bluuebunny/crossref_metadata_2025 huggingface dataset:
Imidazoline Binding Domains on MAO‐B: Localization and Accessibilitya
Authors: RADDATZ RITA , SAVIC SANDRA L. , LANIER S. M.
Published: February 2006

ABSTRACT: Various imidazoline and guanidinium derivatives elicit diverse cellular responses in both peripheral tissues and the central nervous system that are often difficult to attribute to known receptor signaling systems. Such molecules also exhibit high affinity for membrane proteins (imidazoline binding sites) that are distinct from receptors for known hormones and recognize endogenous bioactive substance(s) that mimic some of the effects of these compounds. These observations suggest a previously uncharacterized cell signaling system. However, limited information on the identity and functionality of this family of imidazoline binding sites has hampered the full understanding of this system. Unexpectedly and of particular significance, recent data indicate that two members of the family of imidazoline binding proteins are identical to the A and B isoforms of monoamine oxidase (MAO). The imidazoline binding domain on MAO is distinct from the enzyme active site that recognizes the mechanism‐based inhibitors such as pargyline and deprenyl and is not equally accessible in all tissues.
Relationship between I2 Imidazoline Binding Sites and Monoamine Oxidase B in Livera
Authors: REMAURY A. , ORDENER C. , SHIH J. , PARINI A.
Published: February 2006

ABSTRACT: Biochemical and pharmacologic studies suggest that I2 imidazoline binding sites (I2BS) represent a heterogeneous family of membrane proteins. Indeed, the imidazoline binding sites located on monoamine oxidases (MAO) A and B display different pharmacologic properties. Recent results suggest that in liver and brain, I2BS may be located on proteins distinct from MAOs. The following observations indicate that in liver and brain, [3H]idazoxan binds exclusively to I2BS located on MAO‐B: (1) size exclusion chromatography of digitonin‐solubilized preparations from rabbit and human liver showed that [3H]idazoxan‐specific binding eluted only in two peaks (∼175,000 and ∼100,000 Da, corresponding to 90% and 10% of the recovered [3H]idazoxan binding) which also contained MAOs as determined by [14C]tyramine oxidation and Western blot analysis; (2) according to previous results obtained in various human and rat tissues, experiments performed in mice liver and brain showed that idazoxan was a potent inhibitor of [125I]‐AZIPI photoincorporation to MAO‐B but not to MAO‐A; (3) in MAO‐deficient transgenic mice, [3H]idazoxan binding to liver and brain membranes was completely abolished in MAO‐B knockout mice and was not affected in MAO‐A knockout mice. Together, these results show that in both liver and brain, I2BS are located exclusively on MAO‐B. The imidazoline binding site on MAO‐A, which photoincorporates [125I]‐AZIPI and displays a low affinity for idazoxan, may not belong to the family of the I2 imidazoline binding sites.
The I1‐Imidazoline Receptor and Its Cellular Signaling Pathwaysa
Authors: ERNSBERGER PAUL
Published: February 2006

ABSTRACT: Two primary questions are addressed. First, do I1‐imidazoline binding sites fulfill all the essential criteria for identification as a true receptor? Second, what are the cellular signaling pathways coupled to this novel receptor? I1‐imidazoline binding sites show specificity in binding assays, linkage to physiologic functions, appropriate anatomic, and cellular and subcellular localization. Most important, binding affinities correlate with functional drug responses. I1‐imidazoline binding sites meet several additional criteria identified with functional receptors: they show physiologic regulation and endogenous ligands and, most crucially, are coupled to cellular signaling events. A series of studies have identified cellular events triggered by I1‐imidazoline receptor occupancy. This receptor is not coupled to conventional pathways downstream of heterotrimeric G‐proteins, such as activation or inhibition of adenylyl or guanylyl cyclases, stimulation of inositol phospholipid hydrolysis, or induction of rapid calcium fluxes. The I1‐imidazoline receptor is coupled to choline phospholipid hydrolysis, leading to the generation of diacylglyceride, arachidonic acid, and eicosanoids. Additional cellular responses include inhibition of Na+/H+ exchange and induction of genes for catecholamine synthetic enzymes. The signaling pathways linked to the I1‐imidazoline receptor are similar to those of the interleukin family, implying that I1‐receptors may belong to the family of neurocytokine receptors.
Agmatine: An Endogenous Ligand at Imidazoline Receptors Is a Novel Neurotransmittera
Authors: REIS DONALD J. , REGUNATHAN SOUNDARARAJAN
Published: February 2006

ABSTRACT:Agmatine, an amine and organic cation, is an endogenous ligand at α2‐adrenergic and imidazoline (I‐) receptors, to which it binds with high affinity. In addition, agmatine has properties of an endogenous neurotransmitter. Thus, agmatine (a) is locally synthesized in brain by a specific enzyme, arginine decarboxylase; (b) is stored in a large number of neurons with selective distribution in the CNS; (c) is associated with small vesicles in axon terminals that, at least in hippocampus, make synaptic asymmetric (excitatory) synapses on pyramidal cells; (d) is released from synaptosomes in a Ca2+‐dependent manner; (e) can be enzymatically degraded by agmatinase in synaptosomes; (f) can be inactivated by selective reuptake; (g) blocks the ligand‐gated NMDA receptor channel at sites distinct from ligand‐binding and polyamine sites; and (h) has systemic actions when administered intraventricularly. Additionally, (i) agmatine is a precursor of brain putrescine and, hence, of higher polyamines, and (j) it competitively inhibits the activity of all isozymes of nitric oxide synthase. Agmatine meets most criteria to establish it as a novel neurotransmitter/neuromodulator in the CNS. However, agmatine differs from forms of clonidine displacing system with respect to distribution, bioactivity, and capacity to interact with antibodies raised to imidazoline‐like drugs. Thus, there are multiple endogenous ligands of the imidazoline receptors, one of which is agmatine.
Identification of Human I1Receptors and Their Relationship to α2‐Adrenoceptors
Authors: DONTENWILL M. , VONTHRON C. , GRENEY H. , MAGNIER C. , HEEMSKERK F. , BOUSQUET P.
Published: February 2006

ABSTRACT:I1imidazoline receptors (I1R) were defined as receptors insensitive to catecholamines and highly sensitive to [3H]clonidine and analogs. By contrast, the I2R subtype is more sensitive to [3H]idazoxan. [3H]clonidine and [3H]idazoxan imidazoline specific binding sites (IBS) have been detected in crude human membranes. Pharmacologic characterization by binding assays clearly differentiates IBS from α2‐adrenoceptors, whereas differences between [3H]clonidine and [3H]idazoxan IBS are less clear in crude preparations. In fact, only moderate affinity for [3H]clonidine was detectable in such preparations. However, purification procedures allowed detection of high affinity [3H]clonidine IBS in the human brain, corresponding to the I1R. Difficulties in the characterization of the I1R in crude membranes are due to multiple factors including heterogeneity of IBS, their low Bmaxvalue, the existence of allosteric modulation, and possibly the presence of natural binding inhibitors. Immunologic studies with specific anti‐idiotypic antibodies revealed a 43‐kD protein as the best candidate for I1R as binding activity coincides with immunodetection. No cross‐reaction was found with anti‐monoamine oxidase (MAO) A/B antibodies and the 43‐kD protein, ruling out the possibility of this protein being an MAO‐associated I2R. Neither anti‐α2A‐ nor anti‐α2B‐specific antibodies were able to immunodetect the 43‐kD protein in crude membrane preparations or in purified fractions. These results and further biochemical characterization (pHi,N‐glycosylation) of the 43‐kD protein definitely assessed that human brain I1R and α2‐adrenoceptors clearly differ physically. However, coexpression of I1R and α2‐adrenoceptors in synaptic plasma membranes of the bovine brainstem reinforce the possibility of a functional relationship between the two types of receptor.
Gene Substitution/Knockout to Delineate the Role of α2‐Adrenoceptor Subtypes in Mediating Central Effects of Catecholamines and Imidazolines
Authors: HEIN L. , LIMBIRD L. E. , EGLEN R. M. , KOBILKA B. K.
Published: February 2006

ABSTRACT: Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. For the three α2‐adrenergic receptors (α2A, α2B, and α2C), genetic mouse models have been developed that can be used to elucidate the physiologic function of each receptor subtype in vivo. Different strategies for homologous recombination in embryonic stem cells were applied to generate lines of mice with gene knockouts of the individual α2‐receptor subtypes (α2A‐KO, α2B‐KO, and α2C‐KO) or with a substitution of a mutant receptor at the wild‐type locus (α2‐D79N). In these transgenic mice, the cardiovascular effects of α2‐agonists and imidazoline;i1 receptor agonists were tested. Stimulation of α2B receptors in vascular smooth muscle produces hypertension and counteracts the clinically beneficial hypotensive effect of stimulating α2A receptors in the central nervous system.
Central Imidazoline‐ and α2‐Receptors Involved in the Cardiovascular Actions of Centrally Acting Antihypertensive Agentsa
Authors: HEAD GEOFFREY A.
Published: February 2006

ABSTRACT: There has been a continuing and yet unresolved debate concerning the existence and contribution of imidazoline receptors to the antihypertensive actions of clonidine‐like agents. Studies from our laboratory have examined the importance of imidazoline receptors and α2‐adrenoceptors in the mechanism of action of centrally acting antihypertensive drugs. We used conscious rabbits and imidazoline and specific α2‐adrenoceptor antagonists to show that second‐generation agents rilmenidine and moxonidine act preferentially through imidazoline receptors but that α2‐adrenoceptors are important for the hypotension produced by clonidine and α‐methyldopa. Using microinjections of the imidazoline antagonists into the rostral ventrolateral medulla (RVLM) of anesthetized rabbits we confirmed the generally held view that this is the major site of sympathoinhibitory actions of centrally acting antihypertensive agents. However, we also found that α2‐adrenoceptors are present in this nucleus and appear to be activated as a consequence of imidazoline receptor activation. In recent studies using a noradrenergic neurotoxin microinjected into the RVLM we found that this treatment selectively blocked the actions of moxonidine but did not affect the level of imidazole proteins, suggesting that I1‐imidazoline receptors may be located presynaptic to the noradrenergic terminal. By contrast, clonidine acts directly on the α2‐adrenoceptors perhaps located on cell bodies in the nucleus. In conclusion, our studies suggest that imidazoline receptors and α2‐adrenoceptors within the RVLM are important for the antihypertensive actions of clonidine‐like drugs.
Imidazoline Recognition Sites and Stomach Functiona
Authors: MOLDERINGS G. J. , BURIAN M. , MENZEL S. , DONECKER K. , HOMANN J. , NILIUS M. , GÖTHERT M.
Published: February 2006

ABSTRACT:Radioligand binding experiments carried out in cell membranes from rat and human stomach revealed the existence of non‐adrenoceptor [3H]clonidine and [3H]idazoxan binding sites and of [3H]DTG (1,2‐di‐(2‐tolyl)guanidine) binding sites. In rat stomach, specific binding was inhibited by imidazolines and guanidines and by non‐imidazoline σ‐site ligands, respectively, at different rank orders of affinity, suggesting the existence of non‐I1/non‐I2[3H]clonidine binding sites, I2‐imidazoline binding sites as well as σ2‐like‐sites. These sites are not directly related to a postsynaptic contractile effect on rat gastric smooth muscle or to acid release from isolated gastric glands. Finally, we demonstrated that the gastric pathogenHelicobacter pyloriis able to form and to release the endogenous imidazoline receptor ligand agmatine and that considerable amounts of agmatine are present in human gastric juice. The quantities of agmatine were higher in gastric juice fromH. pylori‐positive thanH. pylori‐negative patients.
Imidazoline Receptors and Human Brain Disordersa
Authors: GARCÍA‐SEVILLA JESÚS A. , ESCRIBÁ PABLO V. , GUIMÓN JOSÉ
Published: February 2006

ABSTRACT: Major depression, opioid addiction, neurodegenerative diseases, and glial tumors are associated with disturbances of imidazoline receptors (IR) in the human brain. In depression, the level of a 45‐kD IR protein (putative I1‐IR) is increased in the brain of suicide victims (51%) and in platelets of depressed patients (40%). The density of platelet I1‐IR ([125I]‐p‐iodoclonidine binding) is also increased in depression (135%). The 29/30‐kD IR protein (putative I2B‐IR) is downregulated (19%) in suicide victims in parallel with a reduction (40%) in the density of I2B‐IR ([3H]idazoxan binding). Antidepressant drugs induce downregulation of 45‐kD IR protein and I1‐sites in platelets of depressed patients and upregulation of I2‐sites in rat brain. The densities of I2B‐IR and the related 29/30‐kD IR protein are decreased (39% and 28%) in the brain of heroin addicts. The density of I2B‐IR is increased in Alzheimer's disease (63%) and decreased in Huntington's disease (56%). Brain I2B‐IR is not altered in Parkinson's disease. The level of I2‐IR in glial tumors is increased (two fivefold) in parallel with the abundance of the related 29/30‐kD IR protein (39%), whereas the level of 45‐kD IR protein is decreased (39%). The possible functional relevance of these findings in the context of the pathogenesis of these disorders remains to be elucidated.
Anti‐Proliferative and Anti‐Inflammatory Actions of Imidazoline Agents: Are Imidazoline Receptors Involved?
Authors: REGUNATHAN S. , FEINSTEIN D. L. , REIS D. J.
Published: February 2006

ABSTRACT: We have shown that cultured vascular smooth muscle cells (VSMC) and brain astroglial cells express I‐receptors of the I;i2 subtype. While imidazoline agents are anti‐proliferative in smooth muscle cells, they increase the expression of glial fibrillary acidic protein (GFAP) in astrocytes. Because increases in GFAP suppress the induction of calcium‐independent, inducible nitric oxide synthase (NOS‐2), we measured whether idazoxan and related imidazolines and agmatine would also suppress the expression of NOS‐2. Cultured astrocytes and macrophages, RAW 264.7 cell line, were incubated with lipopolysaccharide (LPS, 1 μg/ml) or cytokine mixture in the presence of 1–100 μM of idazoxan, agmatine, or other imidazoline agents. Idazoxan potently (IC50, 10 μM) decreased the activity of NOS‐2 in astrocytes, but was less potent in RAW 264.7 cells. By contrast, agmatine was most potent in RAW 264.7 cells (IC50, 10 μM) but less potent in glial cells and VSMC. Both idazoxan and agmatine decreased the activity of NOS‐2 by reducing the levels of enzyme protein as measured by immunoblot and immunocytochemistry. No specific binding of [3H]‐idazoxan was observed in RAW 264.7 cell membranes. We conclude that idazoxan, agmatine, and selected imidazoline agents inhibit the expression of NOS‐2 and proliferation in primary glial cells and VSMC. While the antiproliferative actions appear mediated by I‐receptors of the I2 type, the anti‐inflammatory response is probably not mediated by I‐receptors but possibly by direct actions on signal transduction enzymes.
Central I1‐Imidazoline Receptors As Targets of Centrally Acting Antihypertensive Drugs: Clinical Pharmacology of Moxonidine and Rilmenidine
Authors: VAN ZWIETEN P. A. , PETERS S. L. M.
Published: February 2006

ABSTRACT: Moxonidine and rilmenidine are moderately selective I1‐receptor stimulants. The imidazoline (I1) agonists cause peripheral sympathoinhibition, triggered at the level of central nervous imidazoline receptors. Imidazoline receptor stimulants are effective antihypertensive agents with a hemodynamic profile that is attractive from a pathophysiologic point of view. The antihypertensive activity of these agents is caused by vasodilatation and reduced peripheral vascular resistance. Left ventricular end‐diastolic and end‐systolic volume is reduced, whereas heart rate, stroke volume, cardiac output, and pulmonary artery pressures are largely unchanged. Long‐term left ventricular hypertrophy is reduced. Both drugs, when applied in a once‐daily dosage schedule, appear to control hypertension in most patients. Both drugs have been compared with representative agents from the major classes of antihypertensive drugs in controlled trials and found to be equally effective in blood pressure control. The incidence and severity of side effects are lower than those for clonidine, particularly with respect to sedation. A rebound (withdrawal) phenomenon has so far not been reported for moxonidine and rilmenidine. Therefore, I1‐receptor stimulants offer the possibility of developing centrally acting agents with a better side‐effect profile than do the classic α2‐adrenoceptor stimulants.
Plasma Agmatine and Platelet Imidazoline Receptors in Depressiona
Authors: HALARIS ANGELOS , ZHU HE , FENG YENGZHENG , PILETZ JOHN E.
Published: February 2006

ABSTRACT: Plasma agmatine concentrations are elevated significantly in depressed patients compared to healthy controls. Treatment with the antidepressant bupropion normalized plasma agmatine levels. Correlational evidence is presented that a change in plasma agmatine levels may lead to similar changes in platelet I1 imidazoline receptors.
A Paradigm for Cancer Treatment Using the Retinoblastoma Gene in a Mouse Model
Authors: NIKITIN ALEXANDER YU. , RILEY DANIEL J. , LEE WEN‐HWA
Published: February 2006

Abstract: Discovery of tumor suppressor genes has provided a rational approach to cancer prevention and treatment. Loss of retinoblastoma susceptibility gene (Rb) function is a rate‐limiting event in the development of human and mouse cancers. Establishment of animal models of cancer associated with Rb deficiency allowed us to develop and test long‐awaited approaches to genetic correction for treating tumors in vivo. Recent studies demonstrated that (1) prevention of carcinogenesis is achieved by correction of gene copy number in Rb+/− mice, and (2) reconstitution of Rb gene functions is sufficient for suppression of neoplasia in immunocompetent mice. These results fulfill a promise of cancer treatment by reconstitution of tumor suppressor function.
Antiangiogenic Domains Shared by Thrombospondins and Metallospondins, a New Family of Angiogenic Inhibitors
Authors: IRUELA‐ARISPE M. LUISA , VÁZQUEZ FRANCISCA , ORTEGA MARIA ASUNCIÓN
Published: February 2006

Abstract: The growth of solid tumors has been shown to depend on neovascularization. By understanding the mechanisms that control the neovascular response, it may be possible to design therapeutic strategies to selectively prevent or halt pathologic vascular growth and restrain cancer progression. Thrombospondin‐1 is an extracellular matrix protein that among several functions suppresses capillary growth in angiogenesis assays. We have demonstrated that within the context of the mammary gland TSP1 can modulate normal development of blood vessels. Expression of TSP1 in transgenic animals under the control of the MMTV promoter was associated with a 50–72% reduction in capillary growth. In addition, TSP1 reduced tumor size in transgenic overexpressors. The data suggest an important role for TSP1 in modulating vascular growth in both normal and pathologic tissues. The antiangiogenic region of TSP1 has been mapped to the type I (properdin) repeats. To identify novel proteins with such a domain, we have cloned two cDNAs (METH‐1 and METH‐2) which also have antiangiogenic properties. In addition to carboxyterminal thrombospondin‐like domains they also contain metalloproteinase and disintegrin sequences. Expression of both proteins is broad but nonoverlapping. Recombinant fragments from these sequences have strong antiangiogenic potential in the CAM and cornea pocket assays. At the same molar ratio, METH‐1 and METH‐2 are about 20‐fold more potent than TSP1. We predict that these proteins are likely endogenous modulators of vascular growth with relevant therapeutic potential in cancer and other disease states.
Intracellular Signaling of the TGF‐β Superfamily by Smad Proteins
Authors: KAWABATA MASAHIRO , IMAMURA TAKESHI , INOUE HIROFUMI , HANAI JUN‐ICHI , NISHIHARA AYAKO , HANYU AKI , TAKASE MASAO , ISHIDOU YASUHIRO , UDAGAWA YOSHIYUKI , OEDA EIICHI , GOTO DAISUKE , YAGI KEN , KATO MITSUYASU , MIYAZONO KOHEI
Published: February 2006

Abstract: TGF‐β is a potent inhibitor of cell growth, and accumulating evidence suggests that perturbation of the TGF‐β signaling pathway leads to tumorigenesis. Smads are recently identified proteins that mediate intracellular signaling of the TGF‐β superfamily. Smads 2 and 3 are phosphorylated by the TGF‐β type I receptor. Smad4 was originally identified as a candidate tumor suppressor gene in pancreatic cancers. Smads 2 and 3 form complexes with Smad4 upon TGF‐β stimulation. The heteromeric Smad complexes translocate into the nucleus, where they activate expression of target genes. Our recent study demonstrated that Smads exist as monomers in the absence of TGF‐β. Smads 2 and 3 form homo‐ as well as hetero‐oligomers with Smad4 upon ligand stimulation. Both homo‐oligomers and hetero‐oligomers directly bind to DNA, suggesting that the signaling pathway of Smads may be multiplex. Smads 2 and 3 associate with transcriptional coactivators such as p300 in a ligand‐dependent manner. p300 enhances transactivation by TGF‐β, suggesting that coactivators link Smads to the basal transcriptional machinery. A missense mutation of Smad2 identified in colorectal and lung cancers was introduced to Smad3. The mutant, Smad3(DE), blocked the activation of wild‐type Smad2 and Smad3. Thus, the missense mutation not only disrupts the function of the wild‐type Smad but also creates a dominant‐negative Smad, which could actively contribute to oncogenesis.
Farnesyltransferase Inhibitors: Preclinical Development
Authors: KOHL NANCY E.
Published: February 2006

Abstract: The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl‐protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell‐active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras‐induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras‐transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is curently being tested in the clinic.
Activation of Apoptosis and Its Inhibition
Authors: MILLER DOUGLAS K.
Published: February 2006

Abstract: The induction of apoptosis, or controlled cell death, by various stimuli has been shown to activate a cascade of endoproteases, called caspases, that cleave numerous cellular proteins necessary for cellular homeostasis. This review discusses this family of proteases together with a variety of mammalian and viral regulatory proteins that act to control this activation.
Strategies to Adapt Adenoviral Vectors for Targeted Delivery
Authors: CURIEL DAVID T.
Published: February 2006

Abstract: The utility of current generation adenoviral vectors for targeted, cell‐specific gene delivery is limited by the promiscuous tropism of the parent virus. To address this issue, we have developed both genetic and immunologic methods to alter viral tropism. Immunologic retargeting has been achieved via conjugates comprised of an antifiber knob Fab and a targeting moiety consisting of a ligand or antireceptor antibody. Gene delivery by this approach has been accomplished via a variety of cellular pathways including receptors for folate, FGF, and EGF. In addition to cell‐specific gene delivery, this strategy has allowed enhanced gene delivery to target cells lacking the native adenoviral receptor, CAR. Of note, this specific and extended gene delivery allowed enhanced survival in murine models of human carcinoma via cancer gene therapy. Genetic strategies to alter adenoviral tropism have included both fiber modification and fiber replacement. In the former, we have identified the HI loop of fiber as a propitious locale for introduction of heterologous peptides. Incorporation of an RGDC peptide at this locale allowed gene delivery via cellular integrins with dramatic efficiency augmentations. As a strategy to achieve both new tropism as well as to ablate native tropism, methods have been developed to replace the fiber protein with heterologous motif which preserves the key trimeric quaternary structure of fiber and allows for propagation. Such a fiber‐replacement virus has been rescued and has demonstrated capacities consistent with its utility as a novel vector agent. These strategies have allowed the achievement of cell‐specific gene delivery via adenoviral vectors and thus have the potential to enhance the utility of this vector agent.
Homeodomain‐Derived Peptides: In and Out of the Cells
Authors: PROCHIANTZ ALAIN
Published: February 2006

Abstract: The internalization of homeodomains and of homeopeptides derived from the third helix of the homeodomain of Antennapedia, a Drosophila transcription factor, is used by some investigators to target exogenous hydrophilic compounds into live cells. In addition to this very practical aspect of drug delivery, translocation across biologic membranes of peptides subsequently addressed to the cell cytoplasm and nucleus raises several questions. A first series of questions pertains to the mechanism of translocation. Thanks to the synthesis of several peptides derived from the third helix of the Antennapedia homeodomain, we began to investigate the mechanism of translocation and we have shown that it is not dependent upon the presence of a chiral receptor and probably involves the formation of inverted micelles. A second series of questions is related to the physiologic significance of the phenomenon. In a first approach, we demonstrated that some full‐length homeoproteins are internalized and secreted in vitro. The mechanism of internalization is probably similar to that of the homeodomain or of its third helix, but secretion involves a different mechanism which requires an association with specialized intracellular membranous structures. The existence of specific mechanisms for homeoprotein internalization and secretion suggests that this class of transcription factors may have important signaling properties.
Monitoring Temperature‐Induced Changes in Tissue during Hyperthermia by Impedance Methodsa
Authors: GERSING EBERHARD
Published: February 2006

Abstract: The electrical conduction in living tissue depends on temperature in two ways: (1) the temperature coefficients of conductivity of the intra‐ and extracellular electrolytes and (2) temperature‐induced fluid volume shifts in the tissue. Measurements in rat skeletal muscle and tumors (DS sarcoma) during hyperthermic treatment reveal that the contribution of fluid volume shifts to changes in conduct‐ance is of the same order of magnitude as the change in fluid conductivity. In skeletal muscles, blood volume changes are caused by the temperature‐dependent regulation of the vessel diameter (vasodilatation). In tumors, fluid content changes irregularly. These effects render temperature measurements by impedance methods, for example, electrical impedance tomography (EIT), questionable. However, monitoring fluid volume changes in tissue and the state of cell membranes is an interesting application of impedance (or admittance) spectroscopy and tomography as well.
A Review of Parameters for the Bioelectrical Characterization of Breast Tissue
Authors: JOSSINET JACQUES , SCHMITT MICHEL
Published: February 2006

Abstract: In the data set collected by the authors in freshly excised breast tissue, the admittance loci generally differed from circular arcs, rendering the calculation of the usual set of parameters impossible. Alternative parameters were used for the analysis of these data. The present study consists of the definition and evaluation of a set of such parameters aimed at the characterization and differentiation of breast tissues. These parameters were defined so that their calculation does not require the fit of circular arcs to the experimental points and is independent of any equivalent circuit model. The results of the statistical analysis showed significant differences between most of the tissue groups, especially between cancerous tissue and all the other groups, which confirmed that impedance spectroscopy can be considered as potentially suitable for breast cancer detection.
Quantitative Analysis of Impedance Spectra of Organs during Ischemia
Authors: GHEORGHIU MIHAELA , GERSING EBERHARD , GHEORGHIU EUGEN
Published: February 2006

Abstract: We have developed a rapid, quantitative procedure to fit the spectra of the real and imaginary part of tissue impedance, providing characteristic parameters: time constants, their distribution, and the amplitudes of associated dispersions. Based on the time course of tissue impedance during ischemia, we have derived the evolution of characteristic parameters for both myocardial and liver tissue. The similar evolution of the distribution of time constants for myocardial and liver tissue is emphasized and discussed.
Requirements for Clinical Use of Bioelectrical Impedance Analysis (BIA)a
Authors: LUKASKI HENRY C.
Published: February 2006

Abstract: The bioelectrical impedance analysis (BIA) method is an attractive tool for use in the clinical assessment of human body composition. Factors such as ease of use, relatively low cost, noninvasive nature, high degree of reproducibility, and safety of operation provide an impetus for the general application of this method. The preponderance of the published applications of BIA focused on applications in healthy populations and indicated a qualitative validity of the method. More recent applications have augmented the quantitative values of the BIA approach and have reported very good specificity and sensitivity. One potential limitation of the BIA approach is the reliance on regression models, derived in restricted samples of human subjects, which restricts the usefulness of the derived model in other patients who differ from the original sample in which the model was developed. Other investigational approaches that use different physical models (bioelectrical impedance spectroscopy and parallel model) have yielded successful and useful measures of human body composition in clinical studies. If BIA is to gain acceptance in clinical diagnosis and evaluation of therapeutic interventions, further efforts will be needed to ascertain more fully the validity, sensitivity, and specificity of biological parameters estimated with the new BIA approaches, and to establish the prognostic values of the BIA estimates of body composition.
Fat‐Free Mass Qualitative Assessment with Bioelectric Impedance Analysis (BIA)
Authors: TALLURI T. , LIETDKE R. J. , EVANGELISTI A. , TALLURI J. , MAGGIA G.
Published: February 2006

Abstract: Body composition studies, when based on two‐compartment volumetric estimates, can hardly assess nutritional states. Phase‐sensitive impedance analysis can be used to reflect directly the proportions between intra‐ and extracellular spaces (ECM/BCM), which is one of the most sensitive indexes of malnutrition. Resistance and reactance values actually measured with BIA are referred to as the series RC model; however, due to the morphology of the FFM, which is composed of cells surrounded by interstitial fluids, in reality this should be modeled as a parallel RC circuit. A nomogram developed with series‐to‐parallel transformations of resistance and reactance measured with commercial BIA on controls and patients shows interesting gender and disease sensitivity and specificity.
Estimation of Extracellular Volume by a Two‐Frequency Measurement
Authors: GOOVAERTS H. G. , FAES TH.J. C. , DE VALK‐DE ROO G. W. , TEN BOLSCHER M. , NETELENBOSCH J. C. , VAN DER VIJGH W.J. F. , HEETHAAR R. M.
Published: February 2006

Abstract: An approach to determine intra‐ and extracellular conduction on the basis of Bode analysis is presented. Estimation of the ratio between intra‐ and extracellular conduction could be performed by phase measurement only, midrange in the bandwidth of interest. An important feature is that the relation between intra‐ and extracellular conduction can be continuously monitored by phase measurement and no curve fitting whatsoever is required. Based on a two‐frequency measurement determining Re at 4 kHz and ϕmax at 64 kHz, it proved possible to estimate extracellular volume (ECV) in 23 patients. Reference values on ECV were determined by sodium bromide. The results show a good correlation (r= 0.90) with the reference method. The average error of ECV estimation was −3.6% (SD 8.4).
The RXc Graph in Evaluating and Monitoring Fluid Balance in Patients with Liver Cirrhosis
Authors: GUGLIELMI FRANCESCO WILLIAM , MASTRONUZZI TECLA , PIETRINI LORENA , PANARESE ALBA , PANELLA CARMINE , FRANCAVILLA ANTONIO
Published: February 2006

Abstract: A recent study, using height‐standardized resistance (R/H) and reactance (Xc/H) and assuming a bivariate distribution, has proposed the “RXc graph”. We applied this new approach for patients with chronic liver disease in differentiating various degrees of fluid unbalance. Our data showed that a 95% confidence ellipse of patients with chronic hepatitis (CH) overlapped that of healthy control subjects (CONTR), while those of patients with liver cirrhosis (CIR), patients with cirrhosis and ascites (ACIR), and patients with cirrhosis, edemas, and ascites (AECIR) were clearly different for both genders. A progressively shorter mean impedance vector proportional to the stage of liver disease and to the degree of fluid unbalance was found. The lower half of the 50% tolerance ellipse for the healthy population proved to be a threshold for cirrhotics, while almost all the subjects with clinically detectable edema fell outside this limit. The RXc graph was shown to be useful in monitoring the treatment of fluid unbalance and for the immediate selection of patients in whom BIA can precisely assess body composition.
Lead Field Theoretical Approach in Bioimpedance Measurements: Towards More Controlled Measurement Sensitivitya
Authors: KAUPPINEN PASI K. , HYTTINEN JARI A. , KÖÖBI TIIT , MALMIVUO JAAKKO
Published: February 2006

Abstract: This study was conducted to demonstrate the potentiality of lead field theoretical approach in analyzing bioimpedance (BI) measurements. Anatomically accurate computer models and the lead field theory were used to develop BI measurement configurations capable of detecting more localized BI changes in the human body. The methods were applied to assess the measurement properties of conventional impedance cardiography (ICG) and such BI measurement configurations as can be derived using (i) the 12‐lead electrocardiography (ECG) and (ii) the international 10‐20 electroencephalography (EEG) electrode systems. Information as to how various electrode configurations are sensitive to detecting conductivity changes in different tissues and organs was thus obtained. Theoretical results with the 12‐lead system suggested that, compared to conventional ICGs, significantly more selective ICG configurations can be derived for cardiovascular structures. In addition to theoretical investigations, clinical test measurements were made with the 12‐lead system to establish whether characteristic waveforms are available. Sensitivity distributions obtained with the 10‐20 electrode system give promise of the possibility of monitoring noninvasively cerebrospinal fluid (CSF) impedance changes related to impending epileptic seizures.
Thoracic Bioimpedance as a Basis for Pacing Controla
Authors: MIN MART , PARVE TOOMAS , KINK ANDRES
Published: February 2006

Abstract: Periodic variations of the thoracic bioimpedance due to breathing and heartbeating carry confidential information that is used for pacing rate control in rate‐adaptive pacemakers. The respiratory parameters‐the respiration rate and tidal volume‐are detected from the filtered breathing signal component (0.1 to 1.0 Hz), and are used for fuzzy feed‐forward adaptive control of the pacing rate to meet the needs of the organism. The cardiac parameters‐the actual heart rate and stroke volume‐are measured from the heartbeating signal component (1.0 to 3.0 Hz) and are proposed for feedback correction of the feed‐forward control to meet the heart's ability. The problems of electrical bioimpedance measurement and design of the rate‐adaptive pacemaker, wherein the intracardiac impedance is used as the main information source for pacing control, are discussed in this paper.
Evaluation of Systolic Performance by Automated Impedance Cardiography
Authors: SCHERHAG ARMIN W. , STASTNY JANA , PFLEGER STEFAN , VOELKER WOLFRAM , HEENE DIETER L.
Published: February 2006

Abstract: Impedance cardiography (ICG) is a noninvasive method for evaluating cardiac function. Left ventricular stroke volume (SV) is the basic hemodynamic parameter derived from thoracic bioimpedance curves. Issues of our study were to investigate the diagnostic value of other indices of left ventricular systolic performance, such as ejection fraction (EF), index of contractility (IC), peak flow index (PFI), and acceleration index (ACI), which can also be calculated by ICG. Forty patients (PTS) with suspected coronary artery disease (CAD) were monitored by automated ICG during pharmacologic stress testing with dobutamine. All PTS underwent subsequent cardiac catheterization. In PTS with single vessel disease, the dobutamine‐induced changes of SV, EF, IC, PFI, and ACI were comparable to those of PTS without CAD. In PTS with multivessel disease, the impaired systolic performance during dobutamine stimulation could be clearly demonstrated. We conclude that automated ICG is a useful method for monitoring SV and other indices of left ventricular systolic performance for detecting PTS with ischemic left ventricular dysfunction during cardiovascular stress.
Impact of Cardiovascular Reactions Using the Impedance Cardiography Method in Borderline Hypertension
Authors: NAWARYCZ T. , OSTROWSKA‐NAWARYCZ L. , KACZMAREK J.
Published: February 2006

Abstract: This paper evaluates the hemodynamics of 30 young men, aged 17‐19 years, with borderline hypertension (BHT) and 29 normotensive (NT) patients within the same age range. The study has been carried out using the impedance cardiography method at rest and under passive orthostatic test, cold test, and hyperventilation test. In the BHT patients, the following features have been observed: increased values of the cardiac index (CI), stroke volume index (SVI), mean blood pressure (MBP), and left ventricle work index (LVWI), as well as the accompanying normal values of the total peripheral resistance index (TPRI). The reactions of the cardiovascular systems during the functional tests are similar in both tested groups; however, they are most clearly distinct in the BHT patients, where the differences are statistically significant. This may support the argument that the activity of the adrenergic system in this group is intensified.
Stroke Volume Variability Cardiovascular Response to Orthostatic Maneuver in Patients with Coronary Artery Diseases
Authors: SIEBERT JANUSZ , WTOREK JERZY , ROGOWSKI JAN
Published: February 2006

Abstract: The dynamics of cardiovascular responses to postural stress have not been fully recognized. To determine whether coronary artery bypass grafting (CABG) has any effect on stroke volume variability (SVV), the power spectrum components of SVV were measured in 60 patients before and at 6 weeks after CABG. Stroke volume was assessed by means of the thoracic bioimpedance method. The thoracic impedance cardiogram and ECG were recorded in the supine and standing positions with controlled breathing rate (0.25 Hz) during 10‐minute periods. The analysis of SVV was done by means of the autoregressive method. The total power, the power in the low‐frequency band LFSV (0.05‐0.15 Hz), the power in the high‐frequency band HFSV (0.15‐0.5 Hz), and the LFSV/HFSV ratio were analyzed. Before CABG, we did not notice any significant changes in the stroke volume spectral power indices. After CABG, all spectral indices were significantly decreased in the standing position.
Assessment of Left Ventricular Systolic Function and Diastolic Time Intervals by the Bioimpedance Polyrheocardiographic System
Authors: ZUBAREV MICHAIL , DUMLER ANDREY , SHUTOV VLADIMIR , POPOV NICOLAY
Published: February 2006

Abstract: In order to detect left ventricular systolic function and diastolic time intervals using a new improved bioimpedance polyrheocardiographic system (BPCS), 110 healthy subjects and 128 patients with myocardial infarction were examined. Twenty‐four simultaneous measurements of cardiac output by thermodilution and BPCS were performed in 11 patients with complicated acute left ventricular failure. Studies demonstrated a high degree of correlation (r= 0.91, p < 0.001). The correlation between the methods of using signals of the second derivative and the subtracted first derivative waveform of BPCS and continuous‐wave Doppler echocardiography of systolic and diastolic time intervals was studied in 51 patients. The methods were closely correlated, especially with respect to left ventricular ejection time (r= 0.95), isovolumic relaxation time (r= 0.85), time to peak filling (r= 0.90), and deceleration of rapid filling time (r= 0.91). New bioimpedance hemodynamic parameters such as peak volume acceleration of ejection (PVAE) and peak power ejection (PPE) in patients with heart failure (NYHA Class I‐III) were studied. Significant reductions of PVAE and PPE in groups of patients with marked progression of heart failure were noted. These results have demonstrated that BPCS is a noninvasive, simple accurate method of assessment of left ventricular systolic function and diastolic time intervals.
Electrical Bioimpedance Related to Structural Differences and Reactions in Skin and Oral Mucosa
Authors: NICANDER INGRID , OLLMAR STIG
Published: February 2006

Abstract: Electrical bioimpedance can reflect structural and chemical changes of the skin and the oral mucosa in the β‐dispersion frequency range. From our measured multifrequency data set, four physically distinct indices have been formulated to distinguish the electrical properties for different anatomical locations and to detect different reactions and conditions of the skin and the oral mucosa. In comparison with the skin, the differences for various anatomical regions were greater in the oral cavity, which showed as well a different impedance pattern after irritant responses. We conclude that the impedance technique is able to classify and quantify different responses and conditions, preferably by using contralateral reference sites, or following a site in time; however, mapping of baseline properties facilitates the use of the method even if a large part of the skin or the oral mucosa is involved. The method has the potential of becoming a diagnostic decision support tool.
Stress Action on Biological Tissue and Tissue Models Detected by the Py Value
Authors: PLIQUETT FRITZ , PLIQUETT UWE
Published: February 2006

Abstract: The Py value, a fast measurable combination of the conductivity at the corner frequencies of the β‐dispersion, is a measure of the relative cell volume concentration in tissue. In many cases, if the biological object is stressed, for instance, by mechanical deformation, shortage of oxygen, electric field strength, temperature rise, or ischemia, Py increases. Depending on the object and the kind of stress, Py plateaus for minutes up to hours and then it decreases continuously. Values of passive electrical parameters of biological tissues are often given without information about the time following a stimulation or stress situation, for example, death, surgery, field application, etc. However, since the passive electrical properties change with time, information about their history, for example, time after death, should be given.
From Concept to Market in Industrial Impedance Applications
Authors: DAVEY CHRISTOPHER , TODD ROBERT , BARRETT JOHN
Published: February 2006

Abstract: This paper discusses some of the technical aspects of converting a laboratory idea into a commercial product. The example used is the development of the Aber Instruments Biomass Monitor, which is now used worldwide in industry for the pitching of yeast in breweries and for biomass measurements in the pharmaceutical industry. Although the issues raised will relate to instrumentation in a production environment, many of the themes will be equally applicable to medical instruments.
Biomass Monitoring Using Impedance Spectroscopya
Authors: BRAGOS R. , GÁMEZ X. , CAIRÓ J. , RIU P. J. , GÒDIA F.
Published: February 2006

Abstract: The biomass density in biotechnological processes is often determined by indirect and manual methods. Electrical impedance spectroscopy can provide on‐line viable biomass density estimators. In this work, we present two linear estimators obtained with this technique. Four different microorganisms were measured. The detection threshold was approximately 1 g/L (dry weight) for bacteria and 0.5 g/L for yeast. Liposome suspensions were also used to validate the methods. The monitoring of the continuous growth of a yeast culture is also presented.
Inductively Coupled Wideband Transceiver for Bioimpedance Spectroscopy (IBIS)a
Authors: SCHARFETTER HERMANN , NINAUS WOLFGANG , PUSWALD BERNHARD , PETROVA GALIDIA I. , KOVACHEV DIMITER , HUTTEN HELMUT
Published: February 2006

Abstract:Most measurement devices for bioimpedance spectroscopy are coupled to the measured object (tissue) via electrodes. At frequencies > 500 kHz, they suffer from artifacts due to stray capacitances between electrode leads as well as between the ground and object. The noninvasive measurement of the brain conductivity is hardly possible with surface electrodes. These disadvantages can be obviated by inductive coupling. The aim of this work was the development of a wideband transceiver for inductive impedance spectroscopy. In order to define its specifications, a feasibility study has been carried out with a simulation model for three different coil systems above a homogeneous conducting plate. According to simulation results, all systems render it possible to resolve conductivity changes down to 10−3(Ωm)−1at frequencies > 50 kHz. The transceiver electronics must then provide a resolution of ≥1 μV and an excitation current of up to 1 A. The realized receiver matches these specifications with an S/N ratio of 22 dB at 1 μV in the frequency range of 50 kHz to 5 MHz.