bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of grazer immigration and nutrient enrichment on an open algae‐grazer system
Authors: K. Roll Sandra , Diehl Sebastian , D. Cooper Scott
Published: December 2004

After disturbance, recovery dynamics of local populations depend on arrival rates of immigrants and local growth conditions. We studied the effects of herbivore immigration rates and nutrient enrichment on the dynamics of grazing insect larvae, benthic microalgae, and filamentous macroalgae recovering from low local densities in an open stream system. The two types of algae approximate a trade‐off between capabilities for growing at low resource levels and resisting herbivory. Many microalgae achieve relatively high growth rates at low nutrient levels but are vulnerable to grazers, whereas many macroalgae require high nutrient levels for growth but become increasingly defended with filament growth. We hypothesized that macroalgae should benefit more strongly than microalgae from increasing nutrient levels and decreasing grazer immigration rates, because both conditions increase macroalgal chances to grow into a size refuge from herbivory.

We created a gradient of nutrient concentrations and manipulated drift immigration rates of macroinvertebrates. Macro‐ and microalgal biomass and the relative contribution of macroalgae to total algal biomass increased with increasing nutrient enrichment and decreased with increasing grazer immigration. Grazer densities responded positively to nutrient enrichment. The densities of large baetids responded positively to higher immigration rates of large baetids, whereas small baetids and chironomid larvae showed the opposite response. Per capita emigration of small baetids decreased with increasing algal biomass. The data suggest that large baetids negatively affected algal biomass and that small baetid and chironomid densities tracked resource levels set by nutrient enrichment and large baetids. Our experiments highlight the prospects of integrating disturbance with nutrient supply, immigration rates and local trophic interactions (determining recovery trajectories) into conceptual models of open system dynamics. We suggest that recovery trajectories towards micro‐ or macroalgal dominated states may depend on the spatial scale of disturbance relative to the movement ranges of migrating grazers and to nutrient supply.
Spatial and temporal heterogeneity of trophic variables in a deep lake as reflected by repeated singular samplings
Authors: Mehner Thomas , Hölker Franz , Kasprzak Peter
Published: December 2004

Approaches to compare the strength of pelagic trophic cascades often use singular sampling programs for measuring trophic variables, thus potentially neglecting the spatial and temporal heterogeneity in the distribution of fish, zooplankton and phytoplankton. Here, we compared the composition of six trophic variables from three trophic levels in a deep oligotrophic lake within temporal (diel and seasonal) and spatial (horizontal and vertical) sampling resolutions. Mean values and ratios between the variables were compared between day and night, in three sampling months, four lake basins, and three water depths. Factor analysis was used to determine abiotic variables which may explain the heterogeneous distribution of the trophic variables. All six trophic variables were strongly heterogeneously distributed between the sampling months and the water depths, whereas horizontal and day–night differences were lower. Distribution of fish, zooplankton and phytoplankton correlated with water temperature and nutrient concentrations. Accordingly, for the use in comparative and meta‐analyses, singular sampling programs in deep lakes have to integrate the entire water depth and are best repeated over several seasons. Alternatively, mean water temperature and nutrient concentrations may be used as covariates to diminish the unexplained variance between samples from different lakes.
Differences in habitat quality explain nestedness in a land snail meta‐community
Authors: Hylander Kristoffer , Nilsson Christer , Gunnar Jonsson Bengt , Göthner Tove
Published: December 2004

We set up two alternative hypotheses on how environmental variables could foster nestedness; one of “nested habitats” and another of “nested habitat quality”. The former hypothesis refers to situations where the nestedness of species depends on a nestedness of discrete habitats. The latter considers situations where all species in an assemblage increase in abundance along the same environmental gradient, but differ in specialisation or tolerance. We tested whether litter‐dwelling land snails (terrestrial gastropods) in boreal riparian forest exhibited a nested community structure, whether such a pattern was related to differences in environmental variables among sites, and which of the two hypotheses that best could account for the found pattern. We sampled litter from 100 m2plots in 29 mature riparian forest sites along small streams in the boreal zone of Sweden. The number of snail species varied between 3 and 14 per site. Ranking the species‐by‐site matrix by PCA scores of the first ordination axis revealed a similarly significant nested pattern as when the matrix was sorted by number of species, showing that the species composition in this meta‐community can be properly described as nested. Several environmental variables, most notably pH index, were correlated with the first PCA axis. All but two species had positive eigenvectors in the PCA ordination and the abundance increased considerably along the gradient for most of the species implying that the hypothesis of “nested habitats” was rejected in favour of the “nested habitat quality” hypothesis. Analyses of nestedness have seldom been performed on equal sized plots, and our study shows the importance of understanding that variation in environmental variables among sites can result in nested communities. The conservation implications are different depending on which of our two hypotheses is supported; a conservation focus on species “hotspots” is more appropriate if the communities are nested because of “nested habitat quality”.
Sexual size dimorphism within species increases with body size in insects
Authors: Teder Tiit , Tammaru Toomas
Published: December 2004

Studies examining interspecific differences in sexual size dimorphism (SSD) typically assume that the degree of sexual differences in body size is invariable within species. This work was conducted to assess validity of this assumption. As a result of a systematic literature survey, datasets for 158 insect species were retrieved. Each dataset contained adult or pupal weights of males and females for two or more different subsets, typically originating from different conditions during immature development. For each species, an analysis was conducted to examine dependence of SSD on body size, the latter variable being used as a proxy of environmental quality. A considerable variation in SSD was revealed at the intraspecific level in insects. The results suggest that environmental conditions may strongly affect the degree, though not the direction of SSD within species. In most species, female size appeared to be more sensitive to environmental conditions than male size: with conditions improving, there was a larger relative increase in female than male size. As a consequence, sexual differences in size were shown to increase with increasing body size in species with female‐biased SSD (females were the larger sex in more than 80% of the species examined). The results were consistent across different insect orders and ecological subdivisions. Mechanisms leading to intraspecific variation in SSD are discussed. This study underlines the need to consider intraspecific variation in SSD in comparative studies.
Multiscale structure in sedimentary basins
Authors: Stewart S. A. , Hay G. J. , Rosin P. L. , Wynn T. J.
Published: December 2004

Hierarchies of superimposed structures are found in maps of geological horizons in sedimentary basins. Mapping based on three‐dimensional (3D) seismic data includes structures that range in scale from tens of metres to hundreds of kilometres. Extraction of structures from these maps without a priori knowledge of scale and shape is analogous to pattern recognition problems that have been widely researched in disciplines outside of Geoscience. A number of these lessons are integrated and applied within a geological context here. We describe a method for generating multiscale representations from two‐dimensional sections and 3D surfaces, and illustrate how superimposed geological structures can be topologically analysed. Multiscale analysis is done in two stages – generation of scale‐space as a geometrical attribute, followed by identification of significant scale‐space objects. Results indicate that Gaussian filtering is a more robust method than conventional moving average filtering for deriving multiscale geological structure. We introduce the concept of natural scales for identifying the most significant scales in a geological cross section. In three dimensions, scale‐dependent structures are identified via an analogous process as discrete topological entities within a four‐dimensional scale‐space cube. Motivation for this work is to take advantage of the completeness of seismic data coverage to see ‘beyond the outcrop’ and yield multiscale geological structure. Applications include identifying artefacts, scale‐specific features and large‐scale structural domains, facilitating multiscale structural attribute mapping for reservoir characterisation, and a novel approach to fold structure classification.
Stratigraphic expression of the lateral propagation and growth of isolated fault‐related uplifts
Authors: Bernal Asdrúbal , Hardy Stuart , Gawthorpe Rob , Finch Emma
Published: December 2004

The lateral propagation of faults and folds is known to be an important process during the development of mountain belts, but little is known about the manner in which along‐strike fault–fold growth is expressed in pre‐ and syntectonic (growth) strata. We use a coupled tectonic and stratigraphic model to investigate the along‐strike stratigraphic expression of fault‐related folds/uplifts that grow in both the transport and strike directions. We consider faults that propagate following a quadratic (nonself‐similar evolution) or linear (self‐similar evolution) scaling law, using different slip distributions per episode of fault propagation, under general background sedimentation. We find that the long‐strike geometry of pre‐ and syntectonic strata and the geometry of growth axial surfaces reflect the mode of fault propagation. The geometry of strata observed in the model is similar to that observed in natural contractional structures when: (1) the evolution of the fault is nonself‐similar, or (2) the fault grows as a result of thrust faulting events with similar displacements along strike that are terminated abruptly at the fault tips.
Regional three‐dimensional gravity modelling of the NE Atlantic margin
Authors: Kimbell G S , Gatliff R W , Ritchie J D , Walker A S D , Williamson J P
Published: December 2004

A series of three‐dimensional models has been constructed for the structure of the crust and upper mantle over a large region spanning the NE Atlantic passive margin. These incorporate isostatic and flexural principles, together with gravity modelling and integration with seismic interpretations. An initial isostatic model was based on known bathymetric/topographic variations, an estimate of the thickness and density of the sedimentary cover, and upper mantle densities based on thermal modelling. The thickness of the crystalline crust in this model was adjusted to equalise the load at a compensation depth lying below the zone of lateral mantle density variations. Flexural backstripping was used to derive alternative models which tested the effect of varying the strength of the lithosphere during sediment loading. The models were analysed by comparing calculated and observed gravity fields and by calibrating the predicted geometries against independent (primarily seismic) evidence. Further models were generated in which the thickness of the sedimentary layer and the crystalline crust were modified in order to improve the fit to observed gravity anomalies. The potential effects of igneous underplating and variable upper mantle depletion were explored by a series of sensitivity trials. The results provide a new regional lithospheric framework for the margin and a means of setting more detailed, local investigations in their regional context. The flexural modelling suggests lateral variations in the strength of the lithosphere, with much of the margin being relatively weak but areas such as the Porcupine Basin and parts of the Rockall Basin having greater strength. Observed differences between the model Moho and seismic Moho along the continental margin can be interpreted in terms of underplating. A Moho discrepancy to the northwest of Scotland is ascribed to uplift caused by a region of upper mantle with anomalously low density, which may be associated with depletion or with a temperature anomaly.
Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation
Authors: Orsolic Nada , Giles Francis J. , Gourdeau Henriette , Golemovic Mirna , Beran Miloslav , Cortes Jorge , Freireich Emil J , Kantarjian Hagop , Verstovsek Srdan
Published: December 2004

The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5‐R and KBM7‐R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0·5–1 μmol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7‐R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0·01 μmol/l) with either IM‐sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5‐R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long‐term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted.
Thalassaemia mutations within the 5′UTR of the human β‐globin gene disrupt transcription
Authors: Sgourou Argyro , Routledge Samantha , Antoniou Michael , Papachatzopoulou Adamantia , Psiouri Lambrini , Athanassiadou Aglaia
Published: December 2004

The mechanisms by which mutations within the 5′ untranslated region (UTR) of the human β‐globin gene (HBB) cause thalassaemia are currently not well understood. We present here the first comprehensive comparative functional analysis of four ‘silent’ mutations in the human β‐globin 5′UTR, namely: +10(−T), +22(G → A), +33(C → G) and +(40–43)(−AAAC), which are present in patients with β‐thalassaemia intermedia. Expression of these genes under the control of the β‐globin locus control region in stable transfected murine erythroleukaemia cells showed that all four mutations decreased steady state levels of mRNA to 61·6%, 68%, 85·2% and 70·6%, respectively, compared with the wildtype gene. These mutations did not interfere with either mRNA transport from the nucleus to the cytoplasm, 3′ end processing or mRNA stability. Nuclear run‐on experiments demonstrated that mutations +10(−T) and +33(C → G) reduced the rate of transcription to a degree that fully accounted for the observed lower level of mRNA accumulation, suggesting a disruption of downstream promoter sequences. Interestingly, mutation +22(G → A) decreased the rate of transcription to a low degree, indicating the existence of a mechanism that acts post‐transcriptionally. Generally, our data demonstrated the significance of functionally analysing mutants of this type in the presence of a full complement of transcriptional regulatory elements within a stably integrated chromatin context in an erythroid cell environment.
Podocalyxin in human haematopoietic cells
Authors: Kerosuo Laura , Juvonen Eeva , Alitalo Riitta , Gylling Mikhail , Kerjaschki Dontscho , Miettinen Aaro
Published: December 2004

Podocalyxin‐like protein (PCLP) is a sialomucin‐type membrane protein structurally related to CD34 and endoglycan. It was first described in glomerular podocytes and endothelial cells. In mice, PCLP is present in haemangioblasts, and in both chicken and mice it is a marker of early haematopoietic stem cells and lineage‐restricted haematopoietic progenitors. Its expression decreases during differentiation of haematopoietic cells. Of mature blood cells, only chicken and rat thrombocytes express PCLP protein. PCLP expression in human haematopoietic cells has not been studied. Here we demonstrate PCLP mRNA in human CD34+ cells, in lineage committed erythroid, megakaryocyte and myeloid progenitors, in K562 leukaemia cells, and in peripheral blood leucocytes. The mRNA expression level was higher in developing cells than in mature leucocytes. By Northern blotting and cDNA sequencing, the haematopoietic and renal PCLP mRNAs were identical. Of the mobilized CD34+ cells, 28% (mean; range 14–61%) expressed PCLP protein and the majority of PCLP+ cells were CD117+. Almost all of the K562 cells expressed PCLP protein. Surprisingly, PCLP protein was not detected in any mature blood cells. These results suggest that human PCLP may be a valuable marker for a subset of haematopoietic stem cells.
Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers
Authors: Stevenson John C. , Oladipo Ayotunde , Manassiev Nick , Whitehead Malcolm I. , Guilford Sandra , Proudler Anthony J.
Published: December 2004

Whether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40–65 years, entered a prospective, double‐blind, randomized, placebo‐controlled clinical trial; 55 women completed the 6‐month study. Women received either transdermal oestradiol 17β 0·05 mg and norethisterone acetate 0·125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E‐selectin (P < 0·01), and angiotensin‐converting‐enzyme (ACE; P = 0·05). Cholesterol (P < 0·05), low‐density lipoproteins (LDL; P < 0·05), high‐density lipoprotein3 (HDL3; P < 0·05) and apolipoproteins AII (P < 0·05) and B (P < 0·05), and fasting insulin (P < 0·05) also decreased in the HRT group. Factor VII coagulation activity decreased (P < 0·01) and plasminogen activator inhibitor‐1 and fibrin D‐dimer increased (P < 0·05) in the HRT group, whilst prothrombin fragment 1 + 2 (P < 0·05) decreased, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)‐2, or in LDL particle size. This transdermal HRT had beneficial effects on vascular function and CHD risk markers.
Development and functional analysis of eosinophils from murine embryonic stem cells
Authors: Hamaguchi‐Tsuru Emi , Nobumoto Atsuya , Hirose Noriyuki , Kataoka Sayo , Fujikawa‐Adachi Kiyomi , Furuya Masato , Tominaga Akira
Published: December 2004

We have established a culture system for the development of eosinophils from murine embryonic stem (ES) cells. After transferring ES cells from embryonic fibroblast cells onto macrophage colony‐stimulating factor‐deficient stromal cells, OP9, ES cells were cultured in the presence of interleukin (IL)‐5 with either IL‐3 or granulocyte–macrophage colony stimulating factor (GM‐CSF) for 20 d to obtain approximately 50% eosinophils. Electron microscopy confirmed the presence of crystallized major basic protein (MBP) in the granules of some of these cells. Neither IL‐5, IL‐3, GM‐CSF nor eotaxin alone could induce eosinophils as efficiently as the conditions described above. Eotaxin induced eosinophil development in combination with either IL‐3 or IL‐5. Levels of GATA‐1, Friend of GATA (FOG)‐1, PU.1, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ, IL‐3 receptor α (IL‐3Rα), GM‐CSF receptor α (GM‐CSFRα), and MBP mRNAs were increased in ES cells 10 d after transfer onto OP9 cells. In contrast, C/EBPɛ, IL‐5Rα, and eosinophil peroxidase mRNAs were induced in response to IL‐3 and IL‐5 after transfer onto OP9 cells. Eosinophils that developed in this system expressed Gr‐1, F4/80, B220, CCR3, IL‐3Rα, IL‐5Rα, and DX5. Finally, eosinophils developed from ES cells produced reactive oxygen species in response to Leishmania as do peripheral blood eosinophils.
Computer‐based drug management in a bone marrow transplant unit: a suitable tool for multiple prescriptions even in critical conditions
Authors: Krampera Mauro , Venturini Francesca , Benedetti Fabio , Oliani Andrea , Carolei Simonetta , Visco Carlo , Aqel Haytam , Pizzolo Giovanni , Scroccaro Giovanna
Published: December 2004

Drug prescription or administration errors are the most common causes of adverse events for hospital patients. Computer‐based systems can be effective in reducing these errors. The aim of this study was to assess whether computer‐based systems are easily exploitable even in critical conditions. The oral and handwritten system for drug management was completely replaced by a computer‐based system in our bone marrow transplant unit, chosen because: (i) the intensive treatments could test the efficiency of the system; (ii) the very frequent occurrence of complications and emergencies could test the flexibility of the system; and (iii) the pre‐existing system could be used as comparison. From May to November 2002, 41 patients were repeatedly admitted to undergo high‐dose chemotherapy, autologous/allogeneic stem cell transplantation or because of severe complications. In 27 consecutive admissions, 2264 drug prescriptions (average, 29 drugs/patient admission) and 36 786 drug administrations (39·8/patient/d) were carried out. Despite the large number of procedures, the computerized system effectively replaced the oral and handwritten transmission of information among medical staff, pharmacists and nurses, and lowered the error risks. In addition, it contributed to medical updating through warnings on potential problems in case of multiple drug prescriptions, and gave the pharmacy a valuable tool to monitor drug use.
Improved survival in steroid‐refractory acute graft versus host disease after non‐myeloablative allogeneic transplantation using a daclizumab‐based strategy with comprehensive infection prophylaxis
Authors: Srinivasan R. , Chakrabarti S. , Walsh T. , Igarashi T. , Takahashi Y. , Kleiner D. , Donohue T. , Shalabi R. , Carvallo C. , Barrett A. J. , Geller N. , Childs R.
Published: December 2004

Approximately 15% of patients undergoing non‐myeloablative allogeneic haematopoietical cell transplantation (NMHCT) develop steroid‐refractory acute‐graft versus host disease (aGVHD), a usually fatal complication. We encountered 18 cases of steroid‐refractory aGVHD in 146 patients, undergoing NMHCT from a related human leucocyte antigen‐compatible donor following cyclophosphamide/fludarabine‐based conditioning. Our initial cohort of steroid‐refractory aGVHD patients treated with antithymocyte globulin (ATG) and mycophenolate mofetil (regimen‐1: n = 6) had high GVHD‐related mortality. Therefore, we investigated an alternative strategy for subsequent patients developing this complication (regimen‐2: n = 12), consisting of daclizumab (alone or combined with infliximab/ATG) and targeted broad spectrum antibacterial and aspergillus prophylaxis in conjunction with rapid tapering of steroids to minimize opportunistic infections. In a retrospective analysis, patients receiving regimen‐2 were significantly more likely to have complete resolution of GVHD compared with those receiving regimen‐1 [12/12 (100%) vs. 1/6 (17%); P < 0·001]. When compared with those receiving regimen‐1, regimen‐2 patients also had a higher probability of survival at day 100 (100% vs. 50%) and day 200 (73% vs. 17%) post‐transplant, and improved overall survival (median 453 d vs. 42 d from aGVHD onset; P < 0·0001). GVHD‐related mortality was 89% for regimen‐1 patients vs. 17% for regimen‐2 patients (P < 0·0001). These data suggest that a co‐ordinated approach using immunoregulatory monoclonal antibodies, pre‐emptive antimicrobial therapy and judicious steroid withdrawal can dramatically improve outcome in steroid‐refractory aGVHD.
Outcomes of an automated procedure for the selection of effective platelets for patients refractory to random donors based on cross‐matching locally available platelet products
Authors: Rebulla Paolo , Morelati Fernanda , Revelli Nicoletta , Villa Maria Antonietta , Paccapelo Cinzia , Nocco Angela , Greppi Noemi , Marconi Maurizio , Cortelezzi Agostino , Fracchiolla Nicola , Martinelli Giovanni , Deliliers Giorgio Lambertenghi
Published: December 2004

In 1999, we implemented an automated platelet cross‐matching (XM) programme to select compatible platelets from the local inventory for patients refractory to random donor platelets. In this study, we evaluated platelet count increments in 40 consecutive refractory patients (8·3% of 480 consecutive platelet recipients) given 569 cross‐match‐negative platelets between April 1999 and December 2001. XM was performed automatically with a commercially available immunoadherence assay. Pre‐, 1‐ and 24‐h post‐transfusion platelet counts (mean ± SD) for the 569 XM‐negative platelet transfusions containing 302 ± 71 × 109 platelets were 7·7 ± 5·5, 32·0 ± 21·0 and 16·8 ± 15·5 × 109/l respectively. Increments were significantly higher (P < 0·05, t‐test) than those observed in the same patients given 303 random platelet pools (dose = 318 ± 52 × 109 platelets) during the month before refractoriness was detected, when pre‐, 1‐ and 24‐h post‐transfusion counts were 7·0 ± 8·6, 15·9 ± 16·1 and 9·6 ± 12·8 × 109/l respectively. The cost of the platelet XM disposable kit per transfusion to produce 1‐h post‐transfusion platelet count increments >10 × 109/l was euro 447. This programme enabled the rapid selection of effective platelets for refractory patients, from the local inventory.
Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients
Authors: Chowdhury Pratima , Saayman Anton G. , Paulus Ulrike , Findlay George P. , Collins Peter W.
Published: December 2004

This study assessed the effect on coagulation tests of fresh frozen plasma (FFP), given according to guidelines compared with higher doses in critically ill patients. Group 1 (10 patients) received 12·2 ml/kg and group 2 (12 patients) 33·5 ml/kg FFP. Prothrombin time, activated partial thromboplastin time and factors I–XII were measured before and after FFP infusion. Factor levels of 30 IU/dl (1 g/l for fibrinogen) were considered haemostatic. A retrospective review showed 10 of 22 (five in group 1 and five in group 2) patients had not required FFP. Of those that needed FFP, one of five in group 1 and seven of seven in group 2 had coagulation factor levels above the target post‐FFP. Increments for group 1 versus 2 were: fibrinogen 0·4 vs. 1·0 g/l, FII 16 vs. 41*, FV 10 vs. 28*, FVII 11 vs. 38*, FVIII 10 vs. 17, FIX 8 vs. 28*, FX 15 vs. 37*, FXI 9 vs. 23 and FXII 30 vs. 44 IU/dl* (*P < 0·01). In vivo recovery of coagulation factors was the same for both groups and the observed increments correlated with the dose of FFP. In conclusion, coagulation screens were poor predictors of coagulation factor levels and current guidelines on the use of FFP result in predictably small increments in coagulation factors in critically ill patients and should be reviewed.
The efficacy and safety of B‐cell depletion with anti‐CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura
Authors: Cooper Nichola , Stasi Roberto , Cunningham‐Rundles Susanna , Feuerstein Michael A. , Leonard John P. , Amadori Sergio , Bussel James B.
Published: December 2004

Because of its B‐cell depleting effect, rituximab has entered clinical trials in several autoimmune conditions. This study assesses the efficacy and safety of rituximab in 57 adults with chronic immune thrombocytopenic purpura (ITP). All patients had platelet counts <30 × 109/l, all had received two or more previous ITP treatments and 31 had undergone splenectomy. Patients received rituximab 375 mg/m2 weekly for 4 weeks. Thirty‐one patients (54%) responded, achieving a platelet count >50 × 109/l: 18 achieved a complete response (CR: platelet count >150 × 109/l) and 13 a partial response (PR: platelet count 50–150 × 109/l). Twenty‐nine responses occurred within 8 weeks of the first infusion. Sixteen of 18 CR patients (28% overall), including eight who had failed splenectomy, continued in CR after a median of 72·5 weeks; 15 of 16 are >1 year from the first infusion. Only two of 13 maintained a PR. Thirty‐three patients experienced grade 1–2 adverse events and one a grade 3 event, but they all completed treatment. Circulating B cells fell to <0·03 × 109/l. No changes in immunoglobulin levels or infectious complications were seen. In summary, rituximab was well tolerated with no immediate complications and induced a lasting, substantial response in 32% of adults with chronic ITP.
A recombinant bispecific single‐chain Fv antibody against HLA class II and FcγRIII (CD16) triggers effective lysis of lymphoma cells
Authors: Bruenke Joerg , Fischer Barbara , Barbin Karin , Schreiter Katja , Wachter Yvonne , Mahr Kerstin , Titgemeyer Fritz , Niederweis Michael , Peipp Matthias , Zunino Susan J. , Repp Roland , Valerius Thomas , Fey Georg H.
Published: December 2004

Bispecific antibodies offer the possibility of improving effector‐cell recruitment for antibody therapy. For this purpose, a recombinant bispecific single‐chain Fv antibody (bsscFv), directed against FcγRIII (CD16) and human leucocyte antigen (HLA) class II, was constructed and tested in functional assays. RNA from the hybridomas 3G8 and F3.3, reacting with CD16 and HLA class II, respectively, was used to generate phage display libraries. From these libraries, reactive phages were isolated and the bsscFv was constructed by connecting both single‐chain Fv components through a 20 amino acid flexible linker. After expression in SF21 insect cells and chromatographic purification, the bsscFv bound specifically and simultaneously to both antigens. The affinities of the anti‐CD16 and the anti‐HLA class II scFv components of the bsscFv were 8·6 × 10−8 mol/l and 13·7 × 10−8 mol/l, respectively, which was approximately sevenfold lower than the F(ab) fragments of the parental antibodies. In antibody‐dependent cellular cytotoxicity experiments with human mononuclear cells as effectors, the bsscFv‐mediated specific lysis of both HLA class II‐positive, malignant human B‐lymphoid cell lines and primary cells from patients with chronic B‐cell lymphocytic leukaemia. Optimal lysis was obtained at bsscFv concentrations of approximately 400 ng/ml, similar to the concentration required for maximum lysis by the corresponding chemically linked bispecific antibody. Thus, this recombinant bsscFv‐antibody is an efficient molecule for effector‐cell mediated lysis of malignant human B‐lymphoid cells.
Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome
Authors: El‐Zimaity Maha M. T. , Kantarjian Hagop , Talpaz Moshe , O'Brien Susan , Giles Francis , Garcia‐Manero Guillermo , Verstovsek Srdan , Thomas Deborah , Ferrajoli Alessandra , Hayes Kimberly , Nebiyou Bekele B. , Zhou Xian , Rios Mary B. , Glassman Armand B. , Cortes Jorge E.
Published: December 2004

Five to 10 per cent of patients with Philadelphia chromosome (Ph)‐positive chronic myelogenous leukaemia (CML) have variant translocations involving chromosomes other than 9 and 22. We investigated the characteristics and outcome of patients with variant translocations treated with imatinib. Among 721 patients, 44 (6%) had variant translocations, involving one (n = 39) or two (n = 4) additional chromosomes. Nineteen patients (44%) were in chronic (12 previously untreated), 24 (55%) in accelerated and one (2%) in blastic phase. A major cytogenetic response was achieved in 14 (74%) patients treated in chronic phase and in 14 (58%) treated in accelerated phase. Six of 13 (46%) evaluable patients had deletion of derivative chromosome 9, and there was a trend for a lower response rate in these patients. We compared the 43 patients in chronic or accelerated phase to 678 patients with classic Ph treated with imatinib. The only significant difference in clinical characteristics was a higher frequency of accelerated phase among those with variant translocations (56%) compared with those with classic translocations (38%). No differences in outcome were evident. In a multivariate analysis, variant Ph translocations had no impact in response rate, overall survival or duration of response. We conclude that patients with variant Ph translocations have a similar prognosis to those with classic Ph translocations when treated with imatinib.
CD21S antigen expression in tumour cells of diffuse large B‐cell lymphomas is an independent prognostic factor indicating better overall survival
Authors: Ogawa Shoko , Yamaguchi Motoko , Oka Kouji , Taniguchi Masanori , Ito Motohiro , Nishii Kazuhiro , Nakase Kazunori , Ohno Toshiyuki , Kita Kenkichi , Kobayashi Tohru , Shiku Hiroshi
Published: December 2004

To evaluate the clinical significance of CD21S expression of diffuse large B‐cell lymphoma (DLBCL) tumour cells, we compared their clinical features, immunophenotype, response to therapy and outcome in relation to CD21S expression. Between 1987 and 1999, frozen sections from 240 DLBCL cases were examined for CD21S expression by immunohistochemical methods. CD21S expression was detected on the tumour cells of 87 (36%) cases. The median age of the CD21S+ DLBCL cases was 65 years (range: 17–84 years), the male–female ratio was 42:45, and they showed the following clinical features: Eastern Cooperative Oncology Group score >1 in 14%, lactate dehydrogenase greater than normal levels in 38%, extranodal sites >1 in 14%, stages III/IV disease at diagnosis in 29%, B symptoms in 17%, and a high/high–intermediate International Prognostic Index (IPI) in 23%. They also showed a better overall survival (P = 0·00001, log‐rank test) and a better complete remission rate (P = 0·00004, chi‐square test) than CD21S− DLBCL. Moreover, CD21S+ DLBCL showed a better survival than CD21S− DLBCL for both low/low–intermediate and high/high–intermediate risk categories of IPI (P = 0·045 and P = 0·0016 respectively). Multivariate analysis identified CD21S expression as an independent factor for survival when compared with the five IPI factors. These findings indicate that CD21S expression of DLBCL tumour cells is a useful prognostic factor for survival.
Expression of cyclin E in resting and activated B‐chronic lymphocytic leukaemia cells: cyclin E/cdk2 as a potential therapeutic target
Authors: Decker Thomas , Hipp Susanne , Hahntow Ines , Schneller Folker , Peschel Christian
Published: December 2004

Disease progression in B‐cell chronic lymphocytic leukaemia (B‐CLL) is determined by the interplay between proliferation kinetics in the proliferating compartment and cell death in the accumulating compartment. Improving our knowledge of cell cycle regulation in B‐CLL cells might therefore be important for identifying therapeutic targets. Cyclin E was detected by Western blotting in purified B‐CLL cells from peripheral blood samples of all 12 patient tested but not in normal peripheral blood B cells. While cyclin‐dependent kinase 2 (cdk2) expression was similar in different samples, p27 and cyclin E expression was highly variable. We further investigated the regulation of p27, cyclin E and cdk2 in an in vitro model of cycling B‐CLL cells. Cyclin E and cdk2 expression was increased in B‐CLL cells stimulated with a CpG‐oligodeoxynucleotide and interleukin‐2, while p27 expression rapidly declined. This was accompanied by the increased formation of cyclin E–cdk2 complexes, which were able to phosphorylate Histone H1 in vitro. Pharmacological inhibition of cdk2 activity with Roscovitine‐inhibited thymidine incorporation and Histone H1 phosphorylation. We conclude that further evaluation of cyclin E and p27 in peripheral blood cells might help to identify prognostic subgroups. In addition, inhibition of Cyclin E–cdk2 activity by Roscovitine might be a new therapeutic strategy in B‐CLL.
Epstein–Barr virus‐associated Hodgkin's lymphoma
Authors: Gandhi Maher K. , Tellam Judy T. , Khanna Rajiv
Published: December 2004

Survivors of Hodgkin's lymphoma (HL) frequently have many years to experience the long‐term toxicities of combined modality therapies. Also, a significant proportion of HL patients will relapse or have refractory disease, and less than half of these patients will respond to current salvage strategies. 30–50% of HL cases are Epstein–Barr virus associated (EBV‐positive HL). The virus is localized to the malignant cells and is clonal. EBV‐positive HL is more frequent in childhood, in older adults (>45 years) and in mixed cellularity cases. The survival of EBV‐positive HL in the elderly and the immunosuppressed is particularly poor. Despite improvements in our understanding of EBV‐positive HL, the true contribution of EBV to the pathogenesis of HL remains unknown. Increased knowledge of the virus’ role in the basic biology of HL may generate novel therapeutic strategies for EBV‐positive HL and the presence of EBV‐latent antigens in the malignant HL cells may represent a target for cellular immunotherapy.
B‐prolymphocytic leukaemia with t(11;14) revisited: a splenomegalic form of mantle cell lymphoma evolving with leukaemia
Authors: Ruchlemer Rosa , Parry‐Jones Nilima , Brito‐Babapulle Vasantha , Attolico Imma , Wotherspoon Andrew C. , Matutes Estella , Catovsky Daniel
Published: December 2004

We reviewed eight cases that were diagnosed before 1995 with B‐prolymphocytic leukaemia (B‐PLL) harbouring t(11;14)(q13;q32) and/or cyclin D1 staining. Thirteen B‐PLL patients without t(11;14) were selected as controls. Peripheral blood, bone marrow and histological sections were re‐examined without cytogenetic information. Final diagnosis was made using morphology, cytogenetics, immunophenotype and immunohistochemistry. Clinical characteristics were similar for both groups except for younger age, male predominance and extranodal involvement in cases with t(11;14). CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)− group (31%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but only 45% of t(11;14)− cases. Histopathological and cytological review of cases with t(11;14) showed an infiltrate with a mixture of cells, some resembling prolymphocytes and others with mantle cell lymphoma (MCL) morphology. Blood films of cases with t(11;14) showed features suggestive of B‐PLL in three, and in others, a mixture of cells resembling MCL and nucleolated ones; none corresponded to the blastoid form of MCL. We suggest that ‘B‐PLL’ with t(11;14) may represent a splenomegalic form of MCL evolving with leukaemia. These cases illustrate the importance of tissue diagnosis with cyclin D1 staining and fluorescence in situ hybridization analysis in B‐cell leukaemia with prolymphocytic features.
Clinical and molecular cytogenetic studies in seven patients with myeloid diseases characterized by i(20q−)
Authors: Li Tianyu , Xue Yongquan , Wu Yafang , Pan Jinlan
Published: December 2004

We report on seven patients with myeloid diseases characterized by i(20q−) anomaly. Four patients were male and three were female, their median age was 57 years. The diagnosis at presentation was myelodysplastic syndrome in six patients, acute myeloid leukaemia in one patient. Four died but three survived and remain anaemic. The survivals were 6 months for patient 1, 7 months for patient 2, 17 d for patient 4 and 28 d for patient 5. Chromosome specimens were prepared by direct and/or short‐term culture of bone marrow cells. Karyotype analysis was performed by R‐ and G‐banding technique, which showed that one of the normal chromosomes 20 was substituted by one or two small metacentric chromosomes in all seven patients. The karyotype was ider(20)(q10)del(20)(q11q13), i.e. i(20q−) in six patients by dual‐colour fluorescence in situ hybridization assay using two probes (a subtelomeric probe for 20q and an unique probe for 20q12). As far as we know, this anomaly has not been reported previously. Thus, we consider that i(20q−) is a novel and rare recurrent chromosomal abnormality that is specifically associated with myeloid diseases and may indicate a poor prognosis.
The effects of folic acid supplements on coagulation status in pregnancy
Authors: Deol Paramjeet S. , Barnes Tim A. , Dampier Karen , John Pasi K. , Oppenheimer Christina , Pavord Sue R.
Published: December 2004

Thromboembolic disease remains the leading cause of maternal death in the UK. Recent literature has proposed that folate status is a strong predictor for venous thrombosis. Using thrombelastography (TEG®), we tested the hypothesis that folic acid supplementation is associated with a reduction in whole blood coagulability. Blood samples and questionnaire data were obtained at a mean gestation of 13·6 weeks (SD: 3·8, range: 6–38 weeks) from unselected consecutive women attending for their antenatal booking scan. Of 588 patients, 439 (74·7%) took folic acid. All TEG® parameters were less hypercoagulable in women that had taken folic acid compared with those that had not: mean maximum amplitude (MA) 60·3 versus 62·1; mean difference 1·8; 95% confidence interval 0·8, 2·8; P = 0·0001; mean coagulation index (CI) 0·54 versus 0·85; mean difference 0·31; 95% confidence interval 0·11, 0·5; P = 0·002. There was no difference in the incidence of the homozygous MTHFR mutation in patients taking folic acid (5·53%) compared with those that were not (4·08%). This study suggests that benefit may be derived from longer‐term treatment, although large multicentre studies are required to determine whether the relative hypocoagulability is associated with a reduction in risk of venous thrombosis.
Low intensity warfarin: is it clinically useful in venous thromboembolism management?
Authors: Bauer Kenneth A.
Published: December 2004

Therapy for a first episode of venous thromboembolism (VTE) typically includes a vitamin K antagonist, such as warfarin, for 3–6 months at an international normalized ratio (INR) of 2–3. After the cessation of warfarin therapy, unprovoked VTE is associated with a recurrence rate of 5–15% per year. Prolonging initial therapy does not reduce the recurrence risk once warfarin is discontinued and is not routinely recommended for such patients. The Prevention of Recurrent Venous Thromboembolism (PREVENT) and Extended Low‐Intensity Anticoagulation for Thromboembolism (ELATE) trials were undertaken to evaluate the efficacy and safety of low‐intensity warfarin (INR 5–2) in this population. While both trials demonstrated that low‐intensity warfarin offers substantial protection against recurrent VTE, only the ELATE trial included a standard intensity arm; this arm showed a significantly lower recurrence rate and a major bleed rate that, surprisingly, was similar to the low‐intensity arm. There still remains no consensus that long‐term warfarin at an INR of 2–3 should be recommended for all patients who sustain a first unprovoked venous thromboembolic event, which largely stems from our current inability to reliably identify those patients most likely to develop recurrences. Given that an individualized approach is required in deciding the duration of anticoagulation, it is the author's belief that low‐intensity warfarin, which the PREVENT trial demonstrated could be monitored every other month, is a useful option for some patients with a first episode of VTE.
Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant’1
Authors: Ferreri Andrés J. M. , Campo Elías , Seymour John F. , Willemze Rein , Ilariucci Fiorella , Ambrosetti Achille , Zucca Emanuele , Rossi Giuseppe , López‐Guillermo Armando , Pavlovsky Miguel A. , Geerts Marie‐Louise , Candoni Anna , Lestani Maurizio , Asioli Silvia , Milani Mario , Piris Miguel A. , Pileri Stefano , Facchetti Fabio , Cavalli Franco , Ponzoni Maurilio ,   the International Extranodal Lymphoma Study Group (IELSG)
Published: December 2004

Despite its recognition as a distinct, extremely rare entity, no large studies of intravascular lymphoma (IVL) have been reported. The clinico‐pathological characteristics of 38 human immunodeficiency virus‐negative patients with IVL diagnosed in Western countries were reviewed to better delineate clinical presentation, clinical variants, natural history and optimal therapy. The IVL is an aggressive and usually disseminated disease (Ann Arbor stage IV in 68% of cases) that predominantly affects elderly patients (median age 70 years, range: 34–90; male:female ratio 0·9), resulting in poor Eastern Cooperative Oncology Group Performance Status (ECOG‐PS >1 in 61%), B symptoms (55%), anaemia (63%) and high serum lactate dehydrogenase level (86%). The brain and skin are the most common sites of disease. In contrast to previous reports, hepatosplenic involvement (26%) and bone marrow infiltration (32%) were found to be common features in IVL, while nodal disease was confirmed as rare (11% of cases). Patients with disease limited to the skin (‘cutaneous variant’; 26% of cases) were invariably females with a normal platelet count, and exhibited a significantly better outcome than the remaining patients, which deserves further investigation. Overall survival was usually poor; however, the early use of intensive therapies could improve outcome in young patients with unfavourable features. ECOG‐PS >1, ‘cutaneous variant’, stage I and chemotherapy use were independently associated with improved survival.