bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphatidylinositol-3-Kinase Signaling Is Required for Erythropoietin-Mediated Acute Protection Against Myocardial Ischemia/Reperfusion Injury
Authors: Cai Zheqing , Semenza Gregg L.
Published: April 2004

Background—

Parenteral administration of recombinant human erythropoietin (rhEPO) to rats induces protection against myocardial ischemia/reperfusion injury 24 hours later. However, the mechanisms by which rhEPO mediates protection have not been determined.

Methods and Results—

rhEPO was perfused into isolated rat hearts over 15 minutes immediately before 30 minutes of no-flow ischemia and 45 minutes of reperfusion. Compared with saline-perfused control hearts, recovery of left ventricular developed pressure was increased in rhEPO-perfused hearts. rhEPO also increased AKT activity and decreased apoptosis. All of these effects were blocked when the phosphatidylinositol-3-kinase inhibitor wortmannin was infused with rhEPO.

Conclusions—

rhEPO provides immediate protection against ischemia/reperfusion injury in the isolated perfused rat heart that is mediated by the phosphatidylinositol-3-kinase pathway.
Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity
Authors: Schupp Michael , Janke Jürgen , Clasen Ronald , Unger Thomas , Kintscher Ulrich
Published: April 2004

Background—

Angiotensin type 1 receptor (AT
1
R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator–activated receptor-γ (PPARγ) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARγ function by ARBs.

Methods and Results—

The ARBs irbesartan and telmisartan (10 μmol/L) potently enhanced PPARγ-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3±0.1-fold induction; telmisartan: 3.1±0.3-fold induction; both
P
<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 μmol/L: 3.6±0.3-fold induction;
P
<0.01), whereas eprosartan up to 100 μmol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 μmol/L) markedly induced transcriptional activity of PPARγ by 3.4±0.9-fold and 2.6±0.6-fold (
P
<0.05), respectively, compared with 5.2±1.1-fold stimulation by the PPARγ ligand pioglitazone (10 μmol/L). Irbesartan and telmisartan also induced PPARγ activity in an AT
1
R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARγ activity independent of their AT
1
R blocking actions.

Conclusions—

The present study demonstrates that a specific subset of ARBs induces PPARγ activity, thereby promoting PPARγ-dependent differentiation in adipocytes. The activation of PPARγ demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.
Ghrelin Inhibits Proinflammatory Responses and Nuclear Factor-κB Activation in Human Endothelial Cells
Authors: Li Wei Gen , Gavrila Dan , Liu Xuebo , Wang Lixing , Gunnlaugsson Skuli , Stoll Lynn L. , McCormick Michael L. , Sigmund Curt D. , Tang Chaosu , Weintraub Neal L.
Published: April 2004

Background—

Ghrelin is a novel growth hormone-releasing peptide that has been shown to improve cachexia in heart failure and cancer and to ameliorate the hemodynamic and metabolic disturbances in septic shock. Because cytokine-induced inflammation is critical in these pathological states and because the growth hormone secretagogue receptor has been identified in blood vessels, we examined whether ghrelin inhibits proinflammatory responses in human endothelial cells in vitro and after administration of endotoxin to rats in vivo.

Methods and Results—

Human umbilical vein endothelial cells (HUVECs) were treated with or without tumor necrosis factor-α (TNF-α), and induction of proinflammatory cytokines and mononuclear cell adhesion were determined. Ghrelin (0.1 to 1000 ng/mL) inhibited both basal and TNF-α-induced cytokine release and mononuclear cell binding. Intravenous administration of ghrelin also inhibited endotoxin-induced proinflammatory cytokine production in rats in vivo. Ghrelin inhibited H
2
O
2
-induced cytokine release in HUVECs, suggesting that the peptide blocks redox-mediated cellular signaling. Moreover, ghrelin inhibited basal and TNF-α-induced activation of nuclear factor-κB. Des-acyl ghrelin had no effect on TNF-α-induced cytokine production in HUVECs, suggesting that the antiinflammatory effects of ghrelin require interaction with endothelial growth hormone secretagogue receptors.

Conclusions—

Ghrelin inhibits proinflammatory cytokine production, mononuclear cell binding, and nuclear factor-κB activation in human endothelial cells in vitro and endotoxin-induced cytokine production in vivo. These novel antiinflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.
Osteoprotegerin Is a Risk Factor for Progressive Atherosclerosis and Cardiovascular Disease
Authors: Kiechl Stefan , Schett Georg , Wenning Gregor , Redlich Kurt , Oberhollenzer Martin , Mayr Agnes , Santer Peter , Smolen Josef , Poewe Werner , Willeit Johann
Published: April 2004

Background—

Osteoprotegerin is a novel member of the tumor necrosis factor receptor superfamily and a soluble decoy receptor of the receptor activator of nuclear factor-κB ligand. Recent experimental research has implicated osteoprotegerin in atherogenesis, but epidemiological confirmation of this concept is sparse.

Methods and Results—

As part of the prospective, population-based Bruneck Study, severity, initiation, and progression of atherosclerosis were assessed in carotid arteries. Cases of incident cardiovascular disease and vascular mortality were carefully recorded over a 10-year period (1990 to 2000). Osteoprotegerin levels were measured in samples obtained at baseline and during follow-up. Serum osteoprotegerin showed a strong association with numerous vascular risk factors, including age, diabetes, markers of systemic inflammation, chronic infection, and smoking. In multivariate analyses, osteoprotegerin was significantly related to severity and 10-year progression of carotid atherosclerosis. Furthermore, a high level of osteoprotegerin was an independent risk factor for incident cardiovascular disease (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 2.2 [1.3 to 3.8];
P
=0.001) and vascular mortality (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 3.1 [1.2 to 8.2];
P
=0.010) but not for mortality due to nonvascular causes.

Conclusions—

Osteoprotegerin is an independent risk factor for the progression of atherosclerosis and onset of cardiovascular disease.
Serum Levels of the Interleukin-1 Receptor Family Member ST2 Predict Mortality and Clinical Outcome in Acute Myocardial Infarction
Authors: Shimpo Masahisa , Morrow David A. , Weinberg Ellen O. , Sabatine Marc S. , Murphy Sabina A. , Antman Elliott M. , Lee Richard T.
Published: April 2004

Background—

Mechanically overloaded cardiomyocytes secrete a soluble interleukin-1 receptor family member called ST2. Serum levels of ST2 are associated with prognosis in nonischemic heart failure, but the predictive value of ST2 in patients with acute myocardial infarction is unknown.

Methods and Results—

ST2 levels were measured in serum from 810 patients with acute myocardial infarction in the Thrombolysis In Myocardial Infarction (TIMI) 14 (362 patients) and Enoxaparin and TNK-tPA With or Without GPIIb/IIIa Inhibitor as Reperfusion Strategy in STEMI (ENTIRE)-TIMI 23 (448 patients) clinical trials. Baseline levels of ST2 were significantly higher in those patients who died (0.379 versus 0.233 ng/mL,
P
=0.0001) or developed new congestive heart failure (0.287 versus 0.233 ng/mL,
P
=0.009) by 30 days. In an analysis of outcomes at 30 days by ST2 quartiles, both death (
P
=0.001) and the combined death/heart failure end point (
P
=0.001) showed a significant graded association with levels of ST2; furthermore, in-hospital death (
P
=0.003) and death/heart failure (
P
=0.004) were also significantly associated with higher ST2 levels. In a logistic regression analysis that controlled for important clinical factors, increasing levels of ST2 remained associated with death at 30 days (
P
=0.047). ST2 levels rose during the first day after infarction and were maximal at 12 hours; ST2 levels at 12 hours were also independently associated with death at 30 days (
P
<0.001).

Conclusions—

Serum levels of the interleukin-1 receptor family member ST2 predict mortality and heart failure in patients with acute myocardial infarction. These data suggest that ST2 may be a useful biomarker and that this novel inflammatory receptor may play a role in cardiac pathophysiology.
Glucocorticoid Treatment Prevents Progressive Myocardial Dysfunction Resulting From Experimental Coronary Microembolization
Authors: Skyschally Andreas , Haude Michael , Dörge Hilmar , Thielmann Matthias , Duschin Alexej , van de Sand Anita , Konietzka Ina , Büchert Astrid , Aker Stephanie , Massoudy Parwis , Schulz Rainer , Erbel Raimund , Heusch Gerd
Published: April 2004

Background—

The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction.

Methods and Results—

Microembolization was induced by injecting microspheres (42-μm diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n=7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n=7) or 30 minutes after (n=5) microembolization. In addition, chronically instrumented dogs received either placebo (n=4) or methylprednisolone (n=4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0±2.1% (mean±SEM) at baseline to 5.8±0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0±0.7% at 4 to 6 hours after microembolization back to baseline (19.1±1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction.

Conclusions—

Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.
Independent Factors Associated With Outcomes of Parachute Mitral Valve in 84 Patients
Authors: Schaverien Mark V. , Freedom Robert M. , McCrindle Brian W.
Published: April 2004

Background—

Parachute mitral valve (PMV) is defined as a unifocal attachment of the mitral valve chordae to a single or dominant papillary muscle and may cause subvalvar obstruction. We sought to determine factors associated with outcomes.

Methods and Results—

Patients (n=84; 64% male) who presented between 1977 and 2001 at a median age of 3 days (range, birth to 5.4 years) were assessed with PMV (without atrioventricular septal defect). Associated cardiac anomalies in 99% included aortic coarctation in 68%, atrial septal defect in 54%, ventricular septal defect in 46%, aortic valve stenosis in 32%, subaortic stenosis in 20%, and left ventricular hypoplasia in 19%, with complex anomalies in 14%. Noncardiac anomalies were noted in 32%. Survival (n=18 deaths) was 82% at 1 year and 79% at 10 years, with independent risk factors including left ventricular hypoplasia (
P
<0.001) and atrial septal defect (
P
<0.003). Freedom from surgical mitral valvotomy (n=11 patients) was 95% at age 6 months and 80% at 10 years, with independent risk factors including the absence of aortic coarctation (
P
<0.02) and the presence of subaortic stenosis (
P
<0.04). There was no significant increase in mean gradient of the PMV over time, but higher gradient was independently associated with the presence of supravalvar mitral stenosis (
P
<0.001), absence of atrial septal defect (
P
<0.04), presence of ventricular septal defect (
P
<0.02), and subsequent mitral valvotomy (
P
<0.01).

Conclusions—

Outcomes for patients with PMV are dependent on the spectrum of associated cardiac lesions. The degree of mitral valve obstruction remains stable, and the majority will not require valvotomy.
Homocysteine Enhances Endothelial Apoptosis via Upregulation of Fas-Mediated Pathways
Authors: Suhara Toshimitsu , Fukuo Keisuke , Yasuda Osamu , Tsubakimoto Maki , Takemura Yukihiro , Kawamoto Hidenobu , Yokoi Toyohiko , Mogi Masaki , Kaimoto Taeko , Ogihara Toshio
Published: April 2004

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However, the underlying mechanism of endothelial cell injury in hyperhomocysteinemia has not been elucidated. In this study, we examined the effect of homocysteine (Hcy) on Fas-mediated apoptosis in endothelial cells. Hcy-induced upregulation of Fas in endothelial cells (ECs) in a dose-dependent manner. At the same time, Hcy increased intracellular peroxide in ECs. Hcy-induced Fas expression was inhibited by the treatment with catalase. Hcy increased NF-κB DNA binding activity, and adenovirus-mediated transfection of a
Iκ-B
mutant (Iκ-B mt) gene inhibited Hcy-induced Fas expression. ECs were sensitive to Fas-mediated apoptosis when exposed to Hcy. Under these condition, Iκ-B mt protected ECs from Fas-mediated apoptosis. In addition, Hcy inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP). Adenovirus-mediated transfection of constitutively active
Akt
gene abolished the Hcy-mediated downregulation of FLIP. These data suggest that upregulation of Fas expression and downregulation of FLIP is a mechanism through which Hcy induces EC apoptosis.
Tooth Loss Is Associated With an Increased Risk of Hypertension in Postmenopausal Women
Authors: Taguchi Akira , Sanada Mitsuhiro , Suei Yoshikazu , Ohtsuka Masahiko , Lee Kaoru , Tanimoto Keiji , Tsuda Mikio , Ohama Koso , Yoshizumi Masao , Higashi Yukihito
Published: April 2004

Tooth loss has been associated with an increased risk of vascular diseases such as coronary heart disease and cerebrovascular disease. Little is known whether hypertension is an important factor linking 2 phenomena in postmenopausal women. We compared an incidence of hypertension and traditional risk factors for vascular diseases between 2 age-matched groups: 67 postmenopausal women with missing teeth and 31 without missing teeth. In addition to blood pressure, serum concentration of total cholesterol, high- and low-density lipoprotein cholesterol and triglycerides, plasma angiotensin-converting enzyme activity, plasma angiotensin II concentration, plasma renin activity, and resting heart rate were measured as traditional risk factors for vascular diseases. Subjects without missing teeth had significantly lower diastolic blood pressure than did subjects with missing teeth (
P
=0.021). The former tended to have lower systolic blood pressure than did the latter (
P
=0.058). There were no significant differences in other variables between subjects with and without missing teeth. The odds ratio of having hypertension in subjects with missing teeth was 3.59 (95% confidence interval, 1.10 to 11.7) after adjustment of obesity, hypercholesterolemia, and hypertriglyceridemia. Our results suggest that hypertension may be an important factor linking tooth loss and an increased risk of vascular diseases in postmenopausal women.
What was the Victim Wearing? Literary, Economic, and Social Contexts for the Parable of the Good Samaritan
Authors: Knowles Michael
Published: April 2004

This study addresses in turn specific scriptural, economic, and social contexts for Luke's parable of the Good Samaritan (Luke 10:30-35). Reference to 2 Chron. 28:15, to contemporary Samaritan economic activity (specifically, oil and wine production), and especially to contemporary conventions of dress furthers our understanding of how the literary and narrative world of the parable relates to the literal and social world of Roman Palestine. Critical categories formulated by Russian literary theorist Mikhail Bakhtin assist in clarifying the function of these references both within the narrative and for subsequent readers of Luke's text.
In Memory of Jesus: Grief Work in the Gospels
Authors: Syreeni Kari
Published: April 2004

It may be unusual to think of the Gospels as grief work, because these documents purport to be about the resurrected and living Jesus. However, once the four canonical Gospels are interpreted from this vantage-point, many typical features of grief work and a complex development from the earliest written document to the later ones can be observed. On what grounds can the notion of grief work be applied to texts written two or three generations after the original loss (the death of Jesus)? The author contends that this is possible because grief work (1) was a matter of the emerging Christian movement at large, (2) is involved in the general notion of "coping" in changing situations, (3) becomes a literary phenomenon with the writing of the Gospels, and (4) continues to have new objects after the original loss. Finally, it is suggested that the resurrection belief itself can be seen as a "coping" device.
Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia
Authors: Kunstfeld Rainer , Hirakawa Satoshi , Hong Young-Kwon , Schacht Vivien , Lange-Asschenfeldt Bernhard , Velasco Paula , Lin Charles , Fiebiger Edda , Wei Xunbin , Wu Yan , Hicklin Daniel , Bohlen Peter , Detmar Michael
Published: April 2004

Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4+ T-lymphocytes and epidermal CD8+ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy.
Impaired platelet responses to thrombin and collagen in AKT-1–deficient mice
Authors: Chen Juhua , De Sarmishtha , Damron Derek S. , Chen William S. , Hay Nissim , Byzova Tatiana V.
Published: April 2004

We investigated the role of Akt-1, one of the major downstream effectors of phosphoinositide 3-kinase (PI3K), in platelet function using mice in which the gene for Akt-1 had been inactivated. Using ex vivo techniques, we showed that Akt-1-deficient mice exhibited impaired platelet aggregation and spreading in response to various agonists. These differences were most apparent in platelets activated with low concentrations of thrombin. Although Akt-1 is not the predominant Akt isoform in mouse platelets, its absence diminished the amount of total phospho-Akt and inhibited increases in intracellular Ca2+ concentration in response to thrombin. Moreover, thrombin-induced platelet α-granule release as well as release of adenosine triphosphate from dense granules was also defective in Akt-1-null platelets. Although the absence of Akt-1 did not influence expression of the major platelet receptors for thrombin and collagen, fibrinogen binding in response to these agonists was significantly reduced. As a consequence of impaired αIIbβ3 activation and platelet aggregation, Akt-1 null mice showed significantly longer bleeding times than wild-type mice. (Blood. 2004;104:1703-1710)
The integrin αMβ2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization
Authors: Hidalgo Andrés , Peired Anna J. , Weiss Linnea A. , Katayama Yoshio , Frenette Paul S.
Published: April 2004

The sulfated polysaccharide fucoidan can rapidly mobilize hematopoietic progenitor cells (HPCs) and long-term repopulating stem cells from the bone marrow (BM) to the circulation. While searching for mechanisms involved in this phenomenon we found that BM myeloid cells bound to fucoidan through the integrin αMβ2 (macrophage antigen-1 [Mac-1]) and L-selectin resulting in αMβ2-independent release of neutrophil elastase, but inhibition of elastase activity did not impair fucoidan-induced mobilization. Mobilization of HPCs by fucoidan was enhanced in animals deficient in αM (αM–/–) compared with wild-type (αM+/+) animals and higher plasma levels of the chemokine CXCL12/stromal cell–derived factor-1 (SDF-1) were achieved in αM–/– mice by fucoidan treatment. However, in chimeric animals harboring αM+/+ and αM–/– HPCs in the BM, αM–/– HPCs were preferentially mobilized by fucoidan, suggesting that the enhanced mobilization is cell intrinsic and does not result from altered microenvironment. Suboptimal doses of granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide (CY) also resulted in enhanced HPC mobilization in αM–/– mice compared with αM+/+ controls, but this difference was overcome when standard doses of G-CSF or CY were administered. Taken together, these data suggest that the integrin αMβ2 participates in the retention of HPCs in the BM.
Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma
Authors: Rizzieri David A. , Akabani Gamal , Zalutsky Michael R. , Coleman R. Edward , Metzler Scott D. , Bowsher James E. , Toaso Bonnie , Anderson Elizabeth , Lagoo Anand , Clayton Steve , Pegram Charles N. , Moore Joseph O. , Gockerman Jon P. , DeCastro Carlos , Gasparetto Cristina , Chao Nelson J. , Bigner Darell D.
Published: April 2004

We report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of 131I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T1/2, 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a “blocking” antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.
Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer
Authors: Dobrzynski Eric , Mingozzi Federico , Liu Yi-Lin , Bendo Elisabeth , Cao Ou , Wang Lixin , Herzog Roland W.
Published: April 2004

Immune responses to the therapeutic gene product are a potentially serious complication in treatment of genetic disease by gene therapy. Induction and maintenance of immunologic hypo-responsiveness to the therapeutic antigen is therefore critical to the success of gene-based treatment of inherited protein deficiency. Here, we demonstrate induction of antigen-specific CD4+ T-cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T-cell receptor (TCR) transgenic mice by hepatic adeno-associated virus (AAV)–mediated gene transfer. Transduced mice maintained stable circulating ova levels without evidence of an immune response. Lymph node cells and splenocytes were hypo-responsive to ova as early as day 10 after gene transfer. Numbers of TCR+CD4+ cells were reduced in secondary lymphoid organs and in the thymus by 1 to 2 months after vector administration. The remaining TCR+CD4+ cell population was anergic to ova antigen in vitro and enriched for CD25+ cells. These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T-cell tolerance to the transgene product, involving anergy and deletion mechanisms.
Expression of the β-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions
Authors: Reid Delyth M , Montoya Maria , Taylor Philip R , Borrow Persephone , Gordon Siamon , Brown Gordon D , Wong Simon Y C
Published: April 2004

Dectin-1 is a pathogen-recognition receptor on macrophages (MΦs), neutrophils, and dendritic cells (DCs). On MΦs and bone marrow-derived DCs, it has been shown to mediate the nonopsonic recognition of and response to soluble and particulate yeast β-glucans. We have optimized the immunohistochemical detection of Dectin-1 and demonstrated its expression on neutrophils, subpopulations of MΦs in splenic red and white pulp, alveolar MΦs, Kupffer cells, and MΦs and DCs in the lamina propria of gut villi. This is consistent with its role in pathogen surveillance. A significant proportion of CD11c+ splenic DCs expressed Dectin-1, but expression was not restricted to any one subset. Dectin-1 expression was low on resident MΦs and DCs of skin and was not detected on resident MΦs or DCs in kidney, heart, brain, or eye. The proposed, additional role of Dectin-1 as a coreceptor for T cell activation is supported by its expression on DCs in the T cell areas of the spleen and lymph nodes. Strong expression of Dectin-1 on subpopulations of MΦs and DCs in the medullary and corticomedullary regions of the thymus suggests a role distinct from pathogen recognition. Tissue localization thus revealed potential roles of Dectin-1 in leukocyte interactions during innate immune responses and T cell development.
Disturbed granulocyte macrophage-colony stimulating factor priming of phosphatidylinositol 3,4,5-trisphosphate accumulation and Rac activation in fMLP-stimulated neutrophils from patients with myelodysplasia
Authors: Fuhler Gwenny M , Cadwallader Karen A , Knol Gerlinde J , Chilvers Edwin R , Drayer A Lyndsay , Vellenga Edo
Published: April 2004

The production of reactive oxygen species (ROS) by human neutrophils is imperative for their bactericidal activity. Proinflammatory agents such as granulocyte macrophage-colony stimulating factor (GM-CSF) can prime ROS production in response to chemoattractants such as N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). In neutrophils from patients suffering from Myelodysplastic syndromes (MDS), a clonal, hematological disorder characterized by recurrent bacterial infections, this GM-CSF priming is severely impaired. In this study, we set out to further delineate the defects in neutrophils from MDS patients. We examined the effect of GM-CSF priming on fMLP-triggered activation of Rac, a small GTPase implicated in neutrophil ROS production. In contrast to healthy neutrophils, activation of Rac in response to fMLP was not enhanced by GM-CSF pretreatment in MDS neutrophils. Furthermore, activation of Rac was attenuated by pretreatment of neutrophils with the phosphatidylinositol 3-kinase (PI-3K) inhibitor LY294002. Unlike healthy neutrophils, fMLP-induced accumulation of the PI-3K lipid product PI(3,4,5)trisphosphate was not increased by GM-CSF pretreatment in MDS neutrophils. The disturbed Rac and PI-3K activation observed in MDS neutrophils did not appear to reflect a general GM-CSF or fMLP receptor-signaling defect, as fMLP-triggered Ras activation could be primed by GM-CSF in MDS and healthy neutrophils. Moreover, fMLP-induced activation of the GTPase Ral was also normal in neutrophils from MDS patients. Taken together, our data suggest that in neutrophils from MDS patients, a defect in priming of the PI-3K–Rac signaling pathway, located at the level of PI-3K, results in a decreased GM-CSF priming of ROS production.
Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils
Authors: Ryckman Carle , Gilbert Caroline , de Médicis Rinaldo , Lussier André , Vandal Karen , Tessier Philippe A
Published: April 2004

The neutrophil cytoplasmic protein S100A8/A9 (along with S100A8 and S100A9) is chemotactic and stimulates neutrophil adhesion by activating the β2-integrin CD11b/CD18. It is also essential to neutrophil migration in vivo in response to monosodium urate monohydrate (MSUM) crystals, the principal etiologic agent of gout. S100A8/A9 is present in the synovial fluid of patients with gout and arthritis and is secreted by activated monocytes; however, its mechanism of release by neutrophils remains unknown. The aim of this study was to identify the mechanism of stimulation of the release of S100A8/A9 by MSUM-activated neutrophils. Here, we show that S100A8/A9 is released by neutrophils stimulated with MSUM crystals and that this release could be enhanced by preincubating neutrophils with granulocyte macrophage-colony stimulating factor. Antibodies directed against CD11b and CD16 blocked the release induced by MSUM crystals, suggesting that Fc receptor for immunoglobulin G (FcγR)IIIB (CD16) and CD11b/CD18 were involved in the stimulation by MSUM crystals. Neutrophil preincubation with the Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine and the Syk tyrosine kinase inhibitor trans-3,3′,4,5′-tetrahydrozystilbene significantly reduced the release of S100A8/A9, suggesting that the Src tyrosine kinase family and Syk were involved. In addition, wortmannin reduced neutrophil release of S100A8/A9, indicating a potential involvement of phosphatidylinolitol-3 kinase in this release. Preincubation of neutrophils with the tubulin depolymerization promoters nocodazole and vincristine reduced MSUM-induced release, suggesting a tubulin-associated pathway of release. These results indicate that S100A8/A9 is released by MSUM crystal-stimulated neutrophils following activation of CD11b, CD16, Src kinases, Syk, and tubulin polymerization.
Cooperative Activation of Cultured Vagal Afferent Neurons by Leptin and Cholecystokinin
Authors: Peters J. H. , Karpiel A. B. , Ritter R. C. , Simasko S. M.
Published: April 2004

To test the hypothesis that leptin can directly activate vagal afferent neurons, we used fluorescence imaging to detect acute changes in cytosolic calcium after leptin application to primary cultures of vagal afferent neurons dissociated from adult rat nodose ganglia. We found that approximately 40% of vagal afferent neurons exposed to leptin (40 ng/ml) responded with rapid and reversible increases in cytosolic calcium. These responses were dependent upon extracellular calcium. As previously reported, about 35% of vagal afferents increase cytosolic calcium in response to the gut-peptide cholecystokinin (CCK). A majority (74%) of neurons that responded to CCK also exhibited increases in cytosolic calcium in response to leptin. In addition, synergistic increases in cytosolic calcium were observed when leptin and CCK were applied in combination. These results demonstrate that leptin acts directly on vagal afferent neurons to trigger acute influxes of extracellular calcium. Our results also suggest cooperation between leptin and CCK in the activation of some vagal afferent neurons. Acute activation of vagal afferents by leptin alone and in combination with CCK may contribute to modulation of visceral reflexes and control of food intake.
The Effect of Cys LT1 Receptor Blockade on Airway Responses to Allergen
Authors: Hendeles Leslie , Davison Donald , Harman Eloise , Sherman James M.
Published: April 2004

Study Objective. To evaluate the effect of a potent experimental leukotriene receptor antagonist, MK‐571, on airway responses to inhaled allergen.

Design. Randomized, double‐blind, placebo‐controlled, crossover trial.

Setting. Clinical research center.

Subjects. Eight male volunteers with allergic asthma.

Interventions. An intravenous loading dose was followed by an 8‐hour infusion of MK‐571 or placebo, with a 7‐ to 14‐day washout between treatments. Allergen challenge was performed after the loading dose and a histamine challenge was performed before and 24 hours after allergen.

Measurements and Main Results. Forced expiratory volume in 1 second was measured serially. MK‐571 provided about 50% protection during maximum early and late responses compared with placebo (p=0.005), but airway obstruction persisted 8–24 hours after allergen on both treatment days. Airway responsiveness to histamine was not significantly attenuated at 24 hours.

Conclusion. Blocking Cys LT1 receptors for 8 hours attenuated the early and late responses but did not interrupt the cascade of events leading to subsequent allergen‐induced airway obstruction and hyperreactivity.

(Pharmacotherapy 1999; 19(11):1243–1251)
Rotavirus Disease and Its Prevention in Infants and Children
Authors: Raebel Marsha A. , Ou Brandon S.
Published: April 2004

Rotavirus disease causes immense morbidity and mortality in developing countries. In the United States, mortality is very rare, but the health care and societal costs of rotavirus‐related morbidity exceed one billion dollars annually. A new vaccine that prevents the illness recently was marketed in the United States. Economic issues surround national recommendations for its use. Economic, safety, and effectiveness issues will be resolved only with surveillance systems that document the effectiveness of immunization programs and their cost‐effectiveness.
In Vitro Activity and Pharmacodynamics of Oral β‐Lactam Antibiotics Against Streptococcus pneumoniae from Southeast Missouri
Authors: Kays Michael B. , Wood Karriann K. , Miles Donald O.
Published: April 2004

Study Objectives. To determine the frequency of reduced susceptibility to penicillin, and to compare the in vitro activity and pharmacodynamics of oral β‐lactam antibiotics against clinical isolates of Streptococcus pneumoniae from southeast Missouri.

Setting. Cape Girardeau, Missouri (population 35,500).

Interventions. Minimum inhibitory concentrations (MICs) were determined for penicillin, amoxicillin, amoxicillin‐clavulanic acid, cefprozil, cefuroxime, cefpodoxime, cefaclor, and loracarbef by E test for 108 isolates of S. pneumoniae. The MIC50, MIC90, and percentage susceptibility were calculated for each agent. Pharmacokinetic variables were obtained from the literature, and serum concentration‐time profiles were simulated for a 25‐kg child taking pediatric dosages commonly administered to treat otitis media. The average time above MIC (T > MIC) was calculated as percentage of the dosing interval using free concentrations and the MIC for each individual isolate. Analysis of variance (Scheffe post hoc test) was used to determine differences among agents for in vitro activity and T > MIC (level of significance, p<0.05).

Measurements and Main Results. The frequency of penicillin‐nonsusceptible S. pneumoniae was 28.7% (31/108). For 25 penicillin‐intermediate isolates, amoxicillin and amoxicillin‐clavulanic acid were significantly more active than cefprozil, cefaclor, and loracarbef. The T > MIC for amoxicillin and amoxicillin‐clavulanic acid, simulated at 13.3 mg/kg every 8 hours, was significantly longer than that for all other (β‐lactams.

Conclusion. Amoxicillin and amoxicillin‐clavulanic acid have superior in vitro activity and longer T > MIC for penicillin‐intermediate isolates than the other oral β‐lactams.
Evaluation of Empiric Vancomycin Therapy in Children with Fever and Neutropenia
Authors: Adcock Kim G. , Akins Ronda L. , Farrington Elizabeth A.
Published: April 2004

A retrospective evaluation was conducted to determine which children admitted for fever and neutropenia required empiric vancomycin therapy, and to develop a clinical pathway for appropriate treatment. Chart review identified 109 admissions of 36 pediatric oncology patients for fever and neutropenia, of which 88 were eligible for analysis. Blood cultures isolated 17 gram‐positive organisms; coagulase‐negative staphylococci and viridans group streptococci were cultured most frequently (82%). We concluded that previous high‐dose cytarabine therapy, inflamed central access site, and hypotension or septic shock are possible indicators of febrile, neutropenic patients at high risk for gram‐positive pathogen isolation. These predictors then were used to determine which children would receive empiric vancomycin therapy.
Vitamin K to Reverse Excessive Anticoagulation: A Review of the Literature
Authors: Taylor Charles T. , Chester Elizabeth A. , Byrd Debbie C. , Stephens Mark A.
Published: April 2004

We conducted an extensive literature review to evaluate the appropriate use, route, and dose of vitamin K to reverse excessive anticoagulation. Issues such as sample size, study design, different patient populations, and various study end points confounded results. Of 18 studies published, 8 enrolled 229 patients to evaluate parenteral vitamin K administration. Nine studies with 288 patients evaluated oral administration, and only 2 retrospective studies (280 patients) compared routes of administration. Reductions in international normalized ratios at 24 hours ranged from 21–42%, 47–86%, 25–67%, and 40–75% for temporary warfarin discontinuation alone, and intravenous, subcutaneous, and oral routes of vitamin K administration, respectively. Methodologically weak studies and indeterminate results plague interpretation of the literature on vitamin K. In general, results of this review support current guidelines for reversing excessive warfarin anticoagulation. However, it is important to realize that the quality of literature on which these recommendations are based is poor and that optimal dose and route of vitamin K administration remain unclear. Large, well‐designed, randomized, controlled trials are necessary to define optimum management strategies for excessively anticoagulated patients.
Treatment of Parkinson's Disease with Ropinirole after Pergolide‐Induced Retroperitoneal Fibrosis
Authors: Lund Brian C. , Neiman Richard F. , Perry Paul J.
Published: April 2004

Pergolide is a dopaminergic agonist used to treat Parkinson's disease but is associated with the development of retroperitoneal fibrosis (RPF). Newer nonergot agents (pramipexole, ropinirole) may not carry this same risk. A patient with a history of pergolide‐induced RPF was treated successfully with ropinirole for 1 year without complications.
Lack of a Pharmacokinetic Interaction at Steady State Between Ropinirole and L‐Dopa in Patients with Parkinson's Disease
Authors: Taylor Anne C. , Beerahee Almisbah , Citerone David R. , Cyronak Matthew J. , Leigh Terry J. , Fitzpatrick Katherine L. , Lopez‐Gil Arturo , Vakil Sarosh D. , Burns Eileen , Lennox Graham
Published: April 2004

Study Objective. To assess the interaction between therapeutic dosages of ropinirole and l‐dopa plus a decarboxylase inhibitor administered at steady state in patients with Parkinson's disease.

Design. Open, 6‐week, overlap trial with random allocation.

Patients. Thirty patients with Parkinson's disease not previously treated with dopamine agonists, of whom 28 produced evaluable pharmacokinetic data for ropinirole and 23 for l‐dopa.

Intervention. Group A (14 patients) received l‐dopa for weeks 1–5 and ropinirole in increasing increments for weeks 2–6; group B (16) received ropinirole for weeks 1–5 and l‐dopa for weeks 5 and 6.

Measurements and Main Results. Primary end points were AUC0–8 and Cmax for ropinirole, and AUC0–8, AUC0–∞, and Cmax for l‐dopa. Secondary end points were Tmax for ropinirole, and Tmax and half‐life for l‐dopa. Coadministration with l‐dopa at steady state did not affect rate or extent of availability of ropinirole: point estimates of the geometric mean ratio for ropinirole plusl‐dopa compared with ropinirole alone for both Cmax and AUC0–8 approximated to unity. The small (16%) increase in peak concentrations of l‐dopa on administration with ropinirole is unlikely to be of clinical consequence, as peak concentrations of l‐dopa are typically highly variable.

Conclusion. There are no pharmacokinetic grounds for adjusting dosages of either ropinirole or l‐dopa when given in combination.
Pharmacokinetics of Ibuprofen in Patients with Cystic Fibrosis
Authors: Murry Daryl J. , Oermann Christopher M. , Ou Ching‐Nan , Rognerud Cheryl , Seilheimer Dan K. , Sockrider Marianna M.
Published: April 2004

Study Objectives. To determine the pharmacokinetic disposition of high doses of ibuprofen in patients with cystic fibrosis (CF), and to evaluate the reliability of intrapatient dosage adjustments to achieve recommended peak ibuprofen plasma concentrations.

Design. First‐order absorption, one‐compartment model was fit to serial ibuprofen concentration‐time data obtained from patients with CF and receiving high doses of ibuprofen 20–30 mg/kg.

Setting. Medical school‐affiliated teaching hospital.

Patients. Ninety‐eight patients with CF (53 males, 45 females; mean age 12.5 yrs).

Measurements and Main Results. The time to achieve apparent maximum ibuprofen concentration (Tmax) ranged from 1–3 hours, with maximum concentrations ranging from 21–150 μg/ml (mean 83 μg/ml). Apparent ibuprofen clearance (Cl/F) was significantly correlated with age (r2 = 0.43, p<0.0001) and measures of body size (body surface area [BSA] r2 = 0.50, p<0.0001). The Cl/F ranged from 21.1–114.7 ml/min/m2 (mean 45.5 ml/min/m2), a 5‐fold difference. The Cl/F normalized to body weight decreased with increasing age (p=0.0009), but when normalized to BSA, there was no age‐related change (p=0.65). Apparent volume of distribution was significantly correlated with age (r2 = 0.69, p<0.0001) and measures of body size (BSA r2 = 0.79, p<0.0001). Fourteen patients had ibuprofen dosage adjustments. The Cl/F was not different among doses; however, Tmax differed by an average of 1.25 hours (range 0–2 hrs).

Conclusion. The substantial variability in ibuprofen disposition and clearance we report is greater than previously described. Individualized dosages and therapeutic drug monitoring may be required to ensure plasma concentrations considered necessary to prevent pulmonary deterioration in patients with CF.
Synthesis of Symmetrical
trans
‐Stilbenes by a Double Heck Reaction of (Arylazo)Amines with Vinyltriethoxysilane: trans‐4,4′‐Dibromostilbene
Authors: Sengupta Saumitra , Sadhukhan Subir K.
Published: April 2004

trans‐4,4′‐Dibromostilbene

R 4‐Bromoaniline; Vinyltriethoxysilane

I 4‐[(Bromophenyl)azo]morpholine

P trans‐4,4′‐Dibromostilbene
(3,4,5‐Trifluorophenyl)Boronic Acid‐Catalyzed Amide Formation From Carboxylic Acids and Amines: N‐Benzyl‐4‐Phenylbutyramide
Authors: Ishihara Kazuaki , Ohara Suguru , Yamamoto Hisashi
Published: April 2004

N‐Benzyl‐4‐phenylbutyramide

R 4‐Phenylbutyric acid; Benzylamine

P N‐Benzyl‐4‐phenylbutyramide
Ammonium Compounds
Authors: Zapp Karl‐Heinz , Wostbrock Karl‐Heinz , Schäfer Manfred , Sato Kimihiko , Seiter Herbert , Zwick Werner , Creutziger Ruthild , Leiter Herbert
Published: April 2004

The article contains sections titled:

1.Ammonium Nitrate1.1.Physical and Chemical Properties1.2.Production1.2.1.From Ammonia and Nitric Acid1.2.2.Conversion of Calcium Nitrate Tetrahydrate1.3.Granulation1.4.Grain Stabilization and Surface Treatment (Conditioning)1.5.Transport Regulations1.6.Safety1.7.Uses1.8.Economic Aspects2.Ammonium Sulfate2.1.Properties2.2.Production2.2.1.From Coke‐Oven Gas2.2.2.From Ammonia and Sulfuric Acid2.2.3.Coproduct in Organic Syntheses2.2.4.From Gypsum2.2.5.Other Processes2.3.Granulation and Storage2.4.Uses2.5.Economic Aspects3.Ammonium Chloride3.1.Properties3.2.Production3.2.1.Modified Solvay (Ammonia ‐ Soda Ash) Process3.2.2.Direct Reaction Between HCl and NH33.2.3.Reaction of Reciprocal Pairs of Salts3.3.Corrosion3.4.Packaging, Storage, Shipping, and Handling3.5.Uses4.Ammonium Carbonates4.1.Ammonium Hydrogencarbonate4.2.Ammonium Carbamate4.3.Ammonium Carbonate4.4.Storage, Transport, and Handling4.5.Uses5.Toxicology and Occupational Health
Isotopes, Natural
Authors: Miller Mark A. , Carey A. Andrew
Published: April 2004

The article contains sections titled:

1.Fundamentals1.1.Definitions and Nomenclature1.2.Survey of Natural Nuclides1.3.Origins of Nuclides1.4.Discovery of Isotopes1.5.Determination of Isotopic Masses and Abundance1.6.Atomic Mass Scales1.7.Variations in Abundance2.Properties of Isotopes2.1.Physical Differences2.1.1.Mass Effects2.1.2.Nuclear Effects2.2.Chemical Differences2.2.1.Equilibrium Effects2.2.2.Kinetic Effects2.2.3.Bonding Effects2.3.Isotope Effects in Nature3.Uses of Isotopes3.1.Nuclear Energy3.2.Research3.2.1.Nuclear Magnetic Resonance3.2.2.Electron Spin Resonance3.2.3.Mössbauer Spectroscopy3.2.4.Isotopic Substitution3.2.5.Cosmology3.2.6.Nuclear Science3.2.7.Materials Science3.2.8.Ecological Research3.2.9.Isotope Chronostratigraphy3.2.10.Anthropology3.3.Medical Uses3.3.1.Magnetic Resonance Imaging3.3.2.Stable Isotopes in Metabolic Studies3.3.3.Stable Isotopes in Medical Diagnosis3.3.4.Stable Isotopes as Radioisotope Precursors3.4.Industrial Uses4.Isotope Separation4.1.The Separation Factor4.1.1.Continuous Processes and Cascades4.1.2.Discontinuous Processes4.2.Separation Processes4.2.1.Distillation4.2.2.Diffusion4.2.3.Gas Centrifugation4.2.4.Nozzle Separation4.2.5.Electromagnetic Separation4.2.6.Exchange Reactions4.2.7.Photochemical Separation4.2.8.Electrolysis4.2.9.Electromigration4.2.10.Other Separation Processes5.Availibility
Laxatives
Authors: Engelhorn Robert , Seeger Ernst , Zwaving Jan H.
Published: April 2004

The article contains sections titled:1.Introduction and History2.Types of Laxatives2.1.Emollients (Lubricants)2.1.1.Paraffinum Liquidum2.1.2.Glycerol2.1.3.Dioctyl Sodium Sulfosuccinate2.2.Bulking Agents2.2.1.Agar2.2.2.Linseed2.2.3.Plantago Seed2.2.4.Methylcellulose2.2.5.Tragacanth2.2.6.Wheat Bran2.3.Osmotically Active Substances2.3.1.Sodium Sulfate2.3.2.Magnesium Sulfate2.3.3.Sugars and Sugar Alcohols2.4.Antiabsorptive and Secretion‐Stimulating Substances and Compounds that Selectively Increase the Rate of Colonic Peristalsis2.4.1.Synthetic Diphenol Laxatives2.4.2.Naturally Occurring Laxatives2.4.3.Anthraquinone Laxatives
Lecithin
Authors: Tanno Hiroyuki
Published: April 2004

The article contains sections titled:1.Introduction2.Production3.Commercial Grades of Lecithin4.Physical Properties5.Chemical Properties6.Uses7.Quality Specifications and Analysis