bluuebunny/crossref_metadata_2025 huggingface dataset:
SM16, an Orally Active TGF-β Type I Receptor Inhibitor Prevents Myofibroblast Induction and Vascular Fibrosis in the Rat Carotid Injury Model
Authors: Fu Kai , Corbley Michael J. , Sun Lihong , Friedman Jessica E. , Shan Feng , Papadatos James L. , Costa Donald , Lutterodt Frank , Sweigard Harry , Bowes Scott , Choi Michael , Boriack-Sjodin P. Ann , Arduini Robert M. , Sun Dongyu , Newman Miki N. , Zhang Xiamei , Mead Jonathan N. , Chuaqui Claudio E. , Cheung H. -Kam , Zhang Xin , Cornebise Mark , Carter Mary Beth , Josiah Serene , Singh Juswinder , Lee Wen-Cherng , Gill Alan , Ling Leona E.
Published: January 2008

Objective—

TGF-β plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis.

Methods and Results—

The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-β and activin-induced Smad2/3 phosphorylation and TGF-β-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle α-actin–positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells.

Conclusion—

These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.
Suppressing PTEN Activity by Tobacco Smoke Plus Interleukin-1β Modulates Dissociation of VE-Cadherin/β-Catenin Complexes in Endothelium
Authors: Barbieri Silvia S. , Ruggiero Luca , Tremoli Elena , Weksler Babette B.
Published: January 2008

Objectives—

Tobacco smoke (TS) interacts with inflammatory cytokines to produce endothelial dysfunction. We hypothesized that interleukin-1β (IL-1β) plus TS (TS/IL-1β) induces disassembly of endothelial junctional complexes of VE-cadherin/β-catenin by suppression of PTEN activity and investigated molecular mechanisms that modulate PTEN-deactivation in this situation.

Methods and Results—

TS/IL-1β exposure, which disrupted adherens junctions and induced nuclear β-catenin accumulation, increased tyrosine phosphorylation (p-Tyr) of VE-cadherin and β-catenin, and reduced PTEN activity. Overexpression or silencing of PTEN modulated p-Tyr of both VE-cadherin and β-catenin, changed assembly of adherens junction complexes, and altered nuclear β-catenin accumulation. In addition, inhibiting ROS production stimulated by TS/IL-1β decreased activation of Src, EGFR and p38MAPK, phosphorylation of PTEN, VE-cadherin and β-catenin, and abrogated the effect of TS/IL-1β to disorganize adherens junctions, resulting in reduced endothelial permeability and decreased nuclear β-catenin accumulation. Finally, exposure of ApoE
−/−
mice to cigarette smoke–induced phosphorylation of Src, EGFR, p-38MAPK, PTEN, and β-catenin, and disrupted VE-cadherin/β-catenin complexes in cardiovascular tissue.

Conclusions—

TS interaction with IL-1β modulates PTEN activity though the ROS/Src/EGFR-p38MAPK pathway. PTEN deactivation is essential to increase VE-cadherin and β-catenin p-Tyr and to disassemble VE-cadherin/β-catenin membrane complexes, events that lead to accumulation of β-catenin within the nucleus.
Vessel Wall–Embedded Dendritic Cells Induce T-Cell Autoreactivity and Initiate Vascular Inflammation
Authors: Han Ji W. , Shimada Kazunori , Ma-Krupa Wei , Johnson Tiffany L. , Nerem Robert M. , Goronzy Jörg J. , Weyand Cornelia M.
Published: January 2008

Human medium-sized and large arteries are targeted by inflammation with innate and adaptive immune responses occurring within the unique microspace of the vessel wall. How 3D spatial arrangements influence immune recognition and cellular response thresholds and which cell populations sense immunoactivating ligands and function as antigen-presenting cells are incompletely understood. To mimic the 3D context of human arteries, bioartificial arteries were engineered from collagen type I matrix, human vascular smooth muscle cells (VSMCs), and human endothelial cells and populated with cells implicated in antigen presentation and T-cell stimulation, including monocytes, macrophages, and myeloid dendritic cells (DCs). Responsiveness of wall-embedded antigen-presenting cells was probed with the Toll-like receptor ligand lipopolysaccharide, and inflammation was initiated by adding autologous CD4
+
T cells. DCs colonized the outermost VSMC layer, recapitulating their positioning at the media–adventitia border of normal arteries. Wall-embedded DCs responded to the microbial product lipopolysaccharide by entering the maturation program and upregulating the costimulatory ligand CD86. Activated DCs effectively stimulated autologous CD4 T cells, which produced the proinflammatory cytokine interferon-γ and infiltrated deeply into the VSMC layer, causing matrix damage. Lipopolysaccharide-triggered macrophages were significantly less efficacious in recruiting T cells and promoting T-cell stimulation. CD14
+
monocytes, even when preactivated, failed to support initial steps of vascular wall inflammation. Innate immune cells, including monocytes, macrophages, and DCs, display differential functions in the vessel wall. DCs are superior in sensing pathogen-derived motifs and are highly efficient in breaking T-cell tolerance, guiding T cells toward proinflammatory and tissue-invasive behavior.
Binding of the P2Y
2
Nucleotide Receptor to Filamin A Regulates Migration of Vascular Smooth Muscle Cells
Authors: Yu Ningpu , Erb Laurie , Shivaji Rikka , Weisman Gary A. , Seye Cheikh I.
Published: January 2008

The functional expression of the G protein–coupled P2Y
2
nucleotide receptor (P2Y
2
R) has been associated with proliferation and migration of vascular smooth muscle cells (SMCs), two processes involved in atherosclerosis and restenosis. Activation of the P2Y
2
R causes dynamic reorganization of the actin cytoskeleton, which transmits biochemical signals and forces necessary for cell locomotion, suggesting that P2Y
2
Rs may be linked to the actin cytoskeleton. Here, we identified filamin A (FLNa) as a P2Y
2
R-interacting protein using a yeast 2-hybrid system screen with the C-terminal region of the P2Y
2
R as bait. The FLNa binding site in the P2Y
2
R is localized between amino acids 322 and 333. Deletion of this region led to selective loss of FLNa binding to the P2Y
2
R and abolished Tyr phosphorylation of FLNa induced by the P2Y
2
R agonist UTP. Using both time-lapse microscopy and the Transwell cell migration assay, we showed that UTP significantly increased SMC spreading on collagen I (6.8 fold;
P
≤0.01) and migration (3.6 fold;
P
≤0.01) of aortic SMCs isolated from wild-type mice, as compared with unstimulated SMCs. UTP-induced spreading and migration of aortic SMCs did not occur with cells isolated from P2Y
2
R knockout mice. Expression of the full-length P2Y
2
R in SMCs isolated from P2Y
2
R knockout mice restored both UTP-induced spreading and migration. In contrast, UTP-induced spreading and migration did not occur in SMCs isolated from P2Y
2
R knockout mice transfected with a mutant P2Y
2
R that does not bind FLNa. Furthermore, ex vivo studies showed that both ATP and UTP (10 μmol/L) promoted migration of SMCs out of aortic explants isolated from wild-type but not P2Y
2
R knockout mice. Thus, this study demonstrates that P2Y
2
R/FLNa interaction selectively regulates spreading and migration of vascular SMCs.
Ambient Particulate Pollutants in the Ultrafine Range Promote Early Atherosclerosis and Systemic Oxidative Stress
Authors: Araujo Jesus A. , Barajas Berenice , Kleinman Michael , Wang Xuping , Bennett Brian J. , Gong Ke Wei , Navab Mohamad , Harkema Jack , Sioutas Constantinos , Lusis Aldons J. , Nel Andre E.
Published: January 2008

Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 μm (PM
2.5
) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 μm (ultrafine particles) with particles of <2.5 μm in genetically susceptible (apolipoprotein E–deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 μm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle–exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM
2.5
or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.
Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism
Authors: Philip-Couderc Pierre , Tavares Nadia Isidoro , Roatti Angela , Lerch René , Montessuit Christophe , Baertschi Alex J.
Published: January 2008

Coordinate adaptation of myocyte metabolism and function is fundamental to survival of the stressed heart, but the mechanisms for this coordination remain unclear. Bioinformatics led us to discover that Foxs are key transcription factors involved. We performed experiments on the mouse atrial cell line HL-1, neonate rat heart myocytes, and an adult rat model of myocardial infarction. In electrophoretic mobility-shift assays, FoxO1 binds to the FoxO concensus site of the KATP channel subunit KIR6.1 promoter. In primary atrial culture, targeting FoxO1 and FoxO3 with siRNA specifically reduces mRNA expression of FoxO1 and -O3 and KIR6.1. Western blots, confocal immunofluorescence, and quantitative RT-PCR was applied for measuring expression of 10 Fox, 6 KATP channel subunits, and 12 metabolic genes. FoxF2, -O1, and -O3 strongly associate with expression of KATP channel subunits (in particular, KIR6.1, SUR1A and SUR2B) in different heart tissues and in the periinfarct zone of the left ventricle. Patch-clamp recordings demonstrate that molecular plasticity of these channels is matched by pharmacological plasticity and increased sensitivity to a metabolic challenge mimicked by the protonophore CCCP. A balance of FoxF2 and FoxO also regulates expression of at least 9 metabolic genes involved in setting the balance of glycolysis and β-oxidation. Bioinformatics shows that the transcriptional mechanisms are highly conserved among chicken, mouse, rat, and human, and Fox are intimately linked to other metabolic sensors. Thus, FoxF2 and -O are key transcription factors coordinating expression of KATP channels and energy metabolism.
Outback Steakhouse in Korea
Authors: Lee Kyuho , Khan Mahmood A. , Ko Jae-Youn
Published: January 2008

Outback Steakhouse Korea has proven to be a successful casual-dining transplant from the United States. Highlighting the company's competitive advantages and core competencies, this study describes the critical success factors for this restaurant company. Key among the success factors is a decentralized structure that takes advantage of the business acumen of managing partners. A flexible approach that allowed the Korean chain to respond to the country's cultural patterns and market preferences is balanced with a strict approach to hiring and training.
Association Between Physical Environment of Secondary Schools and Student Problem Behavior
Authors: Kumar Revathy , O'Malley Patrick M. , Johnston Lloyd D.
Published: January 2008

This article examines various aspects of school physical characteristics relating to problem behavior among students. We hypothesize that an attractive physical environment will be associated with less truancy, cigarette, alcohol, and marijuana use, whereas a negative physical environment will be associated with higher levels of these behaviors. Analyses use data from nationally representative samples of 8th-, 10th-, and 12th-grade students who participated in annual surveys conducted by the Monitoring the Future project from 2000 to 2003. Analyses also use data collected from principals and field interviewers of the same schools. Results based on multilevel logistic and linear regressions indicate that students are sensitive to schools' ambience and that the association of various aspects of the school's physical environment with students' problem behaviors is greater for 10th-grade students than for 8th and 12th-grade students. The implications of these findings for school policies and practices are discussed.
Nonpermanent Residents, Place Attachment, and “Sea Change” Communities
Authors: Kelly Gail , Hosking Karin
Published: January 2008

Rapid population growth and an increase in the number of nonresident second-home owners are altering the environmental, social, and economic stability of many Australian seaside communities. The impact of the growing proportion of nonpermanent residents in these regions has not yet been subject to much research. This article explores the usefulness of place attachment to provide insight into the actions and behavior of second-home owners. Place attachment, or human-place bonding, has been linked to positive behaviors such as environmental conservation, volunteering, and the reverse of neighbourhood decline. This article examines second-home owners' sense of place attachment in Western Australia's Augusta–Margaret River region. Findings indicate positive relationships between levels of place attachment, the amount of time spent in the region, support of local businesses, and contributions to community through membership in voluntary organizations. The relevance of supporting the place attachment of nonpermanent residents in rapidly developing coastal areas is discussed.
Contact With Nature, Sense of Humor, and Psychological Well-Being
Authors: Herzog Thomas R. , Strevey Sarah J.
Published: January 2008

We administered a questionnaire measuring contact with nature, sense of humor, and psychological well-being. Factor analysis of the humor items yielded four factors: humor production, humor appreciation, coping humor, and humor tolerance. Factor analysis of 14 well-being measures yielded three factors: emotional well-being, personal development, and effective functioning. The best sense-of-humor predictor of the well-being measures and factors was humor appreciation. Regression models for each of the well-being factors as dependent variables with humor appreciation and contact with nature as independent variables showed that additive models with both predictors were appropriate for personal development and effective functioning and that a simple model with humor appreciation as the sole predictor was sufficient for emotional well-being. Secondary analyses suggested that contact with nature was the better predictor of effective functioning, whereas sense of humor was the better predictor of personal development.
Celebrating Two Decades of Linguistic Bias Research
Authors: Sutton Robbie M. , Douglas Karen M.
Published: January 2008

The authors introduce a special issue of the Journal of Language and Social Psychology on linguistic bias, celebrating two decades of research since G. R. Semin and K. Fiedler (1988) first published the linguistic category model (LCM). The LCM has been highly cited and generative and provides a parsimonious framework for investigations of the role of language in social—psychological phenomena. Indeed, the articles in this issue are notable for addressing a wide range of such phenomena, underscoring both the success of the LCM so far and its further potential.
Linguistic Bias in Personnel Selection
Authors: Rubini Monica , Menegatti Michela
Published: January 2008

The present research examines how hiring committees strategically use language abstraction to collectively account for their decision to hire a job applicant over the others. In addition, the authors investigate how work interdependence between single members of hiring committees and applicants and common affiliation to the same work organization affect the language used to write individual reports on job candidates. Results of the first study show that selected applicants were described with positive terms at a higher level of abstraction and negative terms at a lower level of abstraction. The second study supports the selection linguistic bias in individually written reports and demonstrates that members of hiring committees describe interdependent applicants and those belonging to their group with negative terms at a lower level of abstraction than other applicants. The implications of the findings for the wider personnel selection context are discussed.
Pulmonary Glomus Tumor
Authors: Dalfior Daniela , Parisi Alice , Cannizzaro Claudia , Bontempini Lamberto , Di Pace Concetta , Menestrina Fabio , Dalla Palma Paolo , Barbareschi Mattia
Published: January 2008

Glomus tumor, also known as glomangioma, is a neoplasm derived from cells of the neuromyoarterial glomus or glomus body. We report a case of glomus tumor of the lung arising in the left lower lobe, incidentally found in a patient who underwent right bilobectomy for a carcinoma localized in the right upper lobe.
Fat-Predominant Mixed Epithelial Stromal Tumor (MEST): Report of a Unique Case Mimicking Angiomyolipoma
Authors: Sireci Anthony N. , Rodriguez Ronald , Swierczynski Sharon L. , Netto George J. , Argani Pedram
Published: January 2008

A unique case of a mixed epithelial stromal tumor (MEST) that was predominantly composed of adipose tissue is reported here. Radiographically and grossly, the lesion was thought to be an angiomyolipoma, based upon its fatty appearance. Microscopically, the lesion was predominantly composed of mature adipose tissue but also contained clusters of bland tubules surrounded by smooth muscle bundles and collagen. By immunohistochemistry, the stroma labeled diffusely for estrogen and progesterone receptors, while the muscle bundles labeled for desmin. Melanocytic markers HMB45 and Melan A, typically positive in angiomyolipoma, were nonreactive. This case expands the morphologic spectrum of MEST to include mimics of angiomyolipoma.
Heterogeneous Distribution of ITGCNU in an Adult Testis: Consequences for Biopsy-Based Diagnosis
Authors: van Casteren Niels J. , Boellaard Willem P. A. , Dohle Gert R. , Weber Robertus F. A. , Kuizinga Marti C. , Stoop Hans , Oosterhuis Wolter J. , Looijenga Leendert H. J.
Published: January 2008

Carcinoma in situ (CIS) of the testis, also referred to as intratubular germ cell neoplasia unclassified (ITGCNU), is currently accepted as the common precursor for all malignant germ cell tumors of adolescents and adults— that is, the seminomatous and nonseminoma cancers. These preinvasive cells have specific cellular characteristics, which can be used for the early diagnosis—routinely done by morphological analysis, sometimes supported by immunohistochemistry—of tissue obtained by an open surgical biopsy. False-negative biopsy results can occur mostly because of the nonrandom distribution of ITGCNU within the testis, misdiagnosis, or suboptimal tissue treatment and analysis. In this article, we demonstrate the potential pitfalls in the diagnosis of ITGCNU. The results support the use of the highly specific and sensitive immunohistochemical marker OCT3/4 for the diagnosis of ITGCNU and provide evidence for the nonrandom distribution of ITGCNU, which is a significant limitation in the diagnosis of this preinvasive lesion.
Immunohistochemical Expression of Estrogen Receptors in Chondrosarcomas and Enchondromas
Authors: Grifone Thomas J. , Haupt Helen M. , Podolski Victoria , Brooks John J.
Published: January 2008

Immunohistochemical expression of estrogen receptors α and β was studied in chondrosarcomas and enchondromas and was correlated with chondrosarcoma grade, type, and dedifferentiation. Estrogen receptor α was studied in 37 chondrosarcomas, 10 enchondromas, and 2 extraskeletal myxoid chondrosarcomas. Estrogen receptor β was studied in 23 chondrosarcomas, 6 enchondromas, and 2 extraskeletal myxoid chondrosarcomas. Ventana prediluted monoclonal anti-ER α (clone 6F11) and Biogenex prediluted polyclonal anti-ER β were used on the Ventana ES autostainer and BenchMark XT IHC/ISH, respectively. Percent of cell staining and intensity (+, ++, or +++) was evaluated. Overall, 61% of conventional chondrosarcoma and 60% of enchondroma were positive for estrogen receptor α. Low-grade chondrosarcoma expressed estrogen receptor α more frequently than high-grade chondrosarcoma ( P ≤ .001). Extraskeletal myxoid chondrosarcomas expressed estrogen receptor α; it was not expressed in dedifferentiated chondrosarcoma. Overall, 89% of conventional chondrosarcomas and 83% of enchondromas were positive for estrogen receptor β. Low-grade chondrosarcomas expressed estrogen receptor β more frequently than high-grade chondrosarcomas ( P ≤ .05). Extraskeletal myxoid chondrosarcomas expressed estrogen receptor β; it was frequently lost in dedifferentiated chondrosarcoma.
Periorbital Subcutaneous Tumor-Like Lesion Due to Dirofilaria repens
Authors: Eccher Albino , Dalfior Daniela , Gobbo Stefano , Martignoni Guido , Brunelli Matteo , Decaminada Walter , Bonetti Franco , Rivasi Francesco , Barbareschi Mattia , Menestrina Fabio
Published: January 2008

Dirofilariasis is a zoonotic infection, which is occasionally seen in humans and rarely found as a subcutaneous orbital swelling. The authors report a case of a 62-year-old woman presented with a 3-month history of a right periorbital subcutaneous nodule. Treatment with antibiotics and corticosteroids was not satisfactory. Magnetic resonance imaging analysis showed a nodule with a central colliquative area. The lesion displaced the eyeball superiorly but did not affect the intraorbital muscles. The patient was subjected to excisional biopsy and the nodule measured 15 mm. Histological findings showed microabscess reaction with heterogeneous lymphoid infiltration. Additional consecutive sections finally showed Dirofilaria repens, curled up in spirals with external cuticular ridges in an environment characterized by epithelioid cells. The lesion did not recur for 5 months. Periorbital swelling can be rarely caused by Dirofilaria repens; therefore, this diagnosis should be considered in all cases of subcutaneous inflammatory or tumor-like lesion of unknown etiology.
Iatrogenic Pulse Granuloma Detected at Prostatectomy
Authors: Nambudripad Roy , Narula Navneet , Wu Mark Li-cheng
Published: January 2008

Pulse granulomas are peculiar reactions to vegetable matter characterized by aggregates of hyaline rings and may be oral or extraoral. Pulse granulomas are important to recognize because they may indicate serious pathologic processes, may simulate neoplasia clinically, and may morphologically be confused with hyaline vasculopathy. We recently encountered a case involving a highly unusual pulse granuloma in a 55-year-old man who underwent prostatectomy for adenocarcinoma. Prior pancolonoscopy and digital rectal examination excluded significant colorectal disease. Microscopy showed a prominent pulse granuloma with demonstrable vegetable matter occupying periprostatic soft tissue. Interestingly, retrospective review of material from prior prostatic core biopsies revealed vegetable matter that appeared identical to the vegetable matter in the pulse granuloma. We conclude that the biopsies transrectally displaced vegetable matter, which provided the nidus for the pulse granuloma. We present the first pulse granuloma to be caused by a biopsy or to occupy periprostatic soft tissue.
Mesothelial Glandular Structures Within Pseudosarcomatous Proliferative Funiculitis—A Diagnostic Pitfall: Report of 17 Cases
Authors: Michal Michal , Hes Ondrej , Kazakov Dmitry V.
Published: January 2008

We describe 17 cases of distinct benign pseudomalignant mesothelial proliferations, involving the spermatic cord. All cases revealed necrosis. The areas adjacent to the necrotic tissue comprised a cellular spindle cell proliferation with a haphazard arrangement of the myofibroblasts that in many areas revealed transitions into plump oval epithelioid cells and into cells with genuine epithelial appearances arranged in linear cords and often luminized into small microcysts. These epithelial cells formed isolated groups with glandular structures arising on the myofibroblastic background. Glandular structures were often situated deeply in the stroma of the spermatic cords. All cellular elements were strongly positive with AE1/AE3 antibody. All myofibroblasts stained with SM-actin antibody. Ultrastructurally, the spindle cells displayed features of myofibroblasts including actin microfilaments, as did the plump epithelioid cells that, additionally, had desmosomes, and the cords of the epithelial cells including those forming glandular structures had characteristics of mesothelias including the characteristic microvilli.
Medullary Sponge Kidney Associated With Multivessel Fibromuscular Dysplasia: Report of a Case With Renovascular Hypertension
Authors: Bisceglia Michele , Galliani Carlos
Published: January 2008

Medullary sponge kidney (MSK) is a congenital anomaly characterized by dilatation of the collecting ducts of Bellini associated with defective urinary acidification and concentration. Medullary nephrocalcinosis/ nephrolithiasis is the usual presentation in adults, however neonatal and childhood cases are being reported with increasing frequency. Among the conditions associated with MSK are Beckwith-Wiedemann syndrome/hemihyperplasia (13%), horseshoe kidney, congenital small kidney, hyperparathyroidism, Caroli syndrome, congenital hepatic fibrosis, Ehlers-Danlos syndrome, Marfan syndrome, immotile cilia syndrome, and arterial fibromuscular dysplasia. This article describes an adult female who underwent nephrectomy for renovascular hypertension due to multivessel fibromuscular dysplasia with small left kidney found to be associated with MSK.
The Factor Structure and Dimensional Scoring of the Generalized Anxiety Disorder Questionnaire for DSM-IV
Authors: Rodebaugh Thomas L. , Holaway Robert M. , Heimberg Richard G.
Published: January 2008

Despite favorable psychometric properties, the Generalized Anxiety Disorder Questionnaire for the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (GAD-Q-IV) does not have a known factor structure, which calls into question use of its original weighted scoring system (usually referred to as the dimensional score). Analyses appropriate to categorical item responses in a large sample of undergraduates were used to establish the scale's factor structure. Analyses indicated that a one-factor structure resulted in good fit. A scoring method based on this one-factor structure was compared with a variety of alternative scoring procedures, and it was found that a method based on factor scores did relatively well but that the previously suggested dimensional score failed to perform better than a simple sum of items. Results support the general unity of the measure but raise doubts regarding its scoring and response options.
Accessibility of Hospitality and Tourism Websites
Authors: Mills Juline E. , Han Jee-Hee , Clay Joan Marie
Published: January 2008

An analysis of twenty websites operated by hospitality and tourism companies found numerous issues that would interfere with the use of those websites by persons with visual impairments. While the U.S. courts have been mixed on the question of whether the Americans with Disabilities Act applies to websites, the wise course is for hotel and tourism companies to ensure that those with visual impairments are easily able to use their sites. One source of design guidelines is the Web Content Accessibility Priority 1 Guidelines, developed by the World Wide Web Consortium.
Creating a Competitive Advantage by Building Resource Capability
Authors: Enz Cathy A.
Published: January 2008

The case of Outback Steakhouse Korea provides almost a textbook example of a five-point framework for competitive advantage. The framework suggests that companies must manage and blend resources in the following five categories: (1) financial resources, (2) physical resources, (3) human resources, (4) organizational knowledge and learning, and (5) general organizational resources (including brand names and relationships with stakeholders). Outback Korea has deftly combined resources in these five categories for considerable advantage and must continue to do so.
RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance
Authors: Roche-Lestienne Catherine , Deluche Lauréline , Corm Sélim , Tigaud Isabelle , Joha Sami , Philippe Nathalie , Geffroy Sandrine , Laï Jean-Luc , Nicolini Franck-Emmanuel , Preudhomme Claude
Published: January 2008

Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)
Authors: Kitada Shinichi , Kress Christina L. , Krajewska Maryla , Jia Lee , Pellecchia Maurizio , Reed John C.
Published: January 2008

Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apo-gossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of gossypol, with apogossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is overexpressed in B cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2–expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than gossypol, with LD50 values of 3 to 5 μM and 7.5 to 10 μM, respectively. In vivo, using the maximum tolerated dose of gossypol for sequential daily dosing, apogossypol displayed superior activity to gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2–transgenic mice. Taken together, these studies indicate that apogossypol is superior to parent compound gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted.
Augmented serum level of major histocompatibility complex class I-related chain A (MICA) protein and reduced NKG2D expression on NK and T cells in patients with cervical cancer and precursor lesions
Authors: Arreygue-Garcia Naela A , Daneri-Navarro Adrian , del Toro-Arreola Alicia , Cid-Arregui Angel , Gonzalez-Ramella Oscar , Jave-Suarez Luis F , Aguilar-Lemarroy Adriana , Troyo-Sanroman Rogelio , Bravo-Cuellar Alejandro , Delgado-Rizo Vidal , Garcia-Iglesias Trinidad , Hernandez-Flores Georgina , del Toro-Arreola Susana
Published: January 2008

Background

Cervical cancer is the second most common cancer in women worldwide. NK and cytotoxic T cells play an important role in the elimination of virus-infected and tumor cells through NKG2D activating receptors, which can promote the lysis of target cells by binding to the major histocompatibility complex class I-related chain A (MICA) proteins. Increased serum levels of MICA have been found in patients with epithelial tumors. The aim of this study was to compare the levels of soluble MICA (sMICA) and NKG2D-expressing NK and T cells in blood samples from patients with cervical cancer or precursor lesions with those from healthy donors.

Methods

Peripheral blood with or without heparin was collected to obtain mononuclear cells or sera, respectively. Serum sMICA levels were measured by ELISA and NKG2D-expressing immune cells were analyzed by flow cytometry. Also, a correlation analysis was performed to associate sMICA levels with either NKG2D expression or with the stage of the lesion.

Results

Significant amounts of sMICA were detected in sera from nearly all patients. We found a decrease in the number of NKG2D-expressing NK and T cells in both cervical cancer and lesion groups when compared to healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing T cells; however, we did not find a significant correlation when the analysis was applied to sMICA and NKG2D expression on NK cells.

Conclusion

Our results show for the first time that high sMICA levels are found in sera from patients with both cervical cancer and precursor lesions when compared with healthy donors. We also observed a diminution in the number of NKG2D-expressing NK and T cells in the patient samples; however, a significant negative correlation between sMICA and NKG2D expression was only seen in T cells.
Comparison of all-cause and malaria-specific mortality from two West African countries with different malaria transmission patterns
Authors: Ndugwa Robert P , Ramroth Heribert , Müller Olaf , Jasseh Momodou , Sié Ali , Kouyaté Bocar , Greenwood Brian , Becher Heiko
Published: January 2008

Background

Malaria is a leading cause of death in children below five years of age in sub-Saharan Africa. All-cause and malaria-specific mortality rates for children under-five years old in a mesoendemic malaria area (The Gambia) were compared with those from a hyper/holoendemic area (Burkina Faso).

Methods

Information on observed person-years (PY), deaths and cause of death was extracted from online search, using key words: "Africa, The Gambia, Burkina Faso, malaria, Plasmodium falciparum, mortality, child survival, morbidity". Missing person-years were estimated and all-cause and malaria-specific mortality were calculated as rates per 1,000 PY. Studies were classified as longitudinal/clinical studies or surveys/censuses. Linear regression was used to investigate mortality trends.

Results

Overall, 39 and 18 longitudinal/clinical studies plus 10 and 15 surveys and censuses were identified for The Gambia and Burkina Faso respectively (1960–2004). Model-based estimates for under-five all-cause mortality rates show a decline from 1960 to 2000 in both countries (Burkina Faso: from 71.8 to 39.0), but more markedly in The Gambia (from 104.5 to 28.4). The weighted-average malaria-specific mortality rate per 1000 person-years for Burkina Faso (15.4, 95% CI: 13.0–18.3) was higher than that in The Gambia (9.5, 95% CI: 9.1–10.1). Malaria mortality rates did not decline over time in either country.

Conclusion

Child mortality in both countries declined significantly in the period 1960 to 2004, possibly due to socio-economic development, improved health services and specific intervention projects. However, there was little decline in malaria mortality suggesting that there had been no major impact of malaria control programmes during this period. The difference in malaria mortality rates across countries points to significant differences in national disease control policies and/or disease transmission patterns.
Quantitative image analysis of intra-tumoral bFGF level as a molecular marker of paclitaxel resistance
Authors: Walsh Colin T , Wei Yong , Wientjes M Guillaume , Au Jessie LS
Published: January 2008

Background

The role of basic fibroblast growth factor (bFGF) in chemoresistance is controversial; some studies showed a relationship between higher bFGF level and chemoresistance while other studies showed the opposite finding. The goal of the present study was to quantify bFGF levels in archived tumor tissues, and to determine its relationship with chemosensitivity.

Methods

We established an image analysis-based method to quantify and convert the immunostaining intensity of intra-tumor bFGF to concentrations; this was accomplished by generating standard curves using human xenograft tumors as the renewable tissue source for simultaneous image analysis and ELISA. The relationships between bFGF concentrations and tumor chemosensitivity of patient tumors (n = 87) to paclitaxel were evaluated using linear regression analysis.

Results

The image analysis results were compared to our previous results obtained using a conventional, semi-quantitative visual scoring method. While both analyses indicated an inverse relationship between bFGF level and tumor sensitivity to paclitaxel, the image analysis method, by providing bFGF levels in individual tumors and therefore more data points (87 numerical values as opposed to four groups of staining intensities), further enabled the quantitative analysis of the relationship in subgroups of tumors with different pathobiological properties. The results show significant correlation between bFGF level and tumor sensitivity to the antiproliferation effect, but not the apoptotic effect, of paclitaxel. We further found stronger correlations of bFGF level and paclitaxel sensitivity in four tumor subgroups (high stage, positive p53 staining, negative aFGF staining, containing higher-than-median bFGF level), compared to all other groups. These findings suggest that the relationship between intra-tumoral bFGF level and paclitaxel sensitivity was context-dependent, which may explain the previous contradictory findings on the merit of using plasma or urine bFGF level as a prognostic indicator.

Conclusion

The present study established a quantitative image analysis method that enabled the measurement of intratumoral bFGF level in archived tissues. The ability to quantify a potential biomarker provided the opportunity to study the relationship between the biomarker and chemosensitivity in tumor subgroups and thereby enabled hypothesis generation for additional translational research.
Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt
Authors: Xing Bin , Xin Tao , Hunter Randy Lee , Bing Guoying
Published: January 2008

Background

Previous studies have suggested that peroxisome proliferator activated receptor-gamma (PPAR-γ)-mediated neuroprotection involves inhibition of microglial activation and decreased expression and activity of inducible nitric oxide synthase (iNOS); however, the underlying molecular mechanisms have not yet been well established. In the present study we explored: (1) the effect of the PPAR-γ agonist pioglitazone on lipopolysaccharide (LPS)-induced iNOS activity and nitric oxide (NO) generation by microglia; (2) the differential role of p38 mitogen-activated protein kinase (p38 MAPK), c-Jun NH(2)-terminal kinase (JNK), and phosphoinositide 3-kinase (PI3K) on LPS-induced NO generation; and (3) the regulation of p38 MAPK, JNK, and PI3K by pioglitazone.

Methods

Mesencephalic neuron-microglia mixed cultures, and microglia-enriched cultures were treated with pioglitazone and/or LPS. The protein levels of iNOS, p38 MAPK, JNK, PPAR-γ, PI3K, and protein kinase B (Akt) were measured by western blot. Different specific inhibitors of iNOS, p38MAPK, JNK, PI3K, and Akt were used in our experiment, and NO generation was measured using a nitrite oxide assay kit. Tyrosine hydroxylase (TH)-positive neurons were counted in mesencephalic neuron-microglia mixed cultures.

Results

Our results showed that pioglitazone inhibits LPS-induced iNOS expression and NO generation, and inhibition of iNOS is sufficient to protect dopaminergic neurons against LPS insult. In addition, inhibition of p38 MAPK, but not JNK, prevented LPS-induced NO generation. Further, and of interest, pioglitazone inhibited LPS-induced phosphorylation of p38 MAPK. Wortmannin, a specific PI3K inhibitor, enhanced p38 MAPK phosphorylation upon LPS stimulation of microglia. Elevations of phosphorylated PPAR-γ, PI3K, and Akt levels were observed with pioglitazone treatment, and inhibition of PI3K activity enhanced LPS-induced NO production. Furthermore, wortmannin prevented the inhibitory effect of pioglitazone on the LPS-induced NO increase.

Conclusion

We demonstrate that pioglitazone protects dopaminergic neurons against LPS insult at least via inhibiting iNOS expression and NO generation, which is potentially mediated via inhibition of p38 MAPK activity. In addition, the PI3K pathway actively participates in the negative regulation of LPS-induced NO production. Our findings suggest that PPAR-γ activation may involve differential regulation of p38 MAPK and of the PI3K/Akt pathway in the regulation of the inflammatory process.
Dermatological conditions in intensive care: a secondary analysis of the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database
Authors: George Susannah MC , Harrison David A , Welch Catherine A , Nolan Kathleen M , Friedmann Peter S
Published: January 2008

Introduction

Dermatology is usually thought of as an outpatient specialty with low mortality, however some skin conditions require intensive care. These conditions are relatively rare and hence are best studied using clinical databases or disease registries. We interrogated a large, high-quality clinical database from a national audit of adult intensive care units (ICUs), with the aim of identifying and characterising patients with dermatological conditions requiring admission to ICU.

Methods

Data were extracted for 476,224 admissions to 178 ICUs in England, Wales and Northern Ireland participating in the Case Mix Programme over the time period December 1995 to September 2006. We identified admissions with dermatological conditions from the primary and secondary reasons for admission to ICU.

Results

A total of 2,245 dermatological admissions were identified. Conditions included infectious conditions (e.g. cutaneous cellulitis, necrotising fasciitis), dermatological malignancies, and acute skin failure (e.g. toxic epidermal necrolysis, Stevens–Johnson syndrome and autoimmune blistering diseases). These represent 0.47% of all ICU admissions, or approximately 2.1 dermatological admissions per ICU per year. Overall mortality was 28.1% in the ICU and 40.0% in hospital. Length of stay in intensive care was longest for those with acute skin failure (median 4.7 days for ICU survivors and 5.1 days for ICU non-survivors).

Conclusion

We have identified patients who not only require intensive care, but also dermatological care. Such patients have high mortality rates and long ICU stays within the spectrum of the UK ICU population, similar to other acute medical conditions. This highlights the importance of skin failure as a distinct entity comparable to other organ system failures.
Biochemical and Structural Characterization of Apolipoprotein A-I Binding Protein, a Novel Phosphoprotein with a Potential Role in Sperm Capacitation
Authors: Jha Kula N. , Shumilin Igor A. , Digilio Laura C. , Chertihin Olga , Zheng Heping , Schmitz Gerd , Visconti Pablo E. , Flickinger Charles J. , Minor Wladek , Herr John C.
Published: January 2008

The physiological changes that sperm undergo in the female reproductive tract rendering them fertilization-competent constitute the phenomenon of capacitation. Cholesterol efflux from the sperm surface and protein kinase A (PKA)-dependent phosphorylation play major regulatory roles in capacitation, but the link between these two phenomena is unknown. We report that apolipoprotein A-I binding protein (AI-BP) is phosphorylated downstream to PKA activation, localizes to both sperm head and tail domains, and is released from the sperm into the media during in vitro capacitation. AI-BP interacts with apolipoprotein A-I, the component of high-density lipoprotein involved in cholesterol transport. The crystal structure demonstrates that the subunit of the AI-BP homodimer has a Rossmann-like fold. The protein surface has a large two compartment cavity lined with conserved residues. This cavity is likely to constitute an active site, suggesting that AI-BP functions as an enzyme. The presence of AI-BP in sperm, its phosphorylation by PKA, and its release during capacitation suggest that AI-BP plays an important role in capacitation possibly providing a link between protein phosphorylation and cholesterol efflux.
Rapid Changes in Anterior Pituitary Cell Phenotypes in Male and Female Mice after Acute Cold Stress
Authors: Senovilla Laura , Núñez Lucía , Villalobos Carlos , García-Sancho Javier
Published: January 2008

The anterior pituitary (AP) is made of five different cell types. The relative abundance and phenotype of AP cells may change in different physiological situations as an expression of pituitary plasticity. Here, we analyze in detail the phenotype of mouse corticotropes and the effects of acute cold stress on AP cell populations. The hormone content and the expression of hypothalamic-releasing hormone (HRH) receptors in all the five AP cell types were studied in the male and female mice at rest and after a 30-min cold stress. Expression of HRH receptors was evidenced by imaging the single-cell cytosolic Ca2+ responses in fura-2-loaded cells. Hormone contents were studied by multiple, simultaneous immunofluorescence of all the five hormones. Corticotropes displayed a striking sexual dimorphism, even in the resting condition. Male corticotropes showed the orthodox phenotype. They were monohormonal, storing only ACTH, and monoreceptorial, responding only to CRH. In contrast, female corticotropes were made of about equal parts of orthodox cells and multifunctional cells, which co-stored additional AP hormones and expressed additional HRH receptors. Cold stress did not modify the number of ACTH containing cells, but, according to immunostaining, it increased the relative abundance of other AP cell types at the expense of the pool of cells storing no hormones. Cold stress also modified the response to CRH and other HRHs. Most of these phenotypical changes presented a strong sexual dimorphism. These results indicate that pituitary plasticity is even larger than previously thought.