bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of fludarabine in the treatment of follicular and mantle cell lymphoma
Authors: Lenz Georg , Hiddemann Wolfgang , Dreyling Martin
Published: July 2004

Advanced‐stage follicular lymphoma (FL) and mantle cell lymphoma (MCL) cannot be cured using conventional chemotherapy. Fludarabine, the most widely used purine analog, exhibits a particularly high level of activity against small lymphocytic lymphoma and chronic lymphocytic leukemia (CLL). Numerous studies have investigated the efficacy of fludarabine as a single agent or in combination with other cytostatic compounds in the treatment of FL and MCL. Hematologic toxicity is the most commonly observed adverse event in patients treated with fludarabine, but serious infectious complications are relatively rare. Fludarabine monotherapy has proven to be particularly effective in the treatment of FL; however, complete responses (CRs) are observed in only approximately 20–40% of all cases. In contrast, combinations containing fludarabine and anthracyclines or alkylating agents have yielded superior response rates and longer periods of progression‐free survival (PFS), and the addition of the anti‐CD20 antibody rituximab appears to yield even better results. In a randomized trial, an immunochemotherapy regimen consisting of a fludarabine‐containing combination and rituximab resulted in superior remission and survival rates compared with the fludarabine‐containing combination alone. In summary, fludarabine has proven to be a safe and effective agent in the treatment of indolent lymphoma. In particular, combinations containing fludarabine, anthracyclines and/or alkylating agents, and rituximab have yielded remarkable CR and PFS rates. Consequently, current research efforts have focused on the use of fludarabine‐containing combinations in the first‐line treatment of FL and MCL. Cancer 2004. © 2004 American Cancer Society.
Patterns of high‐dose morphine use in a home‐care hospice service
Authors: Bercovitch Michaela , Adunsky Abraham
Published: July 2004

BACKGROUND

Management of cancer pain is one of the most important goals of palliative care. Relieving pain is often problematic. High doses of morphine at home may be required to relieve patients' pain, and is therefore feared. The goals of the current study were to assess the feasibility of high‐dose morphine use at home, to characterize the patients, and to examine whether the use of high‐dose morphine might affect their survival.

METHODS

The authors retrospectively studied the medical charts of 661 outpatients, which were completed by a home‐care hospice team. The authors collected data regarding demographic parameters, medical diagnosis, pain type, morphine dosage, use of rescue doses in addition to regular doses, use of coanalgesics and adjuvant treatments, and survival time as associated with morphine dosage. The authors also compared the data of patients receiving high‐dose morphine with those of a group of patients receiving regular doses.

RESULTS

The authors identified 435 patients (65.8%) who received morphine for pain relief. Of these, 396 patients (91%) received a dose of 5–299 mg of morphine per day), 32 patients (7.4%) received 300–599 mg of morphine per day), and 7 patients (1.6%) received very high doses (≥ 600 mg of morphine per day). Overall, 39 patients (9%) received > 299 mg per day. Morphine dosage was found to be inversely correlated (r) with age (r = −0.254; P < 0.001). Male patients required slightly higher dosages than female patients (62.5% of high‐dose and 71% of very high‐morphine groups, respectively). Primary gastrointestinal (P = 0.015) and lung (P = 0.027) carcinomas, as well as metastatic bone disease (P = 0.001), ovarian carcinoma (P = 0.037), and brain tumors (P = 0.0053) were associated with higher and very higher morphine dosages. Adverse effects were similar in the groups receiving regular, high, and very high doses of morphine. The median survival of patients treated with high doses of morphine was 27 days and was 37 days for those treated with very high doses. Patients treated with low doses of morphine survived for 18 days. Patients not treated with morphine survived for 22 days (P = 0.001 by Mantel–Cox analysis; P = 0.029 by Breslow analysis).

CONCLUSIONS

The use of high and very high morphine doses at home proved safe and did not appear to affect the patients' life expectancy adversely. The use of high or very high‐dose morphine should not be a barrier to providing palliative terminal care for home‐care hospice patients. Cancer 2004. © 2004 American Cancer Society.
Idarubicin and standard‐dose cytosine arabinoside in adults with recurrent and refractory acute lymphocytic leukemia
Authors: Karbasian‐Esfahani Merat , Wiernik Peter H. , Novik Yelena , Paietta Elisabeth , Dutcher Janice P.
Published: July 2004

BACKGROUND

Drug resistance and early disease recurrence were major contributing factors in the limited survival of patients with acute lymphocytic leukemia (ALL). New chemotherapeutic agents and drug combinations were employed in refractory patients to overcome drug resistance.

METHODS

The current study evaluated the efficacy of a regimen comprising intravenous bolus injections of idarubicin, 12 mg/m2 daily × 3, and a continuous 7‐day infusion of cytosine arabinoside (ara‐C), 100 mg/m2 daily, in adults with refractory or recurrent ALL. Twenty patients aged 14–75 years were treated.

RESULTS

Six patients (30%) achieved complete remission (CR), 5 (25%) had a partial response (PR), and 9 (45%) did not respond. Recovery of blood counts occurred at a median of 20 days. One patient who achieved CR and one who achieved PR survived 1.5 and 2 years, respectively, after receiving this treatment. The median response and overall survival periods were 2.75 and 6.3 months, respectively. There was no relation between remission duration and previous chemotherapy. Neither leukocyte count at study entry nor patient karyotype was associated with attainment of CR. All patients experienced profound myelosuppression. Gastrointestinal toxicity was mild to moderate, with the exception of one case of World Health Organization Grade 3 mucositis.

CONCLUSIONS

The regimen of idarubicin and ara‐C achieved a 55% overall response rate in patients with recurrent or refractory ALL. This response rate compared favorably with other regimens and was achieved with acceptable toxicity. Response duration was disappointing, however. Cancer 2004. © 2004 American Cancer Society.
Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma
Authors: Leitao Mario M. , Soslow Robert A. , Nonaka Daisuke , Olshen Adam B. , Aghajanian Carol , Sabbatini Paul , Dupont Jakob , Hensley Martee , Sonoda Yukio , Barakat Richard R. , Anderson Sibyl
Published: July 2004

BACKGROUND

Benign uterine leiomyomata (LMA) are hormonally responsive neoplasms. To the authors' knowledge, little is known regarding the hormonal expression patterns of leiomyosarcomas (LMSs) of the uterus. The objective of the current study was to assess the immunohistochemical (IHC) patterns of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) expression in LMA and LMS of the uterus using a tissue microarray. The authors also sought to assess the prognostic value of ER, PR, and AR expression in LMS.

METHODS

Between January 1991 and March 2001, 25 patients were identified with primary uterine LMS for whom tissue was available. A tissue microarray was created with 3 representative cores from each of the LMS cases, as well as from 19 cases with benign uterine LMA. IHC staining was scored as follows: negative (0–1) and positive (2–3). Outcome analyses were performed for LMS only. First recurrence was determined from the time of the initial diagnosis. Survival was determined from the time of the initial diagnosis to last follow‐up.

RESULTS

ER, PR, and AR positivity in LMA compared with LMS was as follows: ER, 78% versus 40% (P = 0.03); PR, 88% versus 38% (P = 0.001); and AR, 32% versus 40% (P = 0.75). There was no difference noted with regard to IHC expression based on stage of LMS. The median overall survival for patients with LMS was 23.5 months (95% confidence interval, 19.5, NR). When adjusted for stage, PR and AR were found to be predictive of a lower risk of recurrence (P = 0.01 and P = 0.035, respectively). ER, PR, and AR were not found to be associated with overall survival after adjustment for stage. Tumor stage was found to be associated with survival (P = 0.005).

CONCLUSIONS

The rate of ER and PR expression was found to be significantly less in uterine LMS compared with LMA. ER, PR, and AR expression was observed in approximately 30–40% of uterine LMS cases. In the current series, PR and AR expression appeared to be associated with disease‐free survival but were not found to correlate with overall survival. Cancer 2004. © 2004 American Cancer Society.
B‐cell subsets in blood and lymphoid organs in Macaca fascicularis
Authors: Vugmeyster Y. , Howell K. , Bakshi A. , Flores C. , Hwang O. , McKeever K.
Published: July 2004

Background

Cynomolgus monkeys (Macaca fascicularis) are widely used animal models in biomedical research. However, the phenotypic characteristics of cynomolgus monkey (CM) B cells in peripheral blood (PB) and lymphoid organs are poorly understood.

Methods

FACS analyses of PB‐, spleen‐, lymph node (LN)‐, and bone marrow (BM)‐derived B cells were performed.

Results

CM peripheral blood B cells have a smaller fraction of CD27− (naive) cells (∼40%), as compared to human blood samples (∼70%). Similar to humans, an early activation marker, CD23, is expressed more on CD27− CM naive B cells, as compared to CD27+ B cells. The mean fraction of B cells exhibiting a memory phenotype is similar to that seen in human blood. Unlike humans, CM blood contains a subset of CD20++CD80+CD21−IgM+/−CD27+CD19+FSC++BAFF‐Rlow B cells that are likely of germinal center origin. Thus, CM blood contains (i) a higher percentage of B cells that express the co‐stimulatory molecule CD80, and (ii) a lower fraction of B cells that are CD21+, as compared to human blood. Due to the relative paucity of information on B‐cell subsets in organs of healthy humans, a direct comparison between human and CM lymphoid organ data is limited. The fraction of CD27+ and CD23+ B cells appears to be similar, while the fraction of CD80+ B cells appears to be higher than that seen in human lymphoid organs. CM spleens and to some extent lymph nodes have a distinct subset of CD21++ cells that are also CD80+/−CD23lowIgM++CD27+/−FSC++. This subset is phenotypically similar to the marginal zone B cells present in human spleen and LN samples. We also provide detailed analyses on the fraction of lymphoid organ B cells that express CD21, CD23, CD32, and/or CD80 B‐cell markers.

Conclusions

In general, cynomolgus monkey B‐cell subsets are similar to those seen in humans, as well as to those seen in other nonhuman primates. However, there are some clear differences between human and cynomolgus monkey B‐cell subsets. These findings have direct implications for a variety of in vivo studies in cynomolgus monkeys, ranging from basic research on primate B‐cell differentiation to models of infectious diseases and trials of new B‐cell targeting therapeutic agents. © 2004 Wiley‐Liss, Inc.
Comparison of CD4 and CD8 lymphocyte counts in HIV‐negative pulmonary TB patients with those in normal blood donors and the effect of antitubercular treatment: Hospital‐based flow cytometric study
Authors: Uppal S. S. , Tewari S. C. , Verma Shashi , Dhot P. S.
Published: July 2004

Background

This study was designed to flow cytometrically determine baseline and sequential values of CD4 and CD8 lymphocyte subsets in patients without the human immunodeficiency virus and with pulmonary tuberculosis (TB) and to correlate these values with those obtained from normal male blood donors and with the radiologic extent of disease and response to therapy.

Methods

We studied 39 male patients without the human immunodeficiency virus and with sputum positive for pulmonary TB who had been admitted to Military Hospital (Cardiothoracic Center) in Pune, India. Clinical, laboratory, and radiologic evaluations of these patients were done. Hematologic parameters were assessed by an automated hematology cell counter (AcT*Diff, Coulter), and T‐cell subsets (CD4 and CD8) were determined flow cytometrically (EPICS‐XL, Coulter).

Results

CD4 counts and percentages of CD4 were significantly lower, but CD8 values were normal, in patients with pulmonary TB when compared with values obtained in normal blood donors. The CD4/CD8 ratio was significantly lower in patients with TB. The CD4 counts normalized with antitubercular treatment. The radiologic extent of disease did not correlate well with the immune parameters studied.

Conclusions

TB is a reversible cause of CD4 lymphocytopenia and is associated with normal numbers of CD8 cells. The radiologic extent of disease does not seem to determine the immune response. © 2004 Wiley‐Liss, Inc.
Detection of residual neuroblastoma cells in bone marrow: Comparison of flow cytometry with immunocytochemistry
Authors: Swerts Katrien , De Moerloose Barbara , Dhooge Catharina , Brichard Bénédicte , Benoit Yves , Laureys Geneviève , Philippé Jan
Published: July 2004

BACKGROUND

Because the cytomorphologic examination of bone marrow (BM) aspirates appears not sensitive enough to detect residual neuroblastoma cells, two four‐color flow cytometric assays using different combinations of CD9, CD81, CD56, CD45, and anti‐GD2 were evaluated.

METHODS

The sensitivity of the flow cytometric assays was assessed by spiking experiments in normal peripheral blood samples. Twenty‐eight BM samples, 12 biopsies, and 3 peripheral blood stem cell (PBSC) preparations from 22 patients with neuroblastoma were analyzed. The results were compared with those of an anti‐GD2 immunocytochemical reference assay.

RESULTS

Flow cytometric and immunocytochemical analyses showed residual neuroblastoma cells in four BM samples. One PBSC preparation and 20 BM samples were negative for both assays. Four BM and two PBSC samples scored positive for the immunocytochemical assay but were negative for the flow cytometric tests. This was due to the limited number of cells that were flow cytometrically analyzed. A strong correlation between the flow cytometric and immunocytochemical tests was found (χ2 = 6.4, P = 0.011).

CONCLUSIONS

When an equal amount of cells is analyzed, the sensitivity of the flow cytometric assays is to be about 10 times lower than that of the immunocytochemical test. However, the flow cytometric assays can be used to screen for residual cells in clinical samples with a sensitivity of one neuroblastoma cell in 104 to 105 normal mononuclear cells. Flow cytometry is simple, quick, and cost effective compared with immunocytochemistry. In addition, the flow cytometric assays can be used to screen for residual neuroblastoma cells in case of a GD2‐negative primary tumor. Therefore we recommend flow cytometry for the detection of residual neuroblastoma cells. © 2004 Wiley‐Liss, Inc.
CD46‐mediated costimulation induces a Th1‐biased response and enhances early TCR/CD3 signaling in human CD4+ T lymphocytes
Authors: Sánchez Alejandra , Feito Maria Jose , Rojo José M.
Published: July 2004

The role of membrane cofactor protein (MCP, CD46) on human T cell activation has been analyzed. Coligation of CD3 and CD46 in the presence of PMA or CD28 costimuli enhanced IL‐2, IFN‐γ, or IL‐10 secretion by CD4+ T lymphocytes. The effect of CD46 on IL‐10 secretion did not require additional costimuli like anti‐CD28 antibodies or phorbol esters. CD46 also enhanced IL‐2 or IFN‐γ secretion by CD4+ blasts. In contrast, IL‐5 secretion was inhibited upon CD46‐CD3 coligation, in all the cells analyzed. These effects were independent of IL‐12 and suggest that CD46 costimulation promotes a Th1‐biased response in human CD4+ T lymphocytes. CD46 enhanced TCR/CD3‐induced tyrosine phosphorylation of CD3ζ and ZAP‐70, as well as the activation of the ERK, JNK, and p38, but did not modify intracellular calcium. The effect of specific inhibitors shows that enhanced ERK activation contributes to augmented IFN‐γ and lower IL‐5 secretion and, consequently, to the Th1 bias. Cross‐linking CD46 alone induced weak tyrosine phosphorylation of CD3ζ and ZAP‐70. However, CD46 cross‐linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti‐CD46 antibodies did not significantly alter TCR/CD3 activation.
Anti‐tumor MHC class Ia‐unrestricted CD8 T cell cytotoxicity elicited by the heat shock protein gp96
Authors: Goyos Ana , Cohen Nicholas , Gantress Jennifer , Robert Jacques
Published: July 2004

In Xenopus as in mammals, gp96 stimulates MHC‐restricted cellular immunity against chaperoned minor histocompatibility (H) antigens (Ag). In adult Xenopus, gp96 also elicits peptide‐specific effectors against MHC class Ia‐negative 15/0 tumors. To determine whether gp96 can generate functionally heterogeneous CD8+ effectors (CTL that kill MHC class Ia+ minor H‐Ag‐disparate lymphoblasts and MHC class Ia– tumor targets), LG‐6 isogenetic frogs were immunized with gp96 purified either from MHC‐identical but minor H‐Ag‐disparate LG‐15 normal tissues or from the MHC class Ia‐negative 15/0 tumor line (derived from LG‐15 frogs). LG‐15 normal liver‐derived gp96 did not induce detectable CD8+ in vitro killing against 15/0 tumor cells. However, 15/0‐derived gp96 did induce killing against both MHC class Ia+ LG‐15 lymphoblasts and the MHC class Ia– 15/0 tumor, but not against another MHC class Ia– tumor (B3B7) or against LG‐6 lymphoblasts. Tumor killing was better when 15/0 rather than normal LG‐15 irradiated stimulators were used, but in vitro stimulation without prior in vivo immunization was ineffective. These data suggest that (1) 15/0‐derived gp96 chaperones minor H‐Ag shared with normal LG‐15 lymphocytes and elicits MHC‐restricted CTL, and (2) 15/0‐derived gp96, but not normal liver‐derived gp96, generates CD8+ effectors that kill 15/0 tumor cells in the absence of MHC class Ia expression.
Lactobacilluscasei reduces CD8+ T cell‐mediated skin inflammation
Authors: Chapat Ludivine , Chemin Karine , Dubois Bertrand , Bourdet‐Sicard Raphaëlle , Kaiserlian Dominique
Published: July 2004

Probiotics, including Lactobacilli, have been postulated to alleviate allergic and inflammatory diseases, but evidence that they exert an anti‐inflammatory effect by immune modulation of pathogenic T cell effectors is still lacking. The aim of this study was to examine whether L. casei could affect antigen‐specific T cell‐mediated skin inflammation. To this end, we used contact hypersensitivity to the hapten 2,4‐dinitrofluorobenzene, a model of allergic contact dermatitis mediated by CD8+ CTL and controlled by CD4+ regulatory T cells. Daily oral administration of fermented milk containing L. casei or L. casei alone decreased skin inflammation by inhibiting the priming/expansion of hapten‐specific IFN‐γ‐producing CD8+ effector T cells. The down‐regulatory effect of the probiotics required the presence of CD4+ T cells, which control the size of the hapten‐specific CD8+ T cell pool primed by skin sensitization. L. casei cell wall was as efficient as live L. casei to regulate both the CHS response and the hapten‐specific CD8+ T cell response, suggesting that cell wall components contribute to the immunomodulatory effect of L. casei. This study provides the first evidence that oral administration of L. casei can reduce antigen‐specific skin inflammation by controlling the size of the CD8+ effector pool.
Expression of individual immunoglobulin genes occurs in an unusual system consisting of multiple independent loci
Authors: Eason Donna D. , Litman Ronda T. , Luer Carl A. , Kerr William , Litman Gary W.
Published: July 2004

Humoral immunity is effected through the rearrangement of immunoglobulin (Ig) genes in individual somatic cells committed to the B lymphocyte lineage. Haplotype or allelic exclusion restricts B lymphocytes to the expression of a single Ig receptor that can sustain further somatic modification. In most species, a specific Ig chain is encoded at a single genetic locus. However, in cartilaginous fish, hundreds of independent Ig heavy‐ (IgH) and Ig light‐chain (IgL) gene loci are present, many of which are joined in the germ line. Ig gene transcripts have been amplified from single peripheral blood lymphocytes isolated from the clearnose skate (Raja eglanteria) using reverse‐transcription PCR, and a single productive IgH transcript was detected in the majority of cells analyzed. Similarly, only a single IgL transcript was detected in over half of the individual cells. Taken together, these findings suggest that a mechanism for haplotype exclusion arose early in the evolution of antibody diversity and is independent of a single genetic locus.
Interplay between cell division and cell death during TCR triggering
Authors: Boissonnas Alexandre , Combadiere Behazine
Published: July 2004

Cell death is crucial to avoid excessive T cell expansion. During primary T cell expansion in response to pathogen or after vaccination, the amount of foreign Ag determines the degree of clonal amplification and death. Here, we studied the balance between cell proliferation and death, as well as susceptibility to cell death, during TCR triggering. After priming of CD4 T cells from AND‐TCR (Vβ3, Vα11)‐transgenic mice with a high dose of pigeon cytochrome c peptide 88–104, the cell expansion rate was significantly reduced by marked clonal elimination compared to lower Ag doses, whereas the number of cell divisions reached was similar at all Ag doses. TCR re‐engagement on activated T cells induced cell death, irrespective of the dose of Ag encountered during primary stimulation. Surprisingly, commitment to apoptosis occurred as early as the first division on all dividing cells both in vitro and in vivo. This phenomenon was highly selective, as activated but non‐dividing cells did not undergo cell death, whereas cells that had divided once became susceptible to cell death. These findings have direct implications for the peripheral homeostatic mechanism following Ag challenge and for designing primary/booster vaccine strategies.
Hydroxamic Acids − An Intriguing Family of Enzyme Inhibitors and Biomedical Ligands
Authors: Marmion Celine J. , Griffith Darren , Nolan Kevin B.
Published: July 2004

This review on hydroxamic acids deals with their efficacy as inhibitors of enzymes including cyclooxygenases, their synthesis, the complexity and structural diversity of their metal complexes, and their ability to act as effective nitric oxide donors. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Heat‐ and Light‐Induced Spin Transition of an Iron(II) Polymer Containing the 1,2,4,5‐Tetrakis(diphenylphosphanyl)benzene Ligand
Authors: Rosa Patrick , Debay Amy , Capes Laurence , Chastanet Guillaume , Bousseksou Azzedine , Le Floch Pascal , Létard Jean‐François
Published: July 2004

A new iron(II) spin‐crossover compound containing a phosphane ligand has been synthesized and characterized by magnetic susceptibility, Mössbauer spectroscopy, and heat capacity and photomagnetic experiments. The [Fe(tppb)Br2] complex [tppb = 1,2,4,5‐tetrakis(diphenylphosphanyl)benzene] exhibits a gradual spin conversion at T1/2 = 184 K, and displays at low temperature a partial photoconversion of the low‐spin (LS) state into the metastable high‐spin (HS) state by irradiating the sample at 530 nm. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
The essential oil of Stachys laetivirens Kotschy & Boiss. ex Rech. ﬁl., endemic in Turkey
Authors: Duman Hayri , Kartal Murat , Altun Levent , Demirci B. , Başer K. Hüsnü Can
Published: July 2004

Water‐distilled essential oil from aerial parts of Stachys laetivirens Kotschy & Boiss. ex Rech. ﬁl. (Labiatae) was analysed by GC and GC/MS. Sixty‐one compounds were characterized representing 85.4% of the oil. The main constituents were found to be nonacosane (23.1%) and phytol (17.9%). Copyright © 2004 John Wiley & Sons, Ltd.
Essential oil composition of Juniperus chinensis from the plains of northern India
Authors: Raina V. K. , Srivastava S. K. , Syamsundar K. V.
Published: July 2004

The volatile leaf oil of Juniperus chinensis L., gown as ornamental tree in the plains of northern India, was examined by GC and GC‐MS. Thirty‐three components representing 94.8% of the oil were characterized with sabinene (19.8%), elemol (18.6%), bornyl acetate (17.5%) and limonene (14.2%) as major constituents. The oil was found to be polymorphic neither for cedrene/thujopsene/cedrol (typical juniper wood oil components) nor for phenolics such as methyl chavicol, safrole, methyl eugenol and elemicin, derived from phenyl propanoid pathway. Copyright © 2004 John Wiley & Sons, Ltd.
Chemical composition of the essential oils from Turkish and Honduras Styrax
Authors: Fernandez Xavier , Lizzani‐Cuvelier Louisette , Loiseau André‐Michel , Perichet Christine , Delbecque Claire , Arnaudo Jean‐François
Published: July 2004

The essential oil composition of two different styrax gums, Asian and American were analysed by GC and GC‐MS. Fifty‐eight components representing more than 99.4% of the oil from Asian styrax gum and 57 components representing more than 99% of the oil from American styrax gum were identiﬁed. The major components were styrene (70.4 and 30.9% respectively), α‐pinene (19.4 and 19.6%) and β‐caryophyllene (0.2 and 20.2%) for the two oils. These results show that we could identify an Asian from an American styrax by relative amounts of styrene and β‐caryophyllene in the essential oils. Copyright © 2004 John Wiley & Sons, Ltd.
The essential oil composition of Pinus mugo Turra from Serbia
Authors: Stevanovic Tatjana , Garneau Francois‐X. , Jean France‐I. , Gagnon Hélène , Vilotic Dragica , Petrovic Slobodan , Ruzic Nenad , Pichette André
Published: July 2004

The chemical composition of the essential oil of the needles and twigs of dwarf pine (Pinus mugo Turra) growing wild in Serbia was investigated. The oil was analysed by GC/MS and the major constituents found were δ‐3‐carene (23.9%), α‐pinene (17.9%), β‐pinene (7.8%) and β‐phellandrene (7.2%). Copyright © 2004 John Wiley & Sons, Ltd.
Characterization of potent aroma compounds in Chrysanthemum coronarium L. (Garland) using aroma extract dilution analysis
Authors: Zheng Cheng Hao , Kim Tae Hwan , Kim Kyoung Heon , Leem Yong Hoon , Lee Hyong Joo
Published: July 2004

Volatile compounds of Chrysanthemum coronarium L. (Garland) from Korea were isolated and analysed by simultaneous distillation–extraction and gas chromatography–mass spectrometry, respectively. Myrcene (31.9%) was the most abundant compound, followed by α‐bisabolol (16.5%), (E,E)‐α‐farnesene (11.0%) and (E)‐β‐farnesene (8.4%). Eighteen aroma‐active compounds were detected by aroma extract dilution analysis conducted on two GC columns with different polarities. (Z)‐3‐Hexenal (green/apple), (E)‐2‐hexenal (green/fruity), methional (boiled potato/roasty), myrcene (metallic/plastic), nonanal (green/waxy) and (E,Z)‐2,6‐nonadienal (cucumber) showed high ﬂavour dilution factors of 33–35 on both columns. Because no single characteristic impact compound represented the total aroma characteristics of C. coronarium, the aroma is considered to be determined by a combination of various aroma‐active compounds with different aroma properties. Copyright © 2004 John Wiley & Sons, Ltd.
Mit den Augen hören und den Händen sprechen
Authors: Unterstell Rembert
Published: July 2004

Die Sprachwissenschaftlerin Ulrike Zeshan
Das Geräusch, das aus der Farbe kommt
Authors: Fastl Hugo , Patsouras Christine
Published: July 2004

Visuelle und akustische Eindrücke werden in der subjektiven Wahrnehmung des Menschen miteinander verbunden. Geräusche und Bilder — ihr neuartiges Zusammenspiel legt die Grundlage für eine Optimierung von Produkten
Mehr Wettbewerb im Interesse der Wissenschaft
Authors: Winnacker Ernst‐Ludwig
Published: July 2004

Wie kann Elite effektiv gefördert werden? Exzellenz‐Cluster können zur Stärkung von Spitzenuniversitäten am Forschungsstandort Deutschland beitragen
Interview mit einer Honigbiene
Authors: Tautz Jürgen , Riederer Markus
Published: July 2004

Waben unterstützen den Informationsaustausch eines Bienenvolks. Im dunklen Bienenstock werden Vibrationssignale ausgesendet und empfangen. So entsteht eine Kommunikation, die einem modernen „Telefonnetz”︁ Pate stehen könnte
Zhuangzi und die Pflege des Lebens
Authors: Jäger Henrik
Published: July 2004

Ein philosophisches und literarisches Meisterwerk des Taoismus gibt Auskunft über das Denken im alten China — „Das wahre Buch vom südlichen Blütenland”︁
Floxed allele for conditional inactivation of the voltage‐gated sodium channel Scn8a (Nav1.6)
Authors: Levin Stephen I. , Meisler Miriam H.
Published: July 2004

The sodium channel gene Scn8a encodes the channel NaV1.6, which is widely distributed in the central and peripheral nervous system. NaV1.6 is the major channel at the nodes of Ranvier in myelinated axons. Mutant alleles of mouse Scn8a result in neurological disorders including ataxia, tremor, paralysis, and dystonia. We generated a floxed allele of Scn8a by inserting loxP sites around the first coding exon. The initial targeted allele containing the neo‐cassette was a severe hypomorph. In vivo deletion of the neo‐cassette by Flp recombinase produced a floxed allele that generates normal expression of NaV1.6 protein. Ubiquitous deletion of the floxed exon by Cre recombinase in ZP3‐Cre transgenic mice produced the Scn8adel allele. The null phenotype of Scn8adel homozygotes confirms the in vivo inactivation of Scn8a. Conditional inactivation of the floxed allele will make it possible to circumvent the lethality that results from complete loss of Scn8a in order to investigate the physiologic role of NaV1.6 in subpopulations of neurons. genesis 39:234–239, 2004. © 2004 Wiley‐Liss, Inc.
Control of bract formation in Drosophila: poxn, kek1, and the EGF‐R pathway
Authors: Layalle Sophie , Ragone Gianluca , Giangrande Angela , Ghysen Alain , Dambly‐Chaudière Christine
Published: July 2004

Summary: In Drosophila, the sensory organs are formed by cells that derive from a precursor cell through a fixed lineage. One exception to this rule is the bract cell that accompanies some of the adult bristles. The bract cell is derived from the surrounding epidermis and is induced by the bristle cells. On the adult tibia, bracts are associated with all mechanosensory bristles, but not with chemosensory bristles. The differences between chemosensory and mechanosensory lineages are controlled by the selector gene pox‐neuro (poxn). Here we show that poxn is also involved in suppressing bract formation near the chemosensory bristles. We have identified the gene kek1, described as an inhibitor of the EGF‐R signaling pathway, in a screen for poxn downstream genes. We show that kek1 can suppress bract formation and can interfere with other steps of sensory development, including SMC determination and shaft differentiation. genesis 39:246–255, 2004. © 2004 Wiley‐Liss, Inc.
Efficient DNA cassette exchange in mouse embryonic stem cells by staggered positive‐negative selection
Authors: Long Qiaoming , Shelton Kathy D. , Lindner Jill , Jones Julie R. , Magnuson Mark A.
Published: July 2004

Recombinase‐mediated cassette exchange (RMCE), when applied to mouse embryonic stem (ES) cells, promises to increase the ease with which genetic alterations can be introduced into targeted genomic loci in the mouse. However, existing selection strategies for identifying ES cells in which replacement DNA cassettes from a carrier plasmid have been exchanged correctly into a defined locus are suboptimal. Here, we report the generation in mouse ES cells of a loxed cassette acceptor (LCA) allele within the glucokinase (gk) gene locus. Using the gkLCA as a test allele, we developed a staggered positive‐negative selection strategy that facilitates efficient identification of ES cell clones in which a DNA replacement cassette from a carrier plasmid has been exchanged correctly into the gkLCA allele. This selection strategy, by facilitating more efficient production of ES cell clones with various replacement DNA cassettes, should accelerate targeted repetitive introduction of gene modifications into the mouse. genesis 39:256–262, 2004. © 2004 Wiley‐Liss, Inc.
New class of Son‐of‐sevenless (Sos) alleles highlights the complexities of Sos function
Authors: Silver Serena J. , Chen Fangli , Doyon Laura , Zink Andrina Williams , Rebay Ilaria
Published: July 2004

The guanine nucleotide exchange factor (GEF) Son‐of‐sevenless (Sos) encodes a complex multidomain protein best known for its role in activating the small GTPase RAS in response to receptor tyrosine kinase (RTK) stimulation. Much less well understood is SOS's role in modulating RAC activity via a separate GEF domain. In the course of a genetic modifier screen designed to investigate the complexities of RTK/RAS signal transduction, a complementation group of 11 alleles was isolated and mapped to the Sos locus. Molecular characterization of these alleles indicates that they specifically affect individual domains of the protein. One of these alleles, SosM98, which contains a single amino acid substitution in the RacGEF motif, functions as a dominant negative in vivo to downregulate RTK signaling. These alleles provide new tools for future investigations of SOS‐mediated activation of both RAS and RAC and how these dual roles are coordinated and coregulated during development. genesis 39:263–272, 2004. © 2004 Wiley‐Liss, Inc.
Transcription cofactor Vgl‐2 is required for skeletal muscle differentiation
Authors: Chen Hsiao‐Huei , Maeda Tomoji , Mullett Steven J. , Stewart Alexandre F.R.
Published: July 2004

TEF‐1 transcription factors regulate gene expression in skeletal muscle but are not muscle‐specific. Instead, TEF‐1 factors rely on the muscle‐specific cofactor Vestigial‐like 2 (Vgl‐2), a protein related to Drosophila vestigial. Previously, we showed that Vgl‐2 promotes skeletal muscle differentiation and activates muscle‐specific promoters. However, the mechanism whereby Vgl‐2 regulates TEF‐1 factors and the requirement for Vgl‐2 for muscle‐specific gene expression were not known. In Drosophila, vestigial alters DNA binding specificity of the TEF‐1 homolog scalloped to drive wing and flight muscle‐specific gene expression. Here, gel mobility shift assays show that Vgl‐2 differentially affects DNA binding of different TEF‐1 factors. Using an antisense morpholino, we blocked the expression of Vgl‐2 and a muscle‐specific gene in the myogenic C2C12 cell line and in chick embryos by electroporation. These results demonstrate that Vgl‐2 is required for muscle gene expression, in part by switching DNA binding of TEF‐1 factors during muscle differentiation. genesis 39:273–279, 2004. © 2004 Wiley‐Liss, Inc.
Hypervolemic hypertension in mice with systemic inactivation of the (floxed) guanylyl cyclase‐A gene by αMHC‐Cre‐mediated recombination
Authors: Skryabin Boris V. , Holtwick Rita , Fabritz Larissa , Kruse Markus N. , Veltrup Ilka , Stypmann Jörg , Kirchhof Paulus , Sabrane Karim , Bubikat Alexander , Voβ Melanie , Kuhn Michaela
Published: July 2004

To dissect the tissue‐specific functions of atrial natriuretic peptide (ANP), we recently introduced loxP sites into the murine gene for its receptor, guanylyl cyclase‐A (GC‐A), by homologous recombination (tri‐lox GC‐A). For either smooth‐muscle or cardiomyocyte‐restricted deletion of GC‐A, floxed GC‐A mice were mated to transgenic mice expressing Cre‐recombinase under the control of the smooth‐muscle SM22 or the cardiac αMHC promoter. As shown in these studies, Cre‐mediated recombination of the floxed GC‐A gene fully inactivated GC‐A function in a cell‐restricted manner. In the present study we show that αMHC‐Cre, but not SM22‐Cre, with high frequency generates genomic recombinations of the floxed GC‐A gene segments which were transmitted to the germline. Alleles with partial or complete deletions were readily recovered from the next generation, after segregation of the Cre‐transgene. We took advantage of this strategy to generate a new mouse line with global, systemic deletion of GC‐A. Doppler‐echocardiographic and physiological studies in these mice demonstrate for the first time the tremendous impact of ANP/GC‐A dysfunction on chronic blood volume homeostasis. genesis 39:288–298, 2004. © 2004 Wiley‐Liss, Inc.
When Small Organisms Have a Big Effect
Authors: Lange Otto L.
Published: July 2004

Living soil crusts exist in all warm and cold arid lands of the world. They not only form remarkably enduring living communities, but also protect the soil effectively against erosion by wind and water
Stimulation for Clinical Research
Authors: Dichgans Johannes
Published: July 2004

New funding to correct deficiencies in medical research: The DFG and the BMBF launch “Clinical Studies”
The Fight against Retroviruses
Authors: Schumann Gerald G.
Published: July 2004

A gene therapeutic approach for treating viral infections places its bets on incorporated enzymes destroying virus particles from within
Another Kind of Heart Murmur
Authors: Wynands Robert , Bison Georg , Weis Antoine
Published: July 2004

New possibilities options in medical diagnostics: the magnetic signals of the human heart are recorded to assess its state of health
Getting a Grip on the Computer World
Authors: Schmidt Günther
Published: July 2004

In computer games or other multimedia applications, the user receives only visual and audio sensations. New touch displays help to transmit tactile sensations
A Hand Full of Technology with Fingertip Control
Authors: Meuser Marcell , Murrenhoff Hubertus
Published: July 2004

Whether as prosthetics or robotic hands — artificial hands are used for a variety of applications. A new, pneumatic robotic hand is making a splash with special grasping and holding abilities
Forskolin increases neuregulin receptors in human Schwann cells without increasing receptor mRNA
Authors: Fregien Nevis L. , White Linda A. , Bunge Mary Bartlett , Wood Patrick M.
Published: July 2004

Forskolin and heregulin synergistically drive human Schwann cell (HSC) proliferation in vitro, but the role of forskolin is not completely understood. To learn how forskolin might affect receptor levels in HSC cultured from adult nerve roots, we first studied expression and localization of HER2 and HER3 in intact roots, using Western blotting and light and electron microscopic immunocytochemistry. We then determined the effect of forskolin and heregulin on receptor expression in HSC cultured from nerve roots using Western blotting and RNase protection assays. HER2 and HER3 were expressed in nonmyelinating Schwann cells in roots and in cultured HSCs before exposure to forskolin. HER2, but not HER3, was also expressed in endoneurial fibroblasts and in cultured nerve root‐derived fibroblasts. Treatment with forskolin for 24 h consistently increased HER2 and HER3 protein levels in HSCs but did not alter HER2 and HER3 mRNA levels. In addition, 24‐h treatment with heregulin alone decreased HER2 and HER3 protein levels, an effect not previously described. When both heregulin and forskolin were present, HER2 and HER3 protein levels were similar to initial control values. The effect of forskolin on receptor levels was mimicked by dibutyryl‐cAMP and receptor levels in both untreated and forskolin treated HSCs were decreased by treatment with the protein kinase A inhibitor H‐89. Following pretreatment of HSCs with forskolin, increased receptor levels were correlated with increased rates of thymidine incorporation into HSCs. These results suggest that forskolin/heregulin synergy might derive, at least in part, from post‐transcriptional effects leading to increased steady‐state receptor levels. © 2004 Wiley‐Liss, Inc.
A novel mechanism of FK506‐mediated neuroprotection: Downregulation of cytokine expression in glial cells
Authors: Zawadzka Malgorzata , Kaminska Bozena
Published: July 2004

Immunosuppressant FK506 is neuroprotective in experimental models of cerebral ischemia, but the molecular mechanisms underlying this neuroprotection remain unknown. We have demonstrated that FK506 inhibits the signaling pathways that regulate hypertrophic/proliferative responses in cultured astrocytes. Ischemia/reperfusion injury is associated with the proliferation and hypertrophy of astrocytes and with inflammatory responses. In the present work, we sought to determine whether FK506 neuroprotection after middle cerebral artery occlusion (MCAo) in rat is mediated via suppression of glia activation and changes in cytokine expression. Neurological deficits, infarct size, and astrocyte/microglial response were quantified in rats subjected to 90 min of MCAo. Changes in the mRNA expression of interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor‐α (TNF‐α) in ipsilateral and contralateral cortices were determined by reverse transcription‐polymerase chain reaction (RT‐PCR). FK506 administered at 1 mg/kg, 60 min after MCAo, produced a significant improvement in neurological function and reduction of infarct volume. In FK506‐treated rats, a significant reduction of IL‐1β, IL‐6, and TNF‐α expression was observed 12 h after reperfusion. FK506 neuroprotection was associated with a significant downregulation of IL‐1β expression in astrocytes and microglia in the injured side. FK506 selectively decreased the levels of TNF‐α, and IL‐1β mRNAs in astrocytes in vitro, with no effect on transforming growth factor‐β 1 (TGF‐β1) and IL‐6 expression. Moreover, FK506 inhibits lipopolysaccharide (LPS)‐induced activation and cytokine expression in microglia in vitro. Our findings suggest that astrocytes and microglia are targets for FK506, and that modulation of glial response and inflammation may be a mechanism of FK506‐mediated neuroprotection in ischemia. © 2004 Wiley‐Liss, Inc.
Absence of the cell cycle inhibitor p21Cip1 reduces LPS‐induced NO release and activation of the transcription factor NF‐κB in mixed glial cultures
Authors: Tusell Josep Maria , Saura Josep , Serratosa Joan
Published: July 2004

We have studied possible differences in glial activation between cells from wild‐type and p21Cip1−/− mice. We compared the effect of serum mitogenic stimulation on proliferation rate and on the total number of glial cells after 7 days of culture. No differences between wild‐type and p21Cip1−/− glial cells were observed. We also compared the effect of lipopolysaccharide (LPS) from Escherichia coli, an agent widely used to induce glial activation. Nitric oxide (NO) and tumor necrosis factor‐α (TNF‐α) release, and nuclear factor kappa‐B (NF‐κB) activation were evaluated as indicators of glial activation. We observed an attenuation of NO release and NF‐κB activation in p21Cip1−/− glial cells when compared with glial cells from wild‐type mice. In contrast, TNF‐α release was enhanced in p21Cip1−/− glia. These results suggest that the cell cycle inhibitor p21Cip1 plays a role in the inflammatory response induced by LPS. © 2004 Wiley‐Liss, Inc.
Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila
Authors: Kretzschmar Doris , Tschäpe Jakob , Bettencourt Da Cruz Alexandre , Asan Esther , Poeck Burkhard , Strauss Roland , Pflugfelder Gert O.
Published: July 2004

Patients with polyglutamine expansion diseases, like Huntington's disease or several spinocerebellar ataxias, first present with neurological symptoms that can occur in the absence of neurodegeneration. Behavioral symptoms thus appear to be caused by neuronal dysfunction, rather than cell death. Pathogenesis in polyglutamine expansion diseases is largely viewed as a cell‐autonomous process in neurons. It is likely, however, that this process is influenced by changes in glial physiology and, at least in the case of DRPLA glial inclusions and glial cell death, seems to be an important part in the pathogenesis. To investigate these aspects in a Drosophila model system, we expressed polyglutamine proteins in the adult nervous system. Glial‐specific expression of a polyglutamine (Q)‐expanded (n = 78) and also a nonexpanded (n = 27) truncated version of human ataxin‐3 led to the formation of protein aggregates and glial cell death. Behavioral changes were observed prior to cell death. This reveals that glia is susceptible to the toxic action of polyglutamine proteins. Neuronal expression of the same constructs resulted in behavioral changes similar to those resulting from glial expression but did not cause neurodegeneration. Behavioral deficits were selective and affected two analyzed fly behaviors differently. Both glial and neuronal aggregates of Q78 and Q27 appeared early in pathogenesis and, at the electron microscopic resolution, had a fibrillary substructure. This shows that a nonexpanded stretch can cause similar histological and behavioral symptoms as the expanded stretch, however, with a significant delay. © 2004 Wiley‐Liss, Inc.
Interaction with antigen‐specific T cells regulates expression of the lactate transporter MCT1 in primary rat astrocytes: Specific link between immunity and homeostasis
Authors: Korn Thomas , Magnus Tim , Jung Stefan
Published: July 2004

Monocarboxylates like lactate are provided by astrocytes and can be used as fuel by neurons and oligodendrocytes. In an autoimmune inflammatory environment, homeostatic functions of astrocytes are incompletely understood. In primary Lewis rat astrocytes, co‐culture with MHC class II‐restricted myelin basic protein (MBP)‐specific T cells in the presence of MBP resulted in a marked upregulation of the astrocytic lactate transporter MCT1 that is to export lactate into the extracellular space. It was evident that the increase in MCT1 was triggered by T cells in an antigen‐dependent manner. The glial isoform of the glucose transporter GLUT1 was not regulated under these conditions. T‐cell blasts that had been pre‐activated by antigen and splenic antigen‐presenting cells (APCs) beforehand also led to an increase in the expression of astrocytic MCT1 after co‐culture. Resting T cells did not induce a relevant upregulation of MCT1 in astrocytes. However, resting T cells stimulated the expression of MCT1 when anti‐MHC class II antibodies, but not when anti‐MHC class I antibodies, were added to the co‐culture. Therefore, even in the presence of inactive T cells, complexation of MHC class II molecules on astrocytes might lead to the regulation of certain astrocytic transport proteins. Consistent with the in vitro experiments, an upregulation of MCT1 was observed in the spinal cord of autoimmune encephalitic rats while GLUT1 expression appeared to be unchanged. This T‐cell‐mediated regulation of MCT1 might contribute to a compensatory or protective mechanism in order to guarantee substrate pools for neurons and oligodendrocytes under inflammatory conditions. © 2004 Wiley‐Liss, Inc.
Glycogen phosphorylase isozyme pattern in mammalian retinal Müller (glial) cells and in astrocytes of retina and optic nerve
Authors: Pfeiffer‐Guglielmi Brigitte , Francke Mike , Reichenbach Andreas , Fleckenstein Burkhard , Jung Günther , Hamprecht Bernd
Published: July 2004

Müller cells, the radially oriented dominant macroglial cells of the retina, are known to contain abundant glycogen as well as the key enzyme for its degradation, glycogen phosphorylase (GP), but the expressed isozyme pattern is unknown. To elucidate the isoform expression pattern, specific antisera directed against the brain (BB) and muscle (MM) isoforms of GP were applied to retinal sections, isolated Müller cells, and sections of the optic nerve. We show that Müller cells of rat, rabbit, guinea pig, and mouse retina exclusively express the BB isoform. Astrocytes of rat and rabbit optic nerve, as well as retina express only the BB isoform. In contrast, astrocytes in the brain and spinal cord as well as the epithelial cells of the pars caeca and of the ciliary body express both the BB and MM isoform. This result may indicate some differences in the role of glycogen in retinal macroglia and brain astrocytes, reflecting a local specialization of macroglia in the retina proper. © 2004 Wiley‐Liss, Inc.