bluuebunny/crossref_metadata_2025_split huggingface dataset:
Daptomycin in experimental murine pneumococcal meningitis
Authors: Mook-Kanamori Barry B , Rouse Mark S , Kang Cheol-In , van de Beek Diederik , Steckelberg James M , Patel Robin 
Published: April 2009

Abstract

Background
Daptomycin, a lipopeptide antibiotic, could be an alternative to vancomycin for treatment of pneumococcal meningitis. We determined the activity of daptomycin versus vancomycin, with dexamethasone as an adjuvant, in a murine model of pneumococcal meningitis.

Methods
Ninety-six 25–30 gram mice were inoculated intracisternally with serotype 3 Streptococcus pneumoniae modified by the integration of a luminescent lux operon. All mice were treated with either dexamethasone 1 mg/kg intraperitoneally every 6 hours alone or in combination with either vancomycin or daptomycin, also administered intraperitoneally. Serum antimicrobial concentrations were selected to approximate those achieved in humans. Following treatment, bioluminescence and cerebrospinal fluid (CSF) bacterial concentrations were determined. Caspase-3 staining was used to assess apoptosis on brain histopathology.

Results
Sixteen hours post intracisternal inoculation, bacterial titers in CSF were 6.8 log10 cfu/ml. Amongst the animals given no antibiotic, vancomycin 50 mg/kg at 16 and 20 hours or daptomycin 25 mg/kg at 16 hours, CSF titers were 7.6, 3.4, and 3.9 log10 cfu/ml, respectively, at 24 hours post infection (p-value, < 0.001 for both vancomycin or daptomycin versus no antibiotic); there was no significant difference in bactericidal activity between the vancomycin and daptomycin groups (p-value, 0.18). CSF bioluminescence correlated with bacterial titer (Pearson regression coefficient, 0.75). The amount of apoptosis of brain parenchymal cells was equivalent among treatment groups.

Conclusion
Daptomycin or vancomycin, when given in combination with dexamethasone, is active in the treatment of experimental pneumococcal meningitis.
Role of educational level in the relationship between Body Mass Index (BMI) and health-related quality of life (HRQL) among rural Spanish women
Authors: García-Mendizábal María José , Carrasco José Miguel , Pérez-Gómez Beatriz , Aragonés Nuria , Guallar-Castillón Pilar , Rodríguez-Artalejo Fernando , López-Abente Gonzalo , Pollán Marina 
Published: April 2009

Abstract

Background
The impact of obesity on health-related quality of life (HRQL) has been little explored in rural areas. The goal of this study is to ascertain the association between obesity and HRQL among Spanish women living in a rural area, and the influence of their educational level.

Methods
Cross-sectional study with personal interview of 1298 women (aged 18 to 60) randomly selected from the electoral rolls of 14 towns in Galicia, a region in the north-west of Spain. HRQL was assessed using the SF-36 questionnaire. The association between body mass index (BMI) and suboptimal scores in the different HRQL dimensions was summarised using odds ratios (ORs), obtained from multivariate logistic regression models. Separate analyses were conducted for women who had finished their education younger than 16 years old and women with secondary education to assess differences in the relationship between BMI and HRQL according to educational level.

Results
Among women with primary or lower education, obesity was associated with a higher prevalence of suboptimal values in the following dimensions: Physical functioning (OR: 1.97; 95%CI: 1.22–3.18); Role-physical (OR: 1.81; 95%CI: 1.04–3.14); General health (OR: 1.76; 95%CI: 1.10–2.81); and Role-emotional (OR: 2.52; 95%CI: 1.27–5.03). In women with higher education, physical functioning was the only dimension associated with obesity (OR: 2.02: 95%CI 0.83–4.97).

Conclusion
The impact of obesity on women's HRQL is greater among those with a lower educational level. This group registered higher prevalence of obesity and poorer self-perceived health.
Antimicrobial effect of farnesol, a Candida albicans quorum sensing molecule, on Paracoccidioides brasiliensis growth and morphogenesis
Authors: Derengowski Lorena S , De-Souza-Silva Calliandra , Braz Shélida V , Mello-De-Sousa Thiago M , Báo Sônia N , Kyaw Cynthia M , Silva-Pereira Ildinete 
Published: April 2009

Abstract

Background
Farnesol is a sesquiterpene alcohol produced by many organisms, and also found in several essential oils. Its role as a quorum sensing molecule and as a virulence factor of Candida albicans has been well described. Studies revealed that farnesol affect the growth of a number of bacteria and fungi, pointing to a potential role as an antimicrobial agent.

Methods
Growth assays of Paracoccidioides brasiliensis cells incubated in the presence of different concentrations of farnesol were performed by measuring the optical density of the cultures. The viability of fungal cells was determined by MTT assay and by counting the colony forming units, after each farnesol treatment. The effects of farnesol on P. brasiliensis dimorphism were also evaluated by optical microscopy. The ultrastructural morphology of farnesol-treated P. brasiliensis yeast cells was evaluated by transmission and scanning electron microscopy.

Results
In this study, the effects of farnesol on Paracoccidioides brasiliensis growth and dimorphism were described. Concentrations of this isoprenoid ranging from 25 to 300 μM strongly inhibited P. brasiliensis growth. We have estimated that the MIC of farnesol for P. brasiliensis is 25 μM, while the MLC is around 30 μM. When employing levels which don't compromise cell viability (5 to 15 μM), it was shown that farnesol also affected the morphogenesis of this fungus. We observed about 60% of inhibition in hyphal development following P. brasiliensis yeast cells treatment with 15 μM of farnesol for 48 h. At these farnesol concentrations we also observed a significant hyphal shortening. Electron microscopy experiments showed that, despite of a remaining intact cell wall, P. brasiliensis cells treated with farnesol concentrations above 25 μM exhibited a fully cytoplasmic degeneration.

Conclusion
Our data indicate that farnesol acts as a potent antimicrobial agent against P. brasiliensis. The fungicide activity of farnesol against this pathogen is probably associated to cytoplasmic degeneration. In concentrations that do not affect fungal viability, farnesol retards the germ-tube formation of P. brasiliensis, suggesting that the morphogenesis of this fungal is controlled by environmental conditions.
Role of hepatitis B surface antigen in the development of hepatocellular carcinoma: regulation of lymphoid enhancer-binding factor 1
Authors: Tian Xiaochen , Li Jinjun , Ma Zhang-Mei , Zhao Chao , Wan Da-Fang , Wen Yu-Mei 
Published: April 2009

Abstract

Background
There are around 350 million of hepatitis B surface antigen (HBsAg) carriers worldwide, and among them, high risk of developing hepatocellular carcinoma (HCC) has been identified by epidemiological studies. To date, the molecular role of HBsAg in HCC development has not been fully studied. We have previously reported that in cell cultures, HBsAg up-regulated the expression of lymphoid enhancer-binding factor 1 (LEF-1), a key component of the Wnt pathway. In this study we aimed to study this effect of HBsAg on LEF-1 in the development of HCC.

Methods
Expression of HBsAg, LEF-1 and its downstream effector genes were compared among 30 HCCs, their peritumor tissue counterparts and 9 normal control liver tissues by quantitative real-time PCR. In addition, immunohistochemical staining studies on HBsAg and LEF-1 expression were conducted among these samples.

Results
The expression of LEF-1 was compared between 13 HBsAg positive HCC tissues and 17 HBsAg negative HCC tissues. Simultaneous detection of LEF-1 and HBsAg was observed in HBsAg positive HCC tissues and, additionally, the simultaneous detection of HBsAg and LEF-1 was more pronounced in peritumor tissues, compared to that in the tumor tissues. The distribution of cellular LEF-1 in peritumor tissues was predominantly in the cytoplasm; while LEF-1 in the tumor tissues was located either exclusively in the nucleus or both in the nucleus and cytoplasm. By real-time PCR, the expression levels of LEF-1 downstream effector genes cyclin D1 and c-myc were higher in peritumor cells compared to that of the tumor cells. However, a 38 kDa truncated isoform of LEF-1, rather than the 55 kDa wild-type LEF-1, was significantly elevated in the HBsAg positive tumor cells.

Conclusion
Data indicate that deregulation of the Wnt pathway by HBsAg occurred in HBV-associated HCCs, but was more pronounced in the peritumor cells. It is speculated that HBsAg could stimulate proliferation and functional modification of hepatocytes via LEF-1 through the Wnt pathway at the pre-malignant stage.
RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteoclast apoptosis in vitro
Authors: Sutherland Karen A , Rogers Helena L , Tosh Denise , Rogers Michael J 
Published: April 2009

Abstract
Introduction
Bisphosphonates are the most widely used class of drug for inhibiting osteoclast-mediated bone loss, but their effectiveness at preventing joint destruction in rheumatoid arthritis has generally been disappointing. We examined whether the ability of bisphosphonates to induce osteoclast apoptosis and inhibit bone resorption in vitro is influenced by the cytokine receptor activator of nuclear factor-kappa B ligand (RANKL), an important mediator of inflammation-induced bone loss.

Methods
Rabbit osteoclasts were treated with the bisphosphonates clodronate or alendronate for up to 48 hours in the absence or presence of RANKL. Changes in cell morphology and induction of apoptosis were examined by scanning electron microscopy, whilst resorptive activity was determined by measuring the area of resorption cavities. Changes in the level of anti-apoptotic proteins, including Mcl-1, Bcl-2, and Bcl-x>L, were determined in rabbit osteoclasts and in cytokine-starved mouse osteoclasts by Western blotting.

Results
RANKL significantly attenuated the ability of both clodronate and alendronate to induce osteoclast apoptosis and inhibit bone resorption. Treatment of rabbit osteoclasts with RANKL was associated with an increase in the anti-apoptotic protein Mcl-1 but not Bcl-2. A role for Mcl-1 in osteoclast survival was suggested using osteoclasts generated from mouse bone marrow macrophages in the presence of RANKL + macrophage colony-stimulating factor (M-CSF) since cytokine deprivation of mouse osteoclasts caused a rapid loss of Mcl-1 (but not Bcl-2 or Bcl-xL), which preceded the biochemical and morphological changes associated with apoptosis. Loss of Mcl-1 from mouse osteoclasts could be prevented by factors known to promote osteoclast survival (RANKL, M-CSF, tumour necrosis factor-alpha [TNF-α], or lipopolysaccharide [LPS]).

Conclusions
RANKL protects osteoclasts from the apoptosis-inducing and anti-resorptive effects of bisphosphonates in vitro. The ability of RANKL (and other pro-inflammatory factors such as TNF-α and LPS) to increase the level of Mcl-1 in osteoclasts may explain the lack of effectiveness of some bisphosphonates in preventing inflammation-induced bone loss.
Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells
Authors: Kang Hee-Kap , Ecklund Diane , Liu Michael , Datta Syamal K 
Published: April 2009

Abstract
Introduction
Lupus patients need alternatives to steroids and cytotoxic drugs. We recently found that apigenin, a non-mutagenic dietary flavonoid, can sensitize recurrently activated, normal human T cells to apoptosis by inhibiting nuclear factor-kappa-B (NF-κB)-regulated Bcl-xL, cyclooxygenase 2 (COX-2), and cellular FLICE-like inhibitory protein (c-FLIP) expression. Because sustained immune activation and hyperexpression of COX-2 and c-FLIP contribute to lupus, we treated SNF1 mice that spontaneously develop human lupus-like disease with apigenin.

Methods
SNF1 mice with established lupus-like disease were injected with 20 mg/kg of apigenin daily and then monitored for development of severe nephritis. Histopathologic changes in kidneys, IgG autoantibodies to nuclear autoantigens in serum and in cultures of splenocytes, along with nucleosome-specific T helper 1 (Th1) and Th17 responses, COX-2 expression, and apoptosis of lupus immune cells were analyzed after apigenin treatment.

Results
Apigenin in culture suppressed responses of Th1 and Th17 cells to major lupus autoantigen (nucleosomes) up to 98% and 92%, respectively, and inhibited the ability of lupus B cells to produce IgG class-switched anti-nuclear autoantibodies helped by these Th cells in presence of nucleosomes by up to 82%. Apigenin therapy of SNF1 mice with established lupus suppressed serum levels of pathogenic autoantibodies to nuclear antigens up to 97% and markedly delayed development of severe glomerulonephritis. Apigenin downregulated COX-2 expression in lupus T cells, B cells, and antigen-presenting cells (APCs) and caused their apoptosis. Autoantigen presentation and Th17-inducing cytokine production by dendritic cells were more sensitive to the inhibitory effect of apigenin in culture, as evident at 0.3 to 3 μM, compared with concentrations (10 to 100 μM) required for inducing apoptosis.

Conclusions
Apigenin inhibits autoantigen-presenting and stimulatory functions of APCs necessary for the activation and expansion of autoreactive Th1 and Th17 cells and B cells in lupus. Apigenin also causes apoptosis of hyperactive lupus APCs and T and B cells, probably by inhibiting expression of NF-κB-regulated anti-apoptotic molecules, especially COX-2 and c-FLIP, which are persistently hyperexpressed by lupus immune cells. Increasing the bioavailability of dietary plant-derived COX-2 and NF-κB inhibitors, such as apigenin, could be valuable for suppressing inflammation in lupus and other Th17-mediated diseases like rheumatoid arthritis, Crohn disease, and psoriasis and in prevention of inflammation-based tumors overexpressing COX-2 (colon, breast).
Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer
Authors: Jacquemier Jocelyne , Charafe-Jauffret Emmanuelle , Monville Florence , Esterni Benjamin , Extra Jean Marc , Houvenaeghel Gilles , Xerri Luc , Bertucci François , Birnbaum Daniel 
Published: April 2009

Abstract
Introduction
Breast cancers are traditionally divided into hormone-receptor positive and negative cases. This classification helps to guide patient management. However, a subgroup of hormone-receptor positive patients relapse irrespective of hormonal therapy. Gene expression profiling has classified breast tumours into five major subtypes with significant different outcome. The two luminal subtypes, A and B, show high expression of ESR1, GATA3 and FOXA1 genes. Prognostic biomarkers for oestrogen receptor (ER)-positive cases include progesterone receptor (PR) and androgen receptor (AR), and proteins related to proliferation or apoptotic resistance. The aim of this study was to identify the best predictors of success of hormonal therapy.

Methods
By immunohistochemistry we studied 10 markers in a consecutive series of 832 cases of breast carcinoma treated at the Paoli-Calmettes Institute from 1990 to 2002 and deposited onto tissue microarrays (TMA). These markers were luminal-related markers ER, PR, AR, FOXA1 and GATA3 transcription factors, proliferation-related Ki67 and CCND1, ERBB2, anti-apoptotic BCL2 and P53. We also measured vascular peritumoural invasion (VPI), size, grade and lymph node involvement. For 143 cases, gene expression profiles were available. Adjuvant chemotherapy and hormonal therapy were given to high- and low-risk patients, respectively. The 162 events observed and taken into account were metastases.

Results
Molecular expression of the 10 parameters and subtype with ER status were strongly correlated. Of the 67 luminal A cases of this series, 63 were ER-positive. Multivariate analyses showed the highly significant prognostic value of VPI (hazard ratio (HR) = 2.47), Ki67 (HR = 2.9), P53 (HR = 2.9) and GATA3 (HR = 0.5) for the 240 patients who received hormonal therapy.

Conclusions
A panel of three antibodies (Ki67, P53 and GATA3) associated with VPI can significantly improve the traditional prognosticators in predicting outcome for ER-positive breast cancer patients receiving hormonal therapy.
Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells
Authors: Bollyky Paul L , Falk Ben A , Wu Rebecca P , Buckner Jane H , Wight Thomas N , Nepom Gerald T 
Published: April 2009

Abstract
The authors describe the immunoregulatory contributions of intact versus fragmented hyaluronan, a prominent component of the extracellular matrix.
The composition of the ECM provides contextual cues to leukocytes in inflamed and healing tissues. One example of this is HA, where LMW–HA, generated during active inflammation, is a TLR ligand and an endogenous “danger signal,” and HMW–HA, predominant in healing or intact tissues, functions in an inverse manner. Our data suggest that HMW–HA actively promotes immune tolerance by augmenting CD4+CD25+ TReg function, and LMW–HA does not. Using a human iTReg model, we demonstrate that HMW–HA but not LMW–HA provides a costimulatory signal through cross–linking CD44 which promotes Foxp3 expression, a critical signaling molecule associated with TReg. This effect, in part, may be mediated by a role for intact HMW–HA in IL–2 production, as TReg are highly IL–2–dependent for their survival and function. We propose that HMW–HA contributes to the maintenance of immune homeostasis in uninjured tissue and effectively communicates an “all–clear” signal to down–regulate the adaptive immune system through TReg after tissue matrix integrity has been restored.
CD4 and CD8: an inside-out coreceptor model for innate immune cells
Authors: Gibbings Derrick , Befus A Dean 
Published: April 2009

Abstract
CD4 and CD8 enhancement of FcR-like signaling is discussed as a potential role when expressed by innate immune cells.
CD8 and CD4 are expressed by several cell types that do not express TCR. These include DCs, macrophages, monocytes, and NK cells. CD8+ monocytes and macrophages are abundant at the site of pathology in many rat disease models, particularly those involving immune complex-mediated pathology. Indeed, in some disease models, CD8+ macrophages correlate with severity of pathology or directly cause pathology or tumor cell killing. Evidence suggests CD8 or CD4 can enhance FcγR-dependent responses of human monocytes. Building on data that key components of TCR and FcγR signaling can substitute one another efficiently, we postulate that CD4 and CD8 operate with FcγR and potentially other receptors to enhance responses of T cells and various innate immune cells. Our model suggests CD8 on myeloid cells may contribute directly to tumor killing and tissue pathology by enhancing FcγR responses. Moreover, the model suggests a role for CD8 in cross-presentation of antibody-associated antigen by DCs and a new mechanism to regulate TCR sensitivity.
IL-21: a new player in the control of isotype switch in Peyer’s patches
Authors: Pistoia Vito , Cocco Claudia 
Published: April 2009

AbstractPeyer’s patches (PP) are lymphoid follicles of the small intestine containing predominantly IgA+ B cells. In this JLB issue, IL-21 is reported to dampen TGF-β1-induced IgG2b but not IgA production by mouse B cells, possibly explaining why IgA+ B cells predominate in PP.
Galectin-8 provides costimulatory and proliferative signals to T lymphocytes
Authors: Tribulatti María Virginia , Cattaneo Valentina , Hellman Ulf , Mucci Juan , Campetella Oscar 
Published: April 2009

AbstractCD4+ T cells are the main lymphocyte target of Galectin-8, which lowers their activation threshold and thus suggesting the lectin involvement in inflammatory diseases.Galectin (Gal) constitute a family of carbohydrate-recognizing molecules ubiquitously expressed in mammals. In the immune system, they regulate many processes such as inflammation, adhesion, and apoptosis. Here, we report the expression in the spleen of the two same Gal-8 splice variants described previously in the thymus. Gal-8 was found to induce two separate biological activities on T lymphocytes: a robust naive CD4+ T cell proliferation in the absence of antigen and notably, a costimulatory signal that synergized the cognate OVA peptide in DO11.10 mice transgenic for TCROVA. The antigen-independent proliferation induced by Gal-8 displayed increased expression of pro- and anti-inflammatory cytokines, thus suggesting the polyclonal expansion of Th1 and Th2 clones. The costimulatory effect on antigen-specific T cell activation was evidenced when the Gal and the peptide were assayed at doses suboptimal to induce T cell proliferation. By mass spectra analysis, several integrins and leukocyte surface markers, including CD45 isoforms, as well as other molecules specific to macrophages, neutrophils, and platelets, were identified as putative Gal-8 counter-receptors. Gal-8 triggered pZAP70 and pERK1/2. Moreover, pretreatment with specific inhibitors of CD45 phosphatase or ERK1/2 prevented its antigen-dependent and -independent T cell-proliferative activities. This seems to be associated with the agonistic binding to CD45, which lowers the activation threshold of the TCR signaling pathway. Taken together, our findings support a distinctive role for locally produced Gal-8 as an enhancer of otherwise borderline immune responses and also suggest that Gal-8 might fuel the reactivity at inflammatory foci.
IFN-α amplifies human naïve B cell TLR-9-mediated activation and Ig production
Authors: Giordani L , Sanchez M , Libri I , Quaranta M G , Mattioli B , Viora M 
Published: April 2009

Abstract
CpG ODN drives B cells to differentiate into plasma cells; IFN-α amplifies the inductive effect of CpG ODN on B cells.
TLRs are a family of molecules that function as sensors for the detection of pathogens. TLR-9, expressed on B cells and pDCs, recognizes CpG motifs of unmethylated bacterial DNA and plays a role in the development of autoimmunity. The present study was designed to investigate the effects of IFN-α in combination with CpG ODN on the activation of CD27– naïve B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T-dependent, specific IgM response by naïve B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the up-regulation of CD38 expression. We found that TLR-9 stimulation with CpG ODN induces IL-1β, TNF-α, IL-10, and IL-6 production. Interestingly, we also found that CpG ODN induces naïve B cell maturation into memory cells, as demonstrated by the induction of CD27, AID mRNA expression, and IgG production. More importantly, our results demonstrate that IFN-α amplifies the inductive effect of CpG ODN on naïve B activation and on Ig production through a mechanism involving TLR-9/MyD88-dependent signaling. Moreover, we found that IFN-α enhances the frequency of CpG ODN-induced memory B cells. Our results may contribute to clarify the events promoting IFN-α-induced amplification of naïve B cell activation via TLR-9 for a better understanding of the pathogenesis of autoimmune disorders and may guide treatments targeting this pathway within B cells.