bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoperfused mouse flow chamber reveals synergistic neutrophil accumulation through P-selectin and E-selectin
Authors: Smith Michael L , Sperandio Markus , Galkina Elena V , Ley Klaus 
Published: April 2004

AbstractTo study rolling of mouse neutrophils on P- and E-selectins in whole blood and without cell isolation, we constructed an autoperfused flow chamber made from rectangular microslides (0.2×2 mm) perfused from a carotid artery catheter. A differential pressure transducer served to measure wall shear stress. Green fluorescent neutrophils rolled on P-selectin but not E-selectin coated at 50 ng/ml, with some rolling on E-selectin at 150 ng/ml. However, when P- and E-selectins were coimmobilized, the resulting number of rolling neutrophils was sixfold and fourfold higher than on P- or E-selectin alone. Velocity and flux analysis shows that P-selectin initiates neutrophil rolling, and a small amount of E-selectin, unable to capture many neutrophils, reduces the rolling velocity of all neutrophils by more than 90%. The unexpected synergism between E- and P-selectins explains why neutrophil recruitment is enhanced when both selectins are expressed.
Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients
Authors: Badolato Raffaele 
Published: April 2004

AbstractThe identification of chemokines has profoundly changed the way we interpret the immune response, elucidating the mechanism by which inflammatory cells are recruited to the site of infection by local secretion of chemoattractants such as CXC chemokine ligand 8 (CXCL8)/interleukin-8, chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1. This novel view of the immune response has been remodeled further following observations that lymphoid tissue development derives from the coordinated secretion of homeostatic chemokines such as CCL19, CCL21, and CXCL13, which mediate recruitment and clustering of the cells involved in lymphoid organogenesis. The study of primary immunodeficiencies has demonstrated that the number of circulating leukocytes is dependent on migration amongst bone marrow, blood circulation, and inflamed tissues. Defects of leukocyte adhesion and chemotaxis as a result of mutations of β2-integrins lead to abnormal leukocytosis and susceptibility to skin infections, as observed in leukocyte adhesion deficiency. Conversely, neutropenia in children with myelokathexis is a result of leukocyte retention in the bone marrow because of the mutations of CXC chemokine receptor 4, which affect the capacity of cells to recirculate between blood and bone marrow. Moreover, the identification of the genetic basis of primary immunodeficiencies has shown that many primary immunodeficiencies such as Wiskott-Aldrich syndrome and common variable immunodeficiencies are characterized by altered migration of leukocytes and/or disregulation of cellular response to chemokines. This paper will be focused on the interpretation of primary immunodeficiencies as defects in leukocyte circulation between blood and primary and secondary organs.
Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-α and IL-6 production
Authors: Akaogi Jun , Yamada Hidehiro , Kuroda Yoshiki , Nacionales Dina C , Reeves Westley H , Satoh Minoru 
Published: April 2004

AbstractProstaglandin E2 (PGE2) can have pro- or anti-inflammatory effects, depending on engagement of different PGE2 receptor (EP) subtypes. The role of EPs in regulating autoimmune inflammation was studied in the murine arthritis/lupus model induced by pristane. Peritoneal macrophages were isolated (biomagnetic beads) from BALB/c, DBA/1, or C57BL/6 mice treated with pristane (intraperitoneally, 3 months earlier) or thioglycolate (3 days earlier) or with untreated controls. EPs, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Cells were cultured unstimulated or stimulated with lipopolysaccharide (LPS) or LPS + interferon-γ in combination with EP subtype-specific agonists. Tumor necrosis factor α (TNF-α) and interleukin (IL)-6 production was tested by enzyme-linked immunosorbent assay (culture supernatant) and flow cytometry. TNF-α mRNA levels also were examined. High levels of EPs (EP4/2&gt;EP1&gt;EP3), iNOS, and COX-2 mRNA were expressed in peritoneal macrophages from pristane-treated but not untreated or thioglycolate-treated mice (RT-PCR). TNF-α production was inhibited 50–70% at 2–24 h by EP4/2 agonists, whereas IL-6 was enhanced up to ∼220%. TNF-α inhibition is mediated partly via the protein kinase A pathway and partly via IL-6. Intracellular TNF-α staining was inhibited 20% by EP4/2 agonists. TNF-α mRNA levels were inhibited 50–70% at 2–24 h, indicating that TNF-α inhibition was partly at the level of transcription. EP1/3 agonists had little effect. Synovial cells from mice with pristane-induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF-α production. PGE2 can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF-α and IL-6. Modification of EP signaling may be a new therapeutic strategy in inflammatory/autoimmune diseases.
Identification of two immunogenic domains of the prion protein—PrP—which activate class II-restricted T cells and elicit antibody responses against the native molecule
Authors: Gregoire Sylvie , Logre Caroline , Metharom Pat , Loing Estelle , Chomilier Jacques , Rosset Martine Bruley , Aucouturier Pierre , Carnaud Claude 
Published: April 2004

AbstractRecent reports suggest that immunity against the prion protein (PrP) retards transmissible spongiform encephalopathies progression in infected mice. A major obstacle to the development of vaccines comes from the fact that PrP is poorly immunogenic, as it is seen as self by the host immune system. Additional questions concern the immune mechanisms involved in protection and the risk of eliciting adverse reactions in the central nervous system of treated patients. Peptide-based vaccines offer an attractive strategy to overcome these difficulties. We have undertaken the identification of the immunogenic regions of PrP, which trigger helper T cells (Th) associated with antibody production. Our results identify two main regions, one between the structured and flexible portion of PrP (98–127) and a second between α 1 and α 2 helix (143–187). Peptides (30-mer) corresponding to these regions elicit class II-restricted Th cells and antibody production against native PrP and could therefore be of potential interest for a peptide-based vaccination.
Vascular viewpoint
Authors: Anand Sonia S 
Published: April 2004

Question: To determine by how much statins reduce serum concentrations of low density lipo-protein (LDL) cholesterol according to drug, dose, and duration of treatment. Population: Patients included in randomized, placebo-controlled trials of six statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin). Design and methods: Meta analysis of 164 short-term, randomized trials including 24 000 drug-treated and 14000 placebo-treated patients. Studies were found by searching Medline, the Cochrane Collaboration, Web of Science databases, and BMJ.com. All double-blind, placebo-controlled trials were considered eligible. Excluded trials were those with no placebo group, any which lasted less than 2 weeks, those that used titrated doses, those that used combination drugs to lower cholesterol, crossover trials, or those with chronic renal failure patients. The efficacy of each statin was defined as the reduction of LDL for a given dose of a statin expressed as the change in the treated group minus that in the placebo group. Results: The doses of atorvastatin, lovastatin, rosuvastatin and simvastatin used to lower LDL by an absolute amount of 1.8 mmol=l or 40% are shown in the table. Pravastatin and fluvastatin were a less effective treatment, with maximum doses (80 mg=day) lowering LDL by 1.58 mmol=l and 1.60 mmol=l, respectively. Statins increased high density lipoprotein cholesterol by 0.07 mmol=l on average with no dose effects observed. For safety outcomes, 1063=14 197 statin patients compared with 923=10 568 control patients reported one or more symptoms possibly associated with the drug. Rhabdomyolysis was observed in eight statin patients compared with five placebo patients. [Table: see text] Conclusion: Statins can lower the LDL cholesterol concentration by an average of 1.8 mmol=l, and the LDL lowering effect varies across statin type and dose: simvastatin, lovastatin, atorvastatin and rosuvastatin appearing more effective, and fluvastatin and pravastatin appearing less effective.
Impact of BRCA1/BRCA2 Counseling and Testing on Newly Diagnosed Breast Cancer Patients
Authors: Schwartz Marc D. , Lerman Caryn , Brogan Barbara , Peshkin Beth N. , Hughes Halbert Chanita , DeMarco Tiffani , Lawrence William , Main David , Finch Clinton , Magnant Colette , Pennanen Marie , Tsangaris Theodore , Willey Shawna , Isaacs Claudine 
Published: April 2004

Purpose Approximately 5% to 10% of newly diagnosed breast cancer patients carry a BRCA1 or BRCA2 mutation. Given these patients' high risk for contralateral breast cancer, bilateral mastectomy is increasingly considered a treatment option for newly diagnosed BRCA1/2 carriers. In the present study, we prospectively evaluated the impact on surgical decision-making of pretreatment genetic counseling and BRCA1/BRCA2 testing among breast cancer patients at high-risk for carrying a mutation. Patients and Methods Participants were 194 newly diagnosed breast cancer patients who had not yet received definitive surgical treatment and who had at least a 10% prior probability of carrying a BRCA1/2 mutation. Participants were offered free genetic counseling and rapid BRCA1/2 testing. Primary analyses focused on the impact of BRCA1/2 test result on subsequent breast cancer surgical treatment. Results Forty-eight percent of patients who were found to carry a BRCA1/2 mutation chose bilateral mastectomy as their definitive breast cancer surgery. In contrast, 24% of patients in whom no mutation was detected and 4% of test decliners opted for bilateral mastectomy. Additional predictors of bilateral mastectomy included patients' self-reports of physician recommendations for BRCA1/2 testing and bilateral mastectomy. Conclusion This study highlights patient interest in and the technical feasibility of offering presurgery BRCA1/2 testing to high-risk patients. Most importantly, these results demonstrate that BRCA1/2 test results significantly affect patients' surgical decision-making. The availability of genetic counseling and testing could serve as a valuable aid to patient decision-making for newly diagnosed breast cancer patients at high-risk for carrying a mutation.
Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III Colon Cancer: Who Benefits and by How Much?
Authors: Gill Sharlene , Loprinzi Charles L. , Sargent Daniel J. , Thomé Stephan D. , Alberts Steven R. , Haller Daniel G. , Benedetti Jacqueline , Francini Guido , Shepherd Lois E. , Francois Seitz Jean , Labianca Roberto , Chen Wei , Cha Stephen S. , Heldebrant Michael P. , Goldberg Richard M. 
Published: April 2004

Purpose Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. Patients and Methods Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. Results Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Conclusion Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs . This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.
Eplerenone, But Not Steroid Withdrawal, Reverses Cardiac Fibrosis in Deoxycorticosterone/ Salt-Treated Rats
Authors: Young Morag , Funder John W. 
Published: April 2004

Abstract
Aldosterone has been thought to act primarily on epithelia to regulate fluid and electrolyte homeostasis. Mineralocorticoid receptors (MR), however, are also expressed in nonepithelial tissues, such as the heart and vascular smooth muscle. Recently, pathophysiological effects of nonepithelial MR activation by aldosterone have been demonstrated in the context of inappropriate mineralocorticoid levels for salt status, including coronary vascular inflammation and cardiac fibrosis. These effects are mostly prevented by the concomitant administration of MR antagonists, but to date, no equivalent studies have determined whether MR blockade can reverse established inflammation and fibrosis. Uninephrectomized rats maintained on 0.9% NaCl solution to drink were treated as follows: group 1 served as controls; group 2 received deoxycorticosterone (DOC; 20 mg/wk) for 4 wk until death, and group 3 received DOC for 8 wk. Group 4 received DOC for 4 wk and no steroid from wk 5–8; group 5 received DOC for 8 wk and eplerenone in their chow during wk 5–8. DOC progressively raised cardiac collagen accumulation at 4 and 8 wk. Rats given DOC for 4 wk and killed at 8 wk showed levels of fibrosis identical to those in animals killed at 4 wk, i.e. persistently elevated above control values. Rats given DOC for 8 wk and eplerenone for the second half of the period showed cardiac collagen levels indistinguishable from control values. Values for inflammatory marker and NAD(P)H oxidase subunit expression in coronary vessels showed a similar pattern of response, with minor variation. Thus, MR antagonists do not only prevent cardiac fibrosis, but also reverse cardiac fibrosis once it is established. In addition, the continuing vascular inflammatory response and fibrosis after DOC withdrawal (group 4) support a role for activation of vascular MR by endogenous glucocorticoids in the context of tissue damage and generation of reactive oxygen species.
Thyroid Hormone Affects Secretory Activity and Uncoupling Protein-3 Expression in Rat Harderian Gland
Authors: Chieffi Baccari Gabriella , Monteforte Rossella , de Lange Pieter , Raucci Franca , Farina Paola , Lanni Antonia 
Published: April 2004

Abstract
The effects of T3 administration on the rat Harderian gland were examined at morphological, biochemical, and molecular levels. T3 induced hypertrophy of the two cell types (A and B) present in the glandular epithelium. In type A cells, the hypertrophy was mainly due to an increase in the size of the lipid compartment. The acinar lumina were filled with lipoproteic substances, and the cells often showed an olocrine secretory pattern. In type B cells, the hypertrophy largely consisted of a marked proliferation of mitochondria endowed with tightly packed cristae, the mitochondrial number being nearly doubled (from 62 to 101/100 μm2). Although the average area of individual mitochondria decreased by about 50%, the total area of the mitochondrial compartment increased by about 80% (from 11 to 19/100 μm2). This could be ascribed to T3-induced mitochondrial proliferation. The morphological and morphometric data correlated well with our biochemical results, which indicated that mitochondrial respiratory activity is increased in hyperthyroid rats. T3, by influencing the metabolic function of the mitochondrial compartment, induces lipogenesis and the release of secretory product by type A cells. Mitochondrial uncoupling proteins 2 and 3 were expressed at both mRNA and protein levels in the euthyroid rat Harderian gland. T3 treatment increased the mRNA levels of both uncoupling protein 2 (UCP2) and UCP3, but the protein level only of UCP3. A possible role for these proteins in the Harderian gland is discussed.
Extrahypothalamic Expression of the Glucagon-Like Peptide-2 Receptor Is Coupled to Reduction of Glutamate-Induced Cell Death in Cultured Hippocampal Cells
Authors: Lovshin J. A. , Huang Q. , Seaberg R. , Brubaker P. L. , Drucker D. J. 
Published: April 2004

AbstractProglucagon-derived glucagon-like peptide-2 (GLP-2) is liberated in enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract, whereas GLP-2 action in the central nervous system remains poorly defined. We identified proglucagon and GLP-2 receptor (GLP-2R) mRNA transcripts by RT-PCR in multiple regions of the developing and adult rat central nervous system. GLP-2R mRNA transcripts were localized by in situ hybridization to the hippocampus, hypothalamus, nucleus of the solitary tract, parabrachial nucleus, supramammillary nucleus, and substantia nigra. The bioactive form of GLP-2, GLP-2-(1–33) was detected by RIA and HPLC analysis in the fetal and adult brainstem and hypothalamus. GLP-2 stimulated increases in cAMP accumulation in postnatal d 8, but not embryonic d 14, dispersed neonatal rat brainstem tissues. The actions of GLP-2 were independent of the GLP-1R antagonist exendin-(9–39), and GLP-2 stimulated cAMP accumulation in hippocampal cell cultures from both wild-type and GLP-1R−/− mice. GLP-2 significantly reduced glutamate-induced excitotoxic injury in hippocampal cells via a protein kinase A-dependent pathway, but had no effect on the rate of cell proliferation. These findings establish the presence of a functional GLP-2-GLP-2R axis in the developing rodent brain and demonstrate that GLP-2 exerts cytoprotective actions in cells derived from the central nervous system.
Penile Development Is Initiated in the Tammar Wallaby Pouch Young during the Period when 5α-Androstane-3α,17β-Diol Is Secreted by the Testes
Authors: Leihy Michael W. , Shaw Geoffrey , Wilson Jean D. , Renfree Marilyn B. 
Published: April 2004

AbstractVirilization of the urogenital tract is under the control of testicular androgens in all mammals. In tammar young, prostate differentiation begins between d 20 and d 40 under the control of the testicular androgen 5α-androstane-3α,17β-diol (5α-adiol), but uncertainties exist about the control of penile development. We performed longitudinal studies up to d 150 of pouch life to define normal penile development and the effects of androgen administration and castration. In control animals the male phallus was longer than the female phallus by d 48. Closure of the urethra in males begins around d 60 and continues to at least d 150. Administration of supraphysiological doses of testosterone to females caused penile development equivalent to that of the male and also induced partial closure of the urethral groove by d 150. Castration of male pouch young at d 25 prevented penile development, whereas the penis in males castrated at d 40, 80, or 120 had partial closure of the urethral groove. Administration of 5α-adiol to females from d 20–40 also caused partial closure of the urethral groove and some growth of the phallus at d 150, whereas 5α-adiol treatment from d 40–80 or 80–120 caused some penile growth but had little effect on urethral development. These findings, together with the fact that we found no sex differences in plasma levels of testosterone, dihydrotestosterone, 5α-adiol, dehydroepiandrosterone, or androstenedione from d 51–227, clearly indicate that the action of 5α-adiol between d 20 and 40 imprints later differentiation of the male penis.
Genetic Background (C57BL/6J Versus FVB/N) Strongly Influences the Severity of Diabetes and Insulin Resistance in ob/ob Mice
Authors: Haluzik Martin , Colombo Carlo , Gavrilova Oksana , Chua Streamson , Wolf Nicole , Chen Min , Stannard Bethel , Dietz Kelly R. , Le Roith Derek , Reitman Marc L. 
Published: April 2004

Abstract
We studied the effects of genetic background on the phenotype of ob/ob mice, a model of severe obesity, insulin resistance, and diabetes caused by leptin deficiency. Despite a comparable degree of obesity and hyperinsulinemia, C57BL/6J ob/ob mice had much milder hyperglycemia and, surprisingly, normal circulating adiponectin levels despite still-prominent signs of insulin resistance. Hyperinsulinemic-euglycemic clamp revealed relatively less whole-body and muscle insulin resistance in C57BL/6J ob/ob mice, whereas liver insulin resistance tended to be more severe than in FVB/N ob/ob mice. C57BL/6J ob/ob mice had also more rapid clearance of circulating triglycerides and more severe hepatic steatosis. We suggest that strain-related distinction in lipid handling is the most important player in the differences in diabetic phenotype and insulin sensitivity, whereas the impact of circulating adiponectin levels on the overall phenotype of ob/ob mice is less important.
Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar
Authors: Hegarty Bronwyn D. , Furler Stuart M. , Oakes Nicholas D. , Kraegen Edward W. , Cooney Gregory J. 
Published: April 2004

AbstractAgonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P &lt; 0.01). This improvement in insulin action was associated with decreased diglyceride (P &lt; 0.05) and long chain acyl coenzyme A (P &lt; 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P &lt; 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P &lt; 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.