bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti‐apostatic selection by wild birds on quasi‐natural morphs of the land snail Cepaea hortensis: a generalised linear mixed models approach
Authors: Allen John A. , Weale Michael E.
Published: December 2004

Anti‐apostatic selection occurs when predators feed disproportionately on rare prey, a process that leads to a decrease in variation within prey populations. Most of the evidence for this phenomenon comes from experiments using artificial prey items distinguished by simple artificial colour differences. We describe an experiment performed at 10 different sites in which we tested whether selection by wild birds is anti‐apostatic when presented with high density populations of shells of the polymorphic land snail, Cepaea hortensis, stuffed with pastry. At each site we presented two sorts of populations in sequence: 45 yellow unbanded with 5 yellow banded, and 5 yellow unbanded with 45 yellow banded. Selection was measured using an analysis based on generalised linear mixed models (GLMMs) that has broad applicability to all resource selection studies where extraneous variance is a problem. Using this analytic method, we found that birds altered their behaviour to produce significant anti‐apostatic selection in direct response to changes in frequency of the quasi‐natural Cepaea morphs.
Pollen limitation and demographic structure in small fragmented populations of Brunsvigia radulosa (Amaryllidaceae)
Authors: Ward Megan , Johnson Steven D.
Published: December 2004

The ecological consequences of disruptions in plant‐pollinator mutualisms are poorly understood. We examined how seed production and recruitment of juveniles in populations of the spectacular grassland geophyte Brunsvigia radulosa (Amaryllidaceae) correlate with various indices of habitat fragmentation, including habitat fragment area, population size and population isolation. The species was found to be self‐incompatible and adapted for pollination primarily by the long‐proboscid fly Philoliche aethiopica (Tabanidae). In places where this fly is locally extinct, carpenter bees appear to act as substitute, though less effective, pollinators. Seed production in B. radulosa showed a significant positive relationship with population size, but not with habitat fragment area or spatial isolation of populations when all three indices of habitat fragmentation were included as predictor variables in multiple regression models. Reduced seed production in small populations was attributable to pollen limitation, as supplemental hand pollinations resulted in proportionally greater increases in seed production in these populations. Pollen limitation appears to have demographic consequences; specifically, the proportion of juvenile plants in populations showed significant positive relationships with current levels of seed production per plant and size of populations. Thus the long term persistence of small B. radulosa populations in habitat fragments may be threatened by a pollination deficit.
Parasites boosts biodiversity and changes animal community structure by trait‐mediated indirect effects
Authors: Mouritsen Kim N. , Poulin Robert
Published: December 2004

Parasitism has long been emphasised as an important process structuring animal communities. However, empirical evidence documenting the impact of parasites in other than simple laboratory settings is lacking. Here we examine the trait‐mediated indirect effects of echinostome trematodes on a New Zealand soft bottom intertidal community of macroinvertebrates. Curtuteria australis and a second related but undescribed trematode both utilise the cockle Austrovenus stutchburyi as second intermediate host in which the parasites infect the foot tissue. Heavily infected cockles are therefore more sessile than lightly infected individuals, and, unable to bury, often rest on the sediment surface. We utilised these behavioural changes in two long term field experiments, respectively manipulating the parasite load of buried cockle (i.e. bioturbation), and the density of surfaced cockles (i.e. surface structures and seabed hydrodynamics). Both high parasite loads in buried cockles and the presence of surfaced cockles increased species richness and generally also the density of certain species and of major systematic and functional groups of benthic macroinvertebrates. Species diversity (alpha) peaked under intermediate densities of surfaced cockles. Our results demonstrate that parasites, solely through their impact on the behaviour of a single community member, can be significant determinants of animal community structure and function.
Prolonged clonal growth: escape route or route to extinction?
Authors: Honnay Olivier , Bossuyt Beatrijs
Published: December 2004

Many plant species have the capability to reproduce sexually as well as clonally. The balance between clonal reproduction and sexual reproduction varies between different species. It was estimated that 66.5% of all central European flora may form independent but genetically identical daughter plants. Also within species there is great variation in the ratio clonal/sexual reproduction. Clonal reproduction can be considered as an alternative life cycle loop that allows persistence of a species in the absence of the ability to complete the normal life cycle (i.e. seed production, germination and recruitment). Plant populations exhibiting prolonged clonal growth have been referred to as ‘remnant populations’. A remnant population in general is defined as “a population capable of persistence during extended time periods despite a negative population growth rate (λ<1) due to longlived life stages and life cycles, including loops, that allow population persistence without completion of the whole life cycle”. Here we argue that prolonged and nearly exclusive clonal growth through environmental suppression of sexual reproduction can ultimately lead to local sexual extinction and to monoclonal populations of a species, and that this may imply significant consequences for population viability. Especially obligate or mainly outcrossing clonal plant species may be vulnerable for sexual extinction. We argue that the consequences of reduced sexual recruitment in clonally propagating plants may be understudied and underestimated and that a re‐evaluation of current ideas on clonality may be necessary.
Behavioral tradeoffs when dispersing across a patchy landscape
Authors: Zollner Patrick A. , Lima Steven L.
Published: December 2004

A better understanding of the behavior of dispersing animals will assist in determining the factors that limit their success and ultimately help improve the way dispersal is incorporated into population models. To that end, we used a simulation model to investigate three questions about behavioral tradeoffs that dispersing animals might face: (i) speed of movement against risk of predation, (ii) speed of movement against foraging, and (iii) perceptual range against risk of predation. The first investigation demonstrated that dispersing animals can generally benefit by slowing from maximal speed to perform anti‐predatory behavior. The optimal speed was most strongly influenced by the disperser's energetic reserves, the risk of predation it faced, the interaction between these two parameters, and the effectiveness of its anti‐predatory behavior. Patch arrangement and the search strategy employed by the dispersers had marginal effects on this tradeoff relative to the above parameters. The second investigation demonstrated that slowing movement to forage during dispersal may increase success and that optimum speed of dispersal was primarily a function of the dispersing animal's energetic reserves, predation risk, and their interaction. The richness (density of food resources) of the interpatch matrix and the patch arrangement had relatively minor impacts on how much time a dispersing animal should spend foraging. The final investigation demonstrated animals may face tradeoffs between dispersing under conditions that involve a low risk of predation but limit their ability to perceive distant habitat (necessitating more time spent searching for habitat) and conditions that are inherently more risky but allow animals to perceive distant habitat more readily. The precise nature of this tradeoff was sensitive to the form of the relationship between predation risk and perceptual range. Our overall results suggest that simple depictions of these behavioral tradeoffs might suffice in spatially explicit population models.
Timing of depth‐dependent lithosphere stretching on the S. Lofoten rifted margin offshore mid‐Norway: pre‐breakup or post‐breakup?
Authors: Kusznir N. J. , Hunsdale R. , Roberts A. M.
Published: December 2004

Depth‐dependent stretching, in which whole‐crustal and whole‐lithosphere extension is significantly greater than upper‐crustal extension, has been observed at both non‐volcanic and volcanic rifted continental margins. A key question is whether depth‐dependent stretching occurs during pre‐breakup rifting or during sea‐floor spreading initiation and early sea‐floor spreading. Analysis of post‐breakup thermal subsidence and upper‐crustal faulting show that depth‐dependent lithosphere stretching occurs on the outer part of the Norwegian volcanic rifted margin. For the southern Lofoten margin, large breakup lithosphere β stretching factors approaching infinity are required within 100 km of the continent–ocean boundary to restore Lower Eocene sediments and flood basalt surfaces (∼54 Ma) to interpreted sub‐aerial depositional environments at sea level as indicated by well data. For the same region, the upper crust shows no significant Palaeocene and Late Cretaceous faulting preceding breakup with upper‐crustal β stretching factors <1.05. Further north on the Lofoten margin, reverse modelling of post‐breakup subsidence with a β stretching factor of infinity predicts palaeo‐bathymetries of ∼1500 m to the west of the Utrøst Ridge and fails to restore Lower Eocene sediments and flood basalt tops to sea level at ∼54 Ma. If these horizons were deposited in a sub‐aerial depositional environment, as indicated by well data to the south, an additional subsidence event younger than 54 Ma is required compatible with lower‐crustal thinning during sea‐floor spreading initiation. For the northern Vøring margin, breakup lithosphere β stretching factors of ∼2.5 are required to restore Lower Eocene sediments and basalts to sea level at deposition, while Palaeocene and Late Cretaceous upper‐crustal β stretching factors for the same region are < 1.1. The absence of significant Palaeocene and late Cretaceous extension on the southern Lofoten and northern Vøring margins prior to continental breakup supports the hypothesis that depth‐dependent stretching of rifted margin lithosphere occurs during sea‐floor spreading initiation or early sea‐floor spreading rather than during pre‐breakup rifting.
Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature
Authors: Yomtovian Roslyn , Niklinski Waldemar , Silver Bernard , Sarode Ravindra , Tsai Han‐Mou
Published: December 2004

Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 has been demonstrated to be the proximate cause of a subset of thrombotic microangiopathic haemolytic anaemias (MAHA) typical for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 gene mutations cause the hereditary form; acquired deficiency has been attributed to presence of an autoantibody, which may represent a specific subset of MAHA best termed ‘autoimmune thrombotic thrombocytopenic purpura’. We describe a patient with relapsing TTP because of ADAMTS13 inhibitors, who failed to achieve sustained remission despite therapies with plasma exchange, steroids, vincristine, staphylococcal protein A and splenectomy. The ADAMTS13 inhibitor titre remained elevated and clinical stability was only maintained by plasma exchange every 2–3 d over a period of 268 d. The patient then received rituximab therapy (eight doses of 375 mg/m2 weekly), during which she required five plasma exchanges in the first 10 d, two exchanges in the next 3 weeks, and none thereafter for 450 d and ongoing. The ADAMTS13 inhibitor titre decreased and enzyme activity increased. We compared this case with that of seven previously reported TTP cases also treated with rituximab; experience suggests that rituximab therapy deserves further investigation for patients with either refractory or relapsing TTP caused by ADAMTS13 inhibitors.
Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma
Authors: Toor Amir A. , Ayers John , Strupeck Joan , Parthasarathy Mala , Creech Steve , Rodriguez Tulio , Stiff Patrick J.
Published: December 2004

Both single and tandem cycles of high dose therapy and autologous peripheral blood stem cell transplantation (ASCT) have been shown to improve survival in multiple myeloma (MM) patients. We report outcomes in 104 MM patients undergoing a single transplant after conditioning with a conventional myeloablative regimen, busulphan and cyclophosphamide. The patients were either in a first (71%), or subsequent remission (29%). Peripheral blood stem cells were mobilized using cyclophosphamide and granulocyte colony stimulating factor. The conditioning regimen consisted of busulphan 0·85 mg/kg given orally every 6 h (16 doses) and cyclophosphamide 60 mg/kg/d given intravenously for 2 d. The entire conditioning, transplant and post‐transplant course were in the outpatient setting for 45% patients. At a median follow‐up of 26 months (range 2–98 months), the median overall and progression‐free survival were 57 months [95% confidence interval (CI) 47–68] and 26 months (95% CI 20–32) respectively. Younger age and higher CD34+cell dose infused were independently predictive of improved overall and progression‐free survival. Busulphan and cyclophosphamide is an effective and well‐tolerated preparative regimen for ASCT that can be given to MM patients in the outpatient setting.
Single nucleotide polymorphisms of the inflammatory cytokine genes in adults with chronic immune thrombocytopenic purpura
Authors: Satoh Takashi , Pandey Janardan P. , Okazaki Yuka , Yasuoka Hidekata , Kawakami Yutaka , Ikeda Yasuo , Kuwana Masataka
Published: December 2004

Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were examined in 84 adult Japanese patients with chronic immune thrombocytopenic purpura (ITP) and 56 race‐matched healthy controls. The SNPs examined were within the genes encoding tumour necrosis factor (TNF)‐α (−238 G/A and −308 G/A), TNF‐β (+252 G/A), and interleukin (IL)‐1β (−511 C/T and +3953 T/C). Of these SNPs, the frequency of the TNF‐β (+252) G/G phenotype was significantly higher in ITP patients than in healthy controls (21% vs. 7%, P = 0·04, odds ratio = 3·6, 95% confidence interval 1·1–11·1), while no significant association was detected for the other SNPs. The distribution of the TNF‐β (+252) phenotype was not associated with human leucocyte antigen class II alleles or the therapeutic response in ITP patients. The frequency of circulating anti‐glycoprotein IIb/IIIa antibody‐producing B cells was significantly higher in ITP patients with the TNF‐β (+252) G/G phenotype than in those with the G/A or A/A phenotype (11·9 ± 4·9 vs. 6·8 ± 4·9 and 3·7 ± 2·8 per 105 peripheral blood mononuclear cells; P = 0·02 and P < 0·001, respectively). These findings suggest that the SNP located at TNF‐β (+252) contributes to susceptibility to chronic ITP by controlling the autoreactive B‐cell responses to platelet membrane glycoproteins.
Abnormal LTC4 synthase RNA degradation in neutrophils from CML patients
Authors: Roos Cecilia , Sjölinder Mikael , Stenke Leif , Tornhamre Susanne
Published: December 2004

Neutrophils from patients with chronic myeloid leukaemia (CML) have an aberrant expression of leukotriene (LT)C4 synthase. In order to learn more about the regulation of this abnormality, LTC4 synthase mRNA expression was determined by reverse transcription polymerase chain reaction. A digoxigenin (DIG)‐labelled LTC4 synthase RNA was synthesized and incubated in cytsolic extracts from CML neutrophils, normal neutrophils and eosinophils. LTC4 synthase mRNA was detected in total but not cytoplasmic RNA from normal neutrophils. In contrast, LTC4 synthase mRNA was found in the cytoplasm of CML neutrophils and in normal eosinophils, which also express the enzyme. The DIG‐labelled LTC4 synthase RNA was, as opposed to normal neutrophils, degraded in cytosolic extracts from CML neutrophils. The degradation was time dependent and cell concentration dependent. Degradation was also seen in eosinophils, indicating that degradation of LTC4 synthase RNA was correlated to the expression of the protein. This study showed that the difference in expression of LTC4 synthase in normal and CML neutrophils was not because of a total lack of LTC4 synthase mRNA in normal neutrophils. However normal neutrophils lack, in contrast to CML neutrophils, LTC4 synthase mRNA in the cytoplasm. This discrepancy is not caused by a stabilized LTC4 synthase RNA in the cytosol of CML neutrophils. Instead an abnormal degradation of LTC4 synthase RNA was found in the cytosol of CML neutrophils.
Clinical follow‐up indicates differential accuracy of magnetic resonance imaging and immunocytology of the cerebral spinal fluid for the diagnosis of neoplastic meningitis – a single centre experience
Authors: Zeiser Robert , Burger Jan A. , Bley Thorsten A. , Windfuhr‐Blum Marissa , Schulte‐Mönting Jürgen , Behringer Dirk M.
Published: December 2004

In patients with neoplastic meningitis (NM), the rapid institution of intrathecal therapy may ameliorate the course of disease, indicating that a timely diagnosis is clinically relevant. As immunocytology (IC) of cerebrospinal fluid and magnetic resonance imaging (MRI), as diagnostic methods, have potential pitfalls, the present study assessed the results of both methods, to determine the predictive capability of the initial evaluations with respect to the risk that the patient would develop NM during the course of their disease. A total of 166 individuals with B‐cell non‐Hodgkin's lymphoma (B‐NHL; n = 95), B‐acute lymphocytic leukaemia (ALL; n = 18), acute myeloid leukaemia (n = 27) or solid tumours (n = 26), with at least one definitive IC and MRI result within 3 weeks, were evaluated at a median follow‐up of 29·5 months (range 6–53 months). IC and MRI results reached the highest concordance (98%) in B‐NHL patients and were most discordant in ALL patients (43%). In haematological malignancies, IC displayed considerable sensitivity, ranging from 89% to 95%, while MRI had very low sensitivity. Conversely, MRI showed high sensitivity (100%) and specificity (92%) in solid tumours. We conclude that IC is of particular value in the diagnosis of NM due to haematological malignancies while MRI is superior to IC in the diagnosis of NM due to solid tumours.
In vivo and in vitro effects of different anaesthetics on platelet function
Authors: Dordoni Pier Lorenza , Frassanito Luciano , Bruno Maria F. , Proietti Rodolfo , Cristofaro Raimondo De , Ciabattoni Giovanni , Ardito Guglielmo , Crocchiolo Roberto , Landolfi Raffaele , Rocca Bianca
Published: December 2004

Different effects of thiopental, propofol and sevoflurane on platelets have been reported. Patients undergoing thyroid surgery were anaesthetized with thiopental–fentanyl–sevoflurane (n = 11) or propofol–fentanyl–sevoflurane (n = 9). Platelet aggregation and thromboxane A2 generation were studied at baseline, and at the end of anaesthesia induction and surgery. Dose–response experiments were also performed in vitro with single agents. Thiopental–fentanyl–sevoflurane significantly reduced collagen‐induced aggregation by the end of induction, while ADP‐induced aggregation and thromboxane generation were unaffected. Propofol–fentanyl–sevoflurane had no effect on platelets. Thiopental dose‐dependently inhibited platelets in vitro, while fentanyl or propofol did not. In conclusion, thiopental reduces platelet function both ex vivo and in vitro and propofol might be considered haemostatically safer.
T cell recognition of bcr/abl in healthy donors and in patients with chronic myeloid leukaemia
Authors: Westermann Jörg , Schlimper Claudia , Richter Günther , Mohm Johannes , Dörken Bernd , Pezzutto Antonio
Published: December 2004

In chronic myeloid leukaemia (CML), peptides from the fusion region of bcr3/abl2 are likely to play a role in anti‐leukaemic T cell immunity. We investigated whether T cells that recognize bcr/abl fusion peptides could be detected in healthy donors and CML patients. T cell responses against bcr3/abl2 fusion peptides were analysed by γ‐interferon enzyme‐linked immunospot assays after prestimulation of peripheral blood mononuclear cells in the presence of anti‐CD3‐antibodies and interleukin‐2. Our results suggest that the T cell repertoire contains bcr3/abl2‐reactive T cells in CML patients who are in cytogenetic remission, but also in some healthy individuals.
The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia
Authors: Kamiguti Aura S. , Lee Edwin S. , Till Kathleen J. , Harris Robert J. , Glenn Mark A. , Lin Ke , Chen Hai Juan , Zuzel Mirko , Cawley John C.
Published: December 2004

Matrix metalloproteinases (MMPs) are important for the pathogenesis and progression of different tumours. MMPs‐2 and ‐9 are the principal MMPs produced by lymphocytes; these enzymes can degrade a number of matrix proteins but are the two main MMPs that digest type IV collagen, the major component of basement membranes. Therefore, these enzymes are potentially important for tissue invasion and remodelling by malignant lymphocytes. This study showed that chronic lymphocytic leukaemia (CLL) cells produce and secrete variable amounts of pro‐MMP‐9, but no MMP‐2 or tissue inhibitor of metalloproteinase  1 (TIMP‐1). The pro‐enzyme was found in monomeric and dimeric forms and also complexed with lipocalin. Moreover, a small fraction of secreted monomer became associated with the cell surface and activated upon cell adhesion to insolubilized type IV collagen. High levels of intracellular MMP‐9 were associated with advanced (stage C) disease and with poor patient survival. Immunohistochemical studies demonstrated that MMP‐9 was associated with areas of tissue invasion and remodelling. The relatively specific MMP‐9 inhibitors, Ro31‐9790 (3 μmol/l) and TIMP‐1, reduced CLL‐cell migration through type IV collagen and through endothelial monolayers suggesting that the enzyme may also be important in malignant cell entry and egress to and from involved tissue. Our data raise the possibility that MMP‐9 modulation may have therapeutic potential in advanced CLL.
Early response predicts thalidomide efficiency in patients with advanced multiple myeloma*
Authors: Waage Anders , Gimsing Peter , Juliusson Gunnar , Turesson Ingemar , Gulbrandsen Nina , Eriksson Tommy , Hjorth Martin , Nielsen Johan Lanng , Lenhoff Stig , Westin Jan , Wislöff Finn ,   for the Nordic Myeloma Study Group
Published: December 2004

Sixty‐five patients who were primary or secondary refractory to melphalan/prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M‐protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half‐life were calculated to be 0·200/h, 0·140/h, 0·886 l/kg, 0·126 l/h/kg and 4·98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks.
Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity
Authors: Orfali Karen A. , Ohene‐Abuakwa Yaw , Ball Sarah E.
Published: December 2004

A detailed family study was undertaken of patients notified to the UK Diamond Blackfan Anaemia (DBA) Registry. RPS19 mutations were detected in 16 of 104 families, including two patients with deletions detected by intragenic loss of heterozygosity of tightly linked polymorphisms. In two further cases, polymorphisms were used to determine the parental allele of origin of RPS19 point mutations. A review of clinical details of patients with mutations and patients in the literature having identical or equivalent mutations revealed evidence for a genotype:phenotype correlation with respect to the prevalence of physical anomalies, and the occurrence of mild or variable haematological severity. Nine of 60 patients had a known family history of DBA. Haematological abnormalities, including raised red cell adenosine deaminase activity, were found in first‐degree relatives of 16 of 51 (31%) of patients not previously considered to have familial DBA. Results of both parents and any siblings were normal in only 35 of 60 (58%) of cases, who were therefore assumed to have sporadic de novo DBA. The classical inheritance pattern for DBA is autosomal dominant; however, 12 of 60 families (20%) had more than one affected child despite normal results in both parents. These results have important implications for genetic counselling, and for the selection of potential sibling bone marrow donors.
α‐Galactosylceramide‐driven expansion of human natural killer T cells is inhibited by prednisolone treatment
Authors: Johansson Ulrika , Macey Marion G. , Kenny Deborah , Provan Drew , Newland Adrian C
Published: December 2004

The mechanisms of action of most treatments in the autoimmune disorders are unclear and steroids remain the first‐line therapy in these diseases. Natural killer T (NKT) cell activity has been implicated in the autoimmune process but whether steroids act via an affect on NKT cell function, such as antigen‐specific proliferative capacity, is unknown. Immune thrombocytopenia (ITP) patients were studied ex vivo for NKT cell expansion in response to the specific NKT cell antigen, α‐galactosylceramide, before, during or after prednisolone treatment. Prednisolone inhibited antigen‐specific NKT cell expansion in ITP patients in remission. Untreated ITP patients also showed reduced NKT cell proliferative capacity, although this was less marked than in treated patients. These results support a role for NKT cells in ITP and aid understanding of the immunosuppressive activities of prednisolone in autoimmune disease.
Haematopoietic stem cell transplantation with non‐myeloablative conditioning in the outpatient setting: results, complications and admission requirements in a single institution
Authors: Petersen Søren L. , Madsen Hans O. , Ryder Lars P. , Svejgaard Arne , Jakobsen Bodil K. , Sengeløv Henrik , Heilmann Carsten , Dickmeiss Ebbe , Vindeløv Lars L.
Published: December 2004

Thirty patients with haematological malignancies received peripheral blood stem cells from human leucocyte antigen (HLA)‐identical sibling donors after non‐myeloablative conditioning with fludarabine and total body irradiation. Twenty‐seven patients received the transplant as an outpatient procedure. All patients engrafted. The probability of acute graft‐versus‐host disease (GVHD) grades II–IV and extensive chronic GVHD was 57% and 80%, respectively. Patients alive on day +365 experienced a median of 44 d (range 4–151) of hospitalization during the first year. In the entire cohort, GVHD accounted for 22%, infections for 18%, thrombotic thrombocytopenic purpura (TTP) for 16% and engraftment syndrome for 14% of the time in hospital. The 1‐year risk of TTP was 26%. Acute GVHD was a risk factor for the development of TTP (P = 0·008). With a median follow‐up of 602 d, the 2‐year estimates for overall survival, progression‐free survival, non‐relapse mortality and relapse related mortality were 68%, 43%, 22% and 13%, respectively. This transplantation regimen is feasible and induces long‐term remissions in heavily pretreated patients. The procedure can be performed in the outpatient setting, but complications could result in a substantial number of admissions during the first year.
No deterioration after 13 years in a stability study of a rabbit brain, plain, thromboplastin, RBT 1010, in rubber‐stoppered ampoules
Authors: Stevenson K. J. , Craig S. , Goodman L. , Kanyike F. B.
Published: December 2004

RBT 1010, a rabbit brain thromboplastin, plain, was prepared at the Thrombosis Reference Centre, Withington Hospital, Manchester, in 1989. The batch has been stored at −20°C, in rubber‐stoppered ampoules, for 13 years. The material was unchanged after this time. This was confirmed in a stability study, in which the reagent was used to test the prothrombin times of a panel of plasmas stored in liquid nitrogen, one from a normal volunteer and two from stable anticoagulated patients. RBT 1010 was also tested in calibrations, according to World Health Organization recommendations, against the reference thromboplastin preparations CRM 149S and RBT 90.
The Bcl‐2 family member Bfl‐1/A1 is strongly repressed in normal and malignant plasma cells but is a potent anti‐apoptotic factor for myeloma cells
Authors: Tarte Karin , Jourdan Michel , Veyrune Jean Luc , Berberich Ingolf , Fiol Geneviève , Redal Nicole , Shaughnessy John , Klein Bernard
Published: December 2004

Terminal B‐cell differentiation is a multi‐step process, from short‐lived plasmablasts to mature long‐lived plasma cells (PC). The anti‐apoptotic Bcl‐2 family member Bfl‐1/A1 plays a critical role in the survival of mature B cells. However, its potential involvement at the later stages of B‐cell development remains highly controversial. Our aim was thus to clarify the place of Bfl‐1/A1 in the biology of normal PC and in the pathogenesis of multiple myeloma (MM), the major PC dyscrasia. Using gene expression profiling and quantifiable reverse transcription polymerase chain reaction experiments, we found a similar down‐regulation of Bfl‐1/A1 in both normal immature plasmablasts and mature PC when compared with B cells. In myeloma cells, the level of Bfl‐1/A1 was low and Bfl‐1/A1 was not a nuclear factor κB‐inducible gene. Collectively, these data demonstrate that Bfl‐1/A1 is not involved in the prolonged survival of normal mature PC, and that Bfl‐1/A1 deregulation is not a common oncogenic event in MM. However, overexpression of Bfl‐1/A1 by retroviral transduction promoted autonomous survival of an interleukin‐6‐dependent myeloma cell line and rendered it less sensitive to dexamethasone. Thus, Bfl‐1/A1 transduction could be an interesting tool to obtain myeloma cell lines from primary samples and to favour the in vitro generation of antibody‐secreting, long‐lived normal PC.
t(11;18)(q21;q21) of mucosa‐associated lymphoid tissue lymphoma results from illegitimate non‐homologous end joining following double strand breaks
Authors: Liu Hongxiang , Hamoudi Rifat A. , Ye Hongtao , Ruskone‐Fourmestraux Agnes , Dogan Ahmet , Isaacson Peter G. , Du Ming‐Qing
Published: December 2004

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

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

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

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

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

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

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

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

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

.
 
Christakis DA,
Zimmerman FJ,
Di Giuseppe DL &
McCarty CA.
 
(
2004
)
Pediatrics
,
113
,
708
–
713
.

Objective

Cross‐sectional research has suggested that television viewing may be associated with decreased attention spans in children. However, longitudinal data of early television exposure and subsequent attentional problems have been lacking. The objective of this study was to test the hypothesis that early television exposure (at ages 1 and 3) is associated with attentional problems at age 7.

Methods

We used the National Longitudinal Survey of Youth, a representative longitudinal data set. Our main outcome was the hyperactivity subscale of the Behavioural Problems Index determined on all participants at age 7. Children who were > 1.2 standard deviations above the mean were classified as having attentional problems. Our main predictor was hours of television watched daily at ages 1 and 3 years.

Results

Data were available for 1278 children at age 1 and 1345 children at age 3. Ten percent of children had attentional problems at age 7. In a logistic regression model, hours of television viewing per day at both ages 1 and 3 were associated with attentional problems at age 7 [1.09 (1.03–1.15) and 1.09 (1.02–1.16), respectively].

Conclusions

Early television exposure is associated with attentional problems at age 7. Efforts to limit television viewing in early childhood may be warranted, and additional research is needed.
Differential major histocompatibility complex class II locus expression on human laryngeal epithelium
Authors: REES L E , AYOUB O , HAVERSON K , BIRCHALL M A , BAILEY M
Published: December 2004

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