bluuebunny/crossref_metadata_2025 huggingface dataset:
TIME AND SPACE ADAPTIVITY FOR THE SECOND-ORDER WAVE EQUATION
Authors: BERNARDI CHRISTINE , SÜLI ENDRE
Published: January 2005

The aim of this paper is to show that, for a linear second-order hyperbolic equation discretized by the backward Euler scheme in time and continuous piecewise affine finite elements in space, the adaptation of the time steps can be combined with spatial mesh adaptivity in an optimal way. We derive a priori and a posteriori error estimates which admit, as much as it is possible, the decoupling of the errors committed in the temporal and spatial discretizations.
SEMI-COERCIVE VARIATIONAL INEQUALITIES WITH UNCERTAIN INPUT DATA.
Authors: HLAVÁČEK IVAN , LOVÍŠEK JÁN
Published: January 2005

A generalization of the Fichera's theory for semi-coercive unilateral boundary value problems is presented. We study the existence of a solution, its uniqueness and continuous dependence on the input data. The results are applied to the theory of shallow elastic shells with uncertain material coefficients, slip limit and loading. Then the method of worst scenario (anti-optimization) is employed.
SPECTRAL PROPERTIES AND SYMMETRIES OF DOUBLE COVERINGS OF GRAPHS WITH APPLICATIONS TO SUPERCONDUCTIVITY
Authors: RUBINSTEIN JACOB , SCHATZMAN MICHELLE
Published: January 2005

Let M be a planar embedded graph, and let [Formula: see text] be its double covering. We count the multiplicity of the ground states of the Laplace operator on [Formula: see text] under certain symmetry constraints. The examples of interest for us are ladder-like graphs made out of n, identical rectangles. We find that in the case of an odd n, the multiplicity of the ground state is 2, and if n, is even, the ground state is simple. This result gives an answer to a conjecture by Parks on the type of phase transitions that can occur in a superconducting ladder: Parks conjectured that in the case when the magnetic field is one half fluxoid per rectangle, the phase transition would be continuous in the case of a ladder made out of two rectangles. Our result indeed implies Parks conjecture and generalizes it to any even ladder. The mathematics of this paper is a mixture of topology, symmetry arguments and comparison theorem between the eigenvalues of Laplace operators on graphs with well chosen boundary conditions.
INTERVAL METHODS IN KNOWLEDGE REPRESENTATION
Authors: KREINOVICH VLADIK
Published: January 2005

This section is maintained by Vladik Kreinovich. Please send you abstract (or copies of papers that you want to see reviewed here) to vladik@cs.utep.edu, or by regular mail to: Vladik Kreinovich, Department of Computer Science, University of Texas at El Paso, El Paso, TX 79968, USA.
Short-term regulation of multidrug resistance-associated protein 3 in rat and human hepatocytes
Authors: Chandra Priyamvada , Zhang Peijin , Brouwer Kim L. R.
Published: January 2005

The short-term regulation of multidrug resistance-associated protein 3 (Mrp3/MRP3) by cAMP and PKC was investigated in sandwich-cultured rat and human hepatocytes and isolated perfused rat livers. The modulator glucagon (500 nM) and the phorbol ester PMA (0.1 μM) were utilized to increase intracellular cAMP and PKC levels, respectively. In glucagon-treated rat hepatocytes, efflux of the Mrp3 substrate 5-(6)-carboxy-2′,7′-dichlorofluorescein (CDF) increased ∼1.5-fold, even in hepatocytes treated with the organic anion transporter (Oatp) inhibitor sulfobromophthalein (BSP). Confocal microscopy revealed more concentrated Mrp3 fluorescence in the basolateral membrane (less diffuse staining pattern) with glucagon treatment. PMA had no effect on Mrp3 activity or localization in sandwich-cultured rat hepatocytes. Glucagon and PMA treatment in isolated perfused rat livers resulted in a threefold increase (14 ± 4.6 μl·min−1·g liver−1) and a fourfold decrease (1.3 ± 0.3 μl·min−1·g liver−1) in CDF basolateral clearance compared with control livers (4.7 ± 2.3 μl·min−1·g liver−1), whereas CDF biliary clearance was not statistically different. In sandwich-cultured human hepatocytes, glucagon treatment resulted in a 1.3-fold increase in CDF efflux and a concomitant increase in MRP3 fluorescence in the basolateral membrane. In summary, cAMP and PKC appear to be involved in the short-term regulation of Mrp3/MRP3, as demonstrated by alterations in activity and localization in rat and human hepatocytes.
Steatohepatitis develops rapidly in transgenic mice overexpressingAbcb11and fed a methionine-choline-deficient diet
Authors: Sundaram Shikha S. , Whitington Peter F. , Green Richard M.
Published: January 2005

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin- Abcb11 (TTR- Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR- Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR- Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR- Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR- Abcb11 mice have 3-fold increases in TNF-α mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR- Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR- Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-α, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR- Abcb11 mice develop a more rapid hepatitis with less steatosis.
Diminished β-cell replication contributes to reduced β-cell mass in fetal sheep with intrauterine growth restriction
Authors: Limesand Sean W. , Jensen Jan , Hutton John C. , Hay William W.
Published: January 2005

Human fetuses with severe intrauterine growth restriction (IUGR) have less pancreatic endocrine tissue and exhibit β-cell dysfunction, which may limit β-cell function in later life and contribute to their increased incidence of noninsulin-dependent diabetes mellitus. Three factors, replication, apoptosis, and neoformation, contribute to fetal β-cell mass. We studied an ovine model of IUGR to understand whether nutrient deficits lead to decreased rates of fetal pancreatic β-cell replication, increased rates of apoptosis, or lower rates of differentiation. At 90% of term gestation, IUGR fetal and pancreatic weights were 58% and 59% less than pair-fed control, respectively. We identified a selective impairment of β-cell mass compared with other pancreatic cell types in IUGR fetuses. Insulin and insulin mRNA contents were less than other pancreatic endocrine hormones in IUGR fetuses, as were pancreatic insulin positive area (42%) and β-cell mass (76%). Pancreatic β-cell apoptosis was not different between treatments. β-cell capacity for cell cycling, determined by proliferating cell nuclear antigen (PCNA) immunostaining, was not different between treatment groups. However, the percentage of β-cells actually undergoing mitosis was 72% lower in IUGR fetuses. These results indicate that in utero nutrient deficits decrease the population of pancreatic β-cells by lengthening G1, S, and G2 stages of interphase and decreasing mitosis near term. Diminished β-cell mass in IUGR infants at birth, if not adequately compensated for after birth, may contribute to insufficient insulin production in later life and, thus, a predisposition to noninsulin-dependent diabetes.
Developmentally regulated thyroid hormone distributor proteins in marsupials, a reptile, and fish
Authors: Richardson Samantha J. , Monk Julie A. , Shepherdley Caroline A. , Ebbesson Lars O. E. , Sin Frank , Power Deborah M. , Frappell Peter B. , Köhrle Josef , Renfree Marilyn B.
Published: January 2005

Thyroid hormones are essential for vertebrate development. There is a characteristic rise in thyroid hormone levels in blood during critical periods of thyroid hormone-regulated development. Thyroid hormones are lipophilic compounds, which readily partition from an aqueous environment into a lipid environment. Thyroid hormone distributor proteins are required to ensure adequate distribution of thyroid hormones, throughout the aqueous environment of the blood, and to counteract the avid partitioning of thyroid hormones into the lipid environment of cell membranes. In human blood, these proteins are albumin, transthyretin and thyroxine-binding globulin. We analyzed the developmental profile of thyroid hormone distributor proteins in serum from a representative of each order of marsupials ( M. eugenii; S.crassicaudata), a reptile ( C. porosus), in two species of salmonoid fishes ( S. salar; O. tshawytsch), and throughout a calendar year for sea bream ( S. aurata). We demonstrated that during development, these animals have a thyroid hormone distributor protein present in their blood which is not present in the adult blood. At least in mammals, this additional protein has higher affinity for thyroid hormones than the thyroid hormone distributor proteins in the blood of the adult. In fish, reptile and polyprotodont marsupial, this protein was transthyretin. In a diprotodont marsupial, it was thyroxine-binding globulin. We propose an hypothesis that an augmented thyroid hormone distributor protein network contributes to the rise in total thyroid hormone levels in the blood during development.
A new formula for predicting alterations in plasma sodium concentration in peritoneal dialysis
Authors: Nguyen Minhtri K. , Kurtz Ira
Published: January 2005

Alterations in the plasma water sodium concentration ([Na+]pw) result from changes in the total exchangeable sodium (Nae), total exchangeable potassium (Ke), and total body water (TBW). The empirical relationship between the [Na+]pw and Nae, Ke, and TBW was originally demonstrated (Edelman IS, Leibman J, O'Meara MP, and Birkenfeld LW. J Clin Invest 37: 1236–1256, 1958), where [Na+]pw = 1.11(Nae + Ke)/TBW − 25.6 ( Eq. 1 ). Based on Eq. 1 , alterations in the [Na+]pw can be predicted by considering changes in the mass balance of Na+, K+, and H2O. In accounting for the mass balance of Na+, K+, and H2O in patients on peritoneal dialysis, considerations must also be taken to determine the modulating effect of dialysate clearance of Na+ and K+ and fluid changes resulting from this therapeutic modality on the [Na+]pw. In this article, we derive a new formula for predicting alterations in the plasma Na+ concentration ([Na+]p) in patients on peritoneal dialysis, taking into consideration the empirical relationship between the [Na+]pw and Nae, Ke, and TBW ( Eq. 1 ) as well as changes in mass balance of Na+ + K+ and H2O.
Morphological Correlates of Triadic Circuitry in the Lateral Geniculate Nucleus of Cats and Rats
Authors: Lam Y.-W. , Cox C. L. , Varela C. , Sherman S. Murray
Published: January 2005

We used an in vitro slice preparation of the lateral geniculate nucleus in cats and rats to study morphological correlates of triadic circuitry in relay cells. The three triadic elements involve a retinal synapse onto a GABAergic dendritic terminal of an interneuron, a synapse from the same retinal terminal onto a relay cell dendrite, and a synapse from the same interneuron terminal onto the same relay cell dendrite. We made whole cell recordings and labeled cells with biocytin. Previous methods were used to identify triadic circuitry based on evidence that the retinal terminal activates a metabotropic glutamate receptor on the interneuronal terminal. Thus application of (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (an agonist to that receptor) increases the rate of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in the relay cell, and if some of this increase remains with further addition of TTX (a TTX-insensitive response), a triad is indicated. We quantified the extent of the TTX-insensitive response and sought morphological correlates. In both rats and cats, this response correlated (negatively) with the number of primary dendrites and (positively) with polarity of the dendritic arbor. There was no correlation with cell size. Curiously, in cats, this response correlated with the presence of appendages at primary dendritic branches, but there was no such correlation in rats. These observations in cats map onto the X/Y classification, with X cells having triads, but it is not clear from our results if a comparable classification exists for rats.
Ionic Current Model of a Hypoglossal Motoneuron
Authors: Purvis Liston K. , Butera Robert J.
Published: January 2005

We have developed a single-compartment, electrophysiological, hypoglossal motoneuron (HM) model based primarily on experimental data from neonatal rat HMs. The model is able to reproduce the fine features of the HM action potential: the fast afterhyperpolarization, the afterdepolarization, and the medium-duration afterhyperpolarization (mAHP). The model also reproduces the repetitive firing properties seen in neonatal HMs and replicates the neuron's response to pharmacological experiments. The model was used to study the role of specific ionic currents in HM firing and how variations in the densities of these currents may account for age-dependent changes in excitability seen in HMs. By varying the density of a fast inactivating calcium current, the model alternates between accelerating and adapting firing patterns. Modeling the age-dependent increase in H current density accounts for the decrease in mAHP duration observed experimentally, but does not fully account for the decrease in input resistance. An increase in the density of the voltage-dependent potassium currents and the H current is required to account for the decrease in input resistance. These changes also account for the age-dependent decrease in action potential duration.
Effect of Chronic Inflammation on Dorsal Horn Nociceptive Neurons in Aged Rats
Authors: Kitagawa Junichi , Kanda Kenro , Sugiura Miho , Tsuboi Yoshiyuki , Ogawa Akiko , Shimizu Kohei , Koyama Natsu , Kamo Hiroshi , Watanabe Tatsuhisa , Ren Ke , Iwata Koichi
Published: January 2005

To elucidate the effect of chronic inflammation on spinal nociceptive neurons in the elderly, we compared nocifensive behavior, peripheral inflammatory responses, and spinal dorsal horn neuronal activities between the aged (29–34 mo) and adult (7–12 mo) male rats after injection of complete Freund's adjuvant (CFA) into the hind paw. Aged rats exhibited a significantly lower mechanical paw withdrawal threshold before inflammation. However, after CFA injection mechanical allodynia developed in both adult and aged rats after CFA injection. The changes of foot temperature and thickness after CFA injection were greater and lasted longer in aged than in adult rats. Sets of 124 wide dynamic range (WDR) neurons (aged: 59, adult: 65) and 26 nociceptive specific (NS) neurons (aged: 13, adult: 13) were recorded from the lumber spinal dorsal horn. NS neurons from the inflamed adult rats showed significantly higher responses to noxious mechanical stimulation than those in aged rats, whereas WDR neurons from inflamed adult and aged rats were similar. Background activity of WDR neurons from the adult rats increased after CFA, whereas WDR neurons of aged rats and NS neurons from either group were not. The afterdischarge followed by noxious mechanical stimulation was significantly greater for WDR neurons in both adult and aged rats, whereas no significant differences were observed in NS neurons. Two days after CFA injection, Fos expression increased similarly in aged and adult rats. Thus the aged rats showed enhanced peripheral inflammatory responses to CFA injection with only a slight change in dorsal horn neuronal activity. Together with our previous finding that nociceptive neurons in aged rats exhibit hyperexcitability, these results suggest that the dorsal horn nociceptive system becomes sensitized with advancing age and its excitability cannot be further increased by inflammation.
Detection of Vascular Adhesion Molecule-1 Expression Using a Novel Multimodal Nanoparticle
Authors: Kelly Kimberly A. , Allport Jennifer R. , Tsourkas Andrew , Shinde-Patil Vivek R. , Josephson Lee , Weissleder Ralph
Published: January 2005

Endothelial vascular adhesion molecule-1 (VCAM-1) is a critical component of the leukocyte–endothelial adhesion cascade, and its strict temporal and spatial regulation make it an ideal target for imaging and therapy. The goal of this study was to develop novel VCAM-1–targeted imaging agents detectable by MRI and fluorescence imaging using phage display–derived peptide sequences and multimodal nanoparticles (NPs). We hypothesized that VCAM-1–mediated cell internalization of phage display–selected peptides could be harnessed as an amplification strategy to chaperone and trap imaging agents inside VCAM-1–expressing cells, thus improving target-to-background ratios. To accomplish our goal, iterative phage display was performed on murine endothelium under physiological flow conditions to identify a family of VCAM-1–mediated cell-internalizing peptides. One specific sequence, containing the VHSPNKK motif that has homology to the α-chain of very late antigen (a known ligand for VCAM-1), was shown to bind VCAM-1 and block leukocyte–endothelial interactions. Compared with VCAM-1 monoclonal antibody, the peptide showed 12-fold higher target-to-background ratios. A VHSPNKK-modified magnetofluorescent NP (VNP) showed high affinity for endothelial cells expressing VCAM-1 but surprisingly low affinity for macrophages. In contrast, a control NP without VCAM-1–targeting sequences showed no affinity for endothelial cells. In vivo, VNP successfully identified VCAM-1–expressing endothelial cells in a murine tumor necrosis factor-α–induced inflammatory model and colocalized with VCAM-1–expressing cells in atherosclerotic lesions present in cholesterol-fed apolipoprotein E apoE−/−mice. These results indicate that: (1) small peptide sequences can significantly alter targeting of NPs, (2) the used amplification strategy of internalization results in high target-to-background ratios, and (3) this technology is useful for in vivo imaging of endothelial markers.
Carotid Plaque Pathology
Authors: Fisher Mark , Paganini-Hill Annlia , Martin Aldana , Cosgrove Michele , Toole James F. , Barnett Henry J.M. , Norris John
Published: January 2005

Background and Purpose—

To determine the relationship between ulceration, thrombus, and calcification of carotid artery atherosclerotic plaques and symptoms of ipsilateral or contralateral stroke.

Methods—

We compared microscopic plaque morphology from patients with and without stroke symptoms ipsilateral or contralateral to the plaque. Plaques were characterized for ulceration, thrombus, and calcification. We analyzed plaques from 241 subjects: 170 patients enrolled in the Asymptomatic Carotid Atherosclerosis Study (ACAS) and 71 patients enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET); 128 subjects had no history of stroke symptoms, 80 subjects had ipsilateral symptoms, and 33 had contralateral symptoms.

Results—

Plaque ulceration was more common in plaques taken from symptomatic patients than those without symptoms (36% versus 14%;
P
<0.001); frequency of ulceration was similar for plaques associated with ipsilateral (34%) and contralateral (42%) symptoms. Thrombus was most common in plaques taken from patients with both ipsilateral symptoms and ulceration. The extent of calcification was unassociated with stroke symptoms.

Conclusion—

Carotid plaque ulceration and thrombosis are more prevalent in symptomatic patients. Ulceration is more common in symptomatic patients regardless of side of carotid symptoms, whereas thrombus is associated with ipsilateral symptoms and plaque ulceration. Preoperative identification of carotid ulceration and thrombus should lead to greater efficacy of stroke prevention by carotid endarterectomy.
A Basic Study of CFRP Laminates with Embedded Prestrained SMA Foils for Aircraft Structures
Authors: Ogisu Toshimichi , Shimanuki Masakazu , Kiyoshima Satoshi , Takeda Nobuo
Published: January 2005

This paper presents some basic research results for the application of the smart materials and structural systems to aircraft structure. The authors conducted quasi-static load-unload tests and fatigue tests on several kinds of quasi-isotropic carbon fiber-reinforced plastic (CFRP) laminates with embedded prestrained shape memory alloy (SMA) foils. The damage behavior and the fatigue behavior were evaluated based on the effects of the recovery stress of SMA, and the relationship between the applied strain and the transverse crack density is discussed. It was found that the developed smart materials achieved a maximum improvement of 34% in the onset strain of the transverse cracks and a maximum improvement of 60% in the onset strain of delamination as compared with the standard CFRP laminates in the static condition. However, the fatigue properties of the smart material were not improved due to the material degradation of the 90°-ply at 80°C. The fatigue test by the multistep strain method using a structural element specimen was used to verify the results of coupon tests. The results indicate the possibility of using coupon data as a design database.
The Cognitive Neuroscience of Human Decision Making: A Review and Conceptual Framework
Authors: Fellows Lesley K.
Published: January 2005

Decision making, the process of choosing between options, is a fundamental human behavior that has been studied intensively by disciplines ranging from cognitive psychology to economics. Despite the importance of this behavior, the neural substrates of decision making are only beginning to be understood. Impaired decision making is recognized in neuropsychiatric conditions such as dementia and drug addiction, and the inconsistencies and biases of healthy decision makers have been intensively studied. However, the tools of cognitive neuroscience have only recently been applied to understanding the brain basis of this complex behavior. This article reviews the literature on the cognitive neuroscience of human decision making, focusing on the roles of the frontal lobes, and provides a conceptual framework for organizing this disparate body of work.
Theta Rhythm of the Hippocampus: Subcortical Control and Functional Significance
Authors: Vertes Robert P. , Hoover Walter B. , Di Prisco Gonzalo Viana
Published: January 2005

The theta rhythm is the largest extracellular synchronous signal that can be recorded from the mammalian brain and has been strongly implicated in mnemonic processes of the hippocampus. We describe (a) ascending brain stem–forebrain systems involved in controlling theta and nontheta (desynchronization) states of the hippocampal electroencephalogram; (b) theta rhythmically discharging cells in several structures of Papez's circuit and their possible functional significance, specifically with respect to head direction cells in this same circuit; and (c) the role of nucleus reuniens of the thalamus as a major interface between the medial prefrontal cortex and hippocampus and as a prominent source of afferent limbic information to the hippocampus. We suggest that the hippocampus receives two main types of input: theta rhythm from ascending brain stem– diencephaloseptal systems and information bearing mainly from thalamocortical/cortical systems. The temporal convergence of activity of these two systems results in the encoding of information in the hippocampus, primarily reaching it from the entorhinal cortex and nucleus reuniens.
Using large-scale perturbations in gene network reconstruction
Authors: MacCarthy Thomas , Pomiankowski Andrew , Seymour Robert
Published: January 2005

Background

Recent analysis of the yeast gene network shows that most genes have few inputs, indicating that enumerative gene reconstruction methods are both useful and computationally feasible. A simple enumerative reconstruction method based on a discrete dynamical system model is used to study how microarray experiments involving modulated global perturbations can be designed to obtain reasonably accurate reconstructions. The method is tested on artificial gene networks with biologically realistic in/out degree characteristics.

Results

It was found that a relatively small number of perturbations significantly improve inference accuracy, particularly for low-order inputs of one or two genes. The perturbations themselves should alter the expression level of approximately 50–60% of the genes in the network.

Conclusions

Time-series obtained from perturbations are a common form of expression data. This study illustrates how gene networks can be significantly reconstructed from such time-series while requiring only a relatively small number of calibrated perturbations, even for large networks, thus reducing experimental costs.
Human resources: the Cinderella of health sector reform in Latin America
Authors: Homedes Núria , Ugalde Antonio
Published: January 2005

Human resources are the most important assets of any health system, and health workforce problems have for decades limited the efficiency and quality of Latin America health systems. World Bank-led reforms aimed at increasing equity, efficiency, quality of care and user satisfaction did not attempt to resolve the human resources problems that had been identified in multiple health sector assessments. However, the two most important reform policies – decentralization and privatization – have had a negative impact on the conditions of employment and prompted opposition from organized professionals and unions. In several countries of the region, the workforce became the most important obstacle to successful reform.

This article is based on fieldwork and a review of the literature. It discusses the reasons that led health workers to oppose reform; the institutional and legal constraints to implementing reform as originally designed; the mismatch between the types of personnel needed for reform and the availability of professionals; the deficiencies of the reform implementation process; and the regulatory weaknesses of the region.

The discussion presents workforce strategies that the reforms could have included to achieve the intended goals, and the need to take into account the values and political realities of the countries. The authors suggest that autochthonous solutions are more likely to succeed than solutions imported from the outside.
Free does not mean affordable: maternity patient expenditures in a public hospital in Bangladesh
Authors: Khan Suhaila H
Published: January 2005

Objective

This study investigated a) the amount and types of out-of-pocket expenditures by patients for nominally free services in a large public hospital in Bangladesh, b) the factors influencing these expenses, and c) the impact of these expenses on household income.

Methods

Eighty-one maternity patients were interviewed during their hospitalization in the Dhaka Medical College Hospital. Patients were selected by quota sample to match the distribution of maternity patient categories in the hospital. Patients were interviewed with a semi-structured, in-depth questionnaire.

Results

All interviewees incurred substantial out-of-pocket expenditures for travel, hospital admission fees, medicine, tests, food, and tips. Only two of the expenditures, travel expenses and admission fees, were not supposed to be provided free of charge by the hospital. The median total per-patient expenditure was $65 (range $2–$350), equivalent to 7% (range 0.04%–225%) of annual household income. Half of all patients reported that their families had to borrow to pay for care at interest rates of 5%–30% per month. A third of these families reported selling jewelry, land or household items to moneylenders. The rural patients reported more difficulty in paying for care than the urban patients. Factors increasing the expenditures were duration of hospitalization, rural residence, and necessary (e.g. C-section, hysterectomy) and unnecessary (e.g. episiotomy) medical procedures.

Conclusion

Free maternity services in Bangladesh impose large out-of-pocket expenditures on patients. Authorities could reduce the burden by reducing the duration of hospital stays, limiting use of medical procedures, eliminating tips, and moving routine services closer to potential users. Fee for service could reduce unofficial expenditures if the fee were lower than and replaced typical unofficial expenditures, otherwise adding service fees without reform of current hospital practices would lead to even more burdensome expenditures and inequities.
T cell responses against tumor associated antigens and prognosis in colorectal cancer patients
Authors: Nagorsen Dirk , Scheibenbogen Carmen , Letsch Anne , Germer Christoph-Thomas , Buhr Heinz-Johannes , Hegewisch-Becker Susanna , Rivoltini Licia , Thiel Eckhard , Keilholz Ulrich
Published: January 2005

Introduction

Spontaneous T cell responses against specific tumor-associated antigens (TAA) are frequently detected in peripheral blood of tumor patients of various histiotypes. However, little is known about whether these circulating, spontaneously occurring, TAA-reactive T cells influence the clinical course of disease.

Methods

Fifty-four HLA-A2 positive colorectal cancer patients had been analyzed for the presence of T cell responses against epitopes derived from the TAA Ep-CAM, her-2/neu, and CEA either by ELISPOT assay or by intracellular cytokine staining. Then, Kaplan-Meier survival analysis was performed comparing T-cell-responders and T-cell-non-responders. For comparison, a group of T-cell-non-responders was compiled stringently matched to T-cell-responders based on clinical criteria and also analyzed for survival.

Results

Sixteen out of 54 patients had a detectable T cell response against at least one of the three tested TAA. Two out of 21 patients (9.5%) with limited stage of disease (UICC I and II) and 14 out of 33 patients (42.4%) with advanced disease (UICC III and IV) were T cell response positive. Comparing all T-cell-responders (n = 16) and all T-cell-non-responders (n = 38), no survival difference was found. In an attempt to reduce the influence of confounding clinical factors, we then compared 16 responders and 16 non-responders in a matched group survival analysis; and again no survival difference was found (p = 0.7).

Conclusion

In summary, we found no evidence that spontaneous peripheral T cell responses against HLA-A2-binding epitopes of CEA, her-2/neu and Ep-CAM are a strong prognostic factor for survival.
Downregulation of Angiogenic Factors in Ewing Tumor Xenografts by the Combination of Human Interferon‐α or Interferon‐β with Ifosfamide
Authors: SANCÉAU JOSIANE , WIETZERBIN JUANA
Published: January 2005

Abstract: Ewing sarcoma is the second most common bone tumor in childhood. Despite aggressive chemotherapy and radiotherapy, the prognosis of metastatic disease remains poor. In a nude mouse model of Ewing tumor xenografts, we recently showed that human type I interferons (IFNs) inhibit the growth of established xenografts. Combined therapy with human IFNs and ifosfamide (IFO), an alkylating agent widely used in high‐dose chemotherapy of Ewing tumors, results in a strong synergistic antitumor effect. We have investigated the effect of IFNs/IFO treatment on the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP‐9), and urokinase plasminogen activator receptor (uPAR), three key mediators of tumor growth and angiogenesis, in tumor xenografts generated either from a primary tumor (EW7) or from a metastatic tumor (COH). COH tumors expressed 5‐fold higher levels of VEGF than EW7 tumors. IFNs/IFO treatment reduced by >70% the amount of VEGF in COH and EW7 tumors. We did not detect constitutive MMP‐9 activity in EW7 tumors. In contrast, the metastasis‐derived COH tumor expressed very high levels of active MMP‐9. Although the total amount of MMP‐9 remained unchanged, active MMP‐9 was reduced by up to 75% in IFNs/IFO‐treated COH tumors. IFNs/IFO treatment triggered in both COH and EW7 tumors the downregulation of uPAR expression, a molecule involved in vascularization and endothelial cell migration. Our results partly explain the mechanism of tumor growth inhibition by IFNs/IFO therapy and provide a rational foundation for the development of a new therapeutic approach to Ewing tumors resistant to conventional chemotherapy.
Increased Intracellular Ionic Content Is Correlated with a Decreased Perichromatin Granule Density in Old Neurons
Authors: BERTONI‐FREDDARI CARLO , FATTORETTI PATRIZIA , MALATESTA MANUELA
Published: January 2005

Abstract: The intracellular content of monovalent ions (Na+, Cl−, and K+) in brain cortical cells from young, adult, and old rats was measured by X‐ray microanalysis. By referring the peak of each ion to the respective value of the dry mass, we obtained the intracellular content as a percentage of dry mass. A significant increase of the intracellular content of Na+, Cl−, and K+ was found in old animals. In the same type of cells from rats of different ages, we estimated the density of perichromatin granules (PGs), the RNA structural correlates containing ribonucleoproteins (RNPs). PGs were discovered by Bernhard's method, which allows the preferential staining of RNPs. The PG density (i.e., the number of PGs/μm2 of nuclear area) was significantly lower (−27.8%) in the neurons of old animals. Taken together, the present findings document that in the nuclei of brain cortical cells of old animals the ionic strength is markedly increased and that this alteration may affect chromatin functions (e.g., DNA template activity). The ionic content of the nucleoplasm is reported to modulate the structure of chromatin molecules and regulate gene expression; thus, the increased content of the three ions found by us in old animals, by increasing the viscosity of the nucleoplasm, may affect gene expression by disturbing the inhibition (negative regulation) or potentiation (positive regulation) of RNA polymerase binding. In physiological aging, increased ionic strength may lead to age‐related DNA dysfunction as well as to alterations in the processing of RNA structural constituents, such as PGs.
Apoptotic Cell Death and Amyloid Precursor Protein Signaling in Neuroblastoma SH‐SY5Y Cells
Authors: VENEZIA VALENTINA , RUSSO CLAUDIO , REPETTO EMANUELA , NIZZARI MARIO , VIOLANI ELISABETTA , CARLO PIA , MARCHETTI BIANCA , SCHETTINI GENNARO
Published: January 2005

Abstract: We have recently shown that the amyloid precursor protein (APP) and a subset of its C‐terminal fragments (CTFs) are tyrosine phosphorylated in human brain and in cultured cells. Tyrosine phosphorylation generates a substrate that is sequentially bound by the adaptor proteins ShcA and Grb2, and this interaction is significantly enhanced in Alzheimer's disease brains. Here we have studied the APP/CTFs phosphorylation and ShcA activation in a human neuroblastoma cell line, SH‐SY5Y, under basal and apoptotic conditions. To commit these cells to apoptosis, we used staurosporin, a well‐known apoptotic inducer and protein kinase C blocker. Our data suggest the following: (1) in normally proliferating SH‐SY5Y cells, full‐length APP is complexed with Grb2[Q3], likely through its SH2 domain; (2) upon induction of apoptosis, APP is degraded and ShcA‐Grb2 coimmunoprecipitates with CTFs recognized by anti‐APP antibodies; and (3) caspase inhibitors partially block the degradation of APP and the coprecipitation of CTFs with ShcA‐Grb2 adaptors. In summary, our data suggest that in SH‐SY5Y cells, tyrosine‐phosphorylated APP is involved in a complex with ShcA‐Grb2 adaptors that is disrupted during apoptosis. The abnormal degradation of APP and consequent increased levels of CTFs (as has been observed in Alzheimer's disease and Down's syndrome) generate a complex between tyrosine‐phosphorylated CTFs and intracellular adaptors. The signaling through APP and its CTFs may have significant relevance for apoptotic cell death in Alzheimer's disease.
Defining the Chemotherapeutic Targets of Histone Deacetylase Inhibitors
Authors: GABRIELLI BRIAN , WARRENER ROBYN , BURGESS ANDREW , BEAMISH HEATHER
Published: January 2005

Abstract: The use of many conventional chemotherapeutic drugs is often severely restricted due to dose‐limiting toxicities, as these drugs target the destruction of the proliferating fraction of cells, often with little specificity for tumor cells over proliferating normal body tissue. Many newer drugs attempt to overcome this shortcoming by targeting defective gene products or cellular mechanisms that are specific to the tumor, thereby minimizing the toxicity to normal tissue. Histone deacetylase inhibitors are an example of this type of tumor‐directed drug, having significant toxicity for tumors but minimal effects on normal tissue. These drugs can affect the transcriptional program by modifying chromatin structure, but it is not yet clear whether specific transcriptional changes are directly responsible for their tumor‐selective toxicity. Recent evidence suggests that transcriptional changes underlie their cytostatic activity, although this is not tumor‐selective and affects all proliferating cells. Here we present evidence that supports an alternative mechanism for the tumor‐selective cytotoxicity of histone deacetylase inhibitors. The target is still likely to be the chromatin histones, but rather than transcriptional changes due to modification of the transcriptionally active euchromatin, we propose that hyperacetylation and disruption of the transcriptionally inactive heterochromatin, particularly the centromeric heterochromatin, and the inability of tumor cells to cell cycle arrest in response to a specific checkpoint, underlies the tumor‐selective cytotoxicity of these drugs.
HDAC‐3 Participates in the Repression of e2f‐Dependent Gene Transcription in Primary Differentiated Neurons
Authors: PANTELEEVA IRINA , ROUAUX CAROLINE , LARMET YVES , BOUTILLIER STÉPHANIE , LOEFFLER JEAN‐PHILIPPE , BOUTILLIER ANNE‐LAURENCE
Published: January 2005

Abstract: Activation of e2f‐1 gene expression is an event that has been now established in many models of neuronal apoptosis. Accumulated E2F‐1 protein has also been observed in post mortem brains obtained from patients suffering from different neurodegenerative diseases. We have previously shown in primary neuronal cultures that e2f‐1 gene transcription was actively repressed in neuroprotective conditions through HDAC‐dependent regulation on the E2F‐responsive elements (E2F‐REs) located in the e2f‐1 gene promoter. Here, we further investigated the protein complex bound to these sites by gel shift analysis. We found that the specific protein binding to E2F‐REs is altered in apoptotic conditions compared to neuroprotective conditions, suggesting that the proteic constituents of the complex are likely to be modified upon apoptosis onset. Indeed, Western blot analysis showed a time‐dependent degradation of the Rb/E2F binding protein HDAC‐3 during apoptosis, a degradation that is caspase‐dependent. Altogether, these data point to HDAC‐3 as a good candidate involved in the active e2f‐1 repression necessary for neuroprotection.
Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial
Authors: Le Cesne A. , Blay J.Y. , Judson I. , Van Oosterom A. , Verweij J. , Radford J. , Lorigan P. , Rodenhuis S. , Ray-Coquard I. , Bonvalot S. , Collin F. , Jimeno J. , Di Paola E. , Van Glabbeke M. , Nielsen O.S.
Published: January 2005

Purpose

This nonrandomized multicenter phase II study was performed to evaluate the activity and safety of Ecteinascidin (ET-743) administered at a dose of 1.5 mg/m2 as a 24-hour continuous infusion every 3 weeks in patients with pretreated advanced soft tissue sarcoma.

Patients and Methods

Patients with documented progressive advanced soft tissue sarcoma received ET-743 as second- or third-line chemotherapy. Antitumor activity was evaluated every 6 weeks until progression, excessive toxicity, or patient refusal.

Results

One hundred four patients from eight European institutions were included in the study (March 1999 to November 2000). A total of 410 cycles were administered in 99 assessable patients. Toxicity mainly involved reversible grade 3 to 4 asymptomatic elevation of transaminases in 40% of patients, and grade 3 to 4 neutropenia was observed in 52% of patients. There were eight partial responses (PR; objective regression rate, 8%), 45 no change (NC; > 6 months in 26% of patients), and 39 progressive disease. A progression arrest rate (PR + NC) of 56% was observed in leiomyosarcoma and 61% in synovialosarcoma. The median duration of the time to progression was 105 days, and the 6-month progression-free survival was 29%. The median duration of survival was 9.2 months.

Conclusion

ET-743 seems to be a promising active agent in advanced soft tissue sarcoma, with no cumulative toxicities. The 6-months progression-free survival observed in advanced soft tissue sarcoma compares favorably with those obtained with other active drugs tested in second-line chemotherapy in previous European Organisation for the Research and Treatment of Cancer trials. The median overall survival was unusually long in these heavily pretreated patients mainly due to the high number of patients who benefit from the drug in terms of tumor control.
Results of Induction Chemotherapy in Children Older Than 1 Year With a Stage 4 Neuroblastoma Treated With the NB 97 French Society of Pediatric Oncology (SFOP) Protocol
Authors: Valteau-Couanet Dominique , Michon Jean , Boneu Andrée , Rodary Chantal , Perel Yves , Bergeron Christophe , Rubie Hervé , Coze Carole , Plantaz Dominique , Bernard Frédéric , Chastagner Pascal , Bouzy Jeannine , Hartmann Olivier
Published: January 2005

Purpose

To test the metastatic response rate in stage 4 neuroblastoma, using dose-intensive induction chemotherapy in a multi-institutional setting.

Patients and Methods

From 1998 to 1999, 47 consecutive children were treated according to N7 protocol. Children received cyclophosphamide 140 mg/kg, doxorubicin 75 mg/m2, and vincristine 0.066 mg/kg (CAV) in cycles 1, 2, 4, and 6, and cisplatinum 200 mg/m2 and etoposide 600 mg/m2 (P/VP) in cycles 3, 5, and 7. The International Neuroblastoma Staging system was used with an emphasis on skeletal evaluation by 123-iodine-metaiodobenzylguanidine (MIBG) scintigraphy. A phase II study evaluating the metastasis complete response rate after induction chemotherapy was conducted in patients who had positive metastatic sites on MIBG scans at diagnosis.

Results

Forty-six patients were assessable for toxicity. Hematologic toxicity was the main toxicity observed. Neutropenia was more frequent after CAV than after P/VP (P < .001). A higher rate of thrombocytopenia was observed after P/VP (P = .03). Forty patients with positive MIBG were assessable for metastatic response, and complete regression of metastases was achieved in 17 patients (ie, 43%; 95% CI, 27% to 59%). Of all 47 patients, 21 achieved complete metastatic response.

Conclusion

The N7 induction chemotherapy protocol was feasible in a multicentric setting. The observed metastasis complete response rate was similar to that obtained in our previous studies and significantly lower than that published in a previous series using the same regimen. In our hands, escalating doses of cyclophosphamide and prolonging conventional chemotherapy with the same drugs failed to improve the metastasis complete response rate.
Mcp6, a meiosis-specific coiled-coil protein ofSchizosaccharomyces pombe, localizes to the spindle pole body and is required for horsetail movement and recombination
Authors: Saito Takamune T. , Tougan Takahiro , Okuzaki Daisuke , Kasama Takashi , Nojima Hiroshi
Published: January 2005

We report here that a meiosis-specific gene of Schizosaccharomyces pombe denoted mcp6+ (meiotic coiled-coil protein) encodes a protein that is required for the horsetail movement of chromosomes at meiosis I. The mcp6+ gene is specifically transcribed during the horsetail phase. Green fluorescent protein (GFP)-tagged Mcp6 appears at the start of karyogamy, localizes to the spindle-pole body (SPB) and then disappears before chromosome segregation at meiosis I. In the mcp6Δ strain, the horsetail movement was either hampered (zygotic meiosis) or abolished (azygotic meiosis) and the pairing of homologous chromosomes was impaired. Accordingly, the allelic recombination rates of the mcp6Δ strain were only 10-40% of the wild-type rates. By contrast, the ectopic recombination rate of the mcp6Δ strain was twice the wild-type rate. This is probably caused by abnormal homologous pairing in mcp6Δ cells because of aberrant horsetail movement. Fluorescent microscopy indicates that SPB components such as Sad1, Kms1 and Spo15 localize normally in mcp6Δ cells. Because Taz1 and Swi6 also localized with Sad1 in mcp6Δ cells, Mcp6 is not required for telomere clustering. In a taz1Δ strain, which does not display telomere clustering, and the dhc1-d3 mutant, which lacks horsetail movement, Mcp6 localized with Sad1 normally. However, we observed abnormal astral microtubule organization in mcp6Δ cells. From these results, we conclude that Mcp6 is necessary for neither SPB organization nor telomere clustering, but is required for proper astral microtubule positioning to maintain horsetail movement.
The importance of leg length discrepancy after total hip arthroplasty
Authors: Konyves A. , Bannister G. C.
Published: January 2005

We assessed leg length discrepancy and hip function in 90 patients undergoing primary total hip arthroplasty before surgery and at three and 12 months after. Function was measured using the Oxford hip score (OHS). After surgery the mean OHS improved by 26 points after three months and by 30 points after 12.

After operation 56 (62%) limbs were long by a mean of 9 mm and this was perceived by 24 (43%) patients after three months and by 18 (33%) after 12. The mean OHS in patients who perceived true lengthening was 27% worse than the rest of the population after three months and 18% worse after 12. In 55 (98%) patients, lengthening occurred in the femoral component. Appropriate placement of the femoral component could significantly reduce a patient’s perception of discrepancy of length.
Urinary Osteocalcin as a Marker of Bone Metabolism
Authors: Ivaska Kaisa K , Käkönen Sanna-Maria , Gerdhem Paul , Obrant Karl J , Pettersson Kim , Väänänen H Kalervo
Published: January 2005

Background: Osteocalcin (OC) is produced by osteoblasts during bone formation, and circulating OC has been used in clinical investigations as a marker of bone metabolism. OC is excreted into urine by glomerular filtration and can be found in urine as midmolecule fragments.

Methods: We developed and evaluated three immunoassays (U-MidOC, U-LongOC, and U-TotalOC) for the detection of various molecular forms of urine OC (U-OC). We evaluated the association of U-OC with other markers of bone turnover and with bone mass in 1044 elderly women and studied seasonal and circadian variation of U-OC.

Results: U-OC correlated with other bone turnover markers [Spearman correlation (r), 0.30–0.57; P <0.0001], demonstrating the association between U-OC and skeletal metabolism. There was also a significant association between bone metabolism assessed by U-OC quartiles and bone mass assessed by total body bone mineral content (P <0.0001). The seasonal effects appeared to be rather small, but we observed a significant circadian rhythm similar to the one reported for serum OC with high values in the morning and low values in the afternoon.

Conclusions: The three immunoassays had unique specificities toward different naturally occurring U-OC fragments. U-OC concentrations measured with any of these assays correlated with bone turnover rates assessed by conventional serum markers of bone metabolism. The measurement of OC in urine samples could be used as an index of bone turnover in monitoring bone metabolism.