bluuebunny/crossref_metadata_2025 huggingface dataset:
4-Aminophenyldiphenylphosphinite (APDPP), a new heterogeneous and acid scavenger phosphinite — Conversion of alcohols, trimethylsilyl, and tetrahydropyranyl ethers to alkyl halides with halogens or N-halosuccinimides
Authors: Iranpoor Nasser , Firouzabadi Habib , Gholinejad Mohammad
Published: September 2006

A new heterogeneous phosphinite, 4-aminophenyldiphenylphosphinite (APDPP), is prepared and used for the efficient conversion of alcohols, trimethylsilyl ethers, and tetrahydropyranyl ethers to their corresponding bromides, iodides, and chlorides in the presence of molecular halogens or N-halosuccinimides. The amino group in this phosphinite acts as an acid scavenger and removes the produced acid. A simple filtration easily removes the phosphinate by-product.Key words: 4-aminophenyldiphenylphosphinite, alcohol, trimethylsilyl ether, tetrahydropyranyl ether, alkyl halide.
FINITE ELEMENT ANALYSIS OF PIEZOELECTRIC ELASTICITY WITH SINGULAR INPLANE ELECTROELASTIC FIELDS
Authors: CHEN MENG-CHENG , ZHU JIAN-JUN , SZE K. Y.
Published: September 2006

An ad hoc one-dimensional finite element formulation is developed for the eigenanalysis of inplane singular electroelastic fields at material and geometric discontinuities in piezoelectric elastic materials by using the eigenfunction expansion procedure and the weak form of the governing equations for prismatic sectorial domains composed of piezoelectrics, composites or air. The order of the electroelastic singularities and the angular variation of the stress and electric displacement fields are obtained with the formulation. The influence of wedge angle, polarization orientation, material types, and boundary and interface conditions on the singular electroelastic fields and the order of their singularity are also examined. The simplicity and accuracy of the formulation are demonstrated by comparison to several analytical solutions for piezoelectric and composite multi-material wedges. The nature and speed of convergence suggests that the present eigensolution could be used in developing hybrid elements for use along with standard elements to yield accurate and computationally efficient solutions to problems having complex global geometries leading to singular electroelastic states.
Insect/Mammal Associations: Effects of Cuterebrid Bot Fly Parasites on Their Hosts
Authors: Slansky Frank
Published: September 2006

The effect of parasites on their hosts has implications for basic and applied ecology (e.g., species’ population dynamics and distributions, biological control, and threats to at-risk species) and coevolution. Cuterebrid bot flies comprise one of the most-studied groups of insect parasites of mammals. Interest in their impact dates from at least 1857, when Cuterebra emasculator was so named because of the erroneous belief that its larvae castrate their hosts. This review addresses the effects of cuterebrid larvae on host biochemistry, physiology, behavior, and ecology. Despite high prevalence (peak values commonly range from 30% to 70%), at average intensities (one to three larvae per host) these parasites generally have little effect on the fitness or population dynamics of their typical hosts. This outcome likely reflects parasite/host coevolution favoring parasites that minimize harmful effects on hosts required for their survival and hosts that best tolerate perennial parasites they cannot avoid. In contrast, aggravated effects occur at higher intensities and with atypical hosts. Additional field studies involving experimental manipulation of infestation and spanning more than a few seasons are required to confirm these conclusions.
Nectar and Pollen Feeding by Insect Herbivores and Implications for Multitrophic Interactions
Authors: Wäckers Felix L. , Romeis Jörg , van Rijn Paul
Published: September 2006

Among herbivorous insects with a complete metamorphosis the larval and adult stages usually differ considerably in their nutritional requirements and food ecology. Often, feeding on plant structural tissue is restricted to the larval stage, whereas the adult stage feeds primarily or exclusively on plant-provided food supplements such as nectar and pollen. Research on herbivore nutritional ecology has largely been divided along these lines. Most studies focus on actual herbivory by larval stages, while nectar and pollen feeding by adult herbivores has been addressed mainly in the light of plant-pollinator interactions. Only recently have we started to realize that the two phenomena are closely interlinked and that nectar and pollen feeding by adult herbivores can have a strong impact on plant-herbivore interactions. Here we address this largely ignored aspect of multitrophic level interactions and discuss its wide-ranging implications.
Modeling mitochondrial function
Authors: Balaban Robert S.
Published: September 2006

The mitochondrion represents a unique opportunity to apply mathematical modeling to a complex biological system. Understanding mitochondrial function and control is important since this organelle is critical in energy metabolism as well as playing key roles in biochemical synthesis, redox control/signaling, and apoptosis. A mathematical model, or hypothesis, provides several useful insights including a rigorous test of the consensus view of the operation of a biological process as well as providing methods of testing and creating new hypotheses. The advantages of the mitochondrial system for applying a mathematical model include the relative simplicity and understanding of the matrix reactions, the ability to study the mitochondria as a independent contained organelle, and, most importantly, one can dynamically measure many of the internal reaction intermediates, on line. The developing ability to internally monitor events within the metabolic network, rather than just the inflow and outflow, is extremely useful in creating critical bounds on complex mathematical models using the individual reaction mechanisms available. However, many serious problems remain in creating a working model of mitochondrial function including the incomplete definition of metabolic pathways, the uncertainty of using in vitro enzyme kinetics, as well as regulatory data in the intact system and the unknown chemical activities of relevant molecules in the matrix. Despite these formidable limitations, the advantages of the mitochondrial system make it one of the best defined mammalian metabolic networks that can be used as a model system for understanding the application and use of mathematical models to study biological systems.
Mg2+ activates the ryanodine receptor type 2 (RyR2) at intermediate Ca2+ concentrations
Authors: Chugun Akihito , Sato Osamu , Takeshima Hiroshi , Ogawa Yasuo
Published: September 2006

To clarify whether activity of the ryanodine receptor type 2 (RyR2) is reduced in the sarcoplasmic reticulum (SR) of cardiac muscle, as is the case with the ryanodine receptor type 1 (RyR1), Ca2+-dependent [3H]ryanodine binding, a biochemical measure of Ca2+-induced Ca2+ release (CICR), was determined using SR vesicle fractions isolated from rabbit and rat cardiac muscles. In the absence of an adenine nucleotide or caffeine, the rat SR showed a complicated Ca2+ dependence, instead of the well-documented biphasic dependence of the rabbit SR. In the rat SR, [3H]ryanodine binding initially increased as [Ca2+] increased, with a plateau in the range of 10–100 μM Ca2+, and thereafter further increased to an apparent peak around 1 mM Ca2+, followed by a decrease. In the presence of these modulators, this complicated dependence prevailed, irrespective of the source. Addition of 0.3–1 mM Mg2+ unexpectedly increased the binding two- to threefold and enhanced the affinity for [3H]ryanodine at 10–100 μM Ca2+, resulting in the well-known biphasic dependence. In other words, the partial suppression of RyR2 is relieved by Mg2+. Ca2+ could be a substitute for Mg2+. Mg2+ also amplifies the responses of RyR2 to inhibitory and stimulatory modulators. This stimulating effect of Mg2+ on RyR2 is entirely new, and is referred to as the third effect, in addition to the well-known dual inhibitory effects. This effect is critical to describe the role of RyR2 in excitation-contraction coupling of cardiac muscle, in view of the intracellular Mg2+ concentration.
Characterization of two splice variants of human organic anion transporting polypeptide 3A1 isolated from human brain
Authors: Huber Robert D. , Gao Bo , Sidler Pfändler Marguerite-Anne , Zhang-Fu Wenting , Leuthold Simone , Hagenbuch Bruno , Folkers Gerd , Meier Peter J. , Stieger Bruno
Published: September 2006

In the present study we isolated two splice variants of organic anion transporting polypeptide 3A1 (OATP3A1_v1 and OATP3A1_v2) from human brain. OATP3A1_v2 lacks 18 amino acids (aa) at the COOH-terminal end (692 aa) but is otherwise similar in sequence to OATP3A1_v1 (710 aa). OATP3A1_v1 exhibits a wide tissue distribution, with expression in testis, various brain regions, heart, lung, spleen, peripheral blood leukocytes, and thyroid gland, whereas OATP3A1_v2 is predominantly expressed in testis and brain. On the cellular and subcellular levels OATP3A1_v1 could be immunolocalized in testicular germ cells, the basolateral plasma membrane of choroid plexus epithelial cells, and neuroglial cells of the gray matter of human frontal cortex. Immunolocalization of OATP3A1_v2 included Sertoli cells in testis, apical and/or subapical membranes in choroid plexus epithelial cells, and neurons (cell bodies and axons) of the gray and white matter of human frontal cortex. The rodent ortholog Oatp3a1 was also widely distributed in rat brain, and its localization included somatoneurons as well as astroglial cells. Transport studies in cRNA-injected Xenopus laevis oocytes and in stably transfected Chinese hamster ovary FlpIn cells revealed a similar broad substrate specificity for both splice variants. Transported substrates include prostaglandin (PG)E1and PGE2, thyroxine, and the cyclic oligopeptides BQ-123 (endothelin receptor antagonist) and vasopressin. These studies provide further evidence for the involvement of OATPs in oligopeptide transport. They specifically suggest that OATP3A1 variants might be involved in the regulation of extracellular vasopressin concentration in human brain and thus might influence the neuromodulation of neurotransmission by cerebral neuropeptides such as vasopressin.
Estrogen rapidly modulates mustard oil-induced visceral hypersensitivity in conscious female rats: a role of CREB phosphorylation in spinal dorsal horn neurons
Authors: Lu Ching-Liang , Hsieh Jen-Chuen , Tsaur Meei-Ling , Huang Yn-Ho , Wang Paulus S. , Wu Learn-Long , Liu Pei-Yi , Chang Full-Young , Lee Shou-Dong
Published: September 2006

This study investigated the effect of sex hormones on mustard oil (MO)-induced visceral hypersensitivity in female rats and analyzed possible involved signaling pathways. Female rats, either intact or ovariectomized (OVX), were prepared for abdominal muscle electromyography in response to colorectal distension after intracolonic instillation of MO. The effect of MO intracolonic sensitization was evaluated in intact rats, OVX rats, and OVX rats pretreated with a single injection of 17β-estradiol (E), progesterone (P), E+P, or vehicle. cAMP-responsive element-binding protein (CREB) and phosphorylated CREB (pCREB) were detected in the superficial dorsal horn of L6 and S1 in MO or mineral oil-treated OVX rats with/without colorectal distension and estrogen replacement. The distal colorectum was removed for histological evaluation of inflammatory severity in MO-treated intact or OVX rats. The MO-treated rats had significantly higher visceromotor reflex than controls (enhanced visceral hypersensitivity), whereas OVX eliminated this hypersensitivity. After a single injection of E or E+P, the rats rapidly restored MO-induced visceral hypersensitivity within 2 h. Estrogen also rapidly induced a dose-dependent increase in pCREB expression in the superficial dorsal horn neurons in MO-treated, but not mineral oil-treated, OVX rats. The present study suggests that estrogen can rapidly modulate visceral hypersensitivity induced by MO intracolonic instillation in conscious female rats, which may involve spinal activation of the cAMP response element-mediated gene induction pathway.
Expression and functional features of NaCT, a sodium-coupled citrate transporter, in human and rat livers and cell lines
Authors: Gopal Elangovan , Miyauchi Seiji , Martin Pamela M. , Ananth Sudha , Srinivas Sonne R. , Smith Sylvia B. , Prasad Puttur D. , Ganapathy Vadivel
Published: September 2006

In this article, we report on the expression and function of a Na+-coupled transporter for citrate, NaCT, in human and rat liver cell lines and in primary hepatocytes from the rat liver. We also describe the polarized expression of this transporter in human and rat livers. Citrate uptake in human liver cell lines HepG2 and Huh-7 was obligatorily dependent on Na+. The uptake system showed a preference for citrate over other intermediates of the citric acid cycle and exhibited a Michaelis constant of ∼6 mM for citrate. The transport activity was stimulated by Li+, and the activation was associated with a marked increase in substrate affinity. Citrate uptake in rat liver cell line MH1C1 was also Na+ dependent and showed a preference for citrate. The Michaelis constant for citrate was ∼10 μM. The transport activity was inhibited by Li+. Primary hepatocytes from the rat liver also showed robust activity for Na+-coupled citrate uptake, with functional features similar to those described in the rat liver cell line. Immunolabeling with a specific anti-NaCT antibody showed exclusive expression of the transporter in the sinusoidal membrane of hepatocytes in human and rat livers. This constitutes the first report on the expression and function of NaCT in liver cells.
Rheological properties of the blood influencing selectin-mediated adhesion of flowing leukocytes
Authors: Abbitt Katherine B. , Nash Gerard B.
Published: September 2006

We studied how the rheological properties of blood influenced capture and rolling adhesion of leukocytes as well as their margination in the bloodstream. When citrated, fluorescently labeled blood was perfused through glass capillaries coated with P-selectin, leukocytes formed numerous rolling attachments. The number of attached leukocytes increased as the hematocrit was increased between 10% and 30% and was essentially constant from 30% to 50%. In EDTA-treated blood, adhesion was absent, and the flux of marginated cells varied little with increasing hematocrit. However, the velocity of marginated leukocytes increased monotonically, whereas the volumetric flow rate was constant, implying that the flow velocity profile became blunted and wall shear rate increased. Thus increasing hematocrit promoted attachment for a given total flow rate, without increasing margination, even though wall shear rate and blood viscosity increased. Blood was diluted to 20% hematocrit with plasma, 40-kDa dextran (to reduce red blood cell aggregation), or 500-kDa dextran (to enhance aggregation). Increasing aggregation correlated with increasing leukocyte adhesion and with more slow-flowing leukocytes near the wall. Thus flowing erythrocytes promote leukocyte adhesion, either by causing margination of leukocytes or by initiating and stabilizing attachments that follow.
Comparison of infarct-derived and control ovine cardiac myofibroblasts in culture: response to cytokines and natriuretic peptide receptor expression profiles
Authors: Jarvis Martin D. , Rademaker Miriam T. , Ellmers Leigh J. , Currie Margaret J. , McKenzie Judith L. , Palmer Barry R. , Frampton Christopher M. , Richards A. Mark , Cameron Vicky A.
Published: September 2006

This study investigated whether gene expression profiles of myofibroblasts derived from infarcted myocardium differ from normal cardiac fibroblasts. We compared the expression of cytoskeletal proteins in cultured ovine cardiac fibroblasts derived from infarcted (ID) and noninfarcted ovine myocardium (NID) and the levels of expression of the natriuretic peptide receptors (NPR)-A and NPR-B in response to treatment with transforming growth factor (TGF)-β1 and/or platelet-derived growth factor (PDGF). Transformation of cultured cardiac fibroblasts to myofibroblasts, as indicated by α-smooth muscle actin and vimentin expression, was independent of the presence of TGF-β1, PDGF, or cell origin. ID fibroblasts had higher basal levels than NID fibroblasts of NPR-A (ID: 58.0 ± 32.2 arbitrary density units, NID: undetectable), NPR-B (ID: 780 ± 155, NID: 330 ± 38 arbitrary density units) and collagen I (ID: 17.2 ± 0.5, NID: 10.5 ± 1.7 pg mRNA/μg total RNA, P < 0.05) but lower levels of α-SMa expression (ID: 50.2 ± 7.9, NID: 76.9 ± 3.2 fluorescence units, P < 0.05). NPR-A mRNA in ID fibroblasts showed a rapid fourfold increase in response to TGF-β1 and/or PDGF at 4 and 2 h, respectively, followed by a profound decline; in NID cells, NPR-A mRNA was undetectable. In ID fibroblasts, cytokines reduced NPR-B mRNA below control levels; in NID fibroblasts, TGF-β1 and PDGF elicited prompt increments in expression: a fourfold increase with TGF-β1 at 8 h and a twofold increase with PDGF at 4 h ( P < 0.05). In summary, transformation of cardiac fibroblasts to myofibroblasts in culture is independent of cytokine treatment. Moreover, whether the cultured cardiac fibroblasts are from infarct tissue is a major determinant of NPR expression levels and cytokine responses, even after four to five passages.
Increased expression of HIF-1α, nNOS, and VEGF in the cerebral cortex of anemic rats
Authors: McLaren Anya T. , Marsden Philip A. , Mazer C. David , Baker Andrew J. , Stewart Duncan J. , Tsui Albert K. Y. , Li Xiaomao , Yucel Yeni , Robb Malcolm , Boyd Shelley R. , Liu Elaine , Yu Julie , Hare Gregory M. T.
Published: September 2006

This study tested the hypothesis that specific hypoxic molecules, including hypoxia-inducible factor-1α (HIF-1α), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF), are upregulated within the cerebral cortex of acutely anemic rats. Isoflurane-anesthetized rats underwent acute hemodilution by exchanging 50% of their blood volume with pentastarch. Following hemodilution, mean arterial pressure and arterial PaO2 values did not differ between control and anemic rats while the hemoglobin concentration decreased to 57 ± 2 g/l. In anemic rats, cerebral cortical HIF-1α protein levels were increased, relative to controls (1.7 ± 0.5-fold, P < 0.05). This increase was associated with an increase in mRNA levels for VEGF, erythropoietin, CXCR4, iNOS, and nNOS ( P < 0.05 for all), but not endothelial NOS. Cerebral cortical nNOS and VEGF protein levels were increased in anemic rats, relative to controls (2.0 ± 0.2- and 1.5 ± 0.4-fold, respectively, P < 0.05 for both). Immunohistochemistry demonstrated increased HIF-1α and VEGF staining in perivascular regions of the anemic cerebral cortex and an increase in the number of nNOS-positive cerebral cortical cells (3.2 ± 1.0-fold, P < 0.001). The nNOS-positive cells costained with the neuronal marker, Neu-N, but not with the astrocytic marker glial fibrillary acidic protein (GFAP). These nNOS-positive neurons frequently sent axonal projections toward cerebral blood vessels. Conversely, VEGF immunostaining colocalized with both neuronal (NeuN) and astrocytic markers (GFAP). In conclusion, acute normotensive, normoxemic hemodilution increased the levels of HIF-1α protein and mRNA for HIF-1-responsive molecules. nNOS and VEGF protein levels were also increased within the cerebral cortex of anemic rats at clinically relevant hemoglobin concentrations.
Taste Responsiveness of Fungiform Taste Cells With Action Potentials
Authors: Yoshida Ryusuke , Shigemura Noriatsu , Sanematsu Keisuke , Yasumatsu Keiko , Ishizuka Satoru , Ninomiya Yuzo
Published: September 2006

It is known that a subset of taste cells generate action potentials in response to taste stimuli. However, responsiveness of these cells to particular tastants remains unknown. In the present study, by using a newly developed extracellular recording technique, we recorded action potentials from the basolateral membrane of single receptor cells in response to taste stimuli applied apically to taste buds isolated from mouse fungiform papillae. By this method, we examined taste-cell responses to stimuli representing the four basic taste qualities (NaCl, Na saccharin, HCl, and quinine-HCl). Of 72 cells responding to taste stimuli, 48 (67%) responded to one, 22 (30%) to two, and 2 (3%) to three of four taste stimuli. The entropy value presenting the breadth of responsiveness was 0.158 ± 0.234 (mean ± SD), which was close to that for the nerve fibers (0.183 ± 0.262). In addition, the proportion of taste cells predominantly sensitive to each of the four taste stimuli, and the grouping of taste cells based on hierarchical cluster analysis, were comparable with those of chorda tympani (CT) fibers. The occurrence of each class of taste cells with different taste responsiveness to the four taste stimuli was not significantly different from that of CT fibers except for classes with broad taste responsiveness. These results suggest that information derived from taste cells generating action potentials may provide the major component of taste information that is transmitted to gustatory nerve fibers.
Large-Scale Organization of Preferred Directions in the Motor Cortex. II. Analysis of Local Distributions
Authors: Naselaris Thomas , Merchant Hugo , Amirikian Bagrat , Georgopoulos Apostolos P.
Published: September 2006

The spatial arrangement of preferred directions (PDs) in the primary motor cortex has revealed evidence for columnar organization and short-range order. We investigated the large-scale properties of this arrangement. We recorded neural activity at sites on a grid covering a large region of the arm area of the motor cortex while monkeys performed a 3D reaching task. Sites were projected to the cortical surface along anatomically defined cortical columns and a PD was extracted from each site with directionally tuned activity. We analyzed the resulting 2D surface map of PDs. Consistent with previous studies, we found that any particular reaching direction was rerepresented at many points across the recorded area. In particular, we determined that the median radius of a cortical region required to represent the full complement of reaching directions is at most 1 mm. We also found that for the majority of regions of this size, the distribution of PDs within them exhibits an enrichment for the representation of forward and backward reaching directions (see companion paper). Finally, we found that the error of a population vector estimate of reaching direction constructed from neural activity within these regions is small on average, but varies significantly across different sections of the motor cortex, with the highest levels of error sustained near the fundus of the central sulcus and lowest levels achieved near the crown. We interpret these findings in the context of two well-known features of motor cortex, that is, its highly distributed anatomical organization and its behaviorally dependent plasticity.
Neural Correlates of Sustained Spatial Attention in Human Early Visual Cortex
Authors: Silver Michael A. , Ress David , Heeger David J.
Published: September 2006

Attention is thought to enhance perceptual performance at attended locations through top-down attention signals that modulate activity in visual cortex. Here, we show that activity in early visual cortex is sustained during maintenance of attention in the absence of visual stimulation. We used functional magnetic resonance imaging (fMRI) to measure activity in visual cortex while human subjects performed a visual detection task in which a variable-duration delay period preceded target presentation. Portions of cortical areas V1, V2, and V3 representing the attended part of the visual field exhibited sustained increases in activity throughout the delay period. Portions of these cortical areas representing peripheral, unattended parts of the visual field displayed sustained decreases in activity. The data were well fit by a model that assumed the sustained neural activity was constant in amplitude over a time period equal to that of the actual delay period for each trial. These results demonstrate that sustained attention responses are present in early visual cortex (including primary visual cortex), in the absence of a visual stimulus, and that these responses correlate with the allocation of visuospatial attention in both the spatial and temporal domains.
Nucleus-Specific Abnormalities of GABAergic Synaptic Transmission in a Genetic Model of Absence Seizures
Authors: Bessaïh Thomas , Bourgeais Laurence , Badiu Carmen I. , Carter David A. , Toth Tibor I. , Ruano Diego , Lambolez Bertrand , Crunelli Vincenzo , Leresche Nathalie
Published: September 2006

Human and experimental studies indicate that molecular genetic changes in GABAA receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABAA inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABAA IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABAB antagonists. These results point to subtle, nucleus-specific, GABAA receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.
Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside
Authors: Beckers Annelies , Organe Sophie , Timmermans Leen , Vanderhoydonc Frank , Deboel Ludo , Derua Rita , Waelkens Etienne , Brusselmans Koen , Verhoeven Guido , Swinnen Johannes V.
Published: September 2006

Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA riboside–induced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention. [Mol Cancer Ther 2006;5(9):2211–7]
Targeting changes in cancer: assessing pathway stability by comparing pathway gene expression coherence levels in tumor and normal tissues
Authors: Huang Ruili , Wallqvist Anders , Covell David G.
Published: September 2006

The purpose of this study is to examine gene expression changes occurring in cancer from a pathway perspective by analyzing the level of pathway coherence in tumor tissues in comparison with their normal counterparts. Instability in pathway regulation patterns can be considered either as a result of or as a contributing factor to genetic instability and possibly cancer. Our analysis has identified pathways that show a significant change in their coherence level in tumor tissues, some of which are tumor type specific, indicating novel targets for cancer type–specific therapies. Pathways are found to have a general tendency to lose their gene expression coherence in tumor tissues when compared with normal tissues, especially for signaling pathways. The selective growth advantage of cancer cells over normal cells seems to originate from their preserved control over vital pathways to ensure survival and altered signaling, allowing excessive proliferation. We have additionally investigated the tissue-related instability of pathways, providing valuable clues to the cellular processes underlying the tumorigenesis and/or growth of specific cancer types. Pathways that contain known cancer genes (i.e., “cancer pathways”) show significantly greater instability and are more likely to become incoherent in tumor tissues. Finally, we have proposed strategies to target instability (i.e., pathways that are prone to changes) by identifying compound groups that show selective activity against pathways with a detectable coherence change in cancer. These results can serve as guidelines for selecting novel agents that have the potential to specifically target a particular pathway that has relevance in cancer. [Mol Cancer Ther 2006;5(9):2417–27]
Evidence for the benefits of prophylaxis in the management of hemophilia A
Authors: Nugent Diane , Hoots W. Keith
Published: September 2006

The optimal treatment of hemophilia has been evolving since the advent of factor VIII concentrates, continues to vary geographically, and remains a source of debate. There now exists an extensive clinical literature that demonstrates clear benefits of prophylaxis for patients with hemophilia A compared to on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. However, the value of these benefits must be weighed against the heavier economic burden of increased factor use. This paper reviews the literature that compares the benefits of prophylaxis with that of on-demand treatment, compares varying prophylaxis dose and administration frequency protocols, and considers the long-term cost-benefit of prophylactic therapy.
Low fasting methionine concentration as a novel risk factor for recurrent venous thrombosis
Authors: Keijzer Miranda , Borm George , Blom Henk , Vollset Stein , Hermus Ad R. M. M. , Ueland Per , den Heijer Martin
Published: September 2006

Hyperhomocysteinemia is a risk factor for venous thrombosis, but the underlying mechanism is unclear. If the thiol-group of homocysteine interferes with components of the clotting system, we expect that high cysteine will be alsoa risk factor for venous thrombosis. If high homocysteine reflects a disturbed methyl-group donation by S-adenosylmethionine, we expect that low methionine will be a risk factor for thrombosis. We performeda case-control study in 185 patients with recurrent venous thrombosis and in 500 control subjects.

We determined methionine, homocysteine, cysteine and assessed the associated thrombotic risk. Low fasting methionine was associated with an increased risk on recurrent venous thrombosis [ORbottom vs. top quartile = 3.3 (95%CI 1.9–5.7)]. Low methionine remained a risk factor [ORbottom vs. top quartile= 3.5 (95%CI 2.0–6.0)] after adjusting for homocysteine and cysteine, whereas the thrombotic risk for homocysteine was lost [OR= 1.0 (95%CI 0.6–1.9)] after adjustment. Cysteine yielded a highest odds ratio of 2.1top vs. bottom quartile (95%CI 1.0–4.0) after adjustment. In conclusion, we found that low fasting methionine is a risk factor for recurrent venous thrombosis.This risk association was stronger for methionine than for homocysteine or cysteine.This supports the hypothesis that impaired methylation may be involved in the pathogenesis of venous thrombosis.
In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura
Authors: Donadelli Roberta , Banterla Federica , Galbusera Miriam , Capoferri Cristina , Bucchioni Sara , Gastoldi Sara , Nosari Silvia , Monteferrante Giuseppe , Ruggeri Zaverio , Bresin Elena , Scheiflinger Friedrich , Rossi Edoardo , Martinez Constantino , Coppo Rosanna , Remuzzi Giuseppe , Noris Marina ,   the International Registry of Recurrent and Familial HUS/TTP
Published: September 2006

Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of the von Willebrand factor (VWF) cleaving protease ADAMTS13.We investigated the spectrum of ADAMTS13 gene mutations in patients with TTP and congenital ADAMTS13 deficiency to establish the consequences on ADAMTS13 processing and activity. We describe five missense (V88M, G1239V, R1060W, R1123C and R1219W), 1 nonsense (W1016Stop) and 1 insertion (82_83insT) mutations. In two patients no mutation was identified despite undetectable protease activity. Expression in HEK293 mammalian cells (V88M, G1239V, R1123C and R1219W) documented that three missense mutants were not secreted, whereas theV88M was secreted at low levels and with reduced activity. We also provide evidence that impaired secretion of ADAMTS13 mutants observed in vitro translates into severely reduced ADAMTS13 antigen levels in patients in vivo. To evaluate whether the small amounts of mutant protease present in the circulation of patients had VWF cleaving activity, WT and mutant rADAMTS13 were stably expressed in Drosophila S2 cells under the influence of the Drosophila BiP protein signal sequence, which allows protein secretion. Drosophila expression system showed a 40–60% protease activity in the mutants. Several single nucleotide polymorphisms (SNPs) within exons and intron boundaries were found in patients, suggesting that the interplay of SNPs could at least in part account for ADAMTS13 functional abnormalities in patients without mutations. In conclusion, defective secretion and impaired activity of the mutants concur to determine an almost complete deficiency of ADAMTS13 activity in patients with a homozygous or two heterozygous ADAMTS13 mutations.
Plasma glycoprotein V levels in the general population: Normal distribution, associated parameters and implications for clinical studies
Authors: Meyer Nicolas , Wolff Valérie , Kientz Daniel , Wiesel Marie-Louise , Gachet Christian , Cazenave Jean-Pierre , Aleil Boris , Lanza François
Published: September 2006

Soluble glycoproteinV (sGPV) isa new plasma marker of thrombosis released from the platelet surface by thrombin. sGPV levels are increased in patients with atherothrombotic diseases, but the determinants of sGPV levels are unknown in the general population. Identification of these potential confounding factors is needed for correct design and analysis of clinical studies on cardiovascular diseases.The aim of this study was to determine the normal range of plasma values and the factors controlling sGPV levels in a population of normal individuals.Three hundred blood donors were recruited at the Etablissement Français du Sang-Alsace for the measurement of plasma levels of sGPV, platelet factor 4 (PF4), thrombin-antithrombin complexes (TAT) and D-dimers.The plasma level of sGPV was (median [interquartile range]) 27.5 [23.5–34.4] µg/l and displayed a Gaussian distribution. sGPV had a lower interindividual coefficient of variation (33%) than PF4 (176%), TAT (87%) or D-dimers (82%). sGPV levels were independent of age and sex but sensitive to red cell (r=0.412; p<0.0001) and platelet counts (r=0.267; p=0.001), total cholesterol (r=−0.313; p<0.0001), food intake (r=0.184; p=0.0014) and smoking (r=−0.154; p=0.039). Contrary to PF4 and TAT, sGPV did not differ between venous and arterial blood samples of 12 healthy individuals. Red cell and platelet counts, total cholesterol, current smoking and recent food intake are important determinants of sGPV levels and must be taken into account in clinical studies using sGPV as a thrombosis marker. Normal distribution of sGPV levels in the general population supports its use in clinical applications.
Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: Frequency distribution in a healthy German population
Authors: Tolou Farzaneh , Dörner Thomas , Kiesewetter Holger , Salama Abdulgabar , Hoppe Berthold
Published: September 2006

Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced bya multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to givea detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, β-fibrinogen –455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1–675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy- Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors.
Does a coxib-associated thrombotic risk limit the clinical use of the compounds as analgesic anti-inflammatory drugs?
Authors: Mukherjee Debabrata
Published: September 2006

Non-steroidal anti-inflammatory agents (NSAIDs) and selective cyclooxygenase (COX-2) inhibitors (coxibs) are commonly used as analgesic and anti-inflammatory agents.Selective COX-2 inhibitors or coxibs were primarily developed asa response to the gastrointestinal toxicity of conventional NSAIDs but may have other side effects. Currently available data suggests definite prothrombotic risk with the coxibs, and the magnitude of risk may vary with individual agents. Based on available data, coxibs should be restricted to use as 2nd-line, possibly as 3rd-line, agents for carefully chosen patients and randomized trials versus placebo or an accepted comparator must be performed to define the overall safety profile in diverse patient populations.The recently announced Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) trial will assess the relative cardiovascular safety of three of the most commonly used pain relievers in the treatment of arthritis patients,ibuprofen,naproxen and celecoxib.The study will enroll patients with osteoarthritis, the most common form of arthritis, who have known coronary heart disease or who have multiple risk factors for heart disease and also some patients with rheumatoid arthritis. Patients will be followed for an average of two years to track the occurrence of serious cardiovascular events, including death, heart attack and stroke. This study should provide some definitive evidence of the relative cardiovascular safety of the available anti-inflammatory agents but would be even more useful if it included an arm where patients were treated with analgesics such as acetaminophen and/or moderate strength narcotics.
Trafficking of G Protein–Coupled Receptors
Authors: Drake Matthew T. , Shenoy Sudha K. , Lefkowitz Robert J.
Published: September 2006

G protein–coupled receptors (GPCRs) play an integral role in the signal transduction of an enormous array of biological phenomena, thereby serving to modulate at a molecular level almost all components of human biology. This role is nowhere more evident than in cardiovascular biology, where GPCRs regulate such core measures of cardiovascular function as heart rate, contractility, and vascular tone. GPCR/ligand interaction initiates signal transduction cascades, and requires the presence of the receptor at the plasma membrane. Plasma membrane localization is in turn a function of the delivery of a receptor to and removal from the cell surface, a concept defined most broadly as receptor trafficking. This review illuminates our current view of GPCR trafficking, particularly within the cardiovascular system, as well as highlights the recent and provocative finding that components of the GPCR trafficking machinery can facilitate GPCR signaling independent of G protein activation.
Palliative care and the need for education - Do we know what makes a difference? A limited systematic review
Authors: Bugge Ellen , Higginson Irene J
Published: September 2006

Caring for patients with progressive illness who need symptomatic and palliative care involves professionals as well as non-professionals. Within the variety of settings that may exist around a patient, education will be constantly needed. A limited systematic review was therefore conducted in order to highlight factors that influence informal adult education.

Methods Eight databases (covering all the years each database covered up to present date), the internet and twenty-two journals were searched. If not available on line, the journals were hand searched. Keywords were ‘professional - instruction - evidence’, combined. The search was augmented by contacting researchers and authors. We included studies describing any adult education setting outside the formally established educational setting (such as classroom/school/university). Outcomes were related to individual responses, not to groups as a whole. We excluded studies including children or those carried out in classroom settings, as well as studies where the outcome referred to the group as a whole. Data were extracted into tables and contrasted, drawing particularly on studies from health care settings. Studies were graded according to their: 1) relevance by using an adjusted Signal score and 2) level of evidence.

Results A total of 81 articles and reviews were found. From these, 28 studies and 5 Cochrane reviews were included. The studies and reviews reflect a spread in design, settings as well as origin. All continents except South America were represented. Many studies indicated that a multi-faceted, personally tailored educational approach gives the best results. This finding was corroborated by the Cochrane reviews. A common finding was that transport (to the educational arena) emerged as an important factor.

Conclusions Multifaceted education, which includes the use of various media, and which is personally tailored is most effective. Examples are such as a combination of verbal and written presentations including information forms, leaflets, alongside a demonstration of practical skills in a real life situation.
Low income women and physician breastfeeding advice: A regional assessment
Authors: Stolzer J , Zeece Pauline
Published: September 2006

Objectives The aims of the pilot study presented here were to determine whether low income women were receiving compendious breastfeeding advice from their attending physicians.

Design This study assessed low income women’s reports of physician breastfeeding advice using a newly designed Likert scaled survey based on the American Surgeon General’s ‘Blueprint for Action on Breastfeeding’1.

Setting Data was collected at a WIC Center in a midwestern American city. WIC is an acronym for Women, Infants, and Children and is a federally regulated programme that provides free formula and free food for low income women who are pregnant, or who are the mothers of children 5 years and under.

Methods Cumulative frequency distributions were used to assess physician breastfeeding advice. Likert scaled questions were used to allow for vacillating degrees of agreement or disagreement. Female participants, 19 years or older, were mothers of infant children and were defined as low income using federal guidelines.

Results Results of this study indicate that low income women are not being informed by their physicians of the multiple ways in which breastfeeding is beneficial for maternal and pediatric populations.

Conclusion The findings of this pilot study suggest that low income women are not receiving compendious breastfeeding information from their attending physicians. Results of this study indicate that physicians are informing low income women of some of the benefits associated with breastfeeding, but are neglecting to inform them of the various ways in which breastfeeding is beneficial for both maternal and pediatric populations.
A preliminary study of the attitudes, triggers and consequences of hazardous drinking in university students
Authors: Faulkner S , Hendry L B , Roderique L , Thomson R
Published: September 2006

Objective The aim of this paper was to investigate drinking patterns, attitudes towards drinking and predictors of binge drinking as well as negative consequences of binge drinking in students.

Design & Method Data was collected by questionnaire from 261 students living on campus at one Welsh university.

Results The results showed that levels of drinking were higher than previous studies have revealed. The major triggers to binge drinking were social, and conformity motives were important predictors of hazardous drinking. The major consequences associated with binge drinking were involvement in illegal activities associated with drug use and unplanned sexual activity. Furthermore, students’ academic careers were adversely affected by heavy drinking as well as their physical and psychological wellbeing.

Conclusions University students living on campus demonstrated dangerously high levels of alcohol consumption and many experienced worrying consequences of this behaviour. It was suggested that further investigations into these problems across a range of universities in the UK would be useful, in order to develop intervention strategies aimed at specific ‘at risk’ groups.