bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein Kinase A Phosphorylation at Serine-2808 of the Cardiac Ca
2+
-Release Channel (Ryanodine Receptor) Does Not Dissociate 12.6-kDa FK506-Binding Protein (FKBP12.6)
Authors: Xiao Bailong , Sutherland Cindy , Walsh Michael P. , Chen S.R. Wayne
Published: January 2004

Dissociation of FKBP12.6 from the cardiac Ca
2+
-release channel (RyR2) as a consequence of protein kinase A (PKA) hyperphosphorylation of RyR2 at a single amino acid residue, serine-2808, has been proposed as an important mechanism underlying cardiac dysfunction in heart failure. However, the issue of whether PKA phosphorylation of RyR2 can dissociate FKBP12.6 from RyR2 is controversial. To additionally address this issue, we investigated the effect of PKA phosphorylation and mutations at serine-2808 of RyR2 on recombinant or native FKBP12.6-RyR2 interaction. Site-specific antibodies, which recognize the serine-2808 phosphorylated or nonphosphorylated form of RyR2, were used to unambiguously correlate the phosphorylation state of RyR2 at serine-2808 with its ability to bind FKBP12.6. We found that FKBP12.6 can bind to both the serine-2808 phosphorylated and nonphosphorylated forms of RyR2. The S2808D mutant thought to mimic constitutive phosphorylation also retained the ability to bind FKBP12.6. Complete phosphorylation at serine-2808 by exogenous PKA disrupted neither the recombinant nor native FKBP12.6-RyR2 complex. Furthermore, binding of site-specific antibodies to the serine-2808 phosphorylation site did not dissociate FKBP12.6 from or prevent FKBP12.6 from binding to RyR2. Taken together, our results do not support the notion that PKA phosphorylation at serine-2808 dissociates FKBP12.6 from RyR2.
Risk Adjustment Effect on Stroke Clinical Trials
Authors: Johnston Karen C. , Connors Alfred F. , Wagner Douglas P. , Haley E. Clarke
Published: January 2004

Background and Purpose—

The ischemic stroke population is heterogeneous. Even in balanced randomized trials, patient heterogeneity biases estimates of the treatment effect toward no effect when dichotomous end points are used. Risk adjustment statistically addresses some of the heterogeneity and can reduce bias in the treatment effect estimate. The purpose of this study was to estimate the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) tPA data set with and without adjustment for baseline differences.

Methods—

Using a prespecified predictive model, we calculated unadjusted and risk-adjusted odds ratios (ORs) for favorable outcome for the Barthel Index, National Institutes of Health Stroke Scale, and Glasgow Outcome Scale for the patients in the NINDS tPA stroke trial. To assess the importance of the difference, a new sample size was calculated through the use of the risk-adjusted analysis.

Results—

We analyzed 615 subjects. The ORs for the Barthel Index were 1.76 (unadjusted) and 2.04 (adjusted). The National Institutes of Health Stroke Scale and Glasgow Outcome Scale analyses also demonstrated increased ORs after adjustment. The estimated sample size required for the adjusted comparison was 13% smaller than the unadjusted sample.

Conclusions—

Risk adjustment in this data set suggests that the true treatment effect was larger than estimated by the unadjusted analysis. Stroke clinical trials should include prospective risk adjustment methodologies.
Therapeutic Window for Use of Hyperbaric Oxygenation in Focal Transient Ischemia in Rats
Authors: Lou Min , Eschenfelder Christoph C. , Herdegen Thomas , Brecht Stephan , Deuschl Günther
Published: January 2004

Background and Purpose—

Hyperbaric oxygenation (HBO) is an attractive procedure that has been used frequently in cerebral ischemia. However, depending on the model of cerebral ischemia and HBO protocol, different and conflicting results were obtained in the past. This study was undertaken to reevaluate the effects of single administration of HBO in 2 models of acute cerebral ischemia: transient or permanent focal ischemia in rats. A comparison of the 2 ischemia models was undertaken to search for a putative therapeutic window.

Methods—

The intraluminal middle cerebral artery occlusion model (MCAO) was used. The effect of single HBO therapy (3 atm absolute, 60 minutes) on transient or permanent focal ischemia, when applied at different times (3, 6, or 12 hours) after MCAO, was investigated; infarct volume and neurological deficits were assessed at 24 hours and up to 7 days.

Results—

HBO had neuroprotective effects on transient MCAO when HBO was initiated within the first 6 hours, while it aggravated the ischemic injury histologically and clinically when initiated 12 hours after MCAO. In permanent MCAO, HBO did not reduce tissue damage regardless of the timing of therapy.

Conclusions—

HBO is highly efficient in reducing infarct volume and improving neurobehavioral outcome in transient MCAO within the first 6 hours. HBO at later time points (≥12 hours) is harmful by increasing infarct volume. In permanent MCAO, HBO failed to improve infarct volume and clinical outcome.
Influence of Recanalization on Outcome in Dural Sinus Thrombosis
Authors: Stolz Erwin , Trittmacher Susan , Rahimi Anousha , Gerriets Tibo , Röttger Carina , Siekmann Ralf , Kaps Manfred
Published: January 2004

Background and Purpose—

Recanalization in dural sinus thrombosis (DST) has been observed previously; however, systematic prospective data are lacking. The influence of recanalization on DST outcome has not yet been thoroughly evaluated.

Methods—

Thirty-seven consecutive patients with DST were prospectively examined. Neurological deficits were graded with the National Institutes of Health Stroke Scale (NIHSS) on hospital admission and discharge. Functional outcome was assessed with the modified Rankin Scale (mRS) on hospital discharge and after 12 months. All patients were treated with intravenous heparin in the acute stage of illness, followed by oral anticoagulation for 12 months. Imaging follow-up with MR angiography and, in a few cases, with CT or conventional angiography was performed on hospital discharge and after 6 and 12 months.

Results—

Twelve-month functional outcome was excellent in 89% of patients with an mRS of 0 or 1. A recanalization rate of 60% was already observed on hospital discharge (22±6 days); thereafter, recanalization rates increased insignificantly. Early recanalization was not related to NIHSS score on hospital discharge or an mRS of 0 on discharge or after 12 months.

Conclusions—

We found a high frequency of early recanalization but without influence on clinical outcome parameters. Frequent imaging follow-ups in DST are not useful because they provide no information on patient outcome.
Effect of a nitrification inhibitor on nematicidal activity of organic and inorganic ammonia-releasing compounds against the root-knot nematode Meloidogyne javanica
Authors: Oka Yuji , Pivonia Shimon
Published: January 2004

The nematicidal activities of ammonium hydroxide, chitin and cottonseed meal applied to soil were enhanced by nitrapyrin, a nitrification inhibitor, in pot experiments. In a field trial, root galling index of tomato plants grown in the soil treated with 250 kg NH4OH-N/ha in combination with nitrapyrin was lower than that of tomato plants grown without nitrapyrin 40 days after planting; however, there was no difference between these treatments in tomato yields and root galling indices at the end of the experiment (128 days). Nitrapyrin inhibited the nitrification of the ammonium added to the soil or released from cottonseed meal for up to 28 days, and kept ammonium concentrations and soil pH values higher for longer periods compared with those in soils treated without nitrapyrin. It is suggested that higher ammonia (NH3) concentrations due to high soil pH and ammonium concentrations in the soil for longer periods caused the enhancement of nematicidal activities by nitrapyrin. The use of ammonia-releasing compounds in combination with a nitrification inhibitor may make nematode control more feasible by reducing the amount of amendments applied.
Molecular and morphological characterisation of the Heterodera avenae species complex (Tylenchida: Heteroderidae)
Authors: Subbotin Sergei , Sturhan Dieter , Rumpenhorst Hans Jürgen , Moens Maurice
Published: January 2004

Species of the Heterodera avenae complex, including populations of H.
arenaria, H. aucklandica, H. australis, H. avenae, H. filipjevi, H. mani, H.
pratensis and H. ustinovi, obtained from different regions of the world were
analysed with PCR-RFLP and sequencing of the ITS-rDNA, RAPD and light
microscopy. Phylogenetic relationships between species and populations of
the H. avenae complex as inferred from analyses of 70 sequences of the ITS
region and of 237 RAPD markers revealed that the cereal cyst nematode H.
avenae is a paraphyletic taxon. The taxonomic status of the Australian
cereal cyst nematode H. australis based on sequences of the ITS-rDNA and
RAPD data is confirmed. Morphometrical and ITS-rDNA sequence analyses
revealed that the Chinese cereal cyst nematode is different from other H.
avenae populations infecting cereals and is related to H. pratensis. Bidera
riparia Kazachenko, 1993 is transferred to the genus Heterodera as H.
riparia (Kazachenko, 1993) comb. n. As a consequence, H. riparia Subbotin,
Sturhan, Waeyenberge & Moens, 1997 becomes a junior secondary homonym
and is renamed as H. ripae nom. nov. Morphological, morphometrical
characters and RFLP profiles for identification of the nine species
presently placed in the H. avenae species complex are given.
Laboratory bioassays of virulence of entomopathogenic nematodes against soil-inhabiting stages of Frankliniella occidentalis Pergande (Thysanoptera: Thripidae)
Authors: Premachandra Dammini , Borgemeister Christian , Berndt Oliver , Ehlers Ralf-Udo , Poehling Hans-Michael
Published: January 2004

The efficacy of entomopathogenic nematodes (EPN) was evaluated in a
laboratory trial against soil-dwelling stages, late second instar larvae and
pupal stages of western flower thrips (WFT), Frankliniella occidentalis
Pergande. Among the six EPN strains assessed for the first time, Steinernema
feltiae (Nemaplus®) and Heterorhabditis bacteriophora (HD01) caused 65 and
59% mortality, respectively. Steinernema carpocapsae (Agriotos) and S.
arenarium (Anomali) caused moderate mortality (40-45%) while Steinernema
spp. (Morocco) and H. bacteriophora (Nematop®) had little effect. In a dose
response study with concentrations of 100, 400 and 800 infective juveniles
(IJ) per cm2 soil of H. bacteriophora (HK3), S. feltiae (Nemaplus®) and H.
bacteriophora (HD01), mortality increased only up to 400 IJ cm-2. The rate
of infectivity of H. bacteriophora (HK3) and S. feltiae (Nemaplus®)
indicated that both strains could survive at least 6 days in the soil and
infect WFT immature stages.
Between-isolate difference in dispersal ability of Bursaphelenchus xylophilus and vulnerability to inhibition by Pinus densiflora
Authors: Togashi Katsumi , Matsunaga Koji
Published: January 2004

Differences among four isolates of Bursaphelenchus xylophilus and one of B.
mucronatus in vulnerability to the inhibitory effect of Pinus densiflora on
nematode dispersal were investigated by inoculating boiled and living branch
sections 5 cm long. The intrinsic dispersal ability and vulnerability to the
inhibitory effect of living branches differed among isolates. Additionally,
the degree of branch inhibition of nematode dispersal was examined by
inoculating the five isolates on 2.5 and 5.0 cm long, P. densiflora living
branch sections. An increase in section length induced an 80% decrease in
the number of nematodes of all isolates passing through the branch. The
extent to which passing nematode number decreased as branch section length
increased can be used to express susceptibility of pine species to pine wilt
disease. Virulence had no relation to intrinsic and realised dispersal rates
in B. xylophilus.
The genus Oigolaimella Paramonov, 1952 (Nematoda: Diplogastridae) and description of O. kruegeri n. sp. and O. ninae n. sp.
Authors: Fürst von Lieven Alexander
Published: January 2004

Oigolaimella kruegeri n. sp. and Oigolaimella ninae n. sp. are described. Oigolaimella kruegeri n. sp. males can be recognised by the lack of the gubernacular keel characteristic of other Oigolaimella species and by the modified distribution pattern of the genital sensillae. Oigolaimella ninae n. sp. can be recognised and distinguished from the other members of the genus by the refractive cuticularised ring formed by the anterior edge of the cheilostomatal collar. Oigolaimella longicauda (Claus, 1862) n. comb. is accepted as a valid species, regarded as a senior synonym of O. agilis (Skwarra, 1921) and redescribed. Oigolaimella diplogaster (von Linstow, 1890) n. comb. is proposed. The phylogenetic relationship of Oigolaimella is discussed and an ecological characterisation of the taxon given on the basis of observations on feeding behaviour and locomotion in the habitat.
Host-finding ability of three entomopathogenic nematode isolates in the presence of plant roots
Authors: Cutler G. Christopher , Webster John
Published: January 2004

The effect of plant roots on the host-finding ability of three isolates of
entomopathogenic nematodes (EPN), Heterorhabditis bacteriophora D-H-Da1,
Steinernema sp. Dongrae and Steinernema sp. BJ was studied. In Petri dish
experiments the overall response of the infective juveniles (IJ) of these
isolates differed from one another, but all were attracted to a Galleria
mellonella larva and to a tomato seedling when either of these targets was
presented with a blank control. The BJ and D-H-Da1 IJ aggregated more around
a tomato root than a G. mellonella larva when these targets were presented
separately, but showed no preference for a G. mellonella-tomato seedling
combination over a blank control. Dongrae IJ showed no preference for a G.
mellonella larva or tomato seedling when each was presented simultaneously
in the same Petri dish. In experiments in pots of soil, plant roots did not
affect the host-finding ability of Dongrae IJ. In contrast, compared to
control pots with no roots, roots of bean plants hindered the ability of BJ
IJ to infect a G. mellonella larva, but tomato roots increased host-finding
by D-H-Da1 IJ. Roots of certain plant species modify the host-finding
ability of EPN, but the extent and direction of the response varied with the
EPN applied.
Nematode communities of anthropogenous birch stands in central Finland
Authors: Räty Mika , Huhta Veikko
Published: January 2004

This study compared the nematode communities in anthropogenous birch (Betula
pendula) stands of different origin with each other and with natural forests
and arable soils at the same latitude in Finland and Scandinavia. Nine
forest sites were investigated in central Finland: three birch stands
planted ca 30 years prior to the study after the clear-cutting of spruce
stands (BS), three birch stands planted ca 30 years earlier on arable soil
(BF) and three natural deciduous forests (D). There were clear differences
between the birch stands established after spruce forest and after arable
cropping, and between these and deciduous forests, but even more between
replicates of similarly managed forests. Total numbers, species diversity,
and populations of most taxa and feeding groups were the lowest in BF sites.
The relative proportion of bacterial feeders and omnivores was higher and
that of plant feeders lower in BS than in D sites. The BS sites were
relatively similar in community structure to natural deciduous forests, and
BF were dissimilar to both, although one deciduous site was similar to one
BF site. Non-metric multidimensional scaling ordination placed the three BS
sites in one cluster, while the BF sites were clearly separated from these
and from each other. Several environmental variables related to soil
moisture and acidity contributed to explain the variation in community
structure. A hypothesis is suggested that the presence of burrowing
earthworms plays a role in regulating populations of nematodes.
Why Caenorhabditis elegans adults sacrifice their bodies to progeny
Authors: Chen Jianjun , Caswell-Chen Edward
Published: January 2004

We present a novel interpretation regarding the ecology and evolution of
matricidal hatching ('bagging') in Caenorhabditis elegans. Subjecting young
and mature adult C. elegans to stress induced matricidal hatching. The
process of egg retention followed by internal hatching under starvation was
reversible, depending on whether adults were returned to food before
internal juveniles caused irreversible harm to the adult. We surface
sterilised adult C. elegans and then starved them to test the hypothesis
that matricidal hatching promotes progeny survival by enhancing to some
degree the transition to the dauer stage. When the surface sterilisation
stress time was short, the parent C. elegans enclosed many progeny that
competed for resources so that apparently only a few progeny obtained
sufficient nutrition to support transition to the dauer stage. Longer
sterilisation stress and starvation resulted in fewer, larger progeny with a
higher proportion reaching the dauer stage, suggesting a direct correlation
between the phenomena. In stressful environments, the production of even a
single, stress-resistant, long-lived dauer, in lieu of progeny that cannot
achieve the dauer, is a fitness advantage. The results are consistent with
the hypothesis. We infer that intra-uterine hatch is a part of the C.
elegans life cycle, and complements androdioecy and the dauer stage to
enhance progeny survival and dispersal under stress. This is a possible
explanation of why a seemingly detrimental behaviour, matricidal hatching,
has been perpetuated in C. elegans through evolutionary time.
Judaic Social Teaching in Christian and Pagan Context
Authors: Neusner Jacob
Published: January 2004

The social teaching of Rabbinic Judaism takes up the narrative of the Torah and recasts it into an account of the norms of Israel's social order. Its recapitulation of the Torah's story regulates relationships between Israelites and corporate Israel, among Israelites in their units of propagation and production, and between corporate Israel and the ever-present, always-sentient God. The details coalesce to yield a clear picture of an entire social order, its relationships and its points of stability and order. To treat any detail apart from its larger context is to miss its point. That point is, Rabbinic Judaism undertakes to realize in the everyday and here and now of the Jews' communal existence the imperatives set forth in the Torah for the formation of God's abode on earth.
Is it Possible to Write a History of Jewish Thought?
Authors: Schwartz Dov
Published: January 2004

In the past few years, traditional scholars and would-be innovators have been locked in controversy over the scholarly study of Qabbalah. The field of Jewish philosophical thought, however, has witnessed no such upheavals. This is not to say that no progress has been made: Texts are being rescued from oblivion; philosophical systems are constantly under review. However, little work has been done in the direction of a new scholarly awareness of the history of Jewish thought wholly outside the area of mysticism. This situation is clearly mirrored in various attempts to write and document the history of Jewish philosophy. In what follows I describe various aspects of current efforts to write the history of ideas in the area of medieval and modern Jewish thought and speculate on what might have been. Without intending to exhaust the topic of the historiography of Jewish ideas, I would like to propose some new goals for future research into Jewish rationalism.
EIN UNERKANNTER QUAESTIONESKOMMENTAR (EXC.THEOD. 4F) UND DIE DEUTUNG DER VERKLÄRUNG CHRISTI IN FRÜHCHRISTLICHEN TEXTEN
Authors: Scholten Clemens
Published: January 2004

There are traces of attempts at a methodical explanation of biblical texts before the appearance of full-scale commentaries on Holy Scripture. The use of exegetical technical forms arose in Christian schools from the necessity to understand the contents of the Bible as coherent. In Clement of Alexandria, exc. Theod. 4f, a hitherto overlooked fragment of an early Christian Quaestiones-commentary has been preserved. The specific interest in Christ's transfiguration concerns his identity with God and the comprehension of his disciples. The differences between heretical and orthodox exegesis do not depend on the choice of methods, as Marc the Magician and Clement demonstrate. The narrative of the transfiguration in the apocryphal Acts of the Apostles testifies to exegetical expertise. Origen considers his own scholarly exegesis as basically debatable.
L'UTILISATION DES PARABOLES DANS L'INTERPRÉTATION DE LA GNOSE (NH XI,1)
Authors: Painchaud Louis
Published: January 2004

Of all the various Nag Hammadi texts that use parables drawn from the New Testament, the Interpretation of Knowledge (NHC XI,1) has attracted the least scholarly attention, no doubt due to the text's extremely lacunous state of conservation. But despite the fact that two thirds of the work have been lost, it is still possible to identify references to the parable of the Sower (IntKnow 5,16-19 ; cf. Mt 13,3b-9 and parallels) and the parable of the Good Samaritan (6,19-23 ; cf. Lk 10,29-35), as well as an amalgamation of allusions to the parable of the Lost Sheep (Mt 18,10-14 and parallels), that of the lamb which must be rescued on the Sabbath (Mt 12,11-12) and the tale of the Good Shepherd ( Jn 10,1-21), at IntKnow 10,20a-38. In this article, the function of this material in the Interpretation of Knowledge will be examined and its use will be situated within the wider context of both gnostic and non-gnostic exegesis in early Christianity.
VALENTINIAN VARIATIONS ON LK 12,8-9/MT 10,32
Authors: Löhr Winrich
Published: January 2004

Clement of Alexandria has preserved a fragment of Herakleon, disciple of Valentinus, which comments on Lk 12,8-9 (11) par. The article interprets Herakleon's fragment as a piece of subtle second century Gospel exegesis, considers it in the context of the early Christian exegesis of Lk 12,8-9 par. and compares it with another Valentinian exegesis of the same verse which is related by Tertullian. Some conjectures as to the form of Herakleon's commentary are attempted: Apparently he first quoted the lemma and then commented on it, carefully discussing verse after verse. Method and form of the fragment are close to Herakleon's 'hypomnemata' on the Gospel of John. Our piece, however, probably formed no part of these 'hypomnemata'—Herakleon being the first known Christian exegete who commented both on the Gospel of Luke (taking into account the Synoptic parallels) and the Gospel of John.
Homing of in vitro expanded Stro-1- or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment
Authors: Bensidhoum Morad , Chapel Alain , Francois Sabine , Demarquay Christelle , Mazurier Christelle , Fouillard Loic , Bouchet Sandrine , Bertho Jean Marc , Gourmelon Patrick , Aigueperse Jocelyne , Charbord Pierre , Gorin Norbert Claude , Thierry Dominique , Lopez Manuel
Published: January 2004

The Stro-1 antigen potentially defines a mesenchymal stem cell (MSC) progenitor subset. We here report on the role of human ex vivo-expanded selected Stro-1+ or Stro-1- MSC subsets on the engraftment of human CD34+ cord blood cells in the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model. The data show that cotransplantation of expanded Stro-1- cells with CD34+ cells resulted in a significant increase of human CD45, CD34, CD19, and CD11b cells detected in blood or in bone marrow (BM) and spleen as compared with the infusion of CD34+ cells alone. Infusion into mice of expanded Stro-1+ and Stro-1- cells (without CD34+ cells) showed that the numbers of Stro-1+-derived (as assessed by DNA analysis of human β-globin with quantitative polymerase chain reaction [PCR]) were higher than Stro-1--derived cells in spleen, muscles, BM, and kidneys, while more Stro-1--derived than Stro-1+-derived cells were found in lungs. The transduction of expanded Stro-1+ cells with an enhanced green fluorescent protein (eGFP) gene did not modify their cytokine release and their homing in NOD/SCID mouse tissues. The difference between the hematopoietic support and the homing capabilities of expanded Stro-1+ and Stro-1- cells may be of importance for clinical therapeutic applications: Stro-1+ cells may rather be used for gene delivery in tissues while Stro-1- cells may rather be used to support hematopoietic engraftment. (Blood. 2004;103:3313-3319)
CD45-associated protein inhibits CD45 dimerization and up-regulates its protein tyrosine phosphatase activity
Authors: Takeda Akiko , Matsuda Akio , Paul Rachelle M. J. , Yaseen Nabeel R.
Published: January 2004

CD45, a receptor-like protein tyrosine phosphatase (PTP), plays an essential role in lymphocyte development and immune responses. Recent evidence suggests that dimerization of CD45 down-regulates its function. However, the mechanisms by which CD45 dimerization is regulated remain unclear, and there is no direct evidence that the PTP activity of CD45 dimers is less than that of monomers. CD45 in lymphocytes associates with CD45-AP (CD45-associated protein). Here we show that T cells from CD45-AP-null mice have a much higher level of CD45 dimers than those of wild-type mice, suggesting that CD45-AP inhibits CD45 dimer formation. This was confirmed with the use of a novel CD45-AP-null T-cell line, ALST-1, that we established from a spontaneous thymic tumor found in a CD45-AP-null mouse. Transfected CD45-AP inhibited CD45 dimer formation in ALST-1 cells in proportion to the amount of CD45-AP expressed. Finally, with the use of microsomal fractions from both mouse thymocytes and ALST-1 transfectants, the PTP activity of CD45 was found to be significantly lower in CD45-AP-negative cells than in CD45-AP-positive cells. Therefore, our results support a model in which binding of CD45-AP to inactive CD45 dimers converts them to active monomers. (Blood. 2004;103:3440-3447)
Unexpectedly, induction of cytotoxic T lymphocytes enhances the humoral response after DNA immunization
Authors: Dyer Christopher M. , Zhan Yifan , Brady Jamie L. , Carbone Francis R. , Smyth Mark J. , Lew Andrew M.
Published: January 2004

Although there are many examples (eg, immune deviation) in which enhanced cellular responses correspond with lower humoral responses, here we demonstrate for the first time 2 models in which cytotoxic T-lymphocyte (CTL) activity is associated with an enhanced antibody response. First, C57BL/6 mice generate a stronger antibody response to ovalbumin DNA immunization than congenic bm1 mice. The latter differ from C57BL/6 mice in that the H-2Kb molecule is mutated so that the immunodominant CTL epitope of ovalbumin is no longer presented. Second, pre-existing CTLs (induced by ovalbumin peptide-priming) increased the antibody response to a second unrelated antigen (β-galactosidase) co-immunized with ovalbumin. One possible mechanism is that CTLs may release antigen from DNA-transfected cells by killing or damaging them, and this freed antigen is then accessible to dendritic cells and B cells. Our finding of CTL-mediated antibody enhancement has important implications for tumor and viral immunobiology and vaccination. (Blood. 2004;103:3073-3075)
Clonality analysis of alveolar B lymphocytes contributes to the diagnostic strategy in clinical suspicion of pulmonary lymphoma
Authors: Zompi Simona , Couderc Louis-Jean , Cadranel Jacques , Antoine Martine , Epardeau Bernard , Fleury-Feith Jocelyne , Popa Natalia , Santoli François , Farcet Jean-Pierre , Delfau-Larue Marie-Hélène
Published: January 2004

The diagnostic procedure of chronic pulmonary opacities may envisage the search for non-Hodgkin lymphoma (NHL). Previous retrospective studies have shown that clonality analysis of bronchoalveolar B lymphocytes could reflect the clonality of pulmonary lymphocytes. Our objective was to define the diagnostic usefulness of bronchoalveolar lavage (BAL) B-lymphocyte clonality analysis in the setting of a clinical suspicion of both primary and secondary pulmonary lymphoma. A prospective BAL fluid B-cell clonality analysis was performed by polymerase chain reaction (PCR) in 106 consecutive patients presenting with a clinical suspicion of pulmonary NHL. Diagnosis was pulmonary B-cell lymphoma for 22 patients (13 primary and 9 secondary). When compared, pulmonary biopsy and BAL fluid have clonal identity. The detection of a strong B-cell clonal population in BAL fluid was associated with the diagnosis of pulmonary NHL (P < .0001), with a 97% specificity and a 95% negative predictive value. Thus, the absence of a dominant B-cell clone detection in BAL fluid could help to dismiss invasive investigations of pulmonary lesions. The detection of a dominant B-cell clone would lead to the performance of a pulmonary biopsy to get histologic diagnosis in primary pulmonary lymphoma and, by contrast, would avoid the need for biopsy in the setting of a secondary pulmonary lymphoma. (Blood. 2004;103: 3208-3215)
Light-chain only multiple myeloma is due to the absence of functional (productive) rearrangement of the IgH gene at the DNA level
Authors: Magrangeas Florence , Cormier Marie-Laure , Descamps Géraldine , Gouy Nadège , Lodé Laurence , Mellerin Marie-Paule , Harousseau Jean-Luc , Bataille Régis , Minvielle Stéphane , Avet-Loiseau Hervé ,   for the Intergroupe Francophone du Myélome
Published: January 2004

Although most multiple myeloma (MM) cases are characterized by the detection of a monoclonal immunoglobulin in the serum, about 15% of the patients present only immunoglobulin light chains, detected either in the urine or serum or both. These patients are designated as having light-chain (LC) MM. Using fiber-fluorescent in situ hybridization, and in contrast to patients and myeloma cell lines secreting heavy chains (who presented a legitimate functional IgH rearrangement in every case), LC MM never displayed a functional IgH recombination. Interestingly, most LC MM cases presented one IgH allele with a germline configuration (including the DJ region), the second allele being usually involved in an illegitimate recombination. Of note, most of these translocations occurred close to (or at) switch regions, even though in some cases, breakpoints involving nonswitch regions were observed. Thus, this study clearly showed that LC MM is due to the absence of legitimate IgH rearrangement at the DNA level, reflecting possible abnormalities in the IgH gene recombinations during B-cell maturation. Furthermore, it showed that this defect did not prevent the activation of the switch process because most of 14q32 translocations observed in LC MM occurred at switch regions.
Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism
Authors: Hamano Akiei , Mimuro Jun , Aoshima Motonori , Itoh Takeyoshi , Kitamura Noboru , Nishinarita Susumu , Takano Katsuhiro , Ishiwata Akira , Kashiwakura Yuji , Niwa Kazuki , Ono Tomoko , Madoiwa Seiji , Sugo Teruko , Matsuda Michio , Sakata Yoichi
Published: January 2004

Thrombophilic dysfibrinogen Tokyo V was identified in a 43-year-old man with recurrent thromboembolism. Based on analyses of the patient fibrinogen genes, the amino acid sequence of the aberrant fibrinogen peptide, and deglycosylation experiments, fibrinogen Tokyo V was shown to have an amino acid substitution of γ Ala327Thr and possibly extra glycosylation at γ Asn325 because the mutation confers the N-linked glycosylation consensus sequence Asn-X-Thr. The mutation resulted in impaired function and hypofibrinogenemia (hypodysfibrinogen). Polymerization of fibrin monomers derived from patient fibrinogen was severely impaired with a partial correction in the presence of calcium, resulting in very low clottability. Additionally, a large amount of soluble cross-linked fibrin was formed upon thrombin treatment in the presence of factor XIII and calcium. However, Tokyo V–derived fibrin was resistant to degradation by tissue plasminogen activator (tPA)–catalyzed plasmin digestion. The structure of Tokyo V fibrin appeared severely perturbed, since there are large pores inside the tangled fibrin networks and fiber ends at the boundaries. Taken together, these data suggest that Tokyo V fibrin clots are fragile, so that fibrinolysis-resistant insoluble fibrin and soluble fibrin polymers may be released to the circulation, partly accounting for the recurrent embolic episodes in the patient. (Blood. 2004;103:3045-3050)
Involvement of casein kinase Iϵ in cytokine-induced granulocytic differentiation
Authors: Okamura Atsuo , Iwata Nobuko , Nagata Aki , Tamekane Akira , Shimoyama Manabu , Gomyo Hiroshi , Yakushijin Kimikazu , Urahama Norinaga , Hamaguchi Miyuki , Fukui Chie , Chihara Kazuo , Ito Mitsuhiro , Matsui Toshimitsu
Published: January 2004

Two closely related casein kinase I (CKI) isoforms, CKIδ and CKIϵ, are ubiquitously expressed in many human tissues, but their specific biologic function remains to be clarified. Here, we provide the first evidence that CKIϵ is involved in hematopoietic cell differentiation. CKIϵ, but not CKIδ, was down-regulated along with human granulocytic differentiation. The specific down-regulation was observed in granulocyte colony-stimulating factor (G-CSF)–induced cell differentiation of murine interleukin-3 (IL-3)–dependent myeloid progenitor 32D cells. Introduction of wild-type (WT)–CKIϵ into 32D cells inhibited the G-CSF–induced cell differentiation, whereas kinase-negative (KN)–CKIϵ promoted the differentiation. Neither WT- nor KN-CKIϵ affected IL-3–dependent cell growth. Moreover, introduction of WT- or KN-CKIδ did not affect the cytokine-induced cell growth and differentiation. While G-CSF–induced activation of signal transducers and activators of transcription 3 (STAT3) was sustained by KN-CKIϵ, STAT3 activation was attenuated by WT-CKIϵ. This may be explained by the fact that the suppressor of cytokine signaling 3 (SOCS3) was stabilized by its physical association with CKIϵ. Such stabilization by CKIϵ was also seen in IL-3–induced β-catenin. The stabilization of downstream components of cytokine and Wnt signaling by CKIϵ might be critical for integration of several intracellular signaling pathways to a cell-specific biologic response in hematopoietic cell self-renewal. (Blood. 2004;103: 2997-3004)
Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm
Authors: Prindull Gregor , Zipori Dov
Published: January 2004

Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression. (Blood. 2004; 103:2892-2899)
Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor
Authors: Kunisaki Yuya , Masuko Sadahiko , Noda Mayuko , Inayoshi Ayumi , Sanui Terukazu , Harada Mine , Sasazuki Takehiko , Fukui Yoshinori
Published: January 2004

Clearance of apoptotic cells by macrophages is considered important for prevention of inflammatory responses leading to tissue damage. The phosphatidylserine receptor (PSR), which specifically binds to phosphatidylserine (PS) exposed on the surface of apoptotic cells, mediates uptake of apoptotic cells in vitro, yet the physiologic relevance of PSR remains unknown. This issue was addressed by generating PSR-deficient (PSR-/-) mice. PSR-/- mice exhibited severe anemia and died during the perinatal period. In the PSR-/- fetal livers, erythroid differentiation was blocked at an early erythroblast stage. In addition, PSR-/- embryos exhibited thymus atrophy owing to a developmental defect of T-lymphoid cells. Clearance of apoptotic cells by macrophages was impaired in both liver and thymus of PSR-/- embryos. However, this did not induce up-regulation of inflammatory cytokines. These results indicate that during embryonic development, PSR-mediated apoptotic cell uptake is required for definitive erythropoiesis and T lymphopoiesis, independently of the prevention of inflammatory responses. (Blood. 2004;103:3362-3364)
Transcriptional profiling of IKK2/NF-κB— and p38 MAP kinasedependent gene expression in TNF-α—stimulated primary human endothelial cells
Authors: Viemann Dorothee , Goebeler Matthias , Schmid Sybille , Klimmek Kerstin , Sorg Clemens , Ludwig Stephan , Roth Johannes
Published: January 2004

Inflammatory stimulation of endothelial cells by tumor necrosis factor α (TNF-α) involves activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein (MAP) kinase signaling pathways. A reliable analysis of the gene expression program elicited by TNF-α and its assignment to distinct signaling pathways is not available. A sophisticated analysis of oligonucleotide microarrays covering more than 13 000 genes allowed definition of the TNF-α-regulated endothelial gene expression profile and novel TNF-α-induced genes. Virtually all TNF-α-inducible genes were dependent on IκB kinase 2 (IKK2)/NF-κB activation, whereas a minor number was additionally modulated by p38. Furthermore, genes suppressed by IKK2/NF-κB were newly identified. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry confirmed reliability of data. Thus, these results define a list of primary candidates for targeted modulation of endothelial functions during inflammation. (Blood. 2004;103:3365-3373)
Phase III Study of N,N-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19
Authors: Reyno Leonard , Seymour Lesley , Tu Dongsheng , Dent Susan , Gelmon Karen , Walley Barbara , Pluzanska Anna , Gorbunova Vera , Garin Avgust , Jassem Jacek , Pienkowski Tadeusz , Dancey Janet , Pearce Laura , MacNeil Mary , Marlin Susan , Lebwohl David , Voi Maurizio , Pritchard Kathleen
Published: January 2004

Purpose

N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer.

Patients and Methods

Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m2 intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m2. Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS).

Results

A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P = .021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected.

Conclusion

This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.
Clinical Cardiac Tolerability of Trastuzumab
Authors: Perez Edith A. , Rodeheffer Richard
Published: January 2004

Purpose

This review provides an update on the current understanding of the clinical cardiac tolerability of trastuzumab, a humanized monoclonal antibody effective in the treatment of patients with advanced breast cancer overexpressing or amplifying HER2.

Methods and Results

We produced a summary of currently available information regarding the incidence and natural history of trastuzumab-associated cardiac dysfunction. Data from new, prospective clinical studies that incorporate close cardiac monitoring and standardized follow-up in patients with either advanced or earlier stages of breast cancer are also presented, and hypotheses regarding potential mechanisms of trastuzumab-related cardiotoxicity are discussed. Patients treated with trastuzumab in the pivotal trials were found to have increased risk for cardiac dysfunction, mostly when used concurrent with anthracyclines. Recent trials have required more stringent and consistent cardiac monitoring criteria and excluded patients with abnormal cardiac function, pre-existing heart disease, and/or high cumulative doses of anthracyclines. Decreases of ejection fraction and a few cases of congestive heart failure (CHF) requiring medical therapy have been detected. Improvements in ejection fraction and the symptoms of CHF have been subsequently noted in a significant number of these patients.

Conclusion

Trastuzumab is associated with an increased risk of asymptomatic decreases in ejection fraction, and, in a small number of patients, CHF that is almost always responsive to medical management. This risk is greatest in patients receiving concurrent anthracyclines. More data are needed to help elucidate the pathophysiology of this syndrome.
Percutaneous Image-Guided Radiofrequency Ablation of Painful Metastases Involving Bone: A Multicenter Study
Authors: Goetz Matthew P. , Callstrom Matthew R. , Charboneau J. William , Farrell Michael A. , Maus Timothy P. , Welch Timothy J. , Wong Gilbert Y. , Sloan Jeff A. , Novotny Paul J. , Petersen Ivy A. , Beres Robert A. , Regge Daniele , Capanna Rodolfo , Saker Mark B. , Grönemeyer Dietrich H.W. , Gevargez Athour , Ahrar Kamran , Choti Michael A. , de Baere Thierry J. , Rubin Joseph
Published: January 2004

Purpose

Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone.

Patients and Methods

Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had ≥ 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory–Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant.

Results

Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P < .0001), 3.0 (P < .0001), and 1.4 (P = .0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion.

Conclusion

RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.
Quality of Life Among Disease-Free Survivors of Rectal Cancer
Authors: Rauch Philippe , Miny Joelle , Conroy Thierry , Neyton Lionel , Guillemin Francis
Published: January 2004

Purpose

To identify factors affecting the quality of life (QoL) of disease-free survivors of rectal cancer.

Patients and Methods

One hundred twenty-one patients in complete remission more than 2 years after diagnosis were asked to complete three QoL questionnaires: the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30; its colorectal module, QLQ-CR38; and the Duke generic instrument.

Results

Patients reported less pain (P = .002) than did controls drawn from the general population. EORTC QLQ-C30 physical scores were also higher among rectal cancer survivors than in the general Norwegian or German population (P = .0005 and P = .002, respectively). Unexpectedly, stoma patients reported better social functioning than did nonstoma patients (P = .005), with less anxiety (P = .008) and higher self-esteem (P = .0002). In the present authors' experience, the QLQ-CR38 does not discriminate between these groups. Residual abdominal or pelvic pain and constipation had the most negative influence on QoL.

Conclusion

QoL is high among rectal cancer survivors, including stoma patients. Simultaneous use of several QoL questionnaires appears to have value in follow-up and in monitoring the effects of therapy. The impact of residual pain and constipation on long-term QoL should be considered when establishing a treatment regimen.