bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cyclical Representation of the UK Conference Sector's Life Cycle: The Use of Refurbishments as Rejuvenation Triggers
Authors: Whitfield Julie
Published: February 2010

Butler's tourism area life cycle (TALC) model is one of the most influential and frequently quoted tourism-related life cycle frameworks. Extensively applied and critiqued, it remains a cornerstone in tourism research. The model classifies the hypothetical temporal development of a
destination into a series of stages, these being exploration, involvement, development, consolidation, stagnation and decline, and/or rejuvenation, which when aggregated are represented diagrammatically as a S-shaped curve. This article presents a theoretical extension of the TALC model, based
on the decade in which UK conference venues initiated their conference product life cycle, and the use of refurbishments as state changing triggers to rejuvenate the conference product life cycle. This theoretical extension is applied to the four conference venue classifications that together
constitute the UK conference sector, namely purpose-built venues, hotels, educational establishments, and visitor attractions. Each of these venue types initiated its life cycle at different times, with individual venues progressing through their life cycle and either stagnating or rejuvenating
through the use of refurbishments at differing times throughout the last five decades. Based on these findings, a linear model can be applied to the development of the UK conference sector. However, undertaking refurbishments, and thus the rejuvenation of the conference venues' life cycle,
are occurring at differing times, and therefore this article forwards the view that today a cyclical model is more appropriate to the UK conference sector.
New microsatellite loci for Narcissus papyraceus (Amarillydaceae) and cross‐amplification in other congeneric species
Authors: Simón Violeta I. , Picó F. Xavier , Arroyo Juan
Published: February 2010

• Premise of the study: Microsatellite loci from a genomic library of the species Narcissus papyraceus were optimized and characterized for studies of population genetics.

• Methods and Results: Eleven markers that were successfully amplified showed polymorphism when tested on 50 individuals from two populations in southern Spain and northern Morocco. Overall, the number of alleles per locus ranged between 4 and 15. Between 8 and 11 loci successfully amplified in other eight Narcissus species.

• Conclusions: These markers will enable genetic diversity studies of N. papyraceus across its distribution range and conduct paternity analyses among individuals differing in flower morphology.
Creating a Paperless Documentation System for Nursing Continuing Education Activities
Authors: Garvey Paula
Published: February 2010

This article describes the process used to convert the required communication, documentation, and peer review process required by the Ohio State Board of Nursing, as well as program evaluation documents, to a completely online “live document” system. Creation of the documentation and review system was accomplished with custom Microsoft Word templates created with Visual Basic for Applications. All templates were created according to nursing continuing education specifications by a constituent member association-approved provider unit within the American Nurses Credentialing Center Accreditation system. Examples of the templates, program review process, and documentation system are included.

J Contin Educ Nurs
2010;41(2):77–82.
Open Access Is Almost Here: Navigating Through Copyright, Fair Use, and the TEACH Act
Authors: Lyons Margaret G.
Published: February 2010

Dealing with the complexities of copyright, fair use, the TEACH Act, and the concept of open access can confuse even the most experienced educator. Online education has added to the dilemma. This article discusses the latest information on copyright issues, current guidelines for interpreting fair use and incorporating the TEACH Act, and recent developments in open access publishing.

J Contin Educ Nurs
2010;41(2):57–64.
Planning Committees: Value for Continuing Nursing Education
Authors: Dickerson Pamela S.
Published: February 2010

Accreditation criteria require the use of planning committees for continuing nursing education activities. More than just meeting a requirement, though, these committees can be valuable tools in guiding development of helpful, effective continuing nursing education learning activities.

J Contin Educ Nurs
2010;41(2):52–53.
Psychotic Depression or Schizophrenia
Authors: Swartz Conrad M.
Published: February 2010

CME Educational Objectives

1.

Discuss differences in diagnosing psychotic depression and schizophrenia.

2.

Review the variety of clinical manifestations of psychotic depression and the basic meaning of the diagnosis of schizophrenia.

3.

Summarize the psychological and psychiatric adverse effects of anti-psychotic drugs.
Schizophrenia and Schizoaffective Are Psychotic Mood Disorders
Authors: Aires Daniel J. , Hurwitz Nathaniel G.
Published: February 2010

CME Educational Objectives

1.

Review the historical reasons for splitting functional psychotic illness into “schizophrenia,” and “schizoaffective disorder,” and “psychotic mood disorder.”

2.

Describe the modern data that link “schizophrenia,” and “schizoaffective disorder,” and “psychotic mood disorder” into a single illness with a spectrum of severity.

3.

Cite the potential to harm patients by splitting functional psychotic illness into “schizophrenia,” and “schizoaffective disorder,” and “psychotic mood disorder.”
Pediatric Education in Office Settings
Authors: Nagappan Suresh , Doyne Emanuel O. , Roberts Kenneth , DeWitt Thomas G.
Published: February 2010

CME EDUCATIONAL OBJECTIVES

1.

Review the key aspects of office-based pediatric training at the medical student and resident levels.

2.

Define logistic issues encountered in office-based training of medical students and pediatric residents.

3.

Discuss the unique challenges posed by training medical students and house staff in the office setting.
Outcomes of Corneal Spherical Aberration-Guided Cataract Surgery Measured by the OPD-Scan
Authors: Solomon Jonathan D.
Published: February 2010

Purpose:

To determine based on preoperative corneal spherical aberration, the practicality of targeting zero total ocular postoperative spherical aberration when selecting an aspheric intraocular lens (IOL).

Methods:

Consecutive cataract patients were selected to receive an aspheric IOL based on corneal spherical aberration. A target of zero postoperative total spherical aberration Z(4,0) was calculated. One of three IOLs was chosen, based on the corneal spherical aberration Z(4,0) measurement at the 6-mm optical zone. The IOL was selected based on the summation of the corneal spherical aberration and the aspheric value of the prolate optic. The intention was an absolute value of zero total spherical aberration. Statistical analysis of the postoperative total ocular wavefront profile was performed to assess the accuracy of aspheric IOL selection.

Results:

Forty eyes of 40 patients were available for postoperative assessment. The Tecnis Z9003 (Abbott Medical Optics) was implanted in 25 eyes with a preoperative corneal spherical aberration of +0.311±0.054 μm, the AcrySof IQ (Alcon Laboratories Inc) in 13 eyes (+0.188±0.034 μm), and the SofPort-Advanced Optic with Violet Shield (Bausch & Lomb) was implanted in 2 eyes (+0.0915 μm). Total postoperative ocular spherical aberration for the entire group measured +0.019±0.051 μm (Tecnis: +0.024±0.058 μm; AcrySof IQ: +0.010±0.035 μm; and SofPort AOV: +0.037 μm). Mean absolute predictive error, for the entire group, measured +0.025±0.020 μm.

Conclusions:

Skiascopy-derived total wavefront measurement of spherical aberration is a reproducible method of aspheric IOL selection and permits more precise control of total ocular spherical aberration.
Pentacam Characterization of Corneas with Fuchs Dystrophy Treated with Descemet Membrane Endothelial Keratoplasty
Authors: Kwon Robert O. , Price Marianne O. , Price Francis W. , Ambrósio Renato , Belin Michael W.
Published: February 2010

Purpose:

To characterize central corneal thickness, curvature, and posterior surface elevation in eyes with Fuchs dystrophy that underwent Descemet membrane endothelial keratoplasty (DMEK) for endothelial decompensation and to compare these characteristics with those in normal eyes.

Methods:

Pre- and postoperative corneal tomography was prospectively evaluated using Pentacam (Oculus Optikgeräte GmbH) imaging on 29 eyes with Fuchs dystrophy treated with DMEK. Results were compared with data from a separate cohort of 198 normal eyes.

Results:

In the Fuchs cohort, the mean preoperative central corneal thickness was 656
μ
m (range: 574 to 731
μ
m). This significantly exceeded the mean thickness of 542
μ
m in the normal cohort (range: 439 to 611
μ
m,
P
<.0001) although the cohort thickness ranges overlapped. One month after DMEK, mean central corneal thickness decreased significantly to 539
μ
m (range: 465 to 669
μ
m,
P
<.0001) with no further significant decrease between 1 and 3 months after DMEK (mean difference = −4
μ
m,
P
=.39). In the Fuchs cohort, keratometry (average Sim K and delta K) did not change significantly after DMEK (
P
=.41 and
P
=.44, respectively); pre- and postoperative values were comparable to those in the normal cohort. The mean forward displacement of the posterior surface increased by 69
μ
m 1 month after DMEK (
P
<.0001) without further significant change between 1 and 3 months.

Conclusions:

After DMEK, central corneal thickness in the Fuchs dystrophy cohort decreased significantly and the posterior corneal surface displaced forward, without significant change in anterior keratometric values or keratometric astigmatism. The preoperative central corneal thickness range in eyes with confluent central guttata overlapped the range in normal corneas.
Transepithelial Corneal Collagen Cross-Linking in Keratoconus
Authors: Leccisotti Antonio , Islam Tahmina
Published: February 2010

Purpose:

To evaluate the clinical effects of transepithelial corneal cross-linking (CXL) on keratoconic eyes pre-treated with substances enhancing epithelial permeability.

Methods:

Prospective, consecutive, single-masked, paired-eye study on 51 patients. The eye with more severe keratoconus was treated; the fellow eye served as the control. Gentamicin, benzalkonium chloride, and ethylenediaminetetraacetic acid were instilled for 3 hours, then oxybuprocaine for 30 minutes. Riboflavin 0.1% in 20% dextran T500 and oxybuprocaine were instilled for 30 minutes. Finally, ultraviolet A irradiation to the central 7.5 mm of the cornea was applied for 30 minutes, while riboflavin was instilled every 5 minutes.

Results:

Mean corrected distance visual acuity improved by 0.036 logMAR after CXL and worsened by 0.039 logMAR in the control eyes (
P
<.05). Safety index was 1.05 after CXL and 0.96 in the control group. Mean spherical equivalent refraction decreased by 0.35 D (less myopic) after CXL and increased by 0.83 diopters (D) in the control eyes (
P
<.05). Mean apex curvature on tangential videokeratography increased by 0.51 D after CXL and by 1.61 D in the control eyes (
P
=.16). Mean average simulated keratometry decreased by 0.10 D after CXL and increased by 0.88 D in the control eyes (
P
<.05). Mean index of surface variance increased (worsened) by 0.9 after CXL and 5.3 in the control eyes (
P
<.05). Mean endothelial cell density was unchanged.

Conclusions:

A limited but favorable effect of transepithelial CXL was noted on keratoconic eyes, without complications. The effect appears to be less pronounced than described in the literature after CXL with de-epithelialization.
Conductive Keratoplasty to Treat Hyperopic Overcorrection After LASIK for Myopia
Authors: Chang John S.M. , Lau Silvania Y.F.
Published: February 2010

Purpose:

To investigate the refractive outcomes and stability of conductive keratoplasty (CK) for retreatment of myopic LASIK overcorrection.

Methods:

Seven eyes (six patients) that were overcorrected after myopic LASIK by +1.00 to +2.75 diopters (D) manifest refraction spherical equivalent (MRSE) were retreated using CK. All eyes had insufficient stromal thickness for LASIK retreatment. LightTouch CK was performed at least 1 year after LASIK. Either 8 or 16 spots were applied at 7- and/or 8-mm zones on the cornea. Uncorrected distance visual acuity, manifest refraction, corrected distance visual acuity (CDVA), and postoperative complications were analyzed.

Results:

Mean MRSE after CK at last follow-up was +0.38±0.52 D (range: −0.38 to +1.13 D). The change in MRSE ranged from −0.63 to −2.38 D. Mean MRSE after CK changed from −0.60±2.07 D (range: −3.38 to +1.50 D) at 1 week to +0.45±0.69 D (range: −0.38 to +1.38 D) at 12 months. Two eyes experienced an initial overcorrection of −2.75 D and −3.38 D, respectively, at 1 week after CK. Cylinder ≤0.75 D was induced in four eyes, whereas one eye had a 0.75-D reduction in cylinder. All eyes had CDVA of logMAR 0.10 or better. Two eyes lost one line of CDVA and no eyes lost more than one line.

Conclusions:

LightTouch CK retreatment for over-corrected myopic LASIK can reduce the hyperopia but produces minimal change in cylinder, and may be appropriate for eyes with insufficient stromal tissue for repeated excimer laser surgery. Early regression occurs commonly.
Implantation of a Complete Corneal Ring in an Intrastromal Pocket for Keratoconus
Authors: Mahmood Haifa , Venkateswaran R.S. , Daxer Albert
Published: February 2010

Purpose:

To evaluate the refractive and visual results of a new treatment for keratoconus using the corneal intrastromal implantation system (CISIS).

Methods:

Six eyes of four patients with keratoconus were treated with CISIS. Follow-up was 1, 3, and 6 months. After creating an intracorneal pocket of 9-mm diameter and 300-μm depth, a flexible full-ring implant was inserted via a 4-mm-wide corneal tunnel.

Results:

No eyes showed loss of lines in uncorrected distance visual acuity (UDVA) or spectacle corrected distance visual acuity (CDVA) at any follow-up examination. Uncorrected and distance corrected visual acuity, keratometry, spherical and cylindrical refractive error as well as spherical equivalent refraction improved significantly (
P
<.05). Mean UDVA improved from 20/260 to 20/48 and mean CDVA improved from 20/41 to 20/27. A significant centralization and decrease of the corneal apex was found. No intra- or postoperative complications were observed.

Conclusions:

The corneal intrastromal implantation system using a complete ring implanted in a stromal pocket can achieve significant improvements in the visual function of patients with keratoconus. Uncorrected distance visual acuity improved by more than seven lines on average and CDVA improved by two lines.
Decision Assistant Wizard to Standardize Optimal Outcomes in Excimer Laser Refractive Corneal Surgery
Authors: Arbelaez Maria Clara , Ewering Tobias , Arba Mosquera Samuel
Published: February 2010

Purpose:

To assess a decision tree analysis system to further optimize refractive surgery outcomes.

Methods:

A 5-step decision tree, the Decision Assistant Wizard, based on previous experience with the SCHWIND AMARIS laser, was applied for selecting a customized refractive surgery treatment mode (aspheric aberration neutral, corneal wavefront-guided, or ocular wavefront-guided) to eliminate or reduce total aberration.

Results:

Using the Decision Assistant Wizard, 6467 LASIK treatments were performed over a 30-month period; 5262 and 112 for myopic and hyperopic astigmatism, respectively, using aspheric aberration neutral (AF) profiles, 560 using corneal wavefront-guided profiles, and 533 using ocular wavefront-guided profiles. Twenty-two (0.3%) retreatments were performed overall; 18 (0.3%) and 0 (0%) after myopic and hyperopic astigmatism, respectively, using AF, 3 (0.5%) after corneal wavefront-guided profiles, and 1 (0.2%) after ocular wavefront-guided profiles.

Conclusions:

Decision assistant wizards may further optimize refractive surgical outcomes by providing the most appropriate ablation pattern based on an eye’s anamnesis, diagnosis, and visual demands. The general principles may be applied to other laser systems; however, specifics will depend on manufacturers’ specifications.
Post-Endoplasmic Reticulum Rescue of Unstable MHC Class I Requires Proprotein Convertase PC7
Authors: Leonhardt Ralf M. , Fiegl Dorothee , Rufer Elke , Karger Axel , Bettin Barbara , Knittler Michael R.
Published: February 2010

The function of the peptide-loading complex (PLC) is to facilitate loading of MHC class I (MHC I) molecules with antigenic peptides in the endoplasmic reticulum and to drive the selection of these ligands toward a set of high-affinity binders. When the PLC fails to perform properly, as frequently observed in virus-infected or tumor cells, structurally unstable MHC I peptide complexes are generated, which are prone to disintegrate instead of presenting Ags to cytotoxic T cells. In this study we show that a second quality control checkpoint dependent on the serine protease proprotein convertase 7 (PC7) can rescue unstable MHC I, whereas the related convertase furin is completely dispensable. Cells with a malfunctioning PLC and silenced for PC7 have substantially reduced MHC I surface levels caused by high instability and significantly delayed surface accumulation of these molecules. Instead of acquiring stability along the secretory route, MHC I appears to get largely routed to lysosomes for degradation in these cells. Moreover, mass spectrometry analysis provides evidence that lack of PLC quality control and/or loss of PC7 expression alters the MHC I-presented peptide profile. Finally, using exogenously applied peptide precursors, we show that liberation of MHC I epitopes may directly require PC7. We demonstrate for the first time an important function for PC7 in MHC I-mediated Ag presentation.
MyD88 Adaptor-Like D96N Is a Naturally Occurring Loss-of-Function Variant of TIRAP
Authors: George Julie , Kubarenko Andriy V. , Rautanen Anna , Mills Tara C. , Colak Elif , Kempf Tore , Hill Adrian V. S. , Nieters Alexandra , Weber Alexander N. R.
Published: February 2010

Signals elicited by TLRs following the detection of microbes are integrated and diversified by a group of four cytoplasmic adaptor molecules featuring an evolutionarily conserved Toll/IL-1R signaling domain. Single nucleotide polymorphisms (SNPs) in TLRs and their adaptor molecules have been shown to influence susceptibility to a range of infectious and other diseases. The adaptor MyD88 adaptor-like (Mal)/Toll/IL-1R–containing adaptor protein is involved in TLR2 and 4 signal transduction by recruiting another adaptor molecule, MyD88, to the plasma membrane. In this study, we used naturally occurring variants of Mal as tools to study the molecular biology of Mal in more detail in cellular model systems and to thereby identify functionally interesting variants whose corresponding nonsynonymous SNPs might be of further epidemiological interest. Of seven reported variants for Mal, we found Mal D96N associated with reduced NF-κB signaling and cytokine production after overexpression in HEK293 and Huh-7 cells. The D96N mutation prevented Mal from recruiting its signaling partner MyD88 to the plasma membrane and altered posttranslational modification of Mal. These findings led us to investigate the frequency of heterozygosity for the corresponding SNP rs8177400 in a Caucasian case-control study on the etiology of lymphoma, a disease in which TLRs have been implicated. Although rs8177400 did not modify lymphoma risk in general, its frequency of heterozygosity was accurately determined to 0.97%. Our data add rs8177400 (D96N) to the list of functionally important variants of Mal and warrant further research into its immunological, epidemiological, and diagnostic relevance.
CC Chemokine Ligand 3 Overcomes the Bacteriocidal and Phagocytic Defect of Macrophages and Hastens Recovery from Experimental Otitis Media in TNF−/− Mice
Authors: Leichtle Anke , Hernandez Michelle , Ebmeyer Joerg , Yamasaki Kenshi , Lai Yuping , Radek Katherine , Choung Yun-Hoon , Euteneuer Sara , Pak Kwang , Gallo Richard , Wasserman Stephen I. , Ryan Allen F.
Published: February 2010

Innate immune mechanisms are crucial in defense against bacterial illnesses in humans, as evidenced by abnormal antibacterial responses due to defects in TLR signaling, seen in children with MyD88 or IL-1R–associated kinase 4 deficiency. Otitis media (OM) is the most common disease of childhood, and the role of innate immune molecules in this disorder remains unclear. In a murine model of OM, we show that, in the absence of TNF, a key effector of innate immunity, this disease is prolonged after middle ear infection with nontypeable Haemophilus influenzae (NTHi). In the absence of TNF, mice fail to upregulate both TLRs and downstream genes and proteins, such as CCL3, resulting in defects in both inflammatory cell recruitment and macrophage function. Peritoneal macrophages of mice lacking TNF have a diminished ability to phagocytose and kill NTHi, and this defect is partially corrected in vitro by exogenous rTNF. Addition of rCCL3 alone or in combination with rTNF restores phagocytosis and killing by TNF-deficient macrophages to that of unstimulated wild-type macrophages. In vivo administration of rCCL3 to animals deficient in TNF fully restores the ability to control OM due to NTHi, whereas a CCL3-blocking Ab impaired the ability of wild-type mice to recover from OM. Thus, CCL3 is a potent downstream effector of TNF-mediated inflammation in vitro and in vivo. Manipulation of CCL3 and/or TNF may prove to be effective therapeutic approaches in OM or other conditions associated with defective TNF generation.
The Association of MHC Class I Proteins with the 2B4 Receptor Inhibits Self-Killing of Human NK Cells
Authors: Betser-Cohen Gili , Mizrahi Saar , Elboim Moran , Alsheich-Bartok Osnat , Mandelboim Ofer
Published: February 2010

The killing activity of NK cells is carried out by several activating NK receptors, which includes NKp46, NKp44, NKp30, NKp80, NKG2D, and 2B4. The ligands of these receptors are either self-derived, pathogen-derived, stress-induced ligands or tumor ligands. Importantly, none of these killer ligands are expressed on NK cells and thus self-killing of NK cells is prevented. A notable exception with this regard, is the ligand of the 2B4 receptor. This unusual receptor can exert both activating and inhibiting signals; however, in human NK cells, it serves mainly as an activating receptor. The ligand of 2B4 is CD48 and in contrast to the ligands of all the other NK activating receptors, CD48 is also present on NK cells. Thus, NK cells might be at risk for self-killing that is mediated via the 2B4-CD48 interaction. In this study, we identify a novel mechanism that prevents this self-killing as we show that the association of the MHC class I proteins with the 2B4 receptor, both present on NK cells, results in the attenuation of the 2B4-mediated self-killing of NK cells.
The Anti-Inflammatory Actions of Platelet Endothelial Cell Adhesion Molecule-1 Do Not Involve Regulation of Endothelial Cell NF-κB
Authors: Privratsky Jamie R. , Tourdot Benjamin E. , Newman Debra K. , Newman Peter J.
Published: February 2010

PECAM-1 is a cell adhesion and signaling receptor that is expressed on many hematopoietic cells and at endothelial cell–cell junctions. Accumulating evidence from a number of in vitro and in vivo model systems suggests that PECAM-1 suppresses cytokine production and vascular permeability induced by a wide range of inflammatory stimuli. In several of these models of inflammatory disease, endothelial, and not leukocyte or platelet, PECAM-1 conferred protection against inflammatory insult. However, the mechanism by which endothelial PECAM-1 functions as an anti-inflammatory protein is poorly understood. It was recently suggested that PECAM-1 exerts its anti-inflammatory effects in endothelial cells by inhibiting the activity of NF-κB, a proinflammatory transcription factor. To confirm and extend these observations, we examined the effect of engaging, cross-linking, or expressing PECAM-1 on NF-κB activation in a variety of human cells. PECAM-1 had no effect on the phosphorylation of the NF-κB inhibitory protein, IκBα; on the nuclear translocation of NF-κB; on the suppression of cytokine-induced transcriptional activation of an NF-κB luciferase reporter plasmid; or on the cytokine-stimulated upregulation of ICAM-1, an NF-κB target gene, in endothelial cells. Taken together, these studies strongly suggest that the anti-inflammatory actions of PECAM-1 in endothelial cells are not likely to involve its regulation of NF-κB.
A Distinct Subset of Proinflammatory Neutrophils Isolated from Patients with Systemic Lupus Erythematosus Induces Vascular Damage and Synthesizes Type I IFNs
Authors: Denny Michael F. , Yalavarthi Srilakshmi , Zhao Wenpu , Thacker Seth G. , Anderson Marc , Sandy Ashley R. , McCune W. Joseph , Kaplan Mariana J.
Published: February 2010

Neutrophil-specific genes are abundant in PBMC microarrays from lupus patients because of the presence of low-density granulocytes (LDGs) in mononuclear cell fractions. The functionality and pathogenicity of these LDGs have not been characterized. We developed a technique to purify LDGs from lupus PBMCs and assessed their phenotype, function, and potential role in disease pathogenesis. LDGs, their autologous lupus neutrophils, and healthy control neutrophils were compared with regard to their microbicidal and phagocytic capacities, generation of reactive oxygen species, activation status, inflammatory cytokine profile, and type I IFN expression and signatures. The capacity of LDGs to kill endothelial cells and their antiangiogenic potential were also assessed. LDGs display an activated phenotype, secrete increased levels of type I IFNs, TNF-α, and IFN-γ, but show impaired phagocytic potential. LDGs induce significant endothelial cell cytotoxicity and synthesize sufficient levels of type I IFNs to disrupt the capacity of endothelial progenitor cells to differentiate into mature endothelial cells. LDG depletion restores the functional capacity of endothelial progenitor cells. We conclude that lupus LDGs are proinflammatory and display pathogenic features, including the capacity to synthesize type I IFNs. They may play an important dual role in premature cardiovascular disease development in systemic lupus erythematosus by simultaneously mediating enhanced vascular damage and inhibiting vascular repair.
IFN-γ Receptor Signaling Regulates Memory CD8+ T Cell Differentiation
Authors: Sercan Özen , Stoycheva Diana , Hämmerling Günter J. , Arnold Bernd , Schüler Thomas
Published: February 2010

IFN-γ regulates multiple processes in the immune system. Although its antimicrobial effector functions are well described, less is known about the mechanisms by which IFN-γ regulates CD8+ T cell homeostasis. With the help of adoptive T cell transfers, we show in this study that IFN-γR signaling in CD8+ T cells is dispensable for expansion, contraction, and memory differentiation in response to peptide vaccination. In contrast, host IFN-γR signaling counterregulates CD8+ T cell responses and the generation of effector memory T cell processes, which are partially regulated by CD11b+ cells. Similar to vaccination-induced proliferation, host IFN-γR signaling limits the expansion of naive CD8+ T cells and their differentiation into effector memory-like T cells in lymphopenic mice. In contrast to peptide vaccination, IFN-γR signaling in CD8+ T cells contributes to memory fate decision in response to lymphopenia, an effect that is fully reversed by high-affinity TCR ligands. In conclusion, we show that host IFN-γR signaling controls the magnitude of CD8+ T cell responses and subsequent memory differentiation under lymphopenic and nonlymphopenic conditions. In contrast, IFN-γR signaling in CD8+ T cells does not affect cell numbers under either condition, but it directs memory fate decision in response to weak TCR ligands.
Matricellular Protein CCN1 Activates a Proinflammatory Genetic Program in Murine Macrophages
Authors: Bai Tao , Chen Chih-Chiun , Lau Lester F.
Published: February 2010

CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-α to be cytotoxic without blocking NF-κB activity and enhancing the apoptotic activity of Fas ligand and TRAIL. In this paper, we show that CCN1 supports the adhesion of macrophages through integrin αMβ2 and syndecan-4, activates NFκB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-α, IL-1α, IL-1β, IL-6, and IL-12b), chemokines (MIP-1α; MCP-3; growth-related oncogenes 1 and 2; and inflammatory protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rβ) and anti-inflammatory factors (TGF-β1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-κB by CCN1, leading to the synthesis of cytokines including TNF-α and inflammatory protein 10; and a delayed response resulting from CCN1-induced TNF-α, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1β and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.
Immunological Property of Antibodies against N-Glycolylneuraminic Acid Epitopes in Cytidine Monophospho–N-Acetylneuraminic Acid Hydroxylase-Deficient Mice
Authors: Tahara Hiroyuki , Ide Kentaro , Basnet Nabin Bahadur , Tanaka Yuka , Matsuda Haruo , Takematsu Hiromu , Kozutsumi Yasunori , Ohdan Hideki
Published: February 2010

The generation of pigs devoid of Galα1,3Galβ1,4GlcNAc (Gal) residues has stimulated interest in non-Gal Ags as potentially important targets for Ab binding leading to rejection of pig organ xenografts in humans. Although N-glycolylneuraminic acid (NeuGc) epitopes, which are widely expressed on the endothelial cells of all mammals except humans, are likely targets of anti–non-Gal Abs, this aspect has not been investigated intensively owing to the absence of an appropriate animal model. In this study, we used CMAH−/− mice, which are completely deficient in NeuGc and thus produce anti-NeuGc Abs. Sera obtained from CMAH−/− mice and healthy human volunteers having anti-NeuGc Abs initiated complement-mediated lysis against CMAH+/+ cells in vitro. The cytotoxic activity of anti-NeuGc Abs was also determined in vivo (i.e., NeuGc-expressing CMAH+/+ mouse splenocytes that had been i.v. injected were completely eliminated in syngeneic CMAH−/− mice). CMAH−/− mice rejected the islets transplanted from syngeneic CMAH+/+ mice. Thus, the anti-NeuGc Ab-mediated response may be crucially involved in xenograft loss. This is the first direct demonstration of the immunogenic property of NeuGc determinants as targets of the corresponding Abs in CMAH+/+-to-CMAH−/− transplantation setting.
Substrain Differences Reveal Novel Disease-Modifying Gene Candidates That Alter the Clinical Course of a Rodent Model of Multiple Sclerosis
Authors: deLuca Leslie E. Summers , Pikor Natalia B. , O’Leary Jennifer , Galicia-Rosas Georgina , Ward Lesley A. , Defreitas Dustin , Finlay Trisha M. , Ousman Shalina S. , Osborne Lucy R. , Gommerman Jennifer L.
Published: February 2010

Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis that is executed in animals by immunization with myelin Ag in adjuvant. The SJL/J autoimmune-prone strain of mouse has been used to model relapsing–remitting multiple sclerosis. However, significant variations in peak scores, timing of onset, and incidence are observed among laboratories, with the postacute (relapse) phase of the disease exhibiting significant inconsistency. We characterized two substrains of SJL/J mice that exhibit profoundly different EAE disease parameters. Induction of EAE in the first SJL/J substrain resulted in many cases of chronic EAE that was dominated by an aggressive B cell response to the immunizing Ag and to endogenous CNS Ags. In contrast, the other SJL/J substrain exhibited a relapsing–remitting form of EAE concomitant with an elevated number of cytokine-producing CD4+ T cells in the CNS. Exploiting these interstrain differences, we performed a genome-wide copy number analysis on the two disparate SJL/J substrains and discovered numerous gene-dosage differences. In particular, one inflammation-associated gene, Naip1, was present at a higher copy number in the SJL/J substrain that exhibited relapsing–remitting EAE. These results demonstrate that substrain differences, perhaps at the level of genomic copy number, can account for variability in the postacute phase of EAE and may drive chronic versus relapsing disease.
Intense Antiextracellular Adaptive Immune Response to Human Cytomegalovirus in Very Old Subjects with Impaired Health and Cognitive and Functional Status
Authors: Vescovini Rosanna , Biasini Claudia , Telera Anna Rita , Basaglia Manuela , Stella Adriano , Magalini Francesca , Bucci Laura , Monti Daniela , Lazzarotto Tiziana , Dal Monte Paola , Pedrazzoni Mario , Medici Maria Cristina , Chezzi Carlo , Franceschi Claudio , Fagnoni Francesco F. , Sansoni Paolo
Published: February 2010

Human aging is characterized by expanded and altered adaptive immune responses to human CMV (HCMV). It is unclear whether this expansion has its origins in age-related homeostatic disturbances or viral reactivation, whether anti-CMV immune surveillance may still be effective, and what are the consequences of this expanded immune response for health and longevity. We conducted an observational cross-sectional study in groups of HCMV-seropositive subjects aged ≥65 y of variable health status to compare the intensity of Ab responses against HCMV with those against EBV and with CD4+ and CD8+ T cell proinflammatory effector responses directed to HCMV-derived pp65 and immediate-early protein 1 synthetic peptides. Ab responses to HCMV, but not to EBV, and anti-HCMV CD4+, but not CD8+, T cell responses were more intense in elderly subjects aged ≥85 y in poor health and were inversely correlated with markers of functional activity and cognitive function. Therefore, humoral and CD4+ T cell anti-HCMV responses were specifically intensified in advanced aging associated with comorbidity and cognitive and functional impairments. Such a distinctive pattern of adaptive immunity indicates that immune responses targeting the extracellular phase of HCMV are increased in these elderly subjects and could represent an indirect effect of localized and undetectable HCMV reactivation. This study demonstrates that the oldest subjects in poor health with physical and mental impairment express intense functional immune responses to extracellular HCMV and suggests that they may be at risk for direct pathogenic effects by HCMV reactivation as well as indirect pathogenic effects linked to proinflammatory anti-HCMV effector responses.
Cutting Edge: Polyinosinic:Polycytidylic Acid Boosts the Generation of Memory CD8 T Cells through Melanoma Differentiation-Associated Protein 5 Expressed in Stromal Cells
Authors: Wang Yaming , Cella Marina , Gilfillan Susan , Colonna Marco
Published: February 2010

Polyinosinic:polycytidylic acid (poly I:C), a synthetic analog of double-stranded viral RNA, serves as a potent adjuvant for vaccination against soluble proteins, pathogens, and tumors. Poly I:C is sensed by both TLR3 in the endosomes and melanoma differentiation-associated protein 5 (MDA5) in the cytoplasm. Although it is known that TLR3 is required for cross-priming of CD8 T cells specific for viral Ags, the role of MDA5 in inducing CD8 T cell responses is still unclear. In this study, we demonstrate that in mice lacking MDA5, the majority of CD8 T cells do not survive after primary immunization with poly I:C and Ag, impairing memory response to subsequent Ag challenge. Furthermore, bone marrow chimera experiments revealed that MDA5 expression in radiation-resistant stromal cells, but not in radiation-sensitive hematopoietic cells, is essential for establishing CD8 T cell memory. We conclude that MDA5 and TLR3 mediate substantially distinct yet complementary functions during poly I:C-mediated activation of Ag-specific CD8 T cell responses.
The Major Locus for Mouse Adenovirus Susceptibility Maps to Genes of the Hematopoietic Cell Surface-Expressed LY6 Family
Authors: Spindler Katherine R. , Welton Amanda R. , Lim Efrem S. , Duvvuru Suman , Althaus Irene W. , Imperiale Jennifer E. , Daoud Adam I. , Chesler Elissa J.
Published: February 2010

Susceptibility to mouse adenovirus type 1 is associated with the major quantitative trait locus Msq1. Msq1 was originally mapped to a 13-Mb region of mouse chromosome (Chr) 15 in crosses between SJL/J and BALB/cJ inbred mice. We have now narrowed Msq1 to a 0.75-Mb interval from 74.68 to 75.43 Mb, defined by two anonymous markers, rs8259436 and D15Spn14, using data from 1396 backcross mice. The critical interval includes 14 Ly6 or Ly6-related genes, including Ly6a (encoding Sca-1/TAP), Ly6e (Sca-2/Tsa1), Ly6g (Gr-1), and gpihbp1 (GPI-anchored high-density lipoprotein–binding protein 1), as well as the gene encoding an aldosterone synthase (Cyp11b2). The Ly6 family members are attractive candidates for virus susceptibility genes because their products are GPI-anchored membrane proteins expressed on lymphoid and myeloid cells, with proposed functions in cell adhesion and cell signaling. To determine interstrain variation in susceptibility and produce additional resources for cloning Msq1, we assayed the susceptibility phenotype of four previously untested inbred mouse strains. Susceptibility of strain 129S6/SvEvTac was subsequently localized to the Ly6 complex region, using polymorphic genetic markers on Chr 15 in a population of 271 (129S6/SvEvTac × BALB/cJ)F1 × BALB/cJ backcross mice. We identified a major 129S6/SvEvTac susceptibility allele, Msq1129S6, on Chr 15 in the same region as Msq1SJL. The results indicate that a major host factor in mouse adenovirus type 1 susceptibility is likely to be a member of the Ly6 gene family.
Antiviral Response Dictated by Choreographed Cascade of Transcription Factors
Authors: Zaslavsky Elena , Hershberg Uri , Seto Jeremy , Pham Alissa M. , Marquez Susanna , Duke Jamie L. , Wetmur James G. , tenOever Benjamin R. , Sealfon Stuart C. , Kleinstein Steven H.
Published: February 2010

The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response. To isolate and identify this network, we studied DCs infected with Newcastle disease virus, which is able to stimulate innate immunity and DC maturation through activation of RIG-I signaling, but lacks the ability to evade the human IFN response. To analyze this experimental model, we developed a new approach integrating genome-wide expression kinetics and time-dependent promoter analysis. We found that the genetic program underlying the antiviral cell-state transition during the first 18 h postinfection could be explained by a single convergent regulatory network. Gene expression changes were driven by a stepwise multifactor cascading control mechanism, where the specific transcription factors controlling expression changed over time. Within this network, most individual genes were regulated by multiple factors, indicating robustness against virus-encoded immune evasion genes. In addition to effectively recapitulating current biological knowledge, we predicted, and validated experimentally, antiviral roles for several novel transcription factors. More generally, our results show how a genetic program can be temporally controlled through a single regulatory network to achieve the large-scale genetic reprogramming characteristic of cell-state transitions.
Transfusion of Nonobese Diabetic Mice with Allogeneic Newborn Blood Ameliorates Autoimmune Diabetes and Modifies the Expression of Selected Immune Response Genes
Authors: Jayaraman Sundararajan , Patel Tejas , Patel Vasu , Ajani Shahnaz , Garza Rebecca , Jayaraman Arathi , Kwon Sung , Singh Rajvir , Rondelli Damiano , Prabhakar Bellur S. , Holterman Mark
Published: February 2010

Although allogeneic bone marrow transplantation has been shown to prevent autoimmune diabetes in heavily irradiated nonobese diabetic (NOD) mice, a similar procedure is not suitable for the treatment of patients with type 1 diabetes because of associated severe side effects. Therefore, we evaluated whether mouse newborn blood (NBB), equivalent to human umbilical cord blood, could be used for diabetes prevention without recipient preconditioning. To test this hypothesis, unconditioned, prediabetic female NOD mice were given a single injection of whole NBB derived from the allogeneic diabetes-resistant mouse strain C57BL/6. Transfusion of allogeneic NBB but not adult blood prevented diabetes incidence in a majority of treated mice for a prolonged period of time. This was accompanied by the release of insulin in response to a challenge with glucose. Invasive cellular infiltration of islets was also substantially reduced in these mice. Although NBB transfusion induced a low level of hematopoietic microchimerism, it did not strictly correlate with amelioration of diabetes. Induction of genes implicated in diabetes, such as Il18, Tnfa, and Inos but not Il4, Il17 or Ifng, was repressed in splenocytes derived from protected mice. Notably, expression of the transcription factor Tbet/Tbx21 but not Gata3 or Rorgt was upregulated in protected mice. These data indicate that allogeneic NBB transfusion can prevent diabetes in NOD mice associated with modulation of selected cytokine genes implicated in diabetes manifestation. The data presented in this study provide the proof of principle for the utility of allogeneic umbilical cord blood transfusion to treat patients with autoimmune diabetes.
Cutting Edge: Mincle Is Essential for Recognition and Adjuvanticity of the Mycobacterial Cord Factor and its Synthetic Analog Trehalose-Dibehenate
Authors: Schoenen Hanne , Bodendorfer Barbara , Hitchens Kelly , Manzanero Silvia , Werninghaus Kerstin , Nimmerjahn Falk , Agger Else Marie , Stenger Steffen , Andersen Peter , Ruland Jürgen , Brown Gordon D. , Wells Christine , Lang Roland
Published: February 2010

The mycobacterial cord factor trehalose-6,6-dimycolate (TDM) and its synthetic analog trehalose-6,6-dibehenate (TDB) are potent adjuvants for Th1/Th17 vaccination that activate Syk-Card9 signaling in APCs. In this study, we have further investigated the molecular mechanism of innate immune activation by TDM and TDB. The Syk-coupling adapter protein FcRγ was essential for macrophage activation and Th17 adjuvanticity. The FcRγ-associated C-type lectin receptor Mincle was expressed in macrophages and upregulated by TDM and TDB. Recombinant Mincle-Fc fusion protein specifically bound to the glycolipids. Genetic ablation of Mincle abolished TDM/TDB-induced macrophage activation and induction of T cell immune responses to a tuberculosis subunit vaccine. Macrophages lacking Mincle or FcRγ were impaired in the inflammatory response to Mycobacterium bovis bacillus Calmette-Guérin. These results establish that Mincle is a key receptor for the mycobacterial cord factor and controls the Th1/Th17 adjuvanticity of TDM and TDB.
Illness Behavior
Authors: Ensalada Leon , Kertay Les
Published: May 2024

Illness behavior refers to the ways in which given symptoms may be perceived, evaluated, and acted on by different persons and can be conscious or unconscious (the latter means unnoticeable and refers to mental processes and content that are significant in determining behavior but of which the person is unaware). Further, consciousness of actions (voluntariness) and consciousness of motives (intentionality) are not necessarily associated. Illness behavior can be learned and reinforced and is a potential confounder in the association between illness or injury and impairment or disability. Illness behavior is not an impairing condition according to the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), and a table in the article describes the characteristics of the symptom magnification syndrome and other related conditions. Three diagnoses—somatic symptom disorders, illness anxiety disorder, and conversion disorder—possibly are ratable using the AMA Guides. Unsupported and insupportable conclusions regarding symptom exaggeration represent substandard practice because of the importance of such conclusions to the disposition of patients who present for assessment of impairment or disability. Similarly, failure to note and account for illness behavior and symptom exaggeration also represent substandard practice because the goal in impairment ratings is to note and account for all evidence related to the impairment, including the extent of illness behaviors.
Social Determinants of Health and the Availability of Cancer Clinical Trials in the United States
Authors: Sekar Rishi Robert , Herrel Lindsey Allison , Stensland Kristian Donald
Published: May 2024

This cohort study investigates whether county-level social determinants of health are associated with cancer clinical trial availability in the United States.
Fatigue Behaviors and Dislocation Evolution of Copper and Aluminum Alloy
Authors: Zhang Mengxiao , Li Juan , Ding Zeming , Song Hongwu , Xu Yong , Zhang Shihong
Published: May 2024

Face‐centered cubic (FCC) metals are widely used in the field of structural materials due to their excellent mechanical properties, and their fatigue behaviors have always been a focus of attention. Herein, 1060 aluminum alloys with different processing states and copper are selected to study the high cycle fatigue performance at room temperature and high temperature. The fracture morphology and dislocation evolution are characterized through characterization methods such as scanning electron microscope and transmission electron microscope. Based on the research, the main movement mode of dislocations (plane slip or wavy slip) are influenced by stacking fault energy (SFE), which further has a significant impact on fatigue performance. When the SFE of the FCC metal is higher, wavy slip dominates and the material is sensitive to temperature changes; on the contrary, during cyclic loadings, metal with lower SFE is dominated by plane slip, due to the reversibility of plane slip, the damage to the material with low SFE under fatigue loading is more uniform.