bluuebunny/crossref_metadata_2025 huggingface dataset:
Is economic liberalisation stimulating innovation in India?
Authors: Bowonder B. , Satish N. G.
Published: April 2003

Before the start of liberalisation in 1991, the Indian economy was an inward looking system under government control. Following the drive to liberalisation it has changed in many ways. For a start, the national system of innovation has been affected by exposure to market forces. Global firms have founded R&D centres in India and large private firms have increased spending on R&D. Patentable innovations have also shown a sharp rise since the opening up of the economy. As a percentage of GNP, however, R&D expenditure is still much lower than that observed in countries such as China, Taiwan, and Brazil. The Indian share of world trade is very low, and so there is a need for further expansion of R&D initiatives. The recently announced revisions to science and technology policy begin to address some of these concerns.
The Indian half of Needham's question: some thoughts on axioms, models, algorithms, and computational positivism
Authors: Narasimha Roddam
Published: April 2003

Much debate has taken place on Joseph Needham's question regarding ‘the failure of China and India to give rise to distinctively modern science while being ahead of Europe for fourteen previous centuries’. It is argued in this paper that while there is probably some truth in many of the sociocultural explanations that have been offered for the failure in India, they are in the final analysis not entirely convincing. The proposal in this paper is in two parts. The first is that the scientific revolution, which was part of a European miracle, was triggered in part by the advent of a variety of technologies from China and the new numeral system and other mathematical inventions from India - both via creative West Asian intermediaries. India had experienced a mathematical (more specifically algoristic or computational) revolution heralded by Ārya-bhata in the fifth century CE. The new computational power unleashed by this revolution combined with the classical Greek penchant for axiomatised modelmaking and a technology empowered experimental philosophy, in what appears to have been a very creative and uniquely European cultural fusion that led to the scientific (and later the industrial) revolution. The second part of the proposal is that there was an epistemological reason why the Indian mathematical revolution did not lead to a corresponding ‘distinctively modern’ scientific one. The Indic approach was basically not that of modelmakers but of ingenious algorisers, and showed a deep and studied distrust of axioms and physical models. This led to an attitude described here as ‘computational positivism’, which considers observation and computation as the only things that matter. In retrospect, that distrust appears not unjustified, especially in the light of twentieth century developments in quantum and classical mechanics and in logic; but it was historically expensive for India, as Europe achieved unreasonably and unexpectedly spectacular successes in science. To the Indians, it was Newton who was the extraordinary epistemological revolutionary, not Heisenberg or Gödel. In summary, Indian science could not move forward without the modelmaking and technology enabled experimental abilities that grew in the West, just as European modelmaking had earlier been unable to progress without the advent of powerful technologies and computational tools whose roots can be traced to China and India.
Overcoming the scientific generation gap in Africa: an urgent priority
Authors: Gaillard Jacques
Published: April 2003

Based on recently completed studies, this paper attempts to provide a realistic picture of the scientific profession in Africa today. Activities in science and technology (S&T) have gone through a process of institutionalisation and professionalisation in Africa over the last thirty years, but these efforts have not been sufficient to create a sustainable dynamic of scientific production or of regeneration of national scientific communities. The situation today is critical, with S&T systems and the working environments of scientists deteriorating in many countries. While institutional mechanisms such as centres of excellence and S&T diasporas can, under certain conditions, contribute to the regionalisation and internationalisation of African science, they will never substitute for the weaknesses of national research systems. In the battle for sustainable development in Africa, nothing will replace home grown scientific capacities, and it is high time for the conditions for their renewal to be created. The results of empirical studies discussed in this article not only provide a vivid picture of the present day conditions of the scientific profession on the African continent, they also contribute to a diagnosis of the situation as one of political urgency.
Inhibition of NF-κB essentially contributes to arsenic-induced apoptosis
Authors: Mathas Stephan , Lietz Andreas , Janz Martin , Hinz Michael , Jundt Franziska , Scheidereit Claus , Bommert Kurt , Dörken Bernd
Published: April 2003

Arsenic can induce apoptosis and is an efficient drug for the treatment of acute promyelocytic leukemia. Currently, clinical studies are investigating arsenic as a therapeutic agent for a variety of malignancies. In this study, Hodgkin/Reed-Sternberg (HRS) cell lines served as model systems to characterize the role of nuclear factor–κB (NF-κB) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive IκB kinase (IKK) as well as NF-κB activity and induced apoptosis in HRS cell lines containing functional IκB proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3–like activity. Furthermore, arsenic treatment down-regulated NF-κB target genes, including tumor necrosis factor-αreceptor–associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive IκB proteins or with a weak constitutive IKK/NF-κB activity showed no alteration of the NF-κB activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-κB pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-κB–p65 in L540Cy HRS cells, which protected the cells from arsenic-induced apoptosis. In addition, treatment of NOD/SCID mice with arsenic trioxide induced a dramatic reduction of xenotransplanted L540Cy Hodgkin tumors concomitant with NF-κB inhibition. We conclude that inhibition of NF-κB contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-κB activity might be a powerful treatment option for Hodgkin lymphoma.
G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases
Authors: Franzke Anke , Piao Wenji , Lauber Jörg , Gatzlaff Patricia , Könecke Christian , Hansen Wiebke , Schmitt-Thomsen Angela , Hertenstein Bernd , Buer Jan , Ganser Arnold
Published: April 2003

Results from experimental models, in vitro studies, and clinical data indicate that granulocyte colony-stimulating factor (G-CSF) stimulation alters T-cell function and induces Th2 immune responses. The immune modulatory effect of G-CSF on T cells results in an unexpected low incidence of acute graft-versus-host disease in peripheral stem cell transplantation. However, the underlying mechanism for the reduced reactivity and/or alloreactivity of T cells upon G-CSF treatment is still unknown. In contrast to the general belief that G-CSF acts exclusively on T cells via monocytes and dendritic cells, our results clearly show the expression of the G-CSF receptor in class I– and II– restricted T cells at the single-cell level both in vivo and in vitro. Kinetic studies demonstrate the induction and functional activity of the G-CSF receptor in T cells upon G-CSF exposure. Expression profiling of T cells from G-CSF–treated stem cell donors allowed identification of several immune modulatory genes, which are regulated upon G-CSF administration in vivo (eg, LFA1-α, ISGF3-γ) and that are likely responsible for the reduced reactivity and/or alloreactivity. Most importantly, the induction of GATA-3, the master transcription factor for a Th2 immune response, could be demonstrated in T cells upon G-CSF treatment in vivo accompanied by an increase of spontaneous interleukin-4 secretion. Hence, G-CSF is a strong immune regulator of T cells and a promising therapeutic tool in acute graft-versus-host disease as well as in conditions associated with Th1/Th2 imbalance, such as bone marrow failure syndromes and autoimmune diseases.
Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro
Authors: Chang Mei , Nakagawa Peggy A. , Williams Shirley A. , Schwartz Michael R. , Imfeld Karen L. , Buzby Jeffrey S. , Nugent Diane J.
Published: April 2003

To determine if megakaryocytes are targeted by immune thrombocytopenic purpura (ITP) autoantibodies, as are platelets, we have studied the effects of ITP plasma on in vitro megakaryocytopoiesis. Umbilical cord blood mononuclear cells were incubated in the presence of thrombopoietin and 10% plasma from either ITP patients (n = 53) or healthy donors. The yield of megakaryocytic cells, as determined by flow cytometry, was significantly reduced in the presence of ITP plasma containing antiplatelet glycoprotein Ib (GPIb) autoantibodies (P < .001) as compared with both the control and patient plasma with no detectable anti-GPIIb/IIIa or anti-GPIb autoantibodies. Platelet absorption of anti-GPIb autoantibodies in ITP plasmas resulted in double the megakaryocyte production of the same plasmas without absorption, whereas platelet absorption of control plasma had no effect on megakaryocyte yield. Furthermore, 2 human monoclonal autoantibodies isolated from ITP patients, 2E7, specific for human platelet glycoprotein IIb heavy chain, and 5E5, specific for a neoantigen on glycoprotein IIIa expressed on activated platelets, had significant inhibitory effects on in vitro megakaryocytopoiesis (P < .001). Taken together, these data indicate that autoantibodies against either platelet GPIb or platelet GPIIb/IIIa in ITP plasma not only are involved in platelet destruction, but may also contribute to the inhibition of platelet production.
Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells
Authors: Sitnicka Ewa , Buza-Vidas Natalija , Larsson Staffan , Nygren Jens M. , Liuba Karina , Jacobsen Sten Erik W.
Published: April 2003

The cytokine tyrosine kinase receptors c-kit and flt3 are expressed and function in early mouse and human hematopoiesis. Through its ability to promote ex vivo expansion and oncoretroviral transduction of primitive human hematopoietic progenitors, the flt3 ligand (FL) has emerged as a key stimulator of candidate human hematopoietic stem cells (HSCs). However, recent studies in the mouse suggest that though it is present on short-term repopulating cells, flt3 is not expressed on bone marrow long-term reconstituting HSCs, the ultimate target for the development of cell replacement and gene therapy. Herein we demonstrate that though only a fraction of human adult bone marrow and cord blood CD34+long-term culture-initiating cells (LTC-ICs) express flt3, most cord blood lymphomyeloid HSCs capable of in vivo reconstituting nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice are flt3+. The striking difference in flt3 and c-kit expression on mouse and candidate human HSCs translated into a corresponding difference in flt3 and c-kit function because FL was more efficient than SCF at supporting the survival of candidate human HSCs. In contrast, SCF is far superior to FL as a viability factor for mouse HSCs. Thus, the present data provide compelling evidence for a contrasting expression and response pattern of flt3 and c-kit on mouse and human HSCs.
Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions
Authors: Billiau An D. , Fevery Sabine , Rutgeerts Omer , Landuyt Willy , Waer Mark
Published: April 2003

A murine model of minor histocompatibility antigen (miHCag)–mismatched bone marrow transplantation (BMT) was used to study the development of immunoregulatory cells in the posttransplantation period and their possible involvement in the dissociated graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity of posttransplantation donor lymphocyte infusions (DLIs). DLI, applied immediately after BMT, induced GVH disease (GVHD), but when DLI was delayed for 3 weeks, GVHD was avoided while a distinct GVL response was allowed to develop. A population of Mac1+Ly6-G+Ly6-C+ immature myeloid cells, found in small numbers in normal mice, strongly expanded in spleens of chimeras, reaching a maximum level at week 3 and returning to base level by week 12. Upon isolation, these cells exhibited interferon-γ (IFN-γ)–dependent, nitric oxide (NO)–mediated suppressor activity toward in vitro alloresponses, suggesting that, after in vivo DLI, they are activated by IFN-γ to produce NO and suppress GVH reactivity. Because not only alloactivated T-cell proliferation but also leukemia cell growth was found susceptible to inhibition by exogenous NO, in vivo activation of these cells after DLI may explain the occurrence of a GVL effect despite suppression of GVHD. This suggested sequence of events was supported by the finding that the ex vivo antihost proliferative response of spleen cells, recovered shortly after in vivo DLI, was characterized by strong mRNA production of the monokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) and of inducible nitric oxide synthase (iNOS). Our data suggest that transiently expanding Mac1+Ly6-G+Ly6-C+ immature myeloid cells (probably as a result of extramedullary myelopoiesis) may play a role in controlling GVH while promoting GVL reactivity of DLI after allogeneic BMT.
Impaired hematopoiesis in mice lacking the transcription factor Sp3
Authors: van Loo Pieter Fokko , Bouwman Peter , Ling Kam-Wing , Middendorp Sabine , Suske Guntram , Grosveld Frank , Dzierzak Elaine , Philipsen Sjaak , Hendriks Rudolf W.
Published: April 2003

As the zinc-finger transcription factor specificity protein 3 (Sp3) has been implicated in the regulation of many hematopoietic-specific genes, we analyzed the role of Sp3 in hematopoiesis. At embryonic day 18.5 (E18.5), Sp3-/- mice exhibit a partial arrest of T-cell development in the thymus and B-cell numbers are reduced in liver and spleen. However, pre–B-cell proliferation and differentiation into immunoglobulin M–positive (IgM+) B cells in vitro are not affected. At E14.5 and E16.5, Sp3-/- mice exhibit a significant delay in the appearance of definitive erythrocytes in the blood, paralleled by a defect in the progression of differentiation of definitive erythroid cells in vitro. Perinatal death of the null mutants precludes the analysis of adult hematopoiesis in Sp3-/- mice. We therefore investigated the ability of E12.5 Sp3-/- liver cells to contribute to the hematopoietic compartment in an in vivo transplantation assay. Sp3-/- cells were able to repopulate the B- and T-lymphoid compartment, albeit with reduced efficiency. In contrast, Sp3-/- cells showed no significant engraftment in the erythroid and myeloid lineages. Thus, the absence of Sp3 results in cell-autonomous hematopoietic defects, affecting in particular the erythroid and myeloid cell lineages.
SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton
Authors: Dyson Jennifer M. , Munday Adam D. , Kong Anne M. , Huysmans Richard D. , Matzaris Maria , Layton Meredith J. , Nandurkar Harshal H. , Berndt Michael C. , Mitchell Christina A.
Published: April 2003

The platelet receptor for the von Willebrand factor (VWF) glycoprotein Ib-IX-V (GPIb-IX-V) complex mediates platelet adhesion at sites of vascular injury. The cytoplasmic tail of the GPIbα subunit interacts with the actin-binding protein, filamin, anchoring the receptor in the cytoskeleton. In motile cells, the second messenger phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3) induces submembraneous actin remodeling. The inositol polyphosphate 5-phosphatase, Src homology 2 domain-containing inositol polyphosphate 5-phosphatase-2 (SHIP-2), hydrolyzes PtdIns(3,4,5)P3 forming phosphatidylinositol 3,4 bisphosphate (PtdIns(3,4)P2) and regulates membrane ruffling via complex formation with filamin. In this study we investigate the intracellular location and association of SHIP-2 with filamin, actin, and the GPIb-IX-V complex in platelets. Immunoprecipitation of SHIP-2 from the Triton-soluble fraction of unstimulated platelets demonstrated association between SHIP-2, filamin, actin, and GPIb-IX-V. SHIP-2 associated with filamin or GPIb-IX-V was active and demonstrated PtdIns(3,4,5)P3 5-phosphatase activity. Following thrombin or VWF-induced platelet activation, detection of the SHIP-2, filamin, and receptor complex decreased in the Triton-soluble fraction, although in control studies the level of SHIP-2, filamin, or GPIb-IX-V immunoprecipitated by their respective antibodies did not change following platelet activation. In activated platelets spreading on a VWF matrix, SHIP-2 localized intensely with actin at the central actin ring and colocalized with actin and filamin at filopodia and lamellipodia. In spread platelets, GPIb-IX-V localized to the center of the platelet and showed little colocalization with filamin at the plasma membrane. These studies demonstrate a functionally active complex between SHIP-2, filamin, actin, and GPIb-IX-V that may orchestrate the localized hydrolysis of PtdIns(3,4,5)P3 and thereby regulate cortical and submembraneous actin.
Factor VII gene intronic mutation in a lethal factor VII deficiency: effects on splice-site selection
Authors: Borensztajn Keren , Sobrier Marie-Laure , Fischer Anne-Marie , Chafa Ouerdia , Amselem Serge , Tapon-Bretaudiére Jacqueline
Published: April 2003

In a patient with lethal factor VII (FVII) deficiency, 2 homozygous nucleotide substitutions were identified in the F7 gene: a IVS7+2T>G transversion involving the IVS7 donor splice site, followed by a mutation at nucleotide 10588 that would result in a missense variation (Arg224Gln). The mutated splice site, located within the first repeat of a minisatellite, is followed by a variable number of pseudo-sites, normally silent. To investigate the consequences of this mutation on F7 splicing, we designed normal and mutant minigenes, spanning exons 5 to 8. In cells transfected with the mutant construct, no normal splicing occurred. Only spliced transcripts including the first minisatellite repeat were observed, resulting from the activation of the most proximal wild-type pseudo-site, which would generate a truncated protein (stop codon upstream of nucleotide 10588). These findings, which suggest the existence of a mechanism selecting one single splice site among multiple cryptic sites, explain the patient's phenotype.
Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells
Authors: Bornhäuser Martin , Storer Barry , Slattery John T. , Appelbaum Frederick R. , Deeg H. Joachim , Hansen John , Martin Paul J. , McDonald George B. , Nichols W. Garrett , Radich Jerald , Woolfrey Ann , Jenke Andreas , Schleyer Eberhard , Thiede Christian , Ehninger Gerhard , Anasetti Claudio
Published: April 2003

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 ± 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.
Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features
Authors: Guarini Anna , Gaidano Gianluca , Mauro Francesca Romana , Capello Daniela , Mancini Francesca , De Propris Maria Stefania , Mancini Marco , Orsini Enrica , Gentile Massimo , Breccia Massimo , Cuneo Antonio , Castoldi Gianluigi , Foa Robert
Published: April 2003

Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10 to 23 years and who never required treatment were extensively characterized. The aim was to identify a distinct and reproducible biologic profile associated with disease stability that may be used to recognize at presentation CLL patients who are likely to have a very benign clinical course and for whom treatment is not indicated. The results obtained indicate that numerous parameters are closely associated with disease stability: a typical CLL morphology and immunophenotype, the lack of expression of the CD38 antigen, the mutated immunoglobulin (Ig) heavy (H) chain variable (V) pattern, the absence of p53 mutations, a CD4/CD8 ratio more than 1, the lack of 17p and 11q deletions and of complex karyotypic aberrations, and the occurrence of the 13q14 deletion. No case displayed the VH3-21 gene, linked in mutated CLL with a poor outcome. In addition, the VH1-69 gene associated with unmutated CLL cases was never detected. These biologic features were coupled with an indolent clinical course characterized by an unmodified clinical stage over time, and by lack of autoimmune phenomena and of major infections requiring parental antibiotics. At a time when aggressive therapeutic strategies are always more frequently used in the management of CLL, the distinctive features of patients with long-lived stable disease should be prospectively identified at presentation.
Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells
Authors: Hinds Kathleen A. , Hill Jonathan M. , Shapiro Erik M. , Laukkanen Mikko O. , Silva Alfonso C. , Combs Christian A. , Varney Timothy R. , Balaban Robert S. , Koretsky Alan P. , Dunbar Cynthia E.
Published: April 2003

Tracking transplanted stem cells using magnetic resonance imaging (MRI) could offer biologic insight into homing and engraftment. Ultrasmall dextran-coated iron oxide particles have previously been developed for uptake into cells to allow MRI tracking. We describe a new application of much larger, micron-scale, iron oxide magnetic particles with enhanced MR susceptibility, which enables detection of single cells at resolutions that can be achieved in vivo. In addition, these larger particles possess a fluorophore for histologic confirmation of cell distribution. We demonstrate highly efficient, nontoxic, endosomal uptake of these particles into hematopoietic CD34+ cells and mesenchymal stem cells documented by confocal and electron microscopy. Labeled cells retain biologic activity with preservation of colony-forming ability and differentiation capacity. MRI studies could detect labeled CD34+ cells and mesenchymal stem cells (MSCs) at single cell resolution. This appears to be a promising tool for serial noninvasive monitoring of in vivo cell homing and localization using MRI.
Polyclonal hematopoiesis maintained in patients with bone marrow failure harboring a minor population of paroxysmal nocturnal hemoglobinuria–type cells
Authors: Ishiyama Ken , Chuhjo Tatsuya , Wang Hongbo , Yachie Akihiro , Omine Mitsuhiro , Nakao Shinji
Published: April 2003

Although a minor population of paroxysmal nocturnal hemoglobinuria (PNH)–type blood cells is often detected in patients with aplastic anemia (AA) and refractory anemia (RA), the significance of such cells in the pathophysiology of bone marrow (BM) failure remains obscure. We therefore examined clonality in peripheral blood granulocytes from 118 female patients with AA or myelodysplastic syndrome using the X chromosome inactivation pattern. Clonality, defined as a clonal population accounting for 35% or more of total granulocytes, was confirmed in 22 of 68 (32.4%) AA patients, in 13 of 44 (29.5%) RA patients, in all 4 RA with excess blasts (RAEB) patients, and in 4 patients with PNH. When the frequency of patients with granulocyte clonality was compared with respect to the presence of increased PNH-type cells, the frequency was significantly lower in AA patients with (PNH+; 21.2%) than without (PNH–; 42.9%) increased numbers of PNH-type cells (P = .049). Clonality was absent in granulocytes from the 15 PNH+ RA patients but present in 13 of 29 (44.8%) PNH– RA patients (P = .0013). The absence of clonality in AA and RA patients before treatment was strongly associated with positive response to immunosuppressive therapy (without clonality, 74.4%; with clonality, 33.3%; P = .0031) in all patients as well as in PNH+ patients (without clonality, 96.2%; with clonality, 66.6%, P = .026). These results suggest that AA and RA with a minor population of PNH-type cells are benign types of BM failure with immune pathophysiology that have little relationship to clonal disorders such as RAEB or acute myeloid leukemia.
Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity
Authors: Rollinson Sara , Levene Adam P. , Mensah Fiona K. , Roddam Philippa L. , Allan James M. , Diss Tim C. , Roman Eve , Jack Andrew , MacLennan Kenneth , Dixon Michael F. , Morgan Gareth J.
Published: April 2003

Gastric marginal zone lymphoma (GMZL) is strongly associated with Helicobacter pylori infection, which induces a chronic inflammatory response. Inflammation can result in DNA damage related to its severity, the cellular antioxidant capacity, and the integrity of DNA repair mechanisms. Interleukin-1 (IL-1) polymorphisms have been shown to be important mediators of inflammation, while glutathione S-transferase GST T1 and GST M1 polymorphisms are believed to affect cellular antioxidant capacity. We aimed to determine whether polymorphisms at the IL-1 and GST T1 and GST M1 loci modulate the risk of developing GMZL. Blood and biopsy samples were obtained for a historical series of 66 GMZL cases, whereas blood samples were available from 163 healthy controls. Genotypes were obtained for GST T1, GST M1, IL-1 RN, and IL-1B-31 using PCR-based techniques. H pylori infection was found in 86.0% of cases, whereas in the control population only 37.4% tested positive. The IL-1 RN 2/2 genotype was significantly associated with risk of GMZL (odds ratio [OR], 5.51; 95% confidence interval [CI] 2.16-14.07), but not the IL-1B-31 genotype. Likewise, the GST T1 null genotype was strongly associated with risk of GMZL (OR, 9.51; 95% CI 4.57-19.81), but not the GST M1 genotype. Evidence was found of effect modification between the IL-1 RN and GST T1 genotypes (P =.02). The combination of the IL-1 RN 2/2 and GST T1 null genotype was most strongly associated with risk of GMZL (OR, 32.29; 95% CI 6.92-150-63). These results support the hypothesis that the risk of developing GMZL is influenced by inter-individual variation in the cellular inflammatory immune responses to H pylori infection, and to antioxidative capacity.
Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness
Authors: Klion Amy D. , Noel Pierre , Akin Cem , Law Melissa A. , Gilliland D. Gary , Cools Jan , Metcalfe Dean D. , Nutman Thomas B.
Published: April 2003

Since serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (> 11.5 ng/mL) were present in 9 of 15 patients with HES and were associated with other markers of myeloproliferation, including elevated B12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25+ mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1–like 1 (FIP1L1) gene to the platelet-derived growth factor receptor α gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness.
Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome
Authors: Yamaguchi Hiroki , Baerlocher Gabriela M. , Lansdorp Peter M. , Chanock Stephen J. , Nunez Olga , Sloand Elaine , Young Neal S.
Published: April 2003

Mutations in the human telomerase RNA (TERC) occur in autosomal dominant dyskeratosis congenita (DKC). Because of the possibility that TERC mutations might underlie seemingly acquired forms of bone marrow failure, we examined blood samples from a large number of patients with aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplasia (MDS). Only 3 of 210 cases showed heterozygous TERC mutations: both nucleotide 305 (n305) (G>A) and n322 (G>A) were within the conserved region (CR) 4–CR5 domain; n450 (G>A) was localized to the boxH/ACA domain. However, only one patient (with a mutation at n305 [G>A]) had clinical characteristics suggesting DKC; her blood cells contained short telomeres and her sister also suffered from bone marrow failure. Another 21 patients with short telomeres did not show TERC mutations. Our results suggest that cryptic DKC, at least secondary to mutations in the TERC gene, is an improbable diagnosis in patients with otherwise typical AA, PNH, and MDS.
Occupational and nonoccupational factors associated with high grade bronchial pre-invasive lesions
Authors: Paris C. , Benichou J. , Bota S. , Sagnier S. , Metayer J. , Eloy S. , Auliac J-B. , Nouvet G. , Thiberville L.
Published: April 2003

Besides tobacco exposure, factors associated with the development of pre-invasive bronchial lesions are not known. Autofluorescence bronchoscopy was used to assess the prevalence of severe dysplasia and carcinomain situ(SD/CIS) of the proximal bronchial tree in relation to occupational or nonoccupational carcinogen exposure.

Among the 241 individuals in this study, the overall prevalence of at least one SD/CIS was 9% (21 subjects). Multivariable analysis revealed significant and independent associations between presence of SD/CIS and: 1) active smoking, relative to former smokers; 2) presence of synchronous invasive lung cancer; 3) duration of asbestos exposure and; 4) exposure to other occupational carcinogens.

The independent associations of synchronous lung cancer with severe dysplasia and carcinoma, after adjusting for both occupational and nonoccupational carcinogen exposures, suggest other mechanisms than a field cancerisation may be involved in the carcinogenesis of these pre-invasive lesions. Moreover, active smokers, patients with recently resected invasive lung cancer and workers occupationally exposed to bronchial carcinogens may represent a population of choice for early cancer endoscopic detection programmes in view of their high severe dysplasia and carcinoma prevalence.
Validity and interpretation of mortality, health service and survey data on COPD and asthma in England
Authors: Hansell A. , Hollowell J. , McNiece R. , Nichols T. , Strachan D.
Published: April 2003

The comparability of asthma and chronic obstructive pulmonary disease (COPD) epidemiology in different English routine data sources was examined to explore their use and validity in investigating environmental influences on respiratory health.

National data were obtained for mortality, emergency hospital admissions, general practitioner contacts and symptoms in the early 1990s. Age/sex patterns, seasonal variations and regional and urban/rural age/sex standardised event ratios were examined. Spearman rank correlations were used to describe consistency of regional rankings across data sets.

Asthma showed inconsistent disease patterns in different data sources and weak correlations for regional rankings but COPD was notably consistent. Unmeasured confounders may partly explain the findings, but individual level adjustment for social class and smoking (possible for symptoms) only partially attenuated the higher COPD rates in northern and urban areas and did not affect findings for asthma.

When epidemiological patterns are consistent across data sources as with chronic obstructive pulmonary disease in England, healthcare use is likely to reflect the underlying prevalence and severity of disease and can be used to study environmental influences. When patterns vary, as with asthma, the validity of the data in relation to its intended use must be carefully considered.
Acute exacerbation of idiopathic pulmonary fibrosis: report of a series
Authors: Ambrosini V. , Cancellieri A. , Chilosi M. , Zompatori M. , Trisolini R. , Saragoni L. , Poletti V.
Published: April 2003

This study describes five cases presenting an acute clinical course of pulmonary fibrosis, in the absence of specific precipitating factors.

A retrospective chart review of five patients with histologically proved usual interstitial pneumonia was carried out in 2001–2002. Clinical data, bronchoalveolar lavage (BAL) findings, high resolution computed tomography and histological features were reported.

On admission all cases presented hypoxemia and dyspnoea, while some showed an increase of carbohydrate antigen 19.9 or laboratory tests typical of infection, although appropriate cultures were all negative. Altogether, four subjects died and only one is on follow-up. A pattern of diffuse ground-glass or alveolar opacification superimposed on reticular and linear findings was evident on lung imaging in all cases. Marked neutrophilia, together with type II reactive cells hyperplasia, was detected on BAL.

Histological findings, from open lung biopsy or autopsy, showed all the aspects of usual interstitial pnemonia with superimposed features of acute lung injury, such as diffuse alveolar damage, with or without hyaline membranes, type II reactive cells hyperplasia and numerous fibroblastic foci. This study also underlines the diagnostic value of bronchoalveolar lavageversusopen lung biopsy.
Induced sputum for diagnosingPneumocystis cariniipneumonia in HIV patients: new data, new issues
Authors: Turner D. , Schwarz Y. , Yust I.
Published: April 2003

The complexity of bronchoalveolar lavage (BAL) has motivated the search for noninvasive methodology to retrieve specimens for detecting the presence of various pulmonary diseases. Induced sputum (IS) has been shown to be a reliable tool in terms of sensitivity and specificity comparable to BAL. Investigators from institutions worldwide have published several reports providing evidence in support of one or the other or a combination of both approaches. Among them are studies demonstrating the sensitivity and specificity of IS in diagnosingPneumocystis cariniipneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS). In 1996, highly active antiretroviral therapy was introduced for routine use and the morbidity from opportunistic infections decreased sharply.

An earlier study showed that cost-effectiveness depends on the prevalence of a given condition in the population. More recent studies have confirmed that prophylaxis against PCP can be stopped after increasing the CD4 cell count, thus reducing the attractiveness of IS as a preferred method for monitoring the course of disease.

This review presents a brief description of the evolution of the bronchoalveolar lavageversusinduced sputum controversy and reconsiders the strengths and weaknesses of the earlier arguments in light of newer data that have emerged with regard toPneumocystis cariniipneumonia in acquired immunodeficiency syndrome.
Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex
Authors: Logan A.G. , Tkacova R. , Perlikowski S.M. , Leung R.S. , Tisler A. , Floras J.S. , Bradley T.D.
Published: April 2003

This study was undertaken to determine whether abolition of obstructive sleep apnoea (OSA) by continuous positive airway pressure (CPAP) could reduce blood pressure (BP) in patients with refractory hypertension.

In 11 refractory hypertensive patients with OSA, the acute effects of CPAP on nocturnal BP were studied during sleep and its longer term effects on 24-h ambulatory BP after 2 months.

During a single night's application, CPAP abolished OSA and reduced systolic BP in stage 2 sleep from 138.3±6.8 to 126.0±6.3 mmHg. There was also a trend towards a reduction in average diastolic BP (from 77.7±4.5 to 72.9±4.5). CPAP usage for 2 months was accompanied by an 11.0±4.4 mmHg reduction in 24-h systolic BP. In addition, both the nocturnal and daytime components of systolic BP fell significantly by 14.4±4.4 and 9.3±3.9 mmHg, respectively. Diastolic BP was reduced significantly at night by 7.8±3.0 mmHg.

In patients with refractory hypertension, acute abolition of obstructive sleep apnoea by continuous positive airway pressure reduces nocturnal blood pressure. These data also suggest that continuous positive airway pressure may reduce nocturnal and daytime systolic blood pressure chronically. Randomised trials are needed to confirm the latter results.
In vitroandin vivocontractile properties of the vastus lateralis muscle in males with COPD
Authors: Debigaré R. , Côté C.H. , Hould F-S. , LeBlanc P. , Maltais F.
Published: April 2003

Peripheral muscle weakness is common in chronic obstructive pulmonary disease (COPD) but it is still under debate whether weakness is due to atrophy or contractile dysfunction.

In vitroandin vivocontractile properties of the vastus lateralis muscle were studied in 16 patients with stable COPD (forced expiratory volume in one second 39±16% of predicted, age 67±4 yrs (mean±sd)) and nine sedentary control subjects. Isometric knee extensor strength was measured while mid-thigh muscle cross-sectional area (MTMCSA) was obtained using computed tomography. Muscle strips from the vastus lateralis obtained through open biopsy were rapidly suspended in an oxygenated Krebs-Ringer solution that was maintained at 35°C with a pH of 7.40 to study their contractile properties.

The isometric knee extensors strength/MTMCSA ratio was 0.50±0.08versus0.58±0.06 kg·cm−2for COPD and control subjects, respectively. The muscle bundle cross-sectional area (CSA) was 4.6±2.1 and 4.4±3.1 mm−2, the length at which active tension was maximum was 15±4 and 15±3 mm, and maximal isometric peak forces normalised for CSA were 4.3±2.7 and 4.8±2.6 N·cm−2for COPD and control subjects, respectively. The force/frequency relationship tended to be shifted to the right in patients with COPD, meaning that a higher stimulation frequency was necessary to produce the same relative force. Patients with COPD had a lower proportion of type I fibre than controls (26±12%versus39±11%) with reciprocal significant increase in type IIb fibre proportion (20±16%versus8±4%). The proportion of type IIa fibres was similar between the two groups.

These results suggest that the contractile properties of the vastus lateralis are preserved in patients with chronic obstructive pulmonary disease. Therefore, the reduction in the quadriceps strength in patients with chronic obstructive pulmonary disease cannot be explained on the basis of an alteration of the contractile apparatus.
eThrombosis: the 21st Century variant of venous thromboembolism associated with immobility
Authors: Beasley R. , Raymond N. , Hill S. , Nowitz M. , Hughes R.
Published: April 2003

The association between immobility with prolonged sitting and venous thromboembolism has been recognised for >60 yrs, most recently with long distance air travel. The case of a 32-yr-old male, in whom immobility associated with sitting for long periods at a computer represented the major provoking risk factor for his life-threatening venous thromboembolism, is presented. The authors propose the term “eThrombosis” to describe this 21st Century variant of venous thromboembolism associated with immobility from prolonged sitting. In view of the widespread use of computers in relation to work, recreation and personal communication, the potential burden of eThrombosis may be considerable.
A nosocomial outbreak of influenza during a period without influenza epidemic activity
Authors: Horcajada J.P. , Pumarola T. , Martínez J.A. , Tapias G. , Bayas J.M. , de la Prada M. , García F. , Codina C. , Gatell J.M. , Jiménez de Anta M.T.
Published: April 2003

The objective of this study was to describe a nosocomial outbreak of influenza during a period without influenza epidemic activity in the community.

Outbreak investigation was carried out in an infectious diseases ward of a tertiary hospital. Presence of two or more of the following symptoms were used to define influenza: cough, sore throat, myalgia and fever. Epidemiological survey, direct immunofluorescence, viral culture, polymerase chain reaction, haemagglutination-inhibition test in throat swabs and serology for respiratory viruses were performed.

Twenty-nine of 57 healthcare workers (HCW) (51%) and eight of 23 hospitalised patients (34%) fulfilled the case definition. Sixteen HCW (55%) and three inpatients (37%) had a definitive diagnosis of influenza A virus infection (subtype H1N1). Among the symptomatic HCW, 93% had not been vaccinated against influenza that season. Affected inpatients were isolated and admissions in the ward were cancelled for 2 weeks. Symptomatic HCW were sent home for 1 week. On the seventeenth day of the outbreak the last case was declared.

The incidence of cases in this outbreak of influenza, which occurred during a period without influenza epidemic activity in the community, was notably high. Epidemiological data suggest transmission from healthcare workers to inpatients. Most healthcare workers were not vaccinated against influenza. Vaccination programmes should be reinforced among healthcare workers.
Inhaled corticosteroids and survival in chronic obstructive pulmonary disease: does the dose matter?
Authors: Sin D.D. , Man S.F.P.
Published: April 2003

Recent data suggest that inhaled corticosteroids reduce the number of clinical exacerbations in chronic obstructive pulmonary disease (COPD). It remains unknown whether a dose/response relationship exists. The present study was conducted to evaluate the long-term impact of varying doses of inhaled corticosteroids on COPD mortality.

Hospital discharge data were used to identify all patients aged ≥65 yrs recently hospitalised due to COPD in Alberta, Canada (n=6,740). The relative risk (RR) for all-cause mortality was compared across different dose categories of inhaled corticosteroids (none and low, medium and high doses) following hospital discharge.

Inhaled corticosteroid therapy after discharge was associated with a 25% relative reduction in risk for all-cause mortality (RR 0.75, 95% confidence interval (CI) 0.68–0.82). Patients on medium- or high-dose therapy showed lower risks for mortality than those on low doses (RR 0.77, 95% CI 0.69–0.86 for low dose; RR 0.48, 95% CI 0.37–0.63 for medium dose; and RR 0.55, 95% CI 0.44–0.69 for high dose).

Use of inhaled corticosteroids following hospital discharge for chronic obstructive pulmonary disease was associated with a significant reduction in the overall mortality rate. Low- was inferior to medium- or high-dose therapy in protecting against mortality in chronic obstructive pulmonary disease.
The effects ofMycobacterium vaccaeon allergen-induced airway responses in atopic asthma
Authors: Camporota L. , Corkhill A. , Long H. , Lordan J. , Stanciu L. , Tuckwell N. , Cross A. , Stanford J.L. , Rook G.A.W. , Holgate S.T. , Djukanovic R.
Published: April 2003

T-helper (Th)2 cytokines play a central role in asthma. Therefore, a double-blind randomised study was conducted to investigate whether heat-killedMycobacterium vaccae(SRL172), a potent downregulator of Th2 cytokines, can reduce allergen-induced airway responses in patients with atopic asthma.

A total 24 male asthmatics participated in this study. A bronchial allergen challenge was performed along with early (EAR) and late asthmatic responses (LAR) 2 weeks before and 3 weeks after a single intradermal injection of SRL172 or placebo. Before and after treatment, serum immunoglobulin (Ig)E levels andin vitroproduction of interleukin (IL)-5 by peripheral blood lymphocytes were studied.

Neither treatment affected the EAR. SRL172 caused a mean 34% reduction of the area under the curve of the forced expiratory volume in one second (FEV1) changes during the LAR, which failed to reach conventional statistical significance when compared with placebo. SRL172 also caused a mean 25% decrease in the maximum fall in FEV1during LAR, but this was not significantly different from placebo. SRL172 caused a reduction in serum IgE and IL-5 synthesisin vitro3 weeks post-treatment (p=0.07).

This study shows a trend toward significance for the effects of heat-killedMycobacterium vaccae(SRL172) on allergen-induced airway responses. Further clinical trials, involving multiple dosing, are needed.