bluuebunny/crossref_metadata_2025 huggingface dataset:
The Case for Integrating Grounded Theory and Participatory Action Research: Empowering Clients to Inform Professional Practice
Authors: Teram Eli , Schachter Candice L. , Stalker Carol A.
Published: October 2005

Grounded theory and participatory action research methods are distinct approaches to qualitative inquiry. Although grounded theory has been conceptualized in constructivist terms, it has elements of positivist thinking with an image of neutral search for objective truth through rigorous data collection and analysis. Participatory action research is based on a critique of this image and calls for more inclusive research processes. It questions the possibility of objective social sciences and aspires to engage people actively in all stages of generating knowledge. The authors applied both approaches in a project designed to explore the experiences of female survivors of childhood sexual abuse with physical therapy and subsequently develop a handbook on sensitive practice for clinicians that takes into consideration the needs and perspectives of these clients. Building on this experience, they argue that the integration of grounded theory and participatory action research can empower clients to inform professional practice.
Understanding the Diabetic Body-Self
Authors: Montez Jennifer Karas , Karner Tracy X.
Published: October 2005

Diabetes is the sixth leading cause of death from disease, shortens the average life span by up to 15 years, and is the main cause of new blindness, kidney failure, and amputations in the United States. Interviews with 2 practitioners and 8 individuals with diabetes illustrate how individuals embody their illness. Interviewed persons with diabetes tended to be most closely associated with the disciplined body type and pursued high levels of bodily control, in contrast to an idealized type, the communicative body, which can be considered an ethical ideal. This framework provides heuristic value by providing insight into the behaviors, needs, and struggles of persons with diabetes, as well as providing a means to more effective treatment and better practitioner-patient relationships.
Thematic Evidence of Psychosocial Thriving in Childhood Cancer Survivors
Authors: Parry Carla , Chesler Mark A.
Published: October 2005

Advances in medical treatment for childhood cancer have resulted in dramatically increased survival rates and a growing population of long-term survivors. Until recently, researchers reported primarily negative psychosocial sequelae of childhood cancer. Emergent conceptual frameworks propose that the assumption of pathology or long-term deficits in functioning might obscure an understanding of the full range of outcomes. Using qualitative interview data (N = 50), the authors explore how cancer can lead to positive psychosocial outcomes, including thriving. The findings suggest that processes of coping, meaning making, and psychospiritual growth are intimately related to long-term psychosocial well-being. The results suggest that in the aftermath of a trauma such as childhood cancer, many outcomes are possible, including thriving.
Disability in Everyday Life
Authors: Lutz Barbara J. , Bowers Barbara J.
Published: October 2005

The authors explored how persons with disabilities perceived the experience of disability in their everyday lives. The findings suggest that the current models in the literature do not address disability adequately. Instead, disability was described as a multifaceted, complex experience that is integrated into the lives of persons with disabilities. The degree to which integration was possible was influenced by three disability-related factors: (a) the fundamental effects of the disabling condition, (b) others’ perceptions of disability, and (c) the need for and use of resources. Important contextual conditions included the environment, time, and experience. Ultimately, it was the match between how these persons perceived themselves and what was important in their lives, and the influence of the three factors that determined how well they were able to integrate disability into their lives. The findings suggest the need for a conceptual model that reflects the personal experience of disability.
Going Home: Formerly Incarcerated African American Men Return to Families and Communities
Authors: Cooke Cheryl L.
Published: October 2005

More than 800,000 African American men are currently incarcerated in prisons or jails in the United States. Most of these men leave prison ill prepared to return to society as workers, or to reintegrate into family settings. Returning from prison is complicated by struggles in the housing and job markets. This article begins with a review of literature exploring drug laws and disproportionate incarceration rates, homelessness, and joblessness. Data from a community-based, qualitative study of African American men following incarceration is presented. A discussion of how incarceration influenced their return to family situations is included that supports the findings by earlier studies on the effects of homelessness and joblessness on individuals and families. The article concludes with recommendations for the development of targeted support systems and offers suggestions for future nursing research with this population.
Estimating Employment Spillover Effects In New York City with an Application to The Stock Transfer Tax
Authors: Schwabish Jonathan A.
Published: October 2005

This article examines the effect of a change in stock market trading volume on employment in the New York City securities industry. This relationship is used as the first stage in an instrumental variables model to determine the effect that securities employment has on other forms of employment in the city. The resulting elasticities imply that a 10 percent decrease in securities industry employment would depress employment in the retail, services, and restaurant sectors by more than 1 percent; in the business services sector by about 4 percent; and in total private jobs by about 1 percent. The elasticities are then applied to New York City employment levels and to a proposal to reinstate the stock transfer tax on the city’s stock markets. At a trading volume decline of 10 percent, these elasticities imply that a stock transfer tax could cost New York City between 30,000 and 42,000 private-sector jobs.
Do Limited Liability Companies Explain Declining State Corporate Tax Revenues?
Authors: Fox William F. , Luna LeAnn
Published: October 2005

The effective state corporate tax rate fell significantly during the past fifteen years despite the very robust growth in corporate book profits. This article examines the causes of the decline with a focus on the effects of the relatively new option of forming limited liability companies (LLCs), state tax policy, and changes in the federal base. The effects are estimated using a simultaneous equation model and a twelve-year panel for U.S. states. The results confirm that the advent and growth of LLCs have been important causes of the decline in corporate tax revenues. In addition, changes in the federal corporate tax base, the propensity of states to grant tax incentives, and the failure of states to require combined reporting have been significant factors in falling corporate tax revenues.
Facing inwards and outwards? Institutional racism, race equality and the role of Black and Asian professional associations
Authors: Phillips Coretta
Published: October 2005

This article considers the role and influence of black and Asian professional associations in the criminal justice services, five years on from the pivotal Lawrence Inquiry (1999) and its assertion that ‘institutional racism’ was endemic in the British police service. Drawing on interviews with Chairpersons of seven professional associations, and a small case study of the Association of Black Probation Officers, the article explores their internal supportive function in assisting members who have experienced various forms of occupational racism. A tentative proposal is made for black and Asian professional associations to develop their external focus to utilize members’ life skills and cultural knowledge to challenge the institutional dynamics of racism within the criminal justice services, and to engage more directly with local black and Asian communities. Such work can be conceptually framed by conceiving of ethnicity as a resource.
Prediction of violent behaviour
Authors: Louw D.A. , Strydom C.C. , Esterhuyse K.G.F.
Published: October 2005

This article focuses on the factors that are deemed important by magistrates and psychologists in the prediction of dangerous or violent behaviour. Five case studies, in which the risk of violence came into play, were presented to the respondents (85 magistrates and 52 psychologists) with the aid of a self-compiled questionnaire. The opinions of the legal practitioners and psychologists concerning the risk of violence that was involved in each case study were tested on the basis of two questions: (i) To what degree is the person in the case study a danger to the community? and (ii) Which risk factors were decisive in respect of Question 1? There was agreement between the two professional groups regarding risk factors. However, in certain cases there was a difference between the two professional groups in respect of the weight allocated to the specific risk factors (for example, psychologists attached more value than the legal practitioners to age, race, gender, the absence of a criminal record, the absence of remorse and drug addiction). Another insight-giving finding was that the opinions of the psychologists concerning risk factors are more substantially supported by existing research than those of magistrates.
Educating policymakers and setting the criminal justice policymaking agenda
Authors: Stolz Barbara
Published: October 2005

During the 1990s, the human trafficking problem emerged as an issue on the international and US policy agendas. Using an expanded case study approach to study the agenda-setting stage, this article examines the role of interest groups in educating US policymakers about the trafficking problem, culminating in the enactment of the trafficking provisions of the ‘Victims of Trafficking and Violence Protection Act of 2000’. Specifically, this article focuses on the participation of ‘nonprofessional criminal justice’ interest groups—purely service groups or groups whose interest in criminal justice policy is of an ad hoc nature—such as human rights, women’s, refugee, and religious organizations. Since the human trafficking agenda-setting stage in the USA was linked to international anti-trafficking efforts, the observations in this article extend beyond US policymaking. They point to the need to study interest group participation, particularly non-professional criminal justice groups, in setting the international criminal justice policy agenda and determining cross-national criminal justice responses to global crime problems.
Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis
Authors: Cooper Nichola , Rao Kanchan , Gilmour Kimberly , Hadad Lema , Adams Stuart , Cale Cathy , Davies Graham , Webb David , Veys Paul , Amrolia Persis
Published: October 2005

Allogeneic stem cell transplantation (SCT) is curative for hemophagocytic lymphohistiocytosis (HLH). However, patients frequently have significant morbidity before transplantation and there is high transplant-related mortality (TRM). Because first-degree HLH is caused by immune dysregulation, a reduced-intensity conditioned (RIC) regimen might be sufficient for cure while decreasing the TRM. Twelve patients with HLH underwent RIC SCT from a matched family/unrelated or haploidentical donor. Eleven were conditioned with fludarabine/melphalan with additional busulphan for haploidentical grafts. One received fludarabine and 2-Gy total body irradiation (TBI). All patients showed engraftment at a median of 14 days. Nine of 12 (75%) are alive and in complete remission (CR) a median of 30 months (range, 9-73 months) after SCT. Two patients died from pneumonitis and one from hepatic rupture. Four patients developed acute graft-versus-host disease (GVHD) and 3 have chronic GVHD. Three of 9 survivors have mixed chimerism but remain free of disease. In summary, RIC compares favorably to conventional SCT with long-term disease control in surviving patients despite a significant incidence of mixed chimerism.
Loss of Tie2 receptor compromises embryonic stem cell–derived endothelial but not hematopoietic cell survival
Authors: Hamaguchi Isao , Morisada Tohru , Azuma Masaki , Murakami Kyoko , Kuramitsu Madoka , Mizukami Takuo , Ohbo Kazuyuki , Yamaguchi Kazunari , Oike Yuichi , Dumont Daniel J. , Suda Toshio
Published: October 2005

Tie2 is a receptor-type tyrosine kinase expressed on hematopoietic stem cells and endothelial cells. We used cultured embryonic stem (ES) cells to determine the function of Tie2 during early vascular development and hematopoiesis. Upon differentiation, the ES cell–derived Tie2+Flk1+ fraction was enriched for hematopoietic and endothelial progenitor cells. To investigate lymphatic differentiation, we used a monoclonal antibody against LYVE-1 and found that LYVE-1+ cells derived from Tie2+Flk1+ cells possessed various characteristics of lymphatic endothelial cells. To determine whether Tie2 played a role in this process, we analyzed differentiation of Tie2-/- ES cells. Although the initial numbers of LYVE-1+ and PECAM-1+ cells derived from Tie2-/- cells did not vary significantly, the number of both decreased dramatically upon extended culturing. Such decreases were rescued by treatment with a caspase inhibitor, suggesting that reductions were due to apoptosis as a consequence of a lack of Tie2 signaling. Interestingly, Tie2-/- ES cells did not show measurable defects in development of the hematopoietic system, suggesting that Tie2 is not essential for hematopoietic cell development.
Laminin stimulates spreading of platelets through integrin α6β1–dependent activation of GPVI
Authors: Inoue Osamu , Suzuki-Inoue Katsue , McCarty Owen J. T. , Moroi Masaaki , Ruggeri Zaverio M. , Kunicki Thomas J. , Ozaki Yukio , Watson Steve P.
Published: October 2005

The extracellular matrix protein, laminin, supports platelet adhesion through binding to integrin α6β1 In the present study, we demonstrate that human laminin, purified from placenta, also stimulates formation of filopodia and lamellipodia in human and mouse platelets through a pathway that is dependent on α6β1 and the collagen receptor GPVI. The integrin α6β1 is essential for adhesion to laminin, as demonstrated using an α6-blocking antibody, whereas GPVI is dispensable for this response, as shown using “knockout” mouse platelets. On the other hand, lamellipodia formation on laminin is completely inhibited in the absence of GPVI, although filopodia formation remains and is presumably mediated via α6β1 Lamellipodia and filopodia formation are inhibited in Syk-deficient platelets, demonstrating a key role for the kinase in signaling downstream of GPVI and integrin α6β1 GPVI was confirmed as a receptor for laminin using surface plasmon resonance spectroscopy and by demonstration of lamellipodia formation on laminin in the presence of collagenase. These results identify GPVI as a novel receptor for laminin and support a model in which integrin α6β1 brings laminin to GPVI, which in turn mediates lamellipodia formation. We speculate that laminin contributes to platelet spreading in vivo through a direct interaction with GPVI.
Down-regulating constitutive activation of the NF-κB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis
Authors: Sors Aurore , Jean-Louis Francette , Pellet Claire , Laroche Liliane , Dubertret Louis , Courtois Gilles , Bachelez Hervé , Michel Laurence
Published: October 2005

Constitutive activation of the nuclear factor-kappaB (NF-κB) pathway has been shown to be involved in the resistance of tumor cells to apoptosis in several human malignancies of the hematopoietic lineage. By using electrophoretic mobility shift assay (EMSA) and confocal microscopic analysis, we demonstrate that NF-κB is constitutively activated in cutaneous T-cell lymphoma (CTCL) cell lines HuT-78, MyLa, and SeAx and in peripheral blood lymphocytes (PBLs) from patients with Sézary syndrome (SS) presenting a high ratio of tumor cells, with evidence of p50 and RelA/p65 in DNA-linked complexes. Transfection of SeAx line with a κB/luciferase reporter plasmid showed that translocated NF-κB complexes were functional. Selective inhibition of NF-κB, by transfecting CTCL cell lines with a super-repressor form of IκBα, led to apoptosis. We evidenced down-regulation of NF-κB activation and induction of CTCL cell apoptosis in the presence of proteasome 26S inhibitors ALLN, MG132, and bortezomib. Bortezomib at nanomolar concentrations inhibited constitutive activation of NF-κB and induced apoptosis of CTCL cells, with evidence of an upregulation of Bax expression. These results demonstrate the key role played by NF-κB in the resistance of CTCL to apoptosis and suggest that bortezomib might be useful for the treatment of patients with advanced stages of CTCL refractory to standard antineoplastic chemotherapy.
Accuracy of Helical Computed Tomography and [18F] Fluorodeoxyglucose Positron Emission Tomography for Identifying Lymph Node Mediastinal Metastases in Potentially Resectable Non–Small-Cell Lung Cancer
Authors: Pozo-Rodríguez Francisco , Martín de Nicolás José L. , Sánchez-Nistal María A. , Maldonado Antonio , García de Barajas Santiago , Calero-García Rosa , Pozo Miguel A. , Martín-Escribano Pedro , Martín-García Isabel , García-Lujan Ricardo , Lopez-Encuentra Angel , Arenas de Pablo Angel
Published: October 2005

Purpose

Computed tomography (CT) and [18F] Fluorodeoxyglucose positron emission tomography (FDG-PET) are considered suitable methods for the noninvasive staging of the mediastinum. Our study was intended to estimate the efficacy of contrast-enhanced helical CT (hCT) and FDG-PET, alone and combined, in the diagnosis of lymph node mediastinal metastases.

Methods

This study was a prospective and blind comparison of the efficacy of hCT and FDG-PET with two alternative reference standards, mediastinoscopy, and mediastinoscopy plus thoracotomy plus a 6-month follow-up to diagnose lymph node mediastinal metastases in 132 consecutive patients with potentially resectable non–small-cell lung cancer (NSCLC). The metastatic disease was assessed histopathologically. Further clinical information was obtained postoperatively after a median follow-up of 42 months.

Results

The prevalence of cN2,3 is 0.28. For hCT the sensitivity and specificity are 0.86 (95% CI, 0.70 to 0.93) and 0.67 (95% CI, 0.56 to 0.75), for PET 0.94 (95% CI, 0.81 to 0.98) and 0.59 (95% CI, 0.49 to 0.68), and for hCT and PET combined in-parallel 0.97 (95% CI, 0.84 to 0.99) and 0.44 (95% CI, 0.34 to 0.53), which translate into a negative predicted probability of 0.98 (95% CI, 0.88 to 1.00). The crude diagnostic odds ratio of PET in the total sample studied is 13.1, in the subgroup hCT+ 11.04 (3.0 to 40 0.1), and in the hCT- 3.5 (0.5 to 21.5). Similar results were obtained for hCT stratified by PET.

Conclusion

hCT and PET perform similarly in the mediastinal staging of NSCLC, both tests are conditionally dependent and provide complementary information, and their diagnostic value mainly resides on the negative results.
Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group
Authors: Rebbeck Timothy R. , Friebel Tara , Wagner Theresa , Lynch Henry T. , Garber Judy E. , Daly Mary B. , Isaacs Claudine , Olopade Olufunmilayo I. , Neuhausen Susan L. , van ′t Veer Laura , Eeles Rosalind , Evans D. Gareth , Tomlinson Gail , Matloff Ellen , Narod Steven A. , Eisen Andrea , Domchek Susan , Armstrong Katrina , Weber Barbara L.
Published: October 2005

Purpose

Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HRT.

Methods

We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years.

Results

Consistent with previous reports, BPO was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95%CI, 0.18 to 0.92). Using mutation carriers without BPO or HRT as the referent group, HRT of any type after BPO did not significantly alter the reduction in breast cancer risk associated with BPO (HR = 0.37; 95% CI, 0.14 to 0.96).

Conclusion

Short-term HRT use does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1/2 mutation carriers.
Endoscopic Ultrasound–Guided Fine-Needle Aspiration in the Diagnosis and Staging of Lung Cancer and Its Impact on Surgical Staging
Authors: Annema Jouke T. , Versteegh Michel I. , Veseliç Maud , Voigt Pieter , Rabe Klaus F.
Published: October 2005

Purpose

The diagnosis and staging of lung cancer critically depends on surgical procedures. Endoscopic ultrasound (EUS) –guided fine-needle aspiration (FNA) is an accurate, safe, and minimally invasive technique for the analysis of mediastinal lymph nodes (LNs) and can additionally detect tumor invasion (T4) in patients with centrally located tumors. The goal of this study was to assess to what extent EUS-FNA could prevent surgical interventions.

Patients and Methods

Two hundred forty two consecutive patients with suspected (n = 142) or proven (n = 100) lung cancer and enlarged (> 1 cm) mediastinal LNs at chest computed tomography were scheduled for mediastinoscopy/tomy (94%) or exploratory thoracotomy (6%). Before surgery, all patients underwent EUS-FNA. If EUS-FNA established LN metastases, tumor invasion, or small-cell lung cancer (SCLC), scheduled surgical interventions were cancelled. Surgical-pathologic verification occurred when EUS-FNA did not demonstrate advanced disease. Cancelled surgical interventions because of EUS findings was the primary end point.

Results

EUS-FNA prevented 70% of scheduled surgical procedures because of the demonstration of LN metastases in non–small-cell lung cancer (52%), tumor invasion (T4) (4%), tumor invasion and LN metastases (5%), SCLC (8%), or benign diagnoses (1%). Sensitivity, specificity, and accuracy for EUS in mediastinal analysis were 91%, 100% and 93%, respectively. No complications were recorded.

Conclusion

EUS-FNA qualifies as the initial staging procedure of choice for patients with (suspected) lung cancer and enlarged mediastinal LNs. Implementation of EUS-FNA in staging algorithms for lung cancer might reduce the number of surgical staging procedures considerably.
Galectin-1: A Link Between Tumor Hypoxia and Tumor Immune Privilege
Authors: Le Quynh-Thu , Shi Gongyi , Cao Hongbin , Nelson Daniel W. , Wang Yingyun , Chen Eunice Y. , Zhao Shuchun , Kong Christina , Richardson Donna , O'Byrne Ken J. , Giaccia Amato J. , Koong Albert C.
Published: October 2005

Purpose

To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression.

Methods

We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CD3 (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes.

Results

SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CD3 staining (P = .01). Expression of galectin-1 and CD3 were significant predictors for overall survival on multivariate analysis.

Conclusion

Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege.
Towards an understanding of adsorption behaviour in non-aqueous systems: adsorption of poly(vinyl pyrrolidone) and poly(ethylene glycol) onto silica from 2H, 3H-perfluoropentane
Authors: Paul Alison , Griffiths Peter C , Rogueda Philippe G
Published: October 2005

The adsorption behaviour of low molecular weight poly(ethylene glycol) (PEG 600) and poly(vinyl pyrrolidone) (PVP K25) to silica particles has been investigated at room temperature (21°C) in the partially fluorinated solvent 2H,3H-perfluoropentane (HPFP). PVP (absorbed amount, Γ = 12 mgg−1) was found to adsorb more strongly than PEG (Γ = 4 mgg−1). Both of these values were higher than observed in water. In a further distinction to the aqueous case, where PVP displaces PEG from the interface, no competitive adsorption effects were observed between these two polymers in HPFP, with the adsorbed amounts of each polymer being unchanged by the presence of the other. The stability of silica suspensions in HPFP was primarily dependent on the presence of PVP; PEG/silica systems were unstable, but PVP/silica and PEG/PVP/silica systems formed stable suspensions. All suspensions were destabilized by the addition of small (0.15 wt%) amounts of water. The observations made in this work would point to a flocculation phenomenon due to the addition of water, and not Ostwald ripening. The mechanism of this destabilization is likely to be water acting as a flocculation bridge between particles.
Pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidine-7-one (DA-8159) and nitroglycerin in rats
Authors: Lee Shin Jung , Bae Soo Kyung , Lee Myung Gull , Kwon Jong Won , You Moohi , Lee Duk Chul
Published: October 2005

The pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d)pyrimidine-7-one (DA-8159), a new erectogenic, and nitroglycerin has been evaluated in rats. Male Sprague-Dawley rats received DA-8159 (30 mgkg−1) as a single intravenous or oral dose with the simultaneous single intravenous administration of nitroglycerin (2.5 mgkg−1). After simultaneous intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUCinf) of DA-8159 (746 vs 457 μg min mL−1) was found to be significantly greater than with DA-8159 alone. Also, after simultaneous intravenous administration total body clearance (CL) (40.2 vs 65.6 mL min−1 kg−1), renal clearance (CLR) (1.65 vs 5.11 mL min−1 kg−1), and nonrenal clearance (CLNR) (38.3 vs 60.2 mL min−1 kg−1) of DA-8159 were significantly slower compared with DA-8159 alone. The slower CLNR of DA-8159 could have been due to the inhibition of the metabolism of DA-8159 by nitroglycerin, since DA-8159 is metabolized via CYP3A1/2 in rats and nitroglycerin inhibits CYP3A1/2 in rats. The slower CLR of DA-8159 could have been due to the urine flow rate-dependent CLR of DA-8159 in rats. After the simultaneous intravenous administration of nitroglycerin and DA-8159, the AUCinf of nitroglycerin was significantly smaller (635 vs 960 μg min mL−1), which could have been due to the cardiac output-dependent CL of nitroglycerin. However, after the oral administration of DA-8159, the pharmacokinetic parameters of DA-8159 with and without the intravenous administration of nitroglycerin became comparable. This was not due to the decrease in nitroglycerin's gastrointestinal absorption of DA-8159, but could have been due to changes in nitroglycerin's intestinal first-pass effect of DA-8159. Human studies are required to determine the administration time of DA-8159 when nitroglycerin is concomitantly taken.
The pharmacokinetics of etanercept in patients with end-stage renal disease on haemodialysis
Authors: Don Burl R , Spin Gregory , Rose Aubri , Nestorov Ivan , Hutmacher Matt , Kaysen George A
Published: October 2005

Inflammation is strongly associated with malnutrition and cardiovascular risk in patients with chronic renal failure on haemodialysis (HD). The acute-phase inflammatory response, defined by the increased synthesis of positive acute-phase proteins, is stimulated by the production of such cytokines as interleukin 6 (IL-6), interleukin 1 (IL-1) and tumour necrosis factor-α TNF-α The availability of cytokine antagonists allows testing of the hypothesis that suppression of inflammation reverses the malnutrition-inflammation syndrome in HD patients. Etanercept is a soluble TNF-α receptor fusion protein used to suppress inflammation in rheumatoid and psoriatic arthritis. Its metabolism in HD patients is unknown. In a study designed to test the safety and pharmacokinetics of etanercept in HD patients, etanercept was administered to six HD patients with albumin levels above 4.2 g dL−1 and C-reactive protein levels <5 mg L−1 (five men, one woman, age range 34–59 years). Etanercept (25 mg) was administered subcutaneously twice weekly immediately after dialysis for 13–16 weeks. Etanercept concentrations were measured pre- and post-dialysis by ELISA. Concentrations were compared graphically to assess whether, firstly, dialysis affects etanercept apparent clearance and, secondly, etanercept kinetics were similar between HD patients and the more extensively studied psoriasis population with normal renal function (PS). The second stage examined model-based parameter predictions of the terminal elimination rate constant (k) for HD patients. Steady-state etanercept levels were comparable between HD and PS patients. Treatment with HD had no effect on etanercept levels. When etanercept was discontinued, the terminal rate constant for HD patients was not significantly different from that observed in PS patients. No adverse effects were noted during the 3-month treatment phase and subsequent 6-month follow-up. Albumin and C-reactive protein levels did not change in these non-inflamed patients during the study period. The pharmacokinetics of etanercept in patients with chronic renal failure on HD are similar to patients with normal renal function. It is, therefore, feasible to administer etanercept to HD patients without adjusting the dose
Synthesis and pharmacological effects of new, N-substituted soft anticholinergics based on glycopyrrolate
Authors: Ji F , Wu W , Dai X , Mori N , Wu J , Buchwald P , Bodor N
Published: October 2005

To reduce the possibility of systemic side-effects in locally administered anticholinergics, two new N-substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in vivo. Because stereospecificity is known to be important at muscarinic receptors, the new compounds SGM and SGE also have been prepared as their pure 2R isomers, 2R-SGM and 2R-SGE, by starting from optically pure (-)-cyclopentylmandelic acid, and the corresponding isomers were indeed found to be more active. The new soft glycopyrrolates were chemically more stable under acidic conditions, and the ethyl esters SGE were more stable than the methyl esters SGM. The new compounds were also found to be quite susceptible to extrahepatic metabolism, having half-lives of 20–30 min in rat plasma (in vitro), consistent with their soft nature. Binding studies at human muscarinic receptors (M1−M4) and guinea-pig ileum assays found 2R-SGM and 2R-SGE to have potencies somewhat less than, but close to, those of glycopyrrolate and N-methylscopolamine. They caused pupil dilation in rabbit eyes, but their mydriatic effects lasted for considerably less time than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that, in agreement with their soft nature, they are locally active, but safe and with a low potential to cause systemic side-effects.
Role of lupeol and its ester on cyclophosphamide-induced hyperlipidaemic cardiomyopathy in rats
Authors: Sudharsan P T , Mythili Y , Sudhahar V , Varalakshmi P
Published: October 2005

Cyclophosphamide, an alkylating agent widely used in cancer chemotherapy, causes fatal cardiotoxicity. In this study, lupeol, a pentacyclic triterpene isolated from Crataeva nurvala stem bark, and its ester, lupeol linoleate, were investigated for their possible hypocholesterolaemic effects against cyclophosphamide-induced lipidaemic instabilities. Male albino Wistar rats were categorized into 6 groups. Group I served as control. Rats in groups II, V and VI were injected intraperitoneally with a single dose of cyclophosphamide (200 mg kg−1) dissolved in saline. Cyclophosphamide-treated groups V and VI respectively received lupeol and lupeol linoleate (50 mg kg−1), dissolved in olive oil, for 10 days by oral gavage. Groups III and IV served as drug controls and were administered lupeol and lupeol linoleate, respectively. Cyclophosphamide administration induced abnormal changes in serum lipoproteins and lipid fractions in both serum and cardiac tissue. The activity of lipid metabolizing enzymes was distorted significantly in the cyclophosphamide-treated rats. The cyclophosphamide-treated rats also showed extensive intermuscular haemorrhage in histology. Lupeol and its ester reversed the above alterations induced by cyclophosphamide. This study encapsulates the early lipaemic abnormalities in the heart tissue of cyclophosphamide-treated rats. Treatment with lupeol linoleate was more effective than lupeol in rendering protection to the cardiac tissue challenged by cyclophosphamide.
Dietary palm olein oil augments cardiac antioxidant enzymes and protects against isoproterenol-induced myocardial necrosis in rats
Authors: Narang D , Sood S , Thomas M , Maulik S K , Dinda A K
Published: October 2005

Wistar rats, 150–200g, of either sex, were fed daily with commercial rat diet supplemented with palm olein oil in two doses (5% v/w (n = 16) and 10% v/w (n = 16) of diet) for 30 days. Control rats (n = 16) were fed with normal diet. On the 29th and 30th days, 8 rats from each group were administred isoproterenol (85 mg/kg, s.c., 24-h interval). On the 31st day, all rats were sacrificed and myocardial tissues were studied for thiobarbituric acid reactive substances (TBARS), antioxidant enzymes and light microscopic changes, along with the ferric-reducing ability of plasma (FRAP). A significant rise in myocardial superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activity and FRAP level were observed in rats fed with palm olein oil. Isoproterenol caused an increase in myocardial oxidative stress in control rats, as evidenced by an increase in myocardial TBARS level, reduction in FRAP and myocardial SOD, catalase and GPx activity, along with focal necrosis of cardiac muscle fibres on light microscopy. The rise in myocardial TBARS and depletion of SOD and catalase activity following isoproterenol administration were prevented in palm-olein-oil-supplemented diet-fed rats at both doses. Isoproterenol-induced myocardial light-microscopic changes were also prevented in the treated groups. The results suggest that dietary palm olein oil caused augmentation of myocardial antioxidant enzymes and protected against isoproterenol-induced myocardial necrosis and associated oxidative stress.
Distribution of sigma receptors in EMT-6 cells: preliminary biological evaluation of PB167 and potential for in-vivo PET
Authors: Colabufo Nicola Antonio , Berardi Francesco , Contino Marialessandra , Niso Mauro , Perrone Roberto , Tortorella Vincenzo , Fazio Ferruccio , Matarrese Mario , Moresco Rosa Maria
Published: October 2005

σ1 and σ2 receptors have been detected in many tissues and are highly expressed in several tumour cell lines from various tissues. The high level of expression observed for σ receptors and their involvement in cell proliferation and apoptosis has led to the development of several σ ligands in order to obtain a molecular probe for in-vivo diagnostic imaging techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT). The EMT-6 cells implanted in mice were a good model for evaluating the proliferation of solid tumours by in-vivo PET. Moreover, we developed the σ ligand PB167, a cyclohexylpiperazine derivative, previously evaluated for σ2 receptor affinity and activity in standard protocols. The related results encouraged us to verify if this compound could be developed as a radiotracer for in-vivo PET in order to visualize σ2 receptors expressed in EMT-6 cells when implanted in mice. This perspective was thought to be favourable because PB167 bears a methoxy substituent on the tetraline nucleus, an easy point for 11C labelling. The aims of this preliminary study were both to assess the relative distribution of σ1 and σ2 receptors in EMT-6 cells and to verify if PB167 could be developed as a σ2 radiotracer for in-vivo PET. The results showed that both σ1 and σ2 receptors were overexpressed in EMT-6 cells and that the ligand PB167 can be positively considered for radiosynthesis preparation in order to suitably visualize σ2 receptors by the in-vivo PET technique and correlate their presence to tumour proliferation.
Dietary fatty acid unsaturation levels, lipoprotein oxidation and circulating chemokine in experimentally induced atherosclerotic rats
Authors: El Seweidy Mohamed M , El-Swefy Sahar E , Abdallah Fatma R , Hashem Reem M
Published: October 2005

The dietary balance of long-chain fatty acids may influence processes involving leukocyte endothelial interactions, such as atherogenesis and inflammation. The relationship between proatherogenic lipoproteins and chemotactic motility is still controversial. However, the interaction of the former can increase recruitment of monocytes to the vessel walls and accelerate the events of atherogenesis. The current study examined the effects of unsaturated fatty acid levels on the oxidative susceptibility of lipoprotein, chemokine expressions and their relationship to atherosclerotic lesion development in experimental rats. Male Wistar rats were fed an atherogenic diet for 4 months and the diet was then supplemented with 10% v/w of virgin olive oil (OO group), sunflower oil (SO group) or fish oil (FO group) for 4 and 8 weeks. Blood samples were collected at four time points: at baseline, after feeding with the atherogenic diet and during the dietary regimen (4 and 8 weeks). Plasma lipid profile and lipoprotein oxidative susceptibility (LOS), C-reactive protein (CRP), monocyte chemoattractant protein (MCP-1), and regulated upon activation normal T-cell expressed and secreted (RANTES) were measured. The superoxide dismutase (SOD) and reduced glutathione (GSH) antioxidant activities were also studied in aortic segments. Histological assessment of the aortic segment was determined. Compared to baseline data, the high-fat and cholesterol-enriched diet increased atheroma formation, plasma LOS and inflammatory indexes (CRP, MCP-1, RANTES). However, it dramatically reduced aortic SOD and GSH contents. Dietary treatment of atherosclerotic rats with OO greatly reduced LOS and remarkably increased aortic SOD and GSH contents as compared to the SO- and FO-treated groups. The FO-supplemented diet had a more pronounced lowering effect on MCP-1 and RANTES compared to the OO and SO diets. In conclusion, this study demonstrated a strong relationship between LOS and circulating levels of chemokines. OO is a potent antioxidant and moderate anti-inflammatory, which effectively reduced aortic atherosclerotic lesions more than the SO- or FO-treated groups in male Wistar rats.
Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein
Authors: Matzno Sumio , Yasuda Shinya , Juman Sachiko , Yamamoto Yukiko , Nagareya-Ishida Noriko , Nakabayashi Toshikatsu , Matsuyama Kenji , Tazuya-Murayama Keiko
Published: October 2005

Rhabdomyolysis is a severe adverse effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin-induced apoptosis by the detection of membrane flip-flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 μm), cerivastatin (3 μm), fluvastatin (3 μm), pravastatin (3 mm), or simvastatin (3 μm)) for 2, 4 or 6 h followed by reacting with FITC-conjugated annexin V for the detection of initial apoptosis signal (flip-flop). Various statin-treated myoblasts were significantly stained with FITC-annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 μm), membrane-associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase-8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin-related Ras depletion. In conclusion, statin-induced apoptosis in muscular tissue was directly initiated by the farnesyl-anchored Ras protein depletion from cell membrane with subsequent apoptosis.
Species differences in the gut stimulatory effects of radish seeds
Authors: Gilani Anwarul Hassan , Ghayur Muhammad Nabeel , Houghton Peter J
Published: October 2005

This study describes the gastrointestinal (GI) prokinetic effects of the aqueous extract of radish seeds (Rs.Cr). Rs.Cr, which tested positive for terpenes, flavonoids, phenols, alkaloids and saponins, showed a spasmogenic effect in isolated rabbit jejunum and ileum, rat stomach fundus and ileum, and guinea-pig ileum and jejunum. Rs.Cr was around 10 times more potent in the guinea-pig tissues and this effect was resistant to atropine, pyrilamine or SB203186 while the spasmogenic effect in the rat and rabbit tissues was atropine sensitive. The extract exhibited atropine-sensitive GI prokinetic and laxative effects in vivo in mice. In the atropinized rabbit jejunum, Rs.Cr produced a spasmolytic effect independent of Ca++ or K+ channels, adrenergic or opioid receptor involvement. Activity-directed fractionation of Rs.Cr yielded four fractions, all showing effects similar to that of the parent extract. Rs.Cr and its fractions were found to be non-lethal up to 10 g kg−1 in mice for 24 h, except for the petroleum fraction, which showed 50% mortality at high doses. Some known radish compounds (spermine, spermidine, putrescine and sinigrin) were also tested and found to be devoid of any activity. The study shows species-specific spasmogenic effects of radish in rabbit, rat and mouse via muscarinic receptors but through an uncharacterized pathway in guinea-pig tissues. Additionally, a dormant relaxant effect was also seen, while the three polyamines and one glucosinolate from radish were found to be inactive, indicating that the compound(s) responsible for the activities reported remains to be isolated.
Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication
Authors: Nunziante Max , Kehler Claudia , Maas Elke , Kassack Matthias U. , Groschup Martin , Schätzl Hermann M.
Published: October 2005

The conversion of the cellular prion protein (PrPc) into a pathogenic isoform (PrPSc) is one of the underlying events in the pathogenesis of the fatal transmissible spongiform encephalopathies (TSEs). Numerous compounds have been described to inhibit prion replication and PrPSc accumulation in cell culture. Among these, the drug suramin induces aggregation and re-targeting of PrPc to endocytic compartments. Plasma membrane and sites of conversion into PrPSc are thereby bypassed. In the present study, a library of suramin analogues was tested as a potential class of new anti-prion compounds and the molecular mechanisms underlying these effects were analysed. Treatment of prion-infected neuroblastoma cells with compounds containing symmetrical aromatic sulfonic acid substitutions inhibited de novo synthesis of PrPSc and induced aggregation and reduction of the half-life of PrPc without downregulating PrPc cell surface expression. Half-molecule compounds lacking the symmetrical bipolar structure or the anionic groups had no effect on PrPSc synthesis or PrPc solubility. Cell surface expression of PrPc was necessary for the activity of effective compounds. Suramin derivatives did not induce aggregation of PrPc when transport along the secretory pathway was compromised, suggesting that their effects occur at a post trans-Golgi network (TGN) site, possibly close to the compartment of conversion into PrPSc. In vitro studies with recombinant PrP demonstrated that the inhibitory effect correlated with direct binding to PrP and induction of insoluble PrP aggregates. Our data reveal an anti-prion effect that differs from those characterising other sulphated polyanions and is dependent on the presence of the symmetrical anionic structure of these molecules.
The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP)
Authors: Remacle Albert G. , Rozanov Dmitri V. , Baciu Peter C. , Chekanov Alexei V. , Golubkov Vladislav S. , Strongin Alex Y.
Published: October 2005

Membrane type-1 matrix metalloproteinase (MT1-MMP) degrades the extracellular matrix, initiates the activation pathway of soluble MMPs and regulates the functionality of cell adhesion signaling receptors, thus playing an important role in many cell functions. Intracellular transport mechanisms, currently incompletely understood, regulate the presentation of MT1-MMP at the cell surface. We have focused our efforts on identifying these mechanisms. To understand the transport of MT1-MMP across the cell, we used substitution and deletion mutants, the trafficking of which was examined using antibody uptake and Chariot delivery experiments. Our experiments have demonstrated that the microtubulin cytoskeleton and the centrosomes (the microtubulin cytoskeleton-organizing centers) are essential for the trafficking and the internalization of MT1-MMP. We determined that after reaching the plasma membrane, MT1-MMP is internalized in the Rab-4-positive recycling endosomes and the Rab-11-positive pericentrosomal recycling endosomes. The microtubular trafficking causes the protease to accumulate in the pericentrosomal region of the cell. We believe that the presence of the transmembrane domain is required for the microtubular vesicular trafficking of MT1-MMP because the soluble mutants are not presented at the cell surface and they are not delivered to the centrosomes. The observed transport mechanisms provide a vehicle for the intracellular targets and, accordingly, for an intracellular cleavage function of MT1-MMP in malignant cells, which routinely overexpress this protease.