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Complementary Mechanisms (complementary + mechanism)
Selected AbstractsCombined therapy in the treatment of hypertensionFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2010Carlos Escobar Abstract The majority of patients with hypertension need at least two antihypertensive agents to achieve blood pressure (BP) objectives. As current European guidelines for the treatment of arterial hypertension recommend, combined therapy is required when monotherapy fails and as a first-line treatment in certain situations, such as subjects at high or very high cardiovascular risk, markedly elevated BP values, or when lower targets are required (<130/80 mmHg). The advantages of combined therapy are well known and include an earlier and higher antihypertensive efficacy because of complementary mechanisms of action, and a lower incidence of side effects due to the possible compensatory responses and, in many cases, the lower doses used. In the present study, available evidence about the efficacy and tolerability of combined therapy for the treatment of hypertension is updated. [source] Your Drug, My Drug, or Our Drugs: How Aggressive Should We Be With Antihypertensive Therapy?JOURNAL OF CLINICAL HYPERTENSION, Issue 2005Joseph L. Izzo Jr. MD In the prevention of hypertensive complications, especially stroke and kidney disease, "lower is better" because for each decrease of 20 mm Hg systolic or 10 mm Hg diastolic pressure in the population, cardiovascular risk is halved. Ideally, the goal for each patient should be to reach the lowest blood pressure that is well tolerated, a value that may be well below the arbitrary threshold value of 140/90 mm Hg. For the majority of "uncomplicated hypertensives," the question of single-drug therapy is essentially moot, because more than one agent is almost always required to optimally control blood pressure. In individuals who already have heart or kidney disease, there are compelling indications for the use of drugs that block the renin-angiotensin system, but the large outcome studies that spawned these recommendations are themselves combination trials. Thus, in virtually all patients, more than one drug is indicated. The best combinations take advantage of long durations of action and complementary mechanisms of action of the component and are not only able to effectively lower blood pressure, but also to favorably affect the natural history of hypertensive complications. Regimens,including fixed-dose combination products,that combine a thiazide diuretic or calcium antagonist with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker are most efficient. In summary, why would an astute clinician (or informed patient) be satisfied with the relatively limited effects of any single class of antihypertensive agents when better overall protection is possible? [source] Changing the pathogenetic roadmap of liver fibrosis?JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7pt1 2008Where did it start; where will it go? Abstract The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes , formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) , the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrix,producing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts. Currently, the generation of matrix-synthesizing fibroblasts by epithelial,mesenchymal transition, by influx of bone marrow,derived fibrocytes into damaged liver tissue, and by differentiation of circulating monocytes to fibroblasts after homing in the injured liver are discussed as important complementary mechanisms to enlarge the pool of (myo-)fibroblasts in the fibrosing liver. Among the molecular mediators, transforming growth factor-beta (TGF-,) plays a central role, which is controlled by the bone-morphogenetic protein (BMP)-7, an important antagonist of TGF-, action. The newly discovered pathways supplement the linear concept of HSC activation to myofibroblasts, point to fibrosis as a systemic response involving extrahepatic organs and reactions, add further evidence to a more or less uniform concept of organ fibrosis in general (e.g. liver, lung, kidney), and offer innovative approaches for the development of non-invasive biomarkers and antifibrotic trials. [source] The Role of Enoxaparin in Interventional Management of Patients with Acute Coronary SyndromesJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 5 2003CINDY L. GRINES M.D., F.A.C.C. Interventional management strategies involving early angiography and percutaneous coronary intervention (PCI) are increasingly widespread in the management of patients with acute coronary syndromes (ACS). Notwithstanding the benefits of early intervention, there is a significant risk of postprocedural thrombotic complications and a need to optimize antithrombotic regimens for use before and during PCI. It is clear that the current standard therapy with unfractionated heparin (UFH) and aspirin can be improved upon, in terms of both efficacy and safety. The low-molecular-weight heparin(s) (LMWHs) offer pharmacologic and practical advantages over UFH. The LMWH enoxaparin has recently emerged as the anticoagulant of choice for the acute management of ACS. Enoxaparin has also demonstrated sustained benefits over UFH in patients proceeding to PCI, and as a procedural anticoagulant. Combination therapy with enoxaparin and a glycoprotein IIb/IIIa inhibitor may further improve the efficacy and safety of antithrombotic treatment during coronary interventions, as a result of the drugs' complementary mechanisms of action. Early clinical evidence supports the use of enoxaparin in combination with glycoprotein IIb/IIIa inhibitors in high-risk patients with ACS. Ongoing, large-scale, randomized controlled studies will help to clarify the role of enoxaparin in interventional cardiology, either as the primary anticoagulant or as part of a combination regimen, and to define optimal regimens for treatment. (J Interven Cardiol 2003;16:357,366) [source] MEK mediates in vitro neural transdifferentiation of the adult newt retinal pigment epithelium cells: Is FGF2 an induction factor?PIGMENT CELL & MELANOMA RESEARCH, Issue 5 2007Kanako Susaki Summary Adult newts can regenerate their entire retinas through transdifferentiation of the retinal pigment epithelium (RPE) cells. As yet, however, underlying molecular mechanisms remain virtually unknown. On the other hand, in embryonic/larval vertebrates, an MEK [mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase] pathway activated by fibroblast growth factor-2 (FGF2) is suggested to be involved in the induction of transdifferentiation of the RPE into a neural retina. Therefore, we examined using culture systems whether the FGF2/MEK pathway is also involved in the adult newt RPE transdifferentiation. Here we show that the adult newt RPE cells can switch to neural cells expressing pan-retinal-neuron (PRN) markers such as acetylated tubulin, and that an MEK pathway is essential for the induction of this process, whereas FGF2 seems an unlikely primary induction factor. In addition, we show by immunohistochemistry that the PRN markers are not expressed until the 1,3 cells thick regenerating retina, which contains retinal progenitor cells, appears. Our current results suggest that the activation of an MEK pathway in RPE cells might be involved in the induction process of retinal regeneration in the adult newt, however if this is the case, we must assume complementary mechanisms that repress the MEK-mediated misexpression of PRN markers in the initial process of transdifferentiation. [source] Nicotinic acetylcholine receptor structure and function in the efferent auditory systemTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2006Lawrence R. Lustig Abstract This article reviews and presents new data regarding the nicotinic acetylcholine receptor subunits ,9 and ,10. Although phylogentically ancient, these subunits have only recently been identified as critical components of the efferent auditory system and medial olivocochlear pathway. This pathway is important in auditory processing by modulating outer hair cell function to broadly tune the cochlea and improve signal detection in noise. Pharmacologic properties of the functionally expressed ,9,10 receptor closely resemble the cholinergic response of outer hair cells. Molecular, immunohistochemical, and knockout mice studies have added further weight to the role this receptor plays in mediating the efferent auditory response. Alternate and complementary mechanisms of outer hair cell efferent activity might also be mediated through the nAChR ,9,10, either through secondary calcium stores, second messengers, or direct protein-protein interactions. We investigated protein-protein interactions using a yeast-two-hybrid screen of the nAChR ,10 intracellular loop against a rat cochlear cDNA library. Among the identified proteins was prosaposin, a precursor of saposins, which have been shown to act as neurotrophic factors in culture, can bind to a putative G0-coupled cell surface receptor, and may be involved in the prevention of cell death. This study and review suggest that nAChR ,9,10 may represent a potential therapeutic target for a variety of ear disorders, including preventing or treating noise-induced hearing loss, or such debilitating disorders as vertigo or tinnitus. Anat Rec Part A, 2006. © 2006 Wiley-Liss, Inc. [source] Wnt/frizzled family members mediate olfactory sensory neuron axon extensionTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 3 2008Diego J. Rodriguez-Gil Abstract A comprehensive model has yet to emerge, but it seems likely that numerous mechanisms contribute to the specificity of olfactory sensory neuron (OSN) axon innervation of the olfactory bulb. Elsewhere in the nervous system the Wnt/Fz family has been implicated in patterning of anterior-posterior axes, cell type specification, cell proliferation, and axon guidance. Because of our work describing cadherin-catenin family member expression in the primary olfactory pathway, and because mechanisms of Wnt-Fz interactions can depend in part on catenins, we were encouraged to explore Wnt-Fz expression and function in OSN axon extension. Here, we show that OSNs express Fz-1, Fz-3, and Wnt-5a, whereas olfactory ensheathing cells (OECs) express Wnt-4. Fz-7 is also expressed in the olfactory nerve by cells that delineate large axon fascicles, but are negative for OEC markers. Fz-1 showed a developmental downregulation. However, in adults it is expressed at different levels across the olfactory epithelium and in restricted glomeruli across the olfactory bulb, suggesting an important role in the formation and maintenance of OSN connections to the olfactory bulb. Reporter TOPGAL mice demonstrated that some OECs located in the inner olfactory nerve layer can respond to Wnt ligands. Of further interest, we show here with in vitro assays that Wnt-5a increases OSN axon outgrowth and alters growth cone morphology. Our data point to a key role for Wnt/Fz molecules in the development of the mouse olfactory system, providing complementary mechanisms required for OSN axon extension and coalescence. J. Comp. Neurol. 511:301,317, 2008. © 2008 Wiley-Liss, Inc. [source] Edge Effects and Seedling Bank Depletion: The Role Played by the Early Successional Palm Attalea oleifera (Arecaceae) in the Atlantic ForestBIOTROPICA, Issue 2 2010Antônio Venceslau Aguiar ABSTRACT In this study, we examined the impacts of Attalea oleifera on the structure of seedling bank and discuss potential mechanisms of palm influence. Seed rain, seedling bank, and palm leaf fall were assessed beneath the canopy and in the vicinity of 16 adult palms across the edges of a large fragment (3500 ha) of the Atlantic forest. Moreover, we examined A. oleifera impacts on seed germination and seedling mortality by experimentally submitting seeds and seedlings to prolonged palm-leaf covering. As expected, seedling bank beneath the adults exhibited reduced abundance and species richness at local and habitat scale. Small to large seeds (3.1,30 mm) were underrepresented in the seed rain below adults palms, while experimental leaf covering drastically reduced both seed germination and seedling survivorship. A. oleifera leaf fall occurred over the whole year (3.6±2.7 leaves/individual/yr), which resulted in deep leaf litter mounds (10.7±9.2 cm). Finally, adult palm density (21.6±11.9 individuals/ha) correlated negatively with seedling density across Attalea clusters. Our results suggest that A. oleifera exerts negative effects on the seedling bank by reducing seedling abundance and richness as a consequence of two complementary mechanisms: impoverished and size-biased seed rain plus reduced seed germination and increased seedling mortality due to prolonged covering by fallen leaves. Abstract in Portuguese is available at http://www.blackwell-synergy.com/loi/btp [source] Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: Identification of genetic indicators that predict patient outcomeCANCER SCIENCE, Issue 3 2007Panayiotis Loukopoulos We analyzed the subchromosomal numerical aberrations of 44 surgically resected pancreatic adenocarcinomas by array-based comparative genomic hybridization. The aberration profile ranged widely between cases, suggesting the presence of multiple or complementary mechanisms of evolution in pancreatic cancer, and was associated with lymph node metastasis and venous or serosal invasion. A large number of small loci, previously uncharacterized in pancreatic cancer, showed non-random loss or gain. Frequent losses at 1p36, 4p16, 7q36, 9q34, 11p15, 11q13, 14q32-33, 16p13, 17p11-13, 17q11-25, 18q21-tel, 19p13, 21q22 and 22q11-12, and gains at 1q25, 2p16, 2q21-37, 3q25, 5p14, 5q11-13, 7q21, 7p22, 8p22, 8q21-23, 10q21, 12p13, 13q22, 15q13-22 and 18q11 were identified. Sixteen loci were amplified recurrently. We identified novel chromosomal alterations that were significantly associated with a range of malignant phenotypes. Gain of LUNX, HCK, E2F1 and DNMT3b at 20q11, loss of p73 at 1p36 and gain of PPM1D at 17q23 independently predicted patient outcome. Expression profiling of amplified genes identified Smurf1 and TRRAP at 7q22.1, BCAS1 at 20q13.2-3, and VCL at 10q22.1 as potential novel oncogenes. Our results contribute to a complete description of genomic structural aberrations and the identification of potential therapeutic targets and genetic indicators that predict patient outcome in pancreatic adenocarcinoma. (Cancer Sci 2007; 98: 392,400) [source] | |||||||||||||