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  • 1
    Electronic Resource
    Electronic Resource
    Zoniporide: A Potent and Selective Inhibitor of the Human Sodium-Hydrogen Exchanger Isoform 1 (NHE-1) (2003)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 21 (2003), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The sodium-hydrogen exchanger isoform-1 (NHE-1) plays an important role in the myocardial response to ischemia-reperfusion; inhibition of this exchanger protects against ischemic injury, including reduction in infarct size. Herein we describe a novel, potent, and highly selective NHE-1 inhibitor, zoniporide (CP-597,396; [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine). Zoniporide inhibits human NHE-1 with an IC50 of 14nM, has 〉150-fold selectivity vs. other NHE isoforms, and potently inhibits ex vivo NHE-1-dependent swelling of human platelets. This compound is well tolerated in preclinical animal models, exhibits moderate plasma protein binding, has a t1/2 of 1.5 h in monkeys, and has one major active metabolite. In both in vitro and in vivo rabbit models of myocardial ischemia-reperfusion injury, zoniporide markedly reduced infarct size without adversely affecting hemodynamics or cardiac function. In the isolated heart (Langendorff), zoniporide elicited a concentration-dependent reduction in infarct size (EC50= 0.25 nM). At 50 nM it reduced infarct size by 83%. This compound was 2.5–20-fold more potent than either eniporide or cariporide (EC50s of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide. In open chest, anesthetized rabbits, zoniporide also elicited a dose-dependent reduction in infarct size (ED50= 0.45 mg/kg/h) and inhibited NHE-1-mediated platelet swelling (93% inhibition at 4 mg/kg/h). Furthermore, zoniporide attenuated postischemic cardiac contractile dysfunction in conscious primates, and reduced both the incidence and duration of ischemia-reperfusion-induced ventricular fibrillation in rats. Zoniporide represents a novel class of potent and selective human NHE-1 inhibitors with potential utility for providing cardio-protection in a clinical setting.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.2003.tb00103.x
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  • 2
    Electronic Resource
    Electronic Resource
    Single-Center Experience with the Helex™ Septal Occluder for Closure of Atrial Septal Defects in Children (2003)
    350 Main Street , Malden , MA 02148 , USA . : Blackwell Science Inc
    Journal of interventional cardiology 16 (2003), S. 0 
    Details
    ISSN: 1540-8183
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Catheter closure of atrial septal defects (ASDs) is an accepted procedure among pediatric cardiologists. We report our early experience with the newest of these devices in clinical trials in the United States. Between April and October 2001, 14 patients were enrolled in an FDA phase II multicenter trial comparing the results of ASD closure using the HELEX™ Septal Occluder to a surgical control group. Of the 14 patients, devices were placed and left in 13, one being removed for an excessive residual leak despite placing the largest device available. Of the remaining 13 patients, all patients had successful closure of their defects. An average of 1.8 devices/patient were deployed, reflecting the learning curve for this new device and new delivery style. Six devices were replaced because of excessive residual leaks, three for premature lock release, and two for improper seating of the device. There were no procedural complications, however, one patient required device removal 4 months postimplant for possible allergic reaction to nickel. The same patient had removal of stainless steel sternal wires for the same reason. At the 6-month follow-up, 11 of 13 patients had complete closure of the ASD, the other two having small, hemodynamically insignificant left to right shunts. In one of these patients, there was complete closure at the 12-month follow-up, whereas the other patient awaits the 1-year evaluation. Early experience at our institution has demonstrated the ease of use of this device, its complete retrievability, and excellent closure of small to moderate ASDs in children. (J Interven Cardiol 2003;16:79–82)
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1540-8183.2003.08005.x
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  • 3
    Electronic Resource
    Electronic Resource
    ASYMMETRIC CELL DIVISION IN C. ELEGANS: Cortical Polarity and Spindle Positioning (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 427-453 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The one-cell Caenorhabditis elegans embryo divides asymmetrically into a larger and smaller blastomere, each with a different fate. How does such asymmetry arise? The sperm-supplied centrosome establishes an axis of polarity in the embryo that is transduced into the establishment of anterior and posterior cortical domains. These cortical domains define the polarity of the embryo, acting upstream of the PAR proteins. The PAR proteins, in turn, determine the subsequent segregation of fate determinants and the plane of cell division. We address how cortical asymmetry could be established, relying on data from C. elegans and other polarized cells, as well as from applicable models. We discuss how cortical polarity influences spindle position to accomplish an asymmetric division, presenting the current models of spindle orientation and anaphase spindle displacement. We focus on asymmetric cell division as a function of the actin and microtubule cytoskeletons, emphasizing the cell biology of polarity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.19.111301.113823
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  • 4
    Electronic Resource
    Electronic Resource
    Regulation of SSAT expression by synaptic activity (2001)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 13 (2001), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neuronal activity is a requirement for the plasticity and normal development of the central nervous system. We have used differential cloning techniques to identify an immediate-early gene (IEG) that is rapidly induced in neurons by activity in both adult and developmental models of plasticity. Here we describe the key regulatory enzyme of polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT), as a neuronal IEG. In the rat brain, kainate-induced seizures result in a 5.5-fold increase in the amount of SSAT mRNA above basal levels and the enzymatic activity is increased twofold. Expression of SSAT mRNA is rapidly and transiently upregulated in the cerebral cortex and hippocampus by seizure-induced neuronal activation. In hippocampal neurons, SSAT expression is dynamically responsive to synaptic activity in the long-term potentiation (LTP) paradigm. In developing brain, region-specific expression of SSAT mRNA is first detected at postnatal day 9 (P9) and subsequently increases through days P15, P20, before reaching maximal level in adult animals. This dynamic transcriptional and translational control suggests that SSAT may play a role in activity-dependent neuronal plasticity and development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.0953-816x.2001.01529.x
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  • 5
    Electronic Resource
    Electronic Resource
    Correction of bronchial challenge data for age and size may affect the results of genetic association studies in children (2003)
    Oxford, UK : Munksgaard International Publishers
    Pediatric allergy and immunology 14 (2003), S. 0 
    Details
    ISSN: 1399-3038
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Meaningful studies of asthma genetics require careful definition of airway hyperresponsiveness (AHR). In children, several studies have emphasized the need for correction of bronchial challenge data for baseline parameters, such as age, gender, lung function and atopic status, when undertaking airway responsiveness measurements. However, few studies have suggested how this should be performed in practice. This study describes a method for the correction of dose–response slopes (DRS) and PC20 values for baseline parameters in children, and illustrates the effect of such corrections on the association of AHR with the glutathione S-transferase GSTP1 Ile105Val polymorphism in children. Skin prick and methacholine challenge testing, measurement of total serum IgE concentration and GSTP1 genotyping were performed in 145 unrelated British children aged 7–18 years. Correction of bronchial challenge results, expressed as both DRS and PC20 values, for age, gender, baseline lung function and atopic status was performed using linear regression and discriminant analysis, respectively. Adjusting bronchial challenge results for the age and size of the child altered AHR status, defined as a PC20 methacholine 〈8 mg/ml, in 37% of children. Correction for baseline parameters also resulted in a significant reduction in mean DRS (original uncorrected DRS 83.6, corrected DRSc 27.4). This had a marked effect on the results of the association study, unmasking a previously unidentified association between the GSTP1 genotype and AHR in children. Age and size adjustment of bronchial challenge data has a significant effect on AHR status and may influence the results of genetic association studies in children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1399-3038.2003.00041.x
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  • 6
    Electronic Resource
    Electronic Resource
    The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving (2000)
    Oxford, UK : Carfax Publishing, part of the Taylor & Francis Group
    Addiction 95 (2000), S. 0 
    Details
    ISSN: 1360-0443
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine , Psychology
    Notes: All drugs of abuse have been shown to act either directly or indirectly by increasing dopamine neurotransmission within the limbic system. Thus, alcohol has been shown to increase dopamine transmission primarily by activating dopamine cell spike activity, whereas psychostimulants increase dopamine transmission by inhibiting the removal of dopamine from the synaptic space after its release. The spike-dependent release of dopamine that is modulated by drugs of abuse to lead to their rewarding actions has been termed the phasic dopamine response. In contrast, with repeated drug administration, dopamine will also accumulate in the extracellular space of the nucleus accumbens in concentrations too low to stimulate postsynaptic receptors, but of sufficient magnitude to activate dopamine release-inhibiting autoreceptors. In addition, the level of extracellular dopamine is proposed to be under the regulatory influence of cortico-accumbens afferents. This steady-state level of extrasynaptic dopamine has been termed the tonic dopamine response. In this paper it is proposed that several of the aspects of drug addiction, withdrawal and craving associated with the continued use of these drugs can be explained on the basis of their effects on tonic versus phasic dopamine system function. Thus, the increase in tonic dopamine levels that occurs with repeated drug administration would serve to oppose phasic dopamine release via stimulation of dopamine terminal autoreceptors, causing the subject to increase drug administration to restore the phasic response. Moreover, after withdrawal from the drugs, exposure to priming doses of drug or to drug-related stimuli are proposed to increase tonic dopamine levels, again triggering drug-seeking behavior in order to restore balance between the tonic and phasic dopamine systems. Therefore, one consequence of continued drug use is that these parameters of dopamine system function that normally serve to keep the system stable will enter into a new steady-state homeostasis, from which the system is particularly susceptible to destabilizing influences that may precipitate relapse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1360-0443.95.8s2.1.x
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  • 7
    Electronic Resource
    Electronic Resource
    DNA-based immunotherapeutics for the treatment of allergic disease (2001)
    Copenhagen : Munksgaard International Publishers
    Immunological reviews 179 (2001), S. 0 
    Details
    ISSN: 1600-065X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: Allergic diseases are a growing health concern in industrialized countries. Despite a number of effective therapeutic options for the prevention and treatment of the pathophysiologic responses which characterize allergic diseases, the induction of true allergen desensitization remains an elusive therapeutic goal. Only immunotherapy (IT) has been shown to have any effect on the underlying hypersensitivities which mediate allergic reactions, and traditional protein-based allergen IT has a limited scope of efficacy. However, a number of reagents collectively termed DNA-based immunotherapeutics have proven highly effective in both the prevention and reversal of Th2-mediated hypersensitivity states in mouse models of allergic disease. Four basic DNA-based immunotherapeutic modalities have been used for these studies. These include immunization with gene vaccines, allergen mixed with immunostimulatory oligodeoxynucleotide (ISS-ODN), and physical allergen–ISS-ODN conjugates (AIC), as well as immunomodulation with ISS-ODN alone. Results from many laboratories have generated guarded optimism that DNA-based immunotherapeutics may be effective for the reversal of allergic hypersensitivity states in humans, and several clinical trials have already been initiated. This review will focus on our present understanding of the biological activities of DNA-based immunotherapeutics and their application to the treatment of allergic diseases.This work was supported by grants AI40682 and AI01490 from the NIH and by a grant from Dynavax Technologies Corporation. J.H.V. is also a Medical Scientist Training Program Trainee.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1600-065X.2001.790111.x
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  • 8
    Electronic Resource
    Electronic Resource
    Antigen–immunostimulatory oligonucleotide conjugates: mechanisms and applications (2004)
    Oxford, UK; Malden, USA : Munksgaard International Publishers
    Immunological reviews 199 (2004), S. 0 
    Details
    ISSN: 1600-065X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary:  Conjugation of protein antigen with immunostimulatory oligonucleotides creates a potent immunogen. Physical linking of oligonucleotides to antigen enhances antigen uptake and targets the adjuvant properties of the oligonucleotides to the antigen-presenting cell. In addition, the conjugated oligonucleotides appear to have improved immunostimulatory abilities compared to free oligonucleotides, presumably due to enhanced activation of Toll-like receptor 9. Immunization with these conjugate preparations elicits antigen-specific antibody responses, a T-helper cell 1-biased cytokine profile from CD4 T cells, and CD8 cytotoxic T-lymphocyte activity that is CD4 independent. The humoral and cellular immune responses induced by these conjugates suggest they can be used to create effective vaccines against infectious pathogens and tumors and to beneficially modulate allergic responses. Indeed, recent clinical trial data show symptom relief and immunomodulation of the allergic response in patients with allergic rhinitis. This review considers the mechanisms of action of antigen–oligonucleotide conjugates and discusses available data regarding their use for the prevention and treatment of infectious, oncologic, and allergic diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0105-2896.2004.00149.x
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  • 9
    Electronic Resource
    Electronic Resource
    The Plasmodium falciparum clag9 gene encodes a rhoptry protein that is transferred to the host erythrocyte upon invasion (2004)
    Oxford, UK : Blackwell Science Ltd
    Molecular microbiology 52 (2004), S. 0 
    Details
    ISSN: 1365-2958
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: The first gene characterizing the clag (cytoadherence linked asexual gene) family of Plasmodium falciparum was identified on chromosome 9. The protein product (Clag9) was implicated in cytoadhesion, the binding of infected erythrocytes to host endothelial cells, but little information on the biochemical characteristics of this protein is available. Other genes related to clag9 have been identified on different chromosomes. These genes encode similar amino acid sequences, but clag9 shows least conservation. Clag9 was detected in schizonts, merozoites and ring-stage parasites after protease digestion and peptide analysis by mass spectrometry. Using antisera raised against unique regions of Clag9 and against RhopH2, a component of the RhopH high-molecular-mass protein complex of merozoites, immunofluorescence co-localized the two proteins to the apical region of merozoites. Immunoelectron microscopy co-localized Clag9 and RhopH2 exclusively to the basal bulb region of rhoptries rather than to their apical ducts. The same Clag9-specific antibodies bound the RhopH complex, and the protein was detected in the complex purified by antibodies to RhopH2. Clag9 protein was also shown to be present in ring-stage parasites, carried through from the previous cycle with the RhopH complex, in a location identical to that of RhopH2. Transcription of the clag9 gene was shown to occur at the same time as the genes for other members of the RhopH complex, rhoph2 and 3. The results indicate that Clag9 is part of the RhopH complex and suggest that, within this complex, the protein previously designated RhopH1 is composed of more than one protein product of the clag gene family. The results cast doubt on a direct role for Clag9 in cytoadhesion; we suggest that the primary role of the RhopH complex is in remodelling the infected red blood cell after invasion by the merozoite. The complex may have multiple functions dependent on its exact composition, which may include, with respect to Clag9, a contribution to the mechanism of cytoadhesion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2958.2003.03969.x
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  • 10
    Electronic Resource
    Electronic Resource
    DNA-based vaccination for the treatment of food allergy (2001)
    Copenhagen : Munksgaard International Publishers
    Allergy 56 (2001), S. 0 
    Details
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: At present, avoidance is the only therapeutic option available for individuals with food allergies. However, studies suggest that DNA-based vaccination might be an effective therapeutic option for the reversal of allergic hypersensitivities, including allergies to foods. Because severe anaphylactic reactions represent a life-threatening risk for individuals with food allergies, we and others have evaluated the effectiveness of DNA-based vaccination for the prevention of anaphylactic hypersensitivity in murine models. Our investigations demonstrated that primary gene and protein/immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) vaccination of subsequently Th2-sensitized mice reduced the risk of death after anaphylactic challenge, significantly. In addition, gene and protein/ISS-ODN vaccination reduced post challenge plasma histamine levels. Analysis of the immune profiles of mice receiving DNA-based vaccines showed that both gene and protein/ISS-ODN vaccination effectively prevented the development of Th2-biased immune profiles after sensitization. In contrast, vaccination with protein alone, the experimental equivalent of the traditional protein-based immunotherapy (IT) reagents used in clinical practice provided no protection from anaphylaxis, nor did it prevent the development of a Th2-biased immune profile after allergen sensitization. These studies justify continued optimism in the potential of DNA-based vaccination for the desensitization of food allergic individuals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1398-9995.2001.00937.x
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