bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics and Prognosis of Chinese Patients with Anti-Glomerular Basement Membrane Disease
Authors: Cui Zhao , Zhao Ming-hui , Xin Gang , Wang Hai-yan
Published: January 2005

Background: Patients with anti-glomerular basement membrane (GBM) disease were predominantly reported in Caucasian population and reports from Chinese were lacking. The general picture of Chinese patients with anti-GBM disease was still unclear. This study is to investigate the characteristics and prognosis of Chinese patients with anti-GBM disease. Methods: Data from 105 patients with anti-GBM disease diagnosed in our hospital, between 1997 and 2002, were analyzed retrospectively. All the 105 sera were screened by enzyme-linked immunosorbent assay (ELISA) using highly purified bovine α(IV)NC1 as solid phase ligands. Clinical and pathological data of 69 patients with complete clinical remission (n = 5), partial remission (n = 10), and treatment failure (n = 54) were compared and the prognostic factors were evaluated. Results: Patients increased chronologically and three quarters of the 105 patients were diagnosed in the last 3 years. Most of the patients were between 20 and 29 years (n = 31) and a smaller second peak was found in patients over 60 years. 25/105 (24%) were also ANCA-positive. Patients with both anti-GBM antibodies and ANCA positive were elder (50 ± 19 vs. 34 ± 15 years, p < 0.01) and female predominant (15/25 vs. 16/80, p < 0.05). 56/97 (58%) patients presented as Goodpasture syndrome, 40/97 (41%) patients presented as rapidly progressive glomerulonephritis and one patient had pulmonary hemorrhage only. The following factors predict poor prognosis: (1) serum creatinine more than 600 µmol/l on diagnosis (p < 0.01); (2) oliguria or anuria on diagnosis (p < 0.01); (3) a high percentage (>85%) of glomeruli had crescents (p < 0.01), and (4) renal involvement before pulmonary hemorrhage (p < 0.05). Patients with serum creatinine over 600 µmol/l on diagnosis had higher levels of anti-GBM antibodies (106 ± 48% vs. 73 ± 40%, p < 0.01). Intensive plasma exchange therapy predicts a better prognosis in the patients with serum creatinine less than 600 µmol/l (p < 0.05). Conclusions: Anti-GBM disease is not rare in China and behaves similarly to elsewhere. Early diagnosis and intensive plasmapheresis might be the most promising approaches to improve the outcome.
Reperfusion after Severe Local Perfusion Deficit Precedes Hemorrhagic Transformation: An MRI Study in Acute Stroke Patients
Authors: Fiehler Jens , Remmele Christian , Kucinski Thomas , Rosenkranz Michael , Thomalla Götz , Weiller Cornelius , Zeumer Hermann , Röther Joachim
Published: January 2005

Background: We applied magnetic resonance imaging to analyze the degree of local diffusion and perfusion abnormalities and the status of reperfusion in regions with subsequent hemorrhagic transformation (HT). Methods: 51 patients with acute ischemic stroke were studied by diffusion- and perfusion-weighted imaging within 3.0 ± 0.8 h, on day 1 and days 5–8. After realignment of the image data sets, the parameter maps of the apparent diffusion coefficient (ADC), cerebral blood flow (CBF) and cerebral blood volume (CBV), and mean transit time were analyzed in the area of subsequent HT. The degree of local diffusion and perfusion impairment in the HT area was compared with the entire diffusion and perfusion abnormality. Reperfusion status was separately assessed for the entire perfusion abnormality and the HT area. Results: HT was observed in 19/51 patients (37.2%) within 8 days after symptom onset. Areas destined for HT revealed a more severe decrease in ADC (to 70 ± 13%; p < 0.01), CBV (to 31 ± 26%; p < 0.001) and CBF (to 28 ± 19%; p < 0.001) compared to the entire perfusion abnormality. Local reperfusion in the HT area was seen in 18/19 patients. The presence of HT did not coincide with a worse clinical outcome. Discussion: HT is the result of reperfusion in the region with the most severe local perfusion impairment and does not influence the neurological outcome.
Misoprostol 50 μg Sublingually versus Vaginally for Labor Induction at Term: A Randomized Study
Authors: Caliskan Eray , Bodur Harika , Ozeren Semih , Corakci Aydin , Ozkan Sabiha , Yucesoy Izzet
Published: January 2005

Objective: To compare the efficacy of misoprostol 50 µg vaginally and 50 µg sublingually for labor induction at term. Materials and Methods: One hundred and sixty women were randomized to receive misoprostol 50 µg vaginally (n = 80) or 50 µg sublingually misoprostol (n = 80). The doses were given every 4 h (maximum 6 doses). Primary outcome measure was number of cesarean deliveries. Induction to delivery time, delivery within 24 h, the number of misoprostol doses given; the need for oxytocin augmentation, tachysystole and uterine hyperstimulation rates and neonatal outcomes were secondary outcome measures. Results: The mean induction to delivery time was 748 ± 379 min in the vaginal group and 711 ± 425 in the sublingual group (p = 0.56). The number of women delivering within 24 h was 73 (91.3%) in the vaginal group and 74 (92.5%) in the sublingual group (p = 0.78). The mean number of misoprostol doses required was significantly higher in the sublingual group (1.9 ± 1.2) compared with the vaginal group (1.1 ± 0.4; p < 0.001). More women in the sublingual group experienced tachysystole (n = 14, 17.5%) compared with the vaginal group (n = 3, 3.8%; p = 0.005). Seven cases (8.8%) in the vaginal group and 12 cases in the sublingual group (15%) required emergent cesarean delivery for fetal heart rate abnormalities (p = 0.22). Other neonatal outcomes including umbilical artery pH, Apgar scores and intensive care unit admission were similar in the two groups. Conclusion: Sublingual misoprostol is as efficacious as vaginal misoprostol for induction of labor. More frequent tachysystole is observed with misoprostol 50 µg sublingually, but neonatal outcomes are similar.
Adrenal Influences on the Inhibitory Effects of Procaterol, a Selective Beta-Two-Adrenoceptor Agonist, on Antigen-Induced Airway Microvascular Leakage and Bronchoconstriction in Guinea Pigs
Authors: Ikezono Katsumi , Kamata Masayuki , Mori Toyoki
Published: January 2005

While the guinea pig has been the preferred choice for use as a model of allergic bronchial asthma in the evaluation of anti-asthmatic drugs, it has been shown that antigen-induced bronchoconstriction in guinea pigs is attenuated by epinephrine released from the adrenal gland. In order to investigate the possible influence of the adrenal gland on the effects of antiexudative and bronchodilative drugs on antigen-induced airway responses, we examined the inhibitory effects of procaterol, a selective β2-adrenoceptor agonist, on antigen-induced airway microvascular leakage and bronchoconstriction in adrenalectomized guinea pigs and compared them with the drug’s effects in sham-operated animals. Guinea pigs sensitized passively with anti-ovalbumin (OA) guinea-pig serum were adrenalectomized or sham-operated under urethane anesthesia and examined 30 min after surgery in the following experiments. (1) Animals were intravenously administered Evans blue dye to quantify airway plasma exudation, and then OA was inhaled for 10 min while measuring pulmonary inflation pressure, a parameter of bronchoconstriction. Procaterol (1, 3, 10, or 30 µg/kg) or saline (control) was administered into the airways 10 min prior to OA inhalation. The amount of extravasated Evans blue dye in the airways was calculated. (2) Venous blood samples were collected during OA or saline inhalation and plasma catecholamine levels were compared. In control animals, OA-induced increases in both the amount of Evans blue dye and in pulmonary inflation pressure were markedly greater in adrenalectomized animals than in sham-operated animals. Procaterol dose-dependently inhibited OA-induced airway microvascular leakage and bronchoconstriction, and its effects were more potent in adrenalectomized animals (significant at 1 µg/kg and higher) than in sham-operated animals (significant at 10 µg/kg and higher). Although the plasma concentration of epinephrine during OA inhalation was approximately 3 times higher than that during saline inhalation in sham-operated animals, no difference was seen in adrenalectomized animals. In conclusion, while procaterol essentially possesses pronounced inhibitory effects on antigen-induced airway microvascular leakage and bronchoconstriction in guinea pigs, the effects are considerably masked by epinephrine released from the adrenal gland.
Fexofenadine Improves the Quality of Life and Work Productivity in Japanese Patients with Seasonal Allergic Rhinitis during the Peak Cedar Pollinosis Season
Authors: Okubo Kimihiro , Gotoh Minoru , Shimada Kenichi , Ritsu Masayo , Okuda Minoru , Crawford Bruce
Published: January 2005

Background: Although currently in its infancy, quality of life (QOL) research in Japan is rapidly expanding and is expected to become a standard outcome measure in clinical trials. In Japan, QOL has not previously been assessed in patients with allergic rhinitis (AR); we report the first clinical study applying the recently validated Japanese translations of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) Questionnaire to assess the effects of the oral antihistamine, fexofenadine, on QOL and work productivity due to cedar pollinosis. Patients and Methods: A randomized, double-blind, placebo-controlled, single-site study was conducted during the peak cedar pollinosis season in Japan. After a 7-day run-in period, subjects were randomized to receive fexofenadine HCl 60 mg twice daily (bid) or placebo for 2 weeks. Results: Overall, 206 Japanese subjects with AR were included in the intention-to- treat population (fexofenadine, n = 104, and placebo, n = 102). Fexofenadine statistically significantly improved overall QOL compared with placebo (p = 0.005) and improvements were reported in the RQLQ domains: activities (p = 0.047), practical problems (p = 0.003), nasal symptoms (p = 0.003) and eye symptoms (p ≤ 0.001). Clinically significant improvements in practical problems, eye symptoms and activity limitations, exceeding the 0.05 level, were observed with fexofenadine. These improvements in QOL were associated with significant symptom relief (p < 0.001 vs. placebo). Improvements in impairment at work were also reported with fexofenadine. Conclusion: In Japan, this is the first clinical study to show that fexofenadine HCl (60 mg b.i.d.) improves overall QOL and work productivity in patients with seasonal AR using validated Japanese instruments.
Effects of TNCB Sensitization in DS-Nh Mice, Serving as a Model of Atopic Dermatitis, in Comparison with NC/Nga Mice
Authors: Matsukura Setsuko , Aihara Michiko , Hirasawa Tsutomu , Ikezawa Zenro
Published: January 2005

Background: It has been predicted that a type-1 and type-2 helper T cell (Th1/Th2) imbalance exists in atopic dermatitis (AD). In DS-Nh mice, an AD mouse model, Staphylococcus aureus increases on the skin surface. Objective: To investigate whether the Th1-dominant response has an influence on the development of AD, we induced chronic allergic hypersensitivity with 2,4,6-trinitrochlorobenzene (TNCB ) in two AD mouse models: NC/Nga mice and DS-Nh mice. Th1 and Th2 cytokine production of splenocytes was assessed under stimulation with staphylococcal enterotoxin B (SEB) which induces a Th1 response in DS-Nh mice with or without TNCB sensitization. Methods: We examined clinical skin changes, transepidermal water loss (TEWL), the number of S. aureus on the skin and the serum IgE levels in these mice treated repeatedly with TNCB under conventional conditions (free of fur mites). The splenocytes of DS-Nh mice were cultured with SEB and the cytokine levels in the supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Results: Significant skin changes were observed on the skin even where TNCB was not applied in both mice treated with TNCB. Increases in S. aureus on the skin and serum IgE levels were detected in DS-Nh mice, but not in NC/Nga mice. In DS-Nh mice, IFN-γ and IL-13 production of splenocytes increased in the mice treated with TNCB. Conclusion: These results suggest that there might be a different mechanism of dermatitis induction between NC/Nga and DS-Nh mice. Th1 responses might play an important role in the development of dermatitis and increase in serum IgE levels in DS-Nh mice through an increase in IL-13 production.
Comparison of the Effect of Pentoxifylline and Captopril on Proteinuria in Patients with Type 2 Diabetes mellitus
Authors: Aminorroaya Ashraf , Janghorbani Mohsen , Rezvanian Hassan , Aminian Taghi , Gharavi Manouchehr , Amini Massoud
Published: January 2005

Objectives: To compare the relative efficacy of pentoxifylline (PTX) and angiotensin-converting enzyme (ACE) inhibitor, captopril in the treatment of proteinuria of type 2 diabetic patients. Design: A randomized open, crossover, clinical trial conducted from October 2000 to March 2001. Setting and Participants: 39 patients with type 2 diabetes age 34–75 years were randomly allocated to the two treatment groups. The first group received PTX (400 mg three times a day) orally for a total of 2 months. The second group received captopril (25 mg three times a day) for 2 months. Response to treatment was assessed at 1, 2, 4, and 8 weeks after start of therapy. Results: Captopril appeared to be equivalent in efficacy and safety to PTX. A significant decrease in proteinuria occurred in both groups. Of the 20 patients treated with PTX, the mean (SD) of 24 h urinary protein decreased from 1.4 (0.7) to 1.0 (0.7) g/24 h (p < 0.05). Correspondingly, in the 19 patients treated with captopril, the mean (SD) of 24 h urinary protein decreased from 1.3 (0.7) to 0.8 (0.7) g/24 h (p < 0. 01). Conclusion: This study demonstrates that treatment with PTX and captopril both significantly reduce overt proteinuria in patients with type 2 diabetes. This effect of ACE inhibition has previously been shown to slow progression to renal failure and we postulate that treatment with PTX may have a similar benefit.
Atrial Natriuretic Peptide Preserves Endothelial Function during Intimal Hyperplasia
Authors: Barber Melissa N. , Gaspari Tracey A. , Kairuz Evette M. , Dusting Gregory J. , Woods Robyn L.
Published: January 2005

Background: Atrial and C-type natriuretic peptides (ANP and CNP), acting through different receptors, have antiproliferative effects in vitro. Beneficial effects of CNP in vivo on early atherosclerosis have been described, but it is not known if ANP is antiproliferative in vivo. In the present study, the effects of chronic in vivo ANP were tested and compared with CNP on endothelial dysfunction and intimal thickening caused by peri-arterial collars. Methods: Non-occlusive collars were placed bilaterally around the common carotid arteries of rabbits. One collar was filled with saline vehicle. The contralateral collar was filled with ANP or CNP (1 or 10 µM, n = 5–7) with slow replacement of peptide via mini-pump (1 or 10 fmol/h). Results: After 7 days, endothelium-dependent vasorelaxation in saline-collared arteries was 33 ± 3% of maximum [averaged over 0.03–1 µM acetylcholine (ACh)] compared to 64 ± 2% in normal (uncollared) arteries (p < 0.05, n = 23). In vivo ANP restored the ACh relaxation to normal (e.g., 57 ± 6%, 1 µM ANP), similar to effects seen with CNP in vivo. Endothelium-independent vasorelaxation of collared-vessels was not altered by either peptide. Intimal hyperplasia induced by the collars was not prevented by peri-arterial natriuretic peptides. In additional rabbits (n = 6), CNP (100 pmol/h) given directly into the lumen of collared carotid arteries for 7 days reduced neointima formation by 16 ± 5% (p < 0.05), whereas ANP given intraluminally (100 pmol/h; n = 6) did not. Conclusions: The more potent actions of CNP on vascular smooth muscle cell migration and proliferation (established in vitro) may explain differences between the peptides on intimal hyperplasia in vivo. The major hallmark of atherosclerosis and restenosis, endothelial dysfunction, was prevented by chronic, peri-arterial administration of ANP or CNP.
Sharing in Christ’s Rule: Tracing a Debate in Earliest Christianity
Authors: Roose Hanna
Published: January 2005

This article traces some major issues concerning a debate among the first Christians as to who will share in Christ’s rule in the [ILLEGIBLE]. In Mt. 19.28—a logion that probably goes back to the historical Jesus—the Twelve are unconditionally appointed as eschatological rulers. After Easter, due to the influence of the passio-iusti tradition (cf. Wis. 3-5), ruling with Christ came to be understood, among some Christian groups, as a reward for martyrs (Rev. 20.4-6; 22.5; Lk. 22.28; 2 Tim. 2.12a; critical of this view is Mk 10.35-45). Paul, by contrast, characterizes eschatological rule as a gift for all who are baptized. In Romans, eschatological life and eschatological reign are blended together (Rom. 5.17) and linked with Paul’s participationist understanding of baptism (Rom. 6.1-4). Ephesians further develops this idea (1.23; 2.6). Thus there is in early Christianity a diversity of views, and some controversy, concerning the hope of sharing in Christ’s rule.
Is Paul’s Gospel Narratable?
Authors: Hays Richard B.
Published: January 2005

Does Paul’s gospel have a narrative substructure? If so, what are the implications for our understanding of Paul’s theology? This review article reflects on the issues raised by Bruce W. Longenecker (ed.), Narrative Dynamics in Paul. The essay has six sections. Section 1 frames the problems. Sections 2-4 respond to issues raised by the book: the method for investigating ‘narrative’ in Paul, the shape and content of Paul’s gospel story, and the hermeneutical implications of a narrative approach. Section 5 offers constructive observations about the fundamental ‘grammar’ of Paul’s gospel narrative. The gospel story is explicated ‘according to the Scriptures’; it posits a tension between the present time and the hoped-for future glory; it focuses not on personal experience but on the death and resurrection of Jesus; and it proclaims a participatory soteriology, so that salvation has an inalienably ecclesial character. Finally, Section 6 replies to Francis Watson’s claim that the gospel is ‘nonnarratable’. On the contrary, as Karl Barth argued, whoever speaks of the gospel must narrate the story of what God has done in Jesus Christ.
Biographic and Psychobehavioral Influences on Body Mass Index in a Nursing Sample
Authors: Allison Sarah
Published: January 2005

The purpose of this study was to investigate the direct influences of age, ethnicity, education, and number of children and the indirect influences of codependency and binge eating on increased body mass index (BMI). In this secondary analysis, data were collected froma convenience sample of 511 nurses who completed a codependency instrument and a personal inventory profile assessing the predictors included in the current path analysis study. The five predictors retained in the final BMI model demonstrated that binge eating, age, and Black ethnicity were positively correlated with BMI and that Asian ethnicity was negatively correlated with BMI. The relationship between binge eating and BMI was augmented by codependency but reduced by Black ethnicity. It was concluded that the path analysis supported hypotheses that Black nurses were overweight for reasons other than binge eating and that participants who scored high on the codependency instrument were more likely to binge eat.
Making Sense of Sex: A Study of Leviticus 18
Authors: Mohrmann Doug C.
Published: January 2005

This study exposes the implicit logic of the sexual laws in Leviticus 18 and thereby throws light on the problematic relationship between these laws and the chapter’s introductory and concluding material. The sexual laws were arranged in a tripartite scheme that addressed relations according to family, clan or tribe, and nation, moving outward from the nearest relations to the most distant. Thus the sexual laws circumscribed both internal and external boundaries in Israelite life. As part of the Holiness Code the sexual laws are presented in Leviticus 18 to define Israel’s life in the face of outside, cultural competitors. The discovery of this scheme in the sexual laws builds upon Mary Douglas’s analysis of other priestly traditions.
The Violent Storm in Lamentations
Authors: Middlemas Jill
Published: January 2005

Using reader-response criticism as a beginning point, this article considers the final form of the book of Lamentations as a violent storm in the shape of a whirlwind. Without stressing that the book was consciously composed to elicit the effect of a whirlwind, it nevertheless shows how this type of storm remains consistent with the overall shape of the book and with images found therein. The storm shape suggests implications for reading in modern theological discussions as well as providing a means of understanding one view of the community’s plight.
From Police Administration to Police Science: The Development of a Police Academic Establishment in the United States
Authors: Hoover Larry T.
Published: January 2005

The police academic establishment began in the United States with an emphasis on the principles approach to administration as defined by O. W. Wilson. It evolved with the field over the last 50 years. Each decade has lent distinctive characteristics to its development. Four changes are necessary for its evolution into a genuine science of policing: launching of systematic strategy research; separation of evaluation of strategy from political or social advocacy; inculcation of respect for police scientists who have preceded—particularly O. W. Wilson; and adoption of an open-minded, scientifically neutral approach to assessing what works in policing. The physical sciences provide an appropriate model in this respect.
‘I’m Gay’: Declarations, Desire, and Coming Out On Prime-Time Television
Authors: Herman Didi
Published: January 2005

Discourses of ‘coming out’ play a significant role in the construction of lesbian and gay sexualities, and in the politics of lesbian and gay movements. Although the critique of ‘identity claiming’ has been well established in the literature, popular culture representations of coming out have only recently begun to proliferate. My focus here is on prime-time television; I explore two lesbian coming out texts in some detail in order to consider how different forms of coming out have different meanings and effects. I argue this is due to the two competing discourses at work: identity versus desire. I also explore what these two seemingly different coming out moments share, how, at the end of the day, they may be more similar than it appears at first. And while much scholarship in the field prefers transgressive acts to identity declarations, I use these case studies to suggest that this critique may be misplaced.
A Vision of Masochism in the Affective Pain of Crash
Authors: McCosker Anthony
Published: January 2005

This article investigates the image of masochism presented by David Cronenberg’s film Crash (1996) and the public controversy that it provoked. The analysis of the film and the media debates and outrage presented in this article follows recent theoretical accounts of masochistic sexuality that emphasize lived experience and corporeality. In the narrative’s unusual couplings and unconventional sexual experiences, there is an intensification of the characters’ inner affective world in a way that is as horrific as it is sensual. It is argued here that the experience of masochism as it is presented in the film cannot be separated from the simultaneous discomfort and zeal the film has generated. Through the film’s uncomfortable eroticization of the imagery of bodily pain and injury, representation moves beyond the frame to provide the basis for a masochistic viewing experience. Masochism encroaches upon everyday life through this film in a way that has had a deep and lasting cultural affect.
‘If You’ve Got a Vagina and an Attitude, that’s a Deadly Combination’: Sex and Heterosexuality in Basic Instinct, Body of Evidence and Disclosure
Authors: Finlay Sara-Jane , Fenton Natalie
Published: January 2005

A large body of work exists on women’s sexuality and its construction and misrepresentation in media texts, yet little research analyses explicit sex scenes in mainstream film. Drawing on textual analyses of the sex scenes in Basic Instinct (P. Verhoeven, 1992), Body of Evidence (U. Edel, 1993) and Disclosure (B. Levinson, 1994), the article addresses these issues more specifically. We argue that a consideration of the heterosexual identities and the heterosexual sexual practice (heterosex) displayed in the films can offer opportunities for the disruption of hegemonic heteronormativity. Two of the films discussed - Body of Evidence and Disclosure - offer powerful, although stereotyped forms of feminine heterosexual identity and subversive sexual practice. The final film considered - Basic Instinct - displays alternative forms of feminine sexuality, but ultimately returns to a publicly sanctioned form of heterosexual identity. Within all three films the coding of heterosex, heterosexuality and feminism incompletely conforms to a heteronormative framing, offering space for the viewer to possibly reassess sex and heterosexuality.
Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization
Authors: Berger Mario , Bergers Gabriele , Arnold Bernd , Hämmerling Günter J. , Ganss Ruth
Published: January 2005

We identified regulator of G-protein signaling-5 (RGS-5) as an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis. In a mouse model of pancreatic islet cell carcinogenesis, RGS-5 is specifically induced in the vasculature of premalignant lesions during the “angiogenic switch” and further elevated in tumor vessels. Similarly, RGS-5 is overexpressed in highly angiogenic astrocytomas but not in hypoxia-inducible factor-1α (HIF-1α)–deficient tumors, which grow along preexisting brain capillaries without inducing neovessels. Elevated levels of RGS-5 in pericytes are also observed during wound healing and ovulation indicating a strong correlation between RGS-5 expression and active vessel remodeling beyond tumor angiogenesis. Moreover, antitumor therapy, which reverses tumor vasculature to an almost normal morphology, results in down-regulation of RGS-5 transcription. Taken together, these data demonstrate for the first time a factor that is specific for “activated” pericytes. This further supports the notion that pericytes, like endothelial cells, undergo molecular changes during neovascularization that makes them a novel target for antiangiogenic therapy.
Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium
Authors: von Hundelshausen Philipp , Koenen Rory R. , Sack Markus , Mause Sebastian F. , Adriaens Wencke , Proudfoot Amanda E. I. , Hackeng Tilman M. , Weber Christian
Published: January 2005

The chemokines platelet factor 4 (PF4) and RANTES (regulated on activation normal T cell expressed and secreted) are secreted by activated platelets and influence multiple cell types and biologic processes. For instance, PF4 inhibits progenitor cell proliferation and angiogenesis, while platelet-derived RANTES is involved in vascular recruitment of monocytes. However, little is known about functional interactions of PF4 and RANTES. Here we show that the presence of PF4 enhanced the arrest of RANTES-stimulated monocytes and monocytic cells on activated endothelial cells under flow conditions, while binding of PF4 to the monocyte surface was increased by RANTES. Both RANTES-triggered arrest and PF4 binding involved monocytic chondroitin sulfate. Ligand blots and surface plasmon resonance revealed a robust heterophilic interaction of PF4 with RANTES but not with RANTES variants defective in higher order oligomerization. The tetrameric mutant E26A bound to the monocyte surface without increasing PF4 binding, and monocyte arrest induced by E26A-RANTES was not enhanced by PF4. Stimulation of monocytes with supernatants of activated platelets triggered arrest involving RANTES and PF4, as shown by inhibition studies. Our results suggest that heterophilic interactions with PF4 require structural motifs important in RANTES oligomerization and amplify RANTES-triggered effects on monocyte adhesion. This may have implications for the modulation of inflammatory recruitment by platelet-derived chemokines.
Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells
Authors: Zheng Yong , Liu Huaizhi , Coughlin Jason , Zheng Jing , Li Liang , Stone James C.
Published: January 2005

B-cell receptor (BCR) signaling activates a number of intracellular signaling molecules including phospholipase C–γ2 (PLC-γ2), which generates membrane diacylglycerol (DAG). DAG recruits both protein kinase C (PKC) and RasGRP family members to the membrane and contributes to their activation. We have hypothesized that membrane colocalization facilitates activation of RasGRP3 by PKC. Here we demonstrate that PKCθ phosphorylates RasGRP3 on Thr133 in vitro, as determined by mass spectrometry. RasGRP3 with a Thr133Ala substitution is a poor PKC substrate in vitro and a poor Ras activator in vivo. Antiphosphopeptide antibodies recognize Thr133-phosphorylated RasGRP3 in B cells after BCR stimulation or DAG analog treatment, but much less so in resting cells. PKC inhibitors block RasGRP3 Thr133 phosphorylation and Ras–extracellular signal-related kinase (Erk) signaling with a similar pattern. After stimulation of T-cell receptor (TCR) or DAG analog treatment of T cells, PKC-catalyzed phosphorylation of RasGRP1 occurs on the homologous residue, Thr184. These studies shed light on the proposed “PKC-Ras pathway” and support the hypothesis that RasGRP phosphorylation by PKC is a mechanism that integrates DAG signaling systems in T and B cells. PKC-mediated regulation of RasGRPs in lymphocytes may generate cooperative signaling in response to increases in DAG. The mast- and myeloid-selective family member RasGRP4 is regulated by different means.
cAMP response element binding protein (CREB) activates transcription via two distinct genetic elements of the human glucose-6-phosphatase gene
Authors: Thiel Gerald , Al Sarraj Jude , Stefano Luisa
Published: January 2005

Background

The enzyme glucose-6-phosphatase catalyzes the dephosphorylation of glucose-6-phosphatase to glucose, the final step in the gluconeogenic and glycogenolytic pathways. Expression of the glucose-6-phosphatase gene is induced by glucocorticoids and elevated levels of intracellular cAMP. The effect of cAMP in regulating glucose-6-phosphatase gene transcription was corroborated by the identification of two genetic motifs CRE1 and CRE2 in the human and murine glucose-6-phosphatase gene promoter that resemble cAMP response elements (CRE).

Results

The cAMP response element is a point of convergence for many extracellular and intracellular signals, including cAMP, calcium, and neurotrophins. The major CRE binding protein CREB, a member of the basic region leucine zipper (bZIP) family of transcription factors, requires phosphorylation to become a biologically active transcriptional activator. Since unphosphorylated CREB is transcriptionally silent simple overexpression studies cannot be performed to test the biological role of CRE-like sequences of the glucose-6-phosphatase gene. The use of a constitutively active CREB2/CREB fusion protein allowed us to uncouple the investigation of target genes of CREB from the variety of signaling pathways that lead to an activation of CREB. Here, we show that this constitutively active CREB2/CREB fusion protein strikingly enhanced reporter gene transcription mediated by either CRE1 or CRE2 derived from the glucose-6-phosphatase gene. Likewise, reporter gene transcription was enhanced following expression of the catalytic subunit of cAMP-dependent protein kinase (PKA) in the nucleus of transfected cells. In contrast, activating transcription factor 2 (ATF2), known to compete with CREB for binding to the canonical CRE sequence 5'-TGACGTCA-3', did not transactivate reporter genes containing CRE1, CRE2, or both CREs derived from the glucose-6-phosphatase gene.

Conclusions

Using a constitutively active CREB2/CREB fusion protein and a mutant of the PKA catalytic subunit that is targeted to the nucleus, we have shown that the glucose-6-phosphatase gene has two distinct genetic elements that function as bona fide CRE. This study further shows that the expression vectors encoding C2/CREB and catalytic subunit of PKA are valuable tools for the study of CREB-mediated gene transcription and the biological functions of CREB.
A Beginner's Guide to NF‐κB Signaling Pathways
Authors: DELHALLE SYLVIE , BLASIUS ROMAIN , DICATO MARIO , DIEDERICH MARC
Published: January 2005

Abstract: Nuclear factor κB (NF‐κB) belongs to a family of heterodimeric transcription factors that play a key role in inflammatory and stress responses as well as in tumor cell resistance to apoptosis. These effects are due to the NF‐κB‐dependent transcription of many proinflammatory and antiapoptotic genes, whose products ensure various cell responses to environmental conditions. The signal transduction pathways leading to NF‐κB activation are well characterized, and the different steps implicated in these pathways involve proteins that could constitute targets for NF‐κB inhibition. Several inhibitors aiming to prevent NF‐κB activity and thus the transcription of target genes are studied, and a few compounds seem particularly promising. We try here to summarize the advantages that can issue from various studies on NF‐κB.
Endogenous Oxidative Stress Induces Distinct Redox Forms of Tumor Necrosis Factor Receptor‐1 in Melanoma Cells
Authors: DOMINICI S , PIERI L , PAOLICCHI A , DE TATA V , ZUNINO F , POMPELLA A
Published: January 2005

Abstract: Receptors of the TNFR superfamily possess abundant thiols in their extracellular domains, which makes them susceptible to redox modulation by prooxidant agents and processes. Previous studies from our laboratory have documented that membrane γ‐glutamyltransferase (GGT) activity can originate reactive oxygen species in the extracellular milieu, during the GGT‐mediated metabolism of extracellular glutathione. The present study was aimed thus to verify a possible redox‐modulating effect of GGT activity on TNFR1 receptors. The thiol‐specific probe maleimide‐polyethylene glycol was used to selectively label the reduced thiol groups in proteins of cell lysates; fractions corresponding to TNFR1 were then identified by immunoblot. In human melanoma Me665/2 cells, expressing varying GGT levels, at least five distinct forms of TNFR1 have been thus identified. The more oxidized forms appear to be prevalent in the 2/60 clone, expressing higher GGT levels, as compared to clone 2/21. Stimulation of GGT activity in the latter induced an increase of the oxidized TNFR1 forms. It is conceivable that different redox states of TNFR1 may correspond to different binding affinity and/or changes in the transducing function of the receptor. As GGT is frequently expressed by malignant tumors, the described phenomena might concur to alter the sensitivity of cancer cells to agents targeted on activation of TNF‐α‐dependent signaling pathways.
Redox Signaling by Ionizing Radiation in Mouse Liver
Authors: AN JEUNG HEE , KIM JIYOUNG , SEONG JINSIL
Published: January 2005

Abstract: Since radiation treatment has been reappraised in the treatment of hepatic tumors, radiation response in the liver is emerging as an interesting new area of investigation. In this study, identification of the repertoire of signaling proteins was performed using a proteomics approach involving cellular responses of liver tissue to ionizing radiation. Approximately 800 protein spots were detected. Among them, at least 28 proteins showed significant quantitative alterations after radiation. The significantly altered proteins were categorized as those related to reactive oxygen species (ROS) metabolism, metabolic pathway proteins, and G‐type proteins. Particularly, the expression levels of proteins related to ROS metabolism, including cytochrome c, glutathione S‐transferase Pi, NADH dehydrogenase, and peroxiredoxin VI, were increased after radiation. It is suggested that although radiation initiates cytotoxic effects, it can also induce a radioprotective antioxidant system.
Hypergravity Stimulates Osteoblast Phenotype Expression: A Therapeutic Hint for Disuse Bone Atrophy
Authors: MORITA SADAO , NAKAMURA HIROSHI , KUMEI YASUHIRO , SHIMOKAWA HITOYATA , OHYA KEIICHI , SHINOMIYA KENICHI
Published: January 2005

Abstract: Physiological actions of osteoblasts are disordered by gravity unloading. We investigated the possibility that the appropriate level of hypergravity could improve osteoblast functions that are susceptible to mechanical unloading. We evaluated hypergravity effects on the 1α,25‐dihydroxyvitamin D3 (VD)‐inducible osteocalcin expression of primary rat osteoblasts. Cell culture plates were centrifuged for 24 h at 3, 6, 12, 24, and 48g in a 37°C incubator. The mRNA levels were analyzed by quantitative RT‐PCR. The mRNA levels for osteocalcin and vitamin D receptor (VD‐R) at 12g were enhanced to 187% and 228% of the 1g control, respectively. However, the excess hypergravity conversely decreased osteocalcin expression. Osteocalcin gene expression was enhanced by VD/VD‐R through the vitamin D‐responsive element in the promoter. The increased osteocalcin expression might reflect the augmented VD‐R expression. Alternatively, Runx2, a master gene of osteoblast differentiation, might be responsible for the osteocalcin induction, since the Runx2 mRNA levels were also increased to 247% of control at 12g. Another VD‐inducible osteoblast phenotype, alkaline phosphatase, was also upregulated at 12g and 24g. The appropriate level of hypergravity enhanced the VD‐inducible expression of osteocalcin, a typical phenotype of osteoblast differentiation. These data suggest molecular features to prevent disuse bone atrophy of long‐term bed‐rest patients.
CXCR4 Activation Induces Epidermal Growth Factor Receptor Transactivation in an Ovarian Cancer Cell Line
Authors: PORCILE CAROLA , BAJETTO ADRIANA , BARBERO SIMONE , PIRANI PAOLO , SCHETTINI GENNARO
Published: January 2005

Abstract: Chemokines are a family of proteins that have pleiotropic biological effects. They are well known to regulate the recruitment and trafficking of leukocytes to sites of inflammation. Chemokines are grouped into four classes based on the positions of key cysteine residues: C, CC, CXC, and CX3C. Stromal cell‐derived factor‐1 (SDF‐1), the ligand of the CXCR4 receptor, is a CXC chemokine and is a highly conserved gene. Ovarian cancer typically disseminates widely in the abdomen, a characteristic that limits curative therapy. The mechanisms that promote ovarian cancer proliferation are incompletely understood. We studied a human ovarian adenocarcinoma cell line (OC 314) and investigated the role of CXCR4 activation by SDF‐1 in human ovarian cancer. We demonstrate that CXCR4 and SDF‐1 mRNA are expressed in OC 314. We show that SDF‐1α induces proliferation in ovarian cancer cells in a dose‐dependent manner. Moreover, we demonstrate that the SDF‐1‐dependent proliferation correlates to the phosphorylation and activation of extracellular signal‐regulated kinases (ERK)1/2, which in turn are correlated to epidermal growth factor (EGF) receptor transactivation. In fact, AG1478, a specific inhibitor of the EGF receptor kinase, blocked both SDF‐1α‐dependent proliferation and ERK1/2 activation.
p42/p44 Mitogen‐Activated Protein Kinase Signal Transduction Pathway Regulates Interleukin‐6 Expression in PC3 Cells, a Line of Hormone‐Refractory Prostate Cancer Cells
Authors: KOUL SWEATY , HUANG MEI , CHATURVEDI LAKSHMI , MEACHAM RANDALL B. , KOUL HARI K.
Published: January 2005

Abstract: The mechanisms that regulate prostate cancer growth and proliferation are not fully understood. IL‐6, a multifunctional cytokine, has been shown to play an important role in prostate cancer biology. Functional role of MAP‐kinase signal transduction pathways in prostate biology has not been evaluated in detail. In the present study we evaluated the effects of modulation of p42/44 MAP kinase signal transduction pathway on IL‐6 expression and secretion by PC3 cells, a line of hormone refractory prostate cancer cells. Results presented, herein, demonstrate that modulation of p42/44 MAP kinase activity results in partial inhibition of synthesis and secretion of IL‐6. These data suggest that modulation of p42/p44 may result in regulation of other survival pathways as well.
Blockade by SB203580 of Cyp1a1 Induction by 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin, and the Possible Mechanism: Possible Involvement of the p38 Mitogen‐Activated Protein Kinase Pathway in Shuttling of Ah Receptor Overexpressed in COS‐7 Cells
Authors: SHIBAZAKI MASAHIKO , TAKEUCHI TAKAHASHI , AHMED SOHEL , KIKUCHIA HIDEAKI
Published: January 2005

Abstract: A transiently overexpressed aryl hydrocarbon receptor (AhR) became translocated into the nucleus of COS‐7 cells without treatment with any ligand, such as 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin. This spontaneous AhR translocation into the nucleus was reduced by pretreatment of the recipient cells with the p38 mitogen‐activated protein (MAP) kinase inhibitor SB203580. Immunofluorescent microscopic analysis revealed that SB203580 treatment increased the fluorescence intensity of AhR within the cytoplasm. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, did not reduce AhR translocation into the nucleus. Moreover, a reporter gene assay showed that the AhR spontaneously translocated into the nucleus activated reporter gene transcription and that SB203580 suppressed its transcriptional activity. From these data we conclude that the p38 MAP kinase pathway is involved in determining AhR cellular localization in COS‐7 cells overexpressing AhR.
Protective Effects of Oligomers of Grape Seed Polyphenols Against β‐Amyloid‐Induced Oxidative Cell Death
Authors: LI MEI‐HUA , JANG JUNG‐HEE , SUN BUXIANG , SURH YOUNG‐JOON
Published: January 2005

Abstract: β‐Amyloid (Aβ) is considered to be responsible for the formation of senile plaques that accumulate in the brains of patients with Alzheimer's disease (AD). There is compelling evidence supporting the notion that Aβ‐induced cytotoxicity is mediated through the generation of reactive oxygen species (ROS). Recently, considerable attention has been focused on a wide array of non‐vitamin antioxidants present in edible plants that are able to scavenge ROS, thereby protecting against oxidative damage. In this study, we have investigated the possible protective effects of formulated polyphenol oligomers (Oligonol) derived from grape seed extracts on Aβ‐induced oxidative cell death. Rat pheochromocytoma (PC12) cells treated with Aβ exhibited increased accumulation of intracellular ROS and underwent apoptosis, as determined by positive in situ terminal end labeling, decreased mitochondrial membrane potential, and the cleavage of poly(ADP‐ribose)polymerase. Oligonal attenuated Aβ‐induced cytotoxicity, apoptotic features, intracellular ROS accumulation, and lipid peroxidation and increased the cellular glutathione pool. Moreover, Aβ transiently induced the activation of nuclear factor κB in PC12 cells, which was suppressed by pretreatment with Oligonol.
Expression of Cell Proliferation and Apoptosis Markers in Papillomas and Cancers of Conjunctiva and Eyelid
Authors: RESZEC JOANNA , SULKOWSKA MARIOLA , KODA MARIUSZ , KANCZUGA‐KODA LUIZA , SULKOWSKI STANISLAW
Published: January 2005

Abstract: Cell proliferation and programmed cell death are considered to be important events in carcinogenesis. The object of our study was to evaluate the expression of the Bcl‐2 protein family (Bcl‐2, Bak, Bax), p53, proliferating cell nuclear antigen (PCNA), and Ki‐67 protein immunoexpression as well as the correlation between the examined markers and some clinicopathological features in papillomas and cancers of conjunctiva and eyelid. Forty‐five squamous cell papillomas (SCP), 11 squamous cell cancers (SCC), and 27 basal cell cancers (BCC) were estimated. In the SCP group, p53 protein expression was observed in 30 cases (66.6%), Ki‐67 in 14 (31.1%), PCNA in 44 (97.8%), Bcl‐2 in 24 (53.3%), Bak in 28 (62.2%), Bax in 31 (68.9%), and Bcl‐xl in 11 (100%). In the SCC group, p53 protein expression was evaluated in 8 cases (72.8%), Ki‐67 in 2 (18.2%), PCNA in 8 (72.7%), Bcl‐2 in 5 (45.4%), Bax and Bak both in 10 (90.9%), and Bcl‐xl in 100%. In the BCC group, p53 protein expression was estimated in 23 cases (85.1%), Ki‐67 in 13 (48.1%), PCNA in 26 (96.2%), Bcl‐2 in 13 (48.1%), Bak in 21 (77.8%), Bax in 22 (81.5%), and Bcl‐xl in 23 (85.2%). We observed a correlation between some clinicopathological features and the examined markers of apoptosis and cell proliferation, which seemed to be important events in cancer development.
Increased Expression and Translocation of Lysosomal Cathepsins Contribute to Macrophage Apoptosis in Atherogenesis
Authors: LI WEI , YUAN XI‐MING
Published: January 2005

Abstract: It has been recently reported that atherosclerotic lesions in both humans and mice express several lysosomal proteases, including cathepsins B, D, L, and S, which may affect plaque development and stability. The mechanisms responsible for the extralysosomal expression of lysosomal cathepsins and the related atherogenic implications remain unknown. We find that the lesion‐dependent expression of cathepsins B and L is mainly in macrophage‐infiltrated areas of human carotid atheroma. These enzymes appear in the cytoplasm and nuclei of apoptotic macrophages (normally confined to the lysosomal compartment) and in the extracellular areas. After exposure to oxidized low‐density lipoprotein (oxLDL) or 7β‐hydroxycholesterol (7β‐OH), macrophages initially transform into foam cells and then undergo apoptotic cell death. The oxidized lipids induce lysosomal destabilization, with leakage to the cytosol of lysosomal enzymes (cathepsins B, D, and L), as detected by cytochemistry and immunocytochemistry. A remarkable increase in cathepsin D mRNA levels was observed after 7β‐OH exposure. Like macrophages within atheroma, intralysosomal cathepsins B and L are translocated to the cytoplasm and nuclei of 7β‐OH‐exposed cells. Our results suggest that endocytosed oxLDL and oxysterols not only destabilize the acidic vacuolar compartment but also cause the upregulation and translocation of lysosomal cathepsins, which may act as cleaving enzymes during the apoptotic process. The increased macrophage apoptosis and nuclear and matrix degradation by lysosomal enzymes in atheroma may play important roles in plaque development and rupture.
Curcumin Stability and Its Effect on Glutathione S‐Transferase P1‐1 mRNA Expression in K562 Cells
Authors: BLASIUS ROMAIN , DUVOIX ANNELYSE , MORCEAU FRANCK , SCHNEKENBURGER MICHAËL , DELHALLE SYLVIE , HENRY ESTELLE , DICATO MARIO , DIEDERICH MARC
Published: January 2005

Abstract: To investigate the stability of curcumin in physiological media, the absorption variation of a curcumin solution was measured in 0.1% and 10% FCS. Under daylight conditions, curcumin degraded very rapidly in 0.1% FCS and was found to be more stable in higher serum concentrations. Under dark conditions, almost no decomposition could be observed after 2 h, whether the measurements were performed in 0.1% or 10% FCS. Furthermore, depending on the medium concentration, differential glutathione S‐transferase P1‐1 mRNA expression could be observed in K562 cells after incubation with curcumin. Indeed, incubation in 0.1% FCS led to a decrease of mRNA expression, whereas incubation in 10% FCS induced an increase of mRNA production.