bluuebunny/crossref_metadata_2025 huggingface dataset:
Inactive and Alone
Authors: Bernhardt Julie , Dewey Helen , Thrift Amanda , Donnan Geoffrey
Published: March 2004

Background and Purpose—

One way that stroke units may improve outcome is by reducing complications of immobility through early mobilization; however, this intervention needs testing. The purpose of this study was to determine the physical activity patterns of stroke patients managed within acute stroke units as a first step in developing an early mobilization protocol.

Methods—

We recruited 64 patients within 14 days after stroke from 5 metropolitan stroke units and observed them for 2 consecutive days at 10-minute intervals between the hours of 8
am
and 5
pm
. At each observation, we ascertained physical activity, location, and other person(s) present. Therapists recorded therapy details.

Results—

The 58 patients who completed the study had a mean age of 71.3 years. Stroke severity ranged from mild (National Institutes of Health Stroke Scale score, 1) to severe (score, 27), and mean time after stroke at observation was 5.6 days (range, 0 to 13 days). Only 9 patients were restricted to bed. During the therapeutic day, patients spent >50% resting in bed, 28% sitting out of bed, and only 13% engaged in activities with the potential to prevent complications and improve recovery of mobility. Patients were alone >60% of the time.

Conclusions—

This is the first multicenter study of physical activity early after stroke. We believe the next step is to conduct a randomized controlled trial to evaluate the effect of increased levels of physical activity early after stroke compared with current standards of care.
Dynamic Autoregulation Testing in the Posterior Cerebral Artery
Authors: Haubrich C. , Wendt A. , Diehl R.R. , Klötzsch C.
Published: March 2004

Background and Purpose—

Dynamic autoregulation has been studied predominantly in the middle cerebral artery (MCA). Because certain clinical conditions, ie, presyncopal symptoms or hypertensive encephalopathy, suggest a higher vulnerability of autoregulation within posterior parts of the brain, we investigated whether the cerebral blood flow velocity (CBFV) is modulated differently within the posterior cerebral artery (PCA).

Methods—

Spontaneous oscillations of CBFV and arterial blood pressure (ABP) in the frequency range of 0.5 to 20 cycles per minute were studied in 30 volunteers (supine and tilted positions). Analysis was based on the “high-pass filter model,” which predicts a specific frequency-dependent phase and amplitude relationship between oscillations in CBFV to ABP. These parameters, characterized as phase shift angles and transfer function gains, were calculated from simultaneously recorded beat-to-beat blood pressure and transcranial Doppler signals of the PCA and MCA by means of cross-spectrum analysis.

Results—

In the MCA and PCA, phase shift angles were decreased, and gains were elevated with increasing oscillation frequency. The PCA gain values in supine and tilted positions were significantly higher than in the MCA.

Conclusions—

The phase and amplitude relationship between CBFV and ABP showed a frequency dependence in the PCA similar to that in the MCA. The study therefore suggests that the high-pass filter model of dynamic cerebral autoregulation can be applied to the PCA. In this model the generally higher gain values in the PCA indicate a lower damping of ABP oscillations, which are transmitted to the posterior part of cerebral circulation.
Transient Ischemic Attacks in Patients With Atrial Fibrillation
Authors: Hart Robert G. , Pearce Lesly A. , Koudstaal Peter J.
Published: March 2004

Background and Purpose—

Transient ischemic attacks (TIAs) are infrequent in patients with atrial fibrillation, and little is known about the long-term prognosis and response to antithrombotic therapy.

Methods—

This study was a pooled analysis of participants in 2 randomized trials, the European Atrial Fibrillation Trial and the Stroke Prevention in Atrial Fibrillation III Trial, comparing those with prior TIA to those with prior stroke.

Results—

Among 834 atrial fibrillation patients with prior TIA (n=222), prior ischemic stroke (n=551), or both (n=61), the mean age was 71 years, 64% were men, and 56% had hypertension. The frequency of major vascular risk factors was similar for both types of cerebral ischemia. The annualized rate of ischemic stroke during aspirin therapy was 7% per year (95% confidence interval, 4 to 12) for prior TIA and 11% per year (95% confidence interval, 9 to 15) for prior stroke (
P
=0.08 for rate difference) and was reduced by 56% (
P
=0.09) and 63% (
P
<0.001), respectively, by anticoagulation.

Conclusions—

Atrial fibrillation patients with TIA have a lower long-term risk of subsequent stroke than those with prior stroke, but their stroke risk during aspirin therapy is still high. For atrial fibrillation patients with either type of cerebral ischemia, recent or remote, secondary prevention with adjusted-dose warfarin instead of aspirin results in substantial absolute reductions in ischemic stroke.
On the Phase Reduction and Response Dynamics of Neural Oscillator Populations
Authors: Brown Eric , Moehlis Jeff , Holmes Philip
Published: March 2004

We undertake a probabilistic analysis of the response of repetitively firing neural populations to simple pulselike stimuli. Recalling and extending results from the literature, we compute phase response curves (PRCs) valid near bifurcations to periodic firing for Hindmarsh-Rose, Hodgkin-Huxley, Fitz Hugh-Nagumo, and Morris-Lecar models, encompassing the four generic (codimension one) bifurcations. Phase density equations are then used to analyze the role of the bifurcation, and the resulting PRC, in responses to stimuli. In particular, we explore the interplay among stimulus duration, baseline firing frequency, and population-level response patterns. We interpret the results in terms of the signal processing measure of gain and discuss further applications and experimentally testable predictions.
Robust Formulations for Training Multilayer Perceptrons
Authors: Kärkkäinen Tommi , Heikkola Erkki
Published: March 2004

The connection between robust statistical estimates and nonsmooth optimization is established. Based on the resulting family of optimization problems, robust learning problem formulations with regularization-based control on the model complexity of the multilayer perceptron network are described and analyzed. Numerical experiments for simulated regression problems are conducted, and new strategies for determining the regularization coefficient are proposed and evaluated.
The Black Dandyism of George Walker: A Case Study in Genealogical Method
Authors: Webb Barbara L.
Published: March 2004

Refusing to re-enact caricatures, Walker, at the turn of the 20th century, reclaimed the figure of the dandy from racist minstrelsy and rearticulated it within an African American context.
The Hawaiification of Sipsongbanna: Orality, Power, and Cultural Survival in Southwest China
Authors: Davis Sara
Published: March 2004

Near the Burmese border, ethnic Chinese Tai villagers perform zhangkhap songs based on Buddhist epics and improvised oral poetry. Repressed from the 1950s as through the 'as, zhanghap has revived dramatically in recent years. Tourists are taking notice, but this may not be good news.
At Play in the Cosmos: The Theatre and Ritual of Nicolás Núñez
Authors: Middleton Deborah K.
Published: March 2004

Can people today create their own new transformative rituals? What if these rituals are based both on the performance traditions of Náhuatl-speaking peoples and the later work of Grotowski?
Turning the Neighborhood Inside Out: Imagining a New Detroit in Tyree Guyton's Heidelberg Project
Authors: Walters Wendy S.
Published: March 2004

In Detroit, an artist reclaims recent history and offers it as an everchanging, large-scale environmental performance where discarded objects—carefully presented—embody memory, anger, and hope.
Performances of Self-Disclosure: A Personal History
Authors: Garrick David A.
Published: March 2004

A gay priest, playwright, and theatre professor tells his very personal story of the steps that led to his coming-out at Notre Dame in 1996, and what happened next.
Desdemona's Lament
Authors: Taylor Julie
Published: March 2004

How can Argentine women, after imprisonment and torture, reconstruct what happened to them, represent their experiences, and understand how doing theatre in prison helped them? Men exprisoners acknowledge that women have advanced further in developing strategies that move beyond the hierarchical and authoritarian activism of the Leftist resistance.
Broadway: A Theatre Historian's Perspective
Authors: McNamara Brooks
Published: March 2004

Theatre is a mixed bag of high, low, pop, and media. Scholars pay attention to just about everything—except Broadway. But what is Broadway? A district, a state of mind, a money-making machine, a style of theatre?
The Metonymy of Art: Vietnamese Water Puppetry As a Representation of Modern Vietnam
Authors: Foley Kathy
Published: March 2004

What is the process that makes a specific genre into a symbol of an entire nation? What are the larger issues raised by the metonymy of art? As Vietnam prepares to enter the “world market”, its water puppet theatre enacts rural ideals and socialist ideas.
Postvernacular Yiddish: Language As a Performance Art
Authors: Shandler Jeffrey
Published: March 2004

Within less than a decade, almost half of the world's 11 million Yiddish speakers were murdered, and the language's centuries-old cultural heartland in Eastern Europe was demolished. The implications for Yiddish have been profound, both instrumentally and symbolically. There is at present a heightened awareness of the use of Yiddish as a language of conversation, both on the part of the speakers and on the part of observers. In “postvernacular Yiddish,” every utterance is enveloped in a performative aura and freighted with significance as a speech act quite apart from the meaning of whatever words are spoken.
The Titanic of Everyday Life
Authors: Schechner Richard , Winnacker Susanne
Published: March 2004

In this issue's Critical Acts section, a stage is upended, King Lear is played by a cast of women, a director travels to Karbala, and angels perch on window ledges. In Sjoerd Wagenaar's Strakstuk, the entire stage floor tilts, and props, set pieces, and the theatrical frame itself slide away, leaving the actors clinging to bed frames, much as the passengers of the Titanic held on to the rails of the ship as it listed and sank. In the CalArts production of King Lear, Lear was played by an African American woman, yet it had little to do with racial and sexual identity and everything to do with political power, according to Una Chaudhuri. Lear's director, Travis Preston, chronicles a journey to Karbala that greatly influenced his production. And on his journey through Deborah Warner's Angel Project, James Westcott finds that even the most commonplace is made strange by the meticulous choreography of uncertainty.
Ten Theses on Monsters and Monstrosity
Authors: Weiss Allen S.
Published: March 2004

A simultaneously embodied and disembodying epistemology of Monsters, this is a manifesto of monstrosities through poetry, philosophy, and rhetoric—an encyclopedia in miniature of monsters and their ontologies.
Reanimating the Animated: Disney's Theatrical Productions
Authors: Rozario Rebecca-Anne Do
Published: March 2004

Metamorphosis is the cornerstone of Disney animation. Princes are turned into beasts and lions into matinee idols. Accomplishing this filmic flexibility onstage is central to Disney's expansion into theatrical production. Broadway's Beauty and the Beast, and the productions that came after, show how the elasticity of film animation can be recreated live in the theatre.
Private International Law and Care of Mentally Incapable Persons Re S (Hospital Patient: Foreign Curator)
Authors: Feenan
Published: March 2004

No Abstract
Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine
Authors: Hendriks
Published: March 2004

No Abstract
Court of Justice of the European Communities
Authors: Cambré
Published: March 2004

No Abstract
Confidentiality, testimonial privilege and patients' right to secrecy under the ECHR
Authors: Hendriks
Published: March 2004

No Abstract
Patient Involvement with Non Treatment Decisions
Authors: Gevers
Published: March 2004

No Abstract
The Cornerstones for a Prohibition of Cloning Human Beings laid down in the European Convention on Human Rights and Biomedicine
Authors: Winter
Published: March 2004

The recent debate on the theoretical possibility of cloning human beings is urging society to develope a global legal barrier in order to prohibit the use of this technique on humans. Some national legislation, e.g. Germany, already bans the cloning of human beings. The European Convention on Human Rights and Biomedicine contains three articles which together form the cornerstones for a prohibition of cloning: Article 1 guarantees the identity of human beings, Article 18.2 explicitly prohibits the creation of human embryos for research purposes and Article 13 contains a prohibition on the modification of the genome of any decendants. The prohibition of cloning human beings in the Protocol on Embryo Protection foreseen by the Council of Europe seems a necessary consequence. Furthermore, the forthcoming UNESCO Declaration on the Human Genome and Human Rights should contain such an explicit prohibition.
RGDS peptide induces caspase 8 and caspase 9 activation in human endothelial cells
Authors: Aguzzi Maria Simona , Giampietri Claudia , De Marchis Francesco , Padula Fabrizio , Gaeta Roberto , Ragone Gianluca , Capogrossi Maurizio C. , Facchiano Antonio
Published: March 2004

Peptides containing the Arg-Gly-Asp (RGD) motif inhibit cell adhesion and exhibit a variety of other biologic effects including anticoagulant and antimetastatic activities. The aim of the present study was to examine the anchorage-independent effects of an RGD-containing peptide, Arg-Gly-Asp-Ser (RGDS), on human umbilical vein endothelial cells (HUVECs). Assays were performed on HUVECs seeded onto collagen IV; under these experimental conditions RGDS did not exert antiadhesive effects but significantly reduced FGF-2-dependent chemotaxis after 4 hours of treatment and reduced proliferation after 24 hours of treatment. Experiments carried out with caspase-specific inhibitors indicated that the observed antichemotactic effects required caspase 8 and caspase 9 activation. RGDS activated both caspase 8 and caspase 9 after 4 hours of treatment and caspase 3 after 24 hours of treatment, and markedly enhanced HUVEC apoptosis by transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)/Hoechst staining and fluorescence-activated cell sorting (FACS) analysis. Finally, confocal microscopy showed that RGDS localizes in the cytoplasm of live HUVECs within 4 hours and in vitro experiments showed that RGDS directly interacts with recombinant caspases 8 and 9 in a specific way. In summary, these results indicate that RGDS directly binds and activates caspases 8 and 9, inhibits chemotaxis, and induces apoptosis of HUVECs with a mechanism independent from its antiadhesive effect.
The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis
Authors: Kearney Joseph B. , Kappas Nicholas C. , Ellerstrom Catharina , DiPaola Frank W. , Bautch Victoria L.
Published: March 2004

Sprouting angiogenesis is critical to blood vessel formation, but the cellular and molecular controls of this process are poorly understood. We used time-lapse imaging of green fluorescent protein (GFP)-expressing vessels derived from stem cells to analyze dynamic aspects of vascular sprout formation and to determine how the vascular endothelial growth factor (VEGF) receptor flt-1 affects sprouting. Surprisingly, loss of flt-1 led to decreased sprout formation and migration, which resulted in reduced vascular branching. This phenotype was also seen in vivo, as flt-1-/- embryos had defective sprouting from the dorsal aorta. We previously showed that loss of flt-1 increases the rate of endothelial cell division. However, the timing of division versus morphogenetic effects suggested that these phenotypes were not causally linked, and in fact mitoses were prevalent in the sprout field of both wild-type and flt-1-/- mutant vessels. Rather, rescue of the branching defect by a soluble flt-1 (sflt-1) transgene supports a model whereby flt-1 normally positively regulates sprout formation by production of sflt-1, a soluble form of the receptor that antagonizes VEGF signaling. Thus precise levels of bioactive VEGF-A and perhaps spatial localization of the VEGF signal are likely modulated by flt-1 to ensure proper sprout formation during blood vessel formation. (Blood. 2004;103:4527-4535)
The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT
Authors: Takahashi Shinichiro , McConnell Melanie J. , Harigae Hideo , Kaku Mitsuo , Sasaki Takeshi , Melnick Ari M. , Licht Jonathan D.
Published: March 2004

Fms-like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase (RTK). Between 20% and 30% of acute myeloid leukemia (AML) patients have either an internal tandem duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 receptor leading to the constitutive activation of downstream signaling pathways and aberrant cell growth. The silencing mediator of retinoic and thyroid hormone receptors (SMRT) corepressor mediates transcriptional repression by interacting with transcription factors such as the promyelocytic leukemia zinc finger (PLZF) protein. Previous reports indicate that SMRT interaction with transcription factors can be disrupted by phosphorylation through activation of RTK pathways. We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. Nuclear export was dependent on the SMRT receptor interaction domain (RID), and Flt3-ITD enhances the binding of nuclear-cytoplasm shuttling protein nuclear factor-κB-p65 (NFκB-p65) to this region. These data suggest that activating mutations of Flt3 may disrupt transcriptional repressor function resulting in aberrant gene regulation and abnormal leukemia cell growth. (Blood. 2004;103:4650-4658)
Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency
Authors: Richard Robert E. , Weinreich Michael , Chang Kai-Hsin , Ieremia Jessica , Stevenson Mary M. , Blau C. Anthony
Published: March 2004

In vivo selection may provide a means to increase the relative number of cells of donor origin in recipients with hemopoietic chimerism. We have tested whether in vivo selection using chemical inducers of dimerization (CIDs) can direct the expansion of transduced normal donor erythrocytes in recipients with chimerism using a mouse model of pyruvate kinase deficiency. Marrow cells from normal CBA/N mice were transduced with a vector (F36VmplGFP) that promotes cell growth in the presence of CIDs. Transduced cells were then transplanted into minimally conditioned, pyruvate kinase-deficient recipients (CBA-Pk-1slc/Pk-1slc) to establish stable chimerism. CID administration resulted in expansion of normal donor erythrocytes and improvement of the anemia. The preferential expansion of normal erythrocytes also resulted in a decrease in erythropoietin levels, reducing the drive for production of pyruvate kinase-deficient red blood cells. CID-mediated expansion of genetically modified erythrocytes could prove a useful adjunct to transplantation methods that achieve erythroid chimerism. (Blood. 2004;103:4432-4439)
Identification of Flk-1 target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro
Authors: Zippo Alessio , De Robertis Alessandra , Bardelli Monia , Galvagni Federico , Oliviero Salvatore
Published: March 2004

The tyrosine kinase receptor fetal liver kinase 1 (Flk-1) plays a crucial role in vasculogenesis and angiogenesis, but its target genes remain elusive. Comparing Flk-1+/+ with Flk-1-/- embryonic stem (ES) cells, we identified transcripts regulated by the vascular endothelial growth factor A (VEGF-A)/Flk-1 pathway at an early stage of their differentiation to endothelial and mural precursors. Further analysis of a number of these genes (Nm23-M1, Nm23-M2, Slug, Set, pp32, Cbp, Ship-1, Btk, and Pim-1) showed that their products were transiently up-regulated in vivo in endothelial cells (ECs) during angiogenesis of the ovary, and their mRNA was rapidly induced in vitro by VEGF-A in human umbilical cord vein endothelial cells (HUVECs). Functional analysis by RNA interference (RNAi) in ES cells induced to differentiate demonstrated that Pim-1 is required for their differentiation into ECs and smooth muscle cells (SMCs). In HUVECs, RNAi showed that Pim-1 is required in ECs for VEGF-A-dependent proliferation and migration. The identification of Flk-1 target genes should help in elucidating the molecular pathways that govern the vasculogenesis and angiogenesis processes. (Blood. 2004;103:4536-4544)
Familial eosinophilia: a benign disorder?
Authors: Klion Amy D. , Law Melissa A. , Riemenschneider William , McMaster Mary Lou , Brown Margaret R. , Horne McDonald , Karp Barbara , Robinson Michael , Sachdev Vandana , Tucker Eben , Turner Maria , Nutman Thomas B.
Published: March 2004

Familial eosinophilia (FE) is an autosomal dominant disorder characterized by marked eosinophilia and progression to end organ damage in some, but not all, affected family members. To better define the pathogenesis of FE, 13 affected and 11 unaffected family members (NLs) underwent a detailed clinical evaluation at the National Institutes of Health (NIH). No clinical abnormalities were more frequent in the family members with FE compared with the NLs. There was, however, a decreased prevalence of asthma in family members with FE compared with unaffected family members. Eosinophil morphology as assessed by either light or transmission electron microscopy was normal in family members with and without FE. Although levels of eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) were elevated in patients with FE compared with NL, levels of both granule proteins were lower than in nonfamilial hypereosinophilic syndrome (HES). Similarly, increased surface expression of the activation markers CD69, CD25, and HLA-DR was detected by flow cytometry on eosinophils from patients with FE compared with NL, albeit less than that seen in HES. These data suggest that, despite prolonged marked eosinophilia, FE can be distinguished from HES by a more benign clinical course that may be related to a relative lack of eosinophil activation.
Familial acquired thrombotic thrombocytopenic purpura: ADAMTS13 inhibitory autoantibodies in identical twins
Authors: Studt Jan-Dirk , Hovinga Johanna A. Kremer , Radonic Radovan , Gasparovic Vladimir , Ivanovic Dragutin , Merkler Marijan , Wirthmueller Urs , Dahinden Clemens , Furlan Miha , Lämmle Bernhard
Published: March 2004

Thrombotic thrombocytopenic purpura (TTP) either occurs in a congenital form caused by ADAMTS13 gene mutations or it is acquired and most often due to ADAMTS13 inhibitory autoantibodies. In congenital TTP siblings are often affected, while acquired TTP occurs sporadically and familial clustering has not been described so far. We report identical twin sisters suffering from acquired TTP due to immunoglobulin G (IgG) autoantibodies inactivating ADAMTS13, suggesting an important role of hitherto unidentified genetic determinants of ADAMTS13 inhibitor formation. These cases also demonstrate that familial clustering is not sufficient for unambiguously diagnosing hereditary ADAMTS13 deficiency and congenital TTP. (Blood. 2004;103:4195-4197)
Analysis of T-cell repertoire in hepatitis-associated aplastic anemia
Authors: Lu Jun , Basu Atanu , Melenhorst J. Joseph , Young Neal S. , Brown Kevin E.
Published: March 2004

Hepatitis-associated aplastic anemia (HAA) is a syndrome of bone marrow failure following an acute attack of seronegative hepatitis. Clinical features and liver histology suggest a central role for an immune-mediated mechanism. To characterize the immune response, we investigated the T-cell repertoire (T-cell receptor [TCR] Vβ chain subfamily) of intrahepatic lymphocytes in HAA patients by TCR spectratyping. In 6 of 7 HAA liver samples, a broad skewing pattern in the 21 Vβ subfamilies tested was observed. In total, 62% ± 18% of HAA spectratypes showed a skewed pattern, similar to 68% ± 18% skewed spectratype patterns in 3 of 4 patients with confirmed viral hepatitis. Additionally, the T-cell repertoire had similarly low levels of complexity. In the peripheral blood lymphocytes (PBLs) of a separate group of HAA patients prior to treatment, 60% ± 15% skewed spectratypes were detected, compared with only 18% ± 8% skewed spectratypes in healthy controls. After successful immunosuppressive treatment, an apparent reversion to a normal T-cell repertoire with a corresponding significant increase in T-cell repertoire complexity was observed in the HAA samples. In conclusion, our data suggest an antigen-driven T-cell expansion in HAA and achievement of a normal T-cell repertoire during recovery from HAA. (Blood. 2004;103:4588-4593)
ABC transporter activities of murine hematopoietic stem cells vary according to their developmental and activation status
Authors: Uchida Naoyuki , Dykstra Brad , Lyons Kristin , Leung Frank , Kristiansen Merete , Eaves Connie
Published: March 2004

Primitive hematopoietic cells from several species are known to efflux both Hoechst 33342 and Rhodamine-123. We now show that murine hematopoietic stem cells (HSCs) defined by long-term multilineage repopulation assays efflux both dyes variably according to their developmental or activation status. In day 14.5 murine fetal liver, very few HSCs efflux Hoechst 33342 efficiently, and they are thus not detected as “side population” (SP) cells. HSCs in mouse fetal liver also fail to efflux Rhodamine-123. Both of these features are retained by most of the HSCs present until 4 weeks after birth but are reversed by 8 weeks of age or after a new HSC population is regenerated in adult mice that receive transplants with murine fetal liver cells. Activation of adult HSCs in vivo following 5-fluorouracil treatment, or in vitro with cytokines, induces variable losses in Rhodamine-123 and Hoechst 33342 efflux activities, and HSCs from mdr-1a/1b-/- mice show a dramatic decrease in Rhodamine-123 efflux ability. Thus, the Rhodamine-123 and Hoechst 33342 efflux properties of murine HSCs fluctuate in the same fashion as a number of other HSC markers, suggesting these are regulated by a common control mechanism that operates independently of that regulating the regenerative function of HSCs. (Blood. 2004;103:4487-4495)
The biology of CML blast crisis
Authors: Calabretta Bruno , Perrotti Danilo
Published: March 2004

Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (ie, C/EBPα). Validation of the critical role of certain secondary changes (ie, loss of p53 or C/EBPα function) in murine models of CML blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPα).
Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders
Authors: Ladetto Marco , Compagno Mara , Ricca Irene , Pagano Marco , Rocci Alberto , Astolfi Monica , Drandi Daniela , di Celle Paola Francia , Dell'Aquila Maria , Mantoan Barbara , Vallet Sonia , Pagliano Gloria , De Marco Federica , Francese Roberto , Santo Loredana , Cuttica Alessandra , Marinone Carlo , Boccadoro Mario , Tarella Corrado
Published: March 2004

In this study we investigated telomere restriction fragment (TRF) length in a panel of mature B-cell lymphoproliferative disorders (MBCLDs) and correlated this parameter with histology and histopathogenesis in relation to the germinal center (GC). We assessed 123 MBCLD samples containing 80% or more tumor cells. TRF length was evaluated by Southern blot analysis using a chemiluminescence-based assay. GC status was assessed through screening for stable and ongoing somatic mutations within the immunoglobulin heavy-chain genes. Median TRF length was 6170 bp (range, 1896-11 200 bp) and did not correlate with patient age or sex. TRF length was greater in diffuse large cell lymphoma, Burkitt lymphoma, and follicular lymphoma (medians: 7789 bp, 9471 bp, and 7383 bp, respectively) than in mantle cell lymphoma and chronic lymphocytic leukemia (medians: 3582 bp and 4346 bp, respectively). GC-derived MBCLDs had the longest telomeres, whereas those arising from GC-inexperienced cells had the shortest (P < 10-9). We conclude that (1) TRF length in MBCLD is highly heterogeneous; (2) GC-derived tumors have long telomeres, suggesting that minimal telomere erosion occurs during GC-derived lymphomagenesis; and (3) the short TRF lengths of GC-inexperienced MBCLDs indicates that these neoplasms are good candidates for treatment with telomerase inhibitors, a class of molecules currently the subject of extensive preclinical evaluation. (Blood. 2004;103:4644-4649)
Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin
Authors: Lee Pauline L. , Beutler Ernest , Rao Sreenivas V. , Barton James C.
Published: March 2004

Juvenile hemochromatosis is an early-onset form of iron storage disease characterized by hypogonadotrophic hypogonadism and cardiomyopathy. Recently, the putative causative gene (LOC148738) encoding a protein designated hemojuvelin was cloned. The previously proposed designation of this gene as HFE2 is contrary to established convention, because it is not a member of the HFE family. We suggest that it be designated HJV. We sequenced this gene in members of 2 previously reported kinships that manifest typical juvenile hemochromatosis. In one kinship, 2 previously undescribed mutations of HJV were identified, c.238T>C (C80R) and c.302T>C (L101P). In the second kinship, 2 previously identified mutations, G320V and I222N, were found. These studies confirm that mutations in HJV cause juvenile hemochromatosis. (Blood. 2004;103:4669-4671)
Complete protection from relapsing experimental autoimmune encephalomyelitis induced by syngeneic B cells expressing the autoantigen
Authors: Chen Chiann-Chyi , Rivera Amariliz , Dougherty Joseph P. , Ron Yacov
Published: March 2004

Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS), is a typical CD4+ T-cell-mediated autoimmune disease of the central nervous system (CNS) characterized by perivascular inflammation culminating in focal demyelinations. Like MS, EAE induced by proteolipid protein (PLP) usually follows the form of a relapsing-remitting disease. We have previously described an immunotherapy model in which infusion of autologous B cells expressing the PLP encephalitogenic determinant induced PLP-specific unresponsiveness and protected mice from induction of EAE. Here we show that the same treatment when initiated after disease onset, which resembles the clinical situation presented in MS, completely protects all treated animals from further relapses. We also show that protected animals were unresponsive to PLP as measured by delayed-type hypersensitivity (DTH). This represents a novel immunotherapeutic approach that can be exploited to develop treatments for human MS and other T-cell-mediated autoimmune diseases. (Blood. 2004;103:4616-4618)
Effect of inhaled fluticasone propionate on airway responsiveness in treatment-naive individuals--a lesser benefit in females
Authors: Convery RP , Leitch DN , Bromly C , Ward RJ , Bartlett G , Hendrick DJ
Published: March 2004

A randomized double-blind placebo-controlled parallel group study with inhaled fluticasone propionate over 6 weeks, designed to quantify the beneficial effect on airway responsiveness, and so assess whether short pulses of intermittent prophylactic treatment might serve as an alternative means of managing mild asthma, is reported. The 20-50-yr-old participants, who were recruited from an epidemiological study of the general population, had never knowingly received any regular treatment for asthma. Fluticasone propionate at the maximum recommended dose level (2,000 microg daily) and placebo were administered via metered-dose inhalers, and airway responsiveness was quantified conventionally by the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PD20) at 2-week intervals during the treatment phase and at various intervals subsequently. Compared with placebo fluticasone propionate was associated with a highly significant decrease in airway responsiveness (1.9 doublings of the geometric mean PD20), which was maximal at the end of the 6-week treatment period. No persisting benefit was detectable at the next measurement 2 weeks later, or thereafter. Multiple linear regression analysis showed that the magnitude of the fluticasone propionate effect was significantly greater in males than in females (3.2 versus 1.2 doublings respectively of the geometric mean PD20), but was uninfluenced by current smoking, age or FEV1. In conclusion, in the absence of any possibility of tachyphylaxis, inhaled fluticasone propionate at this dose causes a steadily increasing improvement in airway responsiveness over a 6-week period, which is modified by sex but lost almost immediately on treatment cessation. Short pulses of intermittent prophylactic treatment would not, therefore, be useful as a means of managing mild asthma.
Bronchial hyperresponsiveness and airway inflammation markers in nonasthmatics with allergic rhinitis
Authors: Polosa R , Ciamarra I , Mangano G , Prosperini G , Pistorio MP , Vancheri C , Crimi N
Published: March 2004

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma which is often associated with airways inflammation. However, some patients with allergic rhinitis and no clinical evidence of asthma also exhibit BHR. This study therefore investigated whether inflammatory cell infiltrate is present in the induced sputum of nonasthmatic subjects with allergic rhinitis during the pollen season and examined its relationship with airway hyperresponsiveness to inhaled methacholine and adenosine 5'-monophosphate (AMP). Twenty subjects (12 allergic rhinitis, eight nonallergic controls) underwent methacholine and AMP challenge and sputum induction with hypertonic saline on separate days. Cell differentials were calculated from whole sputum samples. A significantly greater number of eosinophils was found in the sputum of nonasthmatic subjects with allergic rhinitis compared to that of nonallergic controls, their median (range) percentages being 17.5 (4-47) and 1.5 (0-5) (p<0.001) respectively. Although sputum eosinophilia failed to be significantly associated with methacholine responsiveness (r(s)=-0.50; p=0.095), the provocative concentration of AMP causing a 20% fall in forced expiratory volume in one second correlated strongly and significantly with the absolute number of eosinophils (r(s)= -0.73; p=0.007). Eosinophil cationic protein levels in the sputum of rhinitic subjects were significantly elevated compared to controls and correlated with eosinophil number (r(s)=0.67; p=0.017). These findings support the view that bronchial eosinophilia alone is insufficient to cause asthmatic symptoms. Diverse agonists for assessing bronchial hyperresponsiveness are selectively associated with airway inflammation in allergic rhinitis.
Neutrophils in induced sputum arise from central airways
Authors: Moodley YP , Krishnan V , Lalloo UG
Published: March 2004

A high neutrophil count is often found in induced sputum compared to bronchoalveolar lavage fluid (BALF). This study investigated whether such a high neutrophil count may be a response to inhaled hypertonic saline or that the airway compartment sampled by induced sputum has a higher concentration of neutrophils than BALF. Saliva and induced sputum samples were taken at 10 and 20 min following inhalation of 3% hypertonic saline from an ultrasonic nebulizer in 12 healthy nonsmoking subjects. Four days later the 12 subjects underwent bronchoscopy (six following inhalation with 3% saline). Tracheal, proximal bronchial secretions, bronchial washings and BALF samples were obtained. The neutrophil count (% total leukocytes) increased significantly in saliva at 10 and 20 min post nebulization with 3% saline, although there was no change in neutrophils in induced sputum at 10 and 20 min. There was no significant difference in neutrophil count in the subjects who inhaled 3% saline as compared to those who did not, in secretions from the trachea, proximal bronchi, bronchial washings and BALF. Neutrophil counts were significantly higher in the trachea, proximal bronchi and bronchial washings as compared to BALF (p<0.001). It is concluded that neutrophil counts in healthy subjects increase from the peripheral towards the proximal airways, in the absence of hypertonic saline-induced changes. This suggests that the relatively high neutrophil count in induced sputum arises from the proximal airways and is not a response to inhaled hypertonic saline during the procedure.
Clinical and radiological characteristics of lung disease in inflammatory bowel disease
Authors: Mahadeva R , Walsh G , Flower CD , Shneerson JM
Published: March 2004

The pulmonary associations of inflammatory bowel disease (IBD) are poorly characterized. The clinical, physiological and high-resolution computed tomographic thorax characteristics of the lung disease in patients with IBD presenting with respiratory symptoms are described. Detailed clinical information was obtained and standard pulmonary physiological tests and thorax high-resolution computed tomography performed on 14 patients with ulcerative colitis (UC) and three with Crohn's disease (CD), 10 male, aged 38-83 yrs. Respiratory symptoms had been present for 2-50 yrs and extraintestinal manifestations were present in three (17.6%). Normal pulmonary physiology (six patients) was associated with the high resolution computed tomographic changes of bronchiectasis, mosaic perfusion and air trapping suggestive of obliterative bronchiolitis and a pattern of centrilobular nodules and branching linear opacities ("tree in bud" appearance) suggestive of either cellular bronchiolitis or bronchiolectasis with mucoid secretions. Bronchiectasis was found in 13 patients (11 UC, 2 CD), 11 had air trapping and five had a "tree in bud" appearance on computed tomography. One patient had a predominantly peripheral reticular pattern at the lung bases similar to that found in cryptogenic fibrosing alveolitis and one patient had a mixed reticular and ground-glass pattern in the midzones with a patchy distribution in the central and peripheral portions of the lungs with air trapping. Eleven patients (three with alveolitis) exhibited a clinical and/or physiological response to steroids. Pulmonary abnormalities in ulcerative colitis and Crohn's disease can present years after the onset of the bowel disease and can affect any part of the lungs. Early recognition is important as they can be strikingly steroid-responsive.
Budesonide and formoterol inhibit ICAM-1 and VCAM-1 expression of human lung fibroblasts
Authors: Spoelstra FM , Postma DS , Hovenga H , Noordhoek JA , Kauffman HF
Published: March 2004

The glucocorticoid budesonide and the long-acting beta2-adrenoceptor agonist formoterol are used in asthma therapy for their anti-inflammatory and bronchodilating effects, respectively. Since expression of adhesion molecules on resident cells in the lung plays an important role in asthmatic inflammatory responses, the effects of these drugs on the cytokine-induced intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM)-1 expression of human lung fibroblasts were investigated. Budesonide and formoterol were added in the absence or presence of interleukin (IL)-1beta, tumour necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma) or IL-4 to human lung fibroblasts; ICAM-1 and VCAM-1 expression were measured after 8 h using a cell surface enzyme linked immunosorbent assay (ELISA). It was found that both budesonide and formoterol significantly inhibited (p<0.05) the increased expression of ICAM-1 and VCAM-1 after stimulation with IL-1beta (maximal inhibition (median (25-75% percentiles) 50 (48-52) and 61% (42-69), respectively, with budesonide and 55 (50-73) and 86% (64-94), respectively, with formoterol (10(-7) M)), TNF-alpha (maximal inhibition 49 (46-57) and 57% (44-68), respectively, with budesonide and 44 (40-75) and 62% (52-83) respectively, with formoterol), IFN-gamma (maximal inhibition 64% (41-67) with budesonide and 39% (29-49) with formoterol for ICAM-1) and IL-4 (maximal inhibition 82% (69-92) with budesonide and 43% (33-67) with formoterol for VCAM-1) in a dose-dependent manner. The results show that budesonide, as well as formoterol, in probably clinically relevant concentrations inhibits cytokine-induced adhesion molecule expression on human lung fibroblasts from a concentration of 10(-9) M. This inhibitory effect on resident cells may have implications for the infiltration of inflammatory cells into pulmonary tissue during therapy with these drugs in asthma.
Leukotoxin and its diol induce neutrophil chemotaxis through signal transduction different from that of fMLP
Authors: Totani Y , Saito Y , Ishizaki T , Sasaki F , Ameshima S , Miyamori I
Published: March 2004

When injected into animals, leukotoxin (Lx) causes acute lung injury which is associated with neutrophils infiltrating the lung tissues. However, the effect of Lx on neutrophils is still unknown, and recently it has been reported that Lx diol, a hydrolyzed metabolite, should be more potent than Lx in vitro. In this study, the authors examined the effect of Lx and its diol on human neutrophils by assessing their chemotactic response, expression of adhesion molecules, and production of peroxides. Both Lx and its diol induced chemotaxis in human neutrophils via an involvement of pertussis toxin-sensitive G-proteins, but they did not influence the expression of adhesion molecules or the production of peroxides. Furthermore, Lx synergistically affected chemotaxis with N-formyl-methionyl-leucyl-phenylalanine (fMLP), but not with endothelin-1. Neutrophil chemotaxis induced by both Lx and its diol was inhibited by phosphatidylinositol-3-kinase (PI3-K) inhibitors, but not by protein tyrosine kinase (PTK) inhibitors or by protein kinase C (PKC) inhibitors, whereas fMLP-induced chemotaxis was inhibited by PTK inhibitors, but not by PI3-K inhibitors or by PKC inhibitors. These results suggest that neutrophil chemotaxis induced by both Lx and its diol involves pathways different from those induced by fMLP. In conclusion, both leukotoxin and its diol metabolite induce chemotaxis in human neutrophils in a unique way and may act as important bioactive lipids when considering the pathological mechanism of acute lung injury.
Respiratory effects of lipopolysaccharide-induced inflammatory lung injury in mice
Authors: Faffe DS , Seidl VR , Chagas PS , Goncalves de Moraes VL , Capelozzi VL , Rocco PR , Zin WA
Published: March 2004

The pathogenic mechanisms of lipopolysaccharide (LPS)-induced lung injury have not been classified. This study examined the physiological changes after endotoxin inhalation and related those to features of pulmonary inflammation in mice. Pulmonary mechanics, histopathology, and bronchoalveolar lavage fluid (BALF) from BALB/c mice were analysed at different occasions (3, 24, 48 and 72 h) after inhalation of saline or LPS from Escherichia coli (0.3 (L0.3) or 10 mg x mL(-1) (L10)). Mice were sedated, anaesthetized, and ventilated. After chest wall resection static (Est) and dynamic (Edyn) elastances, deltaE (Edyn-Est), resistive (deltaP1) and viscoelastic/inhomogeneous pressures (deltaP2), and deltaP1+deltaP2 (deltaPtot) were obtained by end-inflation occlusion method. Lungs were prepared for histopathology. In parallel groups, tumour necrosis factor (TNF)-alpha, neutrophils, and protein were evaluated in the BALF. L0.3 and L10 showed a time-dependent production of TNF-alpha preceding a massive neutrophil infiltration. In L10 BALF there was an increase in protein level at 24 and 48 h. Est and Edyn increased early in L0.3 (65%, 63%) and L10 (41%, 51%). In L10 deltaE, deltaP2, and deltaPtot showed a gradual rise. At 72 h all groups were similar. L0.3 showed an early increase in cellularity, which returned to normal at 72 h. L10 presented the same pattern with the cell count remaining elevated until 72 h. In conclusion, lipopolysaccharide inhalation led to elastic and viscoelastic pulmonary changes together with tumour necrosis factor-alpha production and neutrophil infiltration in mouse lung.
Venous and arterial changes in pulmonary veno-occlusive disease, mitral stenosis and fibrosing mediastinitis
Authors: Chazova I , Robbins I , Loyd J , Newman J , Tapson V , Zhdaov V , Meyrick B
Published: March 2004

The pathogenesis of pulmonary veno-occlusive disease (PVOD) is not known. The diagnosis of PVOD frequently relies on its histological changes since it is often difficult to distinguish clinically from primary pulmonary hypertension. This study carried out a systematic analysis of the pulmonary venous and arterial remodelling that occurs in PVOD (n=5) and compared these changes to two other diseases affecting the pulmonary veins, mitral stenosis (MS; n=6) and fibrosing mediastinitis (FM; n=2), using established morphometric techniques. In PVOD, pronounced intimal and adventitial thickening were noted in veins of all sizes and arterialization of veins >50 microm external diameter was found. Similar changes were evident in the arterial wall, but intimal thickening was less severe than in the veins and medial thickening was more pronounced in arteries <300 microm external diameter. Eccentric intimal fibrosis of the veins was also noted for the first time in PVOD, although this feature occurred less frequently (approximately one third) than in MS. Less pronounced structural remodelling was also encountered in the veins in cases of MS and FM. The severity of the venous changes in PVOD may aid its diagnosis and lend insight into its pathogenesis. However, the similarity of the vascular changes in each form of venous hypertension also suggests that pathology alone may not always differentiate between these disease states. The similarity of the vascular changes in the three forms of venous hypertension suggests that, as in pulmonary artery hypertension, pressure, per se, is one of the triggers to vascular remodelling.