bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulating viability of a spadefoot toad Pelobates fuscus metapopulation in a landscape fragmented by a road
Authors: Hels Tove , Nachman Gösta
Published: March 2003

A stochastic simulation model allowing for demographic and environmental stochasticity was developed in order to predict the dynamics of a Pelobates fuscus metapopulation. The metapopulation (consisting of ca 1000 adult individuals) was intensively studied in the field for a period of four years and the simulation model was parameterised (sex ratio, age‐specific survival rates, fecundity and dispersal between subpopulations) using field data. A sensitivity analysis revealed that a change in the juvenile yearly survival rate has a relatively larger effect on subpopulation persistence than adult survival rate and fecundity rate have. The probability of subpopulation persistence for one hundred years increased from 0 to 0.6 with a change in juvenile yearly survival rate from 0.35 to 0.40. Varying dispersal rate (from 0 to 1% of the individuals in a subpopulation moving to another subpopulation within a year) showed that four of the five subpopulations are dependent on the last one for persistence, indicating a source‐sink structure of the metapopulation. The subpopulation with the highest estimated juvenile survival has a far higher persistence probability than the others; they in turn would go extinct were it not for the occasional input of individuals from the source subpopulation. The source‐sink structure was also apparent when simulating the isolation effect of the road: persistence of the subpopulation isolated by the road decreases markedly with only a 20% decrease in the number of individuals dispersing to this pond. Environmental stochasticity decreases persistence time of the source subpopulation, but increases persistence time of the unstable ones. This is probably due to the presence of overcompensating density‐dependent factors affecting the subpopulations and to the more general effect of stochasticity: it may temporarily change reproduction and mortality rates, increase time to extinction for unstable subpopulations through a rescue effect; and decrease time to extinction for the more stable subpopulations.
Circulating endothelial cells in vascular disorders: new insights into an old concept
Authors: Dignat‐George Françoise , Sampol José
Published: March 2003

Abstract: The endothelial contribution to vascular disorders has been widely documented in experimental models. However, its implication in human pathology is difficult to investigate, owing to the paucity of non‐invasive methods and of specific endothelial markers. The enumeration of circulating endothelial cells (CEC) released in peripheral blood after vascular injury represents a direct exploration of the endothelium. For this purpose, we have produced a monoclonal antibody (S‐Endo 1), which recognizes CD 146, a molecule expressed on all types of human endothelial cells but absent from haemopoietic cells. Using this antibody, we have designed a specific and sensitive immunocapture test, which allowed us to detect high numbers of CEC in thrombotic, infectious or immunological disorders, while CEC were found to be very rare (<3/ml) in normal subjects. This quantitative approach using CEC might prove useful as a marker of vascular wall injury. Their enumeration is of interest in the clinical follow‐up of vascular disorders, in the evaluation of therapeutic effectiveness or in the direct diagnosis of infectious diseases involving intra‐endothelial microbial agents. Furthermore, an immunological and/or functional study of CEC could allow one to assess their procoagulant and proadhesive properties, as well as their viability, opening new perspectives for CEC investigation in vascular pathology.
Cytogenetic findings in a population‐based series of 787 childhood acute lymphoblastic leukemias from the Nordic countries
Authors: Forestier Erik , Johansson Bertil , Borgström Georg , Kerndrup Gitte , Johannsson Johann , Heim Sverre ,   The NOPHO Leukemia Cytogenetic Study Group
Published: March 2003

Abstract: Different types of leukemia are characterized by different patterns of nonrandom chromosomal aberrations, but the frequencies with which the various karyotypic subtypes are seen differ among cytogenetic laboratories, countries, and geographic regions. During the 12‐yr period 1986–1997, a total of 2054 children (<15 yr of age) were diagnosed with acute lymphoblastic leukemia (ALL) in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). Cytogenetic analyses were successfully performed in 1372 patients, 787 (57%) of whom displayed clonal chromosomal abnormalities. ALL with 47 chromosomes was the most frequent cytogenetic subgroup (63%), with massive hyperdiploidy (52 chromosomes) and chromosome numbers in the tri‐ and tetraploid range, constituting 46% of all abnormal cases. ALL‐associated translocations were found at low frequencies [11q23 translocations in 3.7%, t(9;22)(q34;q11) or del(22q) in 2.2%, t(4;11)(q21;q23) in 2.0%, t(11;19)(q23;p13) in 1.4%, t(1;19)(q23;p13) in 1.3%, and t(8;14)(q24;q32) in 1%]. Two rearrangements not previously reported in childhood ALL, but recurrent in this population‐based material, were identified: der(7;9)(q10;q10) and t(9;12)(q22;p11–12), the molecular genetic consequences of which are unknown. Hyperdiploid childhood leukemias, especially those with a high hyperdiploid modal number, thus seem to be more frequent and ALL‐specific translocations less frequent in the Nordic countries than in other geographic regions. Although technical differences among laboratories cannot be ruled out as a cause of at least some of the frequency differences observed compared with previous studies, systematic differences in exposure to environmental oncogenic factors or in geographic/ethnic origin are an intriguing possibility.
Binding of stromal derived factor‐1α(SDF‐1α) to CXCR4 chemokine receptorin normal human megakaryoblasts butnot in platelets induces phosphorylationof mitogen‐activated protein kinase p42/44 (MAPK), ELK‐1 transcription factor and serine/threonine kinase AKT
Authors: Majka Marcin , Ratajczak Janina , Kowalska M. Anna , Ratajczak Mariusz Z.
Published: March 2003

Abstract: The aim of this study was to identify pathways which are involved in signal transduction from the CXCR4 receptor stimulated by stromal derived factor‐1α (SDF‐1α) in human malignant hematopoietic cells and normal megakaryoblasts. First, we found that activation of CXCR4 in human T cell lines (Jurkat and ATL‐2) rapidly induced phosphorylation of mitogen‐activated protein kinases (MAPK) (p44 ERK‐1 and p42 ERK‐2). Next, we became interested in CXCR4‐mediated signaling in normal hematopoietic cells, and employed human megakaryoblasts, which highly express CXCR4 as a model. We found that stimulation of these cells with SDF‐1α led to the phosphorylation of MAPK and serine/threonine kinase AKT as well. Activation of MAPK further led to the phosphorylation of the nuclear transcription factor ELK‐1. Phosphorylation of ELK‐1 in megakaryoblasts implies that phosphorylated MAPK translocate from cytoplasm into the nucleus where they may phosphorylate some nuclear proteins. Note that neither MAPK nor AKT was phosphorylated in normal human platelets after stimulation by SDF‐1. We conclude that both MAPK and AKT are involved in signal transduction pathways from the CXCR4 receptor in malignant and normal human hematopoietic cells. The biological consequences of MAPK, ELK‐1 and AKT phosphorylation in megakaryoblasts after stimulation with SDF‐1α require further studies.
Acute clinical events in 299 homozygous sickle cell patients living in France
Authors: Neonato Maria Grazia , Guilloud‐Bataille Monique , Beauvais Pierre , Bégué Pierre , Belloy Marie , Benkerrou Malika , Ducrocq Rolande , Maier‐Redelsperger Micheline , De Montalembert Mariane , Quinet Béatrice , Elion Jacques , Feingold Josué , Girot Robert ,   French Study Group on Sickle Cell Disease
Published: March 2003

Abstract: A subset of 299 patients with homozygous sickle cell anaemia, enrolled in the cohort of the French Study Group on sickle cell disease (SCD), was investigated in this study. The majority of patients were children (mean age 10.1±5.8 yr) of first generation immigrants from Western and Central Africa, the others originated from the French West Indies (20.2%). We report the frequency of the main clinical events (mean follow‐up 4.2±2.2 yr). The prevalence of meningitis‐septicaemia and osteomyelitis was, respectively, 11.4% and 12% acute chest syndrome was observed in 134 patients (44.8%). Twenty patients (6.7%) developed stroke with peak prevalence at 10–15 yr of age. One hundred and seventy‐two patients (58%) suffered from one or more painful sickle cell crises, while the others (42.5%) never suffered from pain. The overall frequency of acute anaemic episodes was 50.5%, (acute aplastic anaemia 46%; acute splenic sequestration 26%). A group of 27 patients were asymptomatic (follow‐up >3 yr).

Epistatic mechanisms influencing SCD were studied. Coinherited α‐thalassemia strongly reduced the risk of stroke (p<0.001) and increased that of painful crises (p<0.02). There was a low prevalence of Senegal and Bantu (CAR) βs‐chromosomes in patients with meningitis (p<0.04) and osteomyelitis (p<0.03). Prevalence of Senegal βs‐chromosomes was lower in the asymptomatic group of 27 patients (p<0.02). The patients come from a population of unmixed immigrants in whom the β‐globin gene haplotype strongly reflects the geographic origin and identifies subgroups with a homogenous genetic background. Thus the observed effects might result more from differences in as yet unidentified determinants in the genetic background than from the direct linkage with differences in the β‐globin gene locus.
Renal failure in multiple myeloma: reversibility and impact on the prognosis
Authors: Knudsen Lene Meldgaard , Hjorth Martin , Hippe Erik ,   Nordic Myeloma Study Group
Published: March 2003

Abstract: The purpose of the present study was to analyse the importance and prognostic value of renal failure in multiple myeloma patients. The frequency and reversibility of renal failure in 775 multiple myeloma patients diagnosed between 1984–86 and 1990–92 in the Nordic countries were studied. Renal failure, defined as plasma creatinine >130μmol/l, was observed in 29% of the cases at the time of diagnosis. During the first year after diagnosis 58% achieved normalisation of p‐creatinine, and this was achieved mainly during the first 3 months. Reversibility of renal failure was more frequently observed in patients with moderate renal failure, hypercalcaemia and low Bence‐Jones protein excretion. In a multivariate analysis renal failure, high age, stage III disease and hypercalcaemia were independent prognostic factors for survival. Patients who needed dialysis had a poor prognosis, with a median survival of 3.5 months. A 12‐months landmark analysis showed that reversibility of renal failure was a more important prognostic factor than response to chemotherapy. It is concluded that renal failure in multiple myeloma is reversible in about half the cases, and reversibility of renal failure improves long‐term survival.
Erythropoietin and anemia of cancer
Authors: Erslev Allan J.
Published: March 2003

Abstract: Anemia is a common complication of cancer but its causes differ widely. However, a significant number of patients with even early cancer experience a suppression of the action of erythropoietin on the bone marrow, presumably caused by the release of cytokines. The ensuing anemia may be mild and “asymptomatic”. Nevertheless, it drains physical and emotional vigor so necessary in the fight against the underlying disorder. The therapeutic use of recombinant human erythropoietin has been gratifying and in many cases restored to near normal not only the hemoglobin concentration but also the quality of life.
Diabetes insipidus revealing acute myelogenous leukaemia with a high platelet count, monosomy 7 and abnormalities of chromosome 3: a new entity?
Authors: Lavabre‐Bertrand T. , Bourquard P. , Chiesa J. , Berthéas M.F. , Lefort G. , Taïb J. , Lavabre‐Bertrand C. , Navarro M. , Bureau J.P.
Published: March 2003

Abstract: We describe three cases of acute myeloid leukaemia revealed by diabetes insipidus. The patients were 42, 38 and 39 yr old and they had marked hyperleukocytosis, circulating immature granular cells and a normal or elevated platelet count. The leukaemia was type AML‐M2 according to the FAB classification. Cytogenetic studies showed inversion of chromosome 3 (q21;q26) in 2 cases and a translocation (3;3)(q21;q29?) in the remaining case, both associated with monosomy 7. All the cerebral CT scans were normal. Complete remission was never achieved, and all three patients survived less than 14 months. Desmopressine therapy was active but treatment could not be reduced. The association of dysmegacaryopoiesis with a chromosome 3 abnormality and diabetes insipidus is probably not fortuitous and could represent a new entity.
Prognostic factors in advanced stage Hodgkin's lymphoma: the significance of the number of involved anatomic sites
Authors: Vassilakopoulos T.P. , Angelopoulou M.K. , Siakantaris M.P. , Kontopidou F.N. , Dimopoulou M.N. , Barbounis A. , Grigorakis V. , Karkantaris C. , Anargyrou K. , Chatziioannou M. , Rombos J. , Boussiotis V.A. , Vaiopoulos G. , Kittas C. , Pangalis G.A.
Published: March 2003

Abstract:Background:Advanced Hodgkin's lymphoma (HL) is curable by conventional chemotherapy in 60–70% of patients. The pretreatment identification of a sizeable subgroup of patients with sufficiently low failure‐free survival (FFS) to be eligible for investigational treatment is necessary.Objectives:To determine the prognostic significance of the number of involved sites (NIS) in patients with advanced HL and its relationship to the International Prognostic Score (IPS).Methods:A retrospective review of patients with advanced HL, defined as Ann Arbor stage (AAS) IB, IIB, III or IV, treated with anthracycline‐based regimens. The end‐point was FFS.Results:We identified 277 patients with a median age of 32 yr (14–78), 57% of whom were males. AAS was I in 4% of patients, II in 29%, III in 38% and IV in 29%. B‐symptoms were recorded in 81%. Most patients had nodular sclerosis (64%) and mixed cellularity (26%) histology. IPS was ≥3 in 44% of 242 evaluable patients. The NIS was ≥5 in 32% of the patients and 20% of all patients had both ≥5 involved sites and IPS ≥3. The 10‐yr FFS was 67%, being 76% vs. 50% for patients with ≤4 vs. ≥5 involved sites (P < 0.0001). The NIS (≥ 5), AAS IV and anemia were independent predictors of FFS in multivariate analysis. The NIS remained significant along with IPS, when the latter was included in the analysis. Patients with ≥5 involved sites and IPS ≥3 had 10‐yr FFS overall, and relapse‐free survival of 41%, 45% and 49%, respectively.Conclusions:The NIS was associated with FFS in advanced HL, was independent of IPS, and led to the identification of a sizeable subgroup of patients with 10‐yr FFS of approximately 40%. This factor should be evaluated during the development of prognostic systems.
Acute tumour lysis syndrome following a single‐dose corticosteroid in children with acute lymphoblastic leukaemia
Authors: Duzova Ali , Çetin Mualla , Gümrük Fatma , Yetgin Sevgi
Published: March 2003

Abstract: Acute tumour lysis syndrome (ATLS) is a well recognised complication of treatment of a variety of malignant disorders. It commonly occurs in patients with non‐Hodgkin's lymphoma (NHL) and acute lymphoblastic leukaemia (ALL) with the administration of combined cytotoxic chemotherapy. It is rarely reported after single‐agent corticosteroid therapy. We present two children with acute lymphoblastic leukaemia of T‐cell lineage who developed acute tumour lysis syndrome after a single dose of prednisolone, and methylprednisolone at the beginning of the induction chemotherapy. In the first case (an 11‐yr‐old) ATLS had occurred after an oral dose of prednisolone as small as 12 mg and within 18 h. The second case was a 14‐yr‐old boy with ALL who developed ATLS following a single dose of methylprednisolone. A few similar cases in the English literature are summarised in the report. These cases indicate that acute tumour lysis syndrome may occur after a single dose of corticosteroids. One should be aware of this potentially life‐threatening complication especially while prescribing corticosteroids to patients with NHL and leukaemia.
Prevalence and clinical significance of anticardiolipin and anti‐β2‐glycoprotein‐I antibodies in patients with non‐Hodgkin's lymphoma
Authors: Genvresse I. , Lüftner D. , Späth‐Schwalbe E. , Buttgereit F.
Published: March 2003

Abstract: The association of antiphospholipid antibodies (APA) has been reported in several cases of patients with non‐Hodgkin's lymphoma (NHL) with or without thromboembolic complications. The purpose of this study was to analyse systematically the prevalence of APA and its clinical significance in lymphoma patients. Sera of 90 consecutive unselected patients with NHL were tested for the presence of anticardiolipin (aCL) antibodies and anti‐β2‐glycoprotein‐I (anti‐β2‐GPI) antibodies. The patients were followed up over a median period of 14 months to note the occurrence of thromboembolism. We found APA in 24 out of 90 NHL patients (26.6%). Elevated APA were more often detected in women and in the elderly. The presence of elevated APA was not correlated with the histology and the stage of the lymphoma. None of the 24 patients with elevated APA developed a thromboembolic event in the follow‐up period. Thromboembolic events were observed in 12 patients (13.3%), all with negative APA. High APA titres and the combination of positive aCL‐ and anti‐β2‐GPI antibodies, features which are known to be more strongly correlated with thrombosis among patients with antiphospholipid syndrome and systemic lupus erythematous (SLE), were very uncommon in our cohort of NHL patients (3.3%). Vessel compression by lymphoma but not elevated APA remains the main cause of thrombosis in NHL patients.
Simultaneous measurement of serum thrombopoietin and expression of megakaryocyte c‐Mpl with clinical and laboratory correlates for myelofibrosis with myeloid metaplasia
Authors: Elliott Michelle A. , Yoon Soo‐Young , Kao Pai , Li Chin‐Yang , Tefferi Ayalew
Published: March 2003

Abstract: Objectives: We sought to investigate potential mechanisms of increased serum thrombopoietin (TPO) concentrations in myelofibrosis with myeloid metaplasia (MMM) by simultaneously measuring serum TPO, platelet and megakaryocyte (MK) numbers, and MK c‐Mpl expression. Methods: We studied 17 consecutive patients who had MMM and were not receiving therapy at the time of evaluation. Serum TPO was measured by a two‐site immunochemiluminometric assay. Immunohistochemical staining of c‐Mpl was accomplished with an immunoperoxidase method on simultaneously obtained bone marrow specimens. Results: Our findings confirmed the presence of inappropriately increased serum TPO despite mostly normal or increased peripheral platelet counts and markedly increased bone marrow MK numbers. In addition, we found an inverse correlation between platelet count and serum TPO (P < 0.03) and splenic size (P < 0.04). However, serum TPO did not correlate with either bone marrow MK number or c‐Mpl expression. The lack of correlation of serum TPO and bone marrow megakaryocyte number may be accounted for by the unavoidable inaccuracies in quantifying megakaryocytopoiesis in a disorder of known altered hematopoietic progenitor cell distribution, both intramedullary and extramedullary. The significant inverse correlation between serum TPO and spleen size suggests that this site of extramedullary megakaryocytopoiesis may assume a role in the dysfunctional TPO regulatory axis. Conclusions: These observations suggest some preservation of the negative feedback regulation that appears to be dysfunctional at the MK c‐Mpl level. Consistent with previous observations in animal models, our observations suggest the possibility that altered TPO regulation resulting in sustained ligand excess may have pathogenetic relevance in MMM.
Intracellular T cell cytokines in patients with B cell chronic lymphocytic leukaemia (B‐CLL)
Authors: Rossmann Eva D. , Lewin Nongnit , Jeddi‐Tehrani Mahmood , Österborg Anders , Mellstedt Håkan
Published: March 2003

Abstract: Analysis of cytokine production is a tool to functionally characterise T cells. In this study, spontaneous and polyclonal activation induced cytokine production in T cells were assessed by flow cytometry in patients with B‐CLL. Patients with progressive disease had a significantly increased number of T cells spontaneously producing IL‐2, IL‐4 and GM‐CSF as compared to healthy donors and patients with non‐progressive CLL, which was not the case for TNF‐α and IFN‐γ producing T cells. However, no difference in the frequency of T cells producing these cytokines was seen comparing patients with non‐progressive disease to control donors. Polyclonal activation of B‐CLL T cells in vitro induced an increased proportion of T cells producing these five cytokines in patients as well as in control donors, indicating that T cells in CLL patients might have a relatively well preserved functional capacity. However, the increase in GM‐CSF, TNF‐α and IL‐4 producing T cells was more marked in CLL patients than in controls. Furthermore, following activation, a higher frequency of cytokine‐producing T cells was noted in patients with progressive disease as compared to those with non‐progressive disease. The augmented number of cytokine‐producing T cells in CLL may indicate an up‐regulated capability of T cells to secrete cytokines, especially in patients with progressive CLL. The increased production of the T cell derived cytokines GM‐CSF, TNF‐α, IL‐4 and IL‐2 is interesting, as these cytokines have previously been shown to support growth of B‐CLL leukaemic cells in vitro and as T cells might specifically recognise the autologous leukaemic B cells in vivo. The findings may suggest a role for T cells in the pathogenesis of B‐CLL.
Treatment of intermediate‐ and high‐grade non‐Hodgkin's lymphoma using CEOP versus CNOP
Authors: Economopoulos T. , Dimopoulos M. A. , Mellou S. , Pavlidis N. , Samantas E. , Nicolaides C. , Tsatalas C. , Papadopoulos A. , Papageogriou E. , Papasavvas P. , Fountzilas G.
Published: March 2003

Abstract:Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non‐Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non‐hematological toxicity.Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate‐ and high‐grade NHL. CEOP (arm A) consisted of cyclophosphamide 1000 mg m−2, vincristine 2 mg, E 70 mg m−2on day 1 and prednisone 60 mg on days 1–7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m−2. Randomization was stratified according to stages I–IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups.Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow‐up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P = 0.09). Three‐year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P = 0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G‐CSF was given to 22 and 24 patients, respectively.Conclusion: There were no significant differences in terms of overall response rates, overall survival and time to progression between CEOP and CNOP in the treatment of intermediate‐ and high‐grade NHL. Patients with low or low intermediate IPI risk treated with either CEOP or CNOP showed significantly better survival, response rates and time to progression than those with high intermediate or high IPI risk. Therefore, new improved therapeutic approaches should be developed for the treatment of high IPI risk patients.
Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high‐dose cyclophosphamide
Authors: Auner H.W. , Tinchon C. , Brezinschek R.I. , Eibl M. , Sormann S. , Maizen C. , Linkesch W. , Schmon‐Kampel R. , Quehenberger F. , Tiran A. , Sill H.
Published: March 2003

Abstract: Objectives
: Highly differing rates of cardiac complications associated with high‐dose cyclophosphamide (CY) have been reported, and only one clinical study has been performed on the cardiotoxic effects of CY monotherapy following total body irradiation (TBI).
Patients and methods
: We prospectively evaluated the potential cardiotoxic effects of conditioning with fractionated total body irradiation and high‐dose cyclophosphamide (TBI/CY) by serial measurement of serum cardiac troponin T (cTnT), assessment of systolic and diastolic echocardiographic parameters and analysis of ventricular repolarisation indices (QT‐dispersion and corrected QT‐dispersion) in 30 adult patients with haematological malignancies undergoing haematopoietic stem cell transplantation.
Results:
There was no evidence of pretreatment cardiac dysfunction in any patient. Although cTnT was determined serially for a median of 14 d after completion of conditioning, no elevated levels were observed. Echocardiographic parameters did not show any significant change at a median follow‐up of 5 months except for one patient with evidence of impaired diastolic filling. No significant differences for mean values before and after high‐dose CY were noted for ventricular repolarisation indices. Two patients had a significant increase in corrected QT‐dispersion after CY without any other signs of cardiotoxicity. Congestive heart failure or arrythmias were not observed.
Conclusions : These data suggest that TBI/CY is safe with respect to cardiotoxicity in patients without pre‐existing cardiac dysfunction. Hitherto unknown synergistic cardiotoxic effects of CY with other cytostatic drugs may constitute the major pathogenic factor of myocardial dysfunction after high‐dose chemotherapy.
Diverse role of MMP‐2 and MMP‐9 in the clinicopathological behavior of Hodgkin's lymphoma
Authors: Kuittinen Outi , Soini Ylermi , Turpeenniemi‐Hujanen Taina
Published: March 2003

Abstract: This is the first study to describe the role of MMP‐2 and MMP‐9 in Hodgkin's disease. Strong MMP‐2 expression correlated with a favorable prognosis, while MMP‐9 expression showed a tendency toward an adverse outcome. MMP‐9 expression correlated with B symptoms and decreased new vessel formation. MMP‐2 expression was associated with the nodular sclerosis subtype, and its expression was most pronounced in the vicinity of sclerosis. Neither of the gelatinases nor the extent of neovascularization correlated with tumor stage, the occurence of bulky disease, or extranodal infiltrates. Together, these findings imply that the adverse role of MMP‐9 may be associated with the controlling of immunological processes but not the invasion probabilities or neovascularization of the tumor. The favorable prognostic value of MMP‐2 is surprising in view of the role of MMPs in solid tumors. This, however, may be linked to the basic biological differences of hematological malignancies vs. other tumors.
Myelodysplastic syndrome in transformation to acute myeloid leukemia presenting with diabetes insipidus: due to pituitary infiltration association with abnormalities of chromosomes 3 and 7
Authors: Müller Claudia I. , Engelhardt Monika , Laubenberger Jörg , Kunzmann Regina , Engelhardt Rupert , Lübbert Michael
Published: March 2003

Abstract:A 31‐yr‐old woman with myelodysplastic syndrome (MDS) in transformation to acute myeloid leukemia (AML) presented with initial symptoms of polyuria and polydipsia. Cytogenetics revealed monosomy 7 and translocation (3;3)(q21;q26). The initial symptoms, in conjunction with a low serum level of anti‐diuretic hormone (ADH) and magnetic resonance imaging (MRI) findings demonstrating loss of the ‘bright spot’ of the neurohypophysis, indicated diabetes insipidus (DI), e.g. caused by leukemic infiltration of the neurohypophysis. After induction chemotherapy the patient's bone marrow revealed blast persistence, and following a second course of chemotherapy and normalisation of MRI, an allogeneic peripheral blood stem cell transplantation (PBSCT) from the patient's HLA‐identical brother was performed, resulting in ongoing complete remission. Recently, Lavabre‐Bertrandet al.reported an association of AML with DI, elevated platelet counts, and monosomy 7 and chromosome 3 abnormalities in three patients (Eur. J. Haematol.2001: 66: 66–69). Our report of an MDS with trilineage dysplasia and these karyotypic changes associated with DI indicates that this new entity may also include preleukemic cases.
p53 gene mutations in human skin cancers
Authors: Sarasin Alain , Giglia‐Mari Giuseppina
Published: March 2003

Abstract: The p53 gene is mutated in numerous human cancers. We used it as a molecular target to characterize and try to understand the induction of mutations in human skin cancers. About 40–50% of all skin cancers in normal individuals and 60–80% of the DNA‐repair‐deficient xeroderma pigmentosum patients exhibit p53 mutations. Among these tumors, the melanomas are the less mutated ones. These mutations are characterized by specific signatures believed to be due to the UVB part of the solar spectrum. Different mutation spectra and different hot spots of mutations are found according to histopathological types of skin cancer. These data are interpreted in term of hot spots for DNA lesion induction, speed of local repair or sequence effects. The molecular analysis of these mutagenic characteristics should help us to understand the origin of human skin cancers in the general population.
Conversion of vitamin D3 to 1α,25‐dihydroxyvitamin D3 in human skin equivalents
Authors: Lehmann B. , Rudolph T. , Pietzsch J. , Meurer M.
Published: March 2003

Abstract: These results demonstrate for the first time that human keratinocytes under in vivo‐like conditions have the capacity of the enzymatic hydroxylation of vitamin D3 to hormonally active calcitriol (1α,25(OH)2D3). Supplementation of the culture medium with bovine serum albumin (BSA) up to 1.5% (w/v) amplifies the conversion of vitamin D3 to 1α,25(OH)2D3. The maximum turnover rate of this reaction at 780 nM vitamin D3 in presence of 1.0% (w/v) BSA amounts to approximately 3 pmol 1α,25(OH)2D3 per 106 cells after 6 h of incubation. The hydroxylation of vitamin D3 to 1α,25(OH)2D3 is inhibited by the P‐450 oxidase inhibitor ketoconazole. The generation of 1α,25(OH)2D3 from vitamin D3 has an apparent Michaelis constant (Km) of 2.3×10−6 M. The intrinsic conversion of vitamin D3 to biologically active 1α,25(OH)2D3 may be of importance for the regulation of proliferation and differentiation of keratinocytes.
Ornithine decarboxylase transgenic mice as a model for human atrichia with papular lesions
Authors: Panteleyev A. A. , Christiano A. M. , O'Brien T. G. , Sundberg J. P.
Published: March 2003

Abstract: The hair follicle is characterized by cyclic transformations from active growth and hair fiber production through regression into a resting phase. The growth phase, known as anagen, is associated with rapid rates of cell turnover, and variations in the rate of DNA synthesis in mouse skin throughout the hair cycle are accompanied by changes in the activity of ornithine decarboxylase (ODC), a key enzyme in the synthesis of polyamines, which are actively involved in regulation of normal cell division, differentiation, and growth. Previously, a transgenic mouse was created that overexpressed ODC in the skin using a K6 promoter. The first hair cycle in neonatal transgenic mice appeared to be normal, but by the third week of postnatal life transgenic pups begin to progressively lose hair. The lower portion of the hair follicle was progressively replaced with enlarging cystic structures located in the deep dermis, and the transgenic mice exhibited excessive growth of skin mass resulting in pronounced wrinkling and folding. Interestingly, these findings bore striking resemblance to the rhino mouse phenotype and to human patients with papular atrichia, a rare congenital ectodermal disorder characterized by progressive and irreversible hair loss in early childhood. The similarities in phenotype between transgenic mice and human atrichia with papular lesions suggest that ODC transgenics may represent a useful model for studying this disorder. It appears that ODC plays a functionally important, yet still obscure role in a complex metabolic pathway that is critical in hair follicle function not only in mice, but in humans as well.
Quantitative analysis of UVB‐induced apoptosis in human epidermis
Authors: Hurwitz S. A. , Spandau D. F.
Published: March 2003

Abstract: The quantitative measurement of the induction of apoptosis in cells grown in vitro can be accomplished using a variety of proven methods. However, the quantitative assay of apoptosis within an intact tissue is very laborious and the results can be misleading. We have established a method to quantitatively analyze the induction of apoptosis in human epidermis following UVB irradiation. The assay is based on the activation of the apoptotically induced enzyme caspase 3, using a synthetic caspase 3 substrate. The activation of caspase 3 was shown to correlate with the induction of apoptosis in human keratinocytes cultures as a monolayer. We then demonstrated that the activation of caspase 3 could be measured from UVB‐irradiated whole skin. The induction of apoptosis was confirmed by cellular morphology and terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end‐labeling. Therefore, we concluded that the measurement of caspase 3 specific activity in UVB‐irradiated human epidermis was an efficient, inexpensive, and accurate method to quantitate UVB‐induced apoptosis in vivo.
Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM‐CSF as adjuvant
Authors: Hunger R. E. , Brand C. U. , Streit M. , Eriksen J. A. , Gjertsen M. K. , Saeterdal I. , Braathen L. R. , Gaudernack G.
Published: March 2003

Abstract: The rapidly increasing incidence and mortality rate of malignant melanoma, together with the lack of efficient treatment of the late stages, makes it a serious threat to public health. Innovative new treatments are needed. The proteins of the ras‐family of proto‐oncogenes, functioning as relay switches for signalling pathways between cell surface and nucleus, are involved in cell proliferation, differentiation, apoptosis and transformation. If over‐expressed or mutated they can induce and/or maintain a transformed state of a cell. Codon 61 mutations of N‐ras seem to be involved in melanoma development on sun exposed sites. In order to induce an immune response towards mutated N‐ras proteins we performed a phase 1 feasibility study. Ten melanoma patients were immunized intradermally 6 times with N‐ras peptides (residue 49–73) with 4 codon 61 mutations using GM‐CSF as adjuvant. HLA typing was not used as an inclusion criterion. Eight patients responded with strong delayed type hypersensitivity reactions. In 2 of the patients an in vitro response to the vaccine could also be detected. The specificity of the reaction could be confirmed by cloning of peptide‐specific CD4 positive T cells from peripheral blood of the patients. Intradermal injection of ras peptides using GM‐CSF as adjuvant is simple to perform and seems to be efficient in inducing cellular immune responses. Since a majority of the patients showed positive skin reactions and 2 of the patients analysed showed a T‐helper response to this melanoma specific antigen, these promiscuous HLA class II binding mutant ras peptides may be candidates for inclusion into vaccine cocktails containing various established CTL epitopes.
Melanocyte and gonad activity as potential severity modifying factors in C3H/HeJ mouse alopecia areata
Authors: McElwee K. J. , Silva K. , Beamer W. G. , King L. E. , Sundberg J. P.
Published: March 2003

Abstract: Circumstantial evidence has previously suggested gonad derived steroid hormones and melanogenesis related antigens may modify human alopecia areata (AA). AA‐like hair loss can be induced in C3H/HeJ mice after skin allografts from spontaneous AA‐affected mice. This inducible model was used to evaluate hormones and hair follicle melanocyte presence as disease‐severity modifiers. Ten females and 9 males were gonadectomized and received AA‐affected allografts. All gonadectomized mice had 2–4 weeks delay in AA onset relative to non‐gonadectomized controls. Two females and 4 males failed to develop any AA by 25 weeks after grafting. The experiment was repeated with gonadectomized female and male mice plus non‐gonadectomized mice subcutaneously implanted with silastic capsules containing 80 μg 17β estradiol or 10 mg 5α dihydrotestosterone, respectively. Five of 11 ovariectomized and 9 of 11 non‐ovariectomized, estradiol supplemented females developed AA with extremely rapid progression. Three of 8 castrated, but none of 11 non‐castrated, dihydrotestosterone‐supplemented males expressed AA. In a separate study, 14 mice were freeze‐branded, producing white hair on the dorsal lumbar region, and later received full‐thickness allografts. Thirteen mice developed patchy pigmented and non‐pigmented hair loss. One mouse developed diffuse, pigmented hair loss, but with white hair survival persisting 25 weeks after grafting. The results suggest that gonadal steroid hormones can modulate C3H/HeJ mouse AA where estradiol promoted rapid progression of AA while dihydrotestosterone increased resistance to AA onset. In general, both pigmented and non‐pigmented C3H/HeJ mouse hair is susceptible to AA. Murine AA susceptibility and severity clearly involves an interplay between genetic and epigenetic factors.
Cytokine therapy in dermatology
Authors: Asadullah K. , Sterry W. , Trefzer U.
Published: March 2003

Abstract: Cytokines have been in the focus of scientific interest for some years now. Analysing their expression permitted a better understanding of the pathogenesis of various diseases, including in dermatology. Moreover, they are now far beyond the stage when they were of interest only to the pathophysiological research sector: some cytokine therapies are already being employed as part of the clinical practice.

In fact, several cytokines are used for the treatment of malignant, inflammatory and infectious skin diseases. Their stage of development ranges from advanced, already approved and well established therapies (e.g. IFN‐α and IL‐2 for melanoma) to early explorative trials (e.g. IL‐4 and IL‐10 for psoriasis). Some of the new approaches currently under investigation will actually lead to registration of new drugs for dermatological treatment and to supplement existing therapeutic options. Beside this, the results of clinical trials with cytokines are significantly contributing to our understanding of the pathophysiology of diseases. They will give a better insight into which mechanisms play a greater or lesser part in their development and may generate momentum for still better targeted pharmacological approaches. Here we would like to give an overview about the current stage of cytokine therapy and the prospects for dermatological indications. The terminology and immunobiology of cytokines are also briefly discussed, since for a sensible interpretation of the relevant findings a basic knowledge of these biologically highly active messenger substances is essential.
Induction of skewed Th1/Th2 T‐cell differentiation via subcutaneous immunization with Freund's adjuvant
Authors: Shibaki A. , Katz S. I.
Published: March 2003

Abstract: CD4+ T cells differentiate into at least two distinct subsets, Th1 and Th2, that are characterized by their cytokine‐producing profiles. In this study, we attempted to delineate whether and how CD4+ T‐cell responses could be skewed in one direction or another. BALB/c mice were immunized with chicken ovalbumin (OVA) emulsified with either incomplete or complete Freund's adjuvant (IFA or CFA). When lymph node cells were assessed on day 7, antigen specific proliferation was similarly observed both in the mice immunized with IFA and CFA. In contrast, on day 28 there was a less significant response in the mice primed with IFA than in those primed with CFA. ELISA analyses revealed more Th1 predominant cytokine production by T cells immunized with OVA+CFA rather than in IFA, which resulted in balanced IFN‐γ and IL‐4 production. Flow cytometric analyses of intracellular cytokines confirmed that T cells from mice primed with CFA produced Th1 cytokines more predominantly. When lymph node dendritic cells (DC) were compared for their co‐stimulatory molecule expression, priming with CFA and IFA similarly upregulated CD80 and CD86 expression by lymph node DC, and no significant differences were observed in CD40, 54, 80 and 86 expression between the DC harvested from IFA and CFA immunized mice. In addition, both priming with IFA and CFA similarly induced IL‐12 production by DC. Thus, although the reason(s) for the preferential induction of a Th1/Th2 response remains unknown, these results indicate that a relatively Th1/Th2 skewed response is differentially induced by different types of adjuvants, and induction of a Th1 skewed response may be responsible for long lasting cellular immunity.
IL‐4 and interferon‐γ differentially modulate vascular endothelial growth factor release from normal human keratinocytes and fibroblasts
Authors: Trompezinski S. , Denis A. , Vinche A. , Schmitt D. , Viac J.
Published: March 2003

Abstract: IL‐4 and interferon‐γ (IFN‐γ) are crucial modulators of the immune system and are reported as active antitumor agents and potent inhibitors of angiogenesis. We investigated the effects of these two cytokines on the expression of vascular endothelial growth factor (VEGF), a mediator of major importance in the angiogenesis associated with inflammation, wound healing and tumor invasion and expressed by activated keratinocytes and dermal fibroblasts. Human keratinocytes (HK) and fibroblasts (HF) derived from foreskins, were further cultured during 24 h in defined medium, supplemented or not with the selected growth factors, EGF and TGF‐β1, respectively, before receiving the addition of either IL‐4 or IFN‐γ during 24 and 48 h. In basal conditions, fibroblasts produced smaller amounts of VEGF than keratinocytes; the addition of growth factors to the skin cells induced a drastic increase of VEGF secretion. In HF, the basal level of VEGF secretion was reduced by IFN‐γ and slightly increased by IL‐4 whereas in HK, IFN‐γ enhanced the secretion of VEGF after 48 h and IL‐4 either tended to reduce VEGF secretion or did not exert any effect. Similar but more significant results were observed in skin cells activated by growth‐stimulating factors. The association of IL‐4 and IFN‐γ mimicked the effects of IFN‐γ alone both in HF and HK. Taken together, these results indicate opposite effects of IFN‐γ and IL‐4 on VEGF expression from normal and activated HF and HK. IL‐4 may be considered as a poor modulator of VEGF secretion by dermal and epidermal cells. Conversely, IFN‐γ appears as a prominent and versatile mediator in the desregulated angiogenesis associated with inflammatory skin reactions characterized by a T‐helper type 1 cell‐mediated response.
The effect of topically applied salicylic compounds on serotonin‐induced scratching behaviour in hairless rats
Authors: Thomsen J. S. , Simonsen L. , Benfeldt E. , Jensen S. B. , Serup J.
Published: March 2003

Abstract: There is a strong need for antipruritic substances for treating itch in clinical dermatology. In one recent human study, topically applied acetylsalicylic acid has been described to rapidly decrease histamine‐induced itch. We have established a model for periferally elicited pruritus by injecting serotonin into the rostral back area (neck) in rats. Using this model, we aimed to investigate the antipruritic potential of four different salicylic compounds, which all possess different skin penetration characteristics. Eighteen rats were studied for 6 weeks. Prior to serotonin injections (2 mg/ml, 50 µl), 10 µl of test substances was applied to a circular area 18 mm in diameter. The four substances were salicylic acid, butyl salicylate, diethylamine salicylate and salicylamide, all solubilized in dimethyl isosorbide to a concentration of 5% w/w. Diethylamine salicylate and salicylamide were previously shown to be slowly absorbed through rat skin in contrast to salicylic acid and butyl salicylate. After serotonin injections, scratching was monitored by video recording for 1.5 h. Compared with the vehicle, a lower number of scratch sequences were seen when diethylamine salicylate (P < 0.001) and salicylamide (P = 0.005) had been applied. The numbers of scratch sequences were lower with diethylamine salicylate and salicylamide than with the vehicle throughout the 1.5‐h study period. We conclude that topical application of diethylamine salicylate and salicylamide could suppress serotonin‐induced scratching in rats. The antipruritic effect seems to be related to the slow drug release of the two substances. The results may be clinically relevant as serotonin induces itch in humans.
IL‐4, IL‐5, TGF‐β1 and IFN‐γ mRNAs detected by a new in situ amplification system in cicatricial pemphigoid
Authors: Caproni Marzia , Calzolari Anna , Giomi Barbara , Santucci Marco , Ficarra Giuseppe , Fabbri Paolo
Published: March 2003

Abstract: The process that induces chronic progressive scarring in cicatricial pemphigoid (CP), a rare group of autoimmune mucocutaneous blistering diseases, is still under investigation. The tendency to heal with scar formation observed in CP could be due to the specific localization of the antigen in the basement membrane zone or could depend on the frequent recurrence of the disease in a localized area. The release of soluble fibrogenic factors by inflammatory infiltrating cells has also been considered as pathogenetically relevant. The aim of this study is to evaluate the expression of mRNA for IL‐4, IL‐5, TGF‐β1, IFN‐γ in patients with CP, and investigate the role of the cytokine profile as a possible cause of the clinical features and course of the disease. Fourteen patients (3 male, 11 female; age range 40–72 years) with oral (n = 10), preputial (n = 3) and cutaneous (n = 1) CP were studied. The formalin‐fixed and paraffin‐embedded biopsies were examined by in situ hybridization performing a new amplification system based on biotinyl‐tyramide. As a control, 4 patients (2 male, 2 female; age range 58–73 years) affected by bullous pemphigoid (BP), the most common autoimmune subepidermal blistering disease, were also examined. In CP, IL‐4 mRNA expression was present in 4 out of the 14 cases analysed. IL‐5 was detected in 12 CP biopsies. TGF‐β1 and IFN‐γ mRNAs were identified in 9 and 11 CP cases, respectively. In BP, an IL‐4 hybridization signal could not be observed in any of the cases. By contrast IL‐5, TGF‐β1 and IFN‐γ mRNA analyses were positive in all four BP cases. Our results suggest the presence of a T‐cell population with a mixed cytokine pattern in the cellular infiltrate of both blistering diseases, with a corresponding increase of Th2‐like activity in fully developed lesions, irrespective of the different sites involved. In addition, on the basis of the constant presence of TGF‐β1 mRNA in the different lesional phases of CP, and its overlapping expression in BP, we hypothesize that the involvement of additional factors is responsible for the scarring course typical of CP.