bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dumbbell-type Spinal Solitary Fibrous Tumor With Paraplegia
Authors: Kakimaru Hiroyuki , Matsusaki Masahiko , Sanada Hideaki , Iwata Atsushi , Uchio Yuji 
Published: April 2009

Solitary fibrous tumors are rare tumors that most commonly arise in the pleura. This article describes a case of a large dumbbell-shaped solitary fibrous tumor of the thoracic spine that was causing partial paraplegia. The patient was a 75-year-old woman who presented with swelling of the upper back and weakness of the lower extremities. Magnetic resonance imaging revealed a dumbbell-shaped tumor mass compressing the spinal cord, predominantly at the level of T8. The tumor extended transversely from the bilateral foramen of T8-T10 to the back muscles. The patient experienced increasing weakness of the lower extremities, so a T7-T11 laminectomy was performed and the tumor was excised piecemeal. Microscopically, the tumor was found to be composed of a proliferation of fibroblastic spindle cells. Immunohistochemically, it was strongly positive for CD34 but negative for S100. These findings were consistent with a solitary fibrous tumor. Three months postoperatively, thoracic radiographs showed progression of spinal kyphosis. Posterior fusion with instrumentation was performed. Three years postoperatively, there was no clinical evidence of tumor recurrence.
Spinal solitary fibrous tumors are rare, particularly dumbbell-shaped tumors; to our knowledge, only 2 have been reported in the literature. The correct diagnosis is aided by noting the bland fibrous histology, strong CD34 immunostaining, and absence of S100 and cytokeratin positivity. Although solitary fibrous tumors of the spine are rare, they should be considered in the differential diagnosis of intraspinal lesions, particularly those occurring near pleura.
Augmentation of Bone Healing by Specific Frequency and Amplitude Compressive Strains
Authors: Shadmehr Azadeh , Esteki Ali , Oliaie Gholam R. , Torkaman Giti , Sabbaghian Alireza 
Published: April 2009

A considerable proportion of bone fractures show signs of delayed or impaired healing. A novel device that applies interfragmentary compressive forces to the fracture site was developed and evaluated for its effect on fracture healing.
The midshafts of the right tibias of 16 rabbits were osteotomized, leaving a 2-mm gap. A 4-pin, double-bar external fixator was fixed to the tibias. Interfragmental compressive displacement of 0.5 mm with a frequency of 1 Hz was applied 15 minutes per day. Mechanical stimulation began 1 week postoperatively and continued for 2 and 3 weeks. Control animals received no stimulation. Callus quality and area were assessed by radiographs. Maximum force and total energy absorbed up to failure of the healed bones were determined using a standard 3-point bending test.

Postmortem radiographic examinations showed that mean radiographic measures in both anteroposterior and mediolateral views was significantly larger in experimental groups than controls (
P
=.029). Mechanical measures of the healed bones demonstrated that mean values of maximum force and absorbed energy were significantly higher in the experimental groups than in the control groups (
P
=.029). Both radiographic and mechanical measures were significantly higher after 3 weeks compared to 2 weeks of receiving stimulation (
P
<.05).
ACGME Core Competencies: Where Are We?
Authors: Yaszay Burt , Kubiak Erik , Agel Julie , Hanel Douglas P. 
Published: April 2009

Beginning in July 2002, the Accreditation Council for Graduate Medical Education (ACGME) instructed all residency programs to require their residents to demonstrate competency in 6 core areas: patient care, interpersonal and communication skills, medical knowledge, professionalism, practice-based learning, and systems-based practice. The goal was to have objective markers of performance that would serve as a gauge to determine a program's accreditation.
To determine the experiences of orthopedic residency programs with regard to the ACGME's core competencies, a national survey was administered to orthopedic program directors and selected orthopedic residents. Of those orthopedic programs that responded, most appeared to be complying with the ACGME requirements. Both directors and residents thought patient care and medical knowledge ranked most important, while practice-based learning and systems-based practice were assigned the lowest ranks. Barriers to implementation of the core competencies included low priority compared with clinical duties, lack of faculty or resident education, and lack of formal orthopedic core competencies. Residents and program directors agreed that their programs would benefit from a definition of each of the core competencies, including a greater commitment to the processes involved in surgical procedures.
This study demonstrated a commitment to the core competencies by the programs that responded. The survey also suggested this commitment would be aided by improved definitions of some of the competencies for the orthopedic resident.
IL-4 Is Proangiogenic in the Lung under Hypoxic Conditions
Authors: Yamaji-Kegan Kazuyo , Su Qingning , Angelini Daniel J. , Johns Roger A. 
Published: April 2009

AbstractIL-4-mediated proangiogenic and proinflammatory vascular responses have been implicated in the pathogenesis of chronic lung diseases such as asthma. Although it is well known that hypoxia induces pulmonary angiogenesis and vascular alterations, the underlying mechanism of IL-4 on the pulmonary vasculature under hypoxic conditions remains unknown. In this context, we designed the present study to determine the functional importance of IL-4 for pulmonary angiogenesis under hypoxic conditions using IL-4 knockout (KO) animals. Our results show that hypoxia significantly increased IL-4Rα expression in wild-type (WT) control lungs. Even though hypoxia significantly up-regulated vascular endothelial growth factor (VEGF) receptor expression in the lungs of both genotypes, hypoxia-induced VEGF, VCAM-1, HIF-1α, and ERK phosphorylation were significantly diminished in IL-4 KO lungs as compared with WT control lungs. In addition, hypoxia-induced pulmonary angiogenesis and proliferating activities in the airway and pulmonary artery were significantly suppressed in IL-4 KO lungs as compared with WT control lungs. We also isolated primary lung fibroblasts from these genotypes and stimulated these cells with hypoxia. Hypoxia-induced VEGF production was significantly suppressed in lung fibroblasts from IL-4 KO mice. These in vitro results are in accordance with the in vivo data. Furthermore, we observed a significant increase of hypoxia-induced pulmonary angiogenesis in STAT6 KO mice similar to that in WT controls. In conclusion, IL-4 has proangiogenic properties in the lung under hypoxic conditions via the VEGF pathway, and this is independent of the STAT6 pathway.
Autoantigen Immunization at Different Sites Reveals a Role for Anti-Inflammatory Effects of IFN-γ in Regulating Susceptibility to Experimental Autoimmune Encephalomyelitis
Authors: Pastor Silvia , Minguela Alfredo , Mi Wentao , Ward E. Sally 
Published: April 2009

Abstract
Experimental autoimmune encephalomyelitis is induced in B10.PL (H-2u) mice by immunization with the immunodominant N-terminal epitope of myelin basic protein, Ac1-9. In the present study, we show that the site of immunization impacts disease incidence and severity. This effect is more marked in female mice than in males. Although immunization in the flanks is effective in eliciting disease, delivery of Ag in the footpad and tailbase results in poor induction. Analyses of the immune responses in female mice following different immunization regimens indicates that resistance to disease is accompanied by higher levels of IFN-γ and CD11b+Gr-1int myeloid cells. Such myeloid cells are known to have a suppressive function, and consistent with this knowledge, blockade of IFN-γ results in increased disease activity and decreased levels of splenic CD11b+Gr-1int cells. Conversely, injection of adjuvants (CFA or Pam3CSK4) in the footpad decreases experimental autoimmune encephalomyelitis incidence and severity. Our study indicates that the site of immunization can impact the magnitude of the ensuing inflammatory response, and that at a certain threshold a protective, regulatory circuit can be elicited.
TLR Agonists Prevent the Establishment of Allogeneic Hematopoietic Chimerism in Mice Treated with Costimulation Blockade
Authors: Miller David M. , Thornley Thomas B. , Pearson Todd , Kruger Annie J. , Yamazaki Masahiro , Shultz Leonard D. , Welsh Raymond M. , Brehm Michael A. , Rossini Aldo A. , Greiner Dale L. 
Published: April 2009

Abstract
Activation of TLR4 by administration of LPS shortens the survival of skin allografts in mice treated with costimulation blockade through a CD8 T cell-dependent, MyD88-dependent, and type I IFN receptor-dependent pathway. The effect of TLR activation on the establishment of allogeneic hematopoietic chimerism in mice treated with costimulation blockade is not known. Using a costimulation blockade protocol based on a donor-specific transfusion (DST) and a short course of anti-CD154 mAb, we show that LPS administration at the time of DST matures host alloantigen-presenting dendritic cells, prevents the establishment of mixed allogeneic hematopoietic chimerism, and shortens survival of donor-specific skin allografts. LPS mediates its effects via a mechanism that involves both CD4+ and CD8+ T cells and results from signaling through either the MyD88 or the type I IFN receptor pathways. We also document that timing of LPS administration is critical, as injection of LPS 24 h before treatment with DST and anti-CD154 mAb does not prevent hematopoietic engraftment but administration the day after bone marrow transplantation does. We conclude that TLR4 activation prevents the induction of mixed allogeneic hematopoietic chimerism through type I IFN receptor and MyD88-dependent signaling, which leads to the up-regulation of costimulatory molecules on host APCs and the generation of alloreactive T cells. These data suggest that distinct but overlapping cellular and molecular mechanisms control the ability of TLR agonists to block tolerance induction to hematopoietic and skin allografts in mice treated with costimulation blockade.
Direct Hematological Toxicity and Illegitimate Chromosomal Recombination Caused by the Systemic Activation of CreERT2
Authors: Higashi Atsuko Yoshioka , Ikawa Tomokatsu , Muramatsu Masamichi , Economides Aris N. , Niwa Akira , Okuda Tomohiko , Murphy Andrew J. , Rojas Jose , Heike Toshio , Nakahata Tatsutoshi , Kawamoto Hiroshi , Kita Toru , Yanagita Motoko 
Published: April 2009

Abstract
The CreERT2 for conditional gene inactivation has become increasingly used in reverse mouse genetics, which enables temporal regulation of Cre activity using a mutant estrogen binding domain (ERT2) to keep Cre inactive until the administration of tamoxifen. In this study, we present the severe toxicity of ubiquitously expressed CreERT2 in adult mice and embryos. The toxicity of Cre recombinase or CreERT2 in vitro or in vivo organisms are still less sufficiently recognized considering the common use of Cre/loxP system, though the toxicity might compromise the phenotypic analysis of the gene of interest. We analyzed two independent lines in which CreERT2 is knocked-in into the Rosa26 locus (R26CreERT2 mice), and both lines showed thymus atrophy, severe anemia, and illegitimate chromosomal rearrangement in hematopoietic cells after the administration of tamoxifen, and demonstrated complete recovery of hematological toxicity in adult mice. In the hematopoietic tissues in R26CreERT2 mice, reduced proliferation and increased apoptosis was observed after the administration of tamoxifen. Flow cytometric analysis revealed that CreERT2 toxicity affected several hematopoietic lineages, and that immature cells in these lineages tend to be more sensitive to the toxicity. In vitro culturing of hematopoietic cells from these mice further demonstrated the direct toxicity of CreERT2 on growth and differentiation of hematopoietic cells. We further demonstrated the cleavage of the putative cryptic/pseudo loxP site in the genome after the activation of CreERT2 in vivo. We discussed how to avoid the misinterpretation of the experimental results from potential toxic effects due to the activated CreERT2.
Molecular Dissection of Antibody Responses against Pneumococcal Surface Protein A: Evidence for Diverse DH-Less Heavy Chain Gene Usage and Avidity Maturation
Authors: Rohatgi Soma , Dutta Debjani , Tahir Suhail , Sehgal Devinder 
Published: April 2009

AbstractImmunization of human volunteers with a single dose of pneumococcal surface protein A (PspA) stimulates broad cross-reactive Abs to heterologous PspA molecules that, when transferred, protect mice from fatal infection with Streptococcus pneumoniae. In this study, we report the molecular characterization of 36 mouse mAbs generated against the extracellular domain of PspA (PspA3–286) from strain R36A. Abs to PspA3–286 were encoded by diverse VH and Vκ families/genes. The H chain CDR3 and L chain CDR3 lengths were 3–13 (7.8 ± 0.5) and 8–9 (8.7 ± 0.2) codons, respectively. Unexpectedly, seven hybridomas expressed H chains that lack DH gene-derived amino acids. Nontemplate-encoded addition(s) were observed in the H chain expressed in six of these seven hybridomas; Palindromic addition(s) were absent. Absence of DH gene-derived amino acids did not prevent anti-PspA3–286 mAbs from attaining average relative avidity. Avidity maturation occurred during primary IgG anti-PspA3–286 polyclonal Ab response in PspA3–286- and R36A-immunized mice. Compared with PspA3–286-immunized mice, the relative avidity of the primary polyclonal IgG Abs was higher in R36A immunized mice on days 72, 86, and 100. Two pairs of clonally related hybridomas were observed. DH genes expressed in the majority (75.9%) of the hybridomas used reading frame 3. Analysis of replacement/silent mutation ratio in the CDR and framework regions provided evidence for Ag-driven selection in 11 mAbs. Based on epitope localization experiments, the mAbs were classified into 12 independent groups. ELISA additivity assay indicated that members within a group recognized topographically related epitopes. This study provides molecular insights into the biology of DH-less Abs.
Galectin-1 Tunes TCR Binding and Signal Transduction to Regulate CD8 Burst Size
Authors: Liu Scot D. , Tomassian Tamar , Bruhn Kevin W. , Miller Jeff F. , Poirier Françoise , Miceli M. Carrie 
Published: April 2009

AbstractT cell burst size is regulated by the duration of TCR engagement and balanced control of Ag-induced activation, expansion, and apoptosis. We found that galectin-1-deficient CD8 T cells undergo greater cell division in response to TCR stimulation, with fewer dividing cells undergoing apoptosis. TCR-induced ERK signaling was sustained in activated galectin-1-deficient CD8 T cells and antagonized by recombinant galectin-1, indicating galectin-1 modulates TCR feed-forward/feedback loops involved in signal discrimination and procession. Furthermore, recombinant galectin-1 antagonized binding of agonist tetramers to the TCR on activated OT-1 T cells. Finally, galectin-1 produced by activated Ag-specific CD8 T cells negatively regulated burst size and TCR avidity in vivo. Therefore, galectin-1, inducibly expressed by activated CD8 T cells, functions as an autocrine negative regulator of peripheral CD8 T cell TCR binding, signal transduction, and burst size. Together with recent findings demonstrating that gal-1 promotes binding of agonist tetramers to the TCR of OT-1 thymocytes, these studies identify galectin-1 as a tuner of TCR binding, signaling, and functional fate determination that can differentially specify outcome, depending on the developmental and activation stage of the T cell.
Locally Administered TLR7 Agonists Drive Systemic Antitumor Immune Responses That Are Enhanced by Anti-CD40 Immunotherapy
Authors: Broomfield Steve A. , van der Most Robbert G. , Prosser Amy C. , Mahendran Sathish , Tovey Michael G. , Smyth Mark J. , Robinson Bruce W. S. , Currie Andrew J. 
Published: April 2009

Abstract
Topical application of tumors with the TLR7 agonist imiquimod is an effective adjunct treatment for a range of primary dermatological cancers. However, for therapy to be effective against a broad range of solid tumor types, it must promote a strong systemic antitumor response that targets metastases in addition to primary tumor. We therefore investigated the potential of locally delivered imiquimod to stimulate an effective systemic antitumor response in a murine model of malignant mesothelioma (AB1-HA) with primary and distal tumors (dual tumor). Persistent delivery of imiquimod into primary tumor significantly retarded tumor growth in all treated mice compared with vehicle control. This local antitumor immune response required both CD8 T cells and NK cells, but not CD4 T cells, and was reliant on type I IFN induction. In vivo CTL studies and Ly6A/E staining of lymphocytes suggested that local imiquimod treatment had indeed induced a systemic, Ag-specific CD8 response. However, notably this response was not sufficient to retard the growth of an untreated distal tumor. Because local imiquimod treatment did not induce significant CD4 T cell responses, we investigated the efficacy of combining imiquimod with agonistic CD40 Ab (as a surrogate for CD4 T cell help). Combination of locally delivered imiquimod with systemic anti-CD40 immunotherapy not only significantly enhanced the local antitumor response, with 30% complete resolution, but it was also effective at significantly retarding growth of distal tumor. These results demonstrate that antitumor responses induced by locally delivered TLR7 agonists can be harnessed systemically for treating distal tumor.
Inflammation Recapitulates the Ontogeny of Lymphoid Stromal Cells
Authors: Peduto Lucie , Dulauroy Sophie , Lochner Matthias , Späth Gerald F. , Morales Miguel A. , Cumano Ana , Eberl Gérard 
Published: April 2009

Abstract
Stromal cells in lymphoid tissues regulate lymphocyte recruitment and survival through the expression of specific chemokines and cytokines. During inflammation, the same signals recruit lymphocytes to the site of injury; however, the “lymphoid” stromal (LS) cells producing these signals remain poorly characterized. We find that mouse inflammatory lesions and tumors develop gp38+ LS cells, in recapitulation of the development of LS cells early during the ontogeny of lymphoid organs and the intestine, and express a set of genes that promotes the development of lymphocyte-permissive tissues. These gp38+ LS cells are induced by a robust pathway that requires myeloid cells but not known Toll- or NOD-like receptors, the inflammasome, or adaptive immunity. Parabiosis and inducible genetic cell fate mapping experiments indicate that local precursors, presumably resident fibroblasts rather that circulating precursors, massively proliferate and give rise to LS cells during inflammation. Our results show that LS cells are both programmed during ontogeny and reinduced during inflammation.
The Avidity and Lytic Efficiency of the CTL Response to HTLV-1
Authors: Kattan Tarek , MacNamara Aidan , Rowan Aileen G. , Nose Hirohisa , Mosley Angelina J. , Tanaka Yuetsu , Taylor Graham P. , Asquith Becca , Bangham Charles R. M. 
Published: April 2009

Abstract
In human T-lymphotropic virus type 1 (HTLV-1) infection, a high frequency of HTLV-1-specific CTLs can co-exist stably with a high proviral load and the proviral load is strongly correlated with the risk of HTLV-1-associated inflammatory diseases. These observations led to the hypothesis that HTLV-1 specific CTLs are ineffective in controlling HTLV-1 replication but contribute to the pathogenesis of the inflammatory diseases. But evidence from host and viral immunogenetics and gene expression microarrays suggests that a strong CTL response is associated with a low proviral load and a low risk of HAM/TSP. Here, we quantified the frequency, lytic activity and functional avidity of HTLV-1-specific CD8+ cells in fresh, unstimulated PBMCs from individuals with natural HTLV-1 infection. The lytic efficiency of the CD8+ T cell response—the fraction of autologous HTLV-1-expressing cells eliminated per CD8+ cell per day—was inversely correlated with both the proviral load and the rate of spontaneous proviral expression. The functional avidity of HTLV-1-specific CD8+ cells was strongly correlated with their lytic efficiency. We conclude that efficient control of HTLV-1 in vivo depends on the CTL lytic efficiency, which depends in turn on CTL avidity of Ag recognition. CTL quality determines the position of virus-host equilibrium in persistent HTLV-1 infection.
α2-Macroglobulin Capture Allows Detection of Mast Cell Chymase in Serum and Creates a Reservoir of Angiotensin II-Generating Activity
Authors: Raymond Wilfred W. , Su Sharon , Makarova Anastasia , Wilson Todd M. , Carter Melody C. , Metcalfe Dean D. , Caughey George H. 
Published: April 2009

AbstractHuman chymase is a highly efficient angiotensin II-generating serine peptidase expressed by mast cells. When secreted from degranulating cells, it can interact with a variety of circulating antipeptidases, but is mostly captured by α2-macroglobulin, which sequesters peptidases in a cage-like structure that precludes interactions with large protein substrates and inhibitors, like serpins. The present work shows that α2-macroglobulin-bound chymase remains accessible to small substrates, including angiotensin I, with activity in serum that is stable with prolonged incubation. We used α2-macroglobulin capture to develop a sensitive, microtiter plate-based assay for serum chymase, assisted by a novel substrate synthesized based on results of combinatorial screening of peptide substrates. The substrate has low background hydrolysis in serum and is chymase-selective, with minimal cleavage by the chymotryptic peptidases cathepsin G and chymotrypsin. The assay detects activity in chymase-spiked serum with a threshold of ∼1 pM (30 pg/ml), and reveals native chymase activity in serum of most subjects with systemic mastocytosis. α2-Macroglobulin-bound chymase generates angiotensin II in chymase-spiked serum, and it appears in native serum as chymostatin-inhibited activity, which can exceed activity of captopril-sensitive angiotensin-converting enzyme. These findings suggest that chymase bound to α2-macroglobulin is active, that the complex is an angiotensin-converting enzyme inhibitor-resistant reservoir of angiotensin II-generating activity, and that α2-macroglobulin capture may be exploited in assessing systemic release of secreted peptidases.
Cutting Edge: Shift in Antigen Dependence by an Antiviral MHC Class Ib-Restricted CD8 T Cell Response during Persistent Viral Infection
Authors: Swanson Phillip A. , Hofstetter Amelia R. , Wilson Jarad J. , Lukacher Aron E. 
Published: April 2009

Abstract
The requirement for Ag in maintaining memory CD8 T cells often differs between infections that are acutely resolved and those that persist. Using the mouse polyoma virus (PyV) persistent infection model, we recently described a novel CD8 T cell response directed to a PyV peptide presented by Q9, an MHC class Ib molecule. This antiviral Q9-restricted CD8 T cell response is characterized by a 3-mo expansion phase followed by a long-term plateau phase. In this study, we demonstrate that viral Ag is required for this protracted inflation phase but is dispensable for the maintenance of this Q9-restricted CD8 T cell response. Moreover, proliferation by memory T cells, not recruitment of naive PyV-specific T cells, is primarily responsible for Q9-restricted, anti-PyV CD8 T cell inflation. These data reveal a dynamic shift in Ag dependence by an MHC class Ib-restricted memory CD8 T cell response during a persistent viral infection.