bluuebunny/crossref_metadata_2025 huggingface dataset:
Signalling via CD70, a member of the TNF family, regulates T cell functions
Authors: García Pilar , de Heredia Agustín Beltrán , Bellón Teresa , Carpio Emilio , Llano Manuel , Caparrós Esther , Aparicio Pedro , López-Botet Miguel
Published: June 2004

In the present work, we provide data supporting that CD70, a tumor necrosis factor (TNF)-related molecule, defined as the CD27 ligand (CD27L), may actively regulate T cell functions similarly to other members of the TNF family (i.e., CD40L and CD30L). Cross-linking CD70 with specific monoclonal antibodies (mAb) stimulated cytotoxicity and cytokine production in human T cell clones. Detection of intracellular-free calcium mobilization and mitogen-activated protein kinase phosphorylation upon mAb engagement of CD70 further supported an active signaling role for the TNF-related molecule. Similar results were obtained in the Jurkat leukaemia T cell line stably transfected with CD70; in that system, induction of Akt phosphorylation was detected, indirectly revealing the involvement of the phosphatidylinositol-3 kinase pathway. Stimulation of CD70+ Jurkat cells, with a CD70-specific mAb or with COS-7 cells transiently transfected with CD27, induced transcriptional activity detectable by different reporter gene expression systems. Altogether, our data point out that a reciprocal communication may be established between CD27+ and CD70+ cells during the immune response.
The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation
Authors: Napoleone Emanuela , Di Santo Angelomaria , Peri Giuseppe , Mantovani Alberto , de Gaetano Giovanni , Donati Maria Benedetta , Lorenzet Roberto
Published: June 2004

Pentraxin-3 (PTX3), an acute-phase protein that belongs to the family of the PTXs, is found elevated in septic shock and increased in patients with acute myocardial infarction. As tissue factor (TF) plays a key role in thrombosis and inflammation associated with atherosclerosis and as we have recently reported that PTX3 increases TF synthesis in endothelial cells, we tested whether PTX3 could modulate TF expression in monocytes. Monocytes from peripheral blood of healthy donors were incubated with highly purified PTX3 with or without lipopolysaccharide (LPS). Cells were then disrupted, and procoagulant activity was assessed by a one-stage clotting time. PTX3 enhanced TF activity and antigen from LPS-stimulated monocytes in a dose-dependent way. The effect was specific, as other PTXs, such as C-reactive protein and serum amyloid P component, were ineffective. Moreover, the increase in activity was specific for LPS, as in the presence of other TF-inducing agents such as interleukin-1β and tumor necrosis factor α, PTX3 was not effective. The increase in TF activity requires mRNA synthesis, as assessed by polymerase chain reaction. The mechanism by which PTX3 modulates TF synthesis resides in an enhanced IκB, α phosphorylation and degradation and increased migration of the transacting factor c-Rel/p65 into the nucleus, as determined by Western blot and electro-mobility shift assay. These results show that PTX3 is an enhancer of the expression of TF by mononuclear cells. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. PTX3 increases TF expression, thus potentially playing a role in thrombogenesis and wound healing.
Teacher assessment: the concept of ‘diagnostic competence’
Authors: Edelenbos Peter , Kubanek-German Angelika
Published: June 2004

In the light of recent trends in educational assessment, language testing and the pedagogical discussion about new teacher roles, this article focuses on the skills and abilities required of a language teacher wishing to respond to these developments, with specific reference to the primary (elementary) foreign language classroom. A new concept is introduced ‘diagnostic competence’ defined as the ability to interpret foreign language growth in individual children. In order to arrive at this conceptualization, data from both systematic classroom observation (The Netherlands) and ethnographic studies (Germany) are used to identify and illustrate teachers’ diagnostic activities and processes. On the basis of this evidence, a preliminary description of levels and features of a teacher engaged in such activities is presented.
Tensions between validity and outcomes: teacher assessment of written work of recently arrived immigrant ESL students
Authors: Arkoudis Sophie , O’Loughlin Kieran
Published: June 2004

This article reports on a collaborative study involving ESL1 teachers in an Australian English Language Centre as they work through some of their concerns about reliability and validity in their assessment practices. The focus of this article is on how teachers work with the Curriculum Standards Framework (CSF) as an assessment tool. The discussion focuses on issues relating to the limitations of the CSF and the way in which teachers engage with the CSF to produce a meaningful and accurate assessment reflective of their students’ progress. The teachers’ stories highlight how state-mandated assessment policies are translated into teacher assessment carried out in local educational contexts. Harré’s positioning theory (1999) is used as the framework for interpreting the epistemological authority of the teachers within the assessment exigencies of the education system.
ESL/EFL instructors’ classroom assessment practices: purposes, methods, and procedures
Authors: Cheng Liying , Rogers Todd , Hu Huiqin
Published: June 2004

Student assessment plays a central and important role in teaching and learning. Teachers devote a large part of their preparation time to creating instruments and observation procedures, marking, recording, and synthesizing results in informal and formal reports in their daily teaching. A number of studies of the assessment practices used by teachers in regular school classrooms have been undertaken (e.g., Rogers, 1991; Wilson, 1998; 2000). In contrast, less is known about the assessment practices employed by instructors of English as a Second Language (ESL) and English as a Foreign Language (EFL), particularly at the tertiary level. This article reports a comparative survey conducted in ESL=EFL contexts represented by Canadian ESL, Hong Kong ESL=EFL, and Chinese EFL in which 267 ESL or EFL instructors participated, and documents the purposes, methods, and procedures of assessment in these three contexts. The findings demonstrate the complex and multifaceted roles that assessment plays in different teaching and learning settings. They also provide insights about the nature of assessment practices in relation to the ESL=EFL classroom teaching and learning at the tertiary level.
The oxygen dissociation curve: quantifying the shift
Authors: Hamilton Carole , Steinlechner Barbara , Gruber Eva , Simon Paul , Wollenek Gregor
Published: June 2004

An oxyhaemoglobin dissociation curve (ODC) quantifies the most important function of red blood cells and that is the affinity for oxygen and its delivery to the tissues. Oxygen affinity for haemoglobin plays a critical role in the delivery of oxygen to the tissues and is changed by shifting to the left or right. A shift to the left implies an increased oxygen affinity and, hence, tighter binding due to the higher oxygen saturation in relation to the pO2.On the other hand, a shift to the right corresponds to a decreased oxygen affinity and easier release of oxygen to the tissues. It is well known that the ODC shifts in response to changes in pH, pCO2 and 2,3 diphosphoglycerate. However, how much the ODC shifts has never been quantified. Arterial and venous blood gases were taken during cardiopulmonary bypass and two indices were used to quantify the shift of the ODC; the p50 shift and the SO2 difference. Arterial blood shifted to the right by 49-0.1 mmHg at a pH of 7.24 and shifted to the left by -3.59-0.05 mmHg at a pH of 7.51. The change in arterial saturation was minimal, rising by 0.8% and dropping by -5% and did not correlate to p50 shifting and changes in pH, but demonstrated changes dependent on the concentration of dyshaemoglobins. The venous blood exhibited a greater range of p50 shifting at each pH value. At a pH of 7.24, the p50 shifted to the right by 4.89-2 mmHg and at a pH of 7.51 the p50 shifted to the left by -4±1.8 mmHg. Unlike the arterial blood, the change in saturation correlated well to p50 shifting. It is shown here for the first time how much the curve shifts with changes in pH and how this may be used to evaluate treatment strategies.
Liver blood flow during cardiac surgery
Authors: Chetty Govind , Sharpe David AC , Nandi Jay , Butler Stephen J , Mitchell Ian M
Published: June 2004

Objective: Impairment of liver blood flow and, therefore, potentially liver function, has important short-term consequences because of the liver’s key metabolic importance and role in drug metabolism. The objective of this study was to quantify the effect of cardiac surgery on liver blood flow from before the induction of anaesthesia to 24 hours postoperatively.

Method: Ten patients with no history of liver impairment, moderate or good left ventricular function, and undergoing routine hypothermic coronary artery bypass graft surgery, were entered into the study. Liver blood flow was determined by the clearance of indocyanine green (ICG), expressed as a percentage disappearance rate (PDR).

Results: The mean baseline percentage disappearence rate (PDR) of indocyanine green (ICG) was 19.849-4.47%/min. This increased marginally to 20.429-6.67%/min following the induction of anaesthesia, but after 15 min of cardiopulmonary bypass, the PDR fell to 13.519-3.69%/min; this was significantly lower than all other PDRs measured throughout the study. Prior to extubation, the PDR increased again to 20.019-3.72%-min, and this level was maintained at 12 hours (PDR 20.329-3.53%min) and 24 hours (PDR 20.519-2.27%/min).

Conclusion: The induction of anaesthesia and positive pressure ventilation do not affect liver blood flow. Cardiopulmonary bypass at 308C is associated with a significant reduction in liver blood flow, which returns to normal within 4 / 6 hours of surgery and remains normal for up to 24 hours after surgery.
Period and region
Authors: Wishart David
Published: June 2004

Geographers have long maintained that region and period are similar types of generalization. Yet, while geographers have closely examined the nature of regions and regionalization, historians have remained largely silent on the assumptions that underlie the division of time into periods. Reflection on the nature of period and region reveals many similarities, including their basis in the material world but also the subjectivity of their recognition, the selective nature of their content and boundaries, their tendency to emphasize differences rather than commonalities, and their limited scope as generalizations. The great number of feasible ways of dividing space into regions and time into periods opens the door for alternative narratives, including those which challenge conventional Eurocentric interpretations. In the final analysis, periodization and regionalization should be seen as part and parcel of the art of representation.
Geographies of colonial philanthropy
Authors: Lambert David , Lester Alan
Published: June 2004

Through an examination of the material and imaginative geographies of colonial philanthropy in parts of the British Empire from the late eighteenth century to the midnineteenth century, this paper advocates a more nuanced conception of the heterogeneity of colonial discourse. At the same time, it elaborates a networked conceptualization of empire. Particular attention is paid to the moralities of closeness, distance and connection, the spatial politics of knowledge, and the spatial and temporal translation of the trope of ‘slavery’ within philanthropic discourse. The paper raises colonial philanthropy as an object of inquiry that has relevance for contemporary globalized humanitarianism as well as for cross-cultural tension within former imperial sites.
Pet dogs owned by lupus patients are at a higher risk of developing lupus
Authors: Chiou S-H , Lan J-L , Lin S-L , Chen D-Y , Tsai N-Y , Kuan C-Y , Lin T-Y , Lin F-J , Lee W-M , Chang T-J
Published: June 2004

The aim of this study is to determine whether pet dogs owned by patients with systemic lupus erythematosus (SLE) are at a higher risk of developing SLE. Diagnosis of canine SLE was mainly based on the 11 diagnostic criteria for human SLE and two marked immunological features of canine SLE. Among 59 pet dogs owned by 37 SLE patients, 11 (18.64%) were ANA positive, and three (5.08%) had SLE. In contrast, of 187 pet dogs owned by non-SLE households, nine (4.81%) were ANA positive, and none (0%) had SLE. Among 650 outpatient dogs registered in the veterinary hospital, 34 (5.23%) were ANA positive, and six (0.92%) had SLE. Frequency of ANA and SLE among pet dogs owned by SLE patients was significantly higher than in pet dogs owned by non-SLE households (P 1/4 0.001 for ANA; P 1/4 0.013 for SLE) and in outpatient dogs (P, 0.001 for ANA; P 1/4 0.032 for SLE). With respect to canine SLE development, the relative risk or risk ratio (R)of human SLE contact varied from 5.5 (compared with outpatient dogs) to near the infinite (compared with dogs owned by non-SLE households). The prevalence of canine SLE among pet dogs of SLE patients was therefore estimated to be 508 per 10 000 [95% confidence interval (95% CI), 0-1068]. In conclusion, pet dogs with human SLE contact were at a higher risk of developing SLE. Our results indicate that a common environmental factor or zoonotic agent may be involved in the development of human and canine SLE.
Breast cancer stage at time of detection in women with systemic lupus erythematosus
Authors: Bernatsky S , Clarke A , Ramsey-Goldman R , Boivin J-F , Joseph L , Rajan Raghu , Manzi S
Published: June 2004

Mounting evidence suggests an increased cancer risk in several autoimmune diseases, including systemic lupus erythematosus (SLE). However, greater scrutiny for cancer in subjects with chronic disease (compared to the general population) might explain this apparent association. If so, one would expect cancers in SLE to be diagnosed at earlier stages than in the general population. This might be particularly evident in cancers where screening is available, such as breast cancer. We linked the University of Pittsburgh lupus cohort with the Pennsylvania Cancer Registry to determine the frequency distribution for stage at diagnosis of invasive breast cancers in the SLE subjects. Data on staging of cancers occurring in the general population of Pennsylvania were obtained from The US Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. A lower percentage of women with SLE presented with localized breast cancer (nine of the 16, 56.2%) compared to the general population of women (63.5%). Although not definitive, this evidence suggests that cancers in SLE are not necessarily diagnosed at earlier stages than in the general population.
Scarring alopecia in discoid lupus erythematosus: a clinical, histopathologic and immunopathologic study
Authors: Fabbri P , Amato L , Chiarini C , Moretti S , Massi D
Published: June 2004

Scarring alopecia is a very frequent feature of chronic discoid lupus erythematosus (DLE). So far in the literature, only clinic-pathologic features or histopathologic-immunopathologic traits of DLE scarring alopecia (DLESA) have been reported. We describe the most significant features of clinical morphology, histopathology, serum and tissue immunopathology of 36 DLESA patients (41.9% of all our scarring alopecia patients). Clinically, 33.3% presented a single lesion and 52.7% presented multiple lesions of scarring alopecia, while 13.8% exhibited a picture resembling Pseudopelade of Brocq, with the classic ‘footprints in the snow’ appearance. The most frequent morphologic features were sclero-atrophy (80.5%) and erythema (63.8%). The main histopathologic aspects appeared to be fibrosis (100%), follicular hyperkeratosis (91.4%), epidermal atrophy (88.5%), lymphocytic infiltrate (88.5%), thickened basement membrane (77.1%) and basal vacuolar degeneration (74.2%). Antinuclear antibodies were present in 42.8% of patients and antigastric mucosa, antithyroid and anticardiolipin antibodies in 17-21% of patients. A positive lupus band test was demonstrated in 81.8% of cases and perivascular deposit in 30.3% of patients. Histopathology alone allowed a correct diagnosis only in 68.5% of cases; in the other cases, the diagnosis was assessed also taking into account immunopathologic findings. Our study defines the clinic, histopathologic and immunopathologic features of DLESA patients and points out that a multiparametric approach is mandatory to assess the diagnosis of DLESA.
Turning in the graveyard: trees and the hybrid geographies of dwelling, monitoring and resistance in a Bristol cemetery
Authors: Cloke Paul , Jones Owain
Published: June 2004

This paper explores the historical development of a Victorian cemetery in Bristol - Arnos Vale - in order to discuss how the nonhuman agency of trees has been enrolled into particular networks of environmental change and conservation. We argue that trees have both acted as socialized actors in the narrative of the changing nature of Arnos Vale and contributed significantly to the relational agencies involved. Trees have thereby been implicated in processes of resistance at the site, particularly through their incorporation in practices of monitoring and surveillance. The changing tree presence at Arnos Vale has served to recontextualize and resignify the site, and the monitoring of trees has made this bricolage known, prompting the construction of a significant site of resistance where the privatization of public space has been contested.
Randomized Phase II Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate Cancer
Authors: Dahut William L. , Gulley James L. , Arlen Philip M. , Liu Yinong , Fedenko Katherine M. , Steinberg Seth M. , Wright John J. , Parnes Howard , Chen Clara C. , Jones Elizabeth , Parker Catherine E. , Linehan W. Marston , Figg William D.
Published: June 2004

Purpose

Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC.

Methods

Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m2 intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression.

Results

After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P = .32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group.

Conclusion

In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.
Multicenter Randomized Trial Comparing Sequential With Concomitant Administration of Doxorubicin and Docetaxel As First-Line Treatment of Metastatic Breast Cancer: A Spanish Breast Cancer Research Group (GEICAM-9903) Phase III Study
Authors: Alba Emilio , Martín Miguel , Ramos Manuel , Adrover Encarna , Balil Ana , Jara Carlos , Barnadas Agustí , Fernández-Aramburo Antonio , Sánchez-Rovira Pedro , Amenedo Margarita , Casado Antonio
Published: June 2004

Purpose

This randomized, multicenter, phase III trial evaluated whether sequential doxorubicin and docetaxel (A→T) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC).

Patients and Methods

One hundred forty-four patients were randomly assigned to receive three cycles of doxorubicin 75 mg/m2 every 21 days followed by three cycles of docetaxel 100 mg/m2, every 21 days (A→T) or six cycles of the combination doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (AT) every 21 days. Patients previously treated with anthracyclines received two cycles of doxorubicin followed by four cycles of docetaxel (A→T), or three cycles of AT followed by three cycles of docetaxel 100 mg/m2 every 21 days.

Results

Febrile neutropenia was less common in the A→T arm (29.3% of patients, 6.9% of cycles) compared with the AT arm (47.8% of patients, 14.8% of cycles; P = .02 and P = .0004, respectively). Asthenia, diarrhea, and fever occurred more frequently in the AT arm. The overall responses rates were 61% in the A→T arm (95% CI, 50% to 72%) and 51% in the AT arm (95% CI, 39% to 63%). The median duration of response was 8.7 months (A→T) and 7.6 months (AT); the median time to progression was 10.5 months (A→T) and 9.2 months (AT); the median overall survival was 22.3 months (A→T) and 21.8 months (AT); and no significant differences were found.

Conclusion

A→T significantly reduced febrile neutropenia compared with AT in MBC patients and maintains comparable antitumoral efficacy. A→T represents a valid option for the treatment of MBC.
Topotecan Compared With No Therapy After Response to Surgery and Carboplatin/Paclitaxel in Patients With Ovarian Cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) Randomized Study
Authors: De Placido Sabino , Scambia Giovanni , Di Vagno Giovanni , Naglieri Emanuele , Lombardi Alessandra Vernaglia , Biamonte Rosalbino , Marinaccio Marco , Cartenì Giacomo , Manzione Luigi , Febbraro Antonio , de Matteis Andrea , Gasparini Gianpietro , Valerio Maria Rosaria , Danese Saverio , Perrone Francesco , Lauria Rossella , De Laurentiis Michele , Greggi Stefano , Gallo Ciro , Pignata Sandro
Published: June 2004

Purpose

Topotecan is an active second-line treatment for advanced ovarian cancer. Its efficacy as consolidation treatment after first-line standard chemotherapy is unknown.

Patients and Methods

To investigate whether topotecan (1.5 mg/m2 on days 1 through 5, four cycles, every 3 weeks) prolonged progression-free survival (PFS) for patients responding to standard carboplatin (area under the curve 5) and paclitaxel (175 mg/m2 administered as a 3-hour infusion in six cycles; CP), a multicenter phase III study was performed with an 80% power to detect a 50% prolongation of median PFS. Patients were registered at diagnosis and randomized after the end of CP.

Results

Two hundred seventy-three patients were randomly assigned (topotecan, n = 137; observation, n = 136), with a median age of 56 years. Stage at diagnosis was advanced in three fourths of patients (stage III in 65% of patients; stage IV in 10%); after primary surgery, 46% had no residual disease and 20% were optimally debulked. After CP, 87% reached a clinical complete response, and 13% achieved a partial response. Neutropenia (grade 3/4 in 58% of the patients) and thrombocytopenia (grade 3 in 21%; grade 4 in 3%) were the most frequent toxicities attributed to topotecan. There was no statistically significant difference in PFS between the arms (P = .83; log-rank test): median PFS was 18.2 months in the topotecan arm and 28.4 in the control arm. Hazard ratio of progression for patients receiving topotecan was 1.18 (95% CI, 0.86 to 1.63) after adjustment for residual disease, interval debulking surgery, and response to CP.

Conclusion

The present analysis indicates that consolidation with topotecan does not improve PFS for patients with advanced ovarian cancer who respond to initial chemotherapy with carboplatin and paclitaxel.
Quality of Life in Patients With Gastroenteropancreatic Tumors Treated With [177Lu-DOTA0,Tyr3]octreotate
Authors: Teunissen Jaap J.M. , Kwekkeboom Dik J. , Krenning Eric P.
Published: June 2004

Purpose

To evaluate the quality of life (QoL) in patients with metastatic somatostatin receptor positive gastroenteropancreatic tumors treated with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy.

Patients and Methods

Fifty patients who had been treated with 600 to 800 mCi of 177Lu-octreotate and had a follow-up of at least 3 months were studied. The patients completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 before therapy and at follow-up visit 6 weeks after the last cycle. Overall QoL and specific QoL domains of both the total group of patients and subgroups according to treatment outcome were analyzed. Twenty-four patients had regression, 19 had stable disease, six had progressive disease, and one had nonassessable disease status. Analysis of variance was used for statistical comparison.

Results

A significant improvement in the global health status/QoL scale was observed after therapy with 177Lu-octreotate (P < .01). The score increased significantly six weeks after therapy to a mean of 78.2, up from 69.0 (scale range, 0 to 100). Furthermore, significant improvement was observed in the role, emotional, and social function scales. The symptom scores for fatigue, insomnia, and pain were significantly decreased. Patients with proven tumor regression most frequently had an improvement of QoL domains. Unexpectedly, patients with progressive disease also indicated an improvement in their global health/QoL score.

Conclusion

177Lu-octreotate therapy significantly improved the global health/QoL and several function and symptom scales in patients with metastasized gastroenteropancreatic tumors, but especially in those patients with proven tumor regression.
Prognostic Significance of Molecular Upstaging of Paraffin-Embedded Sentinel Lymph Nodes in Melanoma Patients
Authors: Takeuchi Hiroya , Morton Donald L. , Kuo Christine , Turner Roderick R. , Elashoff David , Elashoff Robert , Taback Bret , Fujimoto Akihide , Hoon Dave S.B.
Published: June 2004

Purpose

Detection of micrometastases in sentinel lymph nodes (SLNs) is important for accurate staging and prognosis in melanoma patients. However, a significant number of patients with histopathology-negative SLNs subsequently develop recurrent disease. We hypothesized that a quantitative realtime reverse transcriptase polymerase chain reaction (qRT) assay using multiple specific mRNA markers could detect occult metastasis in paraffin-embedded (PE) SLNs to upstage and predict disease outcome.

Patients and Methods

qRT was performed on retrospectively collected PE SLNs from 215 clinically node-negative patients who underwent lymphatic mapping and sentinel lymphadenectomy for melanoma and were followed up for at least 8 years. PE SLNs (n = 308) from these patients were sectioned and assessed by qRT for mRNA of four melanoma-associated genes: MART-1 (antigen recognized by T cells-1), MAGE-A3 (melanoma antigen gene-A3 family), GalNAc-T (β1→4-N-acetylgalactosaminyl-transferase), and Pax3 (paired-box homeotic gene transcription factor 3).

Results

Fifty-three (25%) patients had histopathology-positive SLNs by hemotoxylin and eosin and/or immunohistochemistry. Of the 162 patients with histopathology-negative SLNs, 48 (30%) had nodes that expressed at least one of the four qRT markers, and these 48 patients also had a significantly increased risk of disease recurrence by a Cox proportional hazards model analysis (P < .0001; risk ratio, 7.48; 95% CI, 3.70 to 15.15). The presence of ≥ one marker in histopathology-negative SLNs was also a significant independent prognostic factor by multivariate analysis for overall survival (P = .0002; risk ratio, 11.42; 95% CI, 3.17 to 41.1).

Conclusion

Molecular upstaging of PE histopathology-negative SLNs by multiple-marker qRT assay is a significant independent prognostic factor for long-term disease recurrence and overall survival of patients with early-stage melanoma.
A Perspectivist Approach to Theory Construction
Authors: McGuire William J.
Published: June 2004

A perspectivist approach is taken to the theory-construction process in psychological research. This approach assumes that all hypotheses and theories are true, as all are false, depending on the perspective from which they are viewed, and that the purpose of research is to discover which are the crucial perspectives. Perspectivism assumes also that both the a priori conceptual phase of research and the a posteriori empirical phase have both discovery and testing functions. Topics discussed include how the perspectivist approach can improve methodology training and practice (particularly as regards theory construction); what researchers accept as theoretical explanations; the nature of mediational theories; how theories can be formalized, expressed in multiple modalities and for various scaling cases; and how experimental designs can be enriched by theory-guided mediational and interactional variables.
A Personalized Theory of Theory Construction
Authors: Wyer Robert S.
Published: June 2004

This article describes my personal approach to theory construction. I liken the construction of a theory to the solution of a mathematical puzzle in which the answer is not in the back of the book. I touch on (a) the development of a theoretical perspective, (b) the identification of a specific problem, and (c) the development of a theory to address the problem. The article concludes with the view that in the last analysis, any approach is likely to be fruitful so long as one persists in its use and does not shift gears whenever the going gets tough.
Metatheory: Lessons from Social Identity Research
Authors: Abrams Dominic , Hogg Michael A.
Published: June 2004

The value of a metatheoretical perspective is illustrated using our work in the development of the social identity approach. A metatheory places specific research questions within a broader framework and encourages the integration of theorizing for a range of potentially disparate phenomena. It sets parameters for predictions by specific theories and contexts. Resistance to ideas and disputes among theorists often reflect differences in metatheories. However, openness to debate and integration of concepts can turn these to advantage by posing new research questions. These issues are discussed with reference to European and North American perspectives on groups; theorizing about intergroup behavior, motivation, and self-categorization; the connection between laboratory and real-world phenomena; and the linkage of intergroup and intragroup behavior.
Making a Theory Useful: Lessons Handed Down
Authors: Higgins E. Tory
Published: June 2004

What makes a theory useful? Whether one is evaluating and investigating one's own or another's theory, there are some useful lessons to keep in mind. One lesson is that the reason a “good” theory should be testable, be coherent, be economical, be generalizable, and explain known findings is that all of these characteristics serve the primary function of a theory—to be generative of new ideas and new discoveries. Other lessons concern how to develop a theory (whether one's own or an adopted one). One lesson is to know what the theory is and what it is not—don't make it into something else either by “improving” it or by unfairly dismissing it. Know the theory's domain of applicability—do test its limits but don't overextend it. Know when the theory makes a prediction and when it does not—know when it is simply silent. This article concludes by offering the metaphor that the lessons for developing a theory to make it useful have a lot in common with good parenting. For example: Neither spoil nor abuse the theory; neither neglect nor abandon it; support and nurture the theory; don't overprotect it but do defend it; be patient with the theory—don't push it too hard or too fast; and finally, don't forget to love and enjoy it.
The Benefits of Abstract Functional Analysis in Theory Construction: The Case of Interdependence Theory
Authors: Holmes John G.
Published: June 2004

In this article I argue for the benefits of an abstract functional analysis in theory construction, suggesting that an understanding of the nature of situations of interdependence will provide theoretical insights into basic processes in interpersonal relations. That is, mechanisms and basic processes such as social cognition are best understood by describing their functional relation to the social problems with which they were designed to cope, rather than studying them in their own right in isolation from the purpose they serve. I discuss the tenets of ecological psychology, the scientific philosophy underpinning this way of thought. I then link this approach to the development of my own theoretical ideas on trust in close relationships, providing a description of how a functional analysis rooted in the assumptions of interdependence theory shaped the questions I posed and the answers to which I was drawn.
Ion-pairs of ibuprofen: increased membrane diffusion
Authors: Sarveiya Vikram , Templeton John F , Benson Heather A E
Published: June 2004

The purpose of the present study was to determine the influence of pH and ion-pairing on the permeation of ibuprofen across polydimethylsiloxane (PDMS) membrane. The solubility of ibuprofen sodium was determined at a range of pH values. Saturated solutions were then used to determine the influence of pH on diffusion across PDMS as a model membrane. The apparent partition coefficient of ibuprofen sodium between n-octanol and phosphate buffer at various pH values was also investigated. Organic salts of ibuprofen using ethylamine, diethylamine, triethylamine and ethylene diamine as counter-ions were synthesized and the influence of these counter-ionson the permeation of ibuprofen was studied. The presence of ion-pairing was confirmed using 1H NMR and 13C NMR. Diffusion studies at different pH values (4.0, 5.0, 6.0, 7.0 and 8.0) indicated that ibuprofen sodium flux increased significantly with increasing pH from 4.0 to 7.0. Above pH 7.0 a decrease in diffusion was observed. The permeability coefficient increased with an increase in the amount of unionized acid. The apparent partition coefficient was directly related to the steady-state flux. The steady-state flux of ibuprofen increased up to 16-fold using different counter-ions. The highest flux was measured from ibuprofen triethylamine. The flux of ibuprofen salts across a lipophilic membrane can be increased by formation of ion-pairs. The extent of enhancement is associated with the lipophilicity, extent of ion-pairing and reduction in charge over the drug molecule.
Synthesis of (2E)-2-methyl-3-(4-{[4-(quinolin-2-ylmethoxy)phenyl]sulfanyl}phenyl)prop-2-enoic acid (VUFB 20609) and 2-methyl-3-(4-{[4-(quinolin-2-ylmethoxy)phenyl]sulfanyl}phenyl)propanoic acid (VUFB 20584) as potential antileukotrienic agents
Authors: Jampílek J , Doleẑal M , Kuneŝ J , Víchová P , Jun D , Hanika Jir̂í , O'Connor R , Clynes M
Published: June 2004

The Synthesis of (2E)-2-methyl-3-(4-{[4-(quinolin-2-ylmethoxy)phenyl]sulfanyl}phenyl) prop-2-enoic acid (VUFB 20609) and racemic 2-methyl-3-(4-{[4-(quinolin-2-ylmethoxy) phenyl]sulfanyl}phenyl)propanoic acid (VUFB 20584) as new potential antileukotrienic drugs are described. Due to a low reactivity of the 4-substituted aryl bromides (coupling of the 4-substituted aryl bromides do not provide an activating functional group with 4-methoxybenzene-1-thiol), special conditions, in particular specific heterogeneous copper catalysts, were used. Catalytic hydrogenation of the conjugated double bond on Pd/C in the presence of the sulfanyl group is discussed. In-vitro cytotoxicity testing was performed using a microplate colorimetric acid phosphatase assay. Antiplatelet activity was evaluated using an in-vitro test in human platelet-rich plasma. Some substances inhibited arachidonic acid-induced platelet aggregation.
Hypoglycaemic effect of Calamintha officinalis Moench. in normal and streptozotocin-induced diabetic rats
Authors: Lemhadri A , Zeggwagh N-A , Maghrani M , Jouad H , Michel J B , Eddouks M
Published: June 2004

The purpose of this study was to investigate the effects of a water extract from the aerial parts of Calamintha officinalis Moench., after either a single dose or daily oral administration for 15 days, on plasma blood glucose concentrations and basal insulin levels in normal and streptozotocin-induced diabetic rats (STZ diabetic rats). The results clearly demonstrated the hypoglycaemic effect of this plant extract in both normal and STZ diabetic rats. In addition, no changes were observed in basal plasma insulin concentrations after treatment with this plant in normal or STZ diabetic rats, indicating that the underlying mechanism of the plant's pharmacological action seems to be independent of insulin secretion. We conclude that the aqueous C. officinalis extract exhibits a significant hypoglycaemic effect in normal and STZ diabetic rats without affecting basal plasma insulin concentrations, and supports, therefore, its traditional use by the Moroccan population.
In-vitro metabolism of isotetrandrine, a bisbenzylisoquinoline alkaloid, in rat hepatic S9 fraction by high-performance liquid chromatography-atmospheric pressure ionization mass spectrometry
Authors: Wu Wu-Nan , McKown Linda A , Gopaul V Sashi
Published: June 2004

The objective of this study was to investigate the in-vitro metabolism of isotetrandrine, a bisbenzylisoquinoline alkaloid, using rat hepatic S9 fraction and to profile and identify its metabolites using high-performance liquid chromatography-atmospheric pressure ionization mass spectrometry (HPLC-MS) and tandem mass spectrometry (MS/MS). Isotetrandrine was incubated at a concentration of 100 μg mL−1 with male rat hepatic S9 fraction in the presence of an NADPH generating system (Tris buffer, pH 7.4, 37°C). Samples were removed at 60 min after reaction initiation. Unchanged isotetrandrine (∼63% of the sample) and four metabolites were profiled, characterized and tentatively identified using solvent extraction, methyl derivatization, and HPLC-MS and MS/MS techniques. Isotetrandrine metabolites were mainly formed via two main pathways, N-demethylation and isoquinoline ring oxidation. The first pathway produced a major metabolite, N-desmethyl isotetrandrine (∼16% of the sample). The second pathway produced three minor oxidized metabolites, hydroxy-isotetrandrine (∼6% of the sample), oxo-isotetrandrine (∼7% of the sample), and oxo-hydroxy-isotetrandrine (∼7% of the sample). Diazomethane treatment of these metabolites did not produce any methyl derivatives and therefore the hydroxylated sites of the metabolites were tentatively assigned at the heterocyclic moieties of the isoquinoline rings. In conclusion, isotetrandrine is substantially metabolized in this in-vitro rat hepatic system.
Influence of dissolution media composition on drug release and in-vitro/in-vivo correlation for paracetamol matrix tablets prepared with novel carbomer polymers
Authors: Parojĉić J , Durić Z , Jovanović M , Ibrić S , Jovanović D
Published: June 2004

The influence of dissolution media composition on drug release kinetics and in-vitro/in-vivo correlation (IVIVC) for hydrophilic matrix tablets based on Carbopol 971P and Carbopol 71G was investigated. A number of buffered and unbuffered media differing with respect to their pH value, ionic strength and ionic species was evaluated. The observed in-vitro drug release profiles were compared with the hypothetical drug release profiles in-vivo calculated by numerical deconvolution from the results of an in-vivo study. The obtained IVIVC plots were examined using linear and non-linear (proportional odds, proportional hazards and proportional reversed hazards) mathematical models. Although the studied sustained release agents were chemically identical, they exhibited pronounced differences in drug product behaviour both in-vitro and in-vivo. The use of non-linear modelling resulted in an improved level of correlation, especially in the case of Carbopol 71G matrices. The obtained results indicated the susceptibility of drug release kinetics and hence IVIVC in the case of anionic polymer matrices to media composition, and emphasized the need for thorough evaluation of applied media during the development of biorelevant dissolution methodology. Although the use of non-linear modelling could be advantageous, the need for a simple and meaningful nonlinear relationship is pointed out.
5‘-Deiodinase type 1 activity in liver and brain of the thyroxine-treated dystrophic hamster
Authors: Singh Yadhu N , Gleysteen Allison L , Ganschow Stephanie L
Published: June 2004

Dystrophic hamsters (DH), as well as dystrophic patients, exhibit alveolar hypoventilation (AH) and low plasma thyroid hormone levels. Thyroxine (T4) treatment of young DH retards AH development, and improves respiratory function and contractility of skeletal muscles. However, the mechanism responsible for the hypothyroidism in DH is not known. One possible cause of the hypothyroidism is reduced activity of the 5′-deiodinase enzyme system, which converts T4 to the more active triiodothyronine (T3). This study tested the above hypothesis by measuring the serum T3 and T4 levels and the activity of the enzyme type 1 5′-deiodinase (D1) in the liver and brain of normal and dystrophic hamsters before, and 8 weeks after, placebo or T4 treatment. There was no significant difference in T4 level between normal and dystrophic hamsters before or after treatment. However, the T3 level was lower in DH before treatment and 8 weeks after placebo and T4 treatment. Both in the liver and brain, D1 activity in DH was depressed compared with normal hamsters. In the liver, T4 supplementation restored enzyme activity to normal level, while in the brain there was no significant difference. The data indicate that the hypothyroidism in DH may be, in part, due to reduced activity of D1 enzyme, which could be partially reversed by T4 treatment.
β1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance
Authors: Campos Lia S. , Leone Dino P. , Relvas Joao B. , Brakebusch Cord , Fässler Reinhard , Suter Ueli , ffrench-Constant Charles
Published: June 2004

The emerging evidence that stem cells develop in specialised niches highlights the potential role of environmental factors in their regulation. Here we examine the role of β1 integrin/extracellular matrix interactions in neural stem cells. We find high levels of β1 integrin expression in the stem-cell containing regions of the embryonic CNS, with associated expression of the laminin α2 chain. Expression levels of lamininα2 are reduced in the postnatal CNS, but a population of cells expressing high levels of β1 remains. Using neurospheres –aggregate cultures, derived from single stem cells, that have a three-dimensional architecture that results in the localisation of the stem cell population around the edge of the sphere – we show directly thatβ1 integrins are expressed at high levels on neural stem cells and can be used for their selection. MAPK, but not PI3K, signalling is required for neural stem cell maintenance, as assessed by neurosphere formation, and inhibition or genetic ablation of β1 integrin using cre/lox technology reduces the level of MAPK activity. We conclude that integrins are therefore an important part of the signalling mechanisms that control neural stem cell behaviour in specific areas of the CNS.
Modulation of floral development by a gibberellin-regulated microRNA
Authors: Achard Patrick , Herr Alan , Baulcombe David C. , Harberd Nicholas P.
Published: June 2004

Floral initiation and floral organ development are both regulated by the phytohormone gibberellin (GA). For example, in short-day photoperiods, the Arabidopsis floral transition is strongly promoted by GA-mediated activation of the floral meristem-identity gene LEAFY. In addition,anther development and pollen microsporogenesis depend on GA-mediated opposition of the function of specific members of the DELLA family of GA-response repressors. We describe the role of a microRNA (miR159) in the regulation of short-day photoperiod flowering time and of anther development. MiR159 directs the cleavage of mRNA encoding GAMYB-related proteins. These proteins are transcription factors that are thought to be involved in the GA-promoted activation of LEAFY, and in the regulation of anther development. We show that miR159 levels are regulated by GA via opposition of DELLA function, and that both the sequence of miR159 and the regulation of miR159 levels by DELLA are evolutionarily conserved. Finally, we describe the phenotypic consequences of transgenic over-expression of miR159. Increased levels of miR159 cause a reduction in LEAFY transcript levels, delay flowering in short-day photoperiods, and perturb anther development. We propose that miR159 is a phytohormonally regulated homeostatic modulator of GAMYB activity, and hence of GAMYB-dependent developmental processes.
Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis
Authors: Bagheri-Yarmand Rozita , Talukder Amjad H. , Wang Rui-An , Vadlamudi Ratna K. , Kumar Rakesh
Published: June 2004

Emerging data suggest that metastasis-associated protein 1 (MTA1) represses ligand-dependent transactivation functions of estrogen receptor-alpha in cultured breast cancer cells and that MTA1 is upregulated in human breast tumors. However, the role of MTA1 in tumorigenesis in a physiologically relevant animal system remains unknown. To reveal the role of MTA1 in mammary gland development, transgenic mice expressing MTA1 under the control of the mouse mammary tumor virus promoter long terminal repeat were generated. Unexpectedly, we found that mammary glands of these virgin transgenic mice exhibited extensive side branching and precocious differentiation because of increased proliferation of ductal and alveolar epithelial cells. Mammary glands of virgin transgenic mice resemble those from wild-type mice in mid-pregnancy and inappropriately express β-casein, cyclin D1 andβ-catenin protein. Increased ductal growth was also observed in the glands of ovariectomized female mice, as well as of transgenic male mice. MTA1 dysregulation in mammary epithelium and cancer cells triggered downregulation of the progesterone receptor-B isoform and upregulation of the progesterone receptor-A isoform, resulting in an imbalance in the native ratio of progesterone receptor A and B isoforms. MTA1 transgene also increased the expression of progesterone receptor-A target genes Bcl-XL(Bcl2l1) and cyclin D1 in mammary gland of virgin mice, and,subsequently, produced a delayed involution. Remarkably, 30% of MTA1 transgenic females developed focal hyperplastic nodules, and about 7%exhibited mammary tumors within 18 months. These studies establish, for the first time, a potential role of MTA1 in mammary gland development and tumorigenesis. The underlying mechanism involves the upregulation of progesterone receptor A and its targets, Bcl-XL and cyclin D1.