bluuebunny/crossref_metadata_2025 huggingface dataset:
On Thermally Interacting Multiple Boreholes with Variable Heating Strength: Comparison between Analytical and Numerical Approaches
Authors: Koohi-Fayegh Seama , Rosen Marc A.
Published: August 2012

The temperature response in the soil surrounding multiple boreholes is evaluated analytically and numerically. The assumption of constant heat flux along the borehole wall is examined by coupling the problem to the heat transfer problem inside the borehole and presenting a model with variable heat flux along the borehole length. In the analytical approach, a line source of heat with a finite length is used to model the conduction of heat in the soil surrounding the boreholes. In the numerical method, a finite volume method in a three dimensional meshed domain is used. In order to determine the heat flux boundary condition, the analytical quasi-three-dimensional solution to the heat transfer problem of the U-tube configuration inside the borehole is used. This solution takes into account the variation in heating strength along the borehole length due to the temperature variation of the fluid running in the U-tube. Thus, critical depths at which thermal interaction occurs can be determined. Finally, in order to examine the validity of the numerical method, a comparison is made with the results of line source method.
Macro Ck2 Accumulation in Tenofovir-Treated HIV Patients is Facilitated by Ck Oligomer Stabilization but is Not Predictive for Pathology
Authors: Schmid Holger , Tokarska-Schlattner Malgorzata , Füeßl Birgit , Röder Maximilian , Kay Laurence , Attia Stéphane , Lederer Stephan R , Goebel Frank D , Schlattner Uwe , Bogner Johannes R
Published: August 2012

Background

Ubiquitous mitochondrial creatine kinase (uMtCK) accumulates as macroenzyme creatine kinase type 2 (macro CK2) in the serum of HIV-infected patients under a tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimen. The genesis and clinical significance of this finding is unclear.

Methods

A prospective observational 5-year follow-up study was performed on those patients in which macro CK2 appearance was initially described (‘TDF switch study’ cohort). In addition, tenofovir (TFV), its prodrug TDF and its active, intracellular derivative TFV diphosphate (TDP) were tested in vitro for their effects on different key properties of uMtCK to clarify possible interactions of uMtCK with TFV compounds.

Results

In just under 5 years of continuous TDF treatment, only 4/12 (33%) patients remained macro CK2-positive, whereas 8/12 (66%) originally positive patients were macro CK2-negative at the end of follow-up. Prospective clinical follow-up data indicate that macro CK2 appearance under TDF is not associated with significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphataemia suggests subclinical proximal tubular dysfunction in macro-CK2-positive patients, although it was not associated with a significant decrease in estimated glomerular filtration rate. In vitro, TFV, TDF and TDP did not interfere with uMtCK enzyme activity as competitive inhibitors or pseudo-substrates, but TFV and TDF stabilized the native uMtCK octameric structure in dilute solutions.

Conclusions

Appearance of octameric uMtCK as macro CK2 in the serum of TDF-treated patients is suggested to result from a combination of low-level mitochondrial damage caused by subclinical renal tubular dysfunction together with possible compensatory uMtCK overexpression and a putative concomitant stabilization of uMtCK octamers by higher levels of TFV in proximal tubules.
Ribavirin Therapy for Hepatitis E Virus-Induced Acute on Chronic Liver Failure: A Preliminary Report
Authors: Goyal Rohit , Kumar Ajay , Panda Subrat K , Paul Shashi B , Acharya Subrat K
Published: August 2012

Hepatitis E virus (HEV) is a common cause of acute on chronic liver failure (ACLF) in HEV hyperendemic regions with high mortality. Treatment for HEV-induced ACLF is currently not available. Recently, efficacy of ribavirin in genotype 3 chronic hepatitis E patients has been reported; however, whether ribavirin is effective in genotype 1 HEV infection is not yet known. The present study includes four patients with HEV-induced ACLF treated with ribavirin in a genotype 1 HEV hyperendemic region. Diagnosis of ACLF was made by conventional criteria and HEV as the cause of ACLF was confirmed by detection of HEV RNA by reverse transcriptase PCR. Ribavirin dose ranged from 200 to 600 mg/day and was used for a median duration of 12 (range 3–24) weeks. All patients had undetectable HEV in 3–8 weeks, survived and none had serious adverse effects. This preliminary observation from a single centre indicates that ribavirin may be an effective therapeutic agent for HEV-induced ACLF and a randomized control trial is needed to establish its efficacy.
Rheumatic Disease Among Oklahoma Tribal Populations: A Cross-sectional Study
Authors: GADDY JASMINE R. , VISTA EVAN S. , ROBERTSON JULIE M. , DEDEKE AMY B. , ROBERTS VIRGINIA C. , KLEIN WENDY S. , LEVIN JEREMY H. , MOTA FABIO H. , COOPER TINA M. , GRIM GLORIA A. , KHAN SOHAIL , JAMES JUDITH A.
Published: August 2012

Objective.

Rheumatic diseases cause significant morbidity within American Indian populations. Clinical disease presentations, as well as historically associated autoantibodies, are not always useful in making a rapid diagnosis or assessing prognosis. The purpose of our study was to identify autoantibody associations among Oklahoma tribal populations with rheumatic disease.

Methods.

Oklahoma tribal members (110 patients with rheumatic disease and 110 controls) were enrolled at tribal-based clinics. Patients with rheumatic disease (suspected or confirmed diagnosis) were assessed by a rheumatologist for clinical features, disease criteria, and activity measures. Blood samples were collected and tested for common rheumatic disease autoantibodies [antinuclear antibody (ANA), anti-cyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF), anti-Ro, anti-La, anti-Sm, anti-nRNP, anti-ribosomal P, anti-dsDNA, and anticardiolipins].

Results.

In patients with suspected systemic rheumatic diseases, 72% satisfied American College of Rheumatology classification criteria: 40 (36%) had rheumatoid arthritis (RA), 16 (15%) systemic lupus erythematosus, 8 (7%) scleroderma, 8 (7%) osteoarthritis, 4 (4%) fibromyalgia, 2 (2%) seronegative spondyloarthropathy, 1 Sjögren’s syndrome, and 1 sarcoidosis. Compared to controls, RA patient sera were more likely to contain anti-CCP (55% vs 2%; p < 0.001) or RF IgM antibodies (57% vs 10%; p < 0.001); however, the difference was greater for anti-CCP. Anti-CCP positivity conferred higher disease activity scores (DAS28 5.6 vs 4.45; p = 0.021) while RF positivity did not (DAS28 5.36 vs 4.64; p = 0.15). Anticardiolipin antibodies (25% of rheumatic disease patients vs 10% of controls; p = 0.0022) and ANA (63% vs 21%; p < 0.0001) were more common in rheumatic disease patients.

Conclusion.

Anti-CCP may serve as a more specific RA biomarker in American Indian patients, while the clinical significance of increased frequency of anticardiolipin antibodies needs further evaluation.
Comparison of Blood and Synovial Fluid Th17 and Novel Peptidase Inhibitor 16 Treg Cell Subsets in Juvenile Idiopathic Arthritis
Authors: GROSE RANDALL H. , MILLARD DEBORAH J. , MAVRANGELOS CHRIS , BARRY SIMON C. , ZOLA HEDDY , NICHOLSON IAN C. , CHAM WENG TARNG , BOROS CHRISTINA A. , KRUMBIEGEL DOREEN
Published: August 2012

Objective.

Early recognition and treatment of juvenile idiopathic arthritis (JIA) can prevent joint damage and minimize side effects of medication. The balance between proinflammatory and antiinflammatory mechanisms is known to be important in JIA, and we therefore investigated T cell subsets including Th cells, autoaggressive Th17 cells, and regulatory T cells (Treg), including a novel Treg subset in peripheral blood (PB) and synovial fluid (SF) of patients with JIA.

Methods.

Fifty children with JIA were enrolled in our study. Frequency, phenotype, and function of T lymphocytes in PB and SF were characterized using flow cytometry. Migration capabilities of PB and SF cells were compared.

Results.

Synovial T cells showed different phenotype and function compared with PB T cells, with an increased proportion of memory T cells, expression of CCR4, CCR5, CXCR3, interleukin 23R, and an increased ratio of Th17 to Treg. Although Treg were increased in SF compared with the PB, we found a significant decrease in the numbers of peptidase inhibitor 16 (PI16)+ Treg in active joints compared with peripheral blood. Coexpression of CCR4 and CCR6 was reduced on PI16+ Treg in PB and SF of patients with JIA compared with healthy children, however the ability of these cells to migrate toward their ligands was unaffected.

Conclusion.

This is a comprehensive characterization of novel PI16+ Treg and Th17 cells in matched blood and synovial fluid samples of patients with JIA. Despite an increased number of Treg within the inflamed joint, lower numbers of PI16+ Treg but high numbers of Th17 cells might contribute to the inability to control disease.
Time to Disease-modifying Antirheumatic Drug Treatment in Rheumatoid Arthritis and Its Predictors: A National, Multicenter, Retrospective Cohort
Authors: TAVARES RUBEN , POPE JANET E. , TREMBLAY JEAN-LUC , THORNE CARTER , BYKERK VIVIAN P. , LAZOVSKIS JURIS , BLOCKA KENNETH L.N. , BELL MARY J. , LACAILLE DIANE , HITCHON CAROL A. , FITZGERALD AVRIL A. , FIDLER WESLEY K. , BOOKMAN ARTHUR A.M. , HENDERSON JAMES M. , MOSHER DIANNE P. , SHOLTER DALTON E. , KHRAISHI MAJED , HARAOUI BOULOS , CHEN HONG , LI XIUYING , LAUPACIS ANDREAS , BOIRE GILLES , TOMLINSON GEORGE , BOMBARDIER CLAIRE
Published: August 2012

Objective.

To determine the proportion of patients with rheumatoid arthritis (RA) under rheumatologic care treated with disease-modifying antirheumatic drugs (DMARD) within 6 months from symptom onset and the components of time to treatment and its predictors.

Methods.

A historical inception cohort of 339 patients with RA randomly selected from 18 rheumatology practices was audited. The proportion that initiated DMARD treatment within 6 months from symptom onset was estimated using Kaplan-Meier analysis. Time to each component of the care pathway was estimated. Multivariable modeling was used to determine predictors of early treatment using 12 preselected variables available in the clinical charts. Bootstrapping was used to validate the model.

Results.

Within 6 months from symptom onset, 41% (95% CI 36%−46%) of patients were treated with DMARD. The median time to treatment was 8.4 (interquartile range 3.8−24) months. Events preceding rheumatology referral accounted for 78.1% of the time to treatment. The most prominent predictor of increased time to treatment was a concomitant musculoskeletal condition, such as osteoarthritis or fibromyalgia. The significance of other variables was less consistent across the models investigated. Included variables accounted for 0.69 ± 0.03 of the variability in the model.

Conclusion.

Fewer than 50% of patients with RA are treated with DMARD within 6 months from symptom onset. Time to referral to rheumatology represents the greatest component delay to treatment. Concomitant musculoskeletal condition was the most prominent predictor of delayed initiation of DMARD. Implications of these and other findings warrant further investigation.
Rituximab Treatment for Spondyloarthritis. A Nationwide Series: Data from the AIR Registry of the French Society of Rheumatology
Authors: WENDLING DANIEL , DOUGADOS MAXIME , BERENBAUM FRANCIS , BROCQ OLIVIER , SCHAEVERBEKE THIERRY , MAZIERES BERNARD , MARCELLI CHRISTIAN , LePARC JEAN-MARIE , BERTIN PHILIPPE , ROBIN MICHÈLE , SIBILIA JEAN , LAFFORGUE PIERRE , PRATI CLÉMENT , COMBE BERNARD , GOTTENBERG JACQUES-ERIC
Published: August 2012

Objective.

To evaluate the efficacy and safety of rituximab (RTX) in several subsets of spondyloarthritis (SpA) using the data of the AIR (Autoimmunity and Rituximab) registry.

Methods.

All patients receiving RTX for SpA, and prospectively included in the AIR registry from September 2005 to September 2010, were retrospectively analyzed. The response to treatment was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index for axial disease, joint count for peripheral disease, and C-reactive protein reduction.

Results.

Among the 595 patients included in the AIR registry, 26 patients with SpA from 13 centers were reported: ankylosing spondylitis (10), undifferentiated SpA (7), and psoriatic arthritis (9). Mean disease duration was 8.8 years (range 1−40). The extraarticular features found were psoriasis, 12 cases; uveitis, 4 cases; and Crohn’s disease, 3 cases. The mean number of disease-modifying antirheumatic drugs before RTX was 2.4; previous anti-tumor necrosis factor (TNF) agents were taken in 23 cases. The mean number of RTX courses was 1.5 (range 1−5), with a total of 35.6 patient-years. Efficacy was noted in 11/23 cases: 3 out of 3 anti-TNF-naive patients and 8 out of 20 anti-TNF nonresponder patients. No predictive factors of response could be identified, particularly in diagnosis subsets or clinical presentation (axial or peripheral).

Conclusion.

In this nationwide study of several subsets of SpA, RTX had only a moderate efficacy that was more marked in patients who were anti-TNF-naive.
Cytokine Secretion by Pathogen Recognition Receptor-stimulated Dendritic Cells in Rheumatoid Arthritis and Ankylosing Spondylitis
Authors: PREVOSTO CLAUDIA , GOODALL JANE C. , HILL GASTON J.S.
Published: August 2012

Objective.

Interleukin 23 (IL-23) plays a major role in differentiation and survival of IL-17-secreting CD4+ Th17 cells. Having noted a higher frequency of Th17 cells in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) than in healthy donors (HD), we investigated whether IL-23 secretion is increased in these conditions.

Methods.

Monocyte-derived dendritic cells (moDC) were obtained from peripheral blood of 17 HD, 16 patients with RA, and 30 patients with AS, and stimulated with ligands for several pathogen recognition receptors. Messenger RNA (mRNA) expression and cytokine secretion were analyzed by real-time polymerase chain reaction and ELISA, respectively.

Results.

The combination of ligands for Toll-like receptors (TLR) 7/8 and TLR3 led to synergistic secretion of both IL-23 and IL-12p70 from all subjects; similar synergy was seen with TLR2 ligands and curdlan. However, for both combinations, moDC from patients with RA produced significantly lower amounts of IL-23 than moDC from patients with AS; in contrast, IL-12p70 secretion did not differ. Similarly, tumor necrosis factor-α, IL-6, and IL-10 were secreted at comparable levels in all subjects, whereas CXCL8 and CCL3 production was actually enhanced in moDC of patients with RA. Equivalent levels of mRNA for both IL-23p19 and IL-12p35 subunits were found in moDC from all donors, suggesting posttranscriptional regulation of IL-23 production in RA.

Conclusion.

Our observations show that IL-23 production is decreased in RA and maintained in AS. Because increased numbers of CD4+IL-17+ T cells are seen in both diseases, these observations imply that there are different mechanisms underlying chronic inflammation in these 2 forms of inflammatory arthritis.
Bathing People with Dementia: When Education Is Not Enough
Authors: Gaspard Gina , Cox Lottie
Published: August 2012

This qualitative study describes health care assistants’ (HCA) perceptions and experiences related to bathing people with dementia in residential care settings. Data were collected from three focus groups with 18 HCA participants from 12 different residential care facilities. HCAs constructed two definitions of a successful bath, which informed their choice of bathing strategies. Three themes emerged from the data analysis in regard to their bathing strategies: I Know You, I Am All Alone, and I Am Not Prepared. These data informed the development of a framework to guide gerontological nurses in creating and supporting the opportunity for successful bathing.
Mental Health Disparities in the Older Afro-Caribbean Population Living in the United States: Cultural and Practice Perspectives for Mental Health Professionals
Authors: Ellis Horace A.
Published: August 2012

Cultural characteristics play an important role in the lives of many older Afro-Caribbeans as they continue to migrate, acculturate, and assimilate in the United States. Many among this unique cultural subgroup will develop mental illness; however, despite the availability of effective treatment, seeking appropriate care within the formal mental health system continues to be a challenge for this group as a consequence of their cultural heritage. This review describes how these cultural determinants often lead to mental health disparities among older Afro-Caribbeans living in the United States. Suggestions are also included for how mental health nurses and other professionals can incorporate research and practice into the caring model of cultural humility as they continue to come in contact with this population in various clinical settings.
TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model
Authors: Spanier Justin A. , Nashold Faye E. , Olson Julie K. , Hayes Colleen E.
Published: August 2012

Compelling evidence suggests that vitamin D3 insufficiency may contribute causally to multiple sclerosis (MS) risk. Experimental autoimmune encephalomyelitis (EAE) research firmly supports this hypothesis. Vitamin D3 supports 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) synthesis in the CNS, initiating biological processes that reduce pathogenic CD4+ T cell longevity. MS is prevalent in Sardinia despite high ambient UV irradiation, challenging the vitamin D–MS hypothesis. Sardinian MS patients frequently carry a low Ifng expresser allele, suggesting that inadequate IFN-γ may undermine vitamin D3-mediated inhibition of demyelinating disease. Testing this hypothesis, we found vitamin D3 failed to inhibit EAE in female Ifng knockout (GKO) mice, unlike wild-type mice. The two strains did not differ in Cyp27b1 and Cyp24a1 gene expression, implying equivalent vitamin D3 metabolism in the CNS. The 1,25-(OH)2D3 inhibited EAE in both strains, but 2-fold more 1,25-(OH)2D3 was needed in GKO mice, causing hypercalcemic toxicity. Unexpectedly, GKO mice had very low Vdr gene expression in the CNS. Injecting IFN-γ intracranially into adult mice did not increase Vdr gene expression. Correlating with low Vdr expression, GKO mice had more numerous pathogenic Th1 and Th17 cells in the CNS, and 1,25-(OH)2D3 reduced these cells in GKO and wild-type mice without altering Foxp3+ regulatory T cells. Thus, the Ifng gene was needed for CNS Vdr gene expression and vitamin D3-dependent mechanisms that inhibit EAE. Individuals with inadequate Ifng expression may have increased MS risk despite high ambient UV irradiation because of low Vdr gene expression and a high encephalitogenic T cell burden in the CNS.
CD28 Promotes CD4+ T Cell Clonal Expansion during Infection Independently of Its YMNM and PYAP Motifs
Authors: Pagán Antonio J. , Pepper Marion , Chu H. Hamlet , Green Jonathan M. , Jenkins Marc K.
Published: August 2012

CD28 is required for maximal proliferation of CD4+ T cells stimulated through their TCRs. Two sites within the cytoplasmic tail of CD28, a YMNM sequence that recruits PI3K and activates NF-κB and a PYAP sequence that recruits Lck, are candidates as transducers of the signals responsible for these biological effects. We tested this proposition by tracking polyclonal peptide:MHCII-specific CD4+ T cells in vivo in mice with mutations in these sites. Mice lacking CD28 or its cytoplasmic tail had the same number of naive T cells specific for a peptide:MHCII ligand as wild-type mice. However, the mutant cells produced one tenth as many effector and memory cells as wild-type T cells after infection with bacteria expressing the antigenic peptide. Remarkably, T cells with a mutated PI3K binding site, a mutated PYAP site, or both mutations proliferated to the same extent as wild-type T cells. The only observed defect was that T cells with a mutated PYAP or Y170F site proliferated even more weakly in response to peptide without adjuvant than wild-type T cells. These results show that CD28 enhances T cell proliferation during bacterial infection by signals emanating from undiscovered sites in the cytoplasmic tail.
Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells
Authors: Lopez-Ramirez M. Alejandro , Fischer Roman , Torres-Badillo Claudia C. , Davies Heather A. , Logan Karen , Pfizenmaier Klaus , Male David K. , Sharrack Basil , Romero Ignacio A.
Published: August 2012

During neuroinflammation, cytokines such as TNF-α and IFN-γ secreted by activated leukocytes and/or CNS resident cells have been shown to alter the phenotype and function of brain endothelial cells (BECs) leading to blood–brain barrier breakdown. In this study, we show that the human BEC line hCMEC/D3 expresses the receptors for TNF-α, TNF receptor 1 and TNF receptor 2, and for IFN-γ. BEC activation with TNF-α alone or in combination with IFN-γ induced endothelial leakage of paracellular tracers. At high cytokine concentrations (10 and 100 ng/ml), this effect was associated with caspase-3/7 activation and apoptotic cell death as evidenced by annexin V staining and DNA fragmentation (TUNEL) assays. In addition, inhibition of JNK and protein kinase C activation at these doses partially prevented activation of caspase-3/7, although only JNK inhibition was partially able to prevent the increase in BEC paracellular permeability induced by cytokines. By contrast, lower cytokine concentrations (1 ng/ml) also led to effector caspase activation, increased paracellular flux, and redistribution of zonula occludens-1 and VE-cadherin but failed to induce apoptosis. Under these conditions, specific caspase-3 and caspase-9, but not caspase-8, inhibitors partially blocked cytokine-induced disruption of tight and adherens junctions and BEC paracellular permeability. Our results suggest that the concentration of cytokines in the CNS endothelial microenvironment determines the extent of caspase-mediated barrier permeability changes, which may be generalized as a result of apoptosis or more subtle as a result of alterations in the organization of junctional complex molecules.
MyD88 Drives the IFN-β Response to Lactobacillus acidophilus in Dendritic Cells through a Mechanism Involving IRF1, IRF3, and IRF7
Authors: Weiss Gudrun , Maaetoft-Udsen Kristina , Stifter Sebastian A. , Hertzog Paul , Goriely Stanislas , Thomsen Allan R. , Paludan Søren R. , Frøkiær Hanne
Published: August 2012

Type I IFNs are induced by pathogens to protect the host from infection and boost the immune response. We have recently demonstrated that this IFN response is not restricted to pathogens, as the Gram-positive bacterium Lactobacillus acidophilus, a natural inhabitant of the intestine, induces high levels of IFN-β in dendritic cells. In the current study, we investigate the intracellular pathways involved in IFN-β upon stimulation of dendritic cells with L. acidophilus and reveal that this IFN-β induction requires phagosomal uptake and processing but bypasses the endosomal receptors TLR7 and TLR9. The IFN-β production is fully dependent on the TIR adapter molecule MyD88, partly dependent on IFN regulatory factor (IRF)1, but independent of the TIR domain-containing adapter inducing IFN-β MyD88 adapter-like, IRF and IRF7. However, our results suggest that IRF3 and IRF7 have complementary roles in IFN-β signaling. The IFN-β production is strongly impaired by inhibitors of spleen tyrosine kinase (Syk) and PI3K. Our results indicate that L. acidophilus induces IFN-β independently of the receptors typically used by bacteria, as it requires MyD88, Syk, and PI3K signaling and phagosomal processing to activate IRF1 and IRF3/IRF7 and thereby the release of IFN-β.
Immune Mechanism of the Antitumor Effects Generated by Bortezomib
Authors: Chang Chih-Long , Hsu Yun-Ting , Wu Chao-Chih , Yang Yuh-Cheng , Wang Connie , Wu T.-C. , Hung Chien-Fu
Published: August 2012

Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation. Taken together, our data indicate that bortezomib can render tumor cells immunogenic by upregulating the cell surface expression of heat shock protein 60 and heat shock protein 90, as well as improve DC function, which results in potent immune-mediated antitumor effects.
The Adaptor 3BP2 Is Required for Early and Late Events in FcεRI Signaling in Human Mast Cells
Authors: Ainsua-Enrich Erola , Álvarez-Errico Damiana , Gilfillan Alasdair M. , Picado César , Sayós Joan , Rivera Juan , Martín Margarita
Published: August 2012

Adaptor molecules are essential in organizing signaling molecules and in coordinating and compartmentalizing their activity. SH3-binding protein 2 (3BP2) is a cytoplasmic adaptor protein mainly expressed by hematopoietic cells that has been shown to act as a positive regulator in T, B, and NK cell signal transduction. 3BP2 is an important regulator of cytotoxic granule release in NK cells. Mast cells (MCs) similarly degranulate following Ag-dependent aggregation of the FcεRI on the cell surface. Activation of these cells induces the release of preformed inflammatory mediators and the de novo synthesis and secretion of cytokines and chemokines. Thus, MCs participate in both innate and acquired responses. We observed that 3BP2 is expressed in human MCs (huMCs) from diverse origins. Moreover, 3BP2 coimmunoprecipitates with essential MC signaling mediators such as Lyn, Syk, and phospholipase C γ; thus, a role for this adaptor in MC function was postulated. In the present work, we used the short hairpin RNA lentiviral targeting approach to silence 3BP2 expression in huMCs. Our findings point to a requirement for 3BP2 in optimal immediate and late MCs responses such as degranulation and IL-8 or GM-CSF secretion. 3BP2 was determined to be necessary for optimal phosphorylation of Syk, linker for activation of T cells, and phospholipase C γ1, critical signals for calcium release from intracellular stores. Taken together, our results show that by participating in FcεRI- mediated signal transduction 3BP2 is an important regulator of huMC activation. Thus, 3BP2 could be a potential therapeutic target for IgE-dependent MC-mediated inflammatory disease.
Cyclin-Dependent Kinase Inhibitor Cdkn2c Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus
Authors: Potula Hari-Hara S. K. , Xu Zhiwei , Zeumer Leilani , Sang Allison , Croker Byron P. , Morel Laurence
Published: August 2012

The lupus-prone NZM2410 mice present an expanded B1a cell population that we have mapped to the Sle2c1 lupus susceptibility locus. The expression of Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18Ink4c and located within Sle2c1, is significantly lower in B6.Sle2c1 B cells than in B6 B cells. To test the hypothesis that the B1a cell expansion in B6.Sle2c1 mice was due to a defective p18 expression, we analyzed the B1a cell phenotypes of p18-deficient C57BL/6 mice. We found a dose-dependent negative correlation between the number of B1a cells and p18 expression in B cells, with p18-deficient mice showing an early expansion of the peritoneal B1a cell pool. p18 deficiency enhanced the homeostatic expansion of B1a cells but not of splenic conventional B cells, and the elevated number of B6.Sle2c1 B1a cells was normalized by cyclin D2 deficiency. These data demonstrated that p18 is a key regulator of the size of the B1a cell pool. B6.p18−/− mice produced significant amounts of anti-DNA IgM and IgG, indicating that p18 deficiency contributes to humoral autoimmunity. Finally, we have shown that Sle2c1 increases lpr-associated lymphadenopathy and T cell–mediated pathology. B6.p18−/−.lpr mice showed a greater lymphadenopathy than B6.Sle2c1.lpr mice, but their renal pathology was intermediate between that of B6.lpr and B6.Sle2c1.lpr mice. This indicated that p18-deficiency synergizes, at least partially, with lpr-mediated pathology. These results show that Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity.
Tryptophan Depletion and the Kinase GCN2 Mediate IFN-γ–Induced Autophagy
Authors: Fougeray Sophie , Mami Iadh , Bertho Gildas , Beaune Philippe , Thervet Eric , Pallet Nicolas
Published: August 2012

IFN-γ is a master regulator of the immune responses that occur in the transplanted kidney, acting both on the immune system and on the graft itself. The cellular responses to IFN-γ are complex, and emerging evidence suggests that IFN-γ may regulate autophagic functions. Conversely, autophagy modulates innate and adaptive immune functions in various contexts. In this study, we identify a novel mechanism by which IFN-γ activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-γ. Our results indicate that IFN-γ promotes tryptophan depletion, activates the eIF2α kinase general control nonderepressible-2 (GCN2), and leads to an increase in the autophagic flux. Further, tryptophan supplementation and RNA interference directed against GCN2 inhibited IFN-γ–induced autophagy. This process is of functional relevance because autophagy regulates the secretion of inflammatory cytokines and growth factors by human kidney epithelial cells in response to IFN-γ. These findings assign to IFN-γ a novel function in the regulation of autophagy, which, in turn, modulates IFN-γ–induced secretion of inflammatory cytokines.
Cutting Edge: 4-1BB Controls Regulatory Activity in Dendritic Cells through Promoting Optimal Expression of Retinal Dehydrogenase
Authors: Lee Seung-Woo , Park Yunji , Eun So-Young , Madireddi Shravan , Cheroutre Hilde , Croft Michael
Published: August 2012

Dendritic cells (DC) in the gut promote immune tolerance by expressing retinal dehydrogenase (RALDH), an enzyme that promotes retinoic acid, which aids differentiation of Foxp3+ inducible regulatory T cells (iTreg) in the intestinal mucosa. How RALDH expression is regulated is unclear. We found that 4-1BB (CD137), a member of the TNFR family, together with CD103, marked mesenteric lymph node DC with the highest level of RALDH activity, and ligation of 4-1BB maintained RALDH expression in these gut DC. Moreover, 4-1BB signals synergized with those through TLR2 or GM-CSFR to promote RALDH activity in undifferentiated DC. Correspondingly, 4-1BB–deficient mice were impaired in their ability to generate iTreg in the GALT when exposed to oral Ag, and 4-1BB–deficient mesenteric lymph node DC displayed weak RALDH activity and were poor at promoting iTreg development. Thus, our data demonstrate a novel activity of 4-1BB in controlling RALDH expression and the regulatory activity of DC.
Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab
Authors: Lipton Allan , Smith Matthew R. , Ellis Georgiana K. , Goessl Carsten
Published: August 2012

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.
Cohomology computations for Artin groups, Bestvina–Brady groups, and graph products
Authors: Davis Michael W. , Okun Boris
Published: August 2012

We compute:

In the case of arbitrary graph products there is an additional proviso: either all factors are infinite or all are finite.
Isometry groups of proper CAT(0)-spaces of rank one
Authors: Hamenstädt Ursula
Published: August 2012

Let

X

be a proper CAT(0)-space
and let

G

be a closed subgroup of the isometry group

\mathrm{Iso}(X)

of

X

.
We show that if

G

is non-elementary and
contains a rank-one element then its second continuous
bounded cohomology group with coefficients in the regular
representation is non-trivial. As a consequence,
up to passing to an open subgroup of finite index,
either

G

is a compact extension of a totally
disconnected group or

G

is a compact extension
of a simple Lie group of rank one.
Comunicación electoral universitaria a través de la web 2.0
Authors: Vázquez-Gestal Montse , Fernández Souto Ana-Belén , Pérez-Seoane Jesús
Published: August 2012

La pasada primavera tuvieron lugar las elecciones a rector de la Universidad de Vigo y las nuevas tecnologías jugaron un papel extraordinario durante los comicios. Blogs y redes sociales dejaron de ser simples plataformas en las que dar a conocer las promesas electorales de los candidatos para ser utilizados como auténticos medios de expresión en sí mismos. Esto desencadenó una férrea batalla 2.0 en la que los dos aspirantes a rector utilizaron los códigos propios del medio para desarrollar controvertidas campañas virales, extender todo tipo de rumores y mantener un pulso en la red inédito en unas elecciones universitarias. Un análisis comparativo de las estrategias utilizadas por ambos candidatos permitirá comprender las claves de este nuevo uso de la comunicación online.
Physical forces influence the trophic structure of reef fish communities on a remote atoll
Authors: Karnauskas Mandy , Chérubin Laurent M. , Huntington Brittany E. , Babcock Elizabeth A. , Thoney Dennis A.
Published: August 2012

We describe spatial patterns in fish abundance across the lagoonal patch reef system at Glover's Reef Atoll in Belize, and assess the relative influence of physical, biological, and abiotic structural variables on these patterns. Physical factors—specifically, distance from reef channels, current flow, and temperature—play a significant role in structuring overall patterns in fish abundance across the lagoon. The types of variables that best explained trends in abundance of specific groups of fishes were related to feeding habits of these groups. For example, fishes dependent on primary and secondary sources of productivity (herbivores and planktivores) were most highly influenced by physical factors. Abundances of benthophagous fishes were best predicted by benthic habitat variables such as coral cover, while abundance of piscivorous fish groups was best predicted by abiotic structural habitat variables such as reef area. While data on physical oceanographic properties are not normally considered in relation to abundance patterns of reef fishes, we find that such factors are good predictors of abundance for these species. Where physical data are not available, simple distance metrics may serve as reasonable proxies for physical oceanographic processes.
Hypoxic events stimulate nitrogen recycling in a shallow salt‐wedge estuary: The Yarra River estuary, Australia
Authors: Roberts Keryn L. , Eate Vera M. , Eyre Bradley D. , Holland Daryl P. , Cook Perran L. M.
Published: August 2012

The Yarra River estuary is a salt‐wedge estuary prone to periods of stratification‐induced anoxia and hypoxia (O2 < 100 µmol L−1) during low‐flow events. Nitrate reduction pathways were examined using the 15N isotope pairing technique in intact sediment cores, emulating in situ conditions, to evaluate the fate of NO during changing oxygen conditions. Water‐column concentrations of dissolved inorganic carbon (DIC), O2, NH, and NOx (NO + NO) were also measured to examine any deviation from conservative behavior (denoted Δ) in response to oxygen variability within the estuary. The estuary was a source of NH in the anoxic bottom waters. Whole‐system estimates using deviations from conservative behavior and core incubations were in good agreement and showed that NH was regenerated more efficiently relative to DIC under hypoxic conditions. For the whole system, mean ΔDIC : ΔNH ratios under oxic (85 ± 33) and hypoxic (20 ± 3) conditions were significantly different. The more‐efficient NH regeneration during hypoxia was attributed to rapid mineralization rates and cessation of nitrification; dissimilatory nitrate reduction to ammonium (DNRA) was not a significant contributor. Unexpectedly, the denitrification : DNRA ratio was significantly higher under hypoxic conditions, with denitrification contributing 99.1% ± 0.3% of total nitrate reduction. DNRA rates were significantly higher during oxic conditions (123.5 ± 30.7 µmol m−2 h−1) when compared with rates during hypoxia (0.6 ± 0.1 µmol m−2 h−1). The increase in DNRA in the presence of oxygen was attributed to the alleviation of NO limitation during these conditions.
The spectral slope coefficient of chromophoric dissolved organic matter (S275–295) as a tracer of terrigenous dissolved organic carbon in river‐influenced ocean margins
Authors: Fichot Cédric G. , Benner Ronald
Published: August 2012

The present study demonstrates that the spectral slope coefficient of chromophoric dissolved organic matter (CDOM) between 275 nm and 295 nm (S275–295) can be used as a tracer of the percent terrigenous dissolved organic carbon (%tDOC) in river‐influenced ocean margins, where rivers exert an important control on carbon dynamics and CO2 fluxes. Absorption coefficients of CDOM and concentrations of dissolved organic carbon (DOC) and dissolved lignin were measured on a seasonal basis in the Mississippi and Atchafalaya rivers and in surface waters of the northern Gulf of Mexico (NGoM). A strong, linear relationship between lignin concentrations and CDOM absorption coefficients indicated lignin is an important chromophore in this environment. The dual nature of lignin as an important chromophore in CDOM and as a terrigenous component of DOC facilitated development of the tracer. The applicability of the tracer relies on the existence of a strong, nonlinear relationship between S275–295 and the DOC‐normalized lignin yield in rivers and along the freshwater–marine continuum in the NGoM. Physical mixing and the effects of photodegradation on S275–295 and dissolved lignin were largely responsible for maintaining this relationship, suggesting the tracer is applicable to surface waters of most river‐influenced ocean margins. The spectral slope coefficient (S275–295) provides new capabilities to trace tDOC on synoptic scales of relevance to ocean margins and represents an important tool for improving ocean carbon budgets.
A comparative analysis of coastal and shelf‐slope copepod communities in the northern California Current system: Synchronized response to large‐scale forcing?
Authors: Bi Hongsheng , Peterson William T. , Peterson Jay O. , Fisher Jennifer L.
Published: August 2012

The synchrony between coastal and shelf‐slope copepod communities was investigated in the northern California Current (NCC) system, a strong upwelling zone, using time series of zooplankton sampled from a nearshore station (9 km offshore, water depth 62 m) and a shelf‐slope station (46 km offshore, water depth 297 m). Long‐term trends and seasonal changes were constructed for the dissimilarity index (Euclidean distance) between the two stations and for the biomass of three different copepod assemblages at the two stations: cold neritic, southern, and warm neritic copepods. The dissimilarity between the community structures of the two stations showed little variation in the long‐term trend, but exhibited a clear seasonal pattern. All three copepod assemblages showed similar long‐term trends in relation to the large‐scale forcing as indexed by the Pacific Decadal Oscillation at both stations, but variations in the long‐term trend at the nearshore station were much higher than the offshore station. Most copepod groups exhibited regular seasonal patterns at both stations except southern copepods at the nearshore station. All three copepod assemblages exhibited more pronounced seasonal fluctuations at the nearshore station compared with the slope station, and this difference is likely driven by higher productivity nearshore fueled by nutrient‐enriched upwelled water. Copepods in the inshore and offshore waters in the NCC ecosystem showed synchronized response to the large‐scale variability in physical forcing and copepods in the coastal waters were more responsive to local perturbations than were those in the slope waters.
Intercalibration of selected anthropogenic radionuclides for the GEOTRACES Program
Authors: Kenna Timothy C. , Masqué Pere , Luís Mas José , Camara‐Mor Patricia , Chamizo Elena , Scholten Jan , Eriksson Mats , Sanchez‐Cabeza Joan‐Albert , Gastaud Janine , Levy Isabelle , Herrmann Jürgen , Lindahl Patric , Hong Gi‐Hoon , Nielsen Sven
Published: August 2012

As part of the GEOTRACES Program, six laboratories participated in an intercalibration exercise on several anthropogenic radionuclides of interest. The effort was successful for 239,240Pu activity, 240Pu/239Pu isotope ratio, and 137Cs activity measured in filtered seawater samples from the Bermuda Atlantic Time Series station (BATS) and a site on the continental slope of the Northeastern U.S. A limited number of analyses were reported for 237Np, 241Am, 90Sr, and 238Pu in filtered seawater. Intercalibration of any of the isotopes of interest in filtered particulate matter was unsuccessful due to insufficient size of the samples distributed. Methods used were based on traditional radio‐counting techniques and inductively coupled plasma mass spectrometry (ICP‐MS). Although the majority of analyses were performed on samples ≥ 60 L, one lab demonstrated the ability to analyze several of the anthropogenic radionuclides on 10–20 L sample volumes using ICP‐MS.
Advances and Applications in Stem Cell Biology
Authors: Bhattacharyya Shamoli
Published: August 2012

Mesenchymal stem cells have shown great promise as the source of adult stem cells for regenerative medicine. Present research efforts are directed at isolating these cells from various sources, growing them in vitro and maintaining their pluripotency as well as capacity for self renewal. It is crucial to identify the regulatory molecules which directly or indirectly control the proliferative status or influence the niche microenvironment. The main challenge is to understand the basic biology of the stem cells and manipulate them for further therapeutic applications. Considering their malignant potential, stem cells may be a double edged sword. While the benefits of these cells need to be harnessed judiciously, a significant amount of research is required before embarking on widespread use of this tool for the benefit of humanity.

How to cite this article

Bhattacharyya S. Advances and Applications in Stem Cell Biology. J Postgrad Med Edu Res 2012;46(2):75-80.
Prospective Single-Arm Study of Radioprotection by Amifostine in High Dose Radioactive Iodine Therapy for Thyroid Cancer
Authors: Sandhu Ajay , Ioffe Vladimir , Karakla Daniel , Wadsworth J Trad , Mendoza April , Rao Nikhil , Dignan Kathleen , Mason Elizabeth , Goffman Thomas E
Published: August 2012

Purpose

Xerostomia, sialoadenitis, taste dysfunction and nausea are well known toxicities following high dose radioactive iodine (RAI) treatment for well-differentiated thyroid cancer. This prospective study sought to determine the incidence rates for RAI adverse effects and to determine, whether the radioprotector, amifostine could decrease the duration of the adverse effects in single treatment patients.

Materials and methods

Patients with differentiated thyroid cancer received 150 mCi RAI after total thyroidectomy. All patients were pretreated with 1 mg granisetron and 4 mg dexamethasone. Patients in the amifostine arm (n = 27) were prospectively enrolled and received 500 mg amifostine subcutaneously. Adverse effects were scored based on the CTCAE at 1 month, 6 months, and yearly intervals using a physician administered questionnaire. The results were compared with a retrospective no amifostine cohort (n = 22) for whom data was collected with the identical questionnaire.

Results

The overall incidence of xerostomia, sialadenitis, taste dysfunction and nausea in the treatment group was 26, 22, 52 and 26% respectively. Only grades 1 and 2 adverse effects were observed. The mean duration (days) of xerostomia (control vs treatment)—37.3 vs 21.9 (F test, p = 0.016), taste dysfunction—45.5 vs 23.5 (F test, p = 0.001), sialadenitis— 16.8 vs 7.5 and nausea—18.7 vs 5.1.

Conclusion

In patients treated once with high dose RAI, who develop xerostomia, sialoadenitis, taste dysfunction, and/or nausea, the duration of symptoms appears to be reduced by pretreatment with 500 mg of subcutaneous amifostine without significant treatment related adverse effects.

How to cite this article

Sandhu A, Ioffe V, Karakla D, Wadsworth JT, Mendoza A, Rao N, Dignan K, Mason E, Goffman TE. Prospective Single-Arm Study of Radioprotection by Amifostine in High Dose Radioactive Iodine Therapy for Thyroid Cancer. J Postgrad Med Edu Res 2012;46(2):90-94.
Aggressive Angiomyxoma Pelvis Presenting as an Ovarian Tumor with Vault Prolapse
Authors: Dhaliwal Lakhbir , Aggarwal Neelam , Nijhawan Raje , Siwatch Sujata , Saha Subhas Chandra
Published: August 2012

Background

Angiomyxoma is a rare tumor arising from the pelvis. Preoperative diagnosis and treatment may be difficult.

Case report

We report a rare case of aggressive angiomyxoma pelvis that presented as vault prolapse and was misdiagnosed as ovarian tumor.

Conclusion

As surgery is the main treatment, preoperative diagnosis and assessment of extent of the tumor for planning surgery cannot be overemphasized.

Synopsis

Angiomyxoma is a rare pelvic tumor with varied presentation. Preoperative diagnosis and assessment of extent of the tumor are important for its management.

How to cite this article

Siwatch S, Saha SC, Aggarwal N, Dhaliwal L, Nijhawan R. Aggressive Angiomyxoma Pelvis Presenting as an Ovarian Tumor with Vault Prolapse. J Postgrad Med Edu Res 2012;46(2):102-103.