bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Production of Macrophage Inflammatory Protein 1γ (MIP-1γ), Lymphotactin, and MIP-2 by CD4+Th Subsets Polarized In Vitro and In Vivo
Authors: Müller Kerstin , Bischof Susanne , Sommer Frank , Lohoff Michael , Solbach Werner , Laskay Tamás 
Published: October 2003

ABSTRACTDue to differential expression of chemokine receptors, the Th1 and Th2 subsets of CD4+T cells differ in their migratory responses to chemokines. These differences in the migration patterns are likely to play a role in the initiation and regulation of Th1 and Th2 immune responses, inflammatory processes, and T-cell-mediated pathology. In the present study we evaluated the role of activated Th cells as producers of chemokines. Three different sources of murine Th cells were used, i.e., long-term-cultured Th1 and Th2 cell clones, Th1 and Th2 cells differentiated from naïve CD4+spleen and lymph node cells in vitro, and Th1 and Th2 subsets polarized in vivo using a murine experimentalLeishmania majorinfection model. Following stimulation with anti-CD3, macrophage inflammatory protein 1γ (MIP-1γ) and lymphotactin were produced selectively by Th1 cells but not by Th2 cells. In contrast, only Th2 cells produced MIP-2. The possible biological relevance of these data was substantiated by the finding that in vivo-polarized Th1 cells, but not Th2 cells, produced MIP-1γ and lymphotactin while in vivo-polarized Th2 cells secreted MIP-2. The above data demonstrate that Th1 and Th2 cells differ in their ability to produce chemokines, suggesting that Th1 and Th2 subsets differentially contribute to recruitment of cells into inflammatory foci.
Role of Cyclooxygenase Enzymes in a Murine Model of Experimental Cholera
Authors: Gessell-Lee Deborah L. , Popov Vsevolod L. , Boldogh Istvan , Olano Juan P. , Peterson Johnny W. 
Published: October 2003

ABSTRACTNonsteroidal anti-inflammatory drugs (e.g., indomethacin) inhibit and reduce the fluid secretion responses elicited by cholera toxin (CT), but it has not been conclusively determined which cyclooxygenase (COX) isoform is involved in CT's action. This study evaluated the role of the COX enzymes and their arachidonic acid metabolites in experimental cholera. Swiss-Webster mice were dosed with celecoxib and rofecoxib and challenged with CT in ligated small intestinal loops, and intestinal segments from mice deficient in COX-1 and COX-2 were challenged with CT. The effects of CT on fluid accumulation, prostaglandin E2production, mucosal tissue injury, and markers of oxidative stress were measured. Celecoxib and rofecoxib given at 160 μg per mouse inhibited CT-induced fluid accumulation by 48% and 31%, respectively, but there was no significant difference amongcox-1−/−andcox-2−/−mice in response to CT compared to wild-type controls. CT elevated tissue levels of oxidized glutathione and lipid peroxides and elicited small intestinal tissue injury in two of fivecox-1−/−and four of fivecox-2−/−mice. A role for COX-2 in CT's mechanism of action has previously been suggested by the effectiveness of COX-2 inhibitors in reducing CT-induced fluid secretion, but CT challenge of COX-1 and COX-2 knockout mice did not corroborate the pharmacological data. The results of this study show that CT induced oxidative stress in COX-deficient mice and suggest a tissue-protective role for arachidonic acid metabolites in the small intestine against oxidative stress.
Identification of a Gene That Affects the Efficiency of Host Cell Infection by
Legionella pneumophila
in a Temperature-Dependent Fashion
Authors: Ridenour Dennis A. , Cirillo Suat L. G. , Feng Sheng , Samrakandi Mustapha M. , Cirillo Jeffrey D. 
Published: October 2003

ABSTRACT

The ability to infect host cells is critical for the survival and replication of intracellular pathogens in humans. We previously found that many genes involved in the ability of
Legionella pneumophila
to infect macrophages are not expressed efficiently under standard laboratory growth conditions. We have developed an approach using expression of
L. pneumophila
genes from an exogenous constitutive promoter on a low-copy-number vector that allows identification of genes involved in host cell infection. Through the use of this strategy, we found that expression of a gene,
lvhB2
, enhances the efficiency of
L. pneumophila
infection of mammalian cells. The putative protein encoded by
lvhB2
has similarity to structural pilin subunits of type IV secretion systems. We confirmed that this gene plays a role in host cell infection by the construction of an in-frame deletion in the
L. pneumophila lvhB2
gene and complementation of this mutant with the wild-type gene. The
lvhB2
mutant does not display a very obvious defect in interactions with host cells when the bacteria are grown at 37°C, but it has an approximately 100-fold effect on entry and intracellular replication when grown at 30°C. These data suggest that
lvhB2
plays an important role in the efficiency of host cell infection by
L. pneumophila
grown at lower temperatures.
Rhodococcus equiSecreted Antigens Are Immunogenic and Stimulate a Type 1 Recall Response in the Lungs of Horses Immune toR. equiInfection
Authors: Kohler Andrea K. , Stone Diana M. , Hines Melissa T. , Byrne Barbara A. , Alperin Debra C. , Norton Linda K. , Hines Stephen A. 
Published: October 2003

ABSTRACTRhodococcus equiis an opportunistic pathogen in immunocompromised humans and an important primary pathogen in young horses. AlthoughR. equiinfection can produce life-threatening pyogranulomatous pneumonia, most foals develop a protective immune response that lasts throughout life. The antigen targets of this protective response are currently unknown; however,Mycobacterium tuberculosisis a closely related intracellular pathogen and provides a model system. Based on previous studies ofM. tuberculosisprotective antigens released into culture filtrate supernatant (CFS), a bacterial growth system was developed for obtainingR. equiCFS antigens. Potential immunogens for prevention of equine rhodococcal pneumonia were identified by using immunoblots. The 48-h CFS contained five virulence-associated protein bands that migrated between 12 and 24 kDa and were recognized by sera fromR. equi-infected foals and immune adult horses. Notably, the CFS contained the previously characterized proteins VapC, VapD, and VapE, which are encoded by genes on theR. equivirulence plasmid.R. equiCFS was also examined for the ability to stimulate a type 1-like memory response in immune horses. Three adult horses were challenged with virulentR. equi, and cells from the bronchoalveolar lavage fluid were recovered before and 1 week after challenge. In vitro stimulation of pulmonary T-lymphocytes withR. equiCFS resulted in significant proliferation and a significant increase in gamma interferon mRNA expression 1 week after challenge. These results were consistent with a memory effector response in immune adult horses and provide evidence thatR. equiCFS proteins are antigen targets in the immunoprotective response againstR. equiinfection.
Pertussis Toxin Plays an Early Role in Respiratory Tract Colonization byBordetella pertussis
Authors: Carbonetti Nicholas H. , Artamonova Galina V. , Mays R. Michael , Worthington Zoe E. V. 
Published: October 2003

ABSTRACTIn this study, we sought to determine whether pertussis toxin (PT), an exotoxin virulence factor produced exclusively byBordetella pertussis, is important for colonization of the respiratory tract by this pathogen by using a mouse intranasal infection model. By comparing a wild-type Tohama I strain to a mutant strain with an in-frame deletion of theptxgenes encoding PT (ΔPT), we found that the lack of PT confers a significant peak (day 7) colonization defect (1 to 2 log10units) over a range of bacterial inoculum doses and that this defect was apparent within 1 to 2 days postinoculation. In mixed-strain infection experiments, the ΔPT strain showed no competitive disadvantage versus the wild-type strain and colonized at higher levels than in the single-strain infection experiments. To test the hypothesis that soluble PT produced by the wild-type strain in mixed infections enhanced respiratory tract colonization by ΔPT, we coadministered purified PT with the ΔPT inoculum and found that colonization was increased to wild-type levels. This effect was not observed when PT was coadministered via a systemic route. Intranasal administration of purified PT up to 14 days prior to inoculation with ΔPT significantly increased bacterial colonization, but PT administration 1 day after bacterial inoculation did not enhance colonization versus a phosphate-buffered saline control. Analysis of bronchoalveolar lavage fluid samples from mice infected with either wild-type or ΔPT strains at early times after infection revealed that neutrophil influx to the lungs 48 h postinfection was significantly greater in response to ΔPT infection, implicating neutrophil chemotaxis as a possible target of PT activity promotingB.pertussiscolonization of the respiratory tract.
Gonococcal Phospholipase D Modulates the Expression and Function of Complement Receptor 3 in Primary Cervical Epithelial Cells
Authors: Edwards Jennifer L. , Entz David D. , Apicella Michael A. 
Published: October 2003

ABSTRACT

CR3-mediated endocytosis is a primary mechanism by which
Neisseria gonorrhoeae
elicits membrane ruffling and cellular invasion of the cervical epithelia. Our data indicate that, upon infection of cervical epithelia,
N. gonorrhoeae
specifically releases proteins, including a phospholipase D (PLD) homolog, which facilitate membrane ruffling. To elucidate the function of gonococcal PLD in infection of the cervical epithelia, we constructed an
N. gonorrhoeae
PLD mutant. By comparative association and/or invasion assays, we demonstrated that PLD mutant gonococci are impaired in their ability to adhere to and to invade primary cervical cells. This defect can be rescued by the addition of supernatants obtained from wild-type-infected cell monolayers but not by exogenously added
Streptomyces
PLD. The decreased level of total cell association (i.e., adherence and invasion) observed for mutant gonococci is, in part, attributed to the inability of these bacteria to recruit CR3 to the cervical cell surface with extended infection. Using electron microscopy, we demonstrate that gonococcal PLD may be necessary to potentiate membrane ruffling and clustering of gonococci on the cervical cell surface. These data may be indicative of the inability of PLD mutant gonococci to recruit CR3 to the cervical cell surface. Alternatively, in the absence of gonococcal PLD, signal transduction events required for CR3 clustering may not be activated. Collectively, our data indicate that PLD augments CR3-mediated gonococcus invasion of and survival within cervical epithelia.
Evidence for a Novel Gene Expression Program in Peripheral Blood Mononuclear Cells fromMycobacterium aviumsubsp.paratuberculosis-Infected Cattle
Authors: Coussens Paul M. , Colvin Christopher J. , Rosa Guilherme J. M. , Perez Laspiur Juliana , Elftman Michael D. 
Published: October 2003

ABSTRACTA bovine-specific cDNA microarray system was used to compare gene expression profiles of peripheral blood mononuclear cells (PBMCs) from control uninfected (n= 4) and Johne's disease-positive (n= 6) Holstein cows. Microarray experiments were designed so that for each animal, a direct comparison was made between PBMCs stimulated in vitro withMycobacterium aviumsubsp.paratuberculosisand PBMCs stimulated with phosphate-buffered saline (nil-stimulated PBMCs). As expected,M. aviumsubsp.paratuberculosisstimulation of infected cow PBMCs enhanced expression of gamma interferon transcripts. In addition, expression of 15 other genes was significantly affected (>1.25-fold change;P< 0.05) by in vitro stimulation withM. aviumsubsp.paratuberculosis. Similar treatment of control cow PBMCs withM. aviumsubsp.paratuberculosisresulted in significant changes in expression of 13 genes, only 2 of which were also affected in PBMCs from the infected cow PBMCs. To compare gene expression patterns in the two cow infection groups (infected cows and uninfected cows), a mixed-model analysis was performed with the microarray data. This analysis indicated that there were major differences in the gene expression patterns between cells isolated from the two groups of cows, regardless of in vitro stimulation. A total of 86 genes were significantly differentially expressed (P< 0.01) inM. aviumsubsp.paratuberculosis-stimulated PBMCs from infected cows compared to expression in similarly treated PBMCs from control cows. Surprisingly, a larger number of genes (110 genes) were also found to be significantly differentially expressed (P< 0.01) in nil-stimulated cells from the two infection groups. The expression patterns of selected genes were substantiated by quantitative real-time reverse transcriptase PCR. Flow cytometric analysis indicated that there were no gross differences in the relative populations of major immune cell types in PBMCs from infected and control cows. Thus, data presented in this report indicate that the gene expression program of PBMCs fromM. aviumsubsp.paratuberculosis-infected cows is inherently different from that of cells from control uninfected cows.
Characterization of gp70 and Anti-gp70 Monoclonal Antibodies inParacoccidioides brasiliensisPathogenesis
Authors: de Mattos Grosso Daniela , de Almeida Sandro Rogério , Mariano Mario , Lopes Jose Daniel 
Published: October 2003

ABSTRACTParacoccidioidomycosis (PCM) is a systemic granulomatous mycosis whose agent isParacoccidioides brasiliensis. In the culture supernatant, the fungus expresses glycoproteins of from 13 to 148 kDa. A cell surface glycoprotein of 43 kDa is the major antigenic component ofP. brasiliensis. Another expressed glycoprotein, gp70, is recognized by 96% of sera from PCM patients and is able to induce lymphoproliferation. Since, little is known about this glycoprotein, we produced monoclonal antibodies (MAbs) against gp70 to isolate the molecule from total fungus extracts and to investigate its possible role in the pathogenesis of PCM. Using these MAbs, it was observed by confocal microscopy that gp70 is located mainly in the intracellular compartment of the fungus, although it was also detected in the culture supernatant. Based on observations showing that gp43 has a down-regulatory effect on mouse peritoneal macrophages, we tested the effects of gp70 on their phagocytic ability. Purified gp70 was able to inhibit the activity of macrophages through the mannose receptors and also through the Fc receptors; the latter effect was not observed with gp43. gp70 inhibits NO and H2O2liberation by peritoneal macrophages in vitro, as does gp43. Results obtained with gp43 led us to hypothesize that gp70 could act as an escape mechanism for fungal establishment in primary infections. To corroborate this hypothesis, we analyzed the effect of passive immunization of mice during infection withP. brasiliensisusing anti-gp70 MAbs. This treatment almost completely abolished granuloma formation in the lungs, suggesting that the protein facilitates fungal establishment and progression of lesions in primary infection.
Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R
Authors: Van Herpen Esther , Rosso Sonia M. , Serverijnen Lies‐Anne , Yoshida Hirotaka , Breedveld Guido , Van De Graaf Raoul , Kamphorst Wouter , Ravid Rivka , Willemsen Rob , Dooijes Dennis , Majoor‐Krakauer Daniëlle , Kros Johan M. , Crowther R. Anthony , Goedert Michel , Heutink Peter , Van Swieten John C. 
Published: October 2003

AbstractMutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82‐year‐old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick‐like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl‐insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly. Ann Neurol 2003;54:573–581
Valproic acid increases SMN levels in spinal muscular atrophy patient cells
Authors: Sumner Charlotte J. , Huynh Thanh N. , Markowitz Jennifer A. , Perhac J. Stephen , Hill Brenna , Coovert Daniel D. , Schussler Kristie , Chen Xiaocun , Jarecki Jill , Burghes Arthur H. M. , Taylor J. Paul , Fischbeck Kenneth H. 
Published: October 2003

AbstractSpinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7–containing SMN transcript and SMN protein in type I SMA patient–derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA. Ann Neurol 2003;54:647–654
Pulmonary complications in chronic lymphocytic leukemia
Authors: Ahmed Shahid , Siddiqui Anita K. , Rossoff Leonard , Sison Cristina P. , Rai Kanti R. 
Published: October 2003

AbstractBACKGROUNDAlthough pulmonary complications account for significant morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), to the authors' knowledge there are sparse data available in published literature. The authors evaluated pulmonary complications in patients with CLL and identified prognostic variables that predict hospital mortality in these patients.METHODSClinical data were analyzed retrospectively from patients with CLL who required hospitalization for a respiratory illness at a tertiary care institution from January 1993 to December 2001. A logistic regression analysis with a backward elimination procedure was carried out to determine prognostic variables that predict hospital mortality.RESULTSThere were 110 patients who were admitted on 142 occasions with a pulmonary complication. The median age was 75 years (range, 43–97 years), and the male:female ratio was 1.7:1.0. Among 142 admissions, 68% were high risk according to the Rai criteria, 68% of patients admitted had received prior therapy for CLL, and 35% had received treatment within 3 months of admission. The most common pulmonary complications were pneumonias (75%), malignant pleural effusion/and or lung infiltrate due to CLL (9%), pulmonary leukostasis (4%), Richter transformation or nonsmall cell lung carcinoma (3%), and upper airway obstruction (2%). Forty‐four of 110 patients (40%) died. In multivariate analysis, admission absolute neutrophil counts ≤ 0.5 × 109/L (odds ratio, 4.6; 95% confidence interval [95% CI], 1.3–16.6) and blood urea nitrogen (BUN) levels ≥ 20 mg/dL (odds ratio, 3.0; 95% CI, 1.1–8.3) were correlated significantly with mortality.CONCLUSIONSPneumonia was the major pulmonary complication in hospitalized patients with CLL. Severe neutropenia and high BUN levels were correlated significantly with increased mortality. Cancer 2003. © 2003 American Cancer Society.
Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early‐stage breast cancer
Authors:   The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists' Group
Published: October 2003

AbstractBACKGROUNDThe first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow‐up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early‐stage breast cancer, anastrozole was superior to tamoxifen in terms of disease‐free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow‐up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months).METHODSDFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial.RESULTSDFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76–0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor–positive tumors (HR, 0.82; 95% CI, 0.70–0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71–0.96; P = 0.015), with additional benefit for patients with hormone receptor–positive tumors (HR, 0.78; 95% CI, 0.65–0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38–1.02; P = 0.062), and statistical significance was achieved in the hormone receptor–positive subgroup (OR, 0.56; 95% CI, 0.32–0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent.CONCLUSIONSAfter an additional follow‐up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor–positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone‐sensitive early‐stage breast cancer. Cancer 2003. © 2003 American Cancer Society.