bluuebunny/crossref_metadata_2025_split huggingface dataset:
IFN-γ inhibits the proliferation of allergen-activated T lymphocytes from atopic, asthmatic patients by inducing Fas/FasL-mediated apoptosis
Authors: De Rose Virginia , Cappello Paola , Sorbello Valentina , Ceccarini Barbara , Gani Federica , Bosticardo Marita , Fassio Stefania , Novelli Francesco 
Published: May 2004

AbstractThe defect in interferon-γ (IFN-γ) production that results in a T helper cell type 2-dominated response may be responsible for a decrease in the apoptosis of allergen-activated T cells in asthma. We investigated the effect of recombinant IFN-γ on proliferation, Fas/Fas ligand (FasL) expression, and apoptosis in allergen-stimulated peripheral blood mononuclear cells obtained from atopic, asthmatic patients and nonatopic, control subjects. The addition of IFN-γ at the start of cultures markedly inhibited the proliferative response to a specific allergen in cells from all asthmatic patients, whereas no change was observed in cells from nonatopic, control subjects. IFN-γ induced an increase in the expression of Fas and FasL by allergen-stimulated CD4+ T cells from asthmatic patients and caused the apoptosis of these cells. A Fas-blocking monoclonal antibody prevented the inhibitory effect of IFN-γ on allergen-induced proliferation. These results suggest that IFN-γ inhibits the proliferation of allergen-stimulated CD4+ T cells from atopic, asthmatic patients by inducing the surface expression of Fas and FasL, which in turn triggers their apoptotic program. The defect in IFN-γ production involved in the allergic, immune response may therefore be responsible for a decrease in apoptosis of allergen-activated T lymphocytes in the airways of atopic, asthmatic patients.
Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Rα chain
Authors: Ratthé Claude , Girard Denis 
Published: May 2004

AbstractInterleukin-15 (IL-15) is a cytokine that possesses interesting, potential therapeutic properties. However, based on several parameters including activation of neutrophils, it is also recognized as a proinflammatory cytokine. The mechanisms by which IL-15 activates human neutrophil functions are not fully understood. Although these cells express a functional IL-15 receptor (IL-15R) composed of IL-15Rα, IL-2/15Rβ (CD122), and γc (CD132) subunits, the role of each receptor component has not been investigated in IL-15-induced human neutrophil responses. In the present study, fluorescein-activated cell sorter analysis revealed that the ability of IL-15 to enhance neutrophil phagocytosis is not a result of increased expression of IL-15Rα, CD122, or CD132 on the neutrophil cell surface. Pretreatment of neutrophils with specific antibodies to IL-15Rα, CD122, or CD132 was found to inhibit phagocytosis of opsonized-sheep red blood cells by nearly 40%, 21%, and 27%, respectively. As expected, pretreatment of neutrophils with anti-IL-2Rα (CD25) had no effect. Pretreatment of cells with the Syk inhibitor piceatannol was found to significantly inhibit the ability of IL-15 to enhance phagocytosis. In addition, IL-15 was found to induce tyrosine phosphorylation of Syk that was largely inhibited by pretreating cells with piceatannol. Moreover, we found that Syk kinase is physically associated with IL-15Rα. We conclude that IL-15R enhances neutrophil phagocytosis by a Syk-dependent mechanism and that the IL-15Rα chain plays a key role in mediating this response, at least by interacting with Syk kinase.
Cytosolic phospholipase A2 is responsible for prostaglandin E2 and leukotriene B4 formation in phagocyte-like PLB-985 cells: studies of differentiated cPLA2-deficient PLB-985 cells
Authors: Liberty I Furstenberg , Raichel L , Hazan-Eitan Z , Pessach I , Hadad N , Schlaeffer F , Levy R 
Published: May 2004

AbstractOur previously established model of cytosolic phospholipase A2 (cPLA2)-deficient, differentiated PLB-985 cells (PLB-D cells) was used to determine the physiological role of cPLA2 in eicosanoid production. Parent PLB-985 (PLB) cells and PLB-D cells were differentiated toward the monocyte or granulocyte lineages using 5 × 10−8 M 1,25 dihydroxyvitamin D3 or 1.25% dimethyl sulfoxide, respectively. Parent monocyte- or granulocyte-like PLB cells released prostaglandin E2 (PGE2) when stimulated by ionomycin, A23187, opsonized zymosan, phorbol 12-myristate 13-acetate, or formyl-Met-Leu-Phe (fMLP), and monocyte- or granulocyte-like PLB-D cells did not release PGE2 with any of the agonists. The kinetics of cPLA2 translocation to nuclear fractions in monocyte-like PLB cells stimulated with fMLP or ionomycin was in correlation with the kinetics of PGE2 production. Granulocyte-like PLB cells, but not granulocyte-like PLB-D cells, secreted leukotriene B4 (LTB4) after stimulation with ionomycin or A23187. Preincubation of monocyte-like parent PLB cells with 100 ng/ml lipopolysaccharide (LPS) for 16 h enhanced stimulated PGE2 production, which is in correlation with the increased levels of cPLA2 detected in these cells. LPS preincubation was less potent in increasing PGE2 and LTB4 secretion and did not affect cPLA2 expression in granulocyte-like PLB cells, which may be a result of their lower levels of surface LPS receptor expression. LPS had no effect on monocyte- or granulocyte-like PLB-D cells. The lack of eicosanoid formation in stimulated, differentiated cPLA2-deficient PLB cells indicates that cPLA2 contributes to stimulated eicosanoid formation in monocyte- and granulocyte-like PLB cells.
Regulation of interleukin-12 gene expression and its anti-tumor activities by prostaglandin E2 derived from mammary carcinomas
Authors: Mitsuhashi Maki , Liu Jianguo , Cao Shanjin , Shi Xiaoyan , Ma Xiaojing 
Published: May 2004

AbstractInterleukin-12 (IL-12)-mediated immune responses are critical for the control of malignant development. Tumors can actively resist detrimental immunity of the host via many routes. Prostaglandin E2 (PGE2) is one of the major immune-suppressive factors derived from many types of tumors. Here, we show that systemic administration of recombinant IL-12 could therapeutically control the growth of aggressive TS/A and 4T1 mouse mammary carcinomas. However, PGE2 produced by tumors potently inhibits the production of endogenous IL-12 at the level of protein secretion, mRNA synthesis, and transcription of the constituent p40 and p35 genes. The inhibition can be reversed by NS-398, a selective inhibitor of the enzymatic activity of cyclooxygenase 2 in PGE2 synthesis. Moreover, PGE2-mediated inhibition of IL-12 production requires the functional cooperation of AP-1 and AP-1 strongly suppresses IL-12 p40 transcription. Blocking PGE2 production in vivo results in a marked reduction in lung metastasis of 4T1 tumors, accompanied by enhanced ability of peritoneal macrophages to produce IL-12 and spleen lymphocytes to produce interferon-γ. This study contributes to the elucidation of the molecular mechanisms underlying the interaction between a progressive malignancy and the immune defense apparatus.
Exposure of Melanoma Cells to Dacarbazine Results in Enhanced Tumor Growth and Metastasis In Vivo
Authors: Lev Dina Chelouche , Onn Amir , Melinkova Vladislava O. , Miller Claudia , Stone Valerie , Ruiz Maribelis , McGary Eric C. , Ananthaswamy Honnavara N. , Price Janet E. , Bar-Eli Menashe 
Published: May 2004

Purpose In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo. Materials and Methods The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice. Results The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF. Conclusion Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.
Fate of Internalized Thyrotropin-Releasing Hormone Receptors Monitored with a Timer Fusion Protein
Authors: Cook Laurie B. , Hinkle Patricia M. 
Published: May 2004

AbstractTrafficking of TRH receptors was studied in a stable HEK293 cell line expressing receptor fused to a Timer protein (TRHR-Timer) that spontaneously changes from green to red over 10 h. Cells expressing TRHR-Timer responded to TRH with an 11-fold increase in inositol phosphate formation, increased intracellular free calcium, and internalization of 75% of bound [3H][N3-methyl-His2]TRH within 10 min. After a 20-min exposure to TRH at 37 C, 75–80% of surface binding sites disappeared as receptors internalized. When TRH was removed and cells incubated in hormone-free medium, approximately 75% of [3H][N3-methyl-His2]TRH binding sites reappeared at the surface over the next 2 h with or without cycloheximide. Trafficking of TRHR-Timer was monitored microscopically after addition and withdrawal of TRH. In untreated cells, both new (green) and old (red) receptors were seen at the plasma membrane, and TRH caused rapid movement of young and old receptors into cytoplasmic vesicles. When TRH was withdrawn, some TRHR-Timer reappeared at the plasma membrane after several hours, but much of the internalized receptor remained intracellular in vesicles that condensed to larger structures in perinuclear regions deeper within the cell. Strikingly, receptors that moved to the plasma membrane were generally younger (more green) than those that underwent endocytosis. There was no change in the red to green ratio over the course of the experiment in cells exposed to vehicle. The results indicate that, after agonist-driven receptor internalization, the plasma membrane is replenished with younger receptors, arising either from an intracellular pool or preferential recycling of younger receptors.
Regulation of the Human Secretin Gene Is Controlled by the Combined Effects of CpG Methylation, Sp1/Sp3 Ratio, and the E-Box Element
Authors: Lee Leo Tsz-On , Tan-Un Kian-Cheng , Pang Ronald Ting-Kai , Lam David Tai-Wai , Chow Billy Kwok-Chong 
Published: May 2004

AbstractTo unravel the mechanisms that regulate the human secretin gene expression, in this study, we have used secretin-expressing (HuTu-80 cells, human duodenal adenocarcinoma) and non-secretin-expressing [PANC-1 (human pancreatic ductile carcinoma) and HepG2 (human hepatocellular carcinoma) cells] cell models for in vitro and in vivo analyses. By transient transfection assays, within the promoter region (−11 to −341 from ATG, relative to the ATG initiation codon), we have initially identified several functional motifs including an E-box and 2 GC-boxes. Results from gel mobility shift and chromatin immunoprecipitation assays confirmed further that NeuroD, E2A, Sp1, and Sp3 bind to these E- and GC-boxes in HuTu-80 cells in vitro and in vivo, whereas only high levels of Sp3 is observed to bind the promoter in HepG2 cells. In addition, overexpression of Sp3 resulted in a dose-dependent repression of the Sp1-mediated transactivation. Collectively, these data suggest that the Sp1/Sp3 ratio is instrumental to controlling secretin gene expression in secretin-producing and non-secretin-producing cells. The functions of GC-box and Sp proteins prompted us to investigate the possible involvement of DNA methylation in regulating this gene. Consistent with this idea, we found a putative CpG island (−336 to 262 from ATG) that overlaps with the human secretin gene promoter. By methylation-specific PCR, all the CpG dinucleo-tides (26 of them) within the CpG island in HuTu-80 cells are unmethylated, whereas all these sites are methylated in PANC-1 and HepG2 cells. The expressions of secretin in PANC-1 and HepG2 cells were subsequently found to be significantly activated by a demethylation agent, 5′-Aza-2′ deoxycytidine. Taken together, our data indicate that the human secretin gene is controlled by the in vivo Sp1/Sp3 ratio and the methylation status of the promoter.
Coronary Event Secondary Prevention with Statins Irrespective of LDL-Cholesterol
Authors: Kerst Leslie L , Mauro Vincent F 
Published: May 2004

OBJECTIVE: To review the evidence for statin secondary prevention of coronary artery disease in patients with near-optimal or optimal low-density lipoprotein cholesterol (LDL-C). DATA SOURCES: A MEDLINE search (1966-October 2003) was conducted using the search terms HMG-CoA reductase inhibitor, statins, coronary disease, post-myocardial infarction, and average cholesterol. DATA SYNTHESIS: Secondary prevention trials enrolling subjects with near-optimal (<130 mg/dL) or optimal (<100 mg/dL) baseline LDL-C were included. Early statin secondary prevention studies suggested attenuated benefit, but more recent trials challenge this finding. CONCLUSIONS: Statin secondary prevention of coronary artery disease in patients near goal LDL-C is controversial, but recent trial results show promise.
Diabetes Mellitus Non-Glucose Monitoring: Point-of-Care Testing
Authors: Armor Becky L , Britton Mark L 
Published: May 2004

OBJECTIVE: To review and evaluate reimbursable point-of-care testing devices yielding immediate results, other than glucometers, that are available to evaluate and monitor diabetes and its complications and to describe how pharmacists may use these devices. DATA SOURCES: A MEDLINE search (1966-March 2003) was performed using the following search terms: point-of-care systems, clinical diabetes monitoring, decision support systems, glycosylated hemoglobin, and microalbumin. Pertinent company and product Web sites and customer service departments were accessed for information about point-of-care devices and supplies. STUDY SELECTION AND DATA EXTRACTION: All descriptive, evaluative, and comparative articles and product information were reviewed, and relevant information was included. DATA SYNTHESIS: Diabetes mellitus is a complex, chronic metabolic disease that is a challenging management problem and requires routine monitoring for disease control and screening for complications. Point-of-care tests are available to monitor hemoglobin A1c, glucose, fructosamine, ketones, lipid profiles, urinary microalbumin concentrations, and alanine aminotransferase concentrations. Many of these tests are Clinical Laboratory Improvement Amendments (CLIA)—waived and, therefore, practical for pharmacists to use in a variety of settings. Tests for measuring sensation are also discussed. Pharmacists should consider each of these tests in the establishment of a comprehensive diabetes care service. CONCLUSIONS: The availability of many new point-of-care testing methods creates new opportunities for pharmacists to monitor drug therapy and screen for complications in patients with diabetes. Reimbursement is possible since many of these tests are CLIA-waived.
LMWH for Perioperative Anticoagulation in Patients on Chronic Warfarin Therapy
Authors: Heuts Luke M , Arvik Beth M McLendon , Cender Dawn E 
Published: May 2004

OBJECTIVE: To review current data regarding low-molecular-weight heparin (LMWH) use for perioperative anticoagulation in patients receiving chronic warfarin therapy. DATA SOURCES: Data were obtained from the Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy guidelines and a MEDLINE search (1996-January 2003). Search terms included heparin, low-molecular-weight heparin, warfarin, perioperative care, and anticoagulants. DATA SYNTHESIS: Heparin is the most common agent used as bridge therapy for perioperative anticoagulation in patients on chronic warfarin therapy; LMWHs are also used. Studies that evaluated enoxaparin and/or dalteparin were reviewed. CONCLUSIONS: Although published studies demonstrate efficacy and safety of LMWHs, more data are needed to support their use as bridge therapy.
Continuous Subcutaneous Infusion of Opiates at End-of-Life
Authors: Anderson Stacey L , Shreve Scott T 
Published: May 2004

OBJECTIVE: To review pertinent controlled trials using the continuous subcutaneous infusion of opioids (CSIO) at end-of-life and offer insight to pharmacists and clinicians into the appropriate use of this route of administration. DATA SOURCES: A MEDLINE search for information regarding the subcutaneous administration of opioids in terminally ill patients (1975-December 2002) was conducted using the key words subcutaneous, narcotics, morphine, hydromorphone, fentanyl, pain, hospices, and palliative care. Additional references were located through review of bibliographies of the articles cited. Case reports and postsurgical studies were excluded. Searches were limited to English-language studies using humans. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational studies were evaluated, using prospective trials as the evidence base for conclusions and including pertinent retrospective trials as they relate to the subcutaneous infusion of opioids at end-of-life. DATA SYNTHESIS: CSIO is effective and safe for use in terminal illness. Appropriate situations for consideration of CSIO are when difficulties arise in using the oral route, standard oral opiate therapy has failed adequate trials, the patient has limited intravenous access, adequate supervision of the CSIO is present, and CSIO will not unduly limit the functional activity of the patient. CONCLUSIONS: CSIO has a proven role in the management of pain at end-of-life. CSIO should not be considered the first route for administration of opiates, but does offer distinct advantages in the appropriate setting. CSIO continues to be a choice for end-of-life patients and is gradually becoming a standard practice in palliative medicine.
Evaluation of a Physician-Focused Educational Intervention on Medicaid Children with Asthma
Authors: Lee Euni , McNally Diane L , Zuckerman Ilene H 
Published: May 2004

BACKGROUND: The 1990 Omnibus Budget Reconciliation Act mandated drug utilization review in response to inappropriate drug use. In the Pennsylvania Medicaid program, pediatric asthma is associated with high healthcare utilization and cost. OBJECTIVE: To determine the effects of a physician-focused educational intervention on asthma drug use and healthcare utilization. METHODS: Pre- and postintervention comparison design was used in children 5–18 years of age who were enrolled in the Pennsylvania Medicaid fee-for-service program from July 1, 1998, to March 31, 1999 (preintervention), and July 1, 1999, to March 31, 2000 (postintervention). The intervention packet included patients' drug profiles, medical history, monograph with national asthma management guidelines, and patient education materials to physicians. Main outcome measures are changes in asthma drug utilization among high-users of short-acting β2-agonists (SAB). RESULTS: The intervention focused on 2 asthma drug use criteria: (1) high-use of quick-relief medication and (2) use of salmeterol without the availability of a quick-relief medication. The intervention reduced quick-relief medication use by 26% among patients with higher use without significant changes in long-term control drugs. In addition, 82% of the recipients evaluated had a positive change in salmeterol utilization as either having an SAB inhaler added after the intervention or salmeterol discontinued after the intervention. There was no significant change in asthma-related emergency department visits or hospitalizations. CONCLUSIONS: Although the physician responders agreed on the usefulness of the educational materials, the results suggest that the intervention had limited success in improving the pharmacologic management and no effect on the health outcomes. We believe that mailed educational materials to physicians can be effective to change prescribing behavior; however, a more multifaceted intervention may be necessary to improve health outcomes.
Evaluation of Community Pharmacists' Recommendations to Standardized Patient Scenarios
Authors: Rutter Paul M , Horsley Emma , Brown David T 
Published: May 2004

BACKGROUND: Recent trends in the global nonprescription drug market show a massive increase in medicine availability to the general public. This places greater responsibility on community pharmacists to ensure that patients exercise self-care appropriately. This small study examined pharmacist performance in facilitating patient self-care. OBJECTIVE: To determine whether an appropriate course of action was taken by UK community pharmacists practicing in one geographic area when presented with 1 of 2 case scenarios: headache or abdominal pain. METHODS: A covert researcher, posing as a patient, spoke with the pharmacist on duty at each of 30 pharmacies, asking for advice on one of the scenarios. The pharmacist was interviewed and their responses were examined by an expert panel. RESULTS: Thirty pharmacies were visited resulting in 28 consultations, 14 each for both scenarios. Pharmacists performed better when counseling the “patient” with abdominal pain than headache. The majority of questions asked were categorized as being relevant by the panel (66% for headache, 89% for abdominal pain), although in both scenarios, the expected outcome of referral was observed only in 7 of the consultations for headache and in 8 cases for abdominal pain. Questioning centered on quantification and clarification of the presenting problem and rarely on questions related to history taking. CONCLUSIONS: Performance levels of the community pharmacists varied considerably. For all pharmacists to perform well, greater emphasis should be placed on eliciting information from the patient to ensure that the appropriate course of action is taken.
Intrathecal Amikacin for the Treatment of Pseudomonal Meningitis
Authors: Corpus Kimberly A , Weber Kathryn B , Zimmerman Christopher R 
Published: May 2004

OBJECTIVE: To report a case of gram-negative bacillary meningitis (GNBM) secondary to multidrug-resistant Pseudomonas aeruginosa that was treated with intravenous meropenem and intrathecal and intravenous amikacin. CASE SUMMARY: A 76-year-old Arabic woman with previous placement of an extraventricular device developed meningitis secondary to P. aeruginosa as a result of a previous pneumonia. The patient was treated with intravenous meropenem and amikacin, with the addition of intrathecal amikacin, until cerebrospinal cultures remained negative for 18 days. She did not experience any adverse effects as a result of the administration of the intrathecal amikacin. Although the meningitis subsequently resolved, the patient eventually died due to Candida glabrata fungemia. DISCUSSION: Dual therapy is recommended for patients with P. aeruginosa meningitis. In our patient, the increasing resistance to imipenem and resistance to all other potential antibiotics resulted in the use of an alternative administration technique that has not been well documented in recent literature. CONCLUSIONS: In patients who have GNBM due to P. aeruginosa, the combination of intrathecal and intravenous amikacin may be an option for therapy, especially when clinical options are limited by resistance, severity of illness, and location of the infection. More information is required and further study is needed on this topic.