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Receptor Inhibitor (receptor + inhibitor)
Kinds of Receptor Inhibitor Selected AbstractsGlycoprotein IIb/IIIa Receptor Inhibitors in 2008: Do They Still Have a Role?JOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 2 2008DEBABRATA MUKHERJEE M.D. First page of article [source] Alpha-smooth muscle actin expression enhances cell traction forceCYTOSKELETON, Issue 4 2007Jianxin Chen Abstract Using an established corneal stromal cell differentiation model, we manipulated ,-smooth muscle actin (,-SMA) protein expression levels in fibroblasts by treating them with TGF-,1, bFGF, TGF-, type I receptor inhibitor (SB-431542), and siRNA against ,-SMA. The corresponding cell traction forces (CTFs) were determined by cell traction force microscopy. With all these treatments, we found that ,-SMA is not required for CTF induction, but its expression upregulates CTF. This upregulation involves the modification of stress fibers but does not appear to relate to non-muscle myosin II expression or ,-actin expression. Moreover, there exists a linear relationship between ,-SMA protein expression level and CTF magnitude. Finally, CTFs were found to vary among a population of myofibroblasts, suggesting that ,-SMA protein expression levels of individual cells also vary. Cell Motil. Cytoskeleton 2007. © 2006 Wiley-Liss, Inc. [source] Anterior,posterior patterning of neural differentiated embryonic stem cells by canonical Wnts, Fgfs, Bmp4 and their respective antagonistsDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 8 2009Marijke Hendrickx Embryonic stem (ES) cells are pluripotent and can differentiate into every cell type of the body. Next to their potential in regenerative medicine, they are excellent tools to study embryonic development. In this work the processes of neural induction and neural patterning along the antero-posterior (A/P) body axis are studied and evidence suggests a two step mechanism for these events. First, neural induction occurs by default in the primitive ectoderm, forming anterior neural tissue and thereafter, a series of factors can posteriorize this anterior neurectoderm. In a gain-of-function/loss-of-function approach using mouse ES cells, we show that Fgf2 has the strongest caudalizing potential of all Fgfs tested. Furthermore, Bmp4 and Wnt3a, but not Wnt1, can caudalize the neurectodermal cells. The effect of the antagonists of these factors was also examined and though Dkk1 and Noggin clearly have an effect that opposes that of Wnt3a and Bmp4 respectively, they fail to anteriorize the neurectoderm. The patterning effect of SU5402, an Fgf receptor inhibitor, was rather limited. These data confirm that in the mouse, two steps are involved in neural patterning and we show that while Fgf4, Fgf8 and Wnt1 have no strong patterning effect, Fgf2, Wnt3a and Bmp4 are strong posteriorizing factors. [source] Retina development in zebrafish requires the heparan sulfate proteoglycan agrinDEVELOPMENTAL NEUROBIOLOGY, Issue 7 2008I-Hsuan Liu Abstract Recent studies from our laboratory have begun to elucidate the role of agrin in zebrafish development. One agrin morphant phenotype that results from agrin knockdown is microphthalmia (reduced eye size). To begin to understand the mechanisms underlying the role of agrin in eye development, we have analyzed retina development in agrin morphants. Retinal differentiation is impaired in agrin morphants, with retinal lamination being disrupted following agrin morpholino treatment. Pax 6.1 and Mbx1 gene expression, markers of eye development, are markedly reduced in agrin morphants. Formation of the optic fiber layer of the zebrafish retina is also impaired, exhibited as both reduced size of the optic fiber layer, and disruption of retinal ganglion cell axon growth to the optic tectum. The retinotectal topographic projection to the optic tectum is perturbed in agrin morphants in association with a marked loss of heparan sulfate expression in the retinotectal pathway, with this phenotype resembling retinotectal phenotypes observed in mutant zebrafish lacking enzymes for heparan sulfate synthesis. Treatment of agrin morphants with a fibroblast growth factor (Fgf) receptor inhibitor, rescue of the retinal lamination phenotype by transplantation of Fgf8-coated beads, and disruption of both the expression of Fgf-dependent genes and activation of ERK in agrin morphants provides evidence that agrin modulation of Fgf function contributes to retina development. Collectively, these agrin morphant phenotypes provide support for a crucial role of agrin in retina development and formation of an ordered retinotectal topographic map in the optic tectum of zebrafish. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008. [source] IP3 receptor in the hair cells of frog semicircular canal and its possible functional roleEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2006Maria Lisa Rossi Abstract The presence and functional role of inositol trisphosphate receptors (IP3R) was investigated by electrophysiology and immunohistochemistry in hair cells from the frog semicircular canal. Intracellular recordings were performed from single fibres of the posterior canal in the isolated, intact frog labyrinth, at rest and during rotation, in the presence of IP3 receptor inhibitors and drugs known to produce Ca2+ release from the internal stores or to increase IP3 production. Hair cell immunolabelling for IP3 receptor was performed by standard procedures. The drug 2-aminoethoxydiphenyl borate (2APB), an IP3 receptor inhibitor, produced a marked decrease of mEPSP and spike frequency at low concentration (0.1 mm), without affecting mEPSP size or time course. At high concentration (1 mm), 2APB is reported to block the sarcoplasmic-endoplasmic reticulum Ca2+ -ATPase (SERCA pump) and increase [Ca2+]i; at the labyrinthine cytoneural junction, it greatly enhanced the resting and mechanically evoked sensory discharge frequency. The selective agonist of group I metabotropic glutamate receptors (RS)-3,5-dihydroxyphenylglycine (DHPG, 0.6 mm), produced a transient increase in resting mEPSP and spike frequency at the cytoneural junction, with no effects on mEPSP shape or amplitude. Pretreatment with cyclopiazonic acid (CPA, 0.1 mm), a SERCA pump inhibitor, prevented the facilitatory effect of both 2APB and DHPG, suggesting a link between Ca2+ release from intracellular stores and quantal emission. Consistently, diffuse immunoreactivity for IP3 receptors was observed in posterior canal hair cells. Our results indicate the presence and a possibly relevant functional role of IP3-sensitive stores in controlling [Ca2+]i and modulating the vestibular discharge. [source] Dyspnoea after antiplatelet agents: the AZD6140 controversyINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 3 2007V. L. Serebruany Summary Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug. [source] Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and DiazepamALCOHOLISM, Issue 4 2007Evgeny M. Krupitsky Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N -methyl- d -aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. Methods: This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately. Results: All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam. Conclusions: This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal. [source] Thrombin induces neoangiogenesis in the chick chorioallantoic membraneJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003M. Caunt Summary., Most tumors have constitutively active tissue factor on their surface, capable of generating thrombin in the surrounding environment, and thrombosis is associated with cancer. Thrombin is known to induce a malignant phenotype by enhancing tissue adhesion and cell growth in vitro and in vivo in mice. Because tumors require angiogenesis for growth, we examined whether thrombin induces neoangiogenesis in a physiologically intact in vivo model. Thrombin (0.1 U mL,1) induced neoangiogenesis in the chick chorioallantoic membrane over a 24,72-h period by approximately 2,3-fold. This was inhibited by the potent thrombin inhibitor, hirudin and shown to have its mode of action by ligation of the thrombin protease-activated receptor, PAR-1. The thrombin receptor activation peptide, SFLLRNPNDKYEPF (200 µm) also enhanced neoangiogenesis c. 2,3-fold. Thrombin-induced neoangiogenesis was accompanied by the induction of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) mRNA at 24,48 h (approximately 2-fold) as determined by semi-quantitative reverse transcriptase-polymerase chain reaction. Thrombin-induced neoangiogenesis was inhibited to baseline level by the specific angiogenesis receptor inhibitors KDR-Fc (vs. VEGF) and Tie-2-Fc (vs. Ang-1 and Ang-2), as well as the non-specific angiogenesis inhibitor thrombospondin-1. Thrombin-induced neoangiogenesis was also inhibited to baseline level by agents known to inhibit thrombin receptor signaling in other cells: G-coupled protein receptor inhibitor, pertussis toxin (40 pg per egg), protein kinase C inhibitor, bisindolylmaleimide (1 µm per egg), MAP kinase inhibitor, PD980598 (10 µm per egg) and PI3 kinase inhibitor, LY294002 (0.25 µm per egg). Thus angiogenesis is stimulated by thrombosis, which could help explain the enhancement of experimental tumorigenesis by thrombin. [source] The role of angiotensin II in stress urinary incontinence: A rat modelNEUROUROLOGY AND URODYNAMICS, Issue 1 2007Hardeep Phull Abstract Aims Pharmacological treatment for stress urinary incontinence (SUI) is limited to the use of non-selective alpha-agonists, which are often ineffective. Non-adrenergic mechanisms have also been implicated in urethral closure, including angiotensin II (Ang-II), which has been demonstrated throughout the urinary tract. We investigate the role of Ang-II in urethral tone in a rat model of SUI. Methods Abdominal leak point pressure (ALPP) and retrograde urethral pressure profilometry (RLPP) were measured in 70 female virgin rats. Thirty rats underwent pudendal nerve injury (PNT), 30 had circumferential urethrolysis (U-Lys), and 10 had sham surgery. Rats received daily doses of Angiotensin Type 1 (AT-1) receptor inhibitor (20 mg/kg), Angiotensin Type 2 (AT-2) receptor antagonist (10 mg/kg), or Ang-II (2 mg/kg). Results Following U-Lys, RLPP and ALPP decreased from 21.4,±,2.0 and 39.2,±,3.3 mm Hg, to 13.1,±,1.5 and 21.6,±,1.9 mmHg, respectively (P<0.01). After PNT, RLPP, and ALPP decreased from 21.0,±,1.6 and 41.9,±,3.0 mmHg to 13.1,±,1.5 and 24.7,±,3.3 mmHg, respectively (P<0.01). AT-1 inhibitor caused significant decrease in RLPP and ALPP from 21.0,±,6.2 and 41.8,±,9.4 mmHg, to 12.0,±,3.8 and 25.6,±,6.6 mmHg, respectively (P<0.01). Likewise, AT-2 treatment reduced RLPP and ALPP from 21.4,±,6.3 and 40.1,±,1.7 mmHg, to 13.5,±,5.7 and 31.0,±,7.2 mmHg, respectively (P<0.01). Following surgery, Ang-II administration restored RLPP and ALPP to baseline presurgical values. Conclusions AT-1 and AT-2 receptor inhibition significantly lowers urethral resistance, comparable to either neurogenic or urethrolytic injury. Ang-II treatment restored urethral tone in rats with intrinsic sphincter dysfunction. Ang II appears to serve a functional role in the maintenance of urethral tone and stress continence. Neurourol. Urodynam. © 2006 Wiley-Liss, Inc. [source] Papaya fruit softening, endoxylanase gene expression, protein and activityPHYSIOLOGIA PLANTARUM, Issue 3 2007Ashariya Manenoi Papaya (Carica papaya L.) cell wall matrix polysaccharides are modified as the fruit starts to soften during ripening and an endoxylanase is expressed that may play a role in the softening process. Endoxylanase gene expression, protein amount and activity were determined in papaya cultivars that differ in softening pattern and in one cultivar where softening was modified by the ethylene receptor inhibitor 1-methylcyclopropene (1-MCP). Antibodies to the endoxylanase catalytic domain were used to determine protein accumulation. The three papaya varieties used in the study, ,Line 8', ,Sunset', and ,Line 4-16', differed in softening pattern, respiration rate, ethylene production and showed similar parallel relationships during ripening and softening in endoxylanase expression, protein level and activity. When fruit of the three papaya varieties showed the respiratory climacteric and started to soften, the level of endoxylanase gene expression increased and this increase was related to the amount of endoxylanase protein at 32 kDa and its activity. Fruit when treated at less than 10% skin yellow stage with 1-MCP showed a significant delay in the respiratory climacteric and softening, and reduced ethylene production, and when ripe was firmer and had a ,rubbery' texture. The 1-MCP-treated fruit that had the ,rubbery' texture showed suppressed endoxylanase gene expression, protein and enzymatic activity. Little or no delay occurred between endoxylanase gene expression and the appearance of activity during posttranslational processing from 65 to 32 kDa. The close relationship between endoxylanase gene expression, protein accumulation and activity in different varieties and the failure of the 1-MCP-treated fruit to fully soften, supported de novo synthesis of endoxylanase, rapid posttranslation processing and a role in papaya fruit softening. [source] Rimonabant (Acomplia): a novel adjunctive treatment for obesityPRESCRIBER, Issue 2 2007Anthony Barnett MD Rimonabant is the first selective cannabinoid-1 receptor inhibitor for use in the treatment of obesity. In this article Professor Barnett describes its novel mode of action and the results of clinical trials of its efficacy and safety. Copyright © 2007 Wiley Interface Ltd [source] Extracellular ATP inhibits chloride channels in mature mammalian skeletal muscle by activating P2Y1 receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 23 2009Andrew A. VossArticle first published online: 30 NOV 200 ATP is released from skeletal muscle during exercise, a discovery dating back to 1969. Surprisingly, few studies have examined the effects of extracellular ATP on mature mammalian skeletal muscle. This electrophysiological study examined the effects of extracellular ATP on fully innervated rat levator auris longus using two intracellular microelectrodes. The effects of ATP were determined by measuring the relative changes of miniature endplate potentials (mEPPs) and voltage responses to step current pulses in individual muscle fibres. Exposure to ATP (20 ,m) prolonged the mEPP falling phase by 31 ± 7.5% (values ±s.d., n= 3 fibres). Concurrently, the input resistance increased by 31 ± 2.0% and the time course of the voltage responses increased by 59 ± 3.0%. Analogous effects were observed using 2 and 5 ,mATP, and on regions distal from the neuromuscular junction, indicating that physiologically relevant levels of ATP enhanced electrical signalling over the entire muscle fibre. The effects of extracellular ATP were blocked by 200 ,manthracene-9-carboxylic acid, a chloride channel inhibitor, and reduced concentrations of extracellular chloride, indicating that ATP inhibited chloride channels. A high affinity agonist for P2Y receptors, 2-methylthioadenosine-5,- O -diphosphate (2MeSADP), induced similar effects to ATP with an EC50 of 160 ± 30 nm. The effects of 250 nm2MeSADP were blocked by 500 nmMRS2179, a specific P2Y1 receptor inhibitor, suggesting that ATP acts on P2Y1 receptors to inhibit chloride channels. The inhibition of chloride channels by extracellular ATP has implications for muscle excitability and fatigue, and the pathophysiology of myotonias. [source] Multicomponent crystals of erlotinibACTA CRYSTALLOGRAPHICA SECTION C, Issue 1 2010B. Sridhar Erlotinib [systematic name: N -(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine], a small-molecule epidermal growth factor receptor inhibitor, useful for the treatment of non-small-cell lung cancer, has been crystallized as erlotinib monohydrate, C22H23N3O4·H2O, (I), the erlotinib hemioxalate salt [systematic name: 4-amino- N -(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-1-ium hemioxalate], C22H24N3O4+·0.5C2O42,, (II), and the cocrystal erlotinib fumaric acid hemisolvate dihydrate, C22H23N3O4·0.5C4H4O4·2H2O, (III). In (II) and (III), the oxalate anion and the fumaric acid molecule are located across inversion centres. The water molecules in (I) and (III) play an active role in hydrogen-bonding interactions which lead to the formation of tetrameric and hexameric hydrogen-bonded networks, while in (II) the cations and anions form a tetrameric hydrogen-bonded network in the crystal packing. The title multicomponent crystals of erlotinib have been elucidated to study the assembly of molecules through intermolecular interactions, such as hydrogen bonds and aromatic ,,, stacking. [source] Role of the aging vasculature and Erb B-2 signaling in epidermal growth factor-dependent intravasion of breast carcinoma cells,CANCER, Issue 1 2004Daniel J. Price Ph.D. Abstract BACKGROUND The risks for developing breast carcinoma and dying from the disease increase with age. Mortality from breast carcinoma usually is due to metastatic disease. Metastatic cells are able to invade into the vascular tissue in a growth factor-dependent manner. Because breast carcinoma mortality increases with age, examination of breast carcinoma interactions with young and aged endothelial cells is essential. METHODS We studied a series of breast epithelial cells (HMT-3522 cells) that exhibited either noninvasive characteristics (S-1 cells) or epidermal growth factor (EGF)-dependent invasive characteristics (T4-2 cells). RESULTS Increased invasion of HMT-3522 cells was observed across an aged rat brain microvascular endothelial cell (BMEC) monolayer that was isolated from aged rats (24 months) compared with young rats (age 1 month). This increased invasion was inhibited by the specific EGF receptor inhibitor, AG1478, and by the Erb B-2-specific inhibitor, AG825. To analyze further the contribution of Erb B-2 to the EGF-dependent invasion of HMT-3522 cells, T4-2 cells were treated with the Erb B-2-specific therapeutic antibody trastuzumab and with the specific inhibitor AG825 and were then assayed for invasion. Both inhibitors led to a significant decrease in EGF-dependent invasion. Erb B-2 expression was found to be elevated in T4-2 cells (, 5-fold higher) compared with S-1 cells. However, treatment of T4-2 cells with the specific Erb B-2 inhibitor, AG825, failed to inhibit EGF-mediated signaling to phosphatidylinositol 3-kinase or extracellular-regulated kinases 1 and 2. CONCLUSIONS The current study findings indicate that aging of endothelium may contribute to the invasive phenotype of breast carcinoma cells and that "cross-talk" between Erb B-2 and EGF receptor is required for the intravasion of these cells into the surrounding vasculature. Cancer 2004. © 2004 American Cancer Society. [source] Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-, type I receptor inhibitorCANCER SCIENCE, Issue 10 2010Yukimi Taniguchi Tumor cell targeting of drug carriers is a promising strategy and uses the attachment of various ligands to enhance the therapeutic potential of chemotherapy agents. Folic acid is a high-affinity ligand for folate receptor, which is a functional tumor-specific receptor. The transforming growth factor (TGF)-, type I receptor (T,R-I) inhibitor A-83-01 was expected to enhance the accumulation of nanocarriers in tumors by changing the microvascular environment. To enhance the therapeutic effect of folate-linked liposomal doxorubicin (F-SL), we co-administrated F-SL with A-83-01. Intraperitoneally injected A-83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A-83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A-83-01 temporarily changed the tumor vasculature around 3 h post injection. A-83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A-83-01 showed significantly greater antitumor activity than F-SL alone. This study shows that co-administration of T,R-I inhibitor will open a new strategy for the use of FR-targeting nanocarriers for cancer treatment. (Cancer Sci 2010); 00: 000,000 [source] Roles of P2X receptors and Ca2+ sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscleCLINICAL & EXPERIMENTAL ALLERGY, Issue 6 2007T. Oguma Summary Background The release of adenosine triphosphate (ATP) from the airway epithelial cells during the inflammatory process is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. Objective This study was designed to determine whether extracellular ATP is involved in the bronchial hyperresponsiveness as an interaction between epithelium and smooth muscle in the airways. Methods We examined the contractile response to methacholine (MCh) before and after exposure to low concentrations (10 ,m) of ATP in isolated, epithelium-denuded guinea-pig tracheal smooth muscle by measuring isometric tension. Intracellular Ca2+ concentrations ([Ca2+]i) were assessed by fluorescent intensities of fura-2. Results MCh-induced contractile force was increased with no change in [Ca2+]i after exposure to 10 ,m ATP for 15 min. The ability of ATP to enhance the MCh-induced contraction was markedly attenuated by suramin, a non-selective P2 receptor inhibitor. Pre-incubation with ATP,S, a non-hydrolysable analogue of ATP and ,,,-meATP, a P2X agonist, also enhanced the MCh-induced contraction. In contrast, uracil triphosphate, a P2Y agonist, did not affect the MCh-induced contraction. Y-27632, a Rho-kinase inhibitor, suppressed the ability of ATP to enhance the MCh-induced contraction. Moreover, PP1 and PP2, Src tyrosin kinase inhibitors, suppressed the enhancement of MCh-induced contraction by ATP. Conclusion Pre-treatment with ATP induces hyperresponsiveness to MCh mediated by Ca2+ sensitization via the P2X receptor in airway smooth muscle. The present findings suggest the possible involvement of both the Rho-kinase and Src pathways in the intracellular mechanism of this phenomenon. [source] The Role of Aspirin Resistance in the Treatment of Acute Coronary SyndromesCLINICAL CARDIOLOGY, Issue 1 2008F.A.C.C., Gilead I. Lancaster M.D. F.A.C.P. Abstract The TIMI Risk Score recognizes prior aspirin use as an independent risk factor for adverse outcomes in subjects presenting with an acute coronary syndrome. The etiology of this increased risk awaits clarification, but prior aspirin use may be associated with altered thrombus composition which is more resistant to current treatment modalities as compared to thrombus formation in subjects without prior aspirin use. Post hoc analysis of acute coronary syndrome trials has shown that prior aspirin users treated with unfractionated heparin are at particularly high risk. The addition of glycoprotein IIb/IIIa receptor inhibitor to unfractionated heparin or substitution of low-molecular-weight heparin significantly improves outcomes in prior aspirin users. The prognostic significance of prior aspirin use in acute coronary syndromes has important implications not only in clinical practice, but also in the design and interpretation of clinical trials. Copyright © 2007 Wiley Periodicals, Inc. [source] The Impact of Race on the Acute Management of Chest PainACADEMIC EMERGENCY MEDICINE, Issue 11 2003Arvind Venkat MD Abstract Objectives: African Americans with acute coronary syndromes receive cardiac catheterization less frequently than whites. The objective was to determine if such disparities extend to acute evaluation and noninterventional treatment. Methods: Data on adults with chest pain (N= 7,935) presenting to eight emergency departments (EDs) were evaluated from the Internet Tracking Registry of Acute Coronary Syndromes. Groups were selected from final ED diagnosis: 1) acute myocardial infarction (AMI), n= 400; 2) unstable angina/non,ST-elevation myocardial infarction (UA/NSTEMI), n= 1,153; and 3) nonacute coronary syndrome chest pain (non-ACS CP), n= 6,382. American College of Cardiology/American Heart Association guidelines for AMI and UA/NSTEMI were used to evaluate racial disparities with logistic regression models. Odds ratios (ORs) were adjusted for age, gender, guideline publication, and insurance status. Non-ACS CP patients were assessed by comparing electrocardiographic (ECG)/laboratory evaluation, medical treatment, admission rates, and invasive and noninvasive testing for coronary artery disease (CAD). Results: African Americans with UA/NSTEMI received glycoprotein IIb/IIIa receptor inhibitors less often than whites (OR, 0.41; 95% CI = 0.19 to 0.91). African Americans with non-ACS CP underwent ECG/laboratory evaluation, medical treatment, and invasive and noninvasive testing for CAD less often than whites (p < 0.05). Other nonwhites with non-ACS CP were admitted and received invasive testing for CAD less often than whites (p < 0.01). African Americans and other nonwhites with AMI underwent catheterization less frequently than whites (OR, 0.45; 95% CI = 0.29 to 0.71 and OR, 0.40; 95% CI = 0.17 to 0.92, respectively). A similar disparity in catheterization was noted in UA/NSTEMI therapy (OR, 0.53; 95% CI = 0.40 to 0.68 and OR, 0.68; 95% CI = 0.47 to 0.99). Conclusions: Racial disparities in acute chest pain management extend beyond cardiac catheterization. Poor compliance with recommended treatments for ACS may be an explanation. [source] IP3 receptor in the hair cells of frog semicircular canal and its possible functional roleEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2006Maria Lisa Rossi Abstract The presence and functional role of inositol trisphosphate receptors (IP3R) was investigated by electrophysiology and immunohistochemistry in hair cells from the frog semicircular canal. Intracellular recordings were performed from single fibres of the posterior canal in the isolated, intact frog labyrinth, at rest and during rotation, in the presence of IP3 receptor inhibitors and drugs known to produce Ca2+ release from the internal stores or to increase IP3 production. Hair cell immunolabelling for IP3 receptor was performed by standard procedures. The drug 2-aminoethoxydiphenyl borate (2APB), an IP3 receptor inhibitor, produced a marked decrease of mEPSP and spike frequency at low concentration (0.1 mm), without affecting mEPSP size or time course. At high concentration (1 mm), 2APB is reported to block the sarcoplasmic-endoplasmic reticulum Ca2+ -ATPase (SERCA pump) and increase [Ca2+]i; at the labyrinthine cytoneural junction, it greatly enhanced the resting and mechanically evoked sensory discharge frequency. The selective agonist of group I metabotropic glutamate receptors (RS)-3,5-dihydroxyphenylglycine (DHPG, 0.6 mm), produced a transient increase in resting mEPSP and spike frequency at the cytoneural junction, with no effects on mEPSP shape or amplitude. Pretreatment with cyclopiazonic acid (CPA, 0.1 mm), a SERCA pump inhibitor, prevented the facilitatory effect of both 2APB and DHPG, suggesting a link between Ca2+ release from intracellular stores and quantal emission. Consistently, diffuse immunoreactivity for IP3 receptors was observed in posterior canal hair cells. Our results indicate the presence and a possibly relevant functional role of IP3-sensitive stores in controlling [Ca2+]i and modulating the vestibular discharge. [source] A case report of inflammatory nonscarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinibJOURNAL OF CUTANEOUS PATHOLOGY, Issue 12 2009Marinya Pongpudpunth Epidermal growth factor receptor inhibitors (EGFRIs) are new anticancer agents that act by inhibiting EGFR signaling transduction pathways, thus decreasing tumor growth. In more than 30 countries, EGFRIs are currently used in the treatment of a number of solid tumors, and other indications are being sought. In the United States, select EGFRIs have been approved in certain patients with non-small cell lung cancer, metastatic colorectal carcinoma, and advanced squamous cell carcinoma of the head and neck. Various cutaneous side effects of EGFRIs have been reported, including acneiform eruptions, chronic paronychia, xerosis, a seborrheic dermatitis-like eruption, changes in hair texture, and nonscarring alopecia. We present a 60-year-old woman with non-small cell lung cancer who developed a persistent generalized itchy eruption and progressive nonscarring alopecia shortly after initiation of erlotinib (Tarceva). Scalp biopsy showed near-equal number of anagen and catagen/telogen hair follicles, and a superficial and deep perivascular lymphoplasmocytic infiltration. These changes are typical of the nonscarring alopecia induced by EGFRIs. Because it is likely that EGFRIs will be increasingly used, dermatopathologists are likely to see more reactions from these agents. Familiarity with their side effects is essential to accurate diagnosis and effective patient management. [source] Amyloid precursor protein-processing products affect mononuclear phagocyte activation: pathways for sAPP- and A,-mediated neurotoxicityJOURNAL OF NEUROCHEMISTRY, Issue 4 2003Tsuneya Ikezu Abstract Increasing evidence strongly supports the role of glial immunity in the pathogenesis of Alzheimer's disease (AD). To investigate such events we have developed cell systems mimicking the interactions between ,-amyloid precursor protein (APP)-expressing neurons and brain mononuclear phagocytes (MP; macrophages and microglia). MP were co-cultured with neuronal cells expressing wild type APP or familial AD-linked APP mutants. The latter was derived from recombinant adenoviral constructs. Neuronal APP processing products induced MP activation, reactive oxygen species, and neurotoxic activities. These occurred without the addition of pro-inflammatory cytokines and were reversed by depletion of amyloid ,-peptide (A,) and secreted APP (sAPP). Neurotoxic activities were diminished by superoxide dismutase mimetics and NMDA receptor inhibitors. Microglial glutamate secretion was suppressed by the cystine-glutamate antiporter inhibitor and its levels paralleled the depletion of sAPP and A, from conditioned media prepared from APP-expressing neurons. The excitotoxins from activated MP were potent enough to evoke recombinant NMDA receptor-mediated inward currents expressed in vitro in the Xenopus oocytes. These results demonstrate that neuronal APP-processing products can induce oxidative neurotoxicity through microglial activation. [source] Generation of spinal motor neurons from human fetal brain-derived neural stem cells: Role of basic fibroblast growth factorJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2009Paivi M. Jordan Abstract Neural stem cells (NSCs) have some specified properties but are generally uncommitted and so can change their fate after exposure to environmental cues. It is unclear to what extent this NSC plasticity can be modulated by extrinsic cues and what are the molecular mechanisms underlying neuronal fate determination. Basic fibroblast growth factor (bFGF) is a well-known mitogen for proliferating NSCs. However, its role in guiding stem cells for neuronal subtype specification is undefined. Here we report that in-vitro-expanded human fetal forebrain-derived NSCs can generate cholinergic neurons with spinal motor neuron properties when treated with bFGF within a specific time window. bFGF induces NSCs to express the motor neuron marker Hb9, which is blocked by specific FGF receptor inhibitors and bFGF neutralizing antibodies. This development of spinal motor neuron properties is independent of selective proliferation or survival and does not require high levels of MAPK activation. Thus our study indicates that bFGF can play an important role in modulating plasticity and neuronal fate of human NSCs and presumably has implications for exploring the full potential of brain NSCs for clinical applications, particularly in spinal motor neuron regeneration. © 2008 Wiley-Liss, Inc. [source] Cetuximab-induced cutaneous toxicityJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2010H Tomková Abstract Background, Epidermal growth factor receptor inhibitors are recently utilized by oncologists in advanced cases of certain malignancies. However, these agents are associated with numerous cutaneous adverse reactions. Objective, To systematically review the cutaneous toxicity of cetuximab-treated patients. Methods, An analysis of a series of 24 patients (20 men and 4 women) treated with cetuximab (12 patients with head and neck cancer and 12 patients with colorectal cancer) was performed with respect to relevant clinical characteristics. Results, A total of 22 patients (91.7%) developed pustular or maculopapular follicular eruption, often referred to as acneiform rash. One patient (4.2%) developed paronychia in the course of cetuximab therapy. All patients with head and neck cancer had a combination treatment with radiotherapy and experienced radiation dermatitis accompanied by skin xerosis. Anaphylactic reaction was observed in three patients (12.5%). Conclusions, The most frequent cutaneous side effect reported in this series was acneiform eruption. The authors observed that all women with acneiform rash had only limited facial involvement, whereas all but one man experienced more widespread lesions of the face, the back and the chest. We found no association between the extent and severity of cutaneous eruptions (grade 1 vs. grade 2) and patients' response to therapy. [source] Recent advances in the molecular pathology of soft tissue sarcoma: Implications for diagnosis, patient prognosis, and molecular target therapy in the futureCANCER SCIENCE, Issue 2 2009Yoshinao Oda In the present paper, recent advances in the molecular pathology of soft tissue sarcomas (STS) and the implications for their prognostic value are reviewed, and the potential targets of molecular therapy are discussed. According to the molecular genetic aspect, STS are divided into two groups: chromosome translocation-associated sarcomas and sarcomas without specific translocation. In the former group, specific fusion transcripts, such as SS18,SSX, EWS,FLI1, and PAX3,FKHR, could be detected in synovial sarcoma, Ewing's sarcoma and primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma, respectively. The direct or indirect interactions between these fusion transcripts and cell cycle regulators have been elucidated by several investigators. Therefore, these fusion transcripts are promising candidates as molecular targets. As evaluated in carcinomas, alterations of several tumor-suppressor genes and adhesion molecules and overexpression of growth factors and their receptors have been extensively assessed in STS. In mixed-type STS, epidermal growth factor receptor overexpression was associated with decreased overall survival, suggesting the beneficial role of epidermal growth factor receptor inhibitors in STS. In malignant rhabdoid tumor and epithelioid sarcoma, frequent alteration of the SMARCB1/INI1tumor-suppressor gene and the loss of its protein have been demonstrated, indicating that this molecule could be an effective target of these sarcomas. In sarcomas with epithelioid differentiation, such as synovial sarcoma and epithelioid sarcoma, overexpression of dysadherin, which downregulates E-cadherin expression, was a poor prognostic factor. In conclusion, further studies are necessary to search for effective and specific molecules for the inhibition of tumor growth in each type of STS, especially in sarcomas without specific translocation. (Cancer Sci 2009; 100: 200,208) [source] Coronary no-reflow phenomenon: From the experimental laboratory to the cardiac catheterization laboratory,CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS, Issue 7 2008Shereif H. Rezkalla MD Abstract Coronary no-reflow occurs commonly during acute percutaneous coronary intervention, particularly in patients with acute myocardial infarction and those with degenerated vein grafts. It is associated with a guarded prognosis, and thus needs to be recognized and treated promptly. The pathophysiology originates during the ischemic phase and is characterized by localized and diffuse capillary swelling and arteriolar endothelial dysfunction. In addition, leukocytes become activated and are attracted to the lumen of the capillaries, exhibit diapedesis and may contribute to cellular and intracellular edema and clogging of vessels. At the moment of perfusion, the sudden rush of leukocytes and distal atheroemboli further contributes to impaired tissue perfusion. Shortening the door-to-balloon time, use of glycoprotein IIb/IIIa platelet receptor inhibitors and distal protection devices are predicted to limit the development of no-reflow during percutaneous interventions. Distal intracoronary injection of verapamil, nicardipine, adenosine, and nitroprusside may improve coronary flow in the majority of patients. Hemodynamic support of the patient may be needed in some cases until coronary flow improves. © 2008 Wiley-Liss, Inc. [source] Intraoperative floppy iris syndrome (IFIS): a practical approach to medical and surgical considerations in cataract extractionsACTA OPHTHALMOLOGICA, Issue 7 2009Allan Storr-Paulsen Abstract. Intraoperative floppy iris syndrome (IFIS) during cataract surgery is characterized by iris fluttering, iris prolapse towards the incisions, and a progressive pupillary constriction leading to high rates of complications. The syndrome has been reported following the treatment of benign prostatic hyperplasia with ,-1a adrenergic receptor inhibitors, especially tamsulosin. The present paper describes the syndrome and discusses its pharmacological background. Several techniques to prevent and to deal with the syndrome are presented. [source] Optimizing Antiplatelet Therapy in Coronary InterventionsCLINICAL CARDIOLOGY, Issue S6 2000S. B. King III M.D. Abstract Percutaneous coronary intervention has had a dramatic impact on the current practice of cardiology. One of its important limitations, however, is the potential for producing unfavorable outcomes such as acute coronary closure following angioplasty or atherectomy or subacute thrombosis following stent implantation. These complications may lead to death, myocardial infarction, or the need for urgent bypass surgery. One mechanism underlying these clinical events is platelet-mediated thrombosis due to arterial trauma. Therapeutically, platelet activation by thromboxane and adenosine diphosphate (ADP), as well as platelet aggregation by glycoprotein IIb/IIIa (GPIIb/IIIa) receptors, has been inhibited with various pharmacologic agents. c7E3 (abciximab), a monoclonal antibody directed against GPIIb/IIIa, has been shown to have potent effects on reducing both acute and subacute complications. Other parenteral GPIIb/IIIa inhibitors, including peptide and small nonpepude molecules, have also been found to be clinically effective. Oral versions of similar drugs are currently being evaluated, but several have resulted in disappointing efficacy and safety profiles and have failed to show advantages over aspirin. With all antiplatelet agents, in particular GPIIb/IIIa receptor inhibitors, bleeding and vascular complications must be addressed. Inhibition of thromboxane-induced platelet activation with aspirin has been standard therapy for angioplasty and in the global management of vascular disease. Newer agents that block ADP-mediated platelet activation, the thienopyridines, have been found to be synergistic to aspirin in their effects on the complications of coronary intervention. Ticlopidine and, more recently, clopidogrel, in conjunction with aspirin, have become standard therapies for preventing subacute thrombosis after stent implantation. Large-scale clinical trials are ongoing to optimize their use in combination with GPIIb/IIIa inhibitors. [source] | ||||||||||||||||||||||||||||