bluuebunny/crossref_metadata_2025 huggingface dataset:
Population changes of different predators during a water vole cycle in a central European mountainous habitat
Authors: Weber J.‐M. , Aubry S. , Ferrari N. , Fischer C. , Feller N. Lachat , Meia J.‐S. , Meyer S.
Published: March 2003

Population changes in long‐eared owls Asio otus, polecats Mustela putorius, red foxes Vulpes vulpes, stone martens Martes foina and badgers Meles meles were monitored during a water vole Arvicola terrestris scherman cycle in western Switzerland. Long‐eared owls confirmed their status of highly mobile specialist predators in responding strongly and without time lag to water vole population changes. Even though polecats are considered generalists, they exhibited also a strong response to water vole fluctuations. Their numbers tracked water vole densities with a 1‐yr time lag. Marked population changes were also recorded in red foxes and stone martens, but these changes were not related to water vole densities. Lastly, badgers did not show any significant population changes during the water vole cycle. We discuss the possible reasons for these differences and conclude that multi‐factorial approach is clearly required to understand population processes in predator‐prey systems.
Analysis of nest occupancy and nest reproduction in two sympatric raptors: common buzzard Buteo buteo and goshawk Accipiter gentilis
Authors: Krüger Oliver
Published: March 2003

Nest site selection can have important fitness consequences in birds. I analysed the habitat characteristics of 392 nests of two sympatric raptor species (common buzzard Buteo buteo and goshawk Accipiter gentilis) in Germany and their relation to nest occupation rate and nest reproductive success. For common buzzard, multivariate models explained only small proportions of the variance in nest occupation rate and nest reproductive success (13–19%). Important variables related to nest occupation rate were human disturbances, intra‐ and interspecific neighbour density, the amount of forested area and nest tree crown cover. Variables related to nest site reproductive success also included human disturbance, intra‐ and interspecific neighbour density and nest tree crown cover as well as nest distance to the nearest forest edge. In contrast, models for the goshawk explained a much higher proportion of the variation in nest occupation rate and nest reproductive success (41–43%). Important variables related to nest occupation rate were the remoteness of the nest site and direct human disturbance. Variables related to nest site reproductive success were remoteness of the nest site and good hunting habitat. Goshawks seem to be more sensitive to human disturbance than buzzards. A multiple discriminant analysis showed that nest site characteristics substantially overlapped between the species and there is a good evidence that competition for optimal nest sites occurs. Thus, buzzards might be constrained by the dominant goshawk in their nest site selection.
Genetic structure detected in a small population of the endangered plant Anthericum liliago (Anthericaceae) by RAPD analysis
Authors: Peterson Angela , Bartish Igor V. , Peterson Jens
Published: March 2003

We report results showing that the RAPD technique is a powerful method for detailed genetic analysis of a small natural population of the endangered plant species Anthericum liliago L. (Anthericaceae). This population grows on silicate grasslands in central Germany. We investigated all 127 ramets found in the population area. Within the population area, restricted to ca 45 m2, we visually identified three subpopulations. Analysis of 54 RAPD markers revealed a relatively low level of genetic polymorphism (34.6%) and a pronounced subpopulation structure within the studied population. Our results show a significant (p<0.001, r=0.423) correlation between genetic and spatial distances within this population which may be a result of restricted pollen and seed dispersal and of a high selfing rate. In the studied population the ant species Myrmica sabuleti (Meinhart) is probably the main pollinator for A. liliago. These ants have a relatively small radius of movement and therefore pollen transfer mediated by ants probably restricts gene flow in the A. liliago population. We suggest that the time of flowering and the distance between individual plants play an important role in successful pollination and seed production of the investigated A. liliago population.
Geographic variability of ecological niches of plant species: are competition and stress relevant?
Authors: Prinzing Andreas , Durka Walter , Klotz Stefan , Brandl Roland
Published: March 2003

A species’ niche position may differ strongly between geographic regions, for instance due to the effect of competitors or ecophysiological stress. However, it is unclear whether such strong geographic niche variation is the rule or the exception. We compared the niche positions of plant species between central England and eastern central Europe (as available from the literature), using phylogenetically independent contrasts. We found that most species occupied similar niche positions in both regions. More importantly, we found that niche variation was not higher in species susceptible to competitive displacement. Nor was niche variation higher in species that reach the edge of their range and thus suffer ecophysiological stress. We suggest that although these species might be easily displaced in their position along a niche axis, they may only be displaced over a short distance. Overall, ecological mechanisms that cause niche variation at the local scale may be much less relevant at the geographic scale.
Patterns of endemic extinctions among island bird species
Authors: Biber Eric
Published: March 2003

The relationship between island biogeography and the vulnerability of island biota to extinction as a result of human activities was examined. In particular, this study analyzed whether island area, maximum elevation of an island, isolation from the nearest continental landmass, or date of human colonization had statistically significant relationships with the proportion of endemic island bird species that have become endangered or extinct. The study examined islands or island groups with endemic bird species, and which have never been connected to a continental landmass. Both modern and fossil bird species were incorporated into the analysis. Islands that were colonized by humans earliest had the lowest proportion of modern species alone, and modern and fossil species combined, that have gone extinct. However, date of human arrival was not correlated with the proportion of modern species that are endangered. Maximum elevation of an island was negatively correlated with the proportion of modern species that are extinct, and was positively correlated with the proportion of modern species that are endangered. Area was negatively correlated with the proportion of modern species that are endangered. Isolation of islands was not significantly correlated with the proportion of modern species extinct or endangered, but was positively correlated with the proportion of modern and fossil species combined that have gone extinct. These results indicate that the initial spasm of island bird extinctions due to human contact may have, in part, passed. They also indicate that bird species on islands colonized earliest by humans may have had more time to adapt to the presence of man and his commensal species, resulting in reduced extinction rates.
Proteasome inhibitors induce caspase‐dependent apoptosis and accumulationof p21WAF1/Cip1 in human immatureleukemic cells
Authors: Naujokat Cord , Sezer Orhan , Zinke Hartmut , Leclere Anja , Hauptmann Steffen , Possinger Kurt
Published: March 2003

Abstract: The 26S proteasome is a non‐lysosomal multicatalytic protease complex for degrading intracellular proteins by ATP/ubiquitin‐dependent proteolysis. Tightly ordered proteasomal degradation of proteins critical for cell cycle control implies a role of the proteasome in maintaining cell proliferation and cell survival. In this study, we demonstrate that cell‐permeable proteasome inhibitors, lactacystin, benzyloxycarbonyl(Z)‐leucyl‐leucyl‐leucinal (ZLLLal; MG‐132) and4‐hydroxy‐5‐iodo‐3‐nitrophenylacetyl‐leucyl‐leucyl‐leucine vinyl sulfone (NLVS), induce apoptosis abundantly in p53‐defective leukemic cell lines CCRF‐CEM, U937 and K562 as well as in myelogenic and lymphatic leukemic cells obtained from adult individuals with relapsed acute leukemias. Leukemic cell apoptosis induced by the proteasome inhibitors was dependent on activation of caspase‐3 and related caspase family proteases, because caspase‐3 inhibitor N‐acetyl‐l‐aspartyl‐l‐glutamyl‐l‐valyl‐l‐aspartal (Ac‐DEVD‐cho) and, more effectively, the general caspase‐inhibitor N‐benzyloxycarbonyl‐l‐valyl‐l‐alanyl‐l‐aspartate fluoromethylketone (Z‐VAD‐fmk) were capable of blocking apoptosis induced by lactacystin, ZLLLal or NLVS. Induction of apoptosis by lactacystin or ZLLLal was accompanied by cell cycle arrest at G2/M phase and by accumulation and stabilization of cyclin‐dependent kinase inhibitor p21WAF1/Cip and tumor suppressor protein p53. A role of p53 in mediating apoptosis or induction of p21WAF1/Cip1 was ruled out since CCRF‐CEM and U937 cells express non‐functional mutant p53, and K562 cells lack expression of p53. Viability and hematopoietic outgrowth of human CD34+ progenitor cells treated with lactacystin were slightly reduced, whereas treatment of CD34+ cells with ZLLLal or the cytostatic drugs doxorubicin and gemcitabine resulted in markedly reduced viability and hematopoietic outgrowth. These results demonstrate a basic role of the proteasome in maintaining survival of human leukemic cells, and may define cell‐permeable proteasome inhibitors as potently anti‐leukemic agents which exhibit a moderate hematopoietic toxicity in vitro.
Expression of complement regulatory proteins CR1, DAF, MCP and CD59in haematological malignancies
Authors: Guc Dicle , Canpınar Hande , Kucukaksu Can , Kansu Emin
Published: March 2003

Abstract:

Host cells are protected from the lytic effect of the complement system by complement regulatory proteins. This study was designed to investigate the expression of complement regulatory proteins on leukemic blasts which may be susceptible to the lytic effects of the complement system in the circulation. The surface expressions of complement regulatory proteins, complement receptor 1 (CR1, CD35), decay accelerating factor (DAF, CD55), and homologous restriction factor 20 (HRF20, CD59), on peripheral blood and bone marrow blasts were evaluated by using flow cytometry in 16 acute myeloblastic leukemia (AML), 16 acute lymphoblastic leukemia (ALL), 4 chronic lymphocytic leukemia (CLL), 3 chronic myelocytic leukemia (CML) patients and control granulocytes and lymphocytes obtained from 15 healthy volunteers. mRNA expression was investigated by Northern blot analysis. mRNA abundances were calculated after normalization according to 28s rRNA. Surface expressions of CR1 and DAF were marginally (p=0.08 and p=0.08, respectively) lower in AML, and DAF expression was significantly lower (p=0.0008) in ALL patients in comparison to their normal counterparts. Except from a slight increase that is detected for CD59 in CML patients (P=0.06), there was no significant difference between the surface expressions of CD59 in any of the groups studied. Densitometric analysis of autoradiographs obtained from Northern blots revealed that in AML patients, CR1 mRNA expression were 5.5‐fold lower than controls (p=0.06), while DAF mRNA expression was significantly higher (p=0.0046). Furthermore, the mRNA expression of CR1 in ALL patients was found significanly lower than in the control group (p=0.0419). None of the values obtained from the other groups were significantly different from each other. These results suggest that leukemic blasts are protected from the lytic attack of the complement system at all levels, since all of the complement membrane regulatory proteins were expressed in all leukemia types (although at lower amounts in some cases), and it is also possible to use CR1 and DAF as differentiation markers in acute leukemias.
Increased risk of lymphoproliferative disorders in relatives of patients withB‐cell chronic lymphocytic leukemia: relevance of the degree of familial linkage
Authors: Capalbo Silvana , Trerotoli Paolo , Ciancio Angela , Battista Cosima , Serio Gabriella , Liso Vincenzo
Published: March 2003

Abstract: We assessed the familial aggregation of chronic lymphoproliferative diseases (CLD) in 3962 relatives of 169 patients with B‐cell chronic lymphocytic leukemia (B‐CLL). Data collection included a self‐administered questionnaire. The “relative risk” considered the connection between a higher incidence of CLD and the degree of familial linkage with the probands. The model of logistic regression was statistically significant (p<0.001), with the probability of CLD increasing in proportion to the relationship coefficient between parents, siblings and children [(relationship coefficient 0.5; probability of CLD 1.85 (C.I. 95%, range 1.1–3%)]. CLD, particularly B‐CLL, were observed in first‐degree relatives of the patients with B‐CLL more often than in other relatives.
Assessment of peripheral blood lymphocyte subsets in idiopathic myelofibrosis
Authors: Cervantes Francisco , Hernández‐Boluda Juan‐Carlos , Villamor Neus , Serra Angélica , Montserrat Emilio
Published: March 2003

Abstract: The objective of this study was to contribute to a better characterization of the immunological profile of idiopathic myelofibrosis (IM) at presentation by analysing the blood lymphocyte subsets and their possible correlations with other disease features. Absolute blood lymphocytes and lymphocyte subsets were assessed in 31 IM patients, compared with those from 34 healthy individuals, and correlated with the patients' main clinical, hematological and bone marrow histologic features. The mean lymphocyte count of the IM patients was 1.1 (SD 0.6)×109/L, versus 1.6 (SD 0.49)×109/L in controls (p=0.0006), with 24 of the 31 patients (77.4%) showing lymphocytopenia (<1.5×109/L). IM patients had significantly lower counts of CD3, CD4, CD8, and CD3−/CD56+ cells, and significantly higher CD3+/CD56+ lymphocyte counts. Although no significant differences were found between patients and controls with regard to CD19+/CD5+ cell counts, increased CD5+ B‐cell lymphocytes were observed in three IM patients. In one of the latter patients, Ig gene rearrangement analysis of the heavy chain gene demonstrated such a subpopulation to be clonal, but the patient did not develop features of chronic lymphoid leukemia during a 5‐yr follow‐up. No correlation was found between the patients' blood lymphocyte counts and other disease features. We conclude that most IM patients have absolute lymphopenia, decreased T cells and increased cytotoxic T cells at diagnosis, and 10% of them show an increased CD5+ B‐cell subpopulation.
Veno‐occlusive disease of the liver after hemopoietic cell transplantation
Authors: Carreras Enric
Published: March 2003

Abstract: The clinical syndrome of veno‐occlusive disease (VOD) after hemopoietic cell transplantation is characterised by jaundice, painful liver enlargement, and fluid retention with weight gain. Cytoreductive therapy is presumably the primary cause of VOD, but several other agents (and a special susceptibility of the liver) can also play a role in its genesis. The risk of VOD can be predicted before BMT by analysing the presence or absence of the main risk factors. For the diagnosis of VOD most teams worldwide apply the clinical criteria developed by both the Seattle and Baltimore teams. Transjugular liver studies and some biological markers can help establish a correct differential diagnosis. In most cases clinical manifestations improve after several days, but 20–25% of patients could die of VOD. Data regarding whether or not pharmacological prophylactic measures are effective are contradictory. There a few therapeutical approaches directed towards the improvement of venular occlusion; recombinant tissue plasminogen activator and defibrotide can solve some cases of severe VOD.
Prevalence of retinopathy in patients with anemia or thrombocytopenia
Authors: Carraro Maria Cristina , Rossetti Luca , Gerli Gian Carla
Published: March 2003

Abstract: Background and objectives: Fundus lesions can be the accompanying symptom in many hematological diseases. In cases of anemia or thrombocytopenia, the exact mechanism leading to fundus abnormalities is not completely understood. The aim of this study was to calculate the prevalence of fundus lesions in anemic and thrombocytopenic patients, and define the risk factors for retinopathy. Design and methods: This cross‐sectional study involved 226 patients with anemia and/or thrombocytopenia and a control group of 47 age‐matched subjects. The studied variables were age, gender, hemoglobin levels, mean cell volume (MCV), red cell distribution width coefficient variation (RDW‐CV), the type of onset of anemia, platelet counts, mean platelet volume (MPV), platelet distribution width (PDW), the platelet–large‐cell ratio (P‐LCR), prothrombin time (PT) and partial thromboplastin time (PTT). Results: Retinopathy was observed in 28.3% of the patients as a whole, the presence of fundus lesions being closely associated with severe anemia (Hb < 8 g/dL) and severe thrombocytopenia (PLT < 50 × 109/L). Among the patients with concomitant anemia and thrombocytopenia, the incidence of retinopathy was 38%. Age, low hemoglobin levels, platelet counts, RDW‐CV, and increased MCV, MPV and P‐LCR were all significantly associated with the presence of fundus lesions at univariate analysis. Interpretation and conclusions: Retinopathy is a frequent finding in anemic and thrombocytopenic patients, although it is often not significant clinically. As retinal hemorrhages were found in all of the patients with concomitant severe anemia and thrombocytopenia, it is recommended that all such patients undergo routine fundus examinations.
Telomerase regulation and telomere dynamics in germinal centers
Authors: Norrback Karl‐Fredrik , Hultdin Magnus , Dahlenborg Katarina , Osterman Pia , Carlsson Roland , Roos Göran
Published: March 2003

Abstract: Telomere length maintenance, usually executed by telomerase, is a prerequisite for an extended or infinite division potential. Nevertheless most telomerase positive normal cells exhibit telomere shortening. This study details the telomerase expression and telomere dynamics in purified tonsil B cell subsets during the germinal center (GC) reaction. Significant telomere lengthening was observed as naive B cells matured to centroblasts and when centroblasts matured further to centrocytes, resulting in an increase in telomere length of about 4 kbp determined by Southern blotting. Immunopurified cell populations were also studied by fluorescence in situ hybridization and flow cytometry (flow‐FISH) confirming that the GC B cells exhibited lengthened telomeres. These data were further verified in unpurified tonsil cells by combining flow‐FISH and immunophenotyping using selected surface markers. Centroblasts expressed high levels of telomerase activity, which was increased in centrocytes, whereas resting naive, activated naive and memory B cells were telomerase activity negative. Expression levels of the catalytic subunit (hTERT) RNA paralleled the telomerase activity levels. The unique telomere elongation in GC B cells permits extensive proliferation during the GC reaction and provides the memory cells with a substantial increase in division potential. Understanding the telomere biology of GC cells is important in defining requirements for telomere elongation in vivo, with implications for the normal immune system as well as for lymphomas, and could provide insights into how the division potential of cells can be manipulated in vitro.
Cell surface expression of CD25, CD54, and CD95 on B‐ and T‐cells in chronic lymphocytic leukaemia in relation to trisomy 12, atypical morphology and clinical course
Authors: Hjalmar Viktoria , Hast Robert , Kimby Eva
Published: March 2003

Abstract: Background: Surface antigen expression can be used to define subgroups of patients with different clinical courses in chronic lymphocytic leukaemia of the B‐cell type (CLL). Purpose–Methods: To study the clinical significance of functional markers linked to proliferation (CD25), adhesion (CD54), and apoptosis (CD95) on B‐ and T‐cells in 68 patients with CLL using dual colour flow cytometry (FCM). Results: The mean proportion of CD19+ B‐cells expressing CD25 was significantly higher in CLL patients compared to controls (P=0.02), while CD54+ and CD95+ B‐cells did not differ significantly. In CLL with atypical morphology and in patients with trisomy 12, the mean percentage of CD25+ B‐cells was lower than in typical CLL (P<0.02) and in patients with disomic tumor cells (P<0.03). Patients with 30% of CD25+ B‐cells had a shorter median time to treatment than CD25‐negative cases (P=0.01). A low CD54 expression was associated with a prolonged median time to treatment (P=0.004), low WBC counts (P<0.05), and low S‐LDH (P=0.03). A high CD95 expression was correlated with elevated S‐LDH (P=0.02) and a finding of lymphadenopathy (P=0.02). In individual patients there was a strong correlation between B‐ and T‐cell expression of CD25 (P<0.0001), CD54 (P=0.0002), and CD95 (P=0.0002), respectively. Conclusions: CD25 and CD54 expression on CD19+ cells seems to give prognostic information. The strong correlation between the expression of CD25, CD54 and CD95 on B‐and T‐cells suggests that the expression of these antigens is not an inherent characteristic of the malignant B‐cell clone.
Relationship between the clinical manifestations of sickle cell disease and the expression of adhesion molecules on white blood cells
Authors: Okpala Iheanyi , Daniel Yvonne , Haynes Roberta , Odoemene Damian , Goldman John
Published: March 2003

Abstract: Background: The severity of sickle cell disease (SCD) increases with leukocyte count. The biological basis could be that leukocyte adherence to vascular endothelium mediated by adhesion molecules (AMs) facilitates vaso‐occlusion, the basic pathological process in SCD. Objective: To find out if there is a relationship between expression of AMs by leukocytes and the clinical manifestations of SCD. Methods: Flow cytometry was used to study the relationship between leukocyte AM expression and disease manifestations in 100 patients with homozygous (HbSS) sickle cell disease and 34 genotype HbAA controls. The effect of hydroxyurea therapy on AM expression was also examined. We excluded HbSS patients with any other disease, pregnancy in the previous 3 months, or Haemogloben F (HbF) ≥ 10%. Results: Patients with complications of SCD showed high expression of αMβ integrin by the neutrophils; and l‐selectin by lymphocytes and neutrophils (P < 0.03). CD18 was highly expressed by neutrophils in patients with sickle nephropathy (P = 0.018), and l‐selectin by lymphocytes in those with stroke (P = 0.03). Monocyte l‐selectin increased in sickle cell crisis relative to steady state (P = 0.04). Expression of αLβ2 integrin by neutrophils, monocytes, and lymphocytes decreased within a month of hydroxyurea therapy (P < 0.05), with symptomatic improvement in the patients and no more than 3.3% rise in HbF level. Conclusions: The findings suggest that in SCD (1): High steady‐state expression of αMβ2 integrin and l‐selectin by leukocytes predisposes to severe manifestations. (2) Increased leukocyte AM expression above steady‐state levels could be important in the genesis of crisis. (3) The early symptomatic improvement that follows hydroxyurea therapy is mediated via mechanisms independent of increased HbF, and may involve reduced AM expression in leukocytes. (4) Other treatment modalities that reduce leukocyte AM expression might also confer clinical benefit.
The impact of vegetarianism on some haematological parameters
Authors: Obeid Rima , Geisel Jürgen , Schorr Heike , Hübner Ulrich , Herrmann Wolfgang
Published: March 2003

Abstract: Objective
: Subjects adopting a vegetarian diet are liable to vitamin B12 and iron deficiencies. Co‐existing vitamin B12 and iron deficiencies may give an equivocal haematological picture, which may, in turn, delay making an early diagnosis. The current work was undertaken to investigate some haematological parameters in relation to vitamin B12 and iron status in vegetarians.
Subjects and methods
: Twenty‐nine vegans, 64 lacto‐ and lacto‐ovo‐vegetarians, in addition to 20 occasional meat eaters, were enrolled for this study. The total group included 49 males and 64 females aged [mean (SD) = 46(15) yr]. Complete blood count, methylmalonic acid (MMA), homocysteine (HCY), ferritin, and transferrin concentrations and percentage transferrin saturation were assayed, using conventional methods.
Results
: Vegans displayed the highest MMA and HCY levels (median MMA = 708 nmol L

−1
; HCY = 12.8 µmol L

−1
). A lower lymphocyte count and a higher mean corpuscular volume (MCV) were found in vegans compared with lacto‐ or lacto‐ovo‐vegetarians (median = 1.51 × 10
9
vs. 1.83 × 10
9

 L

−1
; 92 vs. 89 fL, respectively). Vitamin B12‐deficient subjects in the higher range of transferrin saturation percentage had higher MCV than vitamin B12‐deficient subjects in the lower transferrin saturation range (mean MCV = 92 vs. 89 fL). A lower platelet count was found in the highest quartile of MMA (mean = 211 × 10
9

 L

−1
) and in the highest quartile of HCY (mean = 215 × 10
9

 L

−1
), compared with the other quartiles. Lower lymphocyte and platelet counts and higher MCV were found in subjects with elevated MMA and HCY, compared to those with normal metabolites. Factors that explained the variations in MCV were red blood cell count, ferritin, transferrin saturation, and methylmalonic acid levels.
Conclusion : vitamin B12 and iron status were compromised by a vegetarian diet. Variations in mean corpuscular volume were determined by iron and vitamin B12 status. Lower lymphocyte and platelet count were accompanied by metabolic evidence that indicated vitamin B12 deficiency.
Complete remission of pure white cell aplasia associated with thymoma, autoimmune thyroiditis and type 1 diabetes
Authors: Fumeaux Zina , Beris Photis , Borisch Bettina , Sarasin François P. , Roosnek Eddy , Dayer Jean‐Michel , Chizzolini Carlo
Published: March 2003

Abstract: Pure white cell aplasia (PWCA) is a rare disorder of unknown origin, often associated with thymoma, characterized by selective neutropenia or pure agranulocytosis, and absence of granulocyte precursors in the bone marrow, but with normal erythroblasts and megakaryocytes. We report a case of PWCA associated with thymoma. Unusual findings in this case report included simultaneous presence of autoimmune thyroiditis, type 1 diabetes, anti‐striated muscle antibodies, and the presence in the peripheral blood of CD8+ T cells that expressed a homogeneous naive phenotype. Neutrophil count became normal on immunosuppressive therapy after thymectomy.
Long‐term hydroxyurea therapy in beta‐thalassaemia patients
Authors: De Paula Erich Vinicius , Lima Carmen Silvia Passos , Arruda Valder Roberval , Alberto Fernando Lopes , Saad Sara Teresinha Ollala , Costa Fernando Ferreira
Published: March 2003

Objective: The study aimed to investigate the use of hydroxyurea (HU) for the treatment of beta‐thalassaemia (β‐thal) patients.

Methods: We examined the haematological effects of orally administered HU (10–20 mg/kg/d) in 11 patients, including four β‐thal major and seven β‐thal intermedia patients. Complete blood count and levels of foetal haemoglobin (HbF), liver enzymes and serum creatinine were evaluated before and during HU. Response to therapy was evaluated at 6 months of treatment.

Results: A substantial increase in haemoglobin (Hb) level (4.1 g/dL), leading to complete withdrawal from a regular transfusion programme, was observed in one unique β‐thal major patient. In the β‐thal intermedia patients, increases in Hb level of 1.3, 1.9 and 2.0 g/dL were observed in three of seven (42.9%) patients during HU therapy. The mean values of Hb, mean corpuscular haemoglobin (MCH), and HbF were higher during HU treatment than baseline values (8.7 vs. 7.7 g/dL, P = 0.05; 26.7 vs. 22.9 pg, P = 0.05; 57.2 vs. 44.9%, P = 0.04; respectively). In contrast, the mean reticulocyte count measured during therapy decreased (97.0 × 109 vs. 632.0 × 109/L, P = 0.03). No correlations were observed between levels of Hb and HbF (r = 0.77, P = 0.10), and levels of Hb and reticulocyte counts (r = 0.26, P = 0.31). No significant toxicity was observed in our patients.

Conclusion: These results suggest that HU may improve Hb levels in β‐thal. Thus, we may conclude that a large trial concerning the response to HU in these patients should be carried out to clarify this issue.
Evidence for a bimodal relation between serum lysozyme and prognosis in 232 patients with acute myeloid leukaemia
Authors: Åström Maria , Bodin Lennart , Hörnsten Per , Wahlin Anders , Tidefelt Ulf
Published: March 2003

Abstract: Lysozyme values are sometimes used as an aid for diagnostic subtyping of acute myeloid leukaemia (AML), since monocytic forms often show high levels. We wanted to study if pretreatment serum lysozyme has any relation to prognosis in AML. For this purpose, 232 adult AML patients who had received remission induction therapy at two hospitals were reviewed retrospectively. Their median age was 65.5 yr. Sixty‐three patients were FAB classified as ‘monocytic’ AML (M4, M5) and 169 as ‘non‐monocytic’ AML (M0, M1, M2, M3, M6). A linear relation was rejected, and a bimodal relation was found between lysozyme and prognosis where values below 20 or above 80 mg L−1 were indicative of better outcome than values in the range 20–80 mg L−1. Analysed in three categories with cut‐off levels at 20 and 80 mg L−1, lysozyme showed an independent effect on complete remission (CR) frequency (P = 0.0003), overall survival (P < 0.0001), and CR duration (P = 0.0005) in multivariate analysis. The hazard ratios (HR) for lysozyme <20, 20–80, and >80 mg L−1 regarding overall survival were 1.0, 3.3, and 0.7. Influence of lysozyme on survival was bimodal both in ‘non‐monocytic’ AML (HR 1.0, 3.0, and 0.1) and M4–M5 (HR 1.0, 10.1, and 1.2). Our finding of a bimodal relation between serum lysozyme and prognosis in AML should be regarded as a new hypothesis and controlled in other studies.
Role of neutrophils in induction of acute inflammation in T‐cell‐mediated immune dermatosis, psoriasis: A neutrophil‐associated inflammation‐boosting loop
Authors: Terui T. , Ozawa M. , Tagami H.
Published: March 2003

Abstract: A growing body of evidence has indicated that T‐cell‐mediated immunity plays an important role in triggering and maintenance of psoriatic lesions. In this review we present our own experimental results as well as those from the literature related to the pathomechanism of the development of inflammatory changes in psoriatic lesions. First of all it is important to acknowledge the fact that psoriatic lesions are not uniform as assumed by many authors but that they are actually rather heterogeneous both clinically and histologically even within the same plaques. Lymphokines produced by activated T cells in psoriatic lesions have a strong influence on the proliferation of the epidermis, whose stimulated kertinocytes released several cytokines, which in turn enhance the activation state of T cells. Thus, they form a vicious cycle, a T‐cell‐mediated inflammation‐sustaining loop. Although the interaction between T‐cell‐mediated immunity and epidermal keratinocytes may well explain the maintenance of background “chronic” inflammatory changes diffusely observed throughout psoriatic lesions, it is not enough to explain the island‐like, “acute” inflammatory changes observed within and at the border of the plaque lesions. Characteristic neutrophil accumulation under the stratum corneum can be observed in the highly inflamed and therapeutically recalcitrant areas of psoriatic lesions. They are chemotactically attracted and activated there by synergistic action of chemokines, IL‐8 and Gro‐α released by the stimulated keratinocytes, and particularly C5a/C5a des arg produced via the alternative complement pathway activation possibly on the surface of corneocytes. In this review, we emphasize that the accumulation of neurophils is not simply a passive event. We think that those stimulated neutrophils are able to influence not only the growth and differentiation of epidermal keratinocytes but also the activation‐state of T cells by aberrant expression of HLA‐DR on their surfaces as well as by their effects. These T cells in turn influence the transepidermal neutrophil migration through the effect of their lymphokines on the keratinocyte production of pro‐inflammatory mediators including C3. Therefore, we propose a neutrophil‐associated inflammation‐boosting loop that may well explain the localized “acute” inflammatory changes scattered over the ‘’chronic” psoriatic plaques as well as in the acutely inflamed lesions of pustular psoriasis.
Hot spot mutations in keratin 2e suggest a correlation between genotype and phenotype in patients with ichthyosis bullosa of Siemens
Authors: Suga Y. , Arin M. J. , Scott G. , Goldsmith L. A. , Magro C. M. , Baden L. A. , Baden H. P. , Roop D. R.
Published: March 2003

Abstract: Ichthyosis bullosa of Siemens (IBS) is a rare disorder of cornification characterized by blister formation in the upper suprabasal layers of the epidermis. Molecular analysis of IBS has identified mutations in the keratin 2e (K2e) gene, which is located in the type II keratin gene cluster on chromosome 12q. We have studied two IBS families and have identified heterozygous point mutations in codon 493 of the K2e gene in both families. Whereas a non‐conservative amino acid substitution at position 117 of the 2B region of K2e (E117K) was associated with a severe phenotype in family 1, family 2 showed mild clinical features as a result of a conservative substitution (E117D). These data suggest a phenotype–genotype correlation in these families.
Alternative subcellular locations of keratinocyte basonuclin
Authors: Iuchi S. , Easley K. , Matsuzaki K. , Weiner L. , O'Connor N. , Green H.
Published: March 2003

Abstract: Basonuclin is a zinc finger protein present in the basal cell layer of the epidermis and in hair follicles. Human basal epidermal cells are often heterogeneous with respect to a nuclear or cytoplasmic location of basonuclin and the protein may be concentrated in either compartment. In mouse and rat epidermis, although clusters of basonuclin may be seen in some basal cell nuclei, the protein is mainly concentrated in the cytoplasm. When epidermis whose basal cells contain predominantly cytoplasmic basonuclin is disaggregated and the cells are cultivated in the presence of supporting 3T3 cells, the basonuclin of the growing keratinocyte colonies is strongly concentrated in the cell nuclei. Transfer of the cells to culture medium without supporting 3T3 cells results in a predominantly cytoplasmic concentration of the basonuclin. This translocation is reversible, since addition of supporting 3T3 cells restores most basonuclin to the nucleus. The nuclear location is associated with more rapid cell growth. We conclude that different states of the keratinocyte require greater or less activity of basonuclin, and the subcellular location of the protein is probably related to the magnitude of its action on the cells.
Cross‐talk between epidermal growth factor receptor and protein kinase C during calcium‐induced differentiation of keratinocytes
Authors: Denning M. F. , Dlugosz A. A. , Cheng C. , Dempsey P. J. , Coffey Jr R. J. , Threadgill D. W. , Magnuson T. , Yuspa S. H.
Published: March 2003

Abstract: The induction of epidermal differentiation by extracellular Ca2+ involves activation of both tyrosine kinase and protein kinase C (PKC) signaling cascades. To determine if the differentiation‐dependent activation of tyrosine kinase signaling can influence the PKC pathway, we examined the tyrosine phosphorylation status of PKC isoforms in primary mouse keratinocytes stimulated to terminally differentiate with Ca2+. Elevation of extracellular Ca2+ induced tyrosine phosphorylation of PKC‐δ, but not the other keratinocyte PKC isoforms (α,ε, η, ζ). We have previously demonstrated that activation of the epidermal growth factor receptor (EGFR) pathway induces PKC‐δ tyrosine phosphorylation in basal keratinocytes (Denning M F, Dlugosz A A, Threadgill D W, Magnuson T, Yuspa S H (1996) J Biol Chem 271: 5325–5331). When basal keratinocytes were stimulated to differentiate by Ca2+, the level of cell‐associated transforming growth factor‐α (TGF‐α) increased 30‐fold, while no increase in secreted TGF‐α was detected. Furthermore, Ca2+‐induced tyrosine phosphorylation of PKC‐δ and phosphotyrosine‐association of the receptor adapter protein Shc was diminished in EGFR −/− keratinocytes, suggesting that EGFR activation may occur during keratinocyte differentiation. Tyrosine phosphorylated PKC‐δ was also detected in mouse epidermis, suggesting that this differentiation‐associated signaling pathway is physiological. These results establish a requirement for the EGFR in Ca2+‐induced tyrosine phosphorylation of PKC‐δ, and document the production of cell‐associated TGF‐α in differentiated keratinocytes which may function independent of its usual mitogenic effects.
Is psoriasis a T‐cell disease?
Authors: Nickoloff B. J. , Schröder J. M. , Von Den Driesch P. , Raychaudhuri S. P. , Farber E. M. , Boehncke W.‐H. , Morhenn V. B. , Rosenberg E. W. , Schön M. P. , Holick M. F.
Published: March 2003

Abstract: The etiology and pathogenesis of psoriasis – one of the most common chronic, inflammatory, hyperproliferative skin disorders of man – have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal‐mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom – infatuated with a T‐cell‐centered approach to inflammatory skin diseases – portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative “pockets of academic resistance” are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.
Bullous pemphigoid sera react specifically with various domains of BP230, most frequently with C‐terminal domain, by immunoblot analyses using bacterial recombinant proteins covering the entire molecule
Authors: Hamada T. , Nagata Y. , Tomita M. , Salmhofer W. , Hashimoto T.
Published: March 2003

Abstract: By immunoblot analyses of normal human epidermal extracts, the 230 kDa bullous pemphigoid antigen (BP230) is recognized by most bullous pemphigoid sera. By polymerase chain reaction using keratinocyte cDNA library as a template, we successfully amplified 3 cDNAs of about 3 kb, which covered whole human BP230 molecule. By inserting the cDNAs into bacterial expression vector pGEX, we prepared 3 different recombinant glutathione‐S‐transferase‐fusion proteins, which roughly presented N‐terminal domain, central rod domain and C‐terminal domain of BP230. By immunoblotting using these 3 recombinant proteins, we demonstrated that the majority of bullous pemphigoid sera reacted clearly with multiple recombinant proteins of BP230, most frequently with C‐terminal domain. We also examined sera of pemphigus vulgaris, pemphigus foliaceus and herpetiform pemphigus that showed BP230‐like protein band by immunoblotting of epidermal extracts, as well as paraneoplastic pemphigus, for reactivity with the 3 recombinant proteins. In the study, we found that only very few of these non‐bullous pemphigoid sera reacted with some of the recombinant proteins. These results indicate that the BP230 is specifically reacted by bullous pemphigoid sera, and that the immunoblotting using the BP230 recombinant proteins should be a useful tool for the diagnosis of bullous pemphigoid.
Comprehensive analysis of gene expression profiles in keratinocytes from patients with generalized atrophic benign epidermolysis bullosa
Authors: Huber Ariana , Yee Carole , Darling Thomas N. , Yancey K. B.
Published: March 2003

Abstract: Generalized atrophic benign epidermolysis bullosa [GABEB (OMIM no. 226650)] is an inherited subepidermal blistering disease typically caused by null mutations in COL17A1, the gene encoding type XVII collagen. Studies of GABEB keratinocytes homozygous for 4003delTC showed that this 2 bp deletion results in markedly reduced COL17A1 transcripts due to nonsense mediated‐mRNA decay. To explore consequences of this null mutation in COL17A1 on the expression of other genes, RNA samples from reference GABEB and normal keratinocytes were profiled in comparative screens of microarrays of known cDNAs (n = 6180) and expressed sequence tags (ESTs) (n = 15 144). All comparative hybridization experiments were performed ≥ twice; data were quantitated by densitometry and analyzed using peak quantification statistical comparative analysis (P‐SCAN) software to identify differentially expressed genes. Representative genes found to be differentially expressed were verified using real‐time reverse transcription‐polymerase chain reaction (RT‐PCR). These experiments determined that expression of nonsense‐mediated mRNA decay trans‐acting factor (NMD‐F), the regulator of nonsense transcripts (i.e. the human homolog of the yeast Upf1 protein), was upregulated in GABEB keratinocytes. NMD‐F was subsequently found to be upregulated in cultured keratinocytes from other GABEB patients homozygous for 4003delTC. These findings indicate that the gene responsible for nonsense‐mediated mRNA decay is upregulated in keratinocytes known to eliminate mutant COL17A1 transcripts via this highly conserved mechanism.
Integrin expression in the dermis during scar formation in humans
Authors: Noszczyk Bartlomiej H. , Klein Eberhard , Holtkoetter Olaf , Krieg Thomas , Majewski Slawomir
Published: March 2003

Abstract: To evaluate changes leading to human wound reorganization we examined by immunohistochemistry the expression of several extracellular matrix (ECM) receptors (α2 chain of VLA‐2, α3 chain of VLA‐3, α6 chain of VLA‐6, αv, and β1/β3 chains of integrins) in a series of biopsies of human skin wounds healing by primary intention. The first time point investigated in this study was day 6 after injury, i.e. when a fibrin clot has been almost completely replaced by the granulation tissue. Gradual changes in integrin expression in granulation tissue and in the dermal scar were observed from the first time point investigated and were characterized by an up‐regulation of α2β1 complex, αv integrin subunit, and β1 integrin subunit. At day 27, the expression of the α2 chain of VLA‐2 in the scar decreased. The expression of αv and β1 integrin subunits decreased but was still detectable by day 35. Vitronectin expression from day 7 onwards was also increased and colocalized to the area of the wounded dermis, and decreased by day 27. Our data suggests that, during the remodelling of the provisional matrix of the wound, dermal fibroblasts express transiently mainly α2 and αv subunits of integrins associated with up‐regulation of the β1 subunit. It seems that up‐regulation of some chains of integrins may be involved in the control of deposition of ECM components associated with wound healing.
Absence of the granular layer and keratohyalin define a morphologically distinct subset of individuals with ichthyosis vulgaris
Authors: Fleckman Philip , Brumbaugh Steven
Published: March 2003

Abstract: The clinical diagnosis of ichthyosis vulgaris (IV) can be difficult. Abnormalities in the granular layer and the ultrastructure of keratohyalin granules (KHG) suggest that morphology may be helpful. To clarify morphologic findings in IV, 41 clinically affected individuals and 21 unaffected family members or age‐ and sex‐matched controls were studied by light microscopy. In these, the granular layer was totally absent in approximately 50% of affected individuals, while present in all controls. Forty‐seven individuals in the light microscopy group were also studied by electron microscopy. Keratohyalin granules were absent in all affected individuals lacking the granular layer by light microscopy. Clinical severity usually correlated with the lack of a granular layer and KHG. Absence of the granular layer was consistent in different anatomic sites and in serial biopsies taken over a 1–3‐year period. In a subset of clinically affected, unrelated subjects with moderate to severe involvement, four out of 11 (36%) had similar findings. Keratinocytes cultured from affected individuals with no KHG expressed virtually no detectable profilaggrin protein in vitro.

The data suggest that a subset of individuals with moderate to severe IV have a consistently absent granular layer and KHG. Absence of the granular layer and lack of KHG correlated almost perfectly; thus light microscopy offers a convenient means of identifying this subtype of IV. However, both morphologic types of IV were observed within single families. Therefore, the relationship between granular layer abnormalities and IV is complex and requires the study of more affected families. One interpretation of the data is that IV is a multigenic disorder in which one of the genes alters profilaggrin expression. We propose this clinical and histologic phenotype as useful for identifying the gene(s) involved and also for determining whether it represents a modifier or a major locus of the disorder.
Ontogeny and dietary specialization in brown trout (Salmo trutta L.) from Loch Ness, Scotland, examined using stable isotopes of carbon and nitrogen
Authors: Grey J.
Published: March 2003

Abstract – The trophic ecology of many fish species in cold temperate lakes is often characterized by a generalist or opportunist strategy. In this study, the diets of polytrophic brown trout in Loch Ness, Scotland, have been examined using stable isotopes of carbon and nitrogen to complement gut content analyses and aging by otolith annuli counts. Using the stable isotope ratios, it was possible to trace trout ontogeny from parr development in a natal river to piscivory in the pelagic. Potential dilution of maternal isotope signatures from eggs to parr was also demonstrated. Despite the low productivity of the loch, intraspecific variability in isotope ratios suggested dietary specialization, rather than opportunism, in some individuals.