bluuebunny/crossref_metadata_2025 huggingface dataset:
Orthodontic undergraduate education: assessment in a modern curriculum
Authors: Bearn David R. , Chadwick Stephen M. , Jack Alan C. , Sackville Andrew
Published: March 2003

This paper describes the problems of assessment for students on an undergraduate orthodontic course which is using problem‐based learning to encourage active self‐learning, deep learning and give students the skills to become effective lifelong learners in the future. Traditional assessment does little to encourage a range of behaviours and skills which are encouraged through problem‐based learning but which must be rewarded, in the minds of the students, by the chosen method of assessment. This is because learner behaviour is driven by assessment. Details of the range of assessment methods available and those chosen on the orthodontic undergraduate course at the University of Manchester Dental School are reported and discussed.
3.2 Ensuring research productivity in the future faculty
Authors: Brodin Pål , Bennett Ian , Appleton John , Bonta Yolanda , Feher Erzebet , Fiehn Nils‐Erik , Greenspan Deborah , Hjorting‐Hansen Erik , Latta Mark , O'Connell Brian , Sidlauskas Antanas , Skaleric Uros
Published: March 2003

The group concluded that the research productivity of a dental school depended to a large extent on the availability of resources, human and economic. Firstly it requires a group of individuals trained and educated to conduct independent research. Secondly, it requires that these individuals had time to spend on research activities. Thirdly, appropriate space and equipment in which to conduct the research were considered prerequisites. Fourthly, they require an ongoing and appropriate budget. Fifthly, it is essential to have an appropriate climate in the school that encourages and rewards research achievement.
3.4 Securing the financial future of the university
Authors: Buchanan Richard N. , Goldberg Jerold , Groeneveld Hans , Alvesalo Lassi , Anderton Robert , Angelopoulos Angie , Bausch J. R. , Haanaes Hans , Nagy Gabor , MacInnis William , Sapelli Pierluigi , Songpaisan Upin
Published: March 2003

The purpose of this paper is to explore current challenges to the financial security of the world's dental schools, analyse and compare current methods of funding dental education, identify best practices and formulate recommendations in order to assist dental educators to meet future fiscal challenges.
Hot summer temperatures may stop movement ofPapilio canadensisbutterflies and genetic introgression south of the hybrid zone in the North American Great Lakes Region
Authors: Scriber J. Mark , Keefover Keegan , Nelson Susan
Published: March 2003

The reasons that the northern tiger swallowtail butterflyPapilio canadensisdoes not move south of the Great Lakes hybrid zone, where it meetsP. glaucus, may be largely due to natural temperature‐induced stress on diapausing pupae. Temperatures of 36°C for only four days killed allP. canadensis(from northern Michigan) and most of thePapilio troilus, a species that lives south of the hybrid zone (sympatrically withP. glaucus). In contrast, interspecific hybrids (P. glaucusmother×P. canadensisfather) had significant adult eclosion or pupal survival at both 30° and 36°C. All surviving hybrid pupae were only females (the heterogametic sex, which are known to express the prolonged diapause due to Haldane effects).  The southern species,P. troilus, had almost all (81%) normal (non‐deformed) adults eclose at 30°C, whereas only 20% of theP. canadensisfemales and ca 30% of theP. canadensismales eclosed to produce non‐deformed adults. Unlike the case withP. troilusandP. canadensis, no hybrid females eclosed at 30°C (only males did). UnlikeP. troilusandP. canadensispupae, hybrid (female) pupae remain viable, some of which have already successfully emerged after the chamber experiments.  A follow‐up study usingP. glaucus,P. canadensis(from Vermont), and their hybrids with more normal lower thermal regimes included (27°, 30°, 33°, and 36°C) again showed higher hybrid survival as uneclosed (living) pupae at 36°C. In addition,P. glaucusandP. canadensisshowed high mortality and wing deformity of eclosing adults at 36°C, suggesting that geographic source of theP. canadensismay reflect differential tolerances of the extreme 36°C temperature.
Landscape issues in plant ecology
Authors: De Blois Sylvie , Domon Gérald , Bouchard André
Published: March 2003

In the last decade, we have seen the emergence and consolidation of a conceptual framework that recognizes the landscape as an ecological unit of interest. Plant ecologists have long emphasized landscape‐scale issues, but there has been no recent attempt to define how landscape concepts are now integrated in vegetation studies. To help define common research paradigms in both landscape and plant ecology, we discuss issues related to three main landscape concepts in vegetation researches, reviewing theoretical influences and emphasizing recent developments. We first focus on environmental relationships, documenting how vegetation patterns emerge from the influence of local abiotic conditions. The landscape is the physical environment. Disturbances are then considered, with a particular attention to human‐driven processes that often overrule natural dynamics. The landscape is a dynamic space. As environmental and historical processes generate heterogeneous patterns, we finally move on to stress current evidence relating spatial structure and vegetation dynamics. This relates to the concept of a landscape as a patch‐corridor‐matrix mosaic. Future challenges involve: 1) the capacity to evaluate the relative importance of multiple controlling processes at broad spatial scale; 2) better assessment of the real importance of the spatial configuration of landscape elements for plant species and finally; 3) the integration of natural and cultural processes and the recognition of their interdependence in relation to vegetation management issues in human landscapes.
Selectivity by moose vs the spatial distribution of aspen: a natural experiment
Authors: Edenius Lars , Ericsson Göran , Näslund Peter
Published: March 2003

Patch use theory predicts that herbivores perceive food as patches and spend more time in high quality patches, i.e. feeding sites providing a high net rate of intake of energy and/or limiting nutrients. The herbivores should accordingly not discriminate among food items in such high quality patches, and food items should thus be eaten in proportion to availability. In contrast, classical diet theory assumes food selection to take place at the level of individual plants, and predicts that the forager should concentrate on the most profitable item until availability drops below some critical threshold.  Here we address how the spatial distribution of European aspen Populus tremula, a highly preferred browse species, affects the selectivity by moose Alces alces at the patch and the tree level. The study was performed in a managed boreal forest landscape in coastal northern Sweden, where aspen occurs highly aggregated almost exclusively in discrete patches. We compared moose’ selectivity for aspen and browsing intensity on aspen ramets and other browse species in aspen patches versus at randomly located sites.  Random sites and aspen stands were utilised equally by moose in terms of overall use of forage. There was no difference in total coverage of forage species and relative moose density. Selectivity for aspen was stronger at random sites than at aspen sites, and the browsing intensity on aspen was similar. We conclude that moose did not perceive aspen stands as discrete patches, and used aspen ramets more in accordance with diet theory. These findings agree with the idea that large generalist herbivores strive to maintain a mixed and balanced diet, causing rare species to be over‐utilised (negative frequency‐dependent food selection). By such selective feeding, moose may reinforce the aggregated distribution of aspen in the managed boreal forest landscape.
Seasonal changes in the numerical responses of predators to cyclic vole populations
Authors: Norrdahl Kai , Korpimäki Erkki
Published: March 2003

Theoretical models predict that a delayed density‐dependent mortality factor with a time lag of ca 9 months is able to drive 3–5‐yr population cycles of northern voles. We studied numerical responses of predators in western Finland during 1986–92, in an area with 3‐yr population cycles of voles. Abundances of small mammals were monitored in several farmland areas (each 3 km2) by snap‐trapping in April, June, August, and October (only in 1986–90), and the abundances of avian, mammalian, and reptilian predators by visual censuses during trapping occasions. The 3‐yr cycle studied was a cycle of Microtus voles (field vole M. agrestis and sibling vole M. rossiaemeridionalis) and their small‐sized predators (small mustelids and vole‐eating birds of prey). The numerical responses of both migratory avian predators and small mustelids to changes in vole densities were more alike than different. In late summer (August), the time lag in the numerical response of all main predators was short (0–4 months), whereas longer time lags prevailed from spring to early summer. The length of the time lag in spring appeared to be related to the length of the winter, which indicates that strong seasonality may create longer time lags to the numerical response of predators at northern latitudes than at more southern latitudes. Our results suggest that, from spring to early summer, predation by migratory avian predators may act in concordance with mustelid predation to produce the long time lag necessary to drive the 3‐yr cycle of voles, whereas almost direct density‐dependent predation by all major predators in late summer may dampen spatial variation in prey densities.
Clone diversity ofEiseniella tetraedra(Oligochaeta: Lumbricidae) along regulated and free‐flowing boreal rivers
Authors: Terhivuo Juhani , Lundqvist Elisabeth , Saura Anssi
Published: March 2003

We have sampled populations of the parthenogenetic and polyploid earthwormEiseniella tetraedraalong the Ume, Vindel and Sävar Rivers in northern Sweden. The Vindel River is one of the last free‐flowing large rivers in NW Europe, while the Ume River, which flows parallel to it, is harnessed with twenty major dams. Clones were identified on the basis of overall enzyme phenotypes that were detected using starch gel electrophoresis. We found that clone pool diversity is higher along the Vindel River than along the Ume River and the clone pool similarity is, in a similar fashion, higher along the free‐flowing river. Evidently the dams stop effectively clone dispersal along the Ume River. Clone diversity is highest at the river mouth. The small free‐running Sävar River had also high clone diversity at the lower course of the river. Clone turnover between years is high. We found no evidence for parallel adaptation of clones along the two rivers.
Oral cyclic megadose methylprednisolone therapy for chronic immune thrombocytopenic purpura in childhood
Authors: Özer Esra Arun , Yaprak Işın , Atabay Berna , Türker Meral , Akşit Sadık , Sarıogˇlu Berrak
Published: March 2003

Abstract: The objectives of this study were to investigate the effectiveness of oral megadose methylprednisolone (OMMP) therapy in children with chronic immune thrombocytopenic purpura (ITP). Twenty‐two patients were given oral methylprednisolone daily for 7 d (30 mg/kg for 3 d and then 20 mg/kg for 4 d). OMMP therapy was repeated once per month if the platelet count was less than 20,000/mm3 at the 30th day of therapy, for up to six courses. The number of platelets of all patients increased gradually during the OMMP therapy, with a peak number at the 7th day, then decreased until the 14th day, and remained relatively stable until 12 months. During the study no patient had a platelet count less than 20,000/mm3 at the 3rd day and 50,000/mm3 at the 7th day. Although the number of platelets was gradually decreased between the 7th and 14th days, it remained above 100,000/mm3 for at least 12 months in the nine patients, and above 20,000/mm3 in the four patients. None of these 13 patients required hospitalization or therapy during the follow‐up period. All of the patients tolerated the medication well. None of them reported side‐effects that were severe enough to discontinue therapy. We conclude that OMMP therapy is a safe, easy and effective therapy in children with refractory chronic ITP, and it may provide long‐term remission in about two thirds of the patients.
Complex chromosomal aberrations in chronic lymphocytic leukemia are associated with cellular drug and irradiation resistance
Authors: Koski Tomi , Karhu Ritva , Visakorpi Tapio , Vilpo Leena , Knuutila Sakari , Vilpo Juhani
Published: March 2003

Abstract: Drug resistance is a major problem in chemotherapy of chronic lymphocytic leukemia (CLL). The genetic basis and molecular pathogenesis of drug resistance in CLL remain poorly understood. Here, we have investigated the association between chromosomal aberrations and cellular resistance of CLL cells against seven drugs, gamma and ultraviolet irradiation. Samples were obtained from 35 patients having a classical form of B‐CLL. Chromosomal aberrations were first analyzed by traditional karyotyping improved by using optimized mitogen combinations. DNA sequence copy number changes throughout the genome were next screened by comparative genomic hybridization. Finally, fluorescence in situ hybridization was used to detect trisomy 12 and loss of Rb and deletions at chromosome 11. The cellular sensitivity in vitro was assessed by the reduction of macromolecular protein synthesis measured as incorporation of radioactive l‐leucine as an endpoint. The overall analysis disclosed a statistically highly significant difference in cellular drug resistance between patients having at least three aberrations compared with patients with fewer or no aberrations. This strongly indicates that complex rather than simple molecular mechanisms are responsible for the drug and irradiation resistance in CLL. According to published results, complex aberrations are constantly associated with poor prognosis in CLL. We demonstrated here that complex chromosomal aberrations were associated with cellular irradiation and drug resistance, which, on the other hand, may be responsible for the poor clinical outcome in CLL.
Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia
Authors: Tefferi A. , Jiménez T. , Gray L. A. , Mesa R. A. , Chen M. G.
Published: March 2003

Abstract: Objective: To describe the experience with liver irradiation in advanced cases of myelofibrosis with myeloid metaplasia (MMM). Methods: Over a 20‐yr period, 14 patients with MMM were treated with a total of 25 courses of liver, abdominal, or abdominal and pelvic irradiation for symptomatic hepatomegaly with (5 patients) or without (9 patients) ascites. All 14 patients had advanced disease and 11 (79%) had previous splenectomy. The median radiation therapy (RT) dose per course was 150 cGy (range 50–1000) administered at a median of six fractions. Four patients received two to six courses. Results: Twelve of the 14 patients (86%) had a transient (median 3 months) subjective response from RT. However, in only 35% of these was there a transient (median 3 months) decrease in palpable liver size. Four of the five patients with ascites experienced a short‐term response from RT. Eight of the 13 patients suitable for evaluation (62%) had treatment‐associated cytopenia, often in the form of anemia and/or thrombocytopenia. At last follow‐up, 10 patients (71%) had died after a median of 7 months (range 0.1–23) and 4 were alive at 3, 20, 33, and 57 months after RT. Conclusions: Low‐dose abdominal RT for symptomatic hepatomegaly or ascites associated with advanced‐stage MMM is myelosuppressive and provides only temporary and mainly subjective and short‐lived relief.
Increased circulating platelet–leukocyte aggregates in myeloproliferative disorders is correlated to previous thrombosis, platelet activation and platelet count
Authors: Jensen Morten Krogh , De Nully Brown Peter , Lund Birgit Villadsen , Nielsen Ove Juul , Hasselbalch Hans Carl
Published: March 2003

Abstract: Platelet–leukocyte adhesion may occur as a consequence of platelet activation and possibly plays a key role in the deposition of activated platelets and fibrin in the thrombotic plug. The aim of the present study was to assess by whole blood flow cytometry the presence of circulating platelet–leukocyte aggregates (PLA) and the platelet–leukocyte response to platelet agonist stimulation (ADP and TRAP) in 50 patients with chronic myeloproliferative disorders (MPD) and 30 controls. PLA were identified as platelet–granulocyte/monocyte aggregates (PGMA), platelet–monocyte aggregates (PMA) and defined as the percentage of leukocytes coexpressing the platelet‐specific marker glycoprotein Ib. Compared to controls the mean percentage of PGMA and PMA was increased in unstimulated whole blood from patients with MPD (7.98 vs. 1.76%; p<0.001 and 12.34 vs. 3.2%; p<0.001, respectively). The percentage of PGMA was correlated to the platelet count (r=0.46; p<0.001), percentage of P‐selectin (r=0.69; p<0.001) and thrombospondin (r=0.58; p<0.001) positive platelets and platelet expression of GPIV (r=0.33; p=0.02). The mean percentage of PGMA and PMA was significantly increased in ADP‐stimulated whole blood of patients (57.14 vs. 47.92%; p=0.009 and 54.91 vs. 45.89%; p<0.001, respectively). Compared to patients without a history of thrombosis, patients having experienced microvascular disturbances or a thrombotic event had a higher mean percentage of PGMA and PMA in non‐stimulated whole blood (10.07 vs. 6.34%; p=0.025 and 14.81 vs. 10.48%; p=0.021, respectively) and a higher percentage of PGMA in ADP stimulated whole blood (64.32 vs. 51.50%; p<0.01). These data document an increased frequency of PLA in non‐stimulated whole blood in MPD associated with a previous history of thrombosis or microvascular disturbances.
Platelet‐derived growth factor (PDGF) in human acute myelogenous leukemia: PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by in vitro cultured acute myelogenous leukemia blasts
Authors: Foss Brynjar , Ulvestad Elling , Bruserud Øystein
Published: March 2003

Abstract: We investigated effects of Platelet‐derived growth factor (PDGF) and Platelet factor 4 (PF‐4) on the functional characteristics of native, human acute myelogenous leukemia (AML) blasts. AML blast expression of the PDGF‐receptor α‐chain was detected for a subset of patients (45%), whereas PDGF‐receptor β‐chain expression was detected for most patients (90%). Constitutive AML blast release of the PDGF‐AB isoform (the major form also derived from normal platelets) was detected for 43% of patients, whereas PDGF‐BB release was not detected for any patient. The PDGF isoforms AA, AB and BB had dose‐dependent and divergent effects on spontaneous and cytokine‐dependent AML blast proliferation, whereas for constitutive cytokine secretion (IL‐1β, IL‐6, TNF‐α) inhibitory effects were rare and all three isoforms usually had no effect or enhanced the constitutive secretion. The PDGF effects were caused by a direct effect on the AML blasts and were not dependent on the presence of serum. The PDGF effects could also be detected after in vitro culture of AML cells in the presence of IL‐4+granulocyte‐macrophage colony stimulating factor. PF‐4 had divergent effects on proliferation and cytokine secretion by native AML blasts. Our results suggest that exogenous (e.g. platelet‐secreted) PDGF and PF‐4 can function as regulators of leukemic hematopoiesis and possibly also modulate the function of residual AML cells in peripheral blood stem cell grafts. On the other hand, endogenous release of PDGF‐AB by native blasts may modulate the function of normal cells in the bone marrow microenvironment (e.g. bone marrow stromal cells).
Bone resorption parameters [carboxy‐terminal telopeptide of type‐I collagen (ICTP), amino‐terminal collagen type‐I telopeptide (NTx), and deoxypyridinoline (Dpd)] in MGUS and multiple myeloma
Authors: Jakob Christian , Zavrski Ivana , Heider Ulrike , Brux Brigitte , Eucker Jan , Langelotz Corinna , Sinha Pranav , Possinger Kurt , Sezer Orhan
Published: March 2003

Abstract: Skeletal morbidity is a major problem in multiple myeloma. Histomorphometric studies have demonstrated that increased bone resorption can be present even in the absence of radiographic abnormalities. To overcome diagnostic problems in estimating the activity of bone resorption, new laboratory parameters that reflect bone metabolism accurately are urgently needed. We analyzed three parameters of osteoclastic bone destruction, i.e. deoxypyridinoline (Dpd) and amino‐terminal collagen type‐I telopeptide (NTx) in urine and carboxy‐terminal telopeptide of type‐I collagen (ICTP) in serum, of 75 patients with multiple myeloma (n = 57) or monoclonal gammopathy of undetermined significance (MGUS, n = 18) by ELISA/RIA techniques. Serum ICTP and urinary Dpd levels increased parallel to the stage of the disease and differed significantly (P < 0.001 for ICTP and P = 0.03 for Dpd) between MGUS, myeloma stage I, and myeloma in stages II and III according to Salmon and Durie. ICTP and Dpd were significantly elevated in patients with multiple myeloma in stage I compared to individuals with MGUS, while no significant difference was found for NTx. In this first study comparing the prognostic relevance of ICTP, NTx, and Dpd in multiple myeloma patients, ICTP was found to be a prognostic factor for overall survival in the Kaplan–Meier analysis (log‐rank test: P < 0.03). Urinary NTx showed borderline significance (P = 0.05), and Dpd had no prognostic value in the survival analysis. Our data show that serum ICTP and urinary Dpd levels increase in parallel to advanced disease stages, and gives the first report on a significant difference in the bone resorption parameters ICTP and Dpd between individuals with MGUS and patients with myeloma in stage I. Among the bone resorption parameters studied serum ICTP was found to be the best prognostic factor for survival in multiple myeloma.
Favourable response to antithymocyte or antilymphocyte globulin in low‐risk myelodysplastic syndrome patients with a ‘non‐clonal’ pattern of X‐chromosome inactivation in bone marrow cells
Authors: Aivado M. , Rong A. , Stadler M. , Germing U. , Giagounidis A. , Strupp C. , Novotny J. , Josten K.M. , Kobbe G. , Hildebrandt B. , Gattermann N. , Aul C. , Haas R. , Ganser A.
Published: March 2003

Abstract: Objective
: Antithymocyte and antilymphocyte globulin (ATG/ALG) have a therapeutic effect in about 30% of patients with myelodysplastic syndromes (MDS). We were interested to know whether responding patients achieve clonal or polyclonal remissions.
Patients
: Ten women with low‐risk MDS received either ALG or ATG. Before treatment and 3, 6, and 12 months later, X‐chromosome inactivation patterns of peripheral blood T lymphocytes were compared with those of peripheral blood granulocytes or bone marrow cells, using the human androgen receptor gene assay and the phosphoglycerate kinase‐1 assay.
Results
: Six women did not respond to therapy. Prior to treatment, four of them had a monoclonal, one had an oligoclonal, and one had a skewed X‐chromosome inactivation pattern (XCIP). Four patients responded to ATG/ALG. Three of them were informative in our X‐inactivation assays, and showed a non‐clonal XCIP which did not change significantly after treatment with ATG/ALG.
Conclusion : A non‐clonal XCIP in the bone marrow was associated with a response to ATG/ALG. Non‐clonal XCIPs do not necessarily imply that there is no pathological clone. By definition, they just indicate that there is no evidence of a clone contributing more than 50% of cells in a sample. Non‐clonal XCIPs may therefore be attributable to incomplete clonal expansion. This, in turn, might be explained by a vigorous immune attack against the MDS clone, which simultaneously causes collateral damage in the remaining normal haemopoiesis. In such patients, ATG/ALG may improve normal haemopoiesis by relieving the immunological pressure on the innocent bystanders.
Erythrocytes as targets for gamma‐glutamyltranspeptidase initiated pro‐oxidant reaction
Authors: Aberkane Hayet , Stoltz Jean‐François , Galteau Marie‐Madeleine , Wellman Maria
Published: March 2003

Abstract: Gamma‐glutamyltranspeptidase (GGT) is a well known cell plasma membrane and serum circulating enzyme. In clinical chemistry, GGT is used as a marker of alcohol consumption and drug uptake. Serum GGT activity varies in hepatobiliary diseases and cancer. This enzyme is involved in glutathione (GSH) metabolism, which is generally associated with antioxidant properties. However, in recent years, findings from our group and from others showed that GGT‐catalysed extracellular metabolism of GSH leads, in the presence of iron, to the generation of reactive oxygen species (ROS). It was demonstrated that those highly reactive species oxidise lipids, cell surface protein thiols or activate transcriptional factors such as Nuclear Factor κB (NFκB). The objective of the present work is to determine whether the red blood cells are targets for plasma GGT‐initiated pro‐oxidant reaction. The results obtained demonstrate that the GGT/GSH/iron system oxidises isolated erythrocyte membranes. A significant release of haemoglobin and a decrease of erythrocyte deformability are also observed. In addition, in vivo studies showed a relationship between plasma GGT activity and erythrocyte deformability in 20 studied subjects. In conclusion, GGT‐mediated ROS production is able to oxidise erythrocytes and thus disturbs their functions.
A prospective study of P‐IMVP‐16/CBDCA: a novel salvage chemotherapy for patients with aggressive non‐Hodgkin's lymphoma who had previously received CHOP therapy as first‐line chemotherapy
Authors: Sawada Michio , Tsurumi Hisashi , Yamada Toshiki , Hara Takeshi , Fukuno Kenji , Goto Hideko , Shimizu Masahito , Kasahara Senji , Yoshikawa Takeshi , Kanemura Nobuhiro , Oyama Masami , Takami Tsuyoshi , Moriwaki Hisataka
Published: March 2003

Abstract: The purpose of this study was to determine the efficacy of salvage chemotherapy with, P‐IMVP‐16/CBDCA, consisting of carboplatin (CBDCA), etoposide (VP‐16), ifosfamide (IFM), and methotrexate (MTX), for patients with aggressive non‐Hodgkin's lymphoma (NHL) who had previously received CHOP [a regimen of cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisolone], as first‐line chemotherapy. The 45 consecutively enrolled patients received methylprednisolone (mPSL) 1000 mg per body for 3 d (from day 1 to day 3), IFM 1000 mg/m2for 5 d (from day 1 to day 5), MTX 30 mg/m2on day 3 and day 10, VP‐16 80 mg/m2for 3 d (from day 1 to day 3), and CBDCA 300 mg/m2on day 1, with granulocyte colony‐stimulating factor every 21 d. Patients 70 yr of age or older were given 75% of the standard dose. The response rate [complete response (CR) plus partial response (PR)] was 55.6% (25/45), including 12 (26.7%) CR and 13 (28.9%) PR. The overall survival rate for the 45 patients was 31.1% at 1 yr and 17.3% at 2 yr. The failure‐free survival rate for the 45 patients was 6.7% at 1 yr and 4.4% at 2 yr. The survival rate for the 25 responders was 48.0% at 1 yr and 24.0% at 2 yr, and the survival rate for the 20 non‐responders was 10.0% at 1 yr (P<0.001). Multivariate analysis demonstrated that prior chemotherapy (reduced‐dose CHOP for age 70 yr or older) and the number of cases of extranodal involvement (>1) were significant unfavorable factors for overall survival. Although the major toxicity was neutropenia, no patient died of infection related to neutropenia. Non‐hematological adverse effects were predominantly mild and tolerable. Unfortunately, the clinical outcome with P‐IMVP‐16/CBDCA was unfavorable, possibly because the study comprised consecutive patients who had received identified intensive chemotherapy, such as biweekly CHOP. Salvage chemotherapy with P‐IMVP‐16/CBDCA is not sufficient to cure relapsed or refractory aggressive NHL. Aggressive NHL should be cured by first‐line chemotherapy with or without hematopoietic stem cell transplantation.
Kinetics of stem cell engraftment and clearance of leukaemia cells after allogeneic stem cell transplantation with reduced intensity conditioning in chronic myeloid leukaemia
Authors: Kreuzer Karl‐Anton , Schmidt Christian Andreas , Schetelig Johannes , Held Thomas K. , Thiede Christian , Ehninger Gerhard , Siegert Wolfgang
Published: March 2003

Abstract: It is hypothesised that an effective graft‐vs.‐leukaemia reaction contributes substantially to the therapeutic effect of reduced intensity conditioning stem cell transplantation in chronic myeloid leukaemia. However, kinetic data on eradication of leukaemia cells and stem cell engraftement which could support this assumption are lacking . Thus, we investigated bcr/abl fusion transcripts and haematopoietic chimerism in 14 patients undergoing such a transplantation protocol. Ten of them obtained a complete molecular remission, and two patients achieved haematologic remissions but remained bcr/abl positive. Weekly determinations of bcr/abl transcript numbers by qualitative and quantitative polymerase chain reaction and donor chimerism revealed that 10 responders cleared bcr/abl positive cells from the peripheral blood within a median of 9 wk (range 3–22 wk). The close relation (P = 0.0075) between the firstoccurrence of graft‐vs.‐host disease and the complete clearance ofbcr/abl positive blood cells argues in favour of an effective graft‐vs.‐leukaemia reaction.
Acute megakaryocytic leukemia presenting as hypercalcemia with skeletal lytic lesions
Authors: Muler Jeffrey H. , Valdez Riccardo , Hayes Curtis , Kaminski Mark S.
Published: March 2003

Abstract:  Acute megakaryocytic leukemia (AML M7) is a rare type of acute myelogenous leukemia in adults, commonly presenting with myelofibrosis. This report describes a case of a 32‐yr‐old male who presented with hypercalcemia and bony lytic lesions, in the absence of myelofibrosis. The diagnosis of AML M7 should be considered in a patient with pancytopenia, lytic lesions and hypercalcemia.
Double Ph‐positive megakaryoblastic transformation of chronic myeloid leukemia
Authors: Hirose Yuko , Masaki Yasufumi , Kawabata Hiroshi , Ogawa Noriyoshi , Wano Yuji , Sugai Susumu
Published: March 2003

Abstract: A 64‐yr‐old Japanese man presented with mild anemia, leukocytosis, and thrombocytosis in November 1999. A diagnosis of chronic myeloid leukemia was made with a positive Ph chromosome, and interferon α treatment was started, 6 million units a day. Two years later, in October 2001, the patient developed leukocytosis, an increased LDH level, and large blasts with basophilic cytoplasm with cytoplasmic projections appeared in the peripheral blood. Bone marrow aspiration revealed increased blasts (59.6%). These blasts were negative on peroxidase stain, positive on acid phosphatase, and weakly positive on α naphthyl butyrate esterase stain and periodic acid‐Schiff stain. Immunohistochemical staining with monoclonal antibodies revealed that these blasts were strongly positive with anti‐CD41 (glycoprotein IIb/IIIa), weakly positive with CD7, CD33, and CD34, and negative with other monoclonal antibodies. A diagnosis of megakaryoblastic transformation from chronic myeloid leukemia was therefore made. Two‐color fluorescence in situ hybridization (FISH) for portions of the major‐bcr and abl genes from bone marrow cells revealed two fused signals in 90.6% and one fused signal in 5.8% of 106 cells. A cytogenetic study revealed that bone marrow cells were 69, XYY, +6, −7, +8, −9, t(9;22)(q34;q11), +11, +13, −15, −16, dic(17;18)(p11;p11), −18, +19, +21, der(22)t(9;22) in six of nine examined cells. These findings confirmed that these megakaryoblasts originated from megakaryocytes of the chronic myeloid leukemia clone.
Can t(8;21) oligoblastic leukemia be called a myelodysplastic syndrome?
Authors: Kaneda Kinuyo , Kojima Kensuke , Takeuchi Makoto , Takimoto Hidetaka , Takaba Seiji , Shinagawa Katsuji , Kobayashi Hajime , Miyata Akira , Hara Masamichi , Tanimoto Mitsune
Published: March 2003

Abstract:  The new World Health Organization (WHO) classification of hematologic malignancies has incorporated t(8;21) myelodysplastic syndromes (MDS) according to the French–American–British classification into the category of acute myeloid leukemia (AML) with t(8;21)(q22;q22), while our knowledge about clinicopathological features of t(8;21) oligoblastic leukemia is still limited. We present our experience with 12 patients meeting the FAB diagnostic criteria of MDS and having t(8;21), who were compared to 43 t(8;21) AML patients. The MDS and AML patients shared most hematomorphologic, immunophenotypic, and clinical features, whereas the differences lay along myeloid maturation. The MDS patients had higher percentages of circulating neutrophils and marrow myeloid cells beyond promyelocytes than the AML patients. The incidence of Auer rods in mature neutrophils in MDS was significantly higher than that in AML, and furthermore, the neutrophils in MDS more commonly contain t(8;21) than in AML. Our findings support the rationale for the WHO classification, and future studies on large patient populations should help clarify whether the spontaneous differentiation potential could be actively associated with a hematological manifestation of t(8;21) leukemias.
Band 3 as a marker of erythrocyte changes in pregnancy
Authors: Belo Luís , Rebelo Irene , Castro Elisabeth M.B. , Catarino Cristina , Pereira‐Leite Luís , Quintanilha Alexandre , Santos‐Silva Alice
Published: March 2003

Abstract:  Modifications in the erythrocyte membrane protein band 3 seem to mark the cell for death. A decrease in band 3 high molecular weight aggregates (HMWAg) and a rise in its proteolytic fragments (Pfrag) were described for younger erythrocytes. The aim of this work was to study the band 3 profile as a marker of erythrocyte changes in pregnancy and postpartum. We performed a cross‐sectional study in non‐pregnant controls (n = 24), in women in the first (n = 64), second (n = 48) and third (n = 67) trimesters of gestation, and also in the puerperium (24–48 h after delivery; n = 32); we also carried out a longitudinal study (n = 23) during the three trimesters of normal pregnancy. We evaluated the band 3 profile (% of band 3 monomer, HMWAg, and Pfrag) and the membrane‐bound haemoglobin. Total serum bilirrubin, glutathione peroxidase activity, red blood cell (RBC) count, haematocrit (Ht), haemoglobin (Hb) concentration, the haematimetric indices, and red cell distribution width were also evaluated. Similar results were found in pregnancy in both the cross‐sectional and longitudinal studies. We found that the RBC count, Hb, and Ht decreased significantly in pregnancy and in puerperium. Band 3 profile in the first trimester of pregnancy, when compared with controls, presented significantly reduced HMWAg and increased Pfrag. Comparing the first with the third trimester, we found a significant reduction in band 3 and a significant rise in Pfrag. However, between these same periods, HMWAg did not decrease. Our data suggest band 3 profile as a marker of erythrocyte changes in pregnancy, which are independent of the ‘physiological anaemia’ of pregnancy. These changes suggest an increase in damaged RBCs, but also an increase in younger RBCs in the maternal circulation.
Diaminofluorene stain detects erythroid differentiation in immature haemopoietic cells treated with EPO, IL‐3, SCF, TGFβ1, MIP‐1α and IFNγ
Authors: McGuckin Colin P. , Forraz Nicolas , Liu Wai M.
Published: March 2003

Abstract: We have combined in vitro clonogenic culture and a highly sensitive stain for haemoglobin to compare the influence of EPO, IL‐3, SCF, TGFβ1, MIP‐1α and IFNγ, to directly stimulate cells in the progenitor compartment to develop towards the erythroid lineage. Three cell lines were chosen, as they exist developmentally arrested in the progenitor compartment, yet in a pliant state of maturation. HEL (erythroleukaemia) and K562 (CML‐derived) cell lines, may, under appropriate stimuli, develop erythroid characters, whilst the third, U937 (as control cell line), may be stimulated by DMSO to differentiate to myeloid cells. After in vitro semi‐solid methylcellulose culture with these cytokines, resulting colonies were stained with 2,7‐diaminofluorene (DAF), which sensitively stains haemoglobin blue. Haemoglobin production was low in HEL and K562 cells and absent in U937. Cytokine analysis showed varying levels of influence depending on the starting level of cell line maturation. EPO and TGFβ1 maximally stimulated haemoglobin production in the HEL and K562 cell lines. This differential cytokine stimulation analysis combined with sensitive DAF haemoglobin detection could be applied in the study of many erythropoiesis‐deficient patients or primitive erythropoiesis.
CD95 (APO‐1/FAS) deficiency in infant acute lymphoblastic leukemia: detection of novel soluble Fas splice variants
Authors: Wood Carla M. , Goodman Patricia A. , Vassilev Alexei O. , Uckun Fatih M.
Published: March 2003

Abstract: Fas (APO‐1/CD95) is a 45‐kDa membrane protein which regulates apoptosis in many lymphoid cell types. In the present study, FAS expression was examined in primary leukemic cells from infants with acute lymphoblastic leukemia (ALL). The cells were resistant to apoptosis induction by an anti‐FAS antibody and expressed nearly undetectable amounts of FAS protein. Molecular analysis of FAS transcripts in these cells revealed no detectable expression of full‐length Fas mRNA after a single round of reverse transcription and polymerase chain reaction (PCR) amplification (RT‐PCR). However, a more sensitive nested RT‐PCR analysis revealed alternatively spliced Fas transcripts in three of five infants (60%) with the remaining two infants showing no detectable Fas mRNA expression. The primary sequence variation of Fas mRNA seen in the samples was a previously described variant lacking exon 6 encoding soluble FAS. However, we also detected the presence of several novel alternatively spliced FAS transcripts in the ALL cells. In one patient, we observed a novel spliced form of soluble Fas, which not only lacked exon 6 but also contained an insertion of an alternative exon 7 (exon 7B). In another, a novel exon 4Del FAS mRNA variant was observed, which contained an additional 4‐bp deletion at the exon 5/6‐splice junction. These variants lack intact transmembrane domains and thus are predicted to encode soluble FAS variants. The low level of expression of functional full length FAS transcripts with corresponding low level of FAS protein expression in the ALL cells contribute to their resistance to CD95‐mediated apoptosis.
Early and intermediate stage Hodgkin's lymphoma – report from the Swedish National Care Programme
Authors: Molin Daniel , Enblad Gunilla , Gustavsson Anita , Ekman Tor , Erlanson Martin , Haapaniemi Eva , Glimelius Bengt
Published: March 2003

Abstract: In Sweden a National Care Programme provides treatment principles for Hodgkin's lymphoma (HL) since 1985, for early and intermediate stages often less extensive than international recommendations. The purpose is to evaluate long‐term results of these principles. A total of 308 patients (167 men and 141 women), 17–59 yr old (median 31), diagnosed during 1985–92, pathological stage (PS) I‐III1A and I‐IIB and clinical stage (CS) I‐IIA, mean follow‐up 8.8 yr, were studied. Staging laparotomy was recommended in CS IIA. Recommended treatment was mantle or mini‐mantle radiotherapy (RT) alone in CS IA, and PS I‐IIA and subtotal nodal irradiation in PS III1A if the disease was not bulky. Patients in PS I‐IIA and III1A with bulky disease, and PS I‐IIB received one cycle of mechlorethamine, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, lacarbazine (MOPP/ABVD) before irradiation. The remaining patients received three to four cycles of MOPP/ABVD with RT to bulky disease. Relapse‐free (RFS), Hodgkin specific (HLS), and overall survival (OS) at 10 yr were 74%, 92% and 85%. In the individual stages, RFS ranged from 53% (PSIII1A) to 90% (PS IA). RFS (P  = 0.006), HLS, and OS were significantly better in patients treated with chemotherapy compared with those treated with RT alone, especially in patients with bulky disease (P = 0.0005). The international prognostic score did not provide any prognostic information. The OS rates are in agreement with results from international centres during that time. The recommended treatment was sufficient to produce the desired results of <20–30% recurrences, except in PS III1A. Most relapses could be salvaged. Patients with risk factors treated with one MOPP/ABVD and RT had an excellent outcome, superior to those without risk factors treated with RT alone. These results favour the trend to treat early and intermediate stages with a short course of chemotherapy followed by limited RT.
Longitudinal trends of hemoglobin levels in a Japanese population – RERF's Adult Health Study subjects
Authors: Yamada Michiko , Lennie Wong F. , Suzuki Gen
Published: March 2003

Abstract: Conflicting results have been reported on the long‐term relationship between hemoglobin (Hb) level and age. We analyzed that relationship over a 40‐yr period in a Japanese population, adjusting for the effects of sex, birth cohort, smoking, and anemia‐associated diseases. We used Hb levels measured biennially between 1958 and 1998 for 4858 Adult Health Study subjects of the Radiation Effects Research Foundation. Using the mixed‐effects model, we showed that the aging Hb profile varied by sex (P < 0.001) and birth cohort (P < 0.001). Male Hb levels peaked in the third and fourth decades and then decreased while female Hb levels dipped slightly in the third decade, peaked in the sixth and seventh, and then decreased. Levels were higher in younger cohorts. The rate of Hb decline after the sixth decade of life was greater for subjects with anemia‐associated diseases (P = 0.002). The annual rate of decline between 70 and 80 yr of age for disease‐free men ranged from 0.083 to 0.042 g/dL and for disease‐free women from 0.049 to 0.036 g/dL. Levels were higher for ever‐smokers (P < 0.001), more so for women than men. A decreasing trend in Hb concentration with advancing age was detected for elderly men and women after controlling for anemia‐associated diseases, suggesting that anemia in the elderly is due not only to disease but also to aging. Cohort and smoking effects on Hb levels were also observed.
Mechanisms underlying UV‐induced immune suppression: implications for sunscreen design
Authors: Ullrich Stephen E. , Kripke Margaret L. , Ananthaswamy Honnavara N.
Published: March 2003

Abstract: The ultraviolet (UV) radiation present in sunlight is immune‐suppressive. Recently we showed that solar‐simulated UV radiation (UVA + UVB; 295–400 nm), applied after immunization, suppressed immunological memory and the elicitation of delayed‐type hypersensitivity to the common opportunistic pathogen, Candida albicans. Further, we found that wavelengths in the UVA region of the solar spectrum (320–400 nm), devoid of UVB, were equally effective in activating immune suppression as UVA + UVB radiation. Here we report on the mechanisms involved. No immune suppression was found in UV‐irradiated mice injected with monoclonal anti‐interleukin (IL)‐10 antibody, or mice exposed to solar‐simulated UV radiation and injected with recombinant IL‐12. Antigen‐specific suppressor T cells were found in the spleens of mice exposed to UVA + UVB radiation. Applying liposomes containing bacteriophage T4N5 to the skin of mice exposed to solar‐simulated UVA + UVB radiation or mice exposed to UVA radiation blocked immune suppression, demonstrating an essential role for UV‐induced DNA damage in the suppression of established immune reactions. These findings indicate that UV radiation activates similar immunological pathways to suppress the induction, or the elicitation, of the immune response.
Effects of solar simulated radiation on the human immune system: influence of phototypes and wavebands
Authors: Young Antony R. , Walker Susan L.
Published: March 2003

Abstract: We have shown that skin‐types I/II are much more susceptible to UVR‐induced suppression of the induction phase of contact hypersensitivity than skin‐types III/IV. Studies with a UVB sunscreen have provided indirect evidence that UVA is more immunosuppressive than it is erythemogenic. Overall, our studies show a lack of direct correlation between erythema and immunosuppression.
Immunohistochemical and molecular characterization of cultured keratinocytes after dispase‐mediated detachment from the growth substratum
Authors: Schaefer B. M. , Wallich R. , Schmolke K. , Fink W. , Bechtel M. , Reinartz J. , Kramer M. D.
Published: March 2003

Abstract: Keratinocyte activation comprises changes in protein and gene expression pattern resulting in phenotypic and functional changes necessary for re‐epithelialization such as the expression of urokinase‐type plasminogen activator (uPA) and its cell surface receptor (uPA‐R; CD87). As uPA and uPA‐R are rapidly induced after dispase‐mediated detachment of cultured normal human epidermal keratinocytes (NHEK) we hypothesized that dispase‐mediated detachment may cause a similar “activation” of keratinocytes with uPA and uPA‐R being only one aspect of a complex “activation reaction”. To test this hypothesis we have comparatively analysed adherent versus detached keratinocyte sheets for selected indicators of keratinocyte activation by immunohistochemistry. Furthermore we have identified genes via subtraction cloning which are up‐regulated upon dispase‐induced detachment. The analyses provided evidence for an increased transcriptional and translational activity in detached keratinocytes, as indicated by over‐expression of several ribosomal components (L3 and S10 ribosomal protein) and transcription factors (initiation factor 4A, elongation factor 1α). Increased proliferative activity was indicated by increased expression of the proliferation markers Ki67, keratin 6 and keratin 17. Finally, several markers of keratinocyte activation such as the integrin chain αv, psoriasin, glutathion‐S‐transferase and heparin‐binding epidermal growth factor‐like growth factor were up‐regulated. Furthermore mevalonate kinase, a molecule as yet unknown to be expressed in keratinocytes, was identified. The findings provide evidence that dispase‐mediated detachment in cultured keratinocytes induces a reaction, which comprises the up‐regulation of a complex array of proliferation‐ and migration‐related molecules. The pattern of which resembles the activation reaction observed in the re‐epithelializing keratinocytes in vivo.
Cytokine expression in primary cutaneous germinal center cell lymphomas
Authors: Asadullah K. , Gellrich S. , Haeußler‐Quade A. , Friedrich M. , Döcke W.‐D. , Jahn S. , Sterry W.
Published: March 2003

Abstract: Physiologically, B‐lymphocytes are not present in the skin. Even in pathological situations they rarely occur. In contrast, primary cutaneous B‐cell lymphomas (CBCL) are characterized by proliferation of B lymphocytes within the skin. This suggests the existence of a certain microenvironment supporting homing and expansion of clonal B cells. Cytokines were demonstrated to be involved in the pathogenesis of cutaneous lymphomas of T‐cell origin. Cytokine expression in cutaneous B‐cell lymphoma lesions, however, has not been investigated so far. Therefore, the mRNA level of several cytokines was analyzed in biopsies from 7 patients with CBCL and compared to pleomorphic T‐cell lymphoma (n=6), psoriasis (n=9), and healthy skin (n=7), using a competitive RT‐PCR approach. An overexpression of TNF‐α, IL‐10, and IL‐6 was found. Enhanced IL‐8 mRNA expression was detected in 2/7 cases. The overexpression of IL‐6 and IL‐10 in CBCL might be of particular importance, since these cytokines are considered to support B‐cell growth. Additionally, the overexpression of IL‐10 may contribute to tumor progression since this immunosuppressive cytokine might be involved in downregulation of immunological tumor surveillance, in part by inhibiting type 1 cytokine formation. In fact, we did not detect IFN‐γ and IL‐2 expression. Taken together, we found a cytokine pattern in CBCL lesions which might contribute to tumor B‐cell growth.