bluuebunny/crossref_metadata_2025 huggingface dataset:
Moderator Factors in First Nation Students at Risk for Psychosocial Problems
Authors: Mykota David B. , Schwean Vicki L.
Published: March 2007

In this study the authors sought to examine the determinants of psychological well-being and risk in First Nation students residing in their home community. The participant sample was drawn from students who resided in a First Nation community and were served by their tribal council in a central western province. All students, Grades 1 to 12, who were registered in a First Nation or provincial school were included. The results of the study indicate that, because academic performance continues to be such a strong predictor of psychosocial well-being, it underscores the importance of the school as an ameliorative factor in the prevention and treatment of behavioral problems. Given this finding, the authors recognize the significance of intervention as a preventive measure for all age groups and the responsibility of federal and provincial funding agencies to continue to make available appropriate educational resources to First Nation communities.
“I Am Not Well-Equipped”
Authors: Heath Nancy L. , Toste Jessica R. , Beettam Erin L.
Published: March 2007

Fifty teachers completed a survey to investigate knowledge, self-perceived knowledge, and attitudes regarding self-injury (SI). Teachers were aware of basic facts concerning SI; however, 78% underestimated prevalence, and only 20% felt knowledgeable. Attitudes were mixed, with 48% finding the idea of SI horrifying; however, 68% disagreeing that SI was “often manipulative.” Principal components analysis indicated that perceived knowledge emerged as a separate construct from attitude s toward SI. Years of teaching experience was related to self-perceived knowledge, but not to attitudes. In addition, 74% of teachers reported having a personal encounter with SI, and 62% felt that SI is increasing in the schools. Qualitative analysis of open-ended questions revealed a strong desire for further knowledge and training. Results indicate that teachers’ perceptions are not consistent with studies of SI in clinical settings but are consistent with recent research in community and school samples. The need for teacher education about SI is emphasized.
Associations Among Academic Achievement, Attention, and Adrenocortical Reactivity in Caribbean Village Children
Authors: Jimerson Shane R. , Durbrow Eric H. , Adam Emma , Gunnar Megan , Bozoky Ingrid K.
Published: March 2007

This study examined associations among academic achievement problems, attention problems, and cortisol levels in 86 children (ages 5 to 12) in St. Vincent, the West Indies. Findings revealed that morning cortisol levels were more elevated at school than at home. Attention problems contributed negatively to academic scores. Children with the most attention problems showed greater school relative to home cortisol elevations than did other children. Once the variance due to attention problems was accounted for, the interaction between attention problems and cortisol elevation explained additional variance in academic scores. There was some evidence that attention problems and cortisol reactivity were associated. Furthermore, greater cortisol reactivity was correlated with the academic difficulties of children who exhibited more attention problems.
Providing Services to Survivors of Domestic Violence
Authors: Eastman Brenda J. , Bunch Shelia Grant
Published: March 2007

Although there is a considerable body of knowledge about domestic violence, a limited proportion focuses on domestic violence in rural settings. Using a nonprobability purposive sampling technique, 93 providers of domestic violence services from rural and urban localities in North Carolina and Virginia were located and asked to complete a self-administered survey soliciting provider perceptions about service consumers, the general public, themselves, and inter- and intra-agency issues. Significant differences were observed between rural and urban providers about service consumer needs and experiences, perceptions about the general public, area resource availability, agency funding, provider training, and worker safety. Implications of these differences are discussed.
Rape Perception and the Function of Ambivalent Sexism and Gender-Role Traditionality
Authors: Yamawaki Niwako
Published: March 2007

This study explores the roles of benevolent sexism (BS), hostile sexism (HS), and gender-role traditionality (GRT) in minimizing rape, blaming the victim, and excusing the rapist. As predicted, hostile sexists minimize the seriousness of the rape in both stranger and date-rape scenarios. In the victim-blame scale, both BS and GRT significantly moderate victim blame in a date but not stranger scenario. BS and GRT moderate the perpetrator-excuse measure in a date scenario but HS is the significant moderator in a stranger scenario. These results show that external observers make different assumptions about a rape incident based on their GRT, BS, and HS levels in different victim-perpetrator relationships.
Autoimmune hemolytic anemia during interferon-beta-I b treatment for multiple sclerosis
Authors: Alanoglu G. , Kilbas S. , Arslan C. , Senol A. , Kutluhan S.
Published: March 2007

A 31-year-old patient with multiple sclerosis (MS), treated with interferon beta-1b (IFNB-1b) for two years, presented with fatigue and dizziness. Coombs' positive autoimmune hemolytic anemia (AIHA) was found. Other potential etiologies of AIHA were ruled out. An association with IFNB-1b was highly suspected. Interferon therapy was discontinued and prednisone therapy instituted. There was resolution of the hemolytic anemia, and prednisone therapy was tapered gradually. To the best of our knowledge, there is no reported case of the development of AIHA associated with IFNB-1b use in MS patients. We conclude that if an unexplained drop in hematocrit occurs with a MS patient receiving IFNB-1b, autoimmune mediated hemolysis should also be considered. Multiple Sclerosis 2007; 13: 683-685. http://msj.sagepub.com
An approach to estimating the intangible costs of multiple sclerosis according to disability in Catalonia, Spain
Authors: Casado V. , Romero L. , Gubieras L. , Alonso L. , Moral E. , Martinez-Yelamos S. , Martinez-Yelamos A. , Carmona O. , Arbizu T.
Published: March 2007

Multiple sclerosis (MS) is a chronic demyelinating disease, which represents a great economic burden to society. Cost-of-illness studies of MS tend to underestimate the intangible costs related to pain, anxiety and helplessness. The purpose of this study was to estimate the intangible costs of MS, and determine whether these costs increase as disability progresses. We studied 211 consecutive patients with MS who attended our MS unit. Patients mean age was 41.6 (SD: 10.7) years, 69% were female, and their mean Expanded Disability Status Scale (EDSS) score was 2.47 (SD: 2.05). Quality-of-life was measured with the EuroQoL visual analogue scale. Quality-adjusted life year (QALY) was calculated for each patient. Patients were grouped into five disability stages according to their EDSS, and QALY was compared between patients and a group of healthy controls matched by age and sex. A benchmark value was ascribed to each QALY lost, and the intangible costs per patient-year were calculated as 0 (EDSS =0), 1100 (EDSS =1-3), 8250 (EDSS =3.5-5.5), 9900 (EDSS =6-7) and 11 000 (EDSS >7.5). Sensitivity analysis showed a similar progression of costs. We conclude that intangible costs are relevant in MS, especially when disability increases. Although the method to calculate the costs remains controversial, we consider that they should be included in cost analysis of MS. Multiple Sclerosis 2007; 13: 800-804. http://msj.sagepub.com
Cerebrovascular reactivity in multiple sclerosis patients
Authors: Uzuner N. , Ozkan S. , Cinar N.
Published: March 2007

A close relationship between multiple sclerosis (MS) lesions and the cerebral vasculature has long been recognised. Some studies have suggested that vascular endothelial cell activation might be an early event in the evolution of MS, and demyelisation may have an ischemic basis in this condition. Hypoxia caused by breath holding (BH) results in autoregulatory vasodilatation, and an increase in CBF to the cortex. The increased CBF can be evaluated by transcranial Doppler (TCD), and can provide information about the vascular integrity. In this study, we aimed to examine the vascular integrity and assess the vasomotor reactivity of MS patients in response to BH in different activation phases of the disease by means of TCD. We studied 12 patients with clinically diagnosed relapsing remitting (RR) MS, according to the Poser criteria. The initial TCD examination was performed in the first two days of an acute exacerbation of disease and prior to any treatment. The second test was performed just after iv methylprednisolone (IVMP) treatment, and the third examination occurred one month later, when the patient was in the remission phase. A group of 11 healthy subjects was also examined by TCD as control. Blood flow velocities were recorded during 30 seconds of normal breathing and 15 seconds BH. Vasomotor reactivity was calculated as a ratio of difference of cerebral flow velocities during BH. There were no significant vasomotor reactivity differences between the controls (55.7%) and the patients during attacks (46.5%), as well as after treatment (48.3%) and during attack free periods (50.9%). There were also no significant changes amongst the patients groups throughout the study. In this study, in different disease activity stages, we observed non-significant cerebrovascular vasomotor reactivity difference between the RRMS patients and the healthy controls, although it was slightly lower in the MS patients. This observation suggests that cerebrovascular reactivity is normal in different disease activity levels. Multiple Sclerosis 2007; 13: 737-741. http://msj.sagepub.com
Bilateral trigeminal enhancement on magnetic resonance imaging in a patient with multiple sclerosis and trigeminal neuralgia
Authors: Pichiecchio A. , Bergamaschi R. , Tavazzi E. , Romani A. , Todeschini A. , Bastianello S.
Published: March 2007

We report on clinical and instrumental findings of a multiple sclerosis (MS) patient with sudden right trigeminal neuralgia (TN). Magnetic resonance imaging (MRI), performed at TN onset, showed enlargement of both trigeminal nerves (TrN) at the root entry zone, with gadolinium enhancement of the cisternal portion. This is the first description of clinical and MRI findings indicative of peripheral involvement of the fifth cranial nerve in a MS patient complaining of TN. Our report shows the concomitant involvement of central and peripheral myelin in MS, and adds further highlights to the question regarding peripheral nerve involvement abnormalities associated with a disease considered limited to the central nervous system (CNS). Multiple Sclerosis 2007; 13: 814-816. http://msj.sagepub.com
An association study of two functional promotor polymorphisms in the myeloperoxidase (MPO) gene in multiple sclerosis
Authors: Lundmark F. , Salter H. , Hillert J.
Published: March 2007

Multiple sclerosis (MS) is a chronic neurological disease affecting the central nervous system (CNS). The disease is characterised by demyelination and axonal loss caused by abnormal immunological responses resulting in accumulating neurological disabilities. MS is considered a complex disease, with both genetic and environmental factors contributing to the pathogenesis. In this study, we have investigated the genetic role of the myeloperoxidase (MPO) gene encoding myeloperoxidase in MS. MPO is an enzyme found in myeloid cells which catalyses the production of hypochlorus acid, a potent microbicidal agent. It also plays an important role in inflammatory processes, where migrating neutrophiles may release active MPO and cause tissue damage. In this study, we investigated two polymorphisms located in the promotor region of the MPO gene, known to influence the expression of MPO, in a large case/control material consisting of 871 Swedish MS patients and 532 Swedish healthy controls. No association was observed with risk of MS. Multiple Sclerosis 2007; 13: 697-700. http://msj.sagepub.com
'They have had to come down to the women for help!' Numerical feminization and the characteristics of women's library employment in England, 1871–1974
Authors: Kerslake Evelyn
Published: March 2007

Existing work on the position of women in English libraries illustrates the role of gender in the establishment of the profession. This paper adds to that work by addressing a gap in the published literature. It provides a broad indication of the numbers of women working in various types of library and the characteristics of their employment in terms of seniority, salaries, access to pensions and hours of work. It explores the period between 1871, when Manchester Free Library began employing women public library workers, and 1974, when local government reorganization changed the largest library workforces, those in public and county libraries.
Reading as a 'necessity of life' on the Tuapeka goldfields in nineteenth-century New Zealand
Authors: Traue J. E.
Published: March 2007

Contrary to the image of the mid-nineteenth-century New Zealand 'gold rush' township as a place consumed by hedonism and greed, such frontier settlements were also places where culture took root, not least in terms of the reading of material supplied by the various types of social library that were speedily established after the discovery in the early 1860s of extensive gold deposits. Gold diggers working in small groups and in geographical isolation, and the merchants, tradesmen, publicans, professionals and officials who followed them into the wilderness, felt keenly the need to connect with the outside world and with the societies they had left behind, and books, periodicals, and newspapers were an effective means of doing this.
'Dublin is also in great need of a library which shall be at once accessible to the public and contain a good supply of modern and foreign books': Dublin's nineteenth-century 'public' libraries
Authors: Cullen Clara
Published: March 2007

This article addresses the 'public' library facilities available in Dublin, Ireland's principal city, in 1850, how these facilities improved in subsequent decades (if at all) and attempts to identify the reasons why Dublin had to wait until 1884 for its first tax-supported, 'free' public library. A version of this paper was first presented at the Fourth Anglo-German Library History Conference, held at the British Library, September 2005. The theme of the conference was 'Libraries and Innovation'.
Innovation and ideology: Walter Hofmann's library work in Dresden-Plauen and Leipzig
Authors: Vodosek Peter
Published: March 2007

Born in Dresden in 1879, the son of an artisan engraver, Walter Hofmann became one of the most innovative and influential, but also most controversial, librarians in early twentieth-century Germany. Hoffman entered librarianship having been commissioned by Ida Bienert, the wife of a wealthy manufacturer, to plan, organize and manage a public library for the inhabitants of Dresden-Plauen, a district of Dresden. The library opened in 1906. The following year Hofmann began to publish his 'pilot' ideas, which soon attracted the attention of professional colleagues. In 1913 the City of Leipzig entrusted him with the responsibility of building a city library system, which allowed him to test his library model on a larger scale. At the same time he began to extend his influence on German librarianship, an influence which continued to increase until the 1930s. His aggressive commitment, his tendency to be polemical, and his authoritarian personality, as well as his inventiveness and knowledge as an expert, made him extremely successful. But these qualities also resulted in factional conflict, the so-called 'Richtungsstreit'. After the Nazis came to power in 1933, Hofman tried to save as much as possible of his achievements, but was forced to retire when his protector, the mayor of Leipzig, Carl Goerdeler, fell from power in 1937. Hofmann passed away in Leipzig in 1952, without having regained his former importance, although his ideas retained a strong following until the 1960s. A critical evaluation of his life's work reveals that his interpretation of education and cultural enrichment was not particularly original and was deeply rooted in nineteenth-century thinking. Hofmann was an ambivalent figure who liked to behave as a reformer but who was in fact, ultimately, a 'conservative revolutionary'.

A version of this paper was first presented at the Fourth Anglo-German Library History Conference, held at the British Library, September 2005. The theme of the conference was 'Libraries and Innovation'.
Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease
Authors: Kim Juyang , Kim Hye J. , Park Keunhee , Kim Jiyoung , Choi Hye-Jeong , Yagita Hideo , Nam Seok H. , Cho Hong R. , Kwon Byungsuk
Published: March 2007

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2→Balb/c (H-2d) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4+ T-cell cytokines and increased apoptosis of donor CD4+ T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4+ T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.
Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration
Authors: Proost Paul , Mortier Anneleen , Loos Tamara , Vandercappellen Jo , Gouwy Mieke , Ronsse Isabelle , Schutyser Evemie , Put Willy , Parmentier Marc , Struyf Sofie , Van Damme Jo
Published: March 2007

CXCR3 ligands were secreted by tissue fibroblasts and peripheral blood–derived mononuclear leukocytes in response to interferon-γ (IFN-γ) and Toll-like receptor (TLR) ligands. Subsequent purification and identification revealed the presence of truncated CXCL11 variants missing up to 6 amino acids. In combination with CD26/dipeptidyl peptidase IV, the metalloprotease aminopeptidase N (APN), identical to the myeloid cell marker CD13, rapidly processed CXCL11, but not CXCL8, to generate truncated CXCL11 forms. Truncated CXCL11 had reduced binding, signaling, and chemotactic properties for lymphocytes and CXCR3- or CXCR7-transfected cells. CD13/APN-truncated CXCL11 failed to induce an intracellular calcium increase but was still able to bind and desensitize CXCR3 for intact CXCL11 signaling. CXCL11 efficiently bound to CXCR7, but CXCL11 was not able to induce calcium signaling or ERK1/2 or Akt phosphorylation through CXCR7. CD26-truncated CXCL11 failed to attract lymphocytes but still inhibited microvascular endothelial cell (HMVEC) migration. However, further processing of CXCL11 by CD13 resulted in significant reduction of inhibition of HMVEC migration. Taken together, during inflammation or cancer, CXCL11 processing by CD13 may lead to a reduced number of tumor-infiltrating lymphocytes and in a more angiogenic environment.
Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl–mediated drug resistance
Authors: Carew Jennifer S. , Nawrocki Steffan T. , Kahue Charissa N. , Zhang Hui , Yang Chunying , Chung Linda , Houghton Janet A. , Huang Peng , Giles Francis J. , Cleveland John L.
Published: March 2007

Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of Bcr-Abl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy.
Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway
Authors: Liu Jizhong , Hamrouni Abdelbasset , Wolowiec Darius , Coiteux Valérie , Kuliczkowski Kazimierz , Hetuin Dominique , Saudemont Aurore , Quesnel Bruno
Published: March 2007

Multiple myeloma (MM) cells inhibit certain T-cell functions. We examined the expression of B7-H1 (PD-L1), a B7-related protein that inhibits T-cell responses, in CD138-purified plasma cells isolated from MM patients, monoclonal gammopathy of undetermined significance patients, and healthy donors. We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-γ and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-γ–mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-γ. IFN-γ–induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-γ or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88. Thus, B7-H1 expression by MM cells represents a possible immune escape mechanism that could be targeted therapeutically through inhibition of MyD88/TRAF6 and MEK/ERK/STAT1.
Group V secretory PLA2 regulates TLR2-dependent eicosanoid generation in mouse mast cells through amplification of ERK and cPLA2α activation
Authors: Kikawada Eriya , Bonventre Joseph V. , Arm Jonathan P.
Published: March 2007

Mast cells may be activated through Toll-like receptors (TLRs) for the dose- and time-dependent release of eicosanoids. However, the signaling mechanisms of TLR-dependent rapid eicosanoid generation are not known. We previously reported a role for group V secretory phospholipase A2 (PLA2) in regulating phagocytosis of zymosan and the ensuing eicosanoid generation in mouse resident peritoneal macrophages, suggesting a role for the enzyme in innate immunity. In the present study, we have used gene knockout mice to define an essential role for MyD88 and cytosolic PLA2α in TLR2-dependent eicosanoid generation. Furthermore, in mast cells lacking group V secretory PLA2, the time course of phosphorylation of ERK1/2 and of cPLA2α was markedly truncated, leading to attenuation of eicosanoid generation in response to stimulation through TLR2, but not through c-kit or FcεRI. These findings provide the first dissection of the mechanisms of TLR-dependent rapid eicosanoid generation, which is MyD88-dependent, requires cPLA2α, and is amplified by group V sPLA2 through its regulation of the sequential phosphorylation and activation of ERK1/2 and cPLA2α. The findings support the suggestion that group V sPLA2 regulates innate immune responses.
Dok-3 plays a nonredundant role in negative regulation of B-cell activation
Authors: Ng Chee-Hoe , Xu Shengli , Lam Kong-Peng
Published: March 2007

p62dok and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210bcr/abl oncoprotein in Ph + chronic myelogenous leukemia. A role for p62dok in FcγRIIB–mediated negative regulation of B-cell proliferation had been established previously. Here, we generated Dok-3−/− mice to assess the function of Dok-3 in B cells. Mice lacking Dok-3 have normal B-cell development but possess higher level of IgM antibodies in their sera. In comparison to wild-type mice, Dok-3−/− mice mounted significantly enhanced humoral immune responses to T cell–independent type I and II antigens. Dok-3–deficient B cells hyperproliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-κB, JNK, and p38MAPK in response to B-cell receptor (BCR) engagement. In the absence of Dok-3, the localization of the inhibitory phosphatase SHIP-1 to the plasma membrane is intact while its phosphorylation is compromised, suggesting that Dok-3 could function to facilitate or sustain the activation of SHIP-1. The phenotype and responses of Dok-3−/− mice and B cells could be differentiated from those of the Dok-1−/− counterparts. Hence, we propose that Dok-3 plays a distinct and nonredundant role in the negative regulation of BCR signaling.
Limiting γc expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors
Authors: Smyth Christine M , Ginn Samantha L , Deakin Claire T , Logan Grant J , Alexander Ian E
Published: March 2007

X-linked severe combined immunodeficiency (SCID-X1) results from mutations in the IL2RG gene, which encodes the common gamma chain (γc) of the receptors for interleukin (IL)-2, 4, 7, 9, 15, and 21. Affected infants typically lack T and natural killer (NK) cells as a consequence of loss of signaling via the IL-7 receptor (IL-7R) and the IL-15R, respectively. In some infants, however, autologous NK cells are observed despite failure of T-cell ontogeny. The mechanisms by which mutations in γc differentially impact T- and NK-cell ontogeny remain incompletely understood. We used SCID-X1 patient–derived EBV-transformed B cells to test the hypothesis that the IL-15R–mediated signaling is preferentially retained as γc expression becomes limiting. Signal transduction via the IL-15R was readily detected in control EBV-transformed B cells, and via the IL-7R when modified to express IL-7Rα. Under the same experimental conditions, patient-derived EBV-transformed B cells expressing trace amounts of γc proved incapable of signal transduction via the IL-7R while retaining the capacity for signal transduction via the IL-15R. An equivalent result was obtained in ED-7R cells modified to express varying levels of γc. Collectively, these results confirm that signal transduction via the IL-15R, and hence NK ontogeny, is preferentially retained relative to the IL-7R as γc expression becomes limiting.
The zebrafish udu gene encodes a novel nuclear factor and is essential for primitive erythroid cell development
Authors: Liu Yanmei , Du Linsen , Osato Motomi , Teo Eng Hui , Qian Feng , Jin Hao , Zhen Fenghua , Xu Jin , Guo Lin , Huang Honghui , Chen Jun , Geisler Robert , Jiang Yun-Jin , Peng Jinrong , Wen Zilong
Published: March 2007

Hematopoiesis is a complex process which gives rise to all blood lineages in the course of an organism's lifespan. However, the underlying molecular mechanism governing this process is not fully understood. Here we report the isolation and detailed study of a newly identified zebrafish ugly duckling (Udu) mutant allele, Udusq1. We show that loss-of-function mutation in the udu gene disrupts primitive erythroid cell proliferation and differentiation in a cell-autonomous manner, resulting in red blood cell (RBC) hypoplasia. Positional cloning reveals that the Udu gene encodes a novel factor that contains 2 paired amphipathic α-helix–like (PAH-L) repeats and a putative SANT-L (SW13, ADA2, N-Cor, and TFIIIB–like) domain. We further show that the Udu protein is predominantly localized in the nucleus and deletion of the putative SANT-L domain abolishes its function. Our study indicates that the Udu protein is very likely to function as a transcription modulator essential for the proliferation and differentiation of erythroid lineage.
Regulation of Toll-like receptor–mediated inflammatory response by complement in vivo
Authors: Zhang Xinhua , Kimura Yuko , Fang Chongyun , Zhou Lin , Sfyroera Georgia , Lambris John D. , Wetsel Rick A. , Miwa Takashi , Song Wen-Chao
Published: March 2007

Toll-like receptors (TLRs) and complement are 2 components of innate immunity that are critical for first-line host defense and elicitation of adaptive immune responses. Many pathogen-associated molecular patterns activate both TLR and complement, but whether and how these 2 systems, when coactivated in vivo, interact with each other has not been well studied. We demonstrate here a widespread regulation of TLR signaling by complement in vivo. The TLR ligands lipopolysacharride (TLR4), zymosan (TLR2/6), and CpG oligonucleotide (TLR9) caused, in a complement-dependent manner, strikingly elevated plasma interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β, and/or decreased plasma IL-12 levels in mice deficient in the membrane complement inhibitor decay-accelerating factor (DAF). A similar outcome was observed in wild-type mice cotreated with the TLR ligands and cobra venom factor, a potent complement activator. The regulatory effect of complement on TLR-induced cytokine production in vivo was mediated by the anaphylatoxin receptors C5aR and C3aR. Additionally, changes in lipopolysaccharide (LPS)–induced cytokine production in DAF-deficient mice correlated with increased mitogen-activated protein kinase and nuclear factor-κB activation in the spleen. These results reveal a strong interaction between complement and TLR signaling in vivo and suggest a novel mechanism by which complement promotes inflammation and modulates adaptive immunity.
Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease
Authors: Svegliati Silvia , Olivieri Attilio , Campelli Nadia , Luchetti Michele , Poloni Antonella , Trappolini Silvia , Moroncini Gianluca , Bacigalupo Andrea , Leoni Pietro , Avvedimento Enrico V. , Gabrielli Armando
Published: March 2007

Extensive chronic graft-versus-host disease (ecGVHD) is characterized by fibrosis similar to that of patients with systemic sclerosis (scleroderma). Since stimulatory autoantibodies against the platelet-derived growth factor (PDGF) receptor (PDGFR) have been found in patients with scleroderma and are responsible for the activation of skin fibroblasts, we tested the hypothesis that these autoantibodies are also present in patients affected by ecGVHD. Serum from 39 patients subjected to allogeneic stem cell transplantation for hematologic malignancies (22 with ecGVHD and 17 without cGVHD) and 20 healthy controls was assayed for the presence of stimulatory autoantibodies to the PDGFR by incubating purified IgG with mouse-embryo fibroblasts lacking PDGFR α or β chains or with the same cells expressing PDGFR α. Stimulatory antibodies to the PDGFR were found selectively in all patients with ecGVHD but in none of the patients without cGVHD. Higher levels were detected in patients with generalized skin involvement and/or lung fibrosis. Antibodies recognized native PDGFR, induced tyrosine phosphorylation, accumulation of reactive oxygen species (ROS), and stimulated type 1 collagen gene expression through the Ha-Ras-ERK1/2-ROS signaling pathway. The biologic activity of these autoantibodies suggests a role in the development of fibrosis and argues for a common pathogenetic trait in ecGVDH and scleroderma phenotypes.
Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice
Authors: Zhao Liang , Sun Liguang , Wang Hongjun , Ma Haixia , Liu Guangwei , Zhao Yong
Published: March 2007

A progressive decline in the integrity of the immune system is one of the physiologic changes during aging. The frequency of autoimmune diseases or immune disorders increases in the aging population, but the state of regulatory T (Treg) cells in aged individuals has not been well determined. In the present study, we investigated the levels, phenotypes, and function of CD4+CD25+ Treg cells in Balb/c mice, which were older than 20 months. Significantly enhanced percentages of CD4+CD25+ Treg cells in the periphery (blood, spleen, and lymph nodes) of the aged mice were observed. These Treg cells showed modified Vβ family distribution, reduced levels of CD45 receptor B and CD62 ligand molecules, as well as normal levels of forkhead box p3. However, when the inhibiting function of Treg cells was assayed in the in vitro assays and in a delayed-type hypersensitivity (DTH) model, CD4+CD25+ Treg cells of aged mice displayed significantly lower inhibiting ability on alloantigen-induced DTH reaction or cytokine productions (IL-2 and IFN-γ) but not cell proliferation of effector T cells, as compared with CD4+CD25+ Treg cells of young mice. In addition, the percentages of CD4+CD8–CD25+ Treg cells in the thymi of aged mice increased significantly, but their total cell numbers decreased markedly in these mice. Our present studies indicated collectively that the percentages, phenotypes, the size of TCR repertoire, and function of CD4+CD25+ Treg cells were altered significantly with aging in mice. The functional defects of CD4+CD25+ Treg cells may shed light on the role of CD4+CD25+ Treg cells in the increased sensitivity to autoimmune diseases of aged populations.
Monocyte p110α phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production
Authors: Lee Jimmy S , Nauseef William M , Moeenrezakhanlou Alireza , Sly Laura M , Noubir Sanaa , Leidal Kevin G , Schlomann Jamie M , Krystal Gerald , Reiner Neil E
Published: March 2007

Mononuclear phagocytes are critical modulators and effectors of innate and adaptive immune responses, and PI-3Ks have been shown to be multifunctional monocyte regulators. The PI-3K family includes eight catalytic isoforms, and only limited information is available about how these contribute to fine specificity in monocyte cell regulation. We examined the regulation of phagocytosis, the phagocyte oxidative burst, and LPS-induced cytokine production by human monocytic cells deficient in p110α PI-3K. We observed that p110α PI-3K was required for phagocytosis of IgG-opsonized and nonopsonized zymosan in differentiated THP-1 cells, and the latter was inhibitable by mannose. In contrast, p110α PI-3K was not required for ingestion serum-opsonized zymosan. Taken together, these results suggest that FcγR- and mannose receptor-mediated phagocytosis are p110α-dependent, whereas CR3-mediated phagocytosis involves a distinct isoform. It is notable that the phagocyte oxidative burst induced in response to PMA or opsonized zymosan was also found to be dependent on p110α in THP-1 cells. Furthermore, p110α was observed to exert selective and bidirectional effects on the secretion of pivotal cytokines. Incubation of p110α-deficient THP-1 cells with LPS showed that p110α was required for IL-12p40 and IL-6 production, whereas it negatively regulated the production of TNF-α and IL-10. Cells deficient in p110α also exhibited enhanced p38 MAPK, JNK, and NF-κB phosphorylation. Thus, p110α PI-3K appears to uniquely regulate important monocyte functions, where other PI-3K isoforms are uninvolved or unable to fully compensate.
Deficient inflammatory response to UV radiation in neonatal mice
Authors: Wolnicka-Glubisz Agnieszka , Damsker Jesse , Constant Stephanie , Corn Stephanie , De Fabo Edward , Noonan Frances
Published: March 2007

Mechanisms of juvenile susceptibility to cancer are not well understood. The immune response in neonates favors nonresponsiveness or TH2-dominant responses, raising the question of a role for neonatal immunity in this susceptibility. We have investigated the postulate that the inflammatory response differs in neonatal and adult skin. We found no inflammatory infiltrate into neonatal mouse skin in response to UV irradiation as a function of time, dose, or wavelength, although UV-induced DNA damage was readily detected. In contrast, UV irradiation of adult mice initiated a dose- and time-dependent influx of inflammatory cells, chiefly CD11b+Ly6G+ neutrophils, into the skin, detected by immunohistochemistry and quantitated by FACS analysis. This inflammatory response was initiated by UVB (290–320 nm) but not by UVA (320–400 nm). Further, in neonates, in contrast to adults, neither topical trinitrochlorobenzene (TNCB) nor i.p. thioglycollate initiated an inflammatory infiltrate. Conversely, topical TNCB applied to neonates was tolerogenic, resulting in a subsequent antigen-specific decrease of the contact-hypersensitivity response in adults. Neonatal blood contained abundant neutrophils, which exhibited impaired chemotaxis to the chemokine growth-related oncogene-α but efficient chemotaxis to the bacterial product fMLP, concomitant with decreased expression of CXCR2 but normal levels of CD11b. We propose this neonatal deficiency in the inflammatory response is a significant, previously unrecognized factor in neonatal immune tolerance and may contribute to neonatal susceptibility to cancer, including melanoma and other UV-induced cancers.
Markers of Myeloproliferative Diseases in Childhood Polycythemia Vera and Essential Thrombocythemia
Authors: Teofili Luciana , Giona Fiorina , Martini Maurizio , Cenci Tonia , Guidi Francesco , Torti Lorenza , Palumbo Giovanna , Amendola Angela , Foà Robin , Larocca Luigi M.
Published: March 2007

Purpose

Polycythemia vera (PV) and essential thrombocythemia (ET) can present in pediatric age as sporadic or familial diseases. To define the biologic profile of childhood PV and ET, we evaluated specific markers in a cohort of pediatric patients affected by PV and ET, including cases with familial occurrence.

Patients and Methods

Thirty-eight children with PV and ET were investigated. The control group included 58 adults with PV and ET. Endogenous erythroid colonies, qualitative reverse transcriptase polymerase chain reaction for polycythemia rubra vera-1 (PRV-1) RNA expression, human androgen receptor assay and allele specific polymerase chain reaction for JAK2 V617F mutation were undertaken in all patients. Thrombopoietin, thrombopoietin receptor (c-mpl), and erythropoietin receptor mutation analysis was performed by direct sequencing in familial cases.

Results

The JAK2 V617F mutation in children with PV was significantly less frequent than in adult PV. The most common myeloproliferative marker found in these patients was PRV-1 RNA overexpression. Children and adults with sporadic ET showed a similar proportion of patients with PRV-1 RNA overexpression, JAK2 V617F mutation, and clonality, while none of the familial ET showed JAK2 V617F mutation and clonality. Also, PRV-1 RNA overexpression was significantly less common. Furthermore, most patients with familial ET exhibited the dominant-positive activating mutation of c-mpl. Finally, children with PV and ET had a significant lower incidence of thrombosis than adults.

Conclusion

This study demonstrates that familial and sporadic ET recognize different pathogenetic mechanisms. Myeloproliferative markers are specific tests for the diagnosis of ET in children with sporadic forms, while a significant proportion of children with PV can prove negative.
Tyrosine Hydroxylase and Dopamine Transporter Expression in Lactotrophs from Postlactating Rats: Involvement in Dopamine-Induced Apoptosis
Authors: Jaubert Arnaud , Drutel Guillaume , Leste-Lasserre Thierry , Ichas François , Bresson-Bepoldin Laurence
Published: March 2007

Cessation of lactation causes a massive loss of surplus lactotrophs in the rat pituitary gland. The factors and mechanisms involved in this phenomenon have not yet been elucidated. Besides its inhibitory control on prolactin secretion and lactotroph proliferation, evidence suggests that dopamine (DA) may be a proapoptotic factor for lactotrophs. We therefore tested the proapoptotic effect of DA on pituitary glands from virgin, lactating, and postlactating rats. By measuring mitochondrial membrane potential loss, caspase-3 activation, and nuclear fragmentation, we show that DA induces apoptosis specifically in lactotrophs from postlactating rats. We then determined that this effect was partly mediated by the DA transporter (DAT) rather than the D2 receptor, as corroborated by the detection of DAT expression exclusively in lactotrophs from postlactating rats. We also observed tyrosine hydroxylase (TH) expression in postlactating lactotrophs that was accompanied by an increase in DA content in the anterior pituitary gland of postlactating compared with virgin rats. Finally, we observed that cells expressing TH coexpressed DAT and cleaved caspase-3. These findings show that DA may play a role in lactotroph regression during the postlactation period by inducing apoptosis. The fact that this process requires DAT and TH expression by lactotrophs themselves suggests that it may be “autocrine” in nature.
Insulin-Like Growth Factor-I Provokes Functional Antagonism and Internalization of β1-Adrenergic Receptors
Authors: Gavi Shai , Yin Dezhong , Shumay Elena , Wang Hsien-yu , Malbon Craig C.
Published: March 2007

Hormones that activate receptor tyrosine kinases have been shown to regulate G protein-coupled receptors, and herein we investigate the ability of IGF-I to regulate the β1-adrenergic receptor. Treating Chinese hamster ovary cells in culture with IGF-I is shown to functionally antagonize the ability of expressed β1-adrenergic receptors to accumulate intracellular cAMP in response to stimulation by the β-adrenergic agonist Iso. The attenuation of β1-adrenergic action was accompanied by internalization of β1-adrenergic receptors in response to IGF-I. Inhibiting either phosphatidylinositol 3-kinase or the serine/threonine protein kinase Akt blocks the ability of IGF-I to antagonize and to internalize β1-adrenergic receptors. Mutation of one potential Akt substrate site Ser412Ala, but not another Ser312Ala, of the β1-adrenergic receptor abolishes the ability of IGF-I to functionally antagonize and to sequester the β1-adrenergic receptor. We also tested the ability of IGF-I to regulate β1-adrenergic receptors and their signaling in adult canine cardiac myocytes. IGF-I attenuates the ability of β1-adrenergic receptors to accumulate intracellular cAMP in response to Iso and promotes internalization of β1-adrenergic receptors in these cardiac myocytes.
Overexpression of γ-Glutamyltransferase in Transgenic Mice Accelerates Bone Resorption and Causes Osteoporosis
Authors: Hiramatsu Kiyoshi , Asaba Yutaro , Takeshita Sunao , Nimura Yuji , Tatsumi Sawako , Katagiri Nobuyoshi , Niida Shumpei , Nakajima Toshihiro , Tanaka Sakae , Ito Masako , Karsenty Gerard , Ikeda Kyoji
Published: March 2007

We previously identified γ-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-κB ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-κB ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.
Pricing and Capacity Rationing for Rentals with Uncertain Durations
Authors: Gans Noah , Savin Sergei
Published: March 2007

We consider a rental firm with two types of customers. Contract customers pay fixed, prenegotiated rental fees and expect a high quality of service. Walk-in customers have no contractual relations with the firm and are “shopping for price.” Given multiple contract and walk-in classes, the rental firm has to decide when to offer service to contract customers and what fees to charge walk-in customers for service.

We formulate this rental management problem as a problem in stochastic control and characterize optimal policies for managing contract and walk-in customers. We also consider static, myopic controls that are simpler to implement, and we analytically establish conditions under which these policies perform optimally. Complementary numerical tests provide a sense of the range of systems for which myopic policies are effective.
Generalized Cox-Ross-Rubinstein Binomial Models
Authors: Chung San-Lin , Shih Pai-Ta
Published: March 2007

This paper generalizes the seminal Cox-Ross-Rubinstein (CRR) binomial model by adding a stretch parameter. The generalized CRR (GCRR) model allows us to fine-tune (via the stretch parameter) the lattice structure so as to efficiently price a range of options, such as barrier options. Our analysis provides insights into the fine structure of convergence of the general binomial model to the Black-Scholes formula. We also discuss how to improve the rate of convergence or the oscillatory behavior of the GCRR model. The numerical results suggest that the GCRR models with various modifications are efficient for pricing a range of options.