bluuebunny/crossref_metadata_2025 huggingface dataset:
Species accumulation curves analysed by a class of null models discovered by Arrhenius
Authors: Ugland Karl I. , Gray John S. , Lambshead P. John D.
Published: December 2004

Arrhenius is mainly given credit for his discovery of the log‐log relationship between number of species and area, but in 1921 he invented the technique of analysing the data with a null model. This achievement, which Arrhenius explicitly stated was more important than the empirical species–area relationship, has been overlooked in the scientific literature. We suggest here that analysis of large communities should be done by a successive addition of predefined subsets of samples. Plotting the resulting accumulation curves in a common diagram usually will reveal heterogeneity between subsamples. We believe that this is a general feature of a counting process, (over space or time), that keeps record of new objects being generated by an unobservable process. We show this by two nonbiological time series: examination scores at the University of Oslo and stock prices on the Oslo stock market. We then apply these ideas to the analysis of the nested accumulation plots obtained from two unusually large community samples, the benthos of the Norwegian continental shelf and of marine areas of Hong Kong. Discontinuities in the accumulation curves can be explained by changes in habitat heterogeneity. These changes may be interpreted as variations in the parameter values in the class of null models discovered by Arrhenius. By selecting appropriate parameter values, the observed accumulation curves (calculated by an analytical expression giving exact values) can be approximated by null curves. This procedure makes it possible to identifying the major factors responsible for the shape of the curves in the accumulation plots.
Being high is better: effects of elevation and habitat on arctic ground squirrel demography
Authors: Gillis Elizabeth A. , Hik David S. , Boonstra Rudy , Karels Tim J. , Krebs Charles J.
Published: December 2004

We investigated the effect of local environment on the demography and population dynamics of arctic ground squirrels (Spermophilus parryii plesius) by comparing reproduction, survival, and population trends of squirrels living in low elevation boreal forest and high elevation alpine tundra sites in southwestern Yukon Territory, Canada. Contrary to the trend for most birds and mammals, reproduction was significantly lower at the lower elevation and females living at higher elevation did not delay the age at which they first reproduced. Even though survival in the boreal forest was lower in summer than in the alpine, it was higher over winter so annual adult female survival was similar between sites.

Sensitivity analysis of model parameters revealed that in the forest, population growth rate (λ) was most sensitive to small changes in adult active season survival whereas for the alpine population, λ was most sensitive to changes in juvenile winter survival. In their respective habitats, these parameters also showed high year to year variation and thus contributed greatly to the population trends observed. Even though ground squirrels persisted in the boreal forest, the measured demographic rates indicate the forest was sink habitat (λ<1) and may have relied on nearby grassy meadows for immigrants. In contrast, the alpine habitat maintained a ground squirrel population in the absence of immigration (λ=1).

The variation in demographic rates between ground squirrels living at high and low elevation may arise from phenotypic responses of squirrels to different habitat structure. Arctic ground squirrels rely on sight to detect predators from a safe distance, and the boreal forest, with its lower visibility and higher predator density, appears to be suboptimal habitat.
The influence of genetic factors and population dynamics on the mating system of the hermaphroditic freshwater snail Biomphalaria pfeifferi
Authors: Charbonnel Nathalie , Rasatavonjizay Rondro , Sellin Elizabeth , Brémond Philippe , Jarne Philippe
Published: December 2004

Although self‐fertilization and its evolutionary consequences have been widely studied, the relative influence of genetic and environmental factors on the determination of mixed‐mating systems remains poorly known. In 1999 and 2000, we surveyed the mating system, the population dynamics and some life‐history traits of four populations of the freshwater snail Biomphalaria pfeifferi, the major intermediate host of Schistosoma mansoni in Africa, in two areas of Madagascar (Itasy and Antananarivo). We confirmed that B. pfeifferi is a predominant selfer, with selfing rates ranging between 80 and 100%. Temporal and geographical variation of the selfing rate was observed at both local and large spatial scale. Historical processes of colonization and invasion of B. pfeifferi in Madagascar could explain the geographical variation of the mating system observed at regional scale. Pure selfing has probably evolved in the two populations of Antananarivo area as a reproductive assurance strategy in a metapopulation where extinction is frequent and migration rare. The reproductive assurance hypothesis does not explain the spatio‐temporal mating system variations observed in Itasy area. However genetic factors including inbreeding depression‐the expression of which can be environmentally mediated‐and metapopulation dynamics could influence the mating system in both populations sampled in Itasy and lead to different levels of evolutionary stable intermediate selfing rate in this region. Our results therefore highlight the influence of environmental heterogeneity and stochasticity on mating system.
Demographic estimation methods for plants with unobservable life‐states
Authors: Kéry Marc , Gregg Katharine B. , Schaub Michael
Published: December 2004

Demographic estimation of vital parameters in plants with an unobservable dormant state is complicated, because time of death is not known. Conventional methods assume that death occurs at a particular time after a plant has last been seen aboveground but the consequences of assuming a particular duration of dormancy have never been tested. Capture–recapture methods do not make assumptions about time of death; however, problems with parameter estimability have not yet been resolved. To date, a critical comparative assessment of these methods is lacking. We analysed data from a 10 year study ofCleistes bifaria, a terrestrial orchid with frequent dormancy, and compared demographic estimates obtained by five varieties of the conventional methods, and two capture–recapture methods. All conventional methods produced spurious unity survival estimates for some years or for some states, and estimates of demographic rates sensitive to the time of death assumption. In contrast, capture–recapture methods are more parsimonious in terms of assumptions, are based on well founded theory and did not produce spurious estimates. InCleistes, dormant episodes lasted for 1–4 years (mean 1.4, SD 0.74). The capture–recapture models estimated ramet survival rate at 0.86 (SE∼0.01), ranging from 0.77–0.94 (SEs≤0.1) in any one year. The average fraction dormant was estimated at 30% (SE 1.5), ranging 16–47% (SEs≤5.1) in any one year. Multistate capture–recapture models showed that survival rates were positively related to precipitation in the current year, but transition rates were more strongly related to precipitation in the previous than in the current year, with more ramets going dormant following dry years. Not all capture–recapture models of interest have estimable parameters; for instance, without excavating plants in years when they do not appear aboveground, it is not possible to obtain independent time‐specific survival estimates for dormant plants. We introduce rigorous computer algebra methods to identify the parameters that are estimable in principle. As life‐states are a prominent feature in plant life cycles, multistate capture–recapture models are a natural framework for analysing population dynamics of plants with dormancy.
Degree distribution in plant–animal mutualistic networks: forbidden links or random interactions?
Authors: Vázquez Diego P.
Published: December 2004

Recent studies show that ecological interaction networks depart from the “scale‐free” topologies observed in many other real world networks. Such a departure has been hypothesized to result from non‐matching biological attributes of species, such as phenology or morphology, that prevent the occurrence of certain interactions (“forbidden links”). Here I compare the topology of 17 plant–animal mutualistic networks with that predicted by a simple null model that assumes that a species’ degree (number of interspecific interactions) is a function of its frequency of interaction. The topology predicted by this null model is strikingly close to that observed in the real networks. Thus, this null model provides a simple alternative interpretation of patterns observed in ecological interaction networks that does not require the existence of non‐matching species traits.
Plant‐mediated effects of drought stress on host preference and performance of a grass miner
Authors: Scheirs Jan , De Bruyn Luc
Published: December 2004

The plant stress hypothesis predicts that environmental stress increases the suitability of plants as food for herbivores, especially for senescence feeders. Yet, performance is enhanced only at moderate stress intensities in several herbivores. Even more paradoxically, a large number of insect species prefer and perform better on vigorously growing plants. In order to test plant stress theory, we conducted a laboratory experiment in which the influence of plant water stress on host preference and the performance of the grass miner Chromatomyia milii was studied. We imposed a gradient of stress intensities, i.e. 25, 50, 75, 150, and 300‐ml weekly‐administered water per grass pot, in order to study the full range of responses of C. milii to water stressed plants. Plant stress intensity was quantified by measuring individual plant mass, foliar water content and the concentration of the photosynthetic pigments chlorophyll a and b. Plant mass had decreased from the 150 and 300‐ml treatments to the lowest water treatment at the end of our experiment, which was mainly a result of a reduction in leaf area and leaf number. Foliar water content was clearly negatively affected by water shortage. Chlorophyll a and b also decreased with water shortage. Finally, the stress intensity measurements showed that plants acclimated to water stress conditions throughout the experiment. Feeding and oviposition preference of C. milii was positively related to water supply. No larvae survived on two lowest water treatments and only 38% survived on the 75‐ml treatment, while more than 80% survived on the 150 and the 300‐ml treatments. Offspring development time was longer on the 75‐ml treatment than on the 150 and the 300‐ml treatments. We also evaluated the mechanisms that could explain the response of C. milii to water stressed plants. Although no relationship between water treatment and foliar amino acid concentration was found, we observed significantly higher foliar protein concentrations in the 25 and the 50‐ml treatments. This supports the hypothesis that abiotic stress causes an increase of nitrogenous compounds in plants. Leaf senescence following self‐pruning, a process by which H. lanatus plants acclimate to drought conditions, was responsible for the dramatically high offspring mortality on the water stressed plants. The shape of the plant stress intensity–herbivore response relationship showed strong variation and depended both on the type of plant stress intensity measure and herbivore response variable involved. Yet, all relationships showed a monotonic increase of herbivore preference and performance with decreasing plant stress intensity. This indicates that C. milii prefers and performs better on vigorously growing plants. We found no support for an increased herbivore performance on moderately or severely stressed plants.
Impact of moose population density on the production and composition of litter in boreal forests
Authors: Persson Inga‐Lill , Pastor John , Danell Kjell , Bergström Roger
Published: December 2004

Recent studies of ungulates have revealed that selective foraging seems to be an important mechanism by which they can affect the structure and species composition of the plant community, and thus quantity (dry mass) and quality (chemical composition) of litter available for decomposers. Such changes in litter production may be especially important in N‐limited systems like boreal forests. We chose moose (Alces alces) as study species to investigate this mechanism. Moose browse mainly in the tree and shrub layers year round, and because of their wide distribution and often high population densities, they can have a significant effect on litter production of trees and shrubs in Swedish boreal forests. The effects of herbivores may also vary along productivity gradients. We therefore simulated browsing and urine and fecal deposition corresponding to 4 different moose densities in exclosures along a pre‐existing forest productivity gradient. Both litter quantity (g dry mass per m2 and year) and contributions of C and N (g dry mass per m2 and year) decreased with increasing level of simulated moose density. High moose densities over extended time can therefore reduce N contributions to soil and therefore eventually reduce site productivity in Swedish boreal forests. This effect of moose was mainly a result of decreased litter quantity, because contradictory to studies from North America, litter quality (C:N ratio and N contribution per mass unit of litter) was not affected by level of simulated moose density.
Salt tectonics driven by differential sediment loading: stability analysis and finite‐element experiments
Authors: Gemmer Lykke , Ings Steven J. , Medvedev Sergei , Beaumont Christopher
Published: December 2004

At many continental margins, differential sediment loading on an underlying salt layer drives salt deformation and has a significant impact on the structural evolution of the basin. We use 2‐D finite‐element modelling to investigate systems in which a linear viscous salt layer underlies a frictional‐plastic overburden of laterally varying thickness. In these systems, differential pressure induces the flow of viscous salt, and the overburden experiences updip deviatoric tension and downdip compression. A thin‐sheet analytical stability criterion for the system is derived and is used to predict conditions under which the sedimentary overburden will be unstable and fail, and to estimate the initial velocities of the system. The analytical predictions are in acceptable agreement with initial velocity patterns of the numerical models.

In addition to initial stability analyses, the numerical model is used to investigate the subsequent finite deformation. As the systems evolve, overburden extension and salt diapirism occur in the landward section and contractional structures develop in the seaward section. The system evolution depends on the relative widths of the salt basin and the length scale of the overburden thickness variation. In narrow salt basins, overburden deformation is localised and characterised by high strain rates, which cause the system to reach a gravitational equilibrium and salt movement to cease earlier than for wide salt basins. Sedimentation enhances salt evacuation by maintaining a differential pressure in the salt. Continued sedimentary filling of landward extensional basins suppresses landward salt diapirism. Sediment progradation leads to seaward propagation of the landward extensional structures and depocentres. At slow sediment progradation rates, the viscous flow can be faster than the sediment progradation, leading to efficient salt evacuation and salt weld formation beneath the landward section. Fast sediment progradation suppresses the viscous flow, leaving salt pillows beneath the prograding wedge.
A physician's guide to transfusion in autoimmune haemolytic anaemia
Authors: Petz Lawrence D.
Published: December 2004

Patients with autoimmune haemolytic anaemia (AIHA) frequently have anaemia of sufficient severity as to require a blood transfusion. However, it is impossible to find compatible blood when, as is frequently the case, the autoantibody in the patient's serum reacts with all normal red blood cells. Further, the autoantibody may mask the presence of a red cell alloantibody capable of causing a haemolytic transfusion reaction. Optimal patient management in this clinical setting requires special compatibility test procedures in the transfusion service laboratory. Equally important is that clinicians must understand the principles of the compatibility tests performed. Provided appropriate compatibility tests are performed, the indications for transfusion in patients with AIHA are not significantly different than for similarly anaemic patients without AIHA. Communication between clinicians and laboratory personnel are important to review the urgency of transfusion and the compatibility test methods used to select the optimal unit of red blood cells for transfusion.
Impairment of death‐inducing signalling complex formation in CD95‐resistant human primary lymphoma B cells
Authors: Lajmanovich Alicia , Irisarri Magdalena , Molens Jean‐Paul , Pasquier Marie‐Anne , Sotto Jean‐Jacques , Bensa Jean‐Claude , Leroux Dominique , Plumas Joël
Published: December 2004

Multiple mechanisms exist by which tumour cells can escape CD95‐mediated apoptosis. Previous studies by our laboratory have shown that primary B cells from non‐Hodgkin's Lymphoma (B‐NHL) were resistant to CD95‐induced cell death. In the current study, we have analysed the mechanisms underlying CD95 resistance in primary human lymphoma B cells. We report that FADD (FAS‐associated death domain protein) and caspase‐8 were constitutively expressed in lymphoma B cells and that the CD95 pathway was blocked upstream to caspase‐8 activation. However, caspase‐8 was processed and functional after treatment with staurosporine (STS). We found that the expression levels of FLICE (FADD‐like interleukin‐1 beta‐converting enzyme)‐Inhibitory Protein (c‐FLIP) and Bcl‐2‐related proteins were heterogeneous in B‐NHL cells and were not related to CD95 resistance. Finally, we report the absence of a CD95‐induced signalling complex [death‐inducing signalling complex (DISC)] in lymphoma B cells, with no FADD and caspase‐8 recruitment to CD95 receptor. In contrast, DISC formation was observed in CD95‐resistant non‐tumoural (NT) B cells. Therefore, we propose that the absence of DISC formation in primary lymphoma B cells may contribute to protect these cells from CD95‐induced apoptosis.
Fludarabine, mitoxantrone and dexamethasone in the treatment of indolent B‐ and T‐cell lymphoid malignancies in Chinese patients
Authors: Ma Shing Y. , Au Wing Y. , Chim Chor S. , Lie Albert K. W. , Lam Clarence C. K. , Tse Eric , Leung Anskar Y. H. , Liang Raymond , Kwong Yok L.
Published: December 2004

The treatment results of indolent lymphoid malignancies in Chinese are poorly reported. The efficacy of FND (fludarabine 25 mg/m2/d, ×3; mitoxantrone 10 mg/m2/d, ×1; dexamethasone 20 mg/d, ×5; monthly cycles, ×6) in 95 Chinese patients with indolent B‐cell malignancies (at diagnosis: 55, relapse/refractory disease: 40) and nine Chinese patients with T‐cell large granular lymphocyte leukaemia (T‐LGL leukaemia) (at diagnosis: two, refractory disease: seven) was evaluated. For B‐cell malignancies, the complete response (CR), partial response (PR) and overall response (OR) rates were 50·5%, 18% and 68·5% respectively. Better results were obtained for primary versus relapse/refractory disease (CR: 60% vs. 37·5%, P = 0·03; OR: 84% vs. 47·5%, P < 0·001; median progression‐free survival (PFS): 44 months vs. 22 months; 2‐year PFS: 66% vs. 47%, P = 0·039; overall survival (OS): not reached vs. 32%; 2‐year OS: 92% vs. 58%, P < 0·001). Responsive patients (CR/PR) had a better median PFS (44 months vs. 5 months, P < 0·001) and OS (67 months vs. 13 months, P < 0·001) than unresponsive patients. For T‐LGL leukaemia, the CR and molecular‐remission rates were 56% and 67% (median follow‐up: 23 months). FND is an active regimen for the treatment of indolent B‐ and T‐cell malignancies in Chinese patients, with results comparable with Western patients with similar indolent lymphomas.
Overexpression of the Ikaros 6 isoform is restricted to t(4;11) acute lymphoblastic leukaemia in children and infants and has a role in B‐cell survival
Authors: Ruiz Anna , Jiang Jie , Kempski Helena , Brady Hugh J. M.
Published: December 2004

The Ikaros transcription factor has been shown to play an important role in the differentiation of both myeloid and lymphoid lineages. Mice heterozygous for a dominant negative (DN) ikaros isoform develop T‐cell leukaemia and lymphoma with 100% penetrance. Overexpression of DN Ikaros isoforms has been reported in some forms of leukaemia, such as childhood acute myelomonocytic and monocytic leukaemias, adult B‐cell acute lymphoblastic leukaemias (B ALL) and in childhood and adult pre‐B ALL. In this study, the expression of Ikaros isoforms in 49 infant and childhood leukaemia patients was analysed by reverse transcription polymerase chain reaction and Western blot analysis. We found overexpression of the DN Ikaros  6 (Ik6) isoform in a subset of leukaemia patients harbouring t(4;11) translocations. To further study the consequences of Ik6 overexpression in B ALL, we inducibly expressed Ik6 in BaF3 cells and found that Ik6 overexpression delayed cell death after interleukin‐3 withdrawal, suggesting that overexpression of Ik6 found in t(4;11) B cells could contribute to leukaemogenesis by preventing the apoptosis of cells in an environment with reduced survival factors.
Transplantation of highly purified CD34+ progenitor cells from alternative donors in children with refractory severe aplastic anaemia
Authors: Benesch Martin , Urban Christian , Sykora Karl W. , Schwinger Wolfgang , Zintl Felix , Lackner Herwig , Lang Peter , Handgretinger Rupert
Published: December 2004

Without transplantation from a human leucocyte antigen‐identical family donor, refractory severe aplastic anaemia (SAA) has an unfavourable prognosis. Conventional transplantation from a matched unrelated donor carries a high rate of mortality. We transplanted large numbers of highly purified CD34+ cells from matched unrelated (n = 4), mismatched unrelated (n = 4) and mismatched related (n = 1) donors into nine children with refractory SAA. The grafts consisted of granulocyte colony‐stimulating factor‐mobilized peripheral positively selected CD34+ cells. A median of 15·1 × 106/kg CD34+ stem cells and 11 × 103/kg CD3+ T‐lymphocytes were infused. No additional pharmacological graft versus host disease (GVHD) prophylaxis was given. At a median follow‐up of 47 (range 37–72) months, eight patients (89%) were in complete remission with >90% donor chimaerism and no evidence of GVHD. One patient died on day +238 as a consequence of GVHD. The use of highly purified mobilized CD34+ stem cells warrants further clinical exploration in children with refractory SAA.
Thrombotic disease in systemic lupus erythematosus is associated with a maintained systemic platelet activation
Authors: Ekdahl Kristina N. , Bengtsson Anders A. , Andersson Jonas , Elgue Graciela , Rönnblom Lars , Sturfelt Gunnar , Nilsson Bo
Published: December 2004

Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis. Platelet‐induced extracellular phosphorylation of plasma proteins suggests that this is due to persistent activation of the platelets. We examined 30 SLE patients (15 with thrombotic disease), 18 non‐SLE patients with deep vein thrombosis (DVT) and 50 healthy controls by analysing β‐thromboglobulin, activated factor XI‐antithrombin complexes and fibrinogen‐bound phosphate. All parameters were elevated in SLE patients, particularly those with thrombosis, but normal in DVT cases and healthy controls. We conclude that thrombotic disease in SLE patients is associated with a persistent systemic platelet activation that may lower the threshold for induction of thrombosis.
Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)‐1α and MIP‐1β correlates with lytic bone lesions in patients with multiple myeloma
Authors: Hashimoto Toshihiro , Abe Masahiro , Oshima Takashi , Shibata Hironobu , Ozaki Shuji , Inoue Daisuke , Matsumoto Toshio
Published: December 2004

Macrophage inflammatory protein (MIP)‐1α and MIP‐1β have been identified as candidates for multiple myeloma (MM)‐derived bone‐resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP‐1α and MIP‐1β secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone‐specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP‐1α and MIP‐1β levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP‐1α and MIP‐1β in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.
Elevated levels of transferrin receptor 2 mRNA, not transferrin receptor 1 mRNA, are associated with increased survival in acute myeloid leukaemia
Authors: Nakamaki Tsuyoshi , Kawabata Hiroshi , Saito Bungo , Matsunawa Manabu , Suzuki Junko , Adachi Daisuke , Tomoyasu Shigeru , Phillip Koeffler H.
Published: December 2004

Transferrin receptor 1 (TfR1) is a type II membrane protein that mediates cellular iron uptake. Transferrin receptor 2(TfR2), another receptor for transferrin (Tf), has recently been cloned. We examined expression levels of TfR1, TfR2‐α (membrane form) and TfR2‐β (non‐membrane form) transcripts in cells from 67 patients with de novo acute myeloid leukaemia (AML) using reverse transcription‐polymerase chain reaction (RT‐PCR), and correlated the results with a variety of clinical features and disease outcomes of these patients. Significant correlations were noted between the levels of both TfR1 and TfR2‐α (r = 0·771, P < 0·001) and TfR1 and TfR2‐β (r = 0·534, P < 0·001). Unexpectedly, initial white blood cell (WBC) counts were inversely correlated with levels of expression of either TfR1(r = −0·357, P = 0·003), TfR2‐α (r = −0·486, P < 0·0001), or TfR2‐β (r = −0·435, P = 0·0003). Only TfR2 expression was significantly associated with either serum iron (r = −0·270, P = 0·045) or serum ferritin (r = −0·364, P = 0·008). Multivariate analyses using Cox's proportional hazard model showed that elevated TfR2‐α, but not TfR1 or TfR2‐β mRNA levels significantly contributed to a better prognosis for AML patients. Furthermore, a group with high expression levels of both TfR2‐α and TfR2‐β survived significantly longer than a group without high expression of both of them (P < 0·01 by log‐rank). The present study suggests that (i) TfRs‐independent iron uptake might have an important role in in vivo proliferation of AML cells; (ii) expression of TfR2 (especially the α form) is a novel prognostic factor for patients with AML.
Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma
Authors: Khan S. B. , Maududi T. , Barton K. , Ayers J. , Alkan S.
Published: December 2004

Multiple myeloma (MM) is a neoplastic proliferation of plasma cells and remains an incurable disease because of the development of drug resistance. Histone deacytylase (HDAC) inhibitors are a new class of chemotherapeutic reagents that cause growth arrest and apoptosis of neoplastic cells. Depsipeptide, a new member of the HDAC inhibitors, was found to be safe in humans and has been shown to induce apoptosis in various cancers. In order to evaluate the effects of depsipeptide, a MM cell line, U266 [interleukin (IL)‐6 dependent], was analysed for viability and apoptosis. The combined effect of depsipeptide with melphalan and changes in BCL‐2 family proteins (BCL‐2, BCL‐XL, BAX and MCL‐1) were also investigated. In addition, the RPMI 8226 cell line (IL‐6 independent), and primary patient myeloma cells were also analysed for apoptosis after depsipeptide treatment. Depsipeptide induced apoptosis in both U266 and RPMI 8226 cell lines in a time‐ and dose‐dependent fashion, and in primary patient myeloma cells. We also demonstrated that depsipeptide had an additive effect with melphalan (10 μmol/l). BCL‐2, BCL‐XL and MCL‐1 showed decreased expression in depsipeptide‐treated samples. Based on recent clinical trials demonstrating minimal clinical toxicity, our study supports the future clinical utilization of depsipeptide in the management of MM.
CD90/Thy‐1 is preferentially expressed on blast cells of high risk acute myeloid leukaemias*
Authors: Buccisano Francesco , Rossi Francesca Maria , Venditti Adriano , Poeta Giovanni Del , Cox Maria Christina , Abbruzzese Elisabetta , Rupolo Maurizio , Berretta Massimiliano , Degan Massimo , Russo Stefania , Tamburini Anna , Maurillo Luca , Principe Maria Ilaria Del , Postorino Massimiliano , Amadori Sergio , Gattei Valter
Published: December 2004

Different transformation mechanisms have been proposed for elderly acute myeloid leukaemia (AML) and secondary AML (sAML) when compared with de novo AML or AML of younger patients. However, little is known regarding differences in the immunophenotypic profile of blast cells in these diseases. We systematically analysed, by flow cytometry, 148 patients affected by de novo (100 cases) or sAML (48 cases). By defining a cut‐off level of 20% of CD34+ cells co‐expressing CD90, the frequency of CD90+ cases was higher in sAML (40%) versusde novo AML (6%, P < 0·001), elderly AML (>60 years) (24%) versus AML of younger patients (10%, P = 0·010) and poor‐ versus good‐risk karyotypes (according to the Medical Research Council classification, P < 0·001). The correlation between CD90 expression, sAML and unfavourable karyotypes was confirmed by analysing the subset of CD34+ AML cases alone (91/148). Consistently, univariate analysis showed that expression of CD90 was statistically relevant in predicting a shorter survival in CD90+ AML patients (P = 0·042). Our results, demonstrating CD90 expression in AML with unfavourable clinical and biological features, suggest an origin of these diseases from a CD90‐expressing haemopoietic progenitor and indicate the use of CD90 as an additional marker of prognostic value in AML.
Early response to therapy and survival in multiple myeloma
Authors: Schaar C. G. , Kluin‐Nelemans J. C. , le Cessie S. , Franck P. F. H. , te Marvelde M. C. , Wijermans P. W.
Published: December 2004

Whether the response to chemotherapy is a prognosticator in multiple myeloma (MM) is still not known. Therefore, the relationship between survival and the rate of monoclonal protein (M‐protein) decrement during the first cycles of therapy was prospectively assessed in 262 patients with newly diagnosed MM that were included in a phase III trial (HOVON‐16). M‐proteins were collected monthly during melphalan–prednisone therapy (MP: melphalan 0·25 mg/kg, prednisone 1·0 mg/kg orally for 5 d every 4 weeks). Patients with light chain disease (n = 18), immunoglobulin M (IgM)‐MM (n = 1) and no immunotyping (n = 1) were excluded. Of the 242 patients studied, 75% had IgG M‐protein and 25% IgA; MM stages: I: 1%, II: 35% and III: 64%. The median M‐protein decrease after the first cycle of MP was 21% for IgG and 27% for IgA, and declined to < 5% after four cycles. An obvious survival advantage was seen for patients who had an M‐protein decrease of at least 30% after the first MP cycle, which became significant when an M‐protein decrease of 40% or more was reached. As established prognostic parameters (Salmon & Durie stage, serum creatinine, and haemoglobin) also remained prognostically significant, we concluded that early response to MP predicts for survival in MM.
Clinical impact of early absolute lymphocyte count after allogeneic stem cell transplantation
Authors: Kim Dong Hwan , Kim Jong Gwang , Sohn Sang Kyun , Sung Woo Jin , Suh Jang Soo , Lee Kun Soo , Lee Kyu Bo
Published: December 2004

The role of repopulating lymphocytes after allogeneic stem cell transplantation (SCT) includes the prevention of serious infections and attacking residual tumour cells in the early post‐transplant phase. Therefore, the current study analysed the role of the absolute lymphocyte count (ALC) on day 21 after SCT in predicting transplant outcomes of 82 patients in terms of the risk of opportunistic infections and recurrence of original disease. The median dose of CD34+, CD3+ and mononuclear cells (MNC) infused was 6·41 × 106/kg, 1·96 × 108/kg and 6·81 × 108/kg respectively. The high ALC group (high ALC on day 21; ≥0·35 × 109/l) was associated with the use of peripheral blood stem cells, matched sibling donors and higher cell doses of MNC, CD3+ and CD4+ cells. The high ALC group also exhibited a better overall survival (56·3% vs. 17·7%) and disease‐free survival (50·1% vs. 15·9%) after 3 years and lower incidences of relapse (33·6% vs. 67·1%) and fungal infections (3·0% vs. 19·5%) after 1 year. The incidence of cytomegalovirus antigenaemia was lower in the high ALC group (47·7% vs. 73·7%). Accordingly, identifying the ALC on day 21 would appear to be a useful and simple measurement to predict those patients with a high risk of opportunistic infections and relapse after allogeneic SCT.
Prospective clinical evaluation of a LightCyclerTM‐mediated polymerase chain reaction assay, a nested‐PCR assay and a galactomannan enzyme‐linked immunosorbent assay for detection of invasive aspergillosis in neutropenic cancer patients and haematological stem cell transplant recipients
Authors: Buchheidt Dieter , Hummel Margit , Schleiermacher Dietlind , Spiess Birgit , Schwerdtfeger Rainer , Cornely Oliver A. , Wilhelm Stefan , Reuter Stefan , Kern Winfried , Südhoff Thomas , Mörz Handan , Hehlmann Rüdiger
Published: December 2004

Invasive aspergillosis (IA) is a considerable clinical problem in neutropenic patients with haematological malignancies but its diagnosis remains difficult. We prospectively evaluated a LightCyclerTM polymerase chain reaction (PCR) assay, a nested‐PCR assay and a galactomannan (GM) enzyme‐linked immunosorbent assay (ELISA) to validate their significance in diagnosing IA. During 205 treatment episodes in 165 patients from six centres, a nested‐PCR assay and GM testing was performed at regular intervals. Positive nested‐PCR results were quantified by a LightCyclerTM PCR assay. Patient episodes were stratified according to the 2002 European Organization for Research and Treatment of Cancer/Mycosis Study Group consensus criteria and the PCR and serology results were correlated with the clinical diagnostic classification. Sensitivity and specificity rates for the nested‐PCR assay were up to 63·6% [95% confidence interval (CI): 30·8–89%) and 63·5% (95% CI: 53·4–72·7%) respectively, and 33·3% and 98·9% (95% CI: 7·5–70·1% and 94·2–99·9%) for GM respectively. The LightCyclerTM PCR assay yielded positive results in 21·4%, lacking discrimination by quantification across the different clinical categories. In this prospective comparison, PCR was superior to GM with respect to sensitivity rates. In patients at high risk for IA, positive results for Aspergillus by PCR of blood samples are highly suggestive for IA and contribute to the diagnosis.
Establishment of a pluripotent preleukaemic stem cell line by expression of the AML1‐ETO fusion protein in Notch1‐immortalized HSCN1cl10 cells
Authors: Delaney Colleen , Bernstein Irwin D.
Published: December 2004

The AML1‐ETO fusion has been associated with up to 40% of acute myeloid leukaemia French–American–British classified M2 cases. This chimaeric protein interferes with normal AML1 function and disrupts critical transcriptional regulation of haematopoiesis. Current evidence suggests that AML1‐ETO alone is insufficient to induce leukaemia, but rather is a co‐operating event in leukaemogenesis. We developed a pluripotent murine haematopoietic stem cell line expressing the AML1‐ETO fusion protein that displays in vitro and in vivo properties consistent with a preleukaemic state, including inhibition of terminal granulocytic differentiation in vitro and the development of non‐lymphoid leukaemias in vivo. This cell line represents a potential platform for the introduction and in vitro rapid screening of candidate genes thought to co‐operate with AML1‐ETO in developing frank leukaemia.
Rituximab in the treatment of alloimmune factor VIII and IX antibodies in two children with severe haemophilia
Authors: Mathias Mary , Khair Kate , Hann Ian , Liesner Ri
Published: December 2004

We report the use of rituximab (Genentech, San Francisco, CA, USA) in two children with severe haemophilia with inhibitors to factors VIII and IX, which failed to respond to conventional immune tolerance therapy. The treatment was well tolerated by both children. The child with haemophilia B had no clinical improvement or fall in CD19 and he is currently being treated with recombinant activated factor VII (NovoSeven, Novo Nordisk, Denmark) for bleeding episodes. The child with haemophilia A had a good clinical response with a negative inhibitor assay at 11 months follow‐up.
The London Cord Blood Bank: analysis of banking and transplantation outcome
Authors: Davey Sue , Armitage Sue , Rocha Vanderson , Garnier Federico , Brown Juliette , Brown Colin J. , Warwick Ruth , Fehily Deidre , Watt Suzanne , Gluckman Eliane , Vora Ajay , Contreras Marcela , Navarrete Cristina V.
Published: December 2004

Cord blood units (n = 5500) stored at the London Cord Blood Bank, including 59 units transplanted into a high risk and heterogeneous group of patients, were analysed. Transplant outcome data was available for 44 patients with a median clinical follow‐up of 14 months (range 3–44 months). Over 40% of the collected units were of ethnic minority origin with a median volume of 79 ml (range 40–240 ml) and a median total nucleated cell (TNC) count of 11·9 × 109/l (range 10·0–24·8 × 109/l). The average patient's weight was 28 kg (range 5–80 kg) and the median age was 8 years (range 0·7–40 years). The median number of nucleated cells infused was 4 × 107/kg (range 1·10–16 × 107/kg). Neutrophil engraftment of 0·5 × 109/l was observed in 33 (74±%) patients with an average time of 28 days (range 11–60). The Kaplan‐Meier estimate of acute graft‐versus‐host disease (grade II >) at day 100 was 37 ± 7% and in 27 (62%) patients, it was grade I or absent. The overall survival and disease‐free survival at 2 years was 49 ± 8% and 41 ± 8%, respectively. Two years after transplantation the survival rate was 69% and 54% for patients receiving a 6/6 or 5/6 HLA matched units, respectively. Infection was the main cause of transplanted related mortality in these patients.
Tumour cell/dendritic cell fusions as a vaccination strategy for multiple myeloma
Authors: Raje Noopur , Hideshima Teru , Davies Faith E. , Chauhan Dharminder , Treon Steven P. , Young Gloria , Tai Yu‐Tzu , Avigan David , Gong Jianlin , Schlossman Robert L. , Richardson Paul , Kufe Donald W. , Anderson Kenneth C.
Published: December 2004

Multiple myeloma (MM) cells express certain tumour‐associated antigens (TAAs) that could serve as targets for active‐specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0‐007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow‐cytometry and dual immunofluorescence microscopy. These FCs induced MM‐specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC‐primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex‐restricted MM‐specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway.
PRV‐1, erythroid colonies and platelet Mpl are unrelated to thrombosis in essential thrombocythaemia
Authors: Vannucchi Alessandro M. , Grossi Alberto , Pancrazzi Alessandro , Antonioli Elisabetta , Guglielmelli Paola , Balestri Francesca , Biscardi Monica , Bulgarelli Simona , Longo Giovanni , Graziano Claudio , Gugliotta Luigi , Bosi Alberto
Published: December 2004

Females with the monoclonal type of essential thrombocythaemia (ET), based on the X‐chromosome inactivation pattern (XCIP), have previously been shown to present a higher incidence of thrombosis than polyclonal ones. We aimed to assess correlations between XCIP, thrombosis, and three epigenetic markers of ET, namely PRV‐1 overexpression, endogenous erythroid colony (EEC) formation, and reduced platelet Mpl content. Fifty‐three (60%) of 88 subjects studied had monoclonal myelopoiesis and presented a 32% incidence of major thrombosis compared with 6% of polyclonal subjects (P = 0·009). The frequency of abnormalities of PRV‐1, EEC, or Mpl was similar in monoclonal and polyclonal subjects (respectively, 28%, 48%, 75%, and 37%, 27%, 63%), and none of them correlated with thrombosis. We conclude that the exploited epigenetic markers constitute independent phenotypic variations and are not clustered according to monoclonality of myelopoiesis in ET; none of them could serve as a surrogate marker of thrombotic risk in male subjects with ET.
Severe prekallikrein deficiency associated with homozygosity for an Arg94Stop nonsense mutation
Authors: Wynne Jones D. , Russell Geoffrey , Allford Sarah L. , Burdon Kathryn , Hawkins Gregory A. , Bowden Donald W. , Minaee Sophie , Mumford Andrew D.
Published: December 2004

An elderly patient with no abnormal bleeding presented with prolongation of the activated partial thromboplastin time (aPTT). Preincubation of plasma with aPTT reagent caused shortening of the abnormal clotting time. Plasma prekallikrein (PK) activity and antigen were <5 u/dL. Molecular analysis showed a homozygous Arg94Stop substitution in the PK gene, predicted to prevent expression of the mutant allele. The five heterozygous offspring of the proband each showed a normal aPTT but reduced PK activity and antigen. This is the first description of a kindred in which absence of expression of one or both PK alleles has been confirmed by genotype.
Expression of two type 2N von Willebrand disease mutations identified in exon 18 of von Willebrand factor gene
Authors: Hilbert L. , Jorieux S. , Fontenay‐Roupie M. , Guicheteau M. , Fressinaud E. , Meyer D. , Mazurier C. ,   the INSERM Network on Molecular Abnormalities in von Willebrand Disease
Published: December 2004

Type 2N von Willebrand disease (VWD) is characterized by a markedly decreased affinity of von Willebrand factor (VWF) for factor VIII (FVIII). The FVIII binding site has been localized within the first 272 amino acid residues of mature VWF, encoded by exons 18–23. Two substitutions in exon 18 of VWF gene, inducing candidate mutations Y795C and C804F were identified in the heterozygous state in two French patients who also displayed the frequent R854Q mutation in exon 20. Expression studies in Cos‐7 cells showed that these abnormalities, which implicate cysteine residues, induced secretion, multimerization and FVIII binding defects of corresponding recombinant VWF. Results from transfection experiments with R854Q, performed to reproduce the hybrid VWF present in patient plasma, were in agreement with those obtained for patient's plasma VWF. These findings confirm the importance of the VWF D’ domain in FVIII binding. In addition, this work shows that exon 18 should preferentially be sequenced in type 2N VWD patients when the frequent R854Q mutation in exon 20 has been excluded or detected in the heterozygous state.
Dyskinesias and associated psychiatric disorders following streptococcal infections
Authors: Reading Richard
Published: December 2004

.
 
Dale RC,
Heyman I,
Surtees RAH,
Church AJ,
Giovannoni G,
Goodman R &
Neville BGR
. (
2004
)

,
89
,
604
–
610
.

Background  The classical extrapyramidal movement disorder following β haemolytic streptococcus (BHS) infection is Sydenham's chorea (SC). Recently, other post‐streptococcal movement disorders have been described, including motor tics and dystonia. Associated emotional and behavioural alteration is characteristic.

Aims  To describe experience of post‐streptococcal dyskinesias and associated comorbid psychiatric features presenting to a tertiary referral centre 1999–2002.

Methods  In all patients, dyskinetic movement disorders followed BHS pharyngeal infection. BHS infection was defined by pharyngeal culture of the organism, or paired streptococcal serology. Movement disorders were classified according to international criteria, and validated by experienced child neurologists. Psychiatric complications were defined using ICD‐10 criteria using a validated psychiatric interview.

Results  In the 40 patients, the following dyskinetic movement disorders were present: chorea (n = 20), motor tics (n = 16), dystonia (n = 5), tremor (n = 3), stereotypies (n = 2), opsoclonus (n = 2) and myoclonus (n = 1). Sixty‐five per cent of  the  chorea  patients  were  female,  whereas  69% of the tic patients were male. ICD‐10 psychiatric diagnoses were made in 62.5%. Using the same psychiatric instrument, only 8.9% of UK children would be expected to have an ICD‐10 psychiatric diagnosis. Emotional disorders occurred in 47.5%, including obsessive‐compulsive disorder (27.5%), generalized anxiety (25%) and depressive episode (17.5%). Additional psychiatric morbidity included conduct disorders (27.5%) and hyperkinetic disorders (15%). Psychiatric, movement and post‐streptococcal autoimmune disorders were commonly observed in family members. At a mean follow‐up of 2.7 years, 72.5% had continuing movement and psychiatric disorders.

Conclusion  Post‐streptococcal dyskinesias occur with significant and disabling psychiatric comorbidity and are potential autoimmune models of common ‘idiopathic’ movement and psychiatric disorders in children. Multiple factors may be involved in disease expression including genetic predisposition, developmental status and the patient's sex.