bluuebunny/crossref_metadata_2025 huggingface dataset:
The benefits and costs of continuing professional development (CPD) for general dental practice: a discussion
Authors: Belfield C. R. , Morris Z. S. , Bullock A. D. , Frame J. W.
Published: March 2003

This paper sets out the benefits and costs of continuing professional development (CPD) for general dental practice. These considerations are important in evaluating CPD yet they are rarely formally assessed. This paper draws on literature specifically on dentistry but also from across the medical profession and the economics of education and training. First, the costs of CPD are itemised with some suggestions as to how costs may be reduced. Second, the benefits are identified and the (limited) evidence on the value of CPD is surveyed. Finally, reasons why some GDPs might not undertake sufficient or appropriate CPD are explored and the need for guidance for dental practitioners is identified.
Concordance between undergraduate dental students and their lecturers in their attitudes towards difficult patients
Authors: Seoane J. , Varela‐Centelles P. , Guimaraes J. , García‐Pola M. J. , González‐Reforma N. , Walsh T. F.
Published: March 2003

The ‘difficult’ patient syndrome is caused by an imbalance in the dentist–patient relationship which may be influenced by human, cultural and psychosocial factors. The aim of this study was to compare the concordance between undergraduate dental students and lecturers in the degree of difficulty assigned to vignettes describing ‘difficult’ patients and to describe the extent to which ratings are influenced by gender, place of study and experience of specific ‘difficult’ patients. A questionnaire with 21 patient‐stereotypes identified as difficult from the specialized literature was prepared. Both students and lecturers had to determine the degree of difficulty of each stereotype on a Likert‐like scale. The students selected were in the final 2 years before graduation in Santiago de Compostela (Spain) and Porto (Portugal) Dental Schools. Lecturers were selected by simple random sampling method. Both lecturers and undergraduate students found more difficulty in those patients classified as aggressive, manipulative help‐rejecters or patients with invasive companions. On the other hand, drug abusers and HIV‐positive patients were ranked as presenting low levels of difficulty. Our results seem to point to the need of improving undergraduate teaching and learning of specific procedures for the management of aggressive or stubborn patients and those with invasive companions.
Preventive practice of Mongolian dental students
Authors: Tseveenjav Battsetseg , Vehkalahti Miira , Murtomaa Heikki
Published: March 2003

To investigate the preventive practice of Mongolian dental students, in relation to their knowledge of preventive care, self‐perceived competency, oral self‐care, and dental health status, a questionnaire was distributed to all (n = 79) clinical‐year students of The Dental School of the Mongolian National Medical University. Dental students' reported preventive practice was explained by their knowledge of preventive care (P = 0.002) and self‐perceived competency (P = 0.002), whereas their study‐year, oral self‐care, and dental health status, expressed as the Tissue Health Index (THI), remained statistically non‐significant in the linear regression model. This explained 28% of the variation in the parameters examined. In logistic regression analysis, a student's study year (OR = 2.5), knowledge of preventive care (OR = 1.1), and THI (OR = 1.8) were related to their highest scores on preventive practice. Preventive practice among Mongolian dental students could be improved by increasing their knowledge, particularly in modern methods for caries‐prevention such as fluoride, sealants, and xylitol. Preventive methods should be integrated into all topics of the dental curriculum and the learning environment should support such training for future oral health professionals.
Providing support for problem‐based learning in dentistry: the Manchester experience
Authors: Hoad‐Reddick Gillian , Theaker Elizabeth
Published: March 2003

The introduction of problem‐based learning (PBL) into any programme demands a period of adjustment on the part of faculty. Similarly, students new to PBL take time to adapt to what is, for the majority of them, an unfamiliar mode of learning. At Manchester, closed loop PBL is used throughout the first and second years of the dental programme; the method is interdisciplinary; there are no subject boundaries. Dental students work in groups of between 10 and 15, facilitated by a tutor from the Department of Biological Sciences, to research topics and share information in a mutually supportive environment. Each week a different problem forms the focus for learning. In this paper, we seek to describe the measures introduced in response to student feedback collected via routine meetings with the senior tutor, after meetings with their academic or personal tutors and through discussion at the staff students' committee, which we at Manchester have taken to facilitate the process of adaptation to PBL. Changes have been made in the areas of recruitment, pre‐admission interviewing, induction (development of an induction booklet and communication skills module) and tutorial support (overhaul of personal tutor system and introduction of peer‐assisted study (PAS) and personal and academic development programmes (PADPs)). Feedback on these changes, gathered via the routes described above, has been positive and continues to be central to our processes of development in these areas. Although the various ways in which PBL has been implemented worldwide may place limits on the transferability of our methods, this paper serves to illustrate some of the means available to support students in the transition to self‐directed learning. The latter is not only an essential component of PBL but also something we should be seeking to foster in all students, no matter what philosophy and method of course delivery are utilized.
1.2 Cognition and learning
Authors: Falk‐Nilsson Eva , Walmsley Damien , Brennan Mark , Fournier Deborah M. , Junfin Glass Birgit , Haden Karl , Kersten Henk , Neumann Laura , Lian Grace Ong Hui , Petersson Kerstin
Published: March 2003

This theme is concerned with the relevance and efficacy of educational methods adopted in dental schools while recognizing the influence of geopolitical issues in different countries and regions. Particular emphasis will be given to examples of best practices and innovations. Cognition and learning are dealt with in many different research areas such as education, psychology, cognitive sciences, brain research, neurolinguistics, gender, etc. and comprise the theoretical foundation for the philosophies, principles and methods underlying the dental education system. Educational methods are many and mixed. This group has used existing knowledge, personal experiences and current literature together with some of the material from the DentEd visits.
Number of endemic and native plant species in the Galápagos Archipelago in relation to geographical parameters
Authors: Willerslev Eske , Hansen Anders J. , Nielsen Kirstine Klitgaard , Adsersen Henning
Published: March 2003

By simple and multiple regression analyses we investigate updated species numbers of endemic and native vascular plants and seed plants in the Galápagos Archipelago in relation to geographical parameters. We find that the best models to describe species numbers are regression models with log‐transformed species numbers as dependent and log‐transformed modified area (i.e. area not covered with barren lava) as an independent variable. This holds both for total species number, for native species number, for endemic species number and for total number of seed plants as well as number of endemic seed plants. For the ratio between endemic and native species, modified area is also the major significant variable, but with a negative regression slope.  Multiple regression models show that some isolation measures are significant contributors and may explain some of the residual variation, but their contribution to total explained variation is in general small.  The results show that the species area relationships are different for native and endemic species. This is discussed in relation to classical island biogeographical models, and the concepts of radiative speciation.
Population dynamics in Oxalis acetosella: the significance of sexual reproduction in a clonal, cleistogamous forest herb
Authors: Berg Henrik
Published: March 2003

I studied demography in three populations of the clonal, cleistogamous herb Oxalis acetosella during three growing seasons, to assess the impact of seedling recruitment relative to ramet recruitment on its population dynamics. I followed each plant in permanent plots, and stage‐classified it according to origin (sexually or vegetatively derived) and reproductive status. I calculated between‐year transition probabilities, and sexual and vegetative fecundities, and used them in projection matrix analyses to simulate the development of populations and obtain the elasticity of each life‐history event. 

In general, non‐flowering adults was the most numerous stage class and flowering new ramets the rarest, whereas the proportions of the other stage classes varied among populations and years. The negative correlation between plant density and survival was not very strong, and mortality seemed to be largely density‐independent. Simulated population growth rates (λ) indicated that one of the populations is declining and the other two are growing, although slowly. The highest elasticities were usually those of stasis in adult plants, whereas elasticities of other matrix entries were low and highly variable. λ was positively correlated with the elasticities of seedling production and survival but negatively correlated with the elasticity of adult survival, indicating that seedling recruitment is more favourable for population growth than is adult stasis. There were no correlations between λ on the one hand and the elasticities of ramet production and survival on the other. 

The results suggest that recruitment from seedlings is important for the growth and long‐term maintenance of O. acetosella populations, as a complement to the rather low vegetative propagation. In this context cleistogamy is an adaptive strategy, maximizing total seed output.
Supplemental feeding reduces natural selection in juvenile red deer
Authors: Schmidt Karoline T. , Hoi Herbert
Published: March 2003

In red deer, variation in winter and spring weather conditions encountered by the mothers during pregnancy and during the first year of life are a main determinant for individual life‐history as well as population dynamics. We tested the hypothesis that supplementary feeding which provides constant food supply throughout winter removes the selective pressure of winter harshness on nutrition‐mediated phenotypic traits. We analysed cohort variation in body weight in calves in October, before their first winter, and in yearlings in June, after their first winter, in a food‐supplemented population in the Eastern Austrian Alps. Over eleven years, cohort body weight varied between years in calves and yearlings. Contrary to studies on non‐supplemented red deer populations we found neither short‐ nor long‐term effects of winter weather on body weight. In calves, autumn body weight was negatively related to April–May and June temperatures, suggesting that cool weather during the main growth period retarded plant senescence and thereby prolonged the period of high protein content of summer forage. In yearlings, variation in June body weight, shortly after the end of the feeding period, was lower after a wet April–May, suggesting a negative effect of a prolonged period of supplemental feeding. For both calves and yearlings intra‐cohort variation in body weight was higher, inter‐cohort variation was lower as compared to non‐supplemented red deer, suggesting that in their first year of life supplemented red deer are under reduced natural selection pressure.
Temperature and hen harrier productivity: from local mechanisms to geographical patterns
Authors: Redpath S. M. , Arroyo B. E. , Etheridge B. , Leckie F. , Bouwman K. , Thirgood S. J.
Published: March 2003

Climate is an important factor limiting demography and distribution patterns in many organisms. For species with a broad geographical distribution, the mechanism by which climate influences demography is likely to vary dramatically from one end of the range to the other. In this paper we first assess, in a Scottish population of hen harriers Circus cyaneus, how temperature and rainfall influence adult behaviour and chick mortality patterns at the nest. We then test for associations between harrier productivity and weather across Scotland, towards the northern edge of the range, and Spain, towards the southern edge of the range. We show that during the nestling period, female brooding time increased in cold weather. Male provisioning rate was negatively related to temperature and rainfall. Chick mortality increased in cold temperatures and was most likely to occur at nests where male prey delivery rates were low relative to temperature. Annual values of harrier fledged brood size across Scotland were positively related to summer temperature suggesting that the patterns seen in one population held at a national scale. In Spain, however, the opposite patterns were observed with fledged brood size being negatively related to temperature. This shows that whilst the impact of weather on productivity may be equally strong at two ends of a geographical range, the mechanisms vary dramatically. Large‐scale predictive models need to take such patterns into account.
Accounting for spatial pattern when modeling organism‐environment interactions
Authors: Keitt Timothy H. , Bjørnstad Ottar N. , Dixon Philip M. , Citron‐Pousty Steve
Published: March 2003

Statistical models of environment‐abundance relationships may be influenced by spatial autocorrelation in abundance, environmental variables, or both. Failure to account for spatial autocorrelation can lead to incorrect conclusions regarding both the absolute and relative importance of environmental variables as determinants of abundance. We consider several classes of statistical models that are appropriate for modeling environment‐abundance relationships in the presence of spatial autocorrelation, and apply these to three case studies: 1) abundance of voles in relation to habitat characteristics; 2) a plant competition experiment; and 3) abundance of Orbatid mites along environmental gradients. We find that when spatial pattern is accounted for in the modeling process, conclusions about environmental control over abundance can change dramatically. We conclude with five lessons: 1) spatial models are easy to calculate with several of the most common statistical packages; 2) results from spatially‐structured models may point to conclusions radically different from those suggested by a spatially independent model; 3) not all spatial autocorrelation in abundances results from spatial population dynamics; it may also result from abundance associations with environmental variables not included in the model; 4) the different spatial models do have different mechanistic interpretations in terms of ecological processes – thus ecological model selection should take primacy over statistical model selection; 5) the conclusions of the different spatial models are typically fairly similar – making any correction is more important than quibbling about which correction to make.
Identification of a new mutation (Gly420Ser), distal to the active site, that leads to factor XIII deficiency
Authors: Kangsadalampai Sasichai , Yenchitsomanus Pa‐thai , Chelvanayagam Gareth , Sawasdee Nunghathai , Laosombat Vichai , Board Philip
Published: March 2003

Abstract: The molecular defects of the factor XIII A subunit gene were studied in a patient with factor XIII deficiency. Mutation analysis was performed on amplified DNA from each exon of this gene by single‐strand conformation polymorphism (SSCP) and DNA sequencing techniques. A substitution of guanine by adenine at nucleotide 1258 in exon 10 of the coagulation factor XIII A subunit gene has been identified in the patient. The mutation results in the replacement of Gly420 by Ser in the core domain of the enzyme. Restriction enzyme analysis of amplified exon 10 DNA confirmed that the patient was homozygous for this mutation. A family study revealed that the mutation was inherited from both parents, who were first cousins. The potential effects of the mutation were predicted by molecular modeling of the amino acid substitution within the coordinates of the crystal structure. The substitution occurred within the core domain of the enzyme at a residue completely conserved among all known members of the transglutamin‐ase family. The model of the mutant protein suggests that although the substitution of Gly420 by Ser causes only minor readjustment of the residues and does not appear to be particularly deleterious in terms of structure, the mutation is, however, likely to decrease the molecule's ability to undergo the conformational change that is thought to be required for full transglutaminase activity. Our data strongly support the previously published information about the functional significance of the residues surrounding, but not forming, the catalytic pocket in the A subunit of factor XIII.
Alpha‐interferon as induction and maintenance therapy in hairy cell leukemia:a long‐term follow‐up analysis
Authors: Damasio E. E. , Clavio M. , Masoudi B. , Isaza A. , Spriano M. , Rossi E. , Casciaro S. , Cerri R. , Risso M. , Nati S. , Siccardi M. , Truini M. , Gobbi M.
Published: March 2003

Abstract: Although in recent years the use of purine analogues has increased the percentage of long‐term complete response the effect on overall survival of HCL patients is not yet clear. This study aimed to evaluate the long‐term outcome (mean follow up of 92 months) of sixty‐four patients receiving IFN as first‐line therapy. IFN was well tolerated and effective. The overall response rate was 91% (PR 65%, CR 13%, GPR 13%). Forty‐one patients (63%) received IFN 3 MU/wk as maintenance therapy. The 10‐yr projected survival rate of responding patients (CR and GPR 100%; PR 95%) and non responders (SD, PD 80%) clearly shows that type of response does not affect survival. Patients receiving IFN maintenance had a statistically higher PFS than those who did not (p<0.01). This study shows that IFN is still one of the standard therapies for this disease, that achieving CR has no primary relevance for the control of the disease, and that good utilization of therapeutic resources may assure HCL patients a survival rate comparable to that of a normal, healthy population.
Polycythaemia vera: bone marrow histopathology under treatment with interferon, hydroxyurea and busulphan
Authors: Kreft A. , Nolde C. , Büsche G. , Buhr T. , Georgii A.
Published: March 2003

Abstract: Little is known about long‐term effects of myelosuppressive therapy on bone marrow of patients with polycythaemia vera, since histopathology from follow‐up biopsies has not been frequently reported. Thus we conducted a retrospective morphometrical analysis of diagnostic and follow‐up biopsies of 62 patients, evaluating fibre content, megakaryocytes and bone marrow cellularity. 8/62 patients were treated with interferon‐α (INF), 11/62 with hydroxyurea (HU) and 11/62 with busulphan (BU). 32/62 served as controls; they were not treated with myelosuppressive drugs but with phlebotomy only. The median observation time was 2.3 yr. Results were compared on the basis of change per time. The bone marrow of the patients with phlebotomies only was characterised by increasing cellularity of haematopoesis, number and volume ratio of megakaryocytes and fibre content. In BU‐ and HU‐treated patients, the haematopoesis was significantly reduced. The IFN patients revealed a reduction of cellularity, which was not significant. The fibre content was reduced by BU only, but not significantly. No correlation between megakaryocytes and fibres was found. – It could be concluded therefore that: 1) fibre proliferation within the bone marrow was not significantly altered by IFN, HU or BU. 2) Cellularity of haematopoesis was reduced significantly by HU and BU but only partly by IFN, corresponding with haematological remission.
Expression of bcl‐2 and bax in cellsisolated from B‐chronic lymphocytic leukemia patients at differentstages of the disease
Authors: Aviram A. , Rabizadeh E. , Zimra Y. , Yeshoron M. , Marmelstein M. , Shaklai M. , Bairey O.
Published: March 2003

Abstract: B‐Chronic lymphocytic leukemia (B‐CLL) is an example of a human malignancy caused by alterations in the pathways of programmed cell death. In this disease the anti‐apoptotic protein, bcl‐2, is overexpressed and may lead to the prolonged survival of a malignant CLL clone. In the present study we examined the expression of bcl‐2 and bax, which has an antagonistic role against the function of bcl‐2, in cells from CLL patients at different stages of the disease, by immunoblot analysis. A direct association between the stage of the disease and the level of bcl‐2 in the patients' cell, was observed. At stages A and B, 33% and 29% of patients, respectively, expressed high levels of bcl‐2, as opposed to 80% of patients at stage C (p=0.019). Bax level was not significantly associated with the stage of the disease, although patients at stage C had higher levels of bax. In this study we found a trend of association between bcl‐2 and bax levels. Analysis including all patients revealed that 65% of the patients who expressed high levels of bcl‐2 had high levels of bax (p=0.058). Of patients in stage C, 45% expressed high levels of both bcl‐2 and bax while 50% and 42% of patients at stages A and B had low levels of both proteins.
Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia
Authors: Nakano Yasuyuki , Naoe Tomoki , Kiyoi Hitoshi , Kitamura Kunio , Minami Saburo , Miyawaki Shuichi , Asou Norio , Kuriyama Kazutaka , Kusumoto Shuya , Shimazaki Chihiro , Akiyama Hideki , Saito Kenji , Nishimura Miki , Motoji Toshiko , Shinagawa Katsuji , Saito Hidehiko , Ohno Ryuzo
Published: March 2003

Abstract: In acute myeloid leukemia (AML), p53 mutations are reportedly infrequent but associated with a poor prognosis. The majority of mutations are missense mutations, which generally lead to accumulation of nuclear p53 protein. However, the prognostic significance of the accumulation remains unknown in AML. In this study, we compared the prognostic value of p53 mutations versus accumulation of the product. p53 mutations were found in 9 (4.5%) of 200 patients with de novo AML. The p53 mutation detectable (mutation+) group had a worse prognosis (p=0.0009) than the mutation not detectable (mutation−) group. Multivariate analysis showed that the p53 mutation was an independent factor (p=0.005) for short overall survival as well as 60 yr or older (p=0.001) and unfavorable karyotypes (p=0.001). In 79 of the 200 patients, the expression of p53 was studied by immunocytochemistry (ICC) using anti‐p53 monoclonal antibody (DO‐7). All samples carrying missense mutations (N=6) were positive for ICC in over 15% of nuclei of each sample, chosen as the optimized cutoff value of p53 accumulation. Accumulation was thus found in 14 of the 79 patients. However, there was no prognostic difference according to the accumulation, because the mutation−/accumulation+ group (N=8) tended to have a good prognosis. These findings indicate that molecular detection of p53 mutations yields better prognostic information than ICC. In a subset of AML, p53 protein might be accumulated without mutation presumably due to upstream signals of p53.
Triple Philadelphia chromosomes with major‐bcr rearrangement in hypotriploid erythroleukaemia
Authors: Yamamoto Katsuya , Nakamura Yuichi , Arai Honoka , Saito Kenji , Furusawa Shinpei
Published: March 2003

Abstract: The Philadelphia (Ph) chromosome is observed in approximately 1% of patients with acute myeloblastic leukaemia (AML), especially subtypes M1 and M2 in the French–American–British classification. We describe here a cytogenetic and molecular investigation of a rare case with Ph‐positive AML M6 (erythroleukaemia). A 63‐yr‐old woman was diagnosed as having erythroleukaemia. Leukaemic cells were positive for CD4 and CD7 as well as CD13, CD33, CD34 and HLA‐DR. They were analyzed by G‐banding, fluorescence in situ hybridization (FISH), Southern blot and reverse transcriptase polymerase chain reaction analyses. The karyotypes at diagnosis were as follows: 61, XX, −X, −1, −2, −3, −4, −5, −7, t(9;22)(q34;q11)×2, −15, −16, −17, −18, +19, +21, +22 [3]/61, idem, −22, +der(22)t(9;22) [36]. FISH with BCR/ABL probes showed that 39% and 57% of interphase nuclei had double and triple BCR/ABL fusion signals, respectively. Chromosome analysis in complete remission showed a normal karyotype in all 20 metaphases, confirming the diagnosis as Ph positive‐acute leukaemia. FISH at relapse showed that 92% of interphase nuclei had triple fusion signals. Rearrangement of major breakpoint cluster region (M‐bcr) in the BCR gene and coexpression of p210‐type (b2a2) and p190‐type (e1a2) BCR/ABL fusion transcripts due to alternative splicing were also detected. We conclude that clonal evolution from double to triple Ph chromosomes may be implicated in the disease progression. Considering other two reported cases, Ph‐positive erythro‐leukaemia appears to be correlated with coexpression of myeloid/T‐lymphoid markers and hyperdiploidy with double or triple Ph chromosomes, although breakpoints in the BCR gene are heterogenous.
Autoerythrocyte sensitization(Gardner–Diamond) syndrome
Authors: Uthman Imad W. , Moukarbel George V. , Salman Salah M. , Salem Ziad M. , Taher Ali T. , Khalil Ismail M.
Published: March 2003

Abstract: We describe the clinical presentation and course of a patient with autoerythrocyte sensitization (Gardner–Diamond) syndrome, and review the literature for similar cases. A 37‐yr‐old female presented with recurrent episodes of painful ecchymotic bruising over the anterior aspect of both thighs. These episodes were precipitated by emotional stress. The diagnosis was confirmed by induction of similar lesions by intradermal injection of the patient's own washed red blood cells and hemoglobin. The lesions did not recur for 6 months after the cause of her emotional stress was relieved. Autoerythrocyte sensitization (Gardner–Diamond) syndrome should be considered in the differential diagnosis of purpura, especially in patients with psychiatric problems.
Treatment of the myeloproliferative disorders with 32P
Authors: Berlin Nathaniel I.
Published: March 2003

Abstract: The use of radioactive phosphorus (32P) to treat the myeloproliferative disorders (chronic leukemia, polycythemia vera and essential thrombocythemia) began in 1939 when John H. Lawrence treated the first patient on the basis of work done in the laboratory anima that found localization of the radioisotope in the spleen, liver, bone and in leukemic cells sufficient to indicate a therapeutic potential. After World War II when 32P became widely available, it was used extensively to treat the chronic leukemias and polycythemia vera. Its use in the treatment of essential thrombocythemia began later in 1950. Today it is not widely used in the treatment of the chronic leukemia, if at all, its use in polycythemia vera appears to have decreased substantially and replaced by hydroxyurea, and its use in the management of essential thrombocythemia is not widespread. In each instance it has been replaced by a drug developed for use in cancer chemotherapy, and in some instances by interferon. It probably has wider use in polycythemia vera in the rest of Western Europe than in the UK, and there are cogent reasons to suggest that it may be the best tool for the treatment of polycythemia vera. Thus have we discarded a treatment modality that in polycythemia vera may be the best?
Novel therapeutic targets in multiple myeloma
Authors: Davies Faith E. , Anderson Kenneth C.
Published: March 2003

Abstract: Multiple myeloma remains an incurable disease, and a new perspective on the approach to therapy is required. The aim of this review is to focus on a number of key areas where recent advances in the biology of the disease have not only yielded an understanding of the disease pathogenesis but have also suggested novel treatment approaches. Factors mediating myeloma cell growth, survival and the complex interaction of myeloma cells with the bone marrowmicroenvironment have provided a framework for the rational design of therapeutic agents. The development of such biologically based treatments which target both the tumour cell and the microenvironment, in order to achieve more complete and selective eradication of myeloma cells and the maintenance of minimal residual disease states, may ultimately lead to improved disease‐free survivial and potentially a cure.
Persistent paraneoplastic neurologic syndrome after successful therapy of Hodgkin's disease
Authors: Maslovsky I. , Volchek L. , Blumental R. , Ducach A. , Lugassy G.
Published: March 2003

Abstract: Paraneoplastic neurologic syndromes may develop in Hodgkin's disease (HD). We describe three young female patients with neurological disorders, not explained by other causes, preceding diagnosis or relapse of HD. The lack of response of the paraneoplastic syndrome to successful treatment of HD among our three patients emphasizes the poor prognosis of longstanding paraneoplastic neurologic symptoms in HD.
Comparison of vincristine, carmustine, melphalan, cyclophosphamide, prednisone (VBMCP) and interferon‐α with melphalan and prednisone (MP) and interferon‐α (IFN‐α) in patients with good‐prognosis multiple myeloma: a prospective randomized study
Authors: Zervas K. , Pouli A. , Gregoraki B. , Anagnostopoulos N. , Dimopoulos M. A. , Bourantas K. , Tzilianos M. , Barbarousi D. , Venetis E. , Vyniou N. , Maniatis A. ,   the Greek Myeloma Study Group
Published: March 2003

Abstract: Objectives: The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan–prednisone, plus interferon in both arms. Methods: Eighty‐nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon‐α (rIFN‐α) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN‐α. The two treatment groups were comparable in terms of pretreatment characteristics. Results: The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN‐α group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN‐α group (p=0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN‐α group and was not reached in the VBMCP/IFN‐α group (p=0.6). Overall survival was long in both treatment groups. The estimated 5‐yr survival was 66% and 62% in the MP/IFN‐α and VBMCP/IFN‐α group, respectively (p=0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN‐α group. Conclusions: The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon‐α has no advantage over conventional MP plus interferon‐α, in regard to response rate, response duration, and overall survival of patients.
An ethnic role for chronic, but not acute, graft‐versus‐host disease after HLA‐identical sibling stem cell transplantation
Authors: Remberger Mats , Aschan Johan , Lönnqvist Berit , Carlens Stefan , Gustafsson Britt , Hentschke Patrik , Klaesson Sven , Mattsson Jonas , Winiarski Jacek , Ljungman Per , Ringdén Olle
Published: March 2003

Abstract: Among 424 HLA identical siblings undergoing stem cell transplantation, 364 were Scandinavians and 60 represented other ethnic groups. The cumulative probabilities of acute graft‐versus‐host disease grades II–IV were similar in both groups, 17% in Scandinavians and 12% in the others,p=0.4. In a multivariate analysis, less effective immune suppression with cyclosporine or methotrexate alone (p=0.001), recipient seropositive for three to four herpes viruses (p=0.004), CMV‐seropositive recipient (p=0.05) and early engraftment (before day 15) (p=0.05) were independent risk‐factors for acute GVHD grades II–IV. The cumulative probabilities of chronic GVHD were 47% and 68% in the two ethnic populations, respectively (p=0.004). In multivariate analysis, higher patient age (p<0.001), non‐Scandinavian population (p<0.001) and immunised female donor to male recipient (p=0.03) were independent risk factors for chronic GVHD. The higher incidence of chronic GVHD could not be explained by differences in HLA antigen frequencies. The cumulative probabilities of relapse were 37% in the both groups. This suggests that the Scandinavian population is more homogeneous with regard to minor histocompatibility antigens important for chronic, but not acute GVHD.
A high serum‐soluble interleukin‐2 receptor level is associated with a poor outcome of aggressive non‐Hodgkin's lymphoma
Authors: Niitsu Nozomi , Iijima Kimiko , Chizuka Aki
Published: March 2003

Abstract: Soluble interleukin‐2 receptor (sIL‐2R) is produced by activated T and B cells, and the level of this receptor is elevated in patients with non‐Hodgkin's lymphoma (NHL). The present study demonstrated that the sIL‐2R level was high in the following groups of patients with aggressive NHL; those aged 60 yr, those with a poor PS, those in Ann Arbor stage III or IV, and those in the high–intermediate or high risk group according to the International Prognostic Index (IPI). Overall survival was significantly poorer when the sIL‐2R level was 2000 U/ml or more. In addition, the overall survival of patients in the low (L) and low–intermediate (L–I) risk groups with an sIL‐2R level of 3000 U/ml or more was significantly poorer, suggesting that the sIL‐2R level could be particularly useful for identifying patients with a poor prognosis among the L and L–I risk groups. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors plus the five IPI prognostic factors showed that the sIL‐2R level was an independent prognostic indicator. In conclusion, the present findings established that the sIL‐2R level is a significant independent prognostic factor in patients with aggressive NHL.
Relative increase of granulocytes with a paroxysmal nocturnal haemoglobinuria phenotype in aplastic anaemia patients:  the high prevalence at diagnosis
Authors: Wang Hongbo , Chuhjo Tatsuya , Yamazaki Hirohito , Shiobara Shintaro , Teramura Masanao , Mizoguchi Hideaki , Nakao Shinji
Published: March 2003

Abstract: To clarify the pathologic significance of granulocytes exhibiting the paroxysmal nocturnal haemoglobinuria (PNH) phenotype in patients with aplastic anaemia (AA), we examined peripheral blood from 100 patients with AA for the presence of granulocytes deficient in glycosylphosphatidylinositol (GPI)‐anchored proteins using a sensitive flow cytometric assay. A significant increase in the frequency of CD55−CD59−CD11b+ granulocytes (>0.003%) compared to normal individuals was observed in 31 of 35 (88.6%) patients with untreated AA at diagnosis. The proportions of patients showing increased PNH granulocytes in treated AA patients with a short (<5 yr) and long (>5 yr) disease duration were 68.6% (11/16) and 20.4% (10/49), respectively. When 19 patients showing increased frequency of PNH granulocytes before therapy were studied 6–12 months after antithymocyte globulin plus cyclosporin A therapy, the frequency decreased to 0.01–90% of pretreatment values in 15 recovering patients. These findings suggest that a relative increase in the number of PNH granulocytes is a common feature of AA at diagnosis, and that it may represent the presence of immunologic pressure to normal haematopoietic stem cells as a cause of AA.
Molecular characterization of (δβ)°/β°‐thalassemia and (δβ)°‐thalassemia/hemoglobin E in Thai patients
Authors: Fucharoen Supan , Pengjam Yutthana , Surapot Satja , Fucharoen Goonnapa , Sanchaisuriya Kanokwan
Published: March 2003

Two cases of the Thai thalassemia patients with compound heterozygosities for (δβ)°/β°‐thalassemia and (δβ)°‐thalassemia/hemoglobin E have been reported. The first case was a 8‐yr‐old boy who had the following hematologic data: Hb 6.5 g/dL, Hct 20.5%, MCV 70.4 fL, MCH 22.3 pg and MCHC 31.7 g/dL. Hemoglobin analysis revealed 1.9% hemoglobin A2 and 91.7% hemoglobin F. The second case, with Hb 13.9 g/dL, Hct 41.5%, MCV 69.5 fL, MCH 22.5 pg and MCHC 32.2 g/dL, was a 16‐yr‐old male who had 46.1% hemoglobin E and 49.8% hemoglobin F. Globin gene analyses showed that both probands carried the same deletional type (δβ)°‐thalassemia trans to the 4 bp deletions in codons 41/42 β°‐thalassemia and to the βE‐globin gene, respectively. Polymerase chain reaction and DNA sequence analyses demonstrated that the 5′ breakpoint of the (δβ)°‐thalassemia deletion was located in the second intron of the δ‐globin gene and that the 3′ breakpoint lay within a cluster of LI repetitive sequences at 4.7 kb 3′ to the β‐globin gene.
Plasmablastic lymphoma in a patient with chronic lymphocytic leukemia heavily pretreated with cladribine (2‐CdA): an unusual variant of Richter's syndrome
Authors: Robak T. , Urbańska‐Ryś H. , Strzelecka B. , Krykowski E. , Bartkowiak J. , B oński J. Z. , Kordek R. , Warzocha K.
Published: March 2003

Abstract: Patients with chronic lymphocytic leukemia (CLL) may develop a large‐cell transformation known as Richter's syndrome (RS). RS usually presents as diffuse large‐cell lymphoma (DLCL) or its immunoblastic variant, and it can be recognized simultaneously with CLL or even 23 yr after its diagnosis. We describe an unusual case of CLL treated with cladribine (2‐CdA) in whom DLCL of the plasmablastic type (PBL) developed 4 yr after CLL (Rai IV) diagnosis and 1.5 yr after the 10th course of 2‐CdA treatment. Immmunologic, cytogenetic, and molecular studies performed at the time of CLL and PBL coappearence indicated that both tumors originated from different B‐cell progenitors. Both malignancies were refractory to VAD (vincristine, doxorubicin, dexamethasone)‐based chemotherapy, and only partial response was achieved with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) salvage treatment. However, the patient died 6 months after the occurrence of RS due to rapid progression of PBL. This is the first description of a CLL patient who developed an unusual plasmablastic variant of RS. Recently, the PBL entity has been identified among DLCL associated with the human immunodeficiency virus (HIV) infection. We suggest that in our CLL patient heavily pretreated with 2‐CdA, PBL arose as a second clone due to the prolonged and severe state of the host's immunosuppression. Overall survival with current strategies is poor, and further insight into the natural history, biology, and treatment of PBL are needed.
Study of cord blood natural killer cell suppressor activity
Authors: El Marsafy S. , Dosquet C. , Coudert M‐C. , Bensussan A. , Carosella E. , Gluckman E.
Published: March 2003

Abstract: We tested the immunosuppressive effect of cord blood (CB) natural killer (NK) cells using highly purified CB NK cells in mixed lymphocyte cultures (MLC) containing autologous CB T cells as responders. Control cultures were done without NK cells. Our findings revealed that CB NK cells induced a dose‐dependent inhibition of T lymphocyte proliferation as evidenced by decreased 3H‐thymidine incorporation in MLC. The T cell alloproliferation was significantly decreased in the presence of an NK cell to responder cell ratio of 0.1, 0.2 or 0.4 compared with control cultures done without NK cells (p=0.02, 0.003 and 0.0002, respectively). T lymphocyte inhibition was also achieved using irradiated CB NK cells and still demonstrable on addition of disparate CB NK and T cells to the MLC.

In agreement with previous reports, adult blood NK cells inhibited the alloreactive T cells in the MLC using adult T lymphocytes as responders. Compared to control cultures done without NK cells, statistically significant inhibition of 3H‐thymidine incorporation in MLC was observed at a ratio of NK cells to responder cells ratio of 0.2 or 0.4 (p=0.02).

To investigate the mechanism whereby CB NK cells can interfere with the development of alloreactive T cells in MLC, we measured the tumour necrosis factor‐α (TNF‐α) concentrations in MLC supernatants using NK cell‐depleted or unseparated CB mononuclear cells (MNC) as responders. The results revealed significantly high levels of TNF‐α in the absence of NK cells (p=0.007). We conclude that CB NK cells suppress alloreactive T lymphocytes as do their counterparts in adult blood. However, the high NK to T cell ratio in CB could contribute to a more marked suppressive potential compared to that in adult blood. The mechanism of NK‐mediated inhibition is likely related to disruption of the TNF‐α pathway of T‐lymphocyte activation.
Changes in murine bone marrow macrophages and erythroid burst‐forming cells following the intravenous injection of liposome‐encapsulated dichloromethylene diphosphonate (Cl2MDP)
Authors: Giuliani A. L. , Wiener E. , Lee M. J. , Brown I. N. , Berti G. , Wickramasinghe S. N.
Published: March 2003

Abstract: In order to explore the effect on bone marrow macrophages of liposome‐encapsulated dichloromethylene diphosphonate (Cl2MDP), mice were injected intravenously with a preparation of such liposomes at a dose known to deplete spleen and liver macrophages. Two days later, the macrophages in the marrow of the femoral bones were quantified by flow cytometry using a macrophage‐specific monoclonal antibody (F4/80), and their ultrastructure and phagocytic activity towards zymosan particles was assessed. To determine the effect on erythropoiesis of liposome‐encapsulated Cl2MDP‐induced changes in bone marrow macrophages, red blood cell parameters and the formation of erythroid burst‐forming unit (BFU‐E)‐derived colonies in vitro were evaluated. In mice injected with liposome‐encapsulated Cl2MDP, there was a 54% and 67% decrease in the total number of bone marrow macrophages as compared to uninjected controls and mice treated with empty liposomes, respectively. Moreover, residual macrophages showed an abnormal ultrastructure, with reduced numbers of crystalloid inclusions and increased numbers of large myelin figures. However, the phagocytic activity of these cells was unimpaired or slightly enhanced. In mice injected with liposome‐encapsulated Cl2MDP there was an approximately 60% decrease in the percentage and total number of circulating reticulocytes and a 54% reduction in the BFU‐E number, demonstrating deregulation of erythropoiesis under conditions of macrophage loss and impairment. The results suggest that mice treated with liposome‐encapsulated Cl2MDP are a model for studying the role of macrophages in erythropoiesis.
Modulation of CD44 in acute lymphoblastic leukemia identifies functional and phenotypic differences of human B cell precursors
Authors: Zittermann Sandra I. , Achino Bibiana I. , Agriello Evangelina E. , Halperín Nora , Ramhorst Rosanna E. , Fainboim Leonardo
Published: March 2003

Abstract: CD44 expression and other B cell markers were analyzed in 38 samples of B cell precursors (BCP) from patients with acute lymphoblastic leukemia (ALL). According to the expression of CD10 and CD44, we established the following five stages of BCP‐ALL phenotypes that may represent different forms of interaction between BCP‐ALL and bone marrow‐adherent cells: stage 1, CD19+, CD44bright, CD10−; stage 2, CD19+, CD44bright, CD10dim/bright; stage 3, CD19+, CD44dim, CD10bright, CD20−/+; stage 4, CD19+, CD44dim, CD10dim, CD20+; and stage 5, CD19+, CD44bright, CD10−, CD20+. Next, we analyzed the modulation of CD44 according to the expression of the different BCP‐ALL phenotypes by incubating the samples under different culture conditions, including addition of stromal cells and interleukin (IL)‐7. In culture, the samples in stages 1 and 2 maintained high expression of CD44 and re‐expressed this molecule when cultured after trypsin treatment, indicating ongoing synthesis of CD44. Similarly, the stage 3 samples cultured in the presence of stromal cells, IL‐7, or both also upregulated CD44 expression in culture. In contrast, the low expression of CD44 on the presumably more mature stage 4 samples was not modified by the addition of stromal cells or IL‐7 or when cultured after trypsin treatment, suggesting that those cells had arrested CD44 synthesis. We concluded that down‐modulation of CD44 occurred in association with differentiation to phenotype stages 3 and 4 and we hypothesized that this down‐modulation might be associated with the exit of BCP‐ALL from the bone marrow.
Cutaneous pleomorphic T‐cell lymphoma coexisting with myelodysplastic syndrome transforming into acute myeloid leukemia: successful treatment with a fludarabine‐containing regimen
Authors: Breccia Massimo , Petti Maria Concetta , D'Elia Gianna Maria , D'Andrea Mariella , Carmosino Ida , Alimena Giuliana
Published: March 2003

Abstract: The coexistence of a primary myelodysplastic syndrome (MDS) and a T‐cell cutaneous non‐Hodgkin's lymphoma is an extremely rare event, which has so far only been reported in a single instance in the literature. We describe herein an additional case in which the lymphoid disease was combined with an MDS at the time of its evolution into acute myeloid leukemia (AML). Both diseases were successfully treated with a regimen containing fludarabine. We discuss possible pathogenetic mechanisms and suggest the use of nonalkylating drugs, such as fludarabine, for the treatment of this rare association of malignancies usually characterized by a very poor response to therapy.
Modulation of platelet caspases and life‐span by anti‐platelet antibodies in mice
Authors: Piguet Pierre F. , Vesin Christian
Published: March 2003

Abstract: Anti‐platelet antibodies are known to contribute to some types of thrombocytopenia. In this work we investigated anti‐platelet antibodies with opposite influence upon activation and kinetics of platelet caspases. A rabbit anti‐platelet antibody induced a profound thrombocytopenia, which was associated with an increase of microparticles in plasma and an activation of platelet caspases, as detected by the binding of a carboxyfluorescein‐labeled fluoromethyl ketone probe (FAM‐VAD‐fmk). Furthermore, microparticles and thrombocytopenia were prevented by the injection of a caspase inhibitor ZVAD‐fmk. In contrast, an anti‐CD18 mAb (M18.2) induced a thrombocytosis, due to an increased platelet life‐span and which was evident in wild‐type (+/+), but not in CD18−/− or CD87−/−, mice indicating a requirement of these two surface molecules. Activation of caspases was decreased in platelets from mice injected with the M 18.2 mAb, as evidenced by a decreased binding of the VAD probe, detected by flow cytometry, or an increase in the level of pro‐caspase‐3, seen on Western blots. These observations indicate firstly, that anti‐platelet antibodies can either promote or inhibit activation of platelet caspases, and secondly, that the activation of caspases regulates platelet life‐span.