bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of the histiocytic marker PG‐M1 in granuloma annulare and rheumatoid nodules of the skin
Authors: Groisman Gabriel M. , Schafer Ion , Amar Mary , Sabo Edmond
Published: March 2003

Background:  The expression of PG‐M1, the most specific histiocytic marker, has not yet been studied in granuloma annulare (GA) and other palisaded granulomas of the skin. We evaluated the reactivity of PG‐M1 with a series of GA and rheumatoid nodules (RN) to establish the sensitivity and potential usefulness of this marker in the diagnosis and characterization of these entities.

Methods:  Histological sections from 30 GA and 15 RN were immunostained with PG‐M1. For comparison, additional sections were stained with KP‐1 and lysozyme. The stains were recorded as negative, weakly positive (1+) and strongly positive (2+).

Results:  PG‐M1 stained all cases of GA (100%). KP‐1 and lysozyme stained 26 (86%) and 18 (60%) GA cases, respectively. PG‐M1 exhibited a significantly stronger staining intensity (1.8 ± 0.07) when compared with KP‐1 (1.4 ± 0.13) (p = 0.018) and with lysozyme (0.9 ± 0.15) (p < 0.0001). All RN were stained by PG‐M1 (100%). KP‐1 and lysozyme stained 14 (93%) and six (40%) RN cases, respectively. PG‐M1 staining intensity (1.6 ± 0.13) was slightly higher than that of KP‐1 (1.4 ± 0.18) (p = 0.27) and significantly higher than that of lysozyme (0.4 ± 0.13) (p < 0.0001).

Conclusions:  PG‐M1 is consistently and strongly expressed by the histiocytic population of GA and RN, being more sensitive and reliable than other histiocytic markers. We recommend its use in difficult cases in which the histiocytic nature of the lesion needs to be confirmed.
Distance learning in academic health education
Authors: Mattheos Nikos , Schittek Martin , Attström Rolf , Lyon H. C.
Published: March 2003

Distance learning is an apparent alternative to traditional methods in education of health care professionals. Non‐interactive distance learning, interactive courses and virtual learning environments exist as three different generations in distance learning, each with unique methodologies, strengths and potential. Different methodologies have been recommended for distance learning, varying from a didactic approach to a problem‐based learning procedure. Accreditation, teamwork and personal contact between the tutors and the students during a course provided by distance learning are recommended as motivating factors in order to enhance the effectiveness of the learning. Numerous assessment methods for distance learning courses have been proposed. However, few studies report adequate tests for the effectiveness of the distance‐learning environment. Available information indicates that distance learning may significantly decrease the cost of academic health education at all levels. Furthermore, such courses can provide education to students and professionals not accessible by traditional methods. Distance learning applications still lack the support of a solid theoretical framework and are only evaluated to a limited extent. Cases reported so far tend to present enthusiastic results, while more carefully‐controlled studies suggest a cautious attitude towards distance learning. There is a vital need for research evidence to identify the factors of importance and variables involved in distance learning. The effectiveness of distance learning courses, especially in relation to traditional teaching methods, must therefore be further investigated.
Orthodontic undergraduate education: developments in a modern curriculum
Authors: Chadwick Stephen M. , Bearn David R. , Jack Alan C. , O'Brien Kevin D.
Published: March 2003

This paper explores some modern concepts of teaching and learning, including cognitive theory, the zone of proximal development, constructivism, andragogy and learning styles and describes how they have informed the development of an undergraduate orthodontic curriculum. The changes described include student‐centred learning, guided self‐learning, and the incorporation of problem‐based learning concepts. The details of the problem‐based learning programme are described together with results of student feedback on the change in teaching and learning style.
Habitat use by beech martens in a fragmented landscape
Authors: Rondinini Carlo , Boitani Luigi
Published: March 2003

We investigated key habitat features used by beech martens occupying a fragmented agricultural landscape. Locations of eight martens were radio‐monitored daily for 4–12 months each. We evaluated the selection of home ranges within a geographic area, as well as the selection of habitat features within home ranges, using random simulations for comparison. Home ranges included more wood and scrub vegetation, and less arable land, than random simulations. They also included a higher proportion of watercourses with continuous vegetation along their verges, and were closer to these watercourses than random simulations. Within home ranges, beech martens used wood and scrub vegetation, and farm buildings, more intensively than expected, and arable land less than expected. On average, beech martens stayed close to watercourses (where most of the wood vegetation occurred) but not to farm buildings, indicating that only the former shaped beech marten movements. By these findings, arable land appeared to act as a seldom traversed barrier, making farm buildings uneasy to reach if they are located far from watercourses.
Internal structure and patterns of contraction in the geographic range of the Iberian lynx
Authors: Rodríguez Alejandro , Delibes Miguel
Published: March 2003

We use reports obtained in a field survey to characterize the internal structure, and to reconstruct the strong contraction in the geographic range of the Iberian lynxLynx pardinusduring a 35‐yr period. Lynx were distributed in one large central population surrounded by smaller peripheral ones. Abundance was autocorrelated, attained high values only in a few scattered sites mostly within the central population, and increased from west to east along major mountain chains. Abundance and occupancy were positively related. The strength of range contraction was similar in both large and small populations. We were able to date two peaks of local extinction, which were accompanied by many events of population fragmentation. We also identified five areas where local extinctions aggregated in space. Lynx relative abundance appeared to be site‐specific, and the probability of local extinction decreased with increasing abundance. We suggest that sublethal deterministic factors operating with similar intensity all over the range, rather than in progression from a focal point, best explain the observed trajectory of contraction. Two factors that meet such characteristics may have had an outstanding role in lynx decline. One of them is myxomatosis, an introduced viral disease that decimated rabbitsOryctolagus cuniculus, the staple prey of the lynx. The other is related to the changes in land use prompted by extensive human emigration from the countryside 40 yr ago. Other stochastic or superimposed deterministic factors may have accounted for regional aggregation of local extinctions. The identification of these factors is very important to reverse the lasting decline of this endangered felid.
Long‐term satellite telemetry of the movements and habitat utilisation by green turtles in the Mediterranean
Authors: Godley B. J. , Richardson S. , Broderick A. C. , Coyne M. S. , Glen F. , Hays G. C.
Published: March 2003

There is a relative paucity of data regarding the at‐sea distribution and behaviour of marine turtles. This is especially true for the critically endangered green turtle Chelonia mydas population in the Mediterranean. Six adult female green turtles were equipped with satellite transmitters and tracked for periods of between 28 and 293 d following their final nesting of the season in northern Cyprus. Data elucidated hitherto unknown migratory pathways and highlighted the importance of North African coastal waters as feeding habitat for adults of this species. For three individuals, instruments transmitted detailed information on dive depth, dive duration and water temperature which afforded novel insights into behaviour during different stages of migration, feeding in the foraging grounds and most remarkably, during a period of midwinter diapause when water temperatures were generally below 25°C. Turtles showed fidelity to specific shallow inshore feeding areas and moved offshore to deeper wintering sites.
The influence of scale and patchiness on spider diversity in a semi‐arid environment
Authors: Whitehouse Mary E. A. , Shochat Eyal , Shachak Moshe , Lubin Yael
Published: March 2003

Semi‐arid scrubland in the Middle East consists of a soil crust matrix overlain with patches of perennial shrubs. To understand factors influencing biodiversity in this vulnerable landscape we need to understand how this mosaic of habitats influences associated fauna. Spiders are particularly abundant in this habitat so we asked if spider diversity differed between habitat patches and if different patch types contained either a subset of the regional species pool or specific species guilds. We also asked whether changes in the fractal nature of the microphytic and macrophytic patch mosaic altered spider diversity in this habitat. We found that the semi‐arid scrubland at Sayeret Shaked Park (Israel) contains different spider communities that require patches of a certain quality to develop fully. Different patch types contain communities of different species, but the community structure of the patches is similar. We suggest that large‐scale environmental factors typical of the site as a whole influence coarse‐grained community structure, while small‐scale differences between patch types result in the specialisation of species to different patch types.
Characteristics of dispersing Ischnura elegans and Coenagrion puella (Odonata): age, sex, size, morph and ectoparasitism
Authors: Conrad Kelvin F. , Willson Karen H. , Whitfield Katherine , Harvey Ian F. , Thomas Chris J. , Sherratt Thomas N.
Published: March 2003

In this study we assessed whether individuals of the damselfly species Ischnura elegans and Coenagrion puella that moved between ponds differed in their mean characteristics from individuals that did not move. Overall, the sex (female) and species (C. puella) that spent the most time away from the breeding site was more likely to move between ponds. Ischnura elegans males that dispersed had significantly longer forewings than males that did not, while male C. puella parasitised by water mites were more likely to disperse than unparasitised males. There was no evidence for differences in dispersal rates among the female colour forms of either I. elegans or C. puella. In general, the differences in dispersal characteristics between sexes and species could be explained by underlying variation in activity and mobility. The majority of dispersal between breeding sites by C. puella and I. elegans did not appear to be directed, but probably arose from chance movements occasionally taking individuals to a different pond from which they emerged.
A balanced view of scale in spatial statistical analysis
Authors: Dungan J. L. , Perry J. N. , Dale M. R. T. , Legendre P. , Citron‐Pousty S. , Fortin M.‐J. , Jakomulska A. , Miriti M. , Rosenberg M. S.
Published: March 2003

Concepts of spatial scale, such as extent, grain, resolution, range, footprint, support and cartographic ratio are not interchangeable. Because of the potential confusion among the definitions of these terms, we suggest that authors avoid the term “scale” and instead refer to specific concepts. In particular, we are careful to discriminate between observation scales, scales of ecological phenomena and scales used in spatial statistical analysis. When scales of observation or analysis change, that is, when the unit size, shape, spacing or extent are altered, statistical results are expected to change. The kinds of results that may change include estimates of the population mean and variance, the strength and character of spatial autocorrelation and spatial anisotropy, patch and gap sizes and multivariate relationships. The first three of these results (precision of the mean, variance and spatial autocorrelation) can sometimes be estimated using geostatistical support‐effect models. We present four case studies of organism abundance and cover illustrating some of these changes and how conclusions about ecological phenomena (process and structure) may be affected. We identify the influence of observational scale on statistical results as a subset of what geographers call the Modifiable Area Unit Problem (MAUP). The way to avoid the MAUP is by careful construction of sampling design and analysis. We recommend a set of considerations for sampling design to allow useful tests for specific scales of a phenomenon under study. We further recommend that ecological studies completely report all components of observation and analysis scales to increase the possibility of cross‐study comparisons.
Clonally related IgA‐ and IgE‐secreting plasma cells in a myeloma patient
Authors: Bakkus M. H. C. , Schots R. , Gomez La Fuente P. B. , Van Riet I. , Thielemans K. , De Waele M. , Van Camp B.
Published: March 2003

Abstract: Objectives: The purpose of this work was to study the clonal relationship between the cells that secrete monoclonal proteins in an IgA/IgE double multiple myeloma patient. Double monoclonal gammopathy is a rare condition in which two types of monoclonal proteins can be found in the serum and/or urine of patients with multiple myeloma or gammopathy of undetermined significance. The study of the relationship between the cells expressing the different monoclonal proteins may provide insight in the pathogenesis of these disorders. Methods: The clonal relationship of the two tumoral plasma cell populations was examined by immunophenotyping and sequence analysis of the variable regions of the immunoglobulin heavy chain genes. Both immunoglobulin sequences were isolated from the bone marrow using a polymerase chain reaction (PCR)‐based cloning strategy. Rare isotype‐switch variants were detected by a myeloma‐specific PCR in combination with different isotype‐specific primers. An in vitro culture system, based on the activation of the CD40 molecule on the B cell, was used in order to isolate and expand myeloma‐related B cells from peripheral blood that could possibly be regarded as myeloma precursor cells. Results: The variable parts of the immunoglobulin heavy chains linked to either Cα or Cε were exactly the same, including the same somatic mutations. From the in vitro CD40 cultures B cells could be isolated that either expressed IgA or IgE with exactly the same variable immunoglobulin part as the myeloma clone. No pre‐switched IgM myeloma‐related B cells could be found. Conclusion: Both cell populations in this IgA/IgE myeloma patient shared a common clonal origin. No evidence for a pre‐switched IgM precursor myeloma cell was found in this patient.
Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders
Authors: Aggerholm Anni , Grønbæk Kirsten , Guldberg Per , Hokland Peter
Published: March 2003

Abstract: The candidate tumour suppressor gene MMAC1/PTEN located at chromosome 10q23.3 has been reported to be frequently mutated in a number of solid tumours. Less is known about its status in leukaemia. In the present study we first analysed 13 leukaemia cell lines for mutations and homozygous deletions in MMAC1/PTEN using PCR and denaturing gradient gel electrophoresis (DGGE). We identified an intragenic deletion including MMAC1/PTEN exons 2–5 in an acute myelocytic leukaemia cell line, HL‐60 blast, and an insertion of four nucleotides in exon 5 in an acute monocytic leukaemia cell line, U937. Analysis of 59 patients with acute myeloid leukaemia (AML), 26 patients with myelodysplastic syndromes (MDS) and 10 patients with chronic myeloid leukaemia (CML) only revealed a polymorphic base substitution in codon 44 in one AML patient, suggesting that mutations in the MMAC1/PTEN gene are infrequent genetic aberrations in myeloid leukaemia.
Successful treatment of thymoma‐associated pure red cell aplasia with intravenous immunoglobulins
Authors: Larroche Claire , Mouthon Luc , Casadevall Nicole , Le Roux Geneviève , Casassus Philippe , Guillevin Loïc
Published: March 2003

Abstract: Repeated cycles of intravenous immunoglobulins (IVIG) have been reported to be successful in a few patients with idiopathic pure red cell aplasia (PRCA) or associated with another pathology. The efficacy of this treatment for PRCA with thymoma has not been reported previously. We describe here the case of a 75‐yr‐old man who presented with PRCA associated with a benign thymoma. After failure of thymectomy, corticosteroids and octreotide, a complete durable remission was obtained after a single 5‐d cycle of IVIG.
Allogeneic or autologous stem cell transplantation (SCT) for relapsed and refractory Hodgkin's disease and non‐Hodgkin's lymphoma: a single‐centre experience
Authors: Nachbaur D. , Oberaigner W. , Fritsch E. , Nussbaumer W. , Gast G.
Published: March 2003

Abstract: Purpose of the study: The aim of the study was to evaluate which patient might benefit most from allogeneic stem cell transplantation (SCT) in the treatment of relapsed and/or refractory lymphoma. Patients and methods: Thirty‐eight consecutive lymphoma patients receiving either autologous (n=24) or allogeneic (n=14) stem cell grafts at our institution from 1986 to 1998 were retrospectively analysed regarding overall survival (OS), disease‐free survival (DFS), transplant‐related mortality (TRM), and relapse incidence (RI). Uni‐ and multivariate analyses were performed to identify patient characteristics predictive for outcome after SCT. Results: The probabilities of OS, DFS, TRM, and relapse were 57%, 51%, 29%, and 30% following autologous and 43%, 43%, 29%, and 38% following allogeneic SCT. Disease status (sensitive versus refractory) and the time interval between diagnosis and SCT were the most powerful predictive parameters for OS and TRM, whereas elevated serum LDH levels were signifcant in determining relapse. Conclusions: In patients with elevated serum LDH levels and bone marrow involvement at the time of transplantation allogeneic was superior to autologous SCT and resulted in better outcome due to a lower relapse incidence strongly suggesting the existence of a graft‐versus‐lymphoma effect.
Cost–utility analysis of high‐dose melphalan with autologous blood stem cell support vs. melphalan plus prednisone in patients younger than 60 years with multiple myeloma
Authors: Gulbrandsen Nina , Wisløff Finn , Nord Erik , Lenhoff Stig , Hjorth Martin , Westin Jan ,   Nordic Myeloma Study Group
Published: March 2003

Abstract: We evaluated the costs and the cost utility of high‐dose melphalan and autologous stem cell support followed by interferon maintenance relative to conventional treatment with melphalan and prednisone, in patients less than 60 yr of age with multiple myeloma. From March 1994 to July 1997, 274 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a prospective, non‐randomized, population‐based, multicenter study to evaluate the treatment with high‐dose melphalan and autologous blood stem cell support. Health‐related quality‐of‐life was measured prior to treatment and during follow‐up, using the EORTC QLQ‐C30 questionnaire. Resource consumption was also recorded prospectively. The intensive treatment yielded a significant increase in median survival time from 44 to 62 months compared to conventionally treated patients. The corresponding gain in quality‐adjusted life years (QALY) was found to be 1.2. Cost per QALY gained by the treatment with high‐dose melphalan and autologous blood stem cell support was estimated at NOK 249,000 (USD 27,000).
Long‐term follow‐up of patients ≥60 yr old with acute myeloid leukaemia treated with intensive chemotherapy
Authors: Öberg G. , Killander A. , Björeman M. , Gahrton G. , Grimfors G. , Gruber A. , Hast R. , Lerner R. , Liliemark J. , Mattson S. , Paul C. , Simonsson B. , Stalfelt A.‐M. , Stenke L. , Tidefelt U. , Udén A.‐M. , Björkholm M. ,   ( Leukaemia Group of Middle Sweden ; LGMS
Published: March 2003

Abstract: It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long‐term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984–88 comparing two intensive chemotherapeutic drug combinations. Ninety patients ≥60‐yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara‐C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty‐four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients ≤70 yr of age was 30/42 (71%) and in patients >70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients ≤70 yr of age, 40% and 12%, respectively (P<0.005). The median cause‐specific survival time was 178 d in the total patient group, and the 2‐, 5‐, and 10‐yr survivals were 22%, 11%, and 8%, respectively. The cause‐specific survival was not significantly different between the two treatment arms. At long‐term follow‐up ≥10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long‐term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.
The Advia 120 red blood cell and reticulocyte indices are useful in diagnosis of iron‐deficiency anemia
Authors: Kotisaari Sanna , Romppanen Jarkko , Penttilä Ilkka , Punnonen Kari
Published: March 2003

Abstract: We have investigated the red blood cell (RBC) and reticulocyte indices of the Advia 120 hematology system in assessment of body iron stores as well as in diagnostics of iron‐deficiency anemia in two separate study populations. The first study population consisted of a total of 34 apparently healthy females who were found to be anemic (Hb < 125 g L−1) in a screening test. The anemic subjects were classified on the basis of plasma transferrin receptor (TfR) concentration into an iron‐deficiency anemia group (TfR concentration 2.4 mg L−1, n = 14) and an adequate iron stores group (TfR concentration < 2.4 mg L−1, n = 20). Another study population consisted of 95 hospital patients of whom 31 had depleted iron stores according to TfR concentration. The same population was classified further on the basis of hemoglobin value (Hb < 125 g L−1 for females, Hb < 135 g L−1 for males) into patients with iron‐deficiency anemia (n = 21) and those with anemia together with adequate iron stores (n = 44). In the population of young anemic female students the percentage of hypochromic RBC (%HYPOm) had a remarkably high ROC AUC of 0.98 when evaluating the diagnostic accuracy for the distinction between the patients with iron‐deficiency anemia and those with anemia and adequate iron stores. Also, among the hospitalized patients %HYPOm had the highest ROC AUC of 0.77. The diagnostic efficiency provided by the red blood cell and reticulocyte indices was considerably lower in the heterogeneous group of hospitalized patients than in the group of female students. Nevertheless, the advanced RBC and reticulocyte indices may prove to be useful tools in the evaluation of iron status and diagnosis of iron‐deficiency anemia.
Three‐step high‐dose sequential chemotherapy in patients with newly diagnosed multiple myeloma
Authors: Ballestrero Alberto , Ferrando Fabio , Miglino Maurizio , Clavio Marino , Gonella Roberta , Garuti Anna , Grasso Raffaella , Ghio Riccardo , Balleari Enrico , Gobbi Marco , Patrone Franco
Published: March 2003

Abstract: Background and objectives: High‐dose chemotherapy (HDT) with autologous peripheral blood progenitor cell (PBPC) transplant has been increasingly used for newly diagnosed multiple myeloma (MM) in recent years. Presently available results suggest an improvement in the complete remission rate and survival as compared to conventional chemotherapy. However, there is no plateau in the survival curves, and experiments with new treatment schedules and conditioning regimens are warranted. Design and methods: In a non‐randomised controlled trial, 20 patients underwent three‐step HDT following conventional vineristine/doxo ulicin/dexamethasone (VAD)‐based induction. In the intensification phase patients received high‐dose cyclophosphamide (HD‐CY), high‐dose etoposide (HD‐VP), and mitoxantrone (NOV) plus melphalan (L‐PAM) with haemopoietic rescue. Maintenance treatment with interferon was given until relapse. Actuarial overall survival (OS) and event‐free survival (EFS) curves were plotted according to the method of Kaplan and Meier. In five of the eight patients achieving complete remission (CR), the molecular disease was monitored by polymerase chain reaction technique (PCR). Results: Overall 18/20 (90%) patients responded, with a CR rate of 40%. After an average follow‐up of 40 months, median EFS and OS are 25.5 and 44.6 months, respectively. Monoclonal cells were detectable in the post‐treatment bone marrow and in the aphereses of the five CR patients monitored by PCR. Conclusion: The present three‐step HDT regimen, including conditioning with mitoxantrone and melphalan, proved to be feasible and safe. Our results are in agreement with the hypothesis that HDT results in an increased remission rate and in prolonged survival in newly diagnosed MM, but a cure is unlikely.
Large‐cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine–rituximab‐containing regimens: natural history‐ or therapy‐related complication?
Authors: Cohen Yossi , Da'as Nael , Libster Diana , Amir Gail , Berrebi Alan , Polliack Aaron
Published: March 2003

Abstract: Novel therapeutic regimens containing purine analogs and monoclonal antibodies have led to significant improvement in the course of indolent lymphoproliferative diseases (LPD). Complete clinical and even molecular remissions have been achieved in an increasing proportion of patients. In parallel to their tumor cytotoxic effect, these agents are inevitably associated with prolonged immunosuppression inherent to their mechanism of antilymphocytic activity. Until now, attention has been paid mainly to opportunistic infection occuring as a result of the above drug‐induced immunosuppression and less to other possible complications, such as malignancy or tumor progression in the immunocompromised host. Here we briefly report nine patients with previously treated indolent LPD in whom the onset of large‐cell transformation occured during or shortly after the initiation of regimens containing these agents before transformation occured. One patient had received rituximab alone, three fludarabine‐containing regimens and five received sequential regimens containing both agents. This ‘switch’ in the histopathology could merely reflect the natural course of progressive lymphoma and be unrelated to the therapy given. The onset of this complication during, or so soon after, administration of these regimens seems to us more than just a chance relationship in these cases; however, we have no conclusive evidence to prove this hypothesis definitively. We draw attention to this phenomenon.
Re‐treatment with cladribine‐based regimens in relapsed patients with B‐cell chronic lymphocytic leukemia
Authors: Robak Tadeusz , Boński Jerzy Z. , Kasznicki Marek , Góra‐Tybor Joanna , Hellmann Andrzej , Konopka Lech , Dmoszyńska Anna , Dwilewicz‐Trojaczek Jadwiga , Wołowiec Dariusz ,   the Polish Leukemia Study Group
Published: March 2003

Abstract: The aim of the study was to determine the effectiveness and toxicity of cladribine (2‐CdA) used alone or in combination with prednisone (P) or cyclophosphamide and mitoxantrone in re‐treatment of patients with progressive B‐cell chronic lymphocytic leukemia (B‐CLL). We analyzed treatment outcome in 40 patients who had responded to previous treatment with 2‐CdA‐based regimens. Criteria for re‐treatment were the same as for the first treatment. The patients were retreated with the same agents if they responded to the first treatment and then relapsed with progressive disease not earlier than 3 months after achieving the first response. Eight patients received 2‐CdA alone (0.12 mg kg−1 d−1) i.v. for 5 d, and 21 patients additionally were given P (30 mg m−2 d−1) orally, also for 5 d. Eleven patients received 2‐CdA for 3 d combined with cyclophosphamide (650 mg m−2) i.v. and mitoxantrone (10 mg m−2) i.v. on day 1 (CMC regimen). The cycles were repeated usually at 4 wk intervals or longer if severe myelosuppression or infections occurred. The therapy was finished if complete remission (CR) was achieved or until maximum of six courses. Overall response (OR) in re‐treatment was obtained in 16 out of 40 (40%) patients (95% CI 16–64), including 62% after 2‐CdA, 33% after 2‐CdA +P and 36% after CMC. CR was obtained in four (10%) patients. Residual disease evaluated in the patients with CR by surface immunophenotyping had been demonstrated in 5 out of 16 (31%) patients after the first treatment and in one out of four (25%) patients after re‐treatment. The median progression‐free survival (PFS) was 16 months (range 3–39) for the first treatment and 9.5 months (range 3–18) for re‐treatment (P=0.34). Grade III or IV neutropenia was observed in 20% patients during the first treatment and in 35% patients during re‐treatment (P=0.1). 2‐CdA‐induced thrombocytopenia occurred in 20% and 42% of the patients, respectively (P=0.05). Anemia was also more frequent during re‐treatment (35%) than during the first treatment (7%) (P=0.007). Autoimmune hemolytic anemia developed in four (10%) of the patients during or after re‐treatment. Severe infections, including pneumonia and herpes reactivation, occurred in 11 patients during the first treatment and in 10 patients during re‐treatment. Twelve (30%) patients died during the study. Infections were the cause of death in six and AIHA in two patients. In conclusion, 2‐CdA applied in monotherapy or in combination with prednisone or cyclophosphamide and mitoxantrone has therapeutic activity in some B‐CLL patients in whom these drugs induced earlier complete or partial remission. However, since the second response is usually shorter and myelotoxicity more pronounced than during the first therapy, more clinical trials to find other therapeutical approaches are necessary.
Pamidronate is superior to ibandronate in decreasing bone resorption, interleukin‐6 and β2‐microglobulin in multiple myeloma
Authors: Terpos Evangelos , Viniou Nora , De La Fuente Josu , Meletis John , Voskaridou Ersi , Karkantaris Christos , Vaiopoulos George , Palermos John , Yataganas Xenophon , Goldman John M , Rahemtulla Amin
Published: March 2003

Abstract: Objectives: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third‐generation aminobisphosphonate, in bone turnover and disease activity in MM patients. Methods: Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N‐terminal cross‐linking telopeptide of type‐I collagen (NTX) and tartrate‐resistant acid phosphatase type 5b (TRACP‐5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, β2‐microglobulin), and interleukin‐6 (IL‐6) were also studied. Results: In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL‐6, paraprotein, CRP, and β2‐microglobulin from the second month of treatment, having no effect on bone formation. TRACP‐5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL‐6, and β2‐microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP‐5b, starting at the fourth month (P = 0.014), that being continued throughout the 10‐month follow‐up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP‐5b, IL‐6, and β2‐microglobulin from the second month for patients of both groups. Conclusions: These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL‐6, and possibly tumour burden in MM. TRACP‐5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.
Expression of nerve growth factor mRNA and its translation products in the anagen hair follicle
Authors: Yardley G. , Relf B. , Lakshmanan J. , Reinshagen M. , Moore G. P. M.
Published: March 2003

Abstract: The cellular localization of NGF mRNA and its translation products have been identified in ovine hair follicles. NGF mRNA was detected in the proliferating cells of the follicle bulb and differentiating cells of the suprabulbar region, but was absent from the outer root sheath. Western analysis revealed the presence of a 73 kDaNGF prohormone in extracts of ovine flank skin, but the mature 13 kDaNGF was absent. Immunohistochemical analysis with antibodies specific to mouse NGF and a pro‐ NGF specific domain localized the NGF prohormone to outer root sheath cells in the upper bulb region of the follicle, adjacent to the zone of keratinization. Antibody binding was also associated with the luminal epithelium of the apocrine sweat gland and the pilary canal of the follicle at its junction with the epidermis. These observations, together with the reported presence of high‐ and low‐affinity NGF receptors in the follicle, implicate the NGF prohormone‐responsive neuronal system in the regulation of hair growth.
Zinc, copper and manganese enhanced keratinocyte migration through a functional modulation of keratinocyte integrins
Authors: Tenaud I. , Leroy S. , Chebassier N. , Dreno B.
Published: March 2003

Abstract: The migration of keratinocytes plays an important role in the re‐epithelialization of cutaneous wounds. Zinc, copper and manganese are used in vivo for their healing properties and their mechanism of action is still only partially known. Thus, they have been shown both to promote keratinocyte proliferation and to modulate integrins expression. The aim of this study was to determine if trace elements induce an increase of the migration of keratinocytes and if this effect is related to the modulation of integrins. Two independent migration assays were used to study keratinocyte migration: the scratch assay using normal human keratinocytes and the modified Boyden chamber using HaCaT cells. Inhibition studies using function‐blocking antibodies directed to α3, α6, αV and β1 subunits were performed to investigate the modulator effect of trace elements on integrin function. In this way, zinc and copper gluconates increased α3, αV and β1 function whereas manganese gluconate seems mainly able to modulate the function of α3 and β1. The stimulating effect of these trace elements on keratinocyte migration does not appear related to α6 subunit. Thus, zinc, copper and manganese enhanced keratinocyte migration and one of the mechanisms was going through a modulation of integrin functions.
The molecular determinants of sunburn cell formation
Authors: Murphy G. , Young A. R. , Wulf H. C. , Kulms D. , Schwarz T.
Published: March 2003

Abstract: Sunburn cell (SBC) formation in the epidermis is a characteristic consequence of ultraviolet radiation (UVR) exposure at doses around or above the minimum erythema dose. SBC have been identified morphologically and biologically as keratinocytes undergoing apoptosis. There is evidence that SBC formation is a protective mechanism to eliminate cells at risk of malignant transformation. The level of DNA photodamage is a major determinant of SBC induction by a process controlled by the tumor suppressor gene p53. However, extra‐nuclear events also contribute to SBC formation, such as the activation of death receptors including CD95/Fas. UVR triggers death receptors either by direct activation of these surface molecules or by inducing the release of their ligands such as CD95 ligand or tumor necrosis factor. Oxidative stress also appears to be involved, probably via mitochondrial pathways, resulting in the release of cytochrome C. Pathways which modify SBC formation are now extensively studied given the importance of apoptosis in eliminating irreparably damaged cells. A greater understanding of the mechanisms that induce and prevent UVR‐induced apoptosis will contribute to our understanding of mechanisms relevant in genomic integrity.
Darier disease – novel mutations in ATP2A2 and genotype–phenotype correlation
Authors: Ringpfeil F. , Raus A. , DiGiovanna J. J. , Korge B. , Harth W. , Mazzanti C. , Uitto J. , Bale S. J. , Richard G.
Published: March 2003

Abstract: Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow‐twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium‐dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in‐frame deletions, and a 19‐basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype–phenotype correlation in our cohort.
Downregulation of human type VII collagen (COL7A1) promoter activity by dexamethasone
Authors: Gras M.‐P. , Verrecchia F. , Uitto J. , Mauviel A.
Published: March 2003

Abstract: Type VII collagen is the major collagenous component of the anchoring fibrils, attachment structures that stabilize the association of the cutaneous basement membrane zone to the underlying dermis. It is expressed by both epidermal keratinocytes and dermal fibroblasts. In this study, we have examined the pharmacological control of COL7A1 gene expression by the glucocorticorticoid dexamethasone. We demonstrate that dexamethasone is a potent transcriptional inhibitor of COL7A1 promoter activity in dermal fibroblasts, and we identify a potential glucocorticoid response element in the region −318/−212 of the promoter. In addition, we have determined that dexamethasone antagonizes transforming growth factor‐β (TGF‐β) activation of the COL7A1 promoter. This effect occurred without dexamethasone interfering with TGF‐β‐induced Smad‐specific gene transcription. These results indicate potential deleterious effects of glucocorticosteroids on epidermal wound healing, as reduced COL7A1 expression likely leads to decreased anchoring fibril formation, which may translate into delayed or impaired reepithelialization.
Genotype–phenotype correlation in skin fragility‐ectodermal dysplasia syndrome resulting from mutations in plakophilin 1
Authors: Hamada T. , South A. P. , Mitsuhashi Y. , Kinebuchi T. , Bleck O. , Ashton G. H. S. , Hozumi Y. , Suzuki T. , Hashimoto T. , Eady R. A. J. , McGrath J. A.
Published: March 2003

Abstract: We report a 42‐year‐old Japanese man with an unusual autosomal recessive genodermatosis. The clinical features comprised normal skin at birth, loss of scalp hair at 3‐months of age after a febrile illness, progressive nail dystrophy during infancy, palmoplantar keratoderma starting around the age of 18 years and trauma‐induced skin fragility and blisters noted from the age of 20 years. Skin biopsy of rubbed non‐lesional skin revealed widening of spaces between adjacent keratinocytes from the suprabasal layer upwards. Electron microscopy demonstrated a reduced number of hypoplastic desmosomes. Immunohistochemical labeling showed a reduction in intercellular staining for the desmosome component plakophilin 1. Mutation analysis revealed a homozygous intron 11 donor splice site mutation in the plakophilin 1 gene, 2021+1 G>A (GenBank no. Z34974). RT‐PCR, using RNA extracted from the skin biopsy, provided evidence for residual low levels of the full‐length wild‐type transcript (∼8%) as well as multiple other near full‐length transcripts, one of which was in frame leading to deletion of 17 amino acids from the 9th arm‐repeat unit of the plakophilin 1 tail domain. Thus, the molecular findings help explain the clinical features in the patient, who has a similar but milder phenotype to previously reported patients with skin fragility‐ectodermal dysplasia syndrome associated with complete ablation of plakophilin 1 (OMIM 604536). This new ‘mitis’ phenotype provides further clinicopathological evidence for the role of plakophilin 1 in keratinocyte cell–cell adhesion and ectodermal development.
Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin
Authors: El‐Domyati M. , Attia S. , Saleh F. , Brown D. , Birk D. E. , Gasparro F. , Ahmad H. , Uitto J.
Published: March 2003

Abstract: Cutaneous aging is a complex biological phenomenon affecting the different constituents of the skin. To compare the effects of intrinsic and extrinsic aging processes, a total of 83 biopsies were collected from sun‐exposed and protected skin of healthy volunteers representing decades from the 1st to the 9th (6–84 years of age). Routine histopathology coupled with computer‐assisted image analysis was used to assess epidermal changes. Immunoperoxidase techniques with antibodies against type I and type III collagens and elastin were used to quantitatively evaluate changes in collagen and elastic fibers and their ultrastructure was examined by transmission electron microscopy. Epidermal thickness was found to be constant in different decades in both sun‐exposed and protected skin; however, it was significantly greater in sun‐exposed skin (P = 0.0001). In protected skin, type I and III collagen staining was altered only after the 8th decade, while in sun‐exposed skin the relative staining intensity significantly decreased from 82.5% and 80.4% in the 1st decade to 53.2% and 44.1% in the 9th decade, respectively (P = 0.0004 and 0.0008). In facial skin the collagen fiber architecture appeared disorganized after the 4th decade. The staining intensity of elastin in protected skin significantly decreased from 49.2% in the 1st decade to 30.4% in the 9th decade (P = 0.05), whereas in sun‐exposed skin the intensity gradually increased from 56.5% in the 1st decade to 75.2% in the 9th decade (P = 0.001). The accumulated elastin in facial skin was morphologically abnormal and appeared to occupy the areas of lost collagen. Collectively, the aging processes, whether intrinsic or extrinsic, have both quantitative and qualitative effects on collagen and elastic fibers in the skin.
Behavior of pike (Esox lucius L.) >50 cm in a turbid reservoir and in a clearwater lake
Authors: Jepsen N. , Beck S. , Skov C. , Koed A.
Published: March 2003

Abstract
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Pike from two different waters were radio‐tagged and released immediately upon recovery. In Bygholm Reservoir 19 pike (52–72 cm) and in Lake Ring 15 pike (53–77 cm) were tagged in late February and early March. Bygholm (58 ha) is a shallow eutrophic reservoir and Ring (22 ha) is a natural mesotrophic lake. The positions of the tagged fish were recorded through weekly trackings and a number of 3‐day tracking sessions during a 9‐month period. Diel activity patterns, home range sizes and habitat utilization by pike was compared between the reservoir and the lake. The pike in the lake occupied larger areas than the pike in the reservoir and were less associated with vegetation. In both waters pike were found more often in, or close to, vegetation during summer than during winter. No difference in average movement of pike was seen between the waters, but pike were more stationary in the reservoir than in the lake. There was no difference in the level of movement between different times of the day, but the diel rhythm of the pike changed significantly over the year. There were large behavioral differences between pike in the lake and in the reservoir and even more variation between individuals within each population.
Effects of kinship on growth and movements of brown trout in field enclosures
Authors: Greenberg L. A. , Hernnäs B. , Brönmark C. , Dahl J. , Eklöv A. , Olsén K. H.
Published: March 2003

Abstract  – The effect of kinship on growth and use of space by individually PIT‐tagged 1+ brown trout was studied for 11 weeks in eight stream enclosures. Each enclosure consisted of two sections, separated by a region containing PIT‐detecting antennae, which enabled us to measure use of sections by all individuals. Two types of sibling groups were tested, a single sibling group, F1, consisting of four individuals that were reared together in hatchery tank ‘a’ (F1a) plus four additional siblings of the same family but raised in hatchery tank ‘b’ (F1b), and a mixed sibling group, consisting of four F1aindividuals plus four siblings from a second family, F2. Based on kin theory and earlier laboratory studies, we expected that growth of the F1aindividuals in the single sibling group to be greater than that of F1aindividuals in the mixed family sibling group, but instead we found just the opposite. The variance of growth did not differ between treatments. Nor was there a difference in time F1aindividuals spent together when they were in mixed versus single sibling groups. We did find that F1aindividuals changed habitat more frequently than F2 individuals in the mixed sibling group but less frequently than F1bin the single sibling groups. Thus, our predictions based on kin theory for growth and behavior of brown trout were not supported by our data, and we suggest that the role of kin recognition for the ecology of salmonids deserves further attention.