead to bone loss have not been completely clarified. The diminished osteoblast function is accompanied by a comparable or even greater increase in osteoclast activity. The receptor activator of nuclear factor‐kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway has been recently recognized as the final, dominant mediator of osteoclast proliferation and activation. There is increased evidence that this pathway interferes in the pathogenesis of thalassaemia‐induced osteoporosis. Currently, bisphosphonates that are potent inhibitors of osteoclast function have been used in TM patients with encouraging results. This review attempts to summarize all the novel data for the biology of bone damage in TM. It also describes the results of all major studies that have investigated the effects of different treatment modalities for TM‐induced osteoporosis, their mode of action, and the future implications of their use.
Bone marrow histopathology in peripheral T‐cell lymphomas
Authors: Dogan Ahmet , Morice William G. 
Published: December 2004

SummaryPeripheral T‐cell lymphomas (PTCL) account for 10–15% of all lymphoproliferative disorders in the western hemisphere. In PTCL, bone marrow biopsy is performed to establish the diagnosis, rule out other pathology, assess the extent of disease and monitor treatment response. The frequency and histology of bone marrow involvement varies greatly between different clinicopathological entities recognized by the World Health Organisation (WHO) classification, reflecting the differences in the underlying biology. Some lymphomas, such as angioimmunoblastic T‐cell lymphoma, show nodular and/or interstitial pattern of infiltration with accompanying reactive changes. Others, including hepatosplenic T‐cell lymphoma and large granular lymphocyte leukaemia, are characterized by intrasinusoidal infiltration. In many instances the pathological features are subtle and immunohistochemical and molecular studies are required for the diagnosis. Histological appearances may overlap with a variety of reactive T‐cell proliferations and other malignancies. Furthermore PTCL frequently induce secondary changes in the marrow that may obscure the neoplastic infiltrate. The diagnosis often requires critical integration of the information obtained from clinical features, peripheral blood, bone marrow aspirate and biopsy findings. In this article we review the histopathology of bone marrow biopsy in PTCL within the context of the new WHO classification.
Hemojuvelin (HJV) mutations in persons of European, African‐American and Asian ancestry with adult onset haemochromatosis
Authors: Lee Pauline L. , Barton James C. , Brandhagen David , Beutler Ernest 
Published: December 2004

SummaryMutations in the chromosome 1q‐linked gene hemojuvelin (HJV) have recently been found to be a cause of juvenile haemochromatosis. We addressed the question of whether hemojuvelin mutations may influence the phenotype of patients with adult‐onset haemochromatosis with or without mutations of the HFE gene. We sequenced the complete coding region of 133 subjects with iron overload. To screen a large number of patients, we also developed conditions for analysis by denaturing high‐performance liquid chromatography (dHPLC). This diagnostic modality detects many mutations of the HJV gene. One patient with severe iron overload was found to be a compound heterozygote for HJV mutations, one of which had previously been identified in patients with juvenile haemochromatosis (G320V) and the other was novel (C321W). A number of other mutations were identified, but none were clearly associated with increases in the body iron burden. Notable among these was a DNA triplet insert, predicting an insertion of glycine, found in two African‐American subjects, one with and one without iron storage disease.
Acquired Glanzmann's thrombasthenia without thrombocytopenia: a severe acquired autoimmune bleeding disorder
Authors: Tholouli Eleni , Hay Charles R. M. , O'Gorman Peter , Makris Michael 
Published: December 2004

SummaryAcquired Glanzmann's thrombasthenia (GT) is an uncommon accompaniment to immune thrombocytopenic purpura. Rarely, GT may present as an acquired autoimmune disorder of platelet function, with rapid onset of a moderate‐to‐severe bleeding tendency, a prolonged bleeding time, but with a normal platelet count and normal platelet glycoprotein (GP) expression. This is caused by an autoantibody with specificity for platelet GP IIb/IIIa or an epitope close to that of the GP, resulting in partial or complete refractoriness of the patient's platelets to ADP, collagen and arachidonic acid. We describe two patients with acquired GT and a normal platelet count, who presented with severe bleeding. The first patient responded gradually to immunosuppressive treatment but eventually developed non‐Hodgkin's lymphoma. The second patient had no other underlying conditions and remitted spontaneously within 2 years.
Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma
Authors: Hernández J. M. , García‐Sanz R. , Golvano E. , Bladé J. , Fernandez‐Calvo J. , Trujillo J. , Soler J. A. , Gardella S. , Carbonell F. , Mateo G. , San Miguel J. F. 
Published: December 2004

SummaryMelphalan–prednisone (MP) has been the gold standard treatment for more than 30 years in elderly multiple myeloma (MM) patients. In order to assess whether the combination of dexamethasone with melphalan (MD) could improve on the efficacy of MP, we have carried out a randomized trial comparing both treatment approaches. A total of 201 patients ≥70 years old were included in the study. The overall response rate was similar after six cycles (MP: 67·9%versus MD: 64·5%) and after 12 cycles (MP: 49·4%versus MD: 46·1%). However, the proportion of complete responses (CR) was higher in the MD arm, particularly after 12 cycles (MD: 22·4%versus MP: 9·1%; P < 0·05). There was no significant difference in event‐free survival (MP: 15·9 months versus MD: 23·3 months). The median overall survival in both arms was almost identical (MP: 29·4 months versus MD: 27·2 months; P = 0·63). No significant differences in haematological toxicity were observed, but non‐haematological toxicity was significantly higher in the MD arm. According to these results MP remains as the gold standard for treatment of MM and should be the reference for comparison of new therapeutic approaches involving novel agents.
Mutations within the protein Z‐dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia
Authors: Van de Water Neil , Tan Tina , Ashton Fern , O'Grady Anna , Day Tony , Browett Peter , Ockelford Paul , Harper Paul 
Published: December 2004

SummaryProtein Z‐dependent protease inhibitor (ZPI) is a serpin that inhibits the activated coagulation factors X and XI. The precise physiological significance of ZPI in the control of haemostasis is unknown although a deficiency of ZPI may be predicted to alter this balance. The coding region of the ZPI gene was screened for mutations using denaturing high‐performance liquid chromatography. 16 mutations/polymorphisms within the coding region of ZPI were identified including two mutations, which generated stop codons at residues R67 and W303. We observed nonsense mutations within the ZPI gene in 4·4% of thrombosis patients (n = 250) compared with 0·8% of controls (n = 250). The difference in distribution of stop codon mutations between thrombosis patients and controls was significant (P = 0·02) with an odds ratio of 5·7 (95% confidence interval, 1·25–26·0). Our results suggest an association between ZPI deficiency and venous thrombosis and we propose that ZPI deficiency is potentially a new form of thrombophilia.
Early television exposure and subsequent attentional problems in children
Authors: Mehmet‐Radji Ozlem 
Published: December 2004

.

Christakis DA,
Zimmerman FJ,
Di Giuseppe DL &
McCarty CA.

(
2004
)
Pediatrics
,
113
,
708
–
713
.
ObjectiveCross‐sectional research has suggested that television viewing may be associated with decreased attention spans in children. However, longitudinal data of early television exposure and subsequent attentional problems have been lacking. The objective of this study was to test the hypothesis that early television exposure (at ages 1 and 3) is associated with attentional problems at age 7.MethodsWe used the National Longitudinal Survey of Youth, a representative longitudinal data set. Our main outcome was the hyperactivity subscale of the Behavioural Problems Index determined on all participants at age 7. Children who were > 1.2 standard deviations above the mean were classified as having attentional problems. Our main predictor was hours of television watched daily at ages 1 and 3 years.ResultsData were available for 1278 children at age 1 and 1345 children at age 3. Ten percent of children had attentional problems at age 7. In a logistic regression model, hours of television viewing per day at both ages 1 and 3 were associated with attentional problems at age 7 [1.09 (1.03–1.15) and 1.09 (1.02–1.16), respectively].ConclusionsEarly television exposure is associated with attentional problems at age 7. Efforts to limit television viewing in early childhood may be warranted, and additional research is needed.
Differential major histocompatibility complex class II locus expression on human laryngeal epithelium
Authors: REES L E , AYOUB O , HAVERSON K , BIRCHALL M A , BAILEY M 
Published: December 2004

SUMMARY
The survival of a laryngeal allograft will be dependent on the immunological composition of the donor larynx and, in particular, on the expression of major histocompatibility complex (MHC) class II antigens on professional and non-professional antigen-presenting cells. Laryngeal and tonsillar biopsies from normal individuals aged 18–78 years were processed and prepared for quantitative, multiple-colour immunofluorescence using mouse antihuman monoclonal antibodies to human leucocyte antigen (HLA)-DR, HLA-DQ and CD45. The laryngeal epithelium expressed HLA-DR locus products at variable levels, but expression of HLA-DQ was virtually absent. Tonsillar epithelial cells expressed HLA-DR at the basal layer only, while HLA-DQ was similarly not expressed. In contrast, both HLA-DR and -DQ locus products were present on lamina propria and intraepithelial leucocytes in both laryngeal and tonsillar mucosae, although at varying levels. The finding that laryngeal epithelial cells express MHC class II antigens has implications for the survival of laryngeal allografts and suggests that they may require significant immunomodulation. In addition, antigen presentation by epithelial cells has been hypothesized to contribute to the immunoregulatory function of mucosal tissues, and the finding that HLA-DQ locus products are only expressed at low levels by laryngeal epithelium raises questions about the repertoire of peptides to which the mucosal immune system can respond.
IgG subclass response toHelicobacter pyloriand CagA antigens in children
Authors: DZIERZANOWSKA-FANGRAT K , RAEISZADEH M , DZIERZANOWSKA D , GLADKOWSKA-DURA M , CELINSKA-CEDRO D , CRABTREE J E 
Published: December 2004

SUMMARYSpecific serum IgG subclass antibodies against Helicobacter pylori antigens and recombinant CagA were analysed in 75 symptomatic children with histologically confirmed H. pylori infection. H. pylori stimulated an IgG1 predominant response, and IgG3 titres showed a positive association with peptic ulcer disease, chronicity of antral inflammation and density of H. pylori colonization. Two methods used for assessing serum IgG CagA antibody status, i.e. Western blotting and enzyme-linked immunosorbent assay (ELISA), were concordant. CagA stimulated an IgG1 and IgG3 predominant humoral response. Total CagA IgG titres were higher in children with active and more severe chronic antral inflammation. These findings suggest that in children the systemic humoral immune response to H. pylori infection may reflect gastroduodenal pathology.
Nasal-associated lymphoid tissue (NALT): frequency and localization in young children
Authors: DEBERTIN A S , TSCHERNIG T , TÖNJES H , KLEEMANN W J , TRÖGER H D , PABST R 
Published: December 2004

SUMMARYIn mucosal immunology nasal-associated lymphoid tissue (NALT) is taken as a constitutive structure of the nasal immune system and as a target tissue in strategies of local defence and an induction site for vaccination. These concepts are based on findings in rodents, but it has not been investigated systematically whether NALT also is present in humans and if so in which amount and localization. In a postmortem study the presence of NALT in humans is documented as a morphologically distinct structure additional to the lymphoid structures of the Waldeyer's ring. Human nasal tissue blocks of 150 children who had died in the first two years of life either of sudden infant death (n = 109) without signs of respiratory tract infections or of different traumatic (n = 22) and natural causes of death (n = 19) were obtained using a specific autopsy-technique and were investigated systematically using histology. Clearly in contrast to rodents human NALT was found disseminated in the nasal mucosa with typical morphological features in 38% of all children, mainly in the middle concha, with similar morphology and frequency in the examined groups. No correlation was found between the presence of NALT and the cause of death and especially the grade of inflammation in general. Therefore, NALT might be the morphological basis for inhalative vaccination strategies in young children and play a role in mucosal host defence.
Polarity of helper T cell subsets represents disease nature and clinical course of experimental autoimmune myocarditis in rats
Authors: FUSE K , KODAMA M , ITO M , OKURA Y , KATO K , HANAWA H , AOKI S , AIZAWA Y 
Published: December 2004

SUMMARYThe mechanisms of progression, remission and relapse of myocarditis remain unclear. To clarify these mechanisms, we focused on T helper-1 (Th1)/T helper-2 (Th2) subsets balance of peripheral lymphocytes and serum cytokine levels during disease progression in rats with experimental autoimmune myocarditis (EAM). Lewis rats were immunized with cardiac myosin on day 0. Blood samples were collected on days 0, 7, 15, 18, 21, 28, 35, 42, 49 and 56 following immunization. We examined percentages of interferon (IFN)-γ and/or interleukin (IL)-4 producing cells in stimulated peripheral CD4-positive lymphocytes using flow cytometry analysis. Serum IFN-γ, IL-2, IL-6 and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA). The percentage of Th1/Th2 subsets in EAM on days 0, 15, 28 and 56 were 2·5 ± 0·5/0·5 ± 0·1%, 19·4 ± 3·2/1·6 ± 0·3%, 2·0 ± 0·5/22·1 ± 5·7% and 3·0 ± 0·4/1·7 ± 0·3%, respectively. Serum levels of Th1 cytokines, IFN-γ and IL-2 significantly increased in the acute phase (from day 15–18) and immediately decreased in the early recovery phase. On the other hand, serum levels of Th2 cytokine, IL-10 significantly increased in the early recovery phase (from day 24–30). These results suggest that induction of acute myocarditis might be associated with systemic Th1 dominance, while recovery is related to systemic Th2 polarity. Thus, analysis of Th1/Th2 balance in peripheral T cells may be useful in disease monitoring in patients with myocarditis and postmyocarditic dilated cardiomyopathy.
Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves’ disease
Authors: PICHURIN P , ALIESKY H , CHEN C-R , NAGAYAMA Y , RAPOPORT B , MCLACHLAN S M 
Published: December 2004

SUMMARYThe role of B cells as antigen-presenting cells is being recognized increasingly in immune responses to infections and autoimmunity. We compared T cell responses in wild-type and B cell-deficient mice immunized with the thyrotrophin receptor (TSHR), the major autoantigen in Graves’ disease. Three B cell-deficient mouse strains were studied: JHD (no B cells), mIgM (membrane-bound monoclonal IgM+ B cells) and (m + s)IgM (membrane-bound and secreted monoclonal IgM). Wild-type and B cell-deficient mice (BALB/c background) were studied 8 weeks after three injections of TSHR or control adenovirus. Only wild-type mice developed IgG class TSHR antibodies and hyperthyroidism. After challenge with TSHR antigen, splenocyte cultures were tested for cytokine production. Splenocytes from TSHR adenovirus injected wild-type and mIgM-mice, but not from JHD- or (m + s)IgM- mice, produced interferon (IFN)-γ in response to TSHR protein. Concanavalin A and pokeweed mitogen induced comparable IFN-γ secretion in all groups of mice except in the JHD strain in which responses were reduced. The absence in (m + s)IgM mice and presence in mIgM mice of an anamnestic response to TSHR antigen was unrelated to lymphoid cell types. Surprisingly, although TSHR-specific antibodies were undetectable, low levels of serum IgG were present in mIgM- but not (m + s)IgM mice. Moreover, IFN-γ production by antigen-stimulated splenocytes correlated with IgG levels. In conclusion, T cell responses to TSHR antigen developed only in mice with IgG-secreting B cells. Consequently, in the TSHR–adenovirus model of Graves’ disease, some normal B cells appear to be required for the development of memory T cells.