bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunomodulatory oligonucleotides as novel therapy for breast cancer: pharmacokinetics,in vitroandin vivoanticancer activity, and potentiation of antibody therapy
Authors: Wang Hui , Rayburn Elizabeth R. , Wang Wei , Kandimalla Ekambar R. , Agrawal Sudhir , Zhang Ruiwen
Published: August 2006

Oligonucleotides containing CpG motifs and immunomodulatory oligonucleotides (IMO) containing a synthetic immunostimulatory dinucleotide and a novel DNA structure have been suggested to have potential for the treatment of various human diseases. In the present study, a newly designed IMO was evaluated in several models of human (MCF-7 and BT474 xenograft) and murine (4T1 syngeneic) breast cancer. Pharmacokinetics studies of the IMO administered by s.c., i.v., p.o., or i.p. routes were also accomplished. The IMO was widely distributed to various tissues by all four routes, with s.c. administration yielding the highest concentration in tumor tissue. The IMO inhibited the growth of tumors in all three models of breast cancer, with the lowest dose of the IMO inhibiting MCF-7 xenograft tumor growth by >40%. Combining the IMO with the anticancer antibody, Herceptin, led to potent antitumor effects, resulting in >96% inhibition of tumor growth. The IMO also exerted in vitro antitumor activity, as measured by cell growth, apoptosis, and proliferation assays in the presence of Lipofectin. This is the first report of the pharmacokinetics of this agent in normal and tumor-bearing mice. Based on the present results, we believe that the IMO is a good candidate for clinical development for breast cancer therapy used either alone or in combination with conventional cancer therapeutic agents. [Mol Cancer Ther 2006;5(8):2106–14]
Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index
Authors: Wood Patricia A. , Du-Quiton Jovelyn , You Shaojin , Hrushesky William J.M.
Published: August 2006

Dysregulated cellular proliferation is a characteristic property of cancer. We show that, despite this fact, cancers maintain high amplitude, circadian rhythms in their growth, DNA synthesis, and mitosis. These patterns are accompanied by the daily traverse of BMAL-1 protein between the cytoplasm, where it is produced, and nucleus, where it influences timing of cancer cell proliferation. This core clock gene product gates cancer cell proliferation by coordinating clock-controlled proteins, thymidylate synthase [thymidylate synthase activity (TSA) cell DNA replication], WEE-1 (cell mitosis), and vascular endothelial growth factor (growth). 5-Fluorouracil (5-FU)–induced host bone marrow and gut toxicity and tumor shrinkage following administration at six equispaced times of day allowed determination of circadian relationships among tumor growth, relevant clock, and clock-controlled proteins and dependence of 5-FU target availability (TSA) in normal and cancer tissues and resultant 5-FU toxic-therapeutic index. The time of day (hours after lights on) of low TSA in each tissue and tumor is respectively associated with greatest toxicity to that tissue and greatest tumor shrinkage. 5-FU treatment near daily awakening results in least damage to bone marrow and gut, greatest antitumor effect, and best survival. This time of day is associated with maximum tumor nuclear BMAL-1 and total cell WEE-1 protein. The described chain of events, for the first time, links cancer cell clock proteins, cancer cell DNA synthesis, proliferation, TSA, and 5-FU toxic-therapeutic index, explaining the dependence of cancer outcome on circadian timing of 5-FU. [Mol Cancer Ther 2006;5(8):2023–33]
The analysis of doxorubicin resistance in human breast cancer cells using antibody microarrays
Authors: Smith Laura , Watson Mark B. , O'Kane Sara L. , Drew Philip J. , Lind Michael J. , Cawkwell Lynn
Published: August 2006

Doxorubicin is considered to be the most effective agent in the treatment of breast cancer patients. Unfortunately, resistance to this agent is common, representing a major obstacle to successful treatment. The identification of novel biomarkers that are able to predict treatment response may allow therapy to be tailored to individual patients. Antibody microarrays provide a powerful new technique, enabling the global comparative analysis of many proteins simultaneously. This technology may identify a panel of proteins to discriminate between drug-resistant and drug-sensitive samples. The Panorama Cell Signaling Antibody Microarray was exploited to analyze the MDA-MB-231 breast cancer cell line and a novel derivative, which displays significant resistance to doxorubicin at clinically relevant concentrations. The microarray comprised 224 antibodies selected from a variety of pathways, including apoptotic and cell signaling pathways. A standard ≥2.0-fold cutoff value was used to determine differentially expressed proteins. A decrease in the expression of mitogen-activated protein kinase–activated monophosphotyrosine (phosphorylated extracellular signal-regulated kinase; 2.8-fold decrease), cyclin D2 (2.5-fold decrease), cytokeratin 18 (2.5-fold decrease), cyclin B1 (2.4-fold decrease), and heterogeneous nuclear ribonucleoprotein m3-m4 (2.0-fold decrease) was associated with doxorubicin resistance. Western blotting was exploited to confirm results from the antibody microarray experiment. These results suggest that antibody microarrays can be used to identify novel biomarkers and further validation may reveal mechanisms of chemotherapy resistance and identify potential therapeutic targets. [Mol Cancer Ther 2006;5(8):2115–20]
Invariant Grids: Method of Complexity Reduction in Reaction Networks
Authors: Gorban Alexander , Karlin Iliya , Zinovyev Andrei
Published: August 2006

Complexity in the description of big chemical reaction networks has both structural (number of species and reactions) and temporal (very different reaction rates) aspects. A consistent way to make model reduction is to construct the invariant manifold which describes the asymptotic system behaviour. In this paper we present a discrete analog of this object: an invariant grid. The invariant grid is introduced independently from the invariant manifold notion and can serve to represent the dynamic system behaviour as well as to approximate the invariant manifold after refinement. The method is designed for pure dissipative systems and widely uses their thermodynamic properties but allows also generalizations for some classes of open systems. The method is illustrated by two examples: the simplest catalytic reaction (Michaelis-Menten mechanism) and the hydrogen oxidation.
Complex Qualitative Models in Biology: A New Approach
Authors: Veber P. , Le Borgne M. , Siegel A. , Lagarrigue S. , Radulescu O.
Published: August 2006

We advocate the use of qualitative models in the analysis of large biological systems. We show how qualitative models are linked to theoretical differential models and practical graphical models of biological networks. A new technique for analyzing qualitative models is introduced, which is based on an efficient representation of qualitative systems. As shown through several applications, this representation is a relevant tool for the understanding and testing of large and complex biological networks.
On the Dynamics of Communication and Cooperation in Artificial Societies
Authors: Eiben A.E. , Schut M.C. , Vink N.
Published: August 2006

This paper compares two fundamental building blocks of complex interaction-based systems: communication and cooperation. We investigate the effectiveness of communication in an environment where the need for cooperation is scalable as well as the available resources. Several aspects of communication are considered: firstly, we compare a centralized with a decentralized communication protocol; secondly, we compare a population that always communicates with one where the entities can (evolutionary) learn to communicate. This work is part of a larger project whose main goal is to investigate the emergence of cooperation and communication in response of (scalable) environmental challenges. Our application context is an artificial society, i.e., a simulation of a societal system that was inspired by the classical SUGARSCAPE that embodies a bottom-up approach to investigate complex effects that do not necessarily have complex causes.
A Theory-Based Dynamical Model of Innovation Processes
Authors: Lane David , Serra Roberto , Villani Marco , Ansaloni Luca
Published: August 2006

We present an agent-based model of innovation processes, based upon a theory of innovation by Lane and Maxfield. The theory inspires and constrains the features of the model, thus reducing the embarasse de richessethat is one of the major methodological problems of agent-based modelling. Artefacts are produced by agents using recipes; the basic dynamics, absent innovation, is one of production and sales, where the external world supplies ‘raw materials’ and external demand. Depending upon the initial conditions, self-sustaining cycles of production and exchange can emerge among the agents. Innovation – that is, the generation of new recipes, in particular desired directions, called ‘goals’ – results in substantial modification of the system dynamics. Two innovation regimes are introduced: a ‘lonely’ mode, in which each agent tries to introduce new products by itself, and a ‘relational’ mode, in which two agents can improve their reciprocal knowledge and can decide to try to jointly develop a new artefact.
Self-Organized Patterns in Production Networks
Authors: Weisbuch Gérard
Published: August 2006

Economic firms interact via supplier/customer interactions. These interactions define a production network. We study here the dynamics of these networks under very simple assumptions and show that they exhibit noticeable patterns of wealth and production. The main dynamical properties of this time/space organization are studied and shown to be shared by a wide class of models.
An Overview of Autonomic Regulation of Parotid Gland Activity: Influence of Orchiectomy
Authors: Busch Lucila , Sterin-Borda Leonor , Borda Enri
Published: August 2006

The parotid gland participates in the digestive process by providing fluid, electrolytes and enzymes that facilitate the onset of digestion. Neurotransmitters, hormones and biologically active peptides regulate its activity. The autonomic system is the main regulatory mechanism of the gland. Sympathetic stimulation induces amylase release through β1-receptor activation and few fluid secretion by α1-receptor activation. The parasympathetic system controls basal activity of the gland acting on M1 and M3 muscarinic acetylcholine receptors and induces the secretion of fluid saliva rich in electrolytes through the modulation of ion channels and the Na+-K+-ATPase activity. In addition, its activation induces amylase release. The mechanisms involved in amylase secretion by isoproterenol and carbachol, as well as the mechanism of the cholinergic regulation of Na+-K+-ATPase activity and the changes observed after orchiectomy, are the scope of this review.
Mesenchymal Progenitor Cells Communicate via Alpha and Beta Integrins with a Three-Dimensional Collagen Type I Matrix
Authors: Heckmann Leslie , Fiedler Jörg , Mattes Thomas , Brenner Rolf E.
Published: August 2006

Background/Aims: The aim of our study was to investigate interactions of mesenchymal progenitor cells (MPCs) with collagen matrices. Methods: Human bone-marrow-derived MPCs were cultivated in collagen type I gels with and without inhibition of β1-integrin by a specific antibody. Collagen gel contraction, cell morphology, expression of integrin subunits and several genes related to matrix synthesis and turnover as well as MPC differentiation were analyzed over 14 days. Results: Human MPCs markedly contracted free-floating collagen gels. Contraction was nearly completely inhibited by blocking β1-integrin. Cellular morphology was elongated in the absence and mostly round in the presence of the antibody. Expression of integrin α1, α2 and β1 subunits showed several changes partly dependent on β1-integrin blocking. Expression of matrix metalloproteinase-1 was elevated irrespective of β1-integrin blocking and tenascin-C was subsequently induced during gel contraction. Spontaneous induction of chondrogenic, osteogenic or adipogenic differentiation was observed neither in the presence nor in the absence of the β1-integrin antibody. Conclusion: Our results indicate that the interaction of human MPCs with fibrillar collagen type I involves β1- and α-integrin subunits and induces changes in gene expression related to extracellular matrix synthesis and turnover but not differentiation to the chondrogenic, osteogenic or adipogenic phenotype.
Organization and Function of the Collagen Fiber System in the Human Temporomandibular Joint Disk and Its Attachments
Authors: Scapino Robert P. , Obrez Ales , Greising Daniel
Published: August 2006

The collagen fiber organization in the anterior band (AB), intermediate zone (IZ) and posterior band (PB) of the disk of the human jaw joint disk and in its attachments was studied under the polarizing microscope. Observations were made on serially sectioned joints (n = 6) and three sets of disk samples sectioned along mutually perpendicular planes (n = 21). The collagen fiber bundles in all disk regions branch and join or are decussated with other bundles. The fibers of the IZ were oriented generally parallel to the disk surfaces. Most of these fibers extend into the AB and PB where they either join with transverse or vertically oriented fiber groups or pass through the bands into the disk attachments. The lateral branching/decussation angles of fibers in the IZ and adjacent regions of the AB and PB were measured in the central region of four disks. The mean angle for all regions was 28 ± 13°. The mean angles in the region transitional between the IZ and AB and in the anterior region of the IZ were significantly greater than those in the posterior part of the IZ (p = 0.001 and 0.050 for the two comparisons). The large caliber, vertically oriented fibers in the AB, IZ and PB were counted in nine specimens. Disk dimensions were also measured in these specimens. The vertically and transversely oriented bundles were more frequent in the band regions. The number of vertically oriented fiber bundles varied within and between the disk bands. Vertical fiber number in the AB was greater laterally than medially (p = 0.04). In the PB the fiber number was greater than in either the AB or IZ (p = 0.000 for both comparisons) and within the PB itself the fiber number was greater in its thicker, medial half (p = 0.014). The fiber number in the AB and IZ was not different. The thickness of the AB, IZ and PB and disk length was measured in sections located laterally, centrally and medially. No difference in disk length was found across these planes. Statistically significant differences were found in regional disk thickness. In all of the mediolateral planes, the AB and PB were thicker than the IZ and the PB was thicker than the AB (p = 0.000 for all comparisons). The IZ was thicker medially than laterally (p = 0.034). The PB was thicker centrally and medially than laterally (p = 0.002 and 0.001, respectively). PB thickness in its central and medial regions was not different. The findings, combined with other evidence, suggest that the fiber system of the disk serves a stress distribution function and that within the AB and PB, the regions containing the greatest number of vertical fibers may also be the sites of greatest compressive stress during jaw function.
Patterns of Frontal Lobe Atrophy in Frontotemporal Dementia: A Volumetric MRI Study
Authors: Perry Richard J. , Graham Andrew , Williams Guy , Rosen Howard , Erzinçlioglu Sharon , Weiner Mike , Miller Bruce , Hodges John
Published: August 2006

Objectives: Frontotemporal dementia (FTD), the second commonest degenerative cause of dementia under the age of 65, often presents with striking changes in behaviour and personality in association with frontal lobe atrophy. Based on the behavioural changes observed in FTD, it is commonly assumed that the orbitofrontal cortex is the earliest and most severely affected frontal sub-region. However, evidence to support this assumption has to date been largely lacking. Methods: Using a novel volumetric MRI method, we performed a detailed volumetric analysis of six frontal regions in 12 subjects with the frontal or behavioural variant of FTD (fvFTD) and 12 age-, education- and sex-matched normal controls. The regions studied were: the orbitofrontal and insula regions (representing the orbitobasal cortex); the inferior and middle frontal regions (representing the dorsolateral prefrontal areas); and the superior frontal and anterior cingulate regions (representing the medial prefrontal areas). Results: As a group, the fvFTD patients showed atrophy involving all six regions. We then segregated the 12 patients into three sub-groups according to their overall degree of atrophy. In the mildest group (n = 3) all regions fell within 2 standard deviations of normal. In the intermediate group (n = 6) only the orbitofrontal region (bilaterally) fell clearly outside the control range (>2 z scores below the control mean); the next most atrophic region in this group was the right insular region. The severe group (n = 3) had generalized atrophy throughout the frontal regions measured. Conclusions: In conclusion, patients with the earliest stages of fvFTD show no significant loss of volume in any frontal lobe area as measured by a novel MRI volumetric technique. When volume loss does occur, changes are initially seen in the orbitofrontal cortex before atrophy becomes more widespread. These results provide some partial support for the often-quoted assumption that the orbitofrontal cortex is the locus of earliest pathology in fvFTD, although these findings must be regarded as preliminary in view of the small numbers of patients involved.
Programmed Cell Death Induced by Japanese Encephalitis Virus YL Vaccine Strain or Its Recombinant Envelope Protein in Varied Cultured Cells
Authors: Chen S.-O. , Chang T.-J. , Stone G. , Chen C.-H. , Liu J.-J.
Published: August 2006

Objective: The Japanese encephalitis virus YL vaccine strain (JEV-YL) was investigated as regards its organ tropism and the role of recombinant envelope glycoprotein in the induction of apoptosis was explored. Methods: Threevaried cell lines (HepG2, Vero and C6) were infected with JEV-YL or transfected with eukaryotic expression plasmids (pcE, pcF1R2, pcF1R1 and pcF2R2) which contain different parts of the envelope gene and phenotypic properties were examined by flow cytometry and DNA fragmentation analysis. Results: After JEV-YL infection, smaller plaque was produced on HepG2 cells than on Vero cells, whereas no cytopathic effect was observed on C6 cells; moreover, by apoptosis and DNA fragmentation assays, the hallmark cytopathic effects were detected in HepG2 and Vero cells but not in C6 cells. Furthermore, cells used in our study transfected with recombinant core plasmid, pcE, which include full-length E gene but the deleted forms (pcF1R2, pcF1R1 and pcF2R2) did not have similar results as JEV-YLs. Conclusions: The JEV-YL vaccine strain had changed cell tropism to liver cells different from other virulent strains which have neural tropism, and in this study we proved that the transient-expressed entire E protein of JEV-YL could induce apoptosis and the mutations of E protein may change the organ tropism of JEV-YL.
Genetic Disorders in the Growth Hormone – Insulin-Like Growth Factor-I Axis
Authors: Walenkamp M.J.E. , Wit J.M.
Published: August 2006

In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083–8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH–insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.
Lipopolysaccharide and TNF-α Produce Very Similar Changes in Gene Expression in Human Endothelial Cells
Authors: Magder S. , Neculcea J. , Neculcea V. , Sladek R.
Published: August 2006

Intracellular signaling pathways regulated by Toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNF-α) both activate NFĸB. This suggests that lipopolysaccharide (LPS) and TNF-α should alter transcription of a common set of genes. We tested this hypothesis by treating first passage human umbilical endothelial cells (HUVEC) for 6 h with LPS (50 ng/ml + 1 µg/ml CD14) or TNF-α (10 ng/ml) and analyzing changes in gene expression by microarray analysis (Affymetrix GeneChips). LPS and TNF-α increased expression of 191 common genes and decreased expression of 102 genes. Regulated transcripts encoded for a large number of chemokines, adhesion molecules, procoagulant factors, and molecules that affect cell integrity. Based on the microarray analysis and subsequent confirmation of specific genes by Northern analysis, all 203 genes altered by LPS were altered by TNF-α. An additional 17 genes were induced only by TNF-α and the expression of 46 was reduced. There were, however, some differences in the kinetics of changes. We also showed that endogenous CD14 was present on these early passage cells and exogenous CD14 was not necessary for most of the LPS response. An autocrine effect from LPS induced expression of TNF-α also was ruled out by blocking TNF-α with monoclonal antibodies. In conclusion, LPS induces a robust alteration in gene expression in HUVEC that is very similar to that induced by TNF-a. This LPS effect on endothelium could play an important role in the innate immune response.
Adenoviral-Mediated Gene Transfer of Nitric Oxide Synthase Isoforms and Vascular Cell Proliferation
Authors: Cooney Ronan , Hynes Sean O. , Duffy Aoife M. , Sharif Faisal , O’Brien Timothy
Published: August 2006

Objective: Many vascular diseases are associated with reduced nitric oxide (NO) bioavailability. Nitric oxide synthase (NOS) gene therapy to the vasculature is a possible treatment for vascular disease as a means of increasing NO bioavailability, and this may be achieved using any of the NOS isoforms. The aim of our study was to compare the effects of adenoviral-mediated overexpression of the most commonly used NOS isoforms eNOS and iNOS on vascular cell proliferation. Methods: Human coronary artery smooth muscle cells (HCSMCs) and human umbilical vein endothelial cells (HUVECs) were transduced with adenoviral vectors encoding eNOS or iNOS at a multiplicity of infection of 100. Control cells were exposed to AdNull (empty vector) or diluent alone. Transgene expression was sought by Western blotting. The Greiss assay was used to measure nitrite levels. Cell proliferation was assessed by cell counting on days 0, 3 and 6. Apoptosis was sought using FACS analysis. Angiogenesis was measured using a commercially available in vitro kit. Results: Expression of both isoforms was detected in transduced cells by Western blot at all three time points. NOS transduction resulted in increased nitrite levels with higher levels seen in iNOS- compared to eNOS-transduced cells. Cell proliferation was diminished in AdeNOS- and AdiNOS-transduced cells compared with non-transduced cells on days 3 and 6 in both HCSMCs and HUVECs. Apoptosis was not detected in either cell line with either of the isoforms at any timepoint studied. Both eNOS and iNOS gene transfer caused a reduction in angiogenesis. Conclusions: NOS gene transfer to both endothelial and vascular smooth muscle cells is antiproliferative and antiangiogenic. The biological effect is identical with both isoforms and there is no evidence to support a differential effect on endothelial and vascular smooth muscle cell biology.
The Role of the Supramammillary Commissure in MR Localization of the Subthalamic Nucleus
Authors: Lee Charles , Young Byron , Sanders Michael F.
Published: August 2006

Purpose: We have discovered a method for localization of the subthalamic nucleus (STN) utilizing the supramammillary commissure (SMC) as reference point. It is our purpose to present our experience and compare our methods with others. Materials and Methods: Sixteen patients targeted for bilateral DBS for 32 total STN targets were studied by 1 mm MP-RAGE images with coronal T2W images. A modified red nucleus and mustache method was applied. The predicted target points were then confirmed with electronic calipers measuring the differences in methods. Results: Modified red nucleus method using Surgiplan®, and EBAL® and BAGM® electronic brain map atlas matched the target loci of 12 mm, –3 mm, –4 mm on an X-, Y-, and Z-coordinate system with zero at the mid-commissural point. From the coronal view Y is fixed at –3 mm. The mustache method was in error with values of X-axis at 14.25 (± 1.41 SD) (p = 0.69), and of Z-axis at –5.0 (± 1.60 SD) (p = 0.55). Three-fourths had moderate to marked ventricular enlargement of the III, but only 3 had enlargement of the frontal horns. Conclusion: The mustache method erred in the X-axis because the thalamocaudate groove was located lateral to the target point of the STN, and in the Z-axis because of varying thicknesses of the SMC. The top of the SMC is directly lateral from the STN target by 12 mm from the anterior and posterior commissures line. The SMC being a recognizable structure with constant relation to the STN should be the target structure.
The Beneficial Effect of Resveratrol on Rat Bladder Contractility and Oxidant Damage following Ischemia/Reperfusion
Authors: Toklu Hale , Alican Inci , Ercan Feriha , Sener Goksel
Published: August 2006

Objective: The present study aimed to investigate the possible beneficial activities of resveratrol (3,5,4′-trans-trihydroxystilbene), a natural phytoalexin, on contractility and oxidant damage after ischemia/reperfusion (I/R) of the rat urinary bladder. Materials and Methods: The abdominal aorta of Sprague-Dawley rats was occluded for 60 min to induce ischemia and then allowed 60 min of reperfusion. Resveratrol (10 mg/kg) or saline was administered intraperitoneally 15 min before ischemia and immediately before reperfusion. In the sham-operated group, the abdominal aorta was left intact and the animals were treated with resveratrol or saline. The bladder samples were either used for functional studies or stored for biochemical assays. Results: In the I/R group, the isometric contractile responses of the bladder strips to carbachol (CCh; 10–8–10–4 mol/l) were lower than those of the control group and were reversed by treatment with resveratrol. Histological evaluation revealed loss of urothelial cells, detachment and loss of urothelial cells and local ulcerated areas and severe inflammatory cell infiltration in the untreated I/R group, and regeneration of luminal mucosa and a significant decrease in the density of the inflammatory cell population in the resveratrol-treated I/R group. Lipid peroxidation and the myeloperoxidase activity of the bladder tissues in the I/R group were higher than in the sham-operated group. Resveratrol treatment in the I/R group decreased these parameters compared with I/R alone. Similarly, the significant decrease in tissue glutathione level in the I/R group compared with controls was also prevented by resveratrol. Conclusion: Treatment with resveratrol almost completely reversed the low contractile responses of the rat urinary bladder to CCh and prevented oxidative tissue damage following I/R.
Self-Reported Fatigue Common among Optimally Treated HIV Patients: No Correlation with Cerebral FDG-PET Scanning Abnormalities
Authors: Andersen Åse B. , Law Ian , Ostrowski Sisse R. , Lebech Anne Mette , Høyer-Hansen Gunilla , Højgaard Liselotte , Gerstoft Jan , Ullum Henrik , Kjær Andreas
Published: August 2006

Objective: It was the aim of this study to determine the prevalence and severity of fatigue among optimally treated HIV patients and to investigate the potential association with systemic inflammation and abnormalities of the distribution of cerebral glucose metabolism. Methods: A cohort of HIV patients (n = 95), known to be HIV positive for 5 years, on anti-retroviral therapy for a minimum of 3 years and with CD4 counts above 0.2 × 109 cells/l, completed a validated fatigue inventory, and plasma was analysed for pro-inflammatory markers including tumour necrosis factor-α, interleukin 6 and soluble urokinase receptor (suPAR) levels. The distribution of the regional cerebral metabolic rate of glucose was measured in a sub-group of patients suffering from severe fatigue (n = 9) and a group with no fatigue (n = 7) using fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Results: Fifteen percent suffered from severe fatigue, but no association with pro-inflammatory markers was found. About 50% of the FDG-PET-scanned patients showed minor abnormalities in the relative cerebral metabolic rate of glucose. These abnormalities were not associated with fatigue but tended to correlate with a short HIV history (p = 0.058), a low CD4 nadir (p = 0.082) and elevated tumour necrosis factor-α levels (p = 0.074). Conclusion: Fatigue is common among optimally treated HIV patients. FDG-PET-described signs of imminent neurodegeneration among HIV patients who had a low CD4 nadir may illustrate an aspect of HIV neuropathogenicity.
Relation of Plasma Thyroid-Stimulating Hormone Levels to Vascular Lesions and Atrophy of the Brain in the Elderly
Authors: Reitz Christiane , Kretzschmar Konrad , Roesler Andreas , von Eckardstein Arnold , Berger Klaus
Published: August 2006

Context: Recent studies suggest that thyroid disease is associated with cardiovascular and peripheral vascular disease. However, little is known about the underlying pathophysiology and the relation with cerebrovascular disease or brain atrophy in the elderly. Objective: To determine if plasma thyroid-stimulating hormone (TSH) levels are associated with vascular brain changes and cortical atrophy in the elderly. Design: Community based, cross-sectional study. Participants and Setting: 268 participants of the Memory and Morbidity in Augsburg Elderly Study, 65–83 years of age and without contraindications for magnetic resonance imaging (MRI) of the brain. Main Outcome Measures: The presence of brain lesions and atrophy was determined using a standardized MRI protocol, an established rating scale and a single rater. Plasma TSH levels were assessed using standard laboratory methods. The association between plasma TSH levels and MRI findings was analyzed using logistic and linear regression models. Results: Higher TSH levels within the normal clinical range were significantly associated with severer cortical atrophy (p = 0.04) and a higher proportion of infarct-like vascular lesions (p = 0.005) in men. These associations were independent of potential confounders, including thyroid hormone therapy, in multivariable regression analysis. No association between plasma TSH levels and both MRI outcomes were observed in women. In addition, neither in men nor in women was an association between TSH levels and white-matter lesions found. Conclusions: Increasing TSH levels even within the normal clinical range are associated with severer brain atrophy and infarct-like vascular lesions in elderly men.
Relationship between 3-Month National Institutes of Health Stroke Scale Score and Dependence in Ischemic Stroke Patients
Authors: Johnston Karen C. , Wagner Douglas P.
Published: August 2006

Background: The National Institutes of Health Stroke Scale (NIHSS) provides a standardized measure of stroke severity and is frequently captured to assess 3-month outcome. Other outcome measures have been assessed for the relationship to dependence; a clinically relevant outcome. The relationship between NIHSS score and functional dependence is unknown. The purpose of this study was to assess the relationship between NIHSS score and accepted measures of dependence in surviving ischemic stroke patients. Methods: 3-month NIHSS scores were compared to residence and Glasgow Outcome Scale (GOS) scores at 3 months in the Randomized Trial of Tirilazad Mesylate in Patients with Acute Stroke (RANTTAS). For residence, patients who were in a nursing home, chronic hospital or substantially dependent on a caregiver were characterized as ‘dependent’. For GOS, a score of 3 (severely disabled) or 4 (vegetative) was characterized as ‘dependent’. The sensitivity, specificity and positive (PPV) and negative predictive values (NPV) for various NIHSS score cut points compared to dependence were calculated. Logistic regression analysis was used to assess the association between the NIHSS score and dependence. Results: In 385 subjects from the RANTTAS, an NIHSS score cut point of ≧15 resulted in 100% of subjects identified as being dependent by residence, sensitivity = 24%, specificity = 100%, PPV = 100% and NPV = 80%. Using GOS as the measure of dependence, the results were almost identical. NIHSS was strongly related to dependence with an area under the receiver operating characteristic curve (AUC) = 0.86 for residence and an AUC = 0.94 for GOS. Conclusions: 3-month NIHSS score is strongly associated with dependence. An NIHSS score of ≧15 at 3 months may be a reasonable estimate of subjects who are highly likely to be dependent at 3 months. These data require validation in an independent data set.
Apolipoprotein E ε4 Allele Is Associated with Vascular Dementia
Authors: Baum Larry , Lam Linda C.W. , Kwok Timothy , Lee Jenny , Chiu Helen F.K. , Mok Vincent C.T. , Wong Adrian , Chen Xiangyan , Cheung Wing Sze , Pang Chi Pui , Ma Suk Ling , Tang Nelson L.S. , Wong Ka Sing , Ng Ho Keung
Published: August 2006

Background/Aims: The apolipoprotein E (ApoE) exon 4 polymorphism has been associated with vascular dementia (VaD) risk. Since not all studies confirm this finding, we explored this association in a case-control study. Methods: We genotyped ApoE in 144 VaD patients and 251 controls. Results: VaD patients were more likely than controls to have ApoE Ε3/Ε4 or Ε4/Ε4 genotypes: 23.6% versus 15.1%, odds ratio (OR) = 1.7, p = 0.036. This association remained significant after adjustment for age, sex, hypertension and diabetes by multiple logistic regression: OR = 1.9, p = 0.030. The association of Ε3/Ε4 or Ε4/Ε4 genotypes with VaD was strong among people with hypertension (OR = 2.9, p = 0.007) or diabetes (OR = 6.5, p = 0.011). The association was absent among people without hypertension (OR = 1.1, p = 0.79) or diabetes (OR = 1.3, p = 0.43). Conclusion: This interaction with hypertension and diabetes should be examined in other studies to confirm or refute this observation.
Urokinase Induces Matrix Metalloproteinase-9/Gelatinase B Expression in THP-1 Monocytes via ERK1/2 and Cytosolic Phospholipase A2 Activation and Eicosanoid Production
Authors: Menshikov Mikhail , Torosyan Narine , Elizarova Eugenia , Plakida Karina , Vorotnikov Alexander , Parfyonova Yelena , Stepanova Victoria , Bobik Alex , Berk Bradford , Tkachuk Vsevolod
Published: August 2006

Objective: Urokinase-type plasminogen activator (uPA) regulates cell migration and invasion by pericellular proteolysis and signal transduction events. We characterized the mechanisms by which uPA regulates matrix metalloproteinase-9 (MMP9) function in THP-1 monocytes. Methods and Results: In THP-1 monocytes, MMP9 production induced by urokinase was completely inhibited by the ERK1/2 inhibitor, PD98059, but not by the p38 mitogen-activated protein kinase inhibitor, SB202190. A dominant negative MEK1 adenovirus also blocked MMP9 expression. The effect of urokinase was completely suppressed by genistein and by herbimycin A indicating that tyrosine kinase(s) are required for MMP9 production. Bisindolylmaleimide, a protein kinase C (PKC) inhibitor, did not decrease MMP9 expression suggesting that PKC activation is not required. Key roles for cytosolic phospholipase A2 (PLA2) and eicosanoid production were shown by complete inhibition with methyl arachidonyl fluorophosphonate (an inhibitor of cytosolic PLA2), and indomethacin (a cyclooxygenase inhibitor), with no effect of monoalide, a secretory PLA2 inhibitor. uPA stimulated phosphorylation of cytosolic PLA2. Conclusions: Induction of MMP9 by uPA in THP-1 monocytes is via a pathway involving MEK1-ERK1/2-mediated activation of cytosolic PLA2 and eicosanoid generation. These data suggest important roles for eicosanoids in monocyte migration induced by uPA and MMP9.
Afferent Connections of the Optic Tectum in Lampreys: An Experimental Study
Authors: de Arriba María del Carmen , Pombal Manuel A.
Published: August 2006

Tectal afferents were studied in adult lampreys of three species (Ichthyomyzon unicuspis, Lampetra fluviatilis, and Petromyzon marinus) following unilateral BDA injections into the optic tectum (OT). In the secondary prosencephalon, neurons projecting to the OT were observed in the pallium, the subhipoccampal lobe, the striatum, the preoptic area and the hypothalamus. Following tectal injections, backfilled diencephalic cells were found bilaterally in: prethalamic eminence, ventral geniculate nucleus, periventricular prethalamic nucleus, periventricular pretectal nucleus, precommissural nucleus, magnocellular and parvocellular nuclei of the posterior commissure and pretectal nucleus; and ipsilaterally in: nucleus of Bellonci, periventricular thalamic nucleus, nucleus of the tuberculum posterior, and the subpretectal tegmentum, as well as in the pineal organ. At midbrain levels, retrogradely labeled cells were seen in the ipsilateral torus semicircularis, the contralateral OT, and bilaterally in the mesencephalic reticular formation and inside the limits of the retinopetal nuclei. In the hindbrain, tectal projecting cells were also bilaterally labeled in the dorsal and lateral isthmic nuclei, the octavolateral area, the sensory nucleus of the descending trigeminal tract, the dorsal column nucleus and the reticular formation. The rostral spinal cord also exhibited a few labeled cells. These results demonstrate a complex pattern of connections in the lamprey OT, most of which have been reported in other vertebrates. Hence, the lamprey OT receives a large number of nonvisual afferents from all major brain areas, and so is involved in information processing from different somatic sensory modalities.
Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus
Authors: Stuetz Anton , Baumann Karl , Grassberger Maximilian , Wolff Klaus , Meingassner Josef G.
Published: August 2006

Using a newly developed model of allergic contact dermatitis in pigs, calcineurin inhibitors of the tacrolimus and ascomycin type were shown to have a highly anti-inflammatory action after topical application. These findings provided the first pharmacological evidence of the efficacy of this novel class of topical agents in the treatment of inflammatory skin diseases, and, thus, their potential to become the first alternative to corticosteroids in more than 40 years. As a result of a large research program into ascomycins, pimecrolimus (Elidel®, SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic®, FK 506). In vitro, pimecrolimus inhibits the transcription and release of pro-inflammatory cytokines in T cells. Similar to the corticosteroids, betamethasone-17-valerate and dexamethasone, pimecrolimus is effective at nanomolar concentrations. Targeting mainly T cells, pimecrolimus has, however, a more specific mode of action. Moreover, in contrast to corticosteroids, pimecrolimus has no effect on Langerhans’ cells, the professional antigen- presenting dendritic cells of the skin that are crucial for local immunosurveillance. When applied topically, pimecrolimus exerts a high and selective anti-inflammatory activity in the skin, shows minimal percutaneous absorption, and has a low potential to affect systemic immunoreactions. Pimecrolimus cream 1% has proven to be well tolerated, safe, and highly effective in clinical studies in patients with atopic dermatitis.
Plasma Soluble Human Leukocyte Antigen G Levels in Asthmatic Children
Authors: Tahan Fulya , Patıroglu Turkan
Published: August 2006

Background: Human leukocyte antigen G (HLA-G) is a nonclassical major histocompatibility complex class I gene. HLA-G stimulates Th2 cytokine secretion by peripheral blood mononuclear cells. The role of soluble HLA-G (sHLA-G) in bronchial asthma is incompletely understood and the plasma level of sHLA-G in asthmatic children has not been investigated. Objective: It was the aim of this study to investigate the plasma level of sHLA-G in asthmatic children. Methods: Asthmatic (n = 53) and healthy children (n = 16) were included in the study. Levels of sHLA-G were determined in plasma using ELISA. Spirometry, total immunoglobulin E and eosinophil counts were obtained and skin testing done with a battery of 25 antigens with appropriate positive and negative controls. Results: No significant difference was observed in the plasma level of sHLA-G between the asthmatic and healthy children (p > 0.05). When we compared atopic asthmatics with healthy controls, we found significantly higher levels of sHLA-G in atopic asthmatics (p < 0.05). There was a significant difference in the peripheral blood eosinophil counts and total immunoglobulin E levels among the groups (p < 0.001). Conclusion: Our study shows that plasma sHLA-G levels do not differ between asthmatic children and healthy controls. However, higher plasma levels of sHLA-G in atopic asthmatics may suggest a role for sHLA-G in atopy. Further investigations are required to better define the mechanism of the production and the role of sHLA-G molecules observed in patients with asthma.
Allergenicity Assessment of Apple Cultivars: Hurdles in Quantifying Labile Fruit Allergens
Authors: Zuidmeer L. , van Leeuwen W.A. , Kleine Budde I. , Breiteneder H. , Ma Y. , Mills C. , Sancho A.I. , Meulenbroek E.J. , van de Weg E. , Gilissen L. , Ferreira F. , Hoffmann-Sommergruber K. , van Ree R.
Published: August 2006

Background: Assessment of allergenicity of foods is important for allergic consumers and regulators. Immunoassays to measure major food allergens are widely applied, often giving variable results. Using the major apple allergen Mal d 1 as a model, we aimed to establish at the molecular level why different immunoassays for assessing allergenicity of apple cultivars produce conflicting outcomes. Methods: Mal d 1 was measured in 53 cultivars from Italy and 35 from The Netherlands, using four different immunoassays. Purified Mal d 1 standards were molecularly characterized by size-exclusion chromatography (SEC) and mass spectrometry (MS). Results: Three immunoassays using an identical standard gave similar results. Minor differences in sample preparation already resulted in significant loss of allergenicity. The fourth assay, using a different Mal d 1 standard, gave 10- to 100-fold lower outcomes. By SEC, this standard was shown to be almost fully aggregated. This aggregation was accompanied by a decrease of the mass of the Mal d 1 molecule by ∼1 kDa as analyzed by MS. The deviating immunoassay was shown to selectively recognize this aggregated form of Mal d 1, whereas the other three assays, including the one based on IgE antibody recognition, preferentially bound non-aggregated allergen. Conclusions: Variable and poorly controllable major allergen modification in both extracts and standards hamper accurate allergenicity assessments of fruits.
Effect of Cyclosporine and Sirolimus on the Expression of Connective Tissue Growth Factor in Rat Experimental Chronic Nephrotoxicity
Authors: Shihab Fuad S. , Bennett William M. , Yi Hong , Andoh Takeshi F.
Published: August 2006

Background/Aims: Connective tissue growth factor (CTGF) is a pro-fibrotic growth factor that acts downstream of transforming growth factor (TGF)-β. However, CTGF regulation remains unknown. We tried to determine the effect of two commonly used immunosuppressants, cyclosporine (CsA) and sirolimus (SRL), on CTGF expression in a model of chronic nephrotoxicity. Methods: Adult Sprague-Dawley rats kept on a low-salt diet were treated daily for 4 weeks with vehicle (VH), SRL (0.3 mg/kg), CsA5 (5 mg/kg), CsA10 (10 mg/kg) or both CsA5 and SRL. CTGF and TGF-β1 expressions were evaluated by Northern blot. Functional and histologic parameters in addition to number of apoptotic cells were determined. Results: At 28 days, both CsA doses were capable of inhibiting CTGF mRNA expression to levels similar to control. On the other hand, SRL increased CTGF expression by 3.5-fold. However, addition of CsA to SRL completely reversed that trend and returned levels to control. The results were different for TGF-β1, which was increased by both CsA and SRL and to a greater extent by the drug combination. Conclusion: Unlike TGF-β, CTGF does not seem to play an important role in CsA-induced chronic nephrotoxicity. In addition, calcineurin-dependent pathways are likely involved in CTGF regulation.
Glomerular Filtration Rate on Admission Independently Predicts Short-Term In-Hospital Mortality after Acute Myocardial Infarction
Authors: Afshinnia Farsad , Ayazi Pedram , Chadow Hal L.
Published: August 2006

Background: Risk of cardiovascular events is higher in patients with chronic kidney disease. The objective is to evaluate whether glomerular filtration rate (GFR) on admission is an independent predictor of short-term mortality in acute myocardial infarction (AMI), after adjusting with physiologic derangements in an acute setting. Methods: 220 consecutive patients with an admitting diagnosis of AMI were enrolled in a 1-year prospective observational study at a tertiary care teaching institute. Data were gathered for history, physical examination and laboratory findings. GFR was calculated based on the Modification of Diet in Renal Disease formula. Abnormal categories of physiological derangement indicators were weighted based on APACHE II guidelines. The endpoint was defined as in-hospital all-cause mortality. Results: There were 31 deaths (14.1%). The GFR (mean ± SD) in survivors as compared to deceased patients was 68.2 ± 33.8 and 41.7 ± 25.1 ml/min/1.73 m2, respectively (p < 0.001). The mean age, white blood cell count, blood urea nitrogen, potassium and blood sugar were higher on admission in patients who died in hospital (p < 0.05), while the mean albumin, mean arterial pressure, pulse and respiratory rate were lower in this group compared to survivors (p < 0.05). After adjusting with other covariates, each 10 ml/min/1.73 m2 decrease in GFR was associated with a 1.29 times increased risk of mortality (95% CI 1.08–1.53, p = 0.004). Conclusion: GFR on admission is an independent predictor of short-term mortality in a patient after AMI.