bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperglycemia Alters Tumor Necrosis Factor-α Release from Mononuclear Cells in Women with Polycystic Ovary Syndrome
Authors: González Frank , Minium Judi , Rote Neal S. , Kirwan John P.
Published: September 2005

Context: Women with polycystic ovary syndrome (PCOS) are often insulin resistant and have chronic low-level inflammation.

Objective: The purpose of this study was to determine the effects of hyperglycemia on lipopolysaccharide (LPS)-stimulated TNFα release from mononuclear cells (MNC) in PCOS.

Design: The study was designed as a prospective controlled study.

Setting: The study was carried out at an academic medical center.

Patients: Sixteen reproductive age women with PCOS (eight lean, eight obese) and 14 age-matched controls (eight lean, six obese) participated in the study.

Main Outcome Measures: Insulin sensitivity (IS) was derived from a 2-h 75-g oral glucose tolerance test (ISOGTT). Percentage of truncal fat was determined by dual-energy absorptiometry. TNFα release was measured from MNC cultured in the presence of LPS from blood samples drawn fasting and 2 h after glucose ingestion.

Results: ISOGTT was lower in women with PCOS compared with controls (3.9 ± 0.4 vs. 6.3 ± 1.0; P < 0.03) and was negatively correlated with percentage of truncal fat (r = 0.56; P < 0.002). Truncal fat was greater in lean women with PCOS compared with lean controls (29.8 ± 2.6 vs. 23.8 ± 2.5%; P < 0.04). The TNFα response was different between obese and lean controls (−96.9 ± 21.2 vs. 24.4 ± 21.6 pg/ml; P < 0.03) and obese and lean women with PCOS (−94.1 ± 34.5 vs. 30.4 ± 17.6 pg/ml; P < 0.002). Fasting plasma C-reactive protein was elevated (P < 0.003) in obese PCOS and obese controls compared with lean controls.

Conclusion: An increase in abdominal adiposity and increased TNFα release from MNC after hyperglycemia may contribute to insulin resistance in lean PCOS patients. In contrast, obese PCOS patients have more profound chronic inflammation, and thus may have LPS tolerance that protects them from relatively mild excursions in blood glucose.
Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction
Authors: Maccarrone Mauro , Barboni Barbara , Paradisi Andrea , Bernabò Nicola , Gasperi Valeria , Pistilli Maria Gabriella , Fezza Filomena , Lucidi Pia , Mattioli Mauro
Published: September 2005

Anandamide (AEA) is the endogenous ligand of cannabinoid (CB) receptors, and as such it plays several central and peripheral activities. Regulation of female fertility by AEA has attracted growing interest, yet a role for this endocannabinoid in controlling sperm function and male fertility in mammals has been scarcely investigated. In this study we report unprecedented evidence that boar sperm cells have the biochemical machinery to bind and degrade AEA, i.e. type-1 cannabinoid receptors (CB1R), vanilloid receptors (TRPV1), AEA-synthesizing phospholipase D (NAPE-PLD), AEA transporter (AMT) and AEA hydrolase (FAAH). We also show that the non-hydrolyzable AEA analogue methanandamide reduces sperm capacitation and, as a consequence, inhibits the process of acrosome reaction (AR) triggered by the zona pellucida, according to a cyclic AMP-dependent pathway triggered by CB1R activation. Furthermore, activation of TRPV1 receptors seems to play a role of stabilization of the plasma membranes in capacitated sperm, as demonstrated by the high incidence of spontaneous AR occurring during the cultural period when TRPV1 activity was antagonized by capsazepine. We show that sperm cells have a complete and efficient endocannabinoid system, and that activation of cannabinoid or vanilloid receptors controls, at different time-points, sperm functions required for fertilization. These observations open new perspectives on the understanding and treatment of male fertility problems.
A unique population of bone marrow cells migrates to skeletal muscle via hepatocyte growth factor/c-met axis
Authors: Rosu-Myles Michael , Stewart Erin , Trowbridge Jennifer , Ito Caryn Y. , Zandstra Peter , Bhatia Mickie
Published: September 2005

Cells expressing the CD45-associated hematopoietic marker are predominantly present in the mammalian bone marrow (BM), but have recently been shown to also reside in the skeletal muscle and potentially participate in muscle repair. Despite the consistent observations, the specific relationship and potential migration of CD45+ cells in the BM versus CD45+ cells residing in the muscle remain unclear, in addition to any understanding of the factors that may regulate the trafficking of CD45+-derived BM cells to skeletal muscle upon i.v. transplantation. Here, transplantation of BM-derived cells fully replaced the CD45+ fraction of skeletal muscle, but gave rise to progenitor cells with distinct hematopoietic lineage capacity from CD45+ cells residing in the BM. Using transwell migration assays, a subset of BM cells was shown to migrate exclusively to mature skeletal muscle cells and not BM-derived stromal cells. Unlike migration of BM cells to stroma, myofiber induced migration of BM-derived cells was not affected by stromal-derived factor-1 (SDF-1) neutralization or CXCR4-blocking antibody, but could be reduced by addition of c-met-blocking antibody and augmented by hepatocyte growth factor (HGF), the putative ligand for c-met. We suggest that the BM compartment consists of a functionally complex population of CD45+ progenitors that includes a subset of HGF/c-met responsive cells capable of migration to skeletal muscle. This previously unappreciated basis for cellular tracking now aids in defining regulatory networks that distinguish the stem cell niche of the BM versus skeletal muscle microenvironments.
Percutaneous Coronary Intervention–Related Bleeding Risk Factors in Current Practice
Authors: Mathis A Scott , Gugger James J
Published: September 2005

BACKGROUND:

Bleeding is a common and costly complication of percutaneous coronary intervention (PCI). Little is known about the risk factors for bleeding complications.

Objective:

To report our PCI-related observations from a single institution and use the information to establish risk factors for short-term bleeding complications, with special focus on examining the importance of renal function.

METHODS:

A retrospective record review was conducted of the admission of 300 patients grouped according to antithrombotic regimen: unfractionated heparin alone (n = 187), bivalirudin (n = 26), and glycoprotein IIb/IIIa antagonist plus heparin (n = 103). Bleeding and ischemic outcomes were tracked. A model was constructed to predict independent bleeding risk factors.

RESULTS:

Treatment groups differed significantly regarding any bleeding (p = 0.001), minor bleeding (p < 0.001), and length of stay (p = 0.01). Multivariate predictors of any bleeding included antithrombotic regimen, creatinine clearance (Clcr) <30 mL/min, and hypertension. Any bleeding was associated with prolonged length of stay. Major bleeding was predicted by Clcr <30 mL/min and was associated with prolonged length of stay and death. Minor bleeding was predicted only by choice of antithrombotic regimen.

CONCLUSIONS:

The major influences on bleeding risk appeared to be Clcr <30 mL/min and choice of antithrombotic regimen. It is important to note that other markers of renal function, including serum creatinine value and serum creatinine at a cutoff level of 1.5 mg/dL, did not predict bleeding events.
Intestinal Pseudo-Obstruction Caused by Diltiazem in a Neutropenic Patient
Authors: Young Rebecca P , Wu Helen
Published: September 2005

OBJECTIVE:

To describe a case of diltiazem-induced intestinal pseudo-obstruction in a neutropenic patient.

CASE SUMMARY:

A 74-year-old male with newly diagnosed acute myelogenous leukemia developed atrial fibrillation on day 12 of induction chemotherapy. He was initially treated with diltiazem 5 mg intravenously every 5–10 minutes for 5 doses and an amiodarone 150-mg loading dose intravenously. Diltiazem 30 mg orally 4 times daily and amiodarone continuous infusion were started thereafter. Amiodarone therapy was discontinued after one day due to an untoward adverse effect. The diltiazem dose was then escalated. By day 14, the patient was receiving diltiazem 120 mg orally 4 times daily. On day 15, he developed increasing abdominal distention with hyperactive bowel sounds. On day 16, a radiographic examination showed multiple dilated loops of both the small and large bowel representing possible intestinal pseudo-obstruction; diltiazem was discontinued that day. Starting on day 18, the patient showed recovery of intestinal pseudo-obstruction without intervention. No further GI complications developed during his remaining hospital course.

DISCUSSION:

Intestinal pseudo-obstruction is usually associated with underlying medical conditions such as trauma, infection, cardiac disease, and after surgery. Medications rarely cause such a condition. Detailed examination of the patient's record indicated neither infection nor other medications contributed to the development of intestinal pseudo-obstruction. Additionally, a radiographic examination ruled out neutropenic enterocolitis, a common gastrointestinal complication in neutropenic patients. Use of the Naranjo probability scale indicated a probable relationship between pseudo-obstruction and diltiazem in this patient.

CONCLUSIONS:

Although calcium-channel blockers rarely cause intestinal pseudo-obstruction, clinicians must be aware of this serious but reversible adverse effect.
Pharmaceutical Care in Community Pharmacy: Practice and Research in the Netherlands
Authors: van Mil JW Foppe
Published: September 2005

OBJECTIVE:

To describe the pharmaceutical care activities and research in community pharmacy in the Netherlands.

FINDINGS:

Pharmaceutical care is well advanced in Dutch pharmacy practice. This is largely due to the fact that clinical pharmacy was already an integrated part of community pharmacy practice by the end of the 1980s. Activities of the International Pharmaceutical Federation (FIP), some wholesale companies, and influential individuals in the Netherlands stimulated universities and the Royal Society for the Advancement of Pharmacy to advance the implementation of pharmaceutical care.

DISCUSSION:

Not all pharmacies in the Netherlands provide pharmaceutical care at the same level, although medication surveillance (concurrent and prospective medication analysis) is part of everyday practice. Implementation of quality assurance systems in community pharmacy practice could be helpful in assuring high levels of care. Similar to those in other countries, Dutch pharmacists are torn between the wish to provide pharmaceutical care and economic considerations, although the financial status of most pharmacies is still (very) healthy. New entrants into the market, such as supermarket and pharmacy chains, seem to put little emphasis on care provision.

CONCLUSIONS:

Pharmaceutical care has been implemented in many Dutch community pharmacies, but not everywhere to the same extent. Due to excellent automated medication surveillance; structured, high-quality medication counseling; and the fact that patients usually visit the same pharmacy, Dutch patients are well protected against many drug-related problems.
Recurrent Mossy Fibers Establish Aberrant Kainate Receptor-Operated Synapses on Granule Cells from Epileptic Rats
Authors: Epsztein Jérôme , Represa Alfonso , Jorquera Isabel , Ben-Ari Yehezkel , Crépel Valérie
Published: September 2005

Glutamatergic mossy fibers of the hippocampus sprout in temporal lobe epilepsy and establish aberrant synapses on granule cells from which they originate. There is currently no evidence for the activation of kainate receptors (KARs) at recurrent mossy fiber synapses in epileptic animals, despite their important role at control mossy fiber synapses. We report that KARs are involved in ongoing glutamatergic transmission in granule cells from chronic epileptic but not control animals. KARs provide a substantial component of glutamatergic activity, because they support half of the non-NMDA receptor-mediated excitatory drive in these cells. KAR-mediated EPSCKAs are selectively generated by recurrent mossy fiber inputs and have a slower kinetics than EPSCAMPA. Therefore, in addition to axonal rewiring, sprouting of mossy fibers induces a shift in the nature of glutamatergic transmission in granule cells that may contribute to the physiopathology of the dentate gyrus in epileptic animals.
Microglial Phagocytosis Induced by Fibrillar β-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines
Authors: Koenigsknecht-Talboo Jessica , Landreth Gary E.
Published: September 2005

Microglia undergo a phenotypic activation in response to fibrillar β-amyloid (fAβ) deposition in the brains of Alzheimer's disease (AD) patients, resulting in their elaboration of inflammatory molecules. Despite the presence of abundant plaque-associated microglia in the brains of AD patients and in animal models of the disease, microglia fail to efficiently clear fAβ deposits. However, they can be induced to do so during Aβ vaccination therapy attributable to anti-Aβ antibody stimulation of IgG receptor (FcR)-mediated phagocytic clearance of Aβ plaques.

We report that proinflammatory cytokines attenuate microglial phagocytosis stimulated by fAβ or complement receptor 3 and argue that this may, in part, underlie the accumulation of fAβ-containing plaques within the AD brain. The proinflammatory suppression of fAβ-elicited phagocytosis is dependent on nuclear factor κB activation. Significantly, the proinflammatory cytokines do not inhibit phagocytosis elicited by antibody-mediated activation of FcR, which may contribute to the efficiency of Aβ vaccination-based therapy. Importantly, the proinflammatory suppression of fAβ phagocytosis can be relieved by the coincubation with anti-inflammatory cytokines, cyclooxygenase inhibitors, ibuprofen, or an E prostanoid receptor antagonist, suggesting that proinflammatory cytokines induce the production of prostaglandins, leading to an E prostanoid receptor-dependent inhibition of phagocytosis. These findings support anti-inflammatory therapies for the treatment of AD.
Neurogenesis and Neuroprotection Induced by Peripheral Immunomodulatory Treatment of Experimental Autoimmune Encephalomyelitis
Authors: Aharoni Rina , Arnon Ruth , Eilam Raya
Published: September 2005

Brain insults such as the autoimmune inflammatory process in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) induce a measure of neurogenesis, but its regenerative therapeutic consequence is limited, because it fails to regenerate functional neurons and compensate the damage. Here, we investigated whether peripheral immunomodulatory treatment for MS/EAE, glatiramer acetate (GA), can enhance neurogenesis and generate neuroprotection in the CNS of EAE-inflicted mice. EAE was induced by myelin oligodendrocyte glycoprotein peptide, either in yellow fluorescent protein (YFP) 2.2 transgenic mice, which selectively express YFP on their neuronal population, or in C57BL/6 mice. Thein situeffect of GA was studied in various brain regions; neuroprotection and neurogeneration were evaluated and quantified by measuring the expression of different neuronal antigens andin vivoproliferation markers. The results demonstrated that in EAE-inflicted mice, neuroproliferation was initially elevated after disease appearance but subsequently declined below that of naive mice. In contrast, GA treatment in various stages of the disease led to sustained reduction in the neuronal/axonal damage typical to the neurodegenerative disease course. Moreover, three processes characteristic of neurogenesis, namely cell proliferation, migration, and differentiation, were augmented and extended by GA treatment in EAE mice compared with EAE-untreated mice and naive controls. The newborn neuroprogenitors manifested massive migration through exciting and dormant migration pathways, into injury sites in brain regions, which do not normally undergo neurogenesis, and differentiated to mature neuronal phenotype. This suggests a direct linkage between immunomodulation, neurogenesis, and anin situtherapeutic consequence in the CNS.
Reelin Modulates NMDA Receptor Activity in Cortical Neurons
Authors: Chen Ying , Beffert Uwe , Ertunc Mert , Tang Tie-Shan , Kavalali Ege T. , Bezprozvanny Ilya , Herz Joachim
Published: September 2005

Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca2+entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.
Rapid Vesicular Release, Quantal Variability, and Spillover Contribute to the Precision and Reliability of Transmission at a Glomerular Synapse
Authors: Sargent Peter B. , Saviane Chiara , Nielsen Thomas A. , DiGregorio David A. , Silver R. Angus
Published: September 2005

The amplitude and shape of EPSC waveforms are thought to be important determinants of information processing and storage in the brain, yet relatively little is known about the origins of EPSC variability or how it affects synaptic signaling. We investigated the stochastic determinants of AMPA receptor-mediated EPSC variability at cerebellar mossy fiber–granule cell (MF-GC) connections by combining multiple-probability fluctuation analysis (MPFA) and deconvolution methods. The properties of MF connections with a single release site and the effects of the rapidly equilibrating competitive antagonist kynurenic acid on EPSCs suggest that receptors are not saturated by glutamate during a quantal event and that quanta sum linearly over a wide range of release probabilities. MPFA revealed an average of five vesicular release sites per MF-GC connection. Our results show that the time course of vesicular release is rapid (decay, τ = 75 μs) and independent of release probability, introducing little jitter in the shape or timing of the quantal component of the EPSC at physiological temperature. Moreover, the peak vesicular release rate per release site after an action potential (AP) (∼3 ms–1) is substantially higher than previously reported for central synapses. Interaction of amplitude fluctuations arising from quantal release and quantal size with the slower, low variability spillover-mediated current produce substantial variability in EPSC shape. Our simulations of MF-GC transmission suggest that quantal variability and transmitter spillover extend the voltage from which AP threshold can be crossed, improving reliability, and that fast vesicular release allows precise signaling across MF connections with heterogeneous weights.
Evaluating Human Embryonic Germ Cells: Concord and Conflict as Pluripotent Stem Cells
Authors: Turnpenny Lee , Spalluto Cosma M. , Perrett Rebecca M. , O'Shea Marie , Hanley Karen Piper , Cameron Iain T. , Wilson David I. , Hanley Neil A.
Published: September 2005

The realization of cell replacement therapy derived from human pluripotent stem cells requires full knowledge of the starting cell types as well as their differentiated progeny. Alongside embryonic stem cells, embryonic germ cells (EGCs) are an alternative source of pluripotent stem cell. Since 1998, four groups have described the derivation of human EGCs. This review analyzes the progress on derivation, culture, and differentiation, drawing comparison with other pluripotent stem cell populations.
Modelling of saline intrusion in marine outfalls
Authors: Shannon N. R. , Mackinnon P. A. , Hamill G.
Published: September 2005

Since their introduction in the 1950s, marine outfalls with diffusers have been prone to saline intrusion, a process in which seawater ingresses into the outfall. This can greatly reduce the dilution and subsequent dispersion of wastewater discharged, sometimes resulting in serious deterioration of coastal water quality. Although long aware of the difficulties posed by saline intrusion, engineers still lack satisfactory methods for its prediction and robust design methods for its alleviation. However, with recent developments in numerical methods and computer power, it has been suggested that commercially available computational fluid dynamics (CFD) software may be a useful aid in combating this phenomenon by improving understanding through synthesising likely behaviour. This document reviews current knowledge on saline intrusion and its implications and then outlines a model-scale investigation of the process undertaken at Queen's University Belfast, using both physical and CFD methods. Results are presented for a simple outfall configuration, incorporating several outlets. The features observed agree with general observations from full-scale marine outfalls, and quantify the intricate internal flow mechanisms associated with saline intrusion. The two-dimensional numerical model was found to represent saline intrusion, but in a qualitative manner, not yet adequate for design purposes. Specific areas requiring further development were identified. The ultimate aim is to provide a reliable, practical and cost effective means by which engineers can minimise saline intrusion through optimised outfall design.
Wave run-up on rubble breakwaters: spectral effects
Authors: Van de Walle B. , De Rouck J. , Troch P. , Geeraerts J. , Frigaard P.
Published: September 2005

Seven sets of data for wave run-up on a rubble mound breakwater were combined and re-analysed, with full-scale, large-scale and small-scale model test results being taken into account. The dimensionless wave run-up value Ru2%/Hm0 was considered, where Ru2% is the wave run-up height exceeded by 2% of the wave run-up events and Hm0 is the significant wave height. The wave run-up data sets were compared and a clear influence of the spectral shape, characterised by the spectral width parameter ε, on wave run-up was noticed: high values of ε correspond to high values of Ru2%/Hm0 and vice versa. Differences in wave run-up results between the various data sets could be explained by a difference in spectral width observed within these data sets. A multi-regression formula was fitted to all wave run-up data. The formula is valid for permeable rubble mound breakwaters covered with either grooved cubes or rip-rap with a slope steeper than 1 : 2, surging waves and a JONSWAP-type wave spectrum.
Can parents adjust to the idea that their child is at risk for a sudden death?: Psychological impact of risk for long QT syndrome
Authors: Hendriks Karin S.W.H. , Grosfeld F.J.M. , van Tintelen J.P. , van Langen I.M. , Wilde A.A.M. , van den Bout J. , ten Kroode H.F.J.
Published: September 2005

Can a parent adjust to the idea that its child is at risk for a sudden death? This question is raised by a diagnostic procedure in which children were tested for an inherited Long QT Syndrome (LQTS). This potentially life‐threatening but treatable cardiac arrhythmia syndrome may cause sudden death, especially in children and young adults. The long‐term psychological effects are described for parents whose children were tested for inherited LQTS. The adverse short‐term impact of such testing has been described previously. The goal of this investigation is to determine whether this distress endures. Thirty‐six parents completed measures of psychological distress. With the twenty‐four parents of carrier children, a semi‐structured interview was held 18 months after DNA disclosure. Parents of carrier children reported more distress than parents of non‐carrier children. Parents of carrier children remained vulnerable to high levels of distress; up to one‐third of these parents showed clinically relevant high levels of distress. High levels of distress were reported by parents of carrier children who (1) were highly distressed at previous assessments, (2) were familiar with the disease for a longer time, (3) had experienced a sudden death in the family, (4) were lesser educated, and who (5) were unsatisfied with the given information. Parents were particularly concerned about possible hazardous behavior during puberty. We conclude that the continuous threat of developing LQTS symptoms despite prophylactic treatment affected the psychological well‐being of the parents for a long time. In light of the tempetuous developments in the areas of cardiac genetics, periodical information on new insight and developments may act as a buffer for the parents' (growing) concerns about their child's inherited disorder. © 2005 Wiley‐Liss, Inc.
Alternating penalty trilinear decomposition algorithm for second‐order calibration with application to interference‐free analysis of excitation–emission matrix fluorescence data
Authors: Xia A‐Lin , Wu Hai‐Long , Fang Dong‐Mei , Ding Yu‐Jie , Hu Le‐Qian , Yu Ru‐Qin
Published: September 2005

A new method, alternating penalty trilinear decomposition (APTLD), is developed for the decomposition of three‐way data arrays. By utilizing the alternating least squares principle and alternating penalty constraints to minimize three different alternating penalty errors simultaneously, the intrinsic profiles are found. The APTLD algorithm can avoid the two‐factor degeneracy problem and relieve the slow convergence problem, which is difficult to handle for the traditional parallel factor analysis (PARAFAC) algorithm. It retains the second‐order advantage of quantification for analytes of interest even in the presence of potentially unknown interferents. In additions, it is insensitive to the estimated component number, thus avoiding the difficulty of determining a correct component number for the model, which is intrinsic in the PARAFAC algorithm. The results of treating one simulated and one real excitation–emission spectral data set showed that the proposed algorithm performs well as long as the model dimensionality chosen is not less than the actual number of components. Furthermore, the performance of the APTLD algorithm sometimes surpasses that of the PARAFAC algorithm in the prediction of concentration profiles even if the component number chosen is the same as the actual number of underlying factors in real samples. Copyright © 2005 John Wiley & Sons, Ltd.
Survival of metastatic breast carcinoma patients over a 20‐year period
Authors: Gennari Alessandra , Conte PierFranco , Rosso Riccardo , Orlandini Cinzia , Bruzzi Paolo
Published: September 2005

BACKGROUND

The expectation of improvement in patient survival with administration of new chemotherapy agents for metastatic breast carcinoma (MBC) is not consistently supported by data from clinical trials, which are often underpowered and have not detected moderate survival advantage. The aim of this study was to evaluate the impact of new agents on prognosis of MBC patients enrolled in clinical trials of first‐line chemotherapy.

METHODS

Between 1983 and 2001, 640 MBC patients were entered into 6 consecutive trials; the present analysis was limited to patients. The date of diagnosis of metastatic breast disease was used to define 5 arbitrarily chosen 3‐year time cohorts, 1983–1986, 1987–1989, 1992–1994, 1995–1997, and 1998–2001. Multivariate proportion of hazard (PH) models were used to evaluate changes in overall survival (OS) and progression‐free survival (PFS) over time and to detect changes associated with the use of taxanes, while adjusting for differences in baseline factors among 5 cohorts.

RESULTS

Patient characteristics were evenly distributed across the 5 cohorts. Median OS was 18 months, 17.2 months, 19.2 months, 26.1 months, and 23.6 months, respectively, in cohorts 1983–1986, 1987–1989, 1992–1994, 1995–1997, 1998–2001 (P< 0.0001). Age, performance status, relapse‐free survival, type of adjuvant treatment, metastatic site, and taxane first‐line chemotherapy were all associated with survival. These data failed to provide an indication of temporal trend and suggested a reduction in hazard of death in two cohorts (1995–1997 and 1998–2001) where taxane was added to first‐line chemotherapy.

CONCLUSIONS

The analysis provided evidence of improvement in prognosis of MBC patients that was associated with use of modern chemotherapeutic agents independent of time. Cancer 2005. © 2005 American Cancer Society.
Synthesis and Structure of the Group 12 Pyrimidinethiolate Complexes ∞3[Zn(S‐2‐N2C4H3)2], ∞2[Cd(S‐2‐N2C4H3)2], [Hg(S‐2‐N2C4H3)2] and[Cd(S‐2‐N2C4H3)2(tmeda)]
Authors: Eichhöfer Andreas , Buth Gernot
Published: September 2005

The pyrimidinethiolate complexes ∞3[Zn(S‐2‐N2C4H3)2],∞2[Cd(S‐2‐N2C4H3)2] and [Hg(S‐2‐N2C4H3)2] have been prepared by reaction of MCl2 (M = Zn, Cd, Hg) with 2 equiv. of Me3SiS‐2‐N2C4H3 in organic solvents, whilst [Cd(S‐2‐N2C4H3)2(tmeda)] was obtained by recrystallisation of∞2[Cd(S‐2‐N2C4H3)2] in TMEDA at 40 °C. The structures of the complexes were determined by single‐crystal X‐ray crystallography, which shows that the different metal atoms each have different coordination environments. The zinc atom in ∞3[Zn(S‐2‐N2C4H3)2] exhibits a tetrahedral coordination with one sulfur and three nitrogen atoms from pyrimidinethiolate ligands, whereas the cadmium atoms in ∞2[Cd(S‐2‐N2C4H3)2] and [Cd(S‐2‐N2C4H3)2(tmeda)] are six‐coordinate with either three sulfur and three nitrogen atoms or two sulfur and four nitrogen atoms. In contrast, the mercury atoms in [Hg(S‐2‐N2C4H3)2] display a distorted square‐planar coordination to a pair of chelating –S‐2‐N2C4H3 ligands with additional weak Hg–S interactions to adjacent molecules. While known cadmium and zinc pyrimidinethiolate complexes consist of one‐dimensional chains, ∞3[Zn(S‐2‐N2C4H3)2] and ∞2[Cd(S‐2‐N2C4H3)2] form either three‐ or two‐dimensional polymeric networks of metal atoms. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Synthesis of (R)‐(–)‐2‐Fluoronorapomorphine — A Precursor for the Synthesis of (R)‐(–)‐2‐Fluoro‐N‐[11C]propylnorapomorphine for Evaluation as a Dopamine D2 Agonist Ligand for PET Investigations
Authors: Søndergaard Kåre , Langgaard Kristensen Jesper , Gillings Nic , Begtrup Mikael
Published: September 2005

2‐Fluoronorapomorphine, the PET labelling precursor to 2‐fluoro‐N‐[11C]propylnorapomorphine, was prepared in 13 steps from codeine in a total yield of 10 %. Codeine was converted in four steps into N‐benzylnorcodeine which was oxidised by using the Swern protocol. Subsequent acid‐catalysed rearrangement afforded N‐benzylnormorphothebaine which was selectively triflylated at the 2‐position and pivaloylated at the 11‐position. The triflate underwent palladium‐catalysed amination with benzophenone imine. Amination conditions required sequential base addition to give substantial conversion of the triflate to the corresponding N‐substituted benzophenone imine. After acidic hydrolysis the resulting aniline was transformed into the 2‐fluoro compound via the Balz–Schiemann reaction. Hydrogenolysis of the N‐benzyl group followed by deprotection of the catechol moiety using BBr3 provided 2‐fluoronorapomorphine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Combined genome‐wide allelotyping and copy number analysis identify frequent genetic losses without copy number reduction in medulloblastoma
Authors: Langdon Jacqueline A. , Lamont Jayne M. , Scott Debbie K. , Dyer Sara , Prebble Emma , Bown Nick , Grundy Richard G. , Ellison David W. , Clifford Steven C.
Published: September 2005

Detailed analysis of mechanisms of genetic loss for specific tumor suppressor genes (TSGs; e.g., RB1, APC and NF1) indicates that TSG inactivation can occur by allelic loss of heterozygosity (LOH), without any alteration in DNA copy number. However, the role and prevalence of such events in the pathogenesis of specific malignancies remains to be established on a genome‐wide basis. We undertook a detailed molecular assessment of chromosomal defects in a panel of nine cell lines derived from primary medulloblastomas, the most common malignant brain tumors of childhood, by parallel genome‐wide assessment of LOH (allelotyping) and copy number aberrations (comparative genomic hybridization and fluorescence in situ hybridization). The majority of genetic losses observed were detected by both copy number and LOH methods, indicating they arise through the physical deletion of chromosomal material. However, a significant proportion of losses (17/42, 40%) represented regions of allelic LOH without any associated copy number reduction; these events involved both whole chromosomes (10/17) and sub‐chromosomal regions (7/17). Using this approach, we identified medulloblastoma‐characteristic alterations, e.g., isochromosome for 17q, MYC amplification and losses on chromosomes 10, 11, and 16, alongside novel regions of genetic loss (e.g., 10q21.1‐26.3, 11q24.1‐qter). This detailed genetic characterization of the majority of medulloblastoma cell lines provides important precedent for the widespread involvement of copy number‐neutral genetic losses in medulloblastoma and demonstrates that combined assessment of copy number aberrations and LOH will be necessary to accurately determine the contribution of chromosomal defects to tumor development. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat. © 2005 Wiley‐Liss, Inc.
Visualizing levels of osteoblast differentiation by a two‐color promoter‐GFP strategy: Type I collagen‐GFPcyan and osteocalcin‐GFPtpz
Authors: Bilic‐Curcic I. , Kronenberg M. , Jiang X. , Bellizzi J. , Mina M. , Marijanovic I. , Gardiner E.M. , Rowe D.W.
Published: September 2005

A 3.9 kb DNA fragment of human osteocalcin promoter and 3.6 kb DNA fragment of the rat collagen type1a1 promoter linked with visually distinguishable GFP isomers, topaz and cyan, were used for multiplex analysis of osteoblast lineage progression. Three patterns of dual transgene expression can be appreciated in primary bone cell cultures derived from the transgenic mice and by histology of their corresponding bones. Our data support the interpretation that strong pOBCol3.6GFPcyan alone is found in newly formed osteoblasts, while strong pOBCol3.6GFPcyan and hOC‐GFPtpz are present in osteoblasts actively making a new matrix. Osteoblasts expressing strong hOC‐GFPtpz and weak pOBCol3.6GFPcyan are also present and may or may not be producing mineralized matrix. This multiplex approach reveals the heterogeneity within the mature osteoblast population that cannot be appreciated by current histological methods. It should be useful to identify and isolate populations of cells within an osteoblast lineage as they progress through stages of differentiation. genesis 43:87–98, 2005. © 2005 Wiley‐Liss, Inc.
Why worry about awareness in choice problems? Econometric analysis of screening for cervical cancer
Authors: Belkar Rochelle , Fiebig Denzil G. , Haas Marion , Viney Rosalie
Published: September 2005

The decision to undertake a screening test is conditional upon awareness of screening. From an econometric perspective there is a potential selection problem, if no distinction is made between aware and unaware non‐screeners. This paper explores this problem through analysis of the determinants of cervical screening in Australia. Cervical cancer is one of the most preventable and curable forms of cancer. Since 1991 there has been a concerted effort in Australia to recommend and encourage women to have Pap smears every two years. The success of this program can be partly gauged by exploring the determinants of screening for cervical cancer. Using unit record data from the 1995 National Health Survey, an econometric model is developed for whether women have ever screened or not. A proportion of women in the sample contend that they have never heard of a Pap test. The analysis characterizes this group of women and accounts for their presence in the modelling. The paper demonstrates failing to model awareness can result in inconsistent parameter estimates even when the degree of censoring in the sample is relatively small. Copyright © 2005 John Wiley & Sons, Ltd.
Smoke‐free laws and bar revenues in California – the last call
Authors: Cowling David W. , Bond Philip
Published: September 2005

California was the first state to implement smoke‐free restaurant and bar laws, in 1995 and 1998, respectively. We analyze how these laws affected the distribution of revenues between bars and restaurants. Critics of smoke‐free bar laws have often claimed that a prohibition on smoking reduces bar revenues. Similar claims are made for the effects of smoke‐free restaurant laws. Such claims implicitly assume that a smoke‐free law reduces expenditures by smokers by more than it increases expenditures by non‐smokers. Using tax revenue data from 1990 to 2002, our analysis suggests that the actual effect is just the opposite: the 1995 smoke‐free restaurant law is associated with anincreasein restaurant revenues, while the 1998 smoke‐free bar law is associated with an increase in bar revenues. Copyright © 2005 John Wiley & Sons, Ltd.
National road casualties and economic development
Authors: Bishai David , Quresh Asma , James Prashant , Ghaffar Abdul
Published: September 2005

Objective: This paper explores why traffic fatalities increase with GDP per capita in lower income countries and decrease with GDP per capita in wealthy countries.

Methods: Data from 41 countries for the period 1992–1996 were obtained on road transport crashes, injuries, and fatalities as well as numbers of vehicles, kilometers of roadway, oil consumption, population, and GDP. Fixed effects regression was used to control for unobservable heterogeneity among countries.

Results: A 10% increase in GDP in a lower income country (GDP/Capita <1600) is expected to raise the number of crashes by 7.9%, the number of traffic injuries by 4.7%, and the number of deaths by 3.1% through a mechanism that is independent of population size, vehicle counts, oil use, and roadway availability. Increases in GDP in richer countries appear to reduce the number of traffic deaths, but do not reduce the number of crashes or injuries, all else equal. Greater petrol use and alcohol use are related to more traffic fatalities in rich countries, all else equal.

Conclusion: In lower income countries a rise in traffic‐related crashes, injuries, and deaths accompanies economic growth. At a threshold of around $1500–$8000 per capita economic growth no longer leads to additional traffic deaths, although crashes and traffic injuries continue to increase with growth. The negative association between GDP and traffic deaths in rich countries may be mediated by lower injury severity and post‐injury ambulance transport and medical care. Copyright © 2005 John Wiley & Sons, Ltd.
Efficient allocation of resources to prevent HIV infection among injection drug users: the Prevention Point Philadelphia (PPP) needle exchange program
Authors: Harris Zoë K.
Published: September 2005

The objective of this study is to determine the allocation of resources within a multi‐site needle exchange program (NEP) that achieves the largest possible reduction in new HIV infections at minimum cost. We present a model that relates the number of injection drug user (IDU) clients and the number of syringes exchanged per client to both the costs of the NEP and the expected reduction in HIV infections per unit time. We show that cost‐effective allocation within a multi‐site NEP requires that sites be located where the density of IDUs is highest, and that the number of syringes exchanged per client be equal across sites. We apply these optimal allocation rules to a specific multi‐site needle exchange program, Prevention Point Philadelphia (PPP). This NEP, we find, needs to add 2 or 3 new sites in neighborhoods with the highest density of IDU AIDS cases, and to increase its total IDU client base by about 28%, from approximately 6400 to 8200 IDU clients. The case‐study NEP also needs to increase its hours of operation at two existing sites, where the number of needles distributed per client is currently sub‐optimal, by 50%. At the optimal allocation, the estimated cost per case of HIV averted would be $2800 (range $2300–$4200). Such a favorable cost‐effectiveness ratio derives primarily from PPP's low marginal costs per distributed needle. Copyright © 2005 John Wiley & Sons, Ltd.
Theta rhythm of navigation: Link between path integration and landmark navigation, episodic and semantic memory
Authors: Buzsáki György
Published: September 2005

Five key topics have been reverberating in hippocampal‐entorhinal cortex (EC) research over the past five decades: episodic and semantic memory, path integration (“dead reckoning”) and landmark (“map”) navigation, and theta oscillation. We suggest that the systematic relations between single cell discharge and the activity of neuronal ensembles reflected in local field theta oscillations provide a useful insight into the relationship among these terms. In rats trained to run in direction‐guided (1‐dimensional) tasks, hippocampal cell assemblies discharge sequentially, with different assemblies active on opposite runs, i.e., place cells are unidirectional. Such tasks do not require map representation and are formally identical with learning sequentially occurring items in an episode. Hebbian plasticity, acting within the temporal window of the theta cycle, converts the travel distances into synaptic strengths between the sequentially activated and unidirectionally connected assemblies. In contrast, place representations by hippocampal neurons in 2‐dimensional environments are typically omnidirectional, characteristic of a map. Generation of a map requires exploration, essentially a dead reckoning behavior. We suggest that omnidirectional navigation through the same places (junctions) during exploration gives rise to omnidirectional place cells and, consequently, maps free of temporal context. Analogously, multiple crossings of common junction(s) of episodes convert the common junction(s) into context‐free or semantic memory. Theta oscillation can hence be conceived as the navigation rhythm through both physical and mnemonic space, facilitating the formation of maps and episodic/semantic memories. © 2005 Wiley‐Liss, Inc.
Activation of peroxisome proliferator‐activated receptor‐γ by troglitazone (TGZ) inhibits human lung cell growth
Authors: Li Mingyue , Lee Tak W. , Mok Tony S.K. , Warner Timothy D. , Yim Anthony P.C. , Chen George G.
Published: September 2005

Peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) is a member of the nuclear hormone receptor superfamily of ligand‐activated transcription factors and a crucial regulator of cellular differentiation. PPAR‐γ ligands have been demonstrated to inhibit growth of several cancer cells. In this study, two human lung cancer cells (NCI‐H23 and CRL‐2066) and one human lung normal cell (CRL‐202) were used for the experiments. The results showed that in consistence with the loss of viability, troglitazone (TGZ) induced apoptosis of CRL‐2066 and NCI‐H23 cells but not CCL‐202 cells. TGZ upregulated PPAR‐γ expression in all the three lung cell lines, especially in the cancer cells. In association of the time‐dependent inhibition of the cell proliferation, TGZ downregulated the expression of Bcl‐w and Bcl‐2 but activated extracellular signal‐regulated kinase (ERK)1/2 and p38, suggesting that the growth‐inhibitory effect of TGZ is associated with the reduction of Bcl‐w and Bcl‐2 and the increase of ERK1/2 and p38 activation. SAPK/JNK activation assay showed a decreased activity in all the three cell lines tested after TGZ treatment. It was also demonstrated that TGZ could activate PPAR‐γ transcriptionally. We conclude that TGZ inhibits growth of human lung cancer cells via the induction of apoptosis and the inhibition of cell growth, at least in part, in a PPAR‐γ‐relevant manner. The mechanism of TGZ is associated with the activation of ERK and p38, the reduction of SAPK/JNK activity, and the alteration of Bcl‐w and Bcl‐2. © 2005 Wiley‐Liss, Inc.
Mitochondrial mechanism of oxidative stress and systemic hypertension in hyperhomocysteinemia
Authors: Tyagi Neetu , Moshal Karni S. , Ovechkin Alexander V. , Rodriguez Walter , Steed Mesia , Henderson Brooke , Roberts Andrew M. , Joshua Irving G. , Tyagi Suresh C.
Published: September 2005

Formation of homocysteine (Hcy) is the constitutive process of gene methylation. Hcy is primarily synthesized by de‐methylation of methionine, in which s‐adenosyl‐methionine (SAM) is converted to s‐adenosyl‐homocysteine (SAH) by methyltransferase (MT). SAH is then hydrolyzed to Hcy and adenosine by SAH‐hydrolase (SAHH). The accumulation of Hcy leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased. In this process, Ca2+‐dependent mitochondrial nitric oxide synthase (mtNOS) and calpain are induced which lead to cytoskeletal de‐arrangement and cellular remodeling. This process generates peroxinitrite and nitrotyrosine in contractile proteins which causes vascular dysfunction. Chronic exposure to Hcy instigates endothelial and vascular dysfunction and increases vascular resistance causing systemic hypertension. To compensate, the heart increases its load which creates adverse cardiac remodeling in which the elastin/collagen ratio is reduced, causing cardiac stiffness and diastolic heart failure in hyperhomocysteinemia. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.
Regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper transcription factors
Authors: Sarraj Jude Al , Vinson Charles , Han Jiahuai , Thiel Gerald
Published: September 2005

Tetrahydrobiopterin is an essential cofactor for the phenylalanine, tyrosine and tryptophan hydroxylases, and the family of nitric oxide synthases. The initial and rate‐limiting enzyme in the biosynthesis of tetrahydrobiopterin is GTP cyclohydrolase I. The proximal promoter of the human GTP cyclohydrolase I gene contains the sequence motif 5′‐TGACGCGA‐3′, resembling a cAMP response element (CRE). The objective of this study was to analyze the regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper (bZIP) transcription factors. A constitutively active mutant of the cAMP response element binding (CREB) protein strongly stimulated GTP cyclohydrolase I promoter activity, indicating that the CRE in the context of the GTP cyclohydrolase I gene is functional. Likewise, GTP cyclohydrolase I promoter/luciferase gene transcription was stimulated following nuclear expression of the catalytic subunit of cAMP‐dependent protein kinase. Constitutively active mutants of activating transcription factor 2 (ATF2) and c‐Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. The fact that stress‐activated protein kinases target the GTP cyclohydrolase I gene was corroborated by expression experiments involving p38 and MEKK1 protein kinases. We conclude that signaling pathways involving either the cAMP‐dependent protein kinase or stress‐activated protein kinases converge to the GTP cyclohydrolase I gene. Hence, enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal‐responsive transcription factors CREB, c‐Jun, and ATF2. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.