bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioral Approaches to Promoting Play
Authors: Stahmer Aubyn C. , Ingersoll Brooke , Carter Cynthia
Published: November 2003

A variety of techniques grounded in behavioral psychology, and more specifically in applied behavior analysis, have been established to increase and improve play skills in children with autistic spectrum disorders. This article introduces a set of efficacious methods, which range from highly structured techniques to more naturalistic strategies. It focuses on object play as other authors in the issue discuss social play in greater depth. Behavioral techniques that are reviewed include: discrete trial training, use of stereotyped behaviors to increase play skills, pivotal response training, reciprocal imitation training, differential reinforcement of appropriate behavior, in vivo modeling and play scripts, and video modeling. A discussion of expanding behavior techniques to teach more complex play as well as training in varied environments is also presented. References are provided to allow the reader to obtain more in-depth information about each technique.
Beyond Echoplaylia
Authors: Schuler Adriana L.
Published: November 2003

The article was written to support the use of play as a medium to extend and enrich the communicative exchanges and, more specifically, the symbolic language of children on the autistic spectrum. The first argument in support of such use of play lies within the features of autistic communication, and particularly the extreme challenges encountered in imaginative play and narrative thought. The second argument on behalf of play lies within the selection of specific inter- vention strategies, which are discussed subsequently. Finally, the article presents a case illustration of how adult facilitated dramatic peer play led to a breakthrough in a range of symbolic behaviours in a 9-year- old girl with autism, who up to that point had not progressed beyond a semi-communicative use of echolalia, best described as ‘situation association’.
What’s ‘home’ Got to do with it?
Authors: Morley David
Published: November 2003

This article focuses on how we can understand the contradictory dynamicsthrough which communications technologies have been domesticated at the same time that domesticity itself has been dislocated. The article addresses questions of historical periodization and the need for a more developed historical perspective on the futurological debates about the new technologies with which so much of media and cultural studies is concerned today.
Television and Nationalism
Authors: Yoshimi Shunya
Published: November 2003

This article attempts to throw some light on the linkage between television and nationalism in contemporary Japan, focusing on: 1) the historical development of TV as a symbolic object in everyday life; 2) TV as a technology of time–space articulation; and 3) the textual formation of TV programs. By the late 1950s, TV sets were placed not in homes, but on street corners, where large numbers of people gathered. The symbolic meaning of the ‘collective’ nature of TV changed after the 1960s. From the early 1960s onwards, when TV entered households, it became an overarching medium linking the family with the state, defining the national consciousness and dominating people’s imaginative views of both the past and the present. This article analyzes the ideological relationship between gender, technology and nationalism in TV images through the postwar period. But TV also provides a flow of information and discursive structures for the horizons of the social imagination. Thus, the article also shows how TV broadcasting was structured around the three nationwide time zones of morning, midday and evening. Through these time zones, it was possible to link domestic memories with national history via its major programs. The stability of TV as a national medium was threatened in all these dimensions from the late 1980s. Increasingly, media became personalized, transgressive and transnational. Despite the gradual break-up of the stable position of TV in households and the national timetable constructed through broadcasting, more powerful and aggressive national times and discourses have come into being in the face of crises. In the context of this contradictory situation, the dominant central TV stations in Japan today are becoming increasingly stagnant while, on the other hand, the internet and independent video journalism are showing greater dynamism.
Enterprising Femininity
Authors: Gray Ann
Published: November 2003

This article introduces a group of ‘enterprising women’ in occupations dealing with ‘impression management’ and ‘care of the self’. It argues that this brand of worker successfully transforms skills acquired through consumption and the making of the feminine into increasingly valuable marketable skills. As such she embodies a blurring of consumption and production and inhabits a particular form of enterprising femininity. Through a reflexive life story method, questions of the role of consumption and self-help literature in the construction of this subjectivity are explored.
‘Mohammed Atta and I&rsquo
Authors: Gullestad Marianne
Published: November 2003

This article uses the popular thought figure of the sleeper as a methodological tool to get a new angle on the cultural analysis of majority–minority relations in Europe. I do so on the basis of an autobiographical essay written by Nazneen Khan, who considers the theoretical possibility that she too might have become a terrorist. The analysis focuses on descent and religion, as specific sources of identification and belonging, and on how and where, in present-day identification, sleeper identities might be identified. The analysis reveals that the definition of the sleeper in the mass media is not the only one possible. This figure can be reconfigured more dynamically and processually as someone who has experienced repeated rejection within structured relations of power influenced by ideologies focusing on blood and religion. In addition, I argue that populist ideas in Europe can themselves be regarded as (racist) sleepers.
The Seers of Menlo Park
Authors: Binkley Sam
Published: November 2003

This article considers the emergence of the postmodern reflexive consumer through an archival case study of one particularly influential lifestyle magazine, the Whole Earth Catalog. This publication is read in the context of the cultural and lifestyle innovations of the ‘new cultural intermediaries’ (Bourdieu, Featherstone) of the 1970s, expressed in a new print media of lifestyle advice. In this print culture, consumers were taught to cultivate a reflexive awareness of their lifestyles through an enhanced sensitivity to the deeper meanings of market messages and consumer choices. On the basis of the advice of non-traditional lifestyle intellectuals, market choices acquired a sense of ‘deep play’ (Geertz) in which the well-being of the self and the planet emerged as the specific stake of lifestyle choices. Combining archival research with theoretical and historical analysis, the findings of this study offer an alternative to postmodern studies of the new consumer culture, which focus on the depthlessnessof consumption as a form of ‘pastiche’ (Jameson).
Understandings of Consumerism in Chile
Authors: van Bavel Ren… , Sell-Trujillo LucÕa
Published: November 2003

This article explores different understandings of consumerism among upper/upper-middle and lower income sectors in Chile. Theoretically, it relies on a cultural approach to rationality and on a Habermasiansystem vs lifeworld interpretation of society. Empirically, it resorts toa corpus of semi-structured interviews and focus groups conducted in Chile in1998. The data suggest that the well off rely on a neoliberal interpretation of economic behaviour and scorn the poor for their tendency to engage in consumerism, while the poor interpret consumerism within their lifeworldas the only way of rising above their impoverished condition. Moreover, means of payment emerges as a relevant criterion for establishing social differences in a class-conscious society where neoliberalism has become the dominant ideology.
G-CSF signaling can differentiate promyelocytes expressing a defective retinoic acid receptor: evidence for divergent pathways regulating neutrophil differentiation
Authors: Maun Noel A. , Gaines Peter , Khanna-Gupta Arati , Zibello Theresa , Enriquez Louie , Goldberg Laura , Berliner Nancy
Published: November 2003

Several lines of investigation suggest that granulocyte colony-stimulating factor (G-CSF) augments all-trans retinoic acid (ATRA)–induced neutrophil differentiation in acute promyelocytic leukemia (APL). We sought to characterize the relationship between G-CSF– and ATRA-mediated neutrophil differentiation. We established a G-CSF receptor-transduced promyelocytic cell line, EPRO-Gr, derived from the granulocyte-macrophage colony-stimulating factor (GM-CSF)–dependent EPRO cell line harboring a dominant-negative retinoic acid receptor alpha (RARα). In EPRO-Gr, neutrophil differentiation occurs either in GM-CSF upon addition of ATRA or upon induction with G-CSF alone. Transient transfection of EPRO-Gr cells with a RARE-containing reporter plasmid demonstrates increased activity in the presence of ATRA, but not G-CSF, while STAT3 phosphorylation occurs only in response to G-CSF. This suggests that ATRA-mediated differentiation of EPRO-Gr cells occurs via a RARE-dependent, STAT3-independent pathway, while G-CSF–mediated differentiation occurs via a RARE-independent, STAT3-dependent pathway. ATRA and G-CSF thus regulate differentiation by divergent pathways. We characterized these pathways in the APL cell line, NB4. ATRA induction of NB4 cells resulted in morphologic differentiation and up-regulation of C/EBPϵ and G-CSFR, but not in STAT3 phosphorylation. The addition of G-CSF with ATRA during NB4 induction resulted in STAT3 phosphorylation but did not enhance differentiation. These results may elucidate how G-CSF and ATRA affect the differentiation of primary and ATRA-resistant APL cells.
Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD–transformed hematopoietic cells
Authors: Bagrintseva Ksenia , Schwab Ruth , Kohl Tobias M. , Schnittger Susanne , Eichenlaub Sabine , Ellwart Joachim W. , Hiddemann Wolfgang , Spiekermann Karsten
Published: November 2003

Activating mutations in the juxtamembrane domain (FLT3-length mutations, FLT3-LM) and in the protein tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) represent the most frequent genetic alterations in acute myeloid leukemia (AML) and define a molecular target for therapeutic interventions by protein tyrosine kinase (PTK) inhibitors. We could show that distinct activating FLT3-TKD mutations at position D835 mediate primary resistance to FLT3 PTK inhibitors in FLT3-transformed cell lines. In the presence of increasing concentrations of the FLT3 PTK inhibitor SU5614, we generated inhibitor resistant Ba/F3 FLT3-internal tandem duplication (ITD) cell lines (Ba/F3 FLT3-ITD-R1-R4) that were characterized by a 7- to 26-fold higher IC50 (concentration that inhibits 50%) to SU5614 compared with the parental ITD cells. The molecular characterization of ITD-R1-4 cells demonstrated that specific TKD mutations (D835N and Y842H) on the ITD background were acquired during selection with SU5614. Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants, in Ba/F3 cells restored the FLT3 inhibitor resistant phenotype. Our data show that preexisting or acquired mutations in the PTK domain of FLT3 can induce drug resistance to FLT3 PTK inhibitors in vitro. These findings provide a molecular basis for the evaluation of clinical resistance to FLT3 PTK inhibitors in patients with AML.
Anoxic induction of ATF-4 through HIF-1–independent pathways of protein stabilization in human cancer cells
Authors: Ameri Kurosh , Lewis Claire E. , Raida Martin , Sowter Heidi , Hai Tsonwin , Harris Adrian L.
Published: November 2003

Hypoxia is a key factor in tumor development, contributing to angiogenesis and radiotherapy resistance. Hypoxia-inducible factor-1 (HIF-1) is a major transcription factor regulating the response of cancer cells to hypoxia. However, tumors also contain areas of more severe oxygen depletion, or anoxia. Mechanisms for survival under anoxia are HIF-1α independent in Caenorhabditis elegans and, thus, differ from the hypoxic response. Here we report a differential response of cancer cells to hypoxia and anoxia by demonstrating the induction of activating transcription factor-4 (ATF-4) and growth arrest DNA damage 153 (GADD153) protein specifically in anoxia and the lack of induction in hypoxia. By applying RNAi, ATF-4 induction in anoxia was shown to be independent of HIF-1α, and desferrioxamine mesylate (DFO) and cobalt chloride induced HIF-1α but not ATF-4 or GADD153. Furthermore, the inductive response of ATF-4 and GADD153 was not related to alterations in or arrest of mitochondrial respiration and was independent of von Hippel-Lindau (VHL) disease mutations. In reoxygenated anoxic cells, ATF-4 had a half-life of less than 5 minutes; adding the proteasome inhibitor to normoxic cells up-regulated ATF-4 protein. Extracts from primary human tumors demonstrated more ATF-4 expression in tumors near necrotic areas. Thus, this study demonstrates a novel HIF-1α–independent anoxic mechanism that regulates ATF-4 induction at the protein stability level in tumor cells.
Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter
Authors: Dingli David , Peng Kah-Whye , Harvey Mary E. , Greipp Philip R. , O'Connor Michael K. , Cattaneo Roberto , Morris John C. , Russell Stephen J.
Published: November 2003

The Edmonston vaccine strain of measles virus (MV-Edm) propagates efficiently in a broad range of human tumor cells, killing them selectively. However, the oncolytic potency of MV-Edm in different human tumor xenograft therapy models is highly variable and there is no convenient way to map the distribution of virus-infected tissues in vivo. To enhance the oncolytic potency of MV-Edm against radiosensitive malignancies and to facilitate noninvasive imaging of infected tissues, we generated a recombinant MV-Edm encoding the human thyroidal iodide symporter (NIS). MV-NIS replicated almost as efficiently as unmodified MV-Edm, and human tumor cells efficiently concentrated radioiodine when infected with MV-NIS. Intratumoral spread of MV-NIS was noninvasively demonstrated by serial gamma-camera imaging of iodine-123 (123I) uptake both in MV-sensitive KAS-6/1 myeloma xenografts, which regressed completely after a single intravenous dose of MV-NIS, and in MM1 myeloma xenografts, which were unresponsive to MVNIS therapy. However, MV-resistant MM1 tumors regressed completely when 131I was administered 9 days after a single intravenous injection of MV-NIS (radiovirotherapy). 131I alone had no effect on MM1 tumor growth. While the potential hematopoietic toxicity of this new therapy requires further evaluation, image-guided radiovirotherapy is a promising new approach to the treatment of multiple myeloma, an incurable but highly radiosensitive plasma cell malignancy. Testing in other radiosensitive cancers is warranted.
Genetics of fibrin clot structure: a twin study
Authors: Dunn Emma J. , Ariëns Robert A. , de Lange Marlies , Snieder Harold , Turney John H. , Spector Timothy D. , Grant Peter J.
Published: November 2003

Coronary artery thrombosis following plaque rupture is an important feature of myocardial infarction, and studies have highlighted the role of coagulation in this condition. Although genetic and environmental influences on the variance in coagulation protein concentrations have been reported, there are no data on the heritability of structure/function of the final phenotype of the coagulation cascade, the fibrin clot. To assess genetic and environmental contributions to fibrin structure, permeation and turbidity studies were performed in 137 twin pairs (66 monozygotic, 71 dizygotic). The environmental influence (e2) on pore size (Ks) (e2 = 0.61 [95% confidence interval (CI), 0.45-0.80]) and fiber size (e2 = 0.54 [95% CI, 0.39-0.73]) was greater than the heritability (h2 = 0.39 [95% CI, 0.20-0.55] and 0.46 [95% CI, 0.27-0.62], respectively). After correction for fibrinogen levels, the environmental effect persisted for Ks (e2 = 0.61), but genetic influence assumed a greater importance in determining fiber size (h2 = 0.73). Multivariate analysis revealed an overlap in the influence of genetic and environmental factors on fibrinogen levels, Ks, and fiber size. Factor XIII B subunit showed environmental and genetic correlation with fibrinogen and fiber size and a genetic correlation with Ks. The results indicate that genetic and environmental influences are important in determining fibrin clot structure/function.
Negative regulation of FcϵRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b
Authors: Qu Xiujuan , Sada Kiyonao , Kyo Shinkou , Maeno Koichiro , Miah S. M. Shahjahan , Yamamura Hirohei
Published: November 2003

Aggregation of the high-affinity immunoglobulin E (IgE) receptor (FcϵRI) on mast cells induces a number of biochemical events, including protein-tyrosine phosphorylation leading to degranulation and multiple cytokine gene transcription. Here, we have demonstrated that a second member of the Cbl family of ubiquitin-protein ligase Cbl-b translocates into the lipid raft after FcϵRI engagement. Overexpression of Cbl-b in the lipid raft inhibits FcϵRI-mediated degranulation and cytokine gene transcription through the distinct mechanism. A point mutation of Cys373 in the RING finger domain of Cbl-b abrogates the suppression of FcϵRI-mediated degranulation but not cytokine gene transcription. The antigen-induced tyrosine phosphorylation of FcϵRI, Syk, phospholipase C-γ (PLC-γ), activation of c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), inhibitor of nuclear factor κB kinase (IKK), and Ca++ influx were all suppressed in the cells overexpressing Cbl-b in the lipid raft. In particular, the expression amount of Gab2 protein and thereby its FcϵRI-mediated tyrosine phosphorylation were dramatically down-regulated by ubiquitin-protein ligase activity of Cbl-b. These results suggest that Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcϵRI-mediated mast cell activation.
Von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate
Authors: Keuren Jeffrey F. W. , Baruch Dominique , Legendre Paulette , Denis Cécile V. , Lenting Peter J. , Girma Jean-Pierre , Lindhout Theo
Published: November 2003

Fibrin is actively involved in platelet reactions essential for thrombus growth, in which von Willebrand factor (VWF) might be an important mediator. The aim of this study was to localize VWF domains that bind to fibrin and to determine their relevance in platelet adhesion. VWF binds specifically to fibrin with an apparent Kd of 2.2 μg/mL. Competition in the presence of 2 complementary fragments, SpIII (residues 1-1365) and SpII (residues 1366-2050), indicated that the high affinity binding site for fibrin is located in the C-terminal part, thus distinct from the A domains. Comparison of 2 deleted rVWF (ΔD4B-rVWF, ΔC1C2-rVWF) suggested that the C1C2 domains contained a fibrin binding site. This site is distinct from RGD, as shown by binding of D1746G-rVWF to fibrin. Perfusion studies at high shear rate demonstrated that C1C2 domains were required for optimal platelet adhesion to fibrin. With the use of a VWF-deficient mouse model, it was found that plasma VWF is critical for platelet tethering and adhesion to fibrin. These results suggest a dual role of fibrin-bound VWF in thrombus formation: first, fibrin-bound VWF is critical in the recruitment of platelets by way of glycoprotein (GP) Ib, and, second, it contributes to stationary platelet adhesion by way of binding to activated αIIbβ3.
Functional differences between hepcidin 1 and 2 in transgenic mice
Authors: Lou Dan-Qing , Nicolas Gaël , Lesbordes Jeanne-Claire , Viatte Lydie , Grimber Gisèle , Szajnert Marie-France , Kahn Axel , Vaulont Sophie
Published: November 2003

Hepcidin is a 25-amino acid peptide involved in iron homeostasis in mice and humans. It is produced in the liver from a larger precursor, and it is detectable in blood and urine. In contrast to the human genome, which contains only one copy of the gene, the mouse genome contains 2 highly similar hepcidin genes, hepc1 and hepc2, which are, however, considerably divergent at the level of the corresponding mature 25-amino acid peptide. This striking observation led us to ask whether hepc1 and hepc2 performed the same biologic activity with regard to iron metabolism in the mouse. We recently described the severe iron-deficient anemia phenotype in transgenic mice overexpressing hepc1 in the liver. Here we report that, in contrast to the hepc1-transgenic mice, none of the 7 founder hepc2-transgenic animals suffered from anemia. They all developed normally with hematologic parameters similar to the nontransgenic littermates. Hepc2 transgenic mRNA level was found to be very high for all lines compared with the level of hepc1 transgene mRNA necessary to produce severe anemia. These data provide evidence that hepc2 does not act on iron metabolism like hepc1 and give clues for the identification of amino acids important for the iron-regulatory action of the mature 25-amino acid peptide. (Blood. 2004;103:2816-2821)
The worldwide distribution of the VHL 598C>T mutation indicates a single founding event
Authors: Liu Enli , Percy Melanie J. , Amos Christopher I. , Guan Yongli , Shete Sanjay , Stockton David W. , McMullin Mary F. , Polyakova Lydia A. , Ang Sonny O. , Pastore Yves D. , Jedlickova Katerina , Lappin Terry R. J. , Gordeuk Victor , Prchal Josef T.
Published: November 2003

The first congenital defect of hypoxia-sensing homozygosity for VHL 598C>T mutation was recently identified in Chuvash polycythemia. Subsequently, we found this mutation in 11 unrelated individuals of diverse ethnic backgrounds. To address the question of whether the VHL 598C>T substitution occurred in a single founder or resulted from recurrent mutational events in human evolution, we performed haplotype analysis of 8 polymorphic markers covering 340 kb spanning the VHL gene on 101 subjects bearing the VHL 598C>T mutation, including 72 homozygotes (61 Chuvash and 11 non-Chuvash) and 29 heterozygotes (11 Chuvash and 18 non-Chuvash), and 447 healthy unrelated individuals from Chuvash and other ethnic groups. The differences in allele frequencies for each of the 8 markers between 447 healthy controls (598C) and 101 subjects bearing the 598T allele (P < 10–7) showed strong linkage disequilibrium. Haplotype analysis indicated a founder effect. We conclude that the VHL 598C>T mutation, the most common defect of congenital polycythemia yet found, was spread from a single founder 14 000 to 62 000 years ago.
Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis
Authors: Wilson Nicholas S. , El-Sukkari Dima , Villadangos José A.
Published: November 2003

Dendritic cells (DCs) change their antigen-presenting properties during maturation. Immature DCs efficiently capture antigens, but are reported to be impaired in their processing and presenting capacity. Upon an encounter with an inflammatory stimulus, DCs undergo a maturation process that leads to efficient presentation of antigens captured at the time of activation, but precludes processing of antigens encountered at later time points. The mechanisms that underlie these developmental changes are controversial. Thus, it is unclear whether immature DCs can present self antigens, and which are the checkpoints that regulate antigen presentation in immature and mature DCs. We have characterized these mechanisms using DCs derived directly from lymphoid organs. Immature lymphoid organ DCs constitutively presented self peptides bound to major histocompatibility complex class II (MHCII) molecules, but these MHCII-peptide complexes were degraded quickly after their transient expression on the cell surface. During maturation, MHC II endocytosis was down-regulated, so that newly generated MHC II–peptide complexes accumulated on the plasma membrane. Simultaneously, MHC II synthesis was down-regulated, thus preventing the turnover of the MHC II–peptide complexes that accumulated early during maturation. Our results demonstrate that immature DCs constitutively present self antigens in the lymphoid organs and characterize the molecular basis of the capacity of DCs to provide “antigenic memory” in vivo.
In vivo exit of c-kit+/CD49dhi/β7+ mucosal mast cell precursors from the bone marrow following infection with the intestinal nematode Trichinella spiralis
Authors: Pennock Joanne L. , Grencis Richard K.
Published: November 2003

We have used the parasite helminth Trichinella spiralis to study the generation and differentiation of mast cell progenitors in the bone marrow of mice, as this infection triggers an intestinal mastocytosis which correlates with parasite expulsion. C-kit+ mast cell progenitors have previously been defined by methylcellulose colony-forming units and by limiting dilution assays in vitro. In vivo experiments have demonstrated the essential requirement by mast cells for specific integrin expression. We have defined 2 c-kit+ populations in the bone marrow, one of which coexpresses CD49d/β7 integrin, a marker essential for small intestine immigration. We have confirmed the phenotype of these cells by using antagonistic anti-c-kit antibody in vivo. Our data show that the loss of c-kit+/β7+ cells from the bone marrow correlates with their appearance in the blood and precedes detection of mature mast cells in the gut by 3 days. This exit correlates with an increase in soluble stem cell factor (SCF) in the serum, suggesting that the c-kit/SCF interaction may be chemotactic or haptotactic in nature. This study shows that during infection the bone marrow environment generates mast cells destined for the intestinal mucosa before their exit into the periphery, indicating a clear interplay between infection site and hematopoietic tissue. (Blood. 2004;103:2655-2660)
Regulation of Insulin-Like Growth Factor (IGF)-I Action by Matrix Metalloproteinase-3 Involves Selective Disruption of IGF-I/IGF-Binding Protein-3 Complexes
Authors: Fowlkes John L. , Serra Delila M. , Bunn R. Clay , Thrailkill Kathryn M. , Enghild Jan J. , Nagase Hideaki
Published: November 2003

IGF-I and IGF-II play important roles in growth and development via interactions with cell-surface receptors; however, in nature, IGFs are sequestered by at least six soluble, high-affinity IGF-binding proteins (IGFBPs), namely IGFBPs 1–6. Herein, we demonstrate that the stromal cell-derived extracellular matrix-degrading metalloproteinase stromelysin 1 (matrix metalloproteinase 3) disrupts IGF/IGFBP-3 complexes and liberates free, intact IGFs, leading to phosphorylation of cell surface type 1 IGF receptors and cellular proliferation. Tissue inhibitor of metalloproteinases (TIMP-1) or an antibody to the type 1 IGF receptor mitigates IGF-mediated cellular proliferation. Thus, these studies suggest that matrix metalloproteinases, beyond their effects on extracellular matrix turnover, regulate cellular proliferation by modulating the bioavailability of IGFs, an event critical for such diverse phenomena as embryo development, morphogenesis, angiogenesis, and tumorigenesis.
Differential Expression of a Cutaneous Corticotropin-Releasing Hormone System
Authors: Slominski Andrzej , Pisarchik Alexander , Tobin Desmond J. , Mazurkiewicz Joseph E. , Wortsman Jacobo
Published: November 2003

We completed the mapping of a cutaneous CRH signaling system in two species with widely different determinants of skin functions, humans and mice. In human skin, the CRH receptor (CRH-R) 1 was expressed in all major cellular populations of epidermis, dermis, and subcutis with CRH-R1α being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels. In mouse skin, the CRH-R2 gene and protein were widely expressed in all cutaneous compartments and in cultured normal and malignant melanocytes. CRH-binding protein mRNA was present in dermal fibroblasts, melanoma cells, and sc fat of human skin and undetectable in mouse skin. The urocortin II gene was expressed equally in mouse and human skin. Taken together with our previous investigations, the present studies document the preferential expression of CRH-R1 in human skin, which mirrors CRH-R2 expression patterns in human and mouse skin. They are likely reflecting different functional activities of human and mouse skin. The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants.
Activation of the Retinoid X Receptor Suppresses Appetite in the Rat
Authors: Ogilvie Kathleen M. , Saladin Régis , Nagy Tim R. , Urcan Mary S. , Heyman Richard A. , Leibowitz Mark D.
Published: November 2003

The retinoid X receptor (RXR), a ubiquitously expressed intracellular receptor, regulates pathways controlling glucose, triglycerides, cholesterol, and bile acid metabolism. In addition to its role in those metabolic pathways, we reported that RXR activation with a pan agonist [e.g. LG100268 (LG268)] decreases both body weight gain (BWG) and food consumption (FC) in obese, insulin-resistant rodents. In parallel with those changes in energy balance, we show here that activation of RXR pathways results in adipose tissue remodeling, particularly within sc fat where the rate of apoptosis is increased 5-fold. This change may underlie the selective decrease in fat mass observed in Zucker fatty rats treated with LG268 for 6 wk. Because FC is strongly correlated with BWG in treated animals, we hypothesized that regulation of FC might be the primary mechanism underlying reduced BWG during RXR agonist administration. Importantly, decreased FC is due to decreased meal size, suggestive of induced satiety rather than malaise and/or aversion to food. Furthermore, administration of LG268 directly into the brain via intracerebroventricular injection also reduces FC, BWG, and insulin, whereas the elevation in triglycerides observed after oral administration is absent. The latter observation suggests that RXR actions on energy balance and lipid homeostasis are separable. Therefore, ligand-mediated activation of either an RXR homodimer or an unidentified heterodimeric complex regulates pathways controlling energy balance at least in part via a central nervous system-mediated mechanism.
Photoperiod Influences the Effects of Exercise and Food Restriction on an Antigen-Specific Immune Response in Siberian Hamsters
Authors: Bilbo Staci D. , Nelson Randy J.
Published: November 2003

Environmental conditions influence the onset and severity of illness and infection and may compromise survival. Energetically challenging conditions during winter may directly induce death through hypothermia, starvation, or shock. The ability to forecast and prepare for the arrival of challenging conditions associated with winter (e.g. low temperatures, decreased food) likely confers survival advantages. Siberian hamsters (Phodopus sungorus) stop reproduction and reduce body mass (∼25%) during short, winter-like day lengths, resulting in energetic savings. Hamsters also increase circulating glucocorticoids and lymphocytes (e.g. T cells, NK cells), and exhibit enhanced antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin during short days (SDs). We tested the hypothesis that Siberian hamsters use SD lengths to signal the onset of winter to mediate the energetic trade-offs among body mass, reproductive function, and immune function. Long-day (LD; 16 h light, 8 h dark) and SD (8 h light, 16 h dark) hamsters were either food restricted (25%) or provided ad libitum (ad lib) food for 4 wk; half of all hamsters in each food condition had voluntary access to a running wheel, and half remained sedentary. SD hamsters enhanced DTH responses compared with LD hamsters under sedentary ad lib conditions. Exercise enhanced DTH in LD hamsters regardless of food intake. Furthermore, food-restriction did not significantly influence DTH in LD hamsters. In contrast, food-restriction suppressed DTH in SD hamsters regardless of activity condition, and exercise modestly enhanced DTH only in SD hamsters with ad lib access to food. In sum, moderate energetic deficiency suppressed DTH in SD (but not LD) hamsters, and this suggests that hamsters may have evolved to enhance immune responses during winter in preparation for increased metabolic stressors.
Inhibition of Testicular Steroidogenesis by the Xenoestrogen Bisphenol A Is Associated with Reduced Pituitary Luteinizing Hormone Secretion and Decreased Steroidogenic Enzyme Gene Expression in Rat Leydig Cells
Authors: Akingbemi Benson T. , Sottas Chantal M. , Koulova Anna I. , Klinefelter Gary R. , Hardy Matthew P.
Published: November 2003

Exposure of humans to bisphenol A (BPA), a monomer in polycarbonate plastics and a constituent of resins used in food packaging and dentistry, is significant. In this report exposure of rats to 2.4 μg/kg·d (a dose that approximates BPA levels in the environment) from postnatal d 21–35 suppressed serum LH (0.21 ± 0.05 ng/ml; vs. control, 0.52 ± 0.04; P < 0.01) and testosterone (T) levels (1.62 ± 0.16 ng/ml; vs. control, 2.52 ± 0.21; P < 0.05), in association with decreased LHβ and increased estrogen receptor β pituitary mRNA levels as measured by RT-PCR. Treatment of adult Leydig cells with 0.01 nm BPA decreased T biosynthesis by 25% as a result of decreased expression of the steroidogenic enzyme 17α-hydroxylase/17–20 lyase. BPA decreased serum 17β-estradiol levels from 0.31 ± 0.02 ng/ml (control) to 0.22 ± 0.02, 0.19 ± 0.02, and 0.23 ± 0.03 ng/ml in rats exposed to 2.4 μg, 10 μg, or 100 mg/kg·d BPA, respectively, from 21–35 d of age (P < 0.05) due to its ability to inhibit Leydig cell aromatase activity. Exposures of pregnant and nursing dams, i.e. from gestation d 12 to postnatal d 21, decreased T levels in the testicular interstitial fluid from 420 ± 34 (control) to 261 ± 22 (P < 0.05) ng/ml in adulthood, implying that the perinatal period is a sensitive window of exposure to BPA. As BPA has been measured in several human populations, further studies are warranted to assess the effects of BPA on male fertility.
Meiotic transmission of epigenetic changes in the cell-division factor requirement of plant cells
Authors: Meins Frederick , Thomas Monique
Published: November 2003

During the development of tobacco plants, cells undergo epigenetic changes that alter their requirement in culture for the cell-division factor cytokinin. Cultured leaf cells alternate between cytokinin-requiring(C–) and cytokinin-independent (C+) states at extremely high rates of approximately 10–2 per cell generation by a process called pseudodirected variation. Here we show that plants regenerated from most C+ clones express the Habituated leaf (Hl) trait, i.e., leaf tissues exhibit the C+ phenotype rather than the wild-type C– phenotype in culture. This new trait then segregates as a monogenic dominant trait indicating that conversion of C– cells to C+ cells is associated with a meiotically transmissible, genetic modification. Two independent mutants, Hl-2 and Hl-3, derived from C+ variants arising in culture were unstable in planta and reverted gametically at rates roughly comparable to pseudodirected variation in culture. Cells of the Hl-2mutant, but not of a stable Hl-1 mutant, reverted phenotypically at high rates in culture. This revertant C– phenotype persisted in some plants regenerated from cloned revertant lines, and then showed irregular segregation in two successive sexual generations. These results show for the first time that meiotically transmissible epimutations can occur reversibly and at high rates in culture.
Lmo2 and Scl/Tal1 convert non-axial mesoderm into haemangioblasts which differentiate into endothelial cells in the absence of Gata1
Authors: Gering Martin , Yamada Yoshihiro , Rabbitts Terence H. , Patient Roger K.
Published: November 2003

The LIM domain protein Lmo2 and the basic helix-loop-helix transcription factor Scl/Tal1 are expressed in early haematopoietic and endothelial progenitors and interact with each other in haematopoietic cells. While loss-of-function studies have shown that Lmo2 and Scl/Tal1 are essential for haematopoiesis and angiogenic remodelling of the vasculature, gain-of-function studies have suggested an earlier role for Scl/Tal1 in the specification of haemangioblasts, putative bipotential precursors of blood and endothelium. In zebrafish embryos, Scl/Tal1 can induce these progenitors from early mesoderm mainly at the expense of the somitic paraxial mesoderm. We show that this restriction to the somitic paraxial mesoderm correlates well with the ability of Scl/Tal1 to induce ectopic expression of its interaction partner Lmo2. Co-injection of lmo2 mRNA with scl/tal1 dramatically extends its effect to head, heart, pronephros and pronephric duct mesoderm inducing early blood and endothelial genes all along the anteroposterior axis. Erythroid development, however, is expanded only into pronephric mesoderm,remaining excluded from head, heart and somitic paraxial mesoderm territories. This restriction correlates well with activation of gata1transcription and co-injection of gata1 mRNA along with scl/tal1 and lmo2 induces erythropoiesis more broadly without ventralising or posteriorising the embryo. While no ectopic myeloid development from the Scl/Tal1-Lmo2-induced haemangioblasts was observed, a dramatic increase in the number of endothelial cells was found. These results suggest that, in the absence of inducers of erythroid or myeloid haematopoiesis, Scl/Tal1-Lmo2-induced haemangioblasts differentiate into endothelial cells.
Delayed loss of residual hearing in Clarion® cochlear implant users
Authors: Barbara M. , Mattioni A. , Monini S. , Chiappini I. , Ronchetti F. , Ballantyne D. , Mancini P. , Filipo R.
Published: November 2003

Hearing threshold has been measured in a group of patients following cochlear implantation with a Clarion® device for the last eight years. The patients had received either a pre-curved carrier or the Hi-Focus I plus Electrode Positioner System (EPS). The assessment was carried out within the first post-operative week as well as at a later stage, between six and 87 months, post-operatively. Residual hearing thresholds were still measurable early after surgery in 24.5 per cent of the patients, without differences between the two different Clarion® models. However, the number of subjects with measurable hearing dropped to 16.3 per cent as observed when hearing was measured at a later stage, with an equal distribution between the two groups of patients. From this study it has been possible to observe that only a limited number of patients maintain residual hearing after Clarion® cochlear implantation, and that this tends to decrease further over time. Nevertheless, the performance of these patients for speech tests did not appear to be affected by deterioration of the pure-tone auditory threshold.
A comparison of survival lifetime of the Provox® and the Provox®2 voice prosthesis
Authors: Lequeux T. , Badreldin A. , Saussez S. , Thill M. P. , Oujjan L. , Chantrain G.
Published: November 2003

The Provox® (Atos Medical AB, Hörby, Sweden) voice prosthesis was developed between 1988 and 1990 and has been used at our centre with regular success since 1993. Since 1996, a second generation of Provox® (Provox®2) has been used, which can be inserted by an anterograde technique. The aim of this study is to compare the survival lifetime of both voice prostheses. The survival time of the two voice prostheses were compared retrospectively in 152 devices placed in 38 patients. A Kaplan-Meier analysis was performed to determine the survival lifetimes and a log rank test was performed to compare the two curves. Clinical factors affecting the lifetime were also analysed with a Kaplan-Meier plot.

The median survival lifetime of the Provox® and Provox®2 were 303 and 144 days respectively. The Kaplan-Meier estimation shows that this difference is statistically significant (p=0.02). It is considered an early failure if it occurs within the first three months. There was a larger number of early failures with the Provox®2 than with the Provox® (p=0.04). Neither the gender nor the age affected the lifetime of the devices. Radiotherapy seemed to lengthen the lifetime of the first valve.

The survival lifetime of the second generation Provox®2 valve is shorter than the lifetime of the first generation Provox®. This could be due to the difference in elasticity of these valves that could lead to a different level of colonization and invasion of the valves by micro-organisms.
Agenesis of the epiglottis and false vocal folds with maxillary hypoplasia in an adult
Authors: Hong Ki Hwan , Yang Yoon Soo
Published: November 2003

Hypoplasia or absence of the epiglottis in an adult is a rarely reported congenital anomaly that usually occurs in association with congenital anomalies of other organ systems. Most epiglottic anomalies usually present in infancy and early childhood with respiratory and feeding problems and the affected individual dies shortly after birth due to multiple congenital anomalies. We present a case of congenital absence of the epiglottis and false vocal folds with hypoplastic maxillae in an adult.
Understanding the Effect of Customer Relationship Management Efforts on Customer Retention and Customer Share Development
Authors: Verhoef Peter C.
Published: November 2003

Scholars have questioned the effectiveness of several customer relationship management strategies. The author investigates the differential effects of customer relationship perceptions and relationship marketing instruments on customer retention and customer share development over time. Customer relationship perceptions are considered evaluations of relationship strength and a supplier's offerings, and customer share development is the change in customer share between two periods. The results show that affective commitment and loyalty programs that provide economic incentives positively affect both customer retention and customer share development, whereas direct mailings influence customer share development. However, the effect of these variables is rather small. The results also indicate that firms can use the same strategies to affect both customer retention and customer share development.
Testing self‐organized criticality in the crust using entropy: A regionalized study of the CMT global earthquake catalogue
Authors: Al‐Kindy F. H. , Main I. G.
Published: November 2003

We test the notion of self‐organized criticality (SOC) and the proximity to the critical point in the brittle crust. If the system were strictly critical, we would expect an infinite correlation length with minimal temporal or spatial predictability. An alternative view is that the Earth is in a self‐organized subcritical (SOSC) state with a finite and systematically fluctuating correlation length. This would imply a system that is sufficiently near‐critical to maintain power law scaling relations over a finite scale range, but can intermittently reach criticality in the form of a single large earthquake when the correlation length becomes effectively infinite over the scale of the observed region. Here we address the question of proximity to criticality from the viewpoint of statistical physics by describing a regionalized study equivalent to the ensemble approach in thermodynamics. Flinn‐Engdahl regionalization of global seismicity is used to calculate the expectation of the logarithm of energy 〈lnE〉 and entropy S from centroid moment tensor (CMT) data for different seismic regions. We compare a phase diagram for S and 〈lnE〉 from the data with an analytical statistical mechanical solution and find that they are in good agreement. The analysis shows systematic spatial heterogeneity in entropy that is associated with the tectonic deformation style. Oceanic ridges are seen to be low entropy (relatively ordered), and subduction zones have higher entropy (less ordered) with collision‐zones scattered at the two extremes. Statistically resolvable phase variations in the system as a whole point toward it being better described as subcritical in the spatial ensemble.
Final chemical results from the Mars Pathfinder alpha proton X‐ray spectrometer
Authors: Foley C. Nicole , Economou Thanasis , Clayton Robert N.
Published: November 2003

The calibrated Pathfinder alpha proton X‐ray spectrometer (APXS) instrument is capable of measuring concentrations of all major and minor rock‐forming elements ranging from carbon through zirconium in atomic number. Therefore it is capable of constraining the petrology of the measured samples. In particular, the Pathfinder data are the first in situ measurements of Martian rocks and may be compared with previous remote‐sensing measurements as well as with the compositions of SNC meteorites. Pathfinder soil and rock sample abundances from the alpha, proton, and X‐ray modes have been quantified. The abundances suggest that (1) the rocks are covered with various amounts of soil; (2) the soil‐free rocks, on a volatile‐free basis, have some element ratios similar to Mars meteorites, yet have different bulk chemistry indicative of more evolved rocks with higher silica abundances; (3) the carbon and nitrogen contents are below detection limits; and (4) the alpha mode oxygen reveals excess amounts of oxygen in some samples, which is indicative of sample‐bound water (contained within minerals or glasses in samples).
Antarctic Oscillation signal on precipitation anomalies over southeastern South America
Authors: Silvestri Gabriel E. , Vera Carolina S.
Published: November 2003

The relation between the Antarctic Oscillation (AAO) and the precipitation in southeastern South America (SESA) is examined. The AAO influence is particularly strong during winter and late spring although of opposite sign. In particular during spring, AAO positive (negative) phases are associated with the intensification of an upper‐level anticyclonic (cyclonic) anomaly, weakened (enhanced) moisture convergence and decreased (increased) precipitation over SESA. The combined influence of both ENSO and AAO on SESA precipitation was also explored and significant correlation values between both oscillations are only observed during spring. Results show that during that particular season, AAO activity produces a strong modulation of the ENSO signal on SESA precipitation.