bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum osteoprotegerin and its ligand in Paget's disease of bone: Relationship to disease activity and effect of treatment with bisphosphonates
Authors: Alvarez L. , Peris P. , Guañabens N. , Vidal S. , Ros I. , Pons F. , Filella X. , Monegal A. , Muñoz‐Gomez J. , Ballesta A. M.
Published: March 2003

Objective

To test the following hypotheses: 1) osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) serum levels in patients with Paget's disease are related to disease activity and are different from those in healthy individuals; 2) interleukin‐6 (IL‐6), a cytokine that has been shown to have higher levels in Paget's disease, modulates these factors; and 3) the antiresorptive effect of bisphosphonates in Paget's disease of bone may be mediated through these local factors.

Methods

The study group comprised 31 patients with Paget's disease who received 400 mg/day of oral tiludronate for 3 months. Serum levels of OPG, RANKL, IL‐6, bone alkaline phosphatase (AP), N‐terminal type I procollagen propeptide, urinary N‐terminal crosslinking telopeptide of type I collagen, and urinary α–C‐terminal crosslinking telopeptide of type I collagen were measured at baseline and 1 month after the end of therapy. In addition, the RANKL:OPG ratio was calculated, and disease activity was evaluated at baseline by quantitative bone scintigraphy.

Results

Mean baseline OPG values were higher in patients with Paget's disease than in healthy control subjects (P < 0.005), but RANKL and IL‐6 values and RANKL:OPG ratios in the 2 groups were similar. OPG concentrations decreased significantly after treatment with tiludronate (P < 0.005), whereas no significant changes were observed in serum RANKL values. No correlation was found between either bone markers or quantitative scintigraphic indices and serum levels of OPG, RANKL, IL‐6, and RANKL:OPG ratios. Serum OPG decreased significantly only in those patients with baseline OPG values >4.1 pM/liter.

Conclusion

Serum OPG increases in Paget's disease and decreases after treatment with tiludronate, especially in patients with the highest OPG values. In contrast, RANKL serum levels and RANKL:OPG ratios are unmodified in patients with Paget's disease. Although serum OPG, RANKL, and IL‐6 values were unrelated to disease activity, the increase in OPG may reflect a protective mechanism of the skeleton to compensate for increased bone resorption.
A rare case of juxtaarticular osteoid osteoma of the calcaneus initially misdiagnosed as juvenile chronic arthritis
Authors: Christodoulou Anastasios , Ploumis Avraam , Karkavelas George , Terzidis Ioannis , Tsagias Ioannis
Published: March 2003

Juxtaarticular osteoid osteoma is frequently misdiagnosed because the symptoms may mimic arthritis, and radiographs may not be characteristic. A rare case of subtalar pain lasting 5 years in a female teenager is presented here. The initial diagnosis was monarticular juvenile chronic arthritis. Family history was misleading because her mother had rheumatoid arthritis (RA).
Expression of pleiotrophin, an embryonic growth and differentiation factor, in rheumatoid arthritis
Authors: Pufe Thomas , Bartscher Michaela , Petersen Wolf , Tillmann Bernhard , Mentlein Rolf
Published: March 2003

Objective

Pleiotrophin (PTN), a 15.3‐kd heparin‐binding peptide, is expressed in mesodermal and neuroectodermal cells during development, but rarely in adult tissues. Since developmentally regulated factors often reappear during disease, we sought to determine whether there was PTN expression in the synovial membranes of patients with rheumatoid arthritis (RA).

Methods

PTN messenger RNA expression was assayed by quantitative reverse transcriptase–polymerase chain reaction. The protein was localized by immunohistochemistry and quantified by enzyme‐linked immunosorbent assay (ELISA). Effects of PTN on cell proliferation in vitro were determined by DNA measurements.

Results

PTN expression in normal adult synovial membranes and cartilage was barely detectable. However, PTN was strongly up‐regulated in synovial tissues from patients with RA. In contrast, samples from patients with pyogenic arthritis had moderate PTN levels, and those from patients with osteoarthritis had only a slight increase in PTN, as measured by ELISA. In RA patients, PTN was localized primarily in synoviocytes but was also found in endothelial cells of blood vessels. In cultured mouse fibroblasts used as a model, PTN expression was up‐regulated by tumor necrosis factor α and was more weakly up‐regulated by epidermal growth factor. Recombinant PTN stimulated the proliferation of cultured human synoviocytes and the monocyte cell line THP‐1, but not human dermal fibroblasts, in which PTN increased the synthesis of vascular endothelial growth factor.

Conclusion

In addition to certain types of cancer, the embryonic growth and differentiation factor PTN is expressed in adults with inflammatory diseases, in particular, RA. Proinflammatory cytokines enhance the expression of PTN. Thus, we propose that PTN is a further paracrine angiogenesis and growth factor for synovial cells in RA.
Inhibition of cartilage degradation: A combined tissue engineering and gene therapy approach
Authors: Kafienah Wael , Al‐Fayez Fayza , Hollander Anthony P. , Barker Michael D.
Published: March 2003

Objective

To determine if tissue‐engineered cartilage can be protected from cytokine‐induced degradation using a gene therapy approach.

Methods

Chemical and pantropic retroviral gene transfer methodologies were compared for their ability to introduce a luciferase reporter gene into adult bovine cartilage chondrocytes grown in monolayer. Pantropic retrovirus was then used to transduce these cells with human tissue inhibitor of metalloproteinases 1 (TIMP‐1), and the stability of expression in monolayer or pellet culture was monitored for 6 weeks. Untransduced and TIMP‐1–transduced cells were also used to tissue engineer 3‐dimensional cartilage constructs that were then challenged with interleukin‐1 (IL‐1) for 4 weeks. Conditioned media and residual cartilage were collected for analysis of matrix components, including type II collagen and proteoglycans, and for TIMP‐1 production and matrix metalloproteinase (MMP) activity.

Results

Chemical transfection of adult bovine chondrocytes gave rise to short‐lived reporter expression that was virtually undetectable after 4 weeks of culture. In contrast, pantropic retroviral transduction gave rise to stable expression that persisted at a high level for at least 6 weeks. Pantropic transduction of the cells with TIMP‐1 gave rise to similar long‐term expression, both in monolayer and pellet cultures. TIMP‐1–transduced tissue‐engineered cartilage also retained TIMP‐1 expression for an additional 4 weeks of culture in the presence of IL‐1. Compared with control samples, TIMP‐1–transgenic cartilage resisted the catabolic effects of IL‐1, with MMP activity reduced to basal levels and a decreased loss of type II collagen.

Conclusion

Pantropic retroviral transduction permits long‐term expression of potentially therapeutic transgenes in adult tissue‐engineered cartilage. While TIMP‐1 transduction could be used to prevent collagen breakdown, alternative transgenes may be necessary to protect cartilage proteoglycans.
Outcome in adults with juvenile idiopathic arthritis: A quality of life study
Authors: Foster Helen E. , Marshall Nicola , Myers Andrea , Dunkley Pippa , Griffiths Ian D.
Published: March 2003

Objective

To evaluate quality of life (QOL) in adults with juvenile idiopathic arthritis (JIA), using validated measures of functional disability and generic health status, and to quantify their educational attainment and employment status.

Methods

The adult rheumatology departmental database was used to identify patients. Functional disability and generic health status/QOL were assessed by the Health Assessment Questionnaire (HAQ) and the Short Form 36‐item health profile (SF‐36), respectively. Educational achievement and employment status were assessed by questionnaire.

Results

Complete data were available for 82 of the 101 patients identified. The median age of patients was 30 years, and the median disease duration was 21 years. No deaths were recorded. All subtypes of JIA were represented. Thirty‐nine percent of patients had active disease (based on the physician global assessment scale score). The median HAQ score was 1.125 (range 0–3). SF‐36 scores for bodily pain, general health, physical functioning, vitality, emotion, and social isolation were significantly worse in patients compared with controls, and this trend increased with increasing age of the patients and disease duration. The SF‐36 mental summation scores of patients were low compared with those of controls, for all subtypes of JIA, and this finding was independent of the degree of functional disability (by HAQ and SF‐36 physical summation scores). The educational attainment of patients was comparable to that of local controls, but unemployment rates for patients were 3‐fold higher than those for controls.

Conclusion

This is the largest study in which the SF‐36 was used to assess generic health status and QOL in adults with JIA. Many patients had active disease in adulthood, and although the physical outcome of adults with JIA is relatively good, a profound effect on generic health status and QOL was demonstrated for all types of JIA. Furthermore, despite excellent educational attainment, there was a high rate of unemployment among patients.
The rising landscape: A visual exploration of superstring revolutions in physics
Authors: Chen Chaomei , Kuljis Jasna
Published: March 2003

Knowledge domain visualization is a visual exploratory approach to the study of the development of a knowledge domain. In this study, we focus on the practical issues concerning modeling and visualizing scientific revolutions. We study the growth patterns of specialties derived from citation and cocitation data on string theory in physics. Special attention is given to the two superstring revolutions since the 1980s. The superstring revolutions are visualized, animated, and analyzed using the general framework of Thomas Kuhn's structure of scientific revolutions. The implications of taking this approach are discussed.
Pathogenic pathways in fluconazole‐induced branchial arch malformations
Authors: Menegola Elena , Broccia Maria L. , Di Renzo Francesca , Giavini Erminio
Published: March 2003

BACKGROUND

A widely‐used antimycotic agent, bis‐triazole fluconazole (FLUCO), is able to produce abnormalities to the branchial apparatus (hypoplasia, agenesis, and fusion) in postimplantation rodent embryos cultured in vitro. The branchial apparatus is a complex and transient structure in vertebrate embryos and is essential for the development of the face skeleton. Branchial arch mesenchyme is formed by two different cellular populations: paraxial mesenchyme and ectomesenchyme, which originate from rhombencephalic neural crest cell (NCC) migration. We investigated the possible pathogenic pathways involved in FLUCO‐related branchial arch abnormalities. Perturbations in physiological apoptosis, cell proliferation, NCC migration and branchial mesenchyme induction have been considered.

METHODS

Rat embryos (9.5‐day postcoitum; 1–3 somites) were exposed in vitro to 0 or 500 μM FLUCO. After 24, 36, or 48 hr of culture, embryos were examined for apoptosis (acridine orange method) and cell proliferation (BrdU incorporation and detection method). Rhombencephalic NCC migration was analyzed using immunostaining of NCC (using anti‐CRABP antibodies) and the extracellular matrix (using anti‐fibronectin antibodies). The differentiative capability of the branchial mesenchymes was investigated using anti‐endothelin and anti‐endothelin‐receptor antibodies.

RESULTS

During the whole culture period, no alterations in physiological apoptosis, cell proliferation, and mesenchymal cell induction were observed in FLUCO‐exposed embryos in comparison to controls. On the contrary, severe alterations in NCC migration pathways were observed in FLUCO‐exposed embryos.

CONCLUSIONS

The findings suggest that FLUCO produces teratogenic effects by interfering with the cellular and molecular mechanisms that control NCC migration. Birth Defects Research (Part A) 67:116–124, 2003. © 2003 Wiley‐Liss, Inc.
Visualization of alginate–poly‐L‐lysine–alginate microcapsules by confocal laser scanning microscopy
Authors: Strand Berit L. , Mørch Yrr A. , Espevik Terje , Skjåk‐Bræk Gudmund
Published: March 2003

Confocal laser scanning microscopy (CLSM) was used to study the distribution of polymers and cross‐linking ions in alginate–poly‐L‐lysine (PLL) –alginate microcapsules made by fluorescent‐labeled polymers. CLSM studies of Ca‐alginate gel beads made in the presence and absence of non‐gelling sodium ions revealed a more inhomogeneous distribution of alginate in beads formed in the absence of non‐gelling ions. In the formation of alginate‐PLL capsules, the polymer gradients in the preformed gel core were destabilized by the presence of non‐gelling ions in the washing step and in the PLL solution. Ca‐alginate gels preserved the inhomogeneous structure by exposure to ion‐free solution in contrast to exposure to non‐gelling ions (Na+). By exchanging Ca2+ with Ba2+ (10 mM), extremely inhomogeneous gel beads were formed that preserved their structure during the washing and exposure to PLL in saline. PLL was shown to bind at the very surface of the alginate core, forming a shell‐like membrane. The thickness of the PLL‐layer increased about 100% after 2 weeks of storage, but no further increase was seen after 2 years of storage. The coating alginate was shown to overlap the PLL layer. No difference in binding could be observed among coating alginates of different composition. This paper shows an easy and novel method to study the distribution of alginate and PLL in intact microcapsules. As the labeling procedures are easy to perform, the method can also be used for a variety of other polymers in other microencapsulation systems. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 386–394, 2003.
Electrochemical optical waveguide lightmode spectroscopy (EC‐OWLS): A pilot study using evanescent‐field optical sensing under voltage control to monitor polycationic polymer adsorption onto indium tin oxide (ITO)‐coated waveguide chips
Authors: Bearinger J. P. , Vörös J. , Hubbell J. A. , Textor M.
Published: March 2003

A new technique has been developed that combines evanescent‐field optical sensing with electrochemical control of surface adsorption processes. This new technique, termed “electrochemical optical waveguide lightmode spectroscopy” (EC‐OWLS), proved efficient in monitoring molecular surface adsorption and layer thickness changes of an adsorbed polymer layer examined in situ as a function of potential applied to a waveguide in a pilot study. For optical sensing, a layer of indium tin oxide (ITO) served as both a high‐refractive‐index waveguide and a conductive electrode. In addition, an electrochemical flow‐through fluid cell was provided, which incorporated working, reference, and counter electrodes, and was compatible with the constraints of optical sensing. Poly(L‐lysine)‐grafted‐poly(ethylene glycol) (PLL‐g‐PEG) served as a model, polycation adsorbate. Adsorption of PLL‐g‐PEG from aqueous buffer solution increased from 125 to 475 ng/cm2 along a sigmoidal path as a function of increasing potential between 0 and 1.5 V versus the Ag reference electrode. Upon buffer rinse, adsorption was partially reversible when a potential of ≥0.93 V was maintained on the ITO waveguide. However, reducing the applied potential back to 0 V before rinsing resulted in irreversible polymer adsorption. PLL‐g‐PEG modified with biotin demonstrated similar adsorption characteristics, but subsequent streptavidin binding was independent of biotin concentration. Applying positive potentials resulted in increased adsorbed mass, presumably due to polymer chain extension and reorganization in the molecular adlayer. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 465–473, 2003.
Calorimetric investigation of anaerobic digestion: Biomass adaptation and temperature effect
Authors: Daverio E. , Spanjers H. , Bassani C. , Ligthart Jos , Nieman H.
Published: March 2003

A high‐resolution bench‐scale calorimeter (Bio‐RC1), specially suited for microbiological studies, has been used to investigate the response of an anaerobic granular sludge to repetitive glucose additions at various temperatures. Through the analysis of heat‐evolution profiles resulting from substrate degradation, significant biological events have been identified: the feeble net heat uptake related to aceticlastic methanogenesis has been evaluated, and the detrimental effect of a nutrient deficiency, which led up to 75% decrease in heat production rate, has been detected. After several glucose pulses under non‐limiting nutrient conditions, a reliable and reproducible reference thermal response, which is an important condition for the application of calorimetric measurements to detect inhibitory effects, was finally obtained. Afterward, glucose additions were repeated at various temperatures, and 57% biomass activity reduction, with respect to the reference value at 35°C, was observed when temperature was fixed at 20°C. Additionally, a preliminary toxicity test was also performed by exposing the biomass to increasing formaldehyde concentrations. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 499–505, 2003.
Changes in the electrochemical interface as a result of the growth of Pseudomonas fluorescens biofilms on gold
Authors: Busalmen Juan Pablo , de Sánchez Susana R.
Published: March 2003

In this study, variations in corrosion potential and polarization resistance of thin‐film gold electrodes as a result of the growth of Pseudomonas fluorescens biofilms on them are presented. The growth of the volumetric cell fraction of biofilms, as determined by optical sectioning and digital image analysis of phase‐contrast images, was found to be exponential during at least 10 hours of incubation. As a consequence of biofilm growth, an exponential decay of the corrosion potential of gold was observed. Most importantly, an increase in polarization resistance of the interface was observed following a strong linear dependence on the mean thickness of biofilms (r = 0.997), as a consequence of oxygen consumption and diffusion limitations. The results presented indicate that the measurement of polarization resistance may be a suitable technique that could be applied easily in industrial or biotechnological systems for monitoring the formation of biofilms. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 619–624, 2003.
NMR Structure of the Single QALGGH Zinc Finger Domain from the Arabidopsis thaliana SUPERMAN Protein
Authors: Isernia Carla , Bucci Enrico , Leone Marilisa , Zaccaro Laura , Di Lello Paola , Digilio Giuseppe , Esposito Sabrina , Saviano Michele , Di Blasio Benedetto , Pedone Carlo , Pedone Paolo V. , Fattorusso Roberto
Published: March 2003

Zinc finger domains of the classical type represent the most abundant DNA binding domains in eukaryotic transcription factors. Plant proteins contain from one to four zinc finger domains, which are characterized by high conservation of the sequence QALGGH, shown to be critical for DNA‐binding activity. The Arabidopsis thaliana SUPERMAN protein, which contains a single QALGGH zinc finger, is necessary for proper spatial development of reproductive floral tissues and has been shown to specifically bind to DNA. Here, we report the synthesis and UV and NMR spectroscopic structural characterization of a 37 amino acid SUPERMAN region complexed to a Zn2+ ion (Zn–SUP37) and present the first high‐resolution structure of a classical zinc finger domain from a plant protein. The NMR structure of the SUPERMAN zinc finger domain consists of a very well‐defined ββα motif, typical of all other Cys2‐His2 zinc fingers structurally characterized. As a consequence, the highly conserved QALGGH sequence is located at the N terminus of the α helix. This region of the domain of animal zinc finger proteins consists of hypervariable residues that are responsible for recognizing the DNA bases. Therefore, we propose a peculiar DNA recognition code for the QALGGH zinc finger domain that includes all or some of the amino acid residues at positions −1, 2, and 3 (numbered relative to the N terminus of the helix) and possibly others at the C‐terminal end of the recognition helix. This study further confirms that the zinc finger domain, though very simple, is an extremely versatile DNA binding motif.
Influence of Solution Composition on the Formation of Crystalline Scales
Authors: Glade H. , Ulrich J.
Published: March 2003

Scale formation is a difficulty encountered with water containing ions of sparingly soluble salts that can readily precipitate on heat transfer surfaces in evaporative concentration operations. Scale formation, hindering the heat transfer process, increases specific energy consumption and operating costs and causes frequent shut down of the evaporator for cleaning. The effects of changes in composition of the solution due to evaporation and CO2 release on the formation of crystalline scales in seawater evaporators are studied. A model that predicts the CO2 release is presented. The carbonate system in the salt solution on its whole flow path through the evaporator and the scaling (crystallization) tendency are described. Simulation results for different process configurations are shown and the differences are discussed, particularly with regard to the incrustation tendency.
Cluster Formation in Precrystalline Solutions
Authors: Sorensen T.J. , Sontum P.C. , Samseth J. , Thorsen G. , Malthe‐Sorenssen D.
Published: March 2003

Small Angle Neutron Scattering (SANS) gives evidence of colloidal structures or clusters in solutions of vanillin in aqueous alcohol. Interpretation of the data gives the same result as the Photon Correlation Spectroscopy technique: stable or metastable fractal clusters. The size of these clusters increases as a function of the parameters that control supersaturation, but is stable with respect to time. These structures, called metastable clusters, are closely related to the observed liquid‐liquid phase separation at high solute concentration. Another type of clusters is found to co‐exist with the metastable clusters at a lower solute concentration. The same type of structures is found in a two‐component system of vanillin in 2‐methyl‐2‐butanol. They slowly grow as a function of time, and are called labile clusters. These colloidal structures are assumed to be precrystalline clusters giving rise to nuclei in crystallization.
Formation of Monodispersed Nano‐ and Micro‐Particles Controlled in Size, Shape, and Internal Structure
Authors: Sugimoto T.
Published: March 2003

Size control of monodispersed particles must normally be performed during the very short nucleation period, because the final particle number is determined by the end of the nucleation and it does not change until the end of the particle growth. On the other hand, the shape control is mainly performed by adsorption of shape controllers during the growth period, although in some cases the crystal structure of the nuclei may have essential influence on the morphology of the grown particles. The internal structure of each particle is often strongly affected by the action of shape controllers. This article deals with the fundamental mechanisms of the nucleation, growth, and structural formation of monodispersed nano‐ and micro‐particles, leading to the control of their size, shape, and internal structure.
Combining univariate calibration information through a mixed‐effects model
Authors: Liao Jason J. Z.
Published: March 2003

It is common practice to calibrate a common value by combining information from different sources such as days, people, instruments and laboratories. Under each individual source a univariate calibration can be used to calibrate the unknown. Then the common unknown can be estimated by combining the estimates from each source as a weighted mean (Johnson DJ, Krishnamoorthy K. J. Am. Statist. Assoc. 1996; 91: 1707–1715) or through a multivariate calibration setting by combining information first and then estimating the common value (Liao JJZ. J. Chemometrics 2001; 15: 789–794). In this paper a mixed‐effects model approach is proposed to combine good characteristics from both approaches. Simulations show that the mixed‐effects model has better bias and mean squared error (MSE) performance than the univariate and multivariate approaches. A real data set is used to demonstrate the good characteristics of the mixed‐effects model approach. Copyright © 2003 John Wiley & Sons, Ltd.
Bestimmung von Ionenaktivitätskoeffizienten in wässrigen Lösungen mit Hilfe ionenselektiver Elektroden
Authors: Schneider A.C. , Pasel C. , Luckas M. , Schmidt K.G. , Herbell J.‐D.
Published: March 2003

No abstracts.
Differences in the pathologic and molecular features of intraductal breast carcinoma between younger and older women
Authors: Rodrigues Neesha A. , Dillon Deborah , Carter Darryl , Parisot Nicole , Haffty Bruce G.
Published: March 2003

BACKGROUND

Patients diagnosed with ductal carcinoma in situ (DCIS) at a young age appear to have a different natural history and biology, including a higher local relapse rate, than patients diagnosed later in life. The current study compared various pathologic and molecular features of DCIS arising in a cohort of young women with those of DCIS arising in a cohort of older women to identify potential biologic differences between these two populations of patients.

METHODS

The study population consisted of 20 patients age < 42 years and 34 patients age > 60 years who were treated at Yale University School of Medicine with breast‐conserving therapy (BCT) and whose archival paraffin blocks were available and had sufficient tumor for staining. The original slides from each case were reviewed and the most representative specimen block from each case was processed for immunohistochemical staining. Pathologic characteristics evaluated for each case included histology, grade, and presence of necrosis. Paraffin‐embedded sections were immunohistochemically evaluated for expression of HER‐2/neu, estrogen receptor (ER), progesterone receptor (PR), bcl‐2, cyclin D1, Ki‐67, and p53.

RESULTS

Although there was no difference in pathologic features of the tumors between the two groups, HER‐2/neu was found to be overexpressed in a greater percentage of the younger population (P = 0.06). There was no apparent difference in expression of the other markers. Of note, HER‐2/neu expression was correlated with high nuclear grade (P = 0.004), necrosis (P = 0.06), and ER and PR negativity (P = 0.01 and P = 0.03, respectively) in the combined population.

CONCLUSIONS

The current study data suggested that HER‐2/neu overexpression in younger patients may characterize a biologic difference in their tumor and may partially contribute to their higher risk of recurrence. Further studies are needed to assess whether this difference holds independent of grade and to evaluate the prognostic significance of HER‐2/neu overexpression in DCIS. Cancer 2003;97:1393–1403. © 2003 American Cancer Society.

DOI 10.1002/cncr.11204
Flow cytometry and quantitative immunohistochemical study of cell cycle regulation proteins in invasive breast carcinoma
Authors: Michels Jean‐Jacques , Duigou Françoise , Marnay Jacques , Henry‐Amar Michel , Delozier Thierry , Denoux Yves , Chasle Jacques
Published: March 2003

BACKGROUND

Between January 11, 1991 and January 8, 1992, 104 patients with previously untreated, invasive, primitive breast carcinoma were admitted to the authors' hospital.

METHODS

For each patient, flow cytometry DNA analyses on frozen samples and on immunohistochemical staining were performed, including Ki‐67, cyclin A, p53, and p21waf1 (p21), with assessment of the percentages of positive nuclei were assessed. Correlations with classic clinicopathologic data and survival (overall, metastasis free, or recurrence free) and a multivariate analysis were performed.

RESULTS

After a multivariate analysis according to a Cox model that was stratified by age, tumor size, tumor grade, lymph node status, and receptor status, among the factors studied, the presence of p21 was the unique remaining prognostic factor for patients with invasive breast carcinoma. Because of the lack of a correlation between p21 and proliferative factors (Ki‐67, S‐phase, and cyclin A), the authors combined p21 with those markers and found that, for the different combinations, after statistical analysis, only p21 combined with S‐phase or with cyclin A and lymph node status were salient survival prognostic factors.

CONCLUSIONS

Immunohistochemical study of proteins involved in the cell cycle and assessment of proliferative activity using flow cytometric DNA analysis aided the authors in singling out correlations of cyclin A and S‐phase, along with p21, with metastasis free survival and overall survival in patients with invasive breast carcinoma. These promising results will require confirmation in a larger series of patients. Cancer 2003;97:1376–86. © 2003 American Cancer Society.

DOI 10.1002/cncr.11209
Impact of very old age on hypothalamic dopaminergic neurons in the female rat: A morphometric study
Authors: Sánchez Hilda Liliana , Silva Liliana Beatriz , Portiansky Enrique Leo , Goya Rodolfo Gustavo , Zuccolilli Gustavo Oscar
Published: March 2003

Dopaminergic neurons of the A12 (tuberoinfundibular dopaminergic system) and A14 (periventricular dopaminergic system) hypothalamic areas exert a tonic inhibitory control of prolactin secretion. Tuberoinfundibular dopaminergic system neuron function is known to decline during aging in rats, but little is known about the impact of extreme age on neuron number and morphology in the two systems. We morphometrically assessed the neurons of the tuberoinfundibular dopaminergic system and the periventricular dopaminergic system in female rats 6 (young, Y), 24 (old, O), and 30–32 (senescent, S) months old. Serial coronal sections of fixed hypothalami were immunohistochemically labeled for tyrosine hydroxylase, and immunoreactive perikarya from the A12 and A14 areas were quantitatively characterized and compared among the three age groups. Radioimmunoassay was used to measure serum prolactin. The number of A12 tyrosine hydroxylase–immunoreactive perikarya showed a steady decline with age, whereas the number of A14 tyrosine hydroxylase–immunoreactive perikarya remained stable from young to old age but showed a sharp drop in the senescent rats. In the old rats, tyrosine hydroxylase–immunoreactive neuronal area (A12 = 135.37 and A14 = 158.79 μm2) was significantly higher than that of young (A12 = 72.56 and A14 = 99.7 μm2) and senescent animals (A12 = 95.5 and A14 = 106.5 μm2). Densitometric assessment of median eminence tyrosine hydroxylase immunoreactivity revealed a steady age‐related reduction of tyrosine hydroxylase content in the median eminence. Serum prolactin levels increased steadily with age. We conclude that, in the female rat, aging brings about a progressive loss of both tuberoinfundibular dopaminergic system and periventricular dopaminergic system neurons, which becomes more conspicuous at extreme ages. J. Comp. Neurol. 458:319–325, 2003. © 2003 Wiley‐Liss, Inc.
Ultrastructural analysis of a putative magnetoreceptor in the beak of homing pigeons
Authors: Fleissner Gerta , Holtkamp‐Rötzler Elke , Hanzlik Marianne , Winklhofer Michael , Fleissner Günther , Petersen Nikolai , Wiltschko Wolfgang
Published: March 2003

With the use of different light and electron microscopic methods, we investigated the subcellular organization of afferent trigeminal terminals in the upper beak of the homing pigeon, Columba livia, which are about 5 μm in diameter and contain superparamagnetic magnetite (SPM) crystals. The SPM nanocrystals are assembled in clusters (diameter, ∼1–2 μm). About 10 to 15 of these clusters occur inside one nerve terminal, arranged along the cell membrane. Each SPM cluster is embedded in a solid fibrous cup, open towards the cell surface, to which the cluster adheres by delicate fiber strands. In addition to the SPM clusters, a second inorganic iron compound has been identified: noncrystalline platelets of iron phosphate (about 500 nm wide and long and maximally 100 nm thick) that occur along a fibrous core of the terminal. The anatomic features suggested that these nerve endings could detect small intensity changes of the geomagnetic field. Such stimuli can induce deformations of the SPM clusters, which could be transduced into primary receptor potentials by mechanosensitive membrane receptor channels. The subepidermal fat cells surrounding the nerve endings prevent the inside from external mechanical stimuli. These structural findings corresponded to conclusions inferred from rock magnetic measurements, theoretical calculations, model experiments, and behavioral data, which also matched previous electrophysiologic recordings from migratory birds. J. Comp. Neurol. 458:350–360, 2003. © 2003 Wiley‐Liss, Inc.
False resurrections: Distinguishing regenerated from spared axons in the injured central nervous system
Authors: Steward Oswald , Zheng Binhai , Tessier‐Lavigne Marc
Published: March 2003

Several recent studies report that axon regeneration can be induced in the mature mammalian nervous system by novel treatments or genetic manipulations. In assessing these reports, it is important to be mindful of the history of regeneration research, which is littered with the corpses of studies that reported regeneration that later proved incorrect. One important reason is the “spared axon conundrum,” in which axons that survive a lesion are mistakenly identified as having regenerated. Here, we illustrate the problem and propose criteria that may be used to identify regenerated vs. spared axons, focusing on the injured spinal cord. J. Comp. Neurol. 459:1–8, 2003. © 2003 Wiley‐Liss, Inc.
“Dormant basket cell” hypothesis revisited: Relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat
Authors: Sloviter Robert S. , Zappone Colin A. , Harvey Brian D. , Bumanglag Argyle V. , Bender Roland A. , Frotscher Michael
Published: March 2003

The “dormant basket cell” hypothesis suggests that postinjury hippocampal network hyperexcitability results from the loss of vulnerable neurons that normally excite insult‐resistant inhibitory basket cells. We have reexamined the experimental basis of this hypothesis in light of reports that excitatory hilar mossy cells are not consistently vulnerable and inhibitory basket cells are not consistently seizure resistant. Prolonged afferent stimulation that reliably evoked granule cell discharges always produced extensive hilar neuron degeneration and immediate granule cell disinhibition. Conversely, kainic acid‐induced status epilepticus in chronically implanted animals produced similarly extensive hilar cell loss and immediate granule cell disinhibition, but only when granule cells discharged continuously during status epilepticus. In both preparations, electron microscopy revealed degeneration of presynaptic terminals forming asymmetrical synapses in the mossy cell target zone, including some terminating on γ‐aminobutyric acid‐immunoreactive elements, but no evidence of axosomatic or axoaxonic degeneration in the adjacent granule cell layer. Although parvalbumin immunocytochemistry and in situ hybridization revealed decreased staining, this apparently was due to altered parvalbumin expression rather than basket cell death, because substance P receptor‐positive interneurons, some of which contained residual parvalbumin immunoreactivity, survived. These results confirm the inherent vulnerability of dendritically projecting hilar mossy cells and interneurons and the relative resistance of dentate inhibitory basket and chandelier cells that target granule cell somata. The variability of hippocampal cell loss after status epilepticus suggests that altered hippocampal structure and function cannot be assumed to cause the spontaneous seizures that develop in these animals and highlights the importance of confirming hippocampal pathology and pathophysiology in vivo in each case. J. Comp. Neurol. 459:44–76, 2003. © 2003 Wiley‐Liss, Inc.
Circuit theory of power factor correction in switching converters
Authors: Tse C. K.
Published: March 2003

This paper discusses the circuit theory aspects of power factor correction in switching converter circuits. The discussion begins with an examination of the requirement of power factor correction in dc/dc converters. Using the concept of zero‐order converter circuits, sufficient conditions for a dc/dc converter circuit to provide power factor correction are derived. The duality principle is applied to generate new converter circuits that can achieve power factor correction. The practical application of power factor correction is considered in conjunction with the requirement of tight output voltage regulation. Detailed study of the circuit configuration that can simultaneously provide power factor correction and output regulation is given. Based on a general three‐port model, the voltage regulator with power factor correction capability is studied in terms of the power flow between the input port, output port and energy storage port. A detailed consideration of the power flow among the three ports leads to the derivation of all possible minimal configurations that can achieve power factor correction and voltage regulation. The efficiencies of these minimal configurations are studied theoretically, leading to the concept of ‘reduced redundant power processing’ which provides important clue to efficiency improvement. Another issue addressed in this paper is the synthesis of practical circuits that can provide power factor correction and output regulation. In particular, four practical minimal configurations that achieve reduced redundant power processing are considered. A systematic synthesis procedure is derived for creating converter circuits that achieve power factor correction and output voltage regulation. The control issue is also investigated in depth, pinpointing the basic requirement on the number of control parameters needed and its relationship with the operating mode. Copyright © 2003 John Wiley & Sons, Ltd.
1,4‐dihydropyridine calcium channel ligands: Selectivity of action. The roles of pharmacokinetics, state‐dependent interactions, channel isoforms, and other factors
Authors: Triggle David J.
Published: March 2003

The selectivity of action of the clinically available calcium channel antagonists depends on a number of factors: 1) Mode of calcium mobilization—intracellular and extracellular sources. 2) Class and subclass of calcium channel involved. 3) Pharmacokinetic considerations, including distribution and interactions with cell membranes. 4) State‐dependent interactions—voltage‐ and frequency‐dependent interactions. 5) Pathologic state of tissue and channel regulation. These factors will be illustrated with particular reference to the 1,4‐dihydropyridine series of ligands. The Ca2+ channel antagonists may be placed in several classes according to their rates of onset and offset of action, and the overall cardiovascular activity of an agent can profoundly alter its hemodynamic response. Additionally, third‐generation agents such as lacidipine and lercenadipine partition extensively into plasma membranes according to membrane composition. Calcium mobilization through the L‐type channel is the dominant target of the available antagonists: hence, systems that rely dominantly or exclusively on other mobilization processes are insensitive. Renal afferent and efferent arterioles that regulate glomerular flow and resistance are sensitive to the powerful vasoconstrictive effects of angiotensin II; however, only the processes in the afferent arteriole are sensitive to the Ca2+ channel antagonists. An important and subtle process for conferring tissue selectivity of action is derived from state‐dependent interactions between channel and drug, whereby, according to the modulated‐receptor hypothesis, drugs may exhibit preferential affinity for or access to different states of the channel—resting, open, or inactivated. Transitions between these states are determined by membrane potential and biochemical factors, including channel phosphorylation. The 1,4‐dihydropyridine series exhibit significant and structure‐dependent voltage‐dependent interactions, which reflect a preferential interaction with open and/or inactivated channel states. The differential pharmacology of the L‐type Ca2+ channel is a further determinant of tissue selectivity. The cardiovascular system expresses three different α1 subunits—CaV1.2A–C—and although a detailed pharmacological comparison is not yet available, there is sufficient evidence to indicate important differences. Thus, the 1,4‐dihydropyridine nisoldipine interacts differentially with recombinant channels derived from cardiac and vascular smooth muscle. A number of disease states, both clinical and experimental, have been associated with changes in Ca2+ channel expression and function, although the causal relationship is often not established. Thus, in cardiac hypertrophy and failure the majority of studies reveal a reduction in L‐type channel number or function. Drug Dev. Res. 58:5–17, 2003. © 2003 Wiley‐Liss, Inc.
Two patterns of ion channelopathies relating to arrhythmias and direct and indirect blockade of ion channels by antiarrhythmic agents
Authors: Dai De‐Zai , Zhang Guang‐Qin , Yang Ping , Ma Yu‐Ping
Published: March 2003

Cardiac arrhythmias remain a major cause of mortality in cardiovascular diseases. Abnormal repolarization of the myocardium which relates to the occurrence of arrhythmias is developed by cardiac ion channelopathies. LQTS is an inherited disorder of mutations in genes encoding K+ and Na+ channels. A novel mutation in the HERG gene was discovered in a patient from an LQTS family. The mutation was at 2184 position by A→C of the cDNA of the HERG gene where tyrosine (TAC) was replaced by an early appearance of STOP (TAA). A loss of 492 amino acids from the nucleotide binding domain to the carboxyl group resulted in channel dysfunction and a prolonged QTc of >460 mS. Another mutation of insertion of 9 bps at the minor site between S1 to the –NH2 terminal and a novel mutation of the HMINK gene to replace serine (AGT) by cysteine (GGT) at position 38 were discovered. These two changes exert no effect on the QT interval. An investigation of ion channelopathies was conducted in a previously developed animal model of cardiac remodeling which was developed by chronic treatment with L‐thyroxine for 10 days and shows significant arrhythmogenesis. The upregulation of IKS in the remodeled myocardium was uncovered as an increment of more than two times over control when depolarizing to +20 mV and +40 mV (P < 0.01). IKr was also upregulated by a marked increment of the current density at 0 mV and +20 mV against control (P <0.01). A suppression of IKS and INa by CPU 86017 was observed by direct drug application with an IC50 for IKS with CPU 86017 of 14.4 µM and a significant suppression of INa by 10 µM CPU 86017 (P <0.01). An indirect effect on IKS and IKr was measured by chronic treatment with propranolol and bepridil on days 8–10 of the L‐thyroxine treatment. A reversal of the enhanced IKS and IKr currents was significant in the propranolol group, but less so in the bepridil group. The effect was associated with a relief of the hypertrophied myocardium and production of MDA. In conclusion, there are two patterns of ion channelopathies for inducing arrhythmias. A mutation in genes produces a selective change in the primary sequence of amino acids of a single ion channel, and cardiac remodeling affects multiple channels rather than a selective influence on a single channel by a primary damage to the lipid membrane and transmembrane signaling system. CPU 86017 exerts its blockade directly on the ion channel itself and propranolol and bepridil by chronic treatment block ion channels by an indirect effect mediated by regression of the insult of the membrane and hyperphosphorylation of the ion channels with stimulation by β‐receptors. Drug Dev. Res. 58:42–50, 2003. © 2003 Wiley‐Liss, Inc.
Contribution of EDHF and the role of potassium channels in the regulation of vascular tone
Authors: Ding Hong , Triggle Chris R.
Published: March 2003

Potassium channels in both endothelial and vascular smooth muscle play an important role in the regulation of vascular tone and are therefore potential targets for new drug development. Endothelial cell potassium channels, notably small conductance and intermediate conductance calcium‐activated K channels (SKCa and IKCa, respectively), are of critical importance for the regulation of synthesis and, possibly, release of nitric oxide (NO) and prostacyclin (PGI2) as well as the elusive endothelium‐derived hyperpolarizing factor (EDHF). EDHF may represent the “third” pathway for endothelium‐dependent relaxation and, if a chemical mediator is involved, EDHF may represent a new class of K‐channel openers. Of interest also is that endothelial cell dysfunction is a common feature of cardiovascular disease and this dysfunction is often associated with a decreased availability of endothelium‐derived NO and, sometimes, an enhanced contribution of EDHF. This raises the question of the possibility that EDHF may play a pathophysiological function. A high degree of heterogeneity exists with respect to the pharmacological properties of EDHF and this may indicate that multiple EDHFs exist with some degree of vessel selectivity. Despite the heterogeneity in the properties of EDHF, a common feature is that a combination of two K‐channel toxins, apamin and charybdotoxin, which target the SKCa and IKCa channels, respectively (charybdotoxin also inhibits large‐conductance KCa, BKCa, and voltage‐gated, KV channels). The requirement for both toxins for inhibiting EDHF is suggestive that a novel K channel may exist in the vasculature; however, to date the discovery of such a channel has remained elusive. Drug Dev. Res. 58:81–89, 2003. © 2003 Wiley‐Liss, Inc.
Bioassay of endothelium‐derived hyperpolarizing factor with abolishment of nitric oxide and the role of gap junctions in the porcine coronary circulation
Authors: Yang Qin , Ge Zhi‐Dong , Yang Cheng‐Qin , Huang Yu , He Guo‐Wei
Published: March 2003

Previous bioassays of endothelium‐derived hyperpolarizing factor (EDHF) were partially related to the residual nitric oxide (NO) resistant to NO synthase inhibitors. Further, the role of gap junctions in EDHF is controversial. We performed a bioassay of EDHF with abolishment of NO production by using the NOS inhibitor NG‐nitro‐l‐arginine (l‐NNA) plus the NO scavenger hemoglobin (Hb) and examined the role of gap junctions/K+ channels related to EDHF in porcine coronary large and microarteries in an organ chamber/myograph. Bradykinin (BK)‐induced EDHF‐mediated relaxation and hyperpolarization (by a microelectrode) were studied with indomethacin (7 µM), l‐NNA (300 µM), and Hb (20 µM). NO concentrations ([NO]) were measured electrochemically. In large coronary arteries, BK increased [NO] (9.3±1.7 nM vs. 166.7±18.3 nM, P<0.01) that was significantly reduced by l‐NNA (49.3±7.8 nM, P<0.01) and eliminated by Hb, and hyperpolarized the downstream endothelium‐denuded artery by 9.0±1.4 mV (P<0.01) that was reduced but not abolished by l‐NNA and Hb (5.6±0.7 mV, P<0.01). In microarteries, elimination of NO decreased but did not abolish the hyperpolarization (−63.8±1.5 mV vs. −56.9±1.6 mV, P=0.01) and relaxation (70.2±5.7% vs. 42.3±4.4%, P<0.01). Charybdotoxin (0.1 µM) and apamin (0.5 µM), but neither glybenclimide (3 µM) nor gap junction inhibitors (18α‐glycyrrhetinic acid, 1‐heptanol, and gap 27) reduced the EDHF‐mediated response. We conclude that in porcine coronary arteries, with the abolishment of NO by NOS inhibitors plus the NO scavenger Hb, the non‐NO EDHF exists and is transferable from an endothelium‐intact artery to an endothelium‐denuded artery. Compared with the significant involvement of calcium‐activated K+ channels, the gap junctions may only play a minimal role in the EDHF‐mediated response even in the microcirculation of the porcine coronary artery. Drug Dev. Res. 58:99–110, 2003. © 2003 Wiley‐Liss, Inc.