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Rational Approach (rational + approach)
Selected AbstractsStenting of Bifurcation Lesions: A Rational ApproachJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 6 2001FSCAI, THIERRY LEFÈVRE M.D. The occurrence of stenosis in or next to coronary bifurcations is relatively frequent and generally underestimated. In our experience, such lesions account for 15%,18% of all percutaneous coronary intervention > (PCI). The main reasons for this are (1) the coronary arteries are like the branches of a tree with many ramifications and (2) because of axial plaque redistribution, especially after stent implantation, PCI of lesions located next to a coronary bifurcation almost inevitably cause plaque shifting in the side branches. PCI treatment of coronary bifurcation lesions remains challenging. Balloon dilatation treatment used to be associated with less than satisfactory immediate results, a high complication rate, and an unacceptable restenosis rate. The kissing balloon technique resulted in improved, though suboptimal, outcomes. Several approaches were then suggested, like rotative or directional atherectomy, but these techniques did not translate into significantly enhanced results. With the advent of second generation stents, in 1996, the authors decided to set up an observational study on coronary bifurcation stenting combined with a bench test of the various stents available. Over the last 5 years, techniques, strategies, and stent design have improved. As a result, the authors have been able to define a rational approach to coronary bifurcation stenting. This bench study analyzed the behavior of stents and allowed stents to be discarded that are not compatible with the treatment of coronary bifurcations. Most importantly, this study revealed that stent deformation due to the opening of a strut is a constant phenomenon that must be corrected by kissing balloon inflation. Moreover, it was observed that the opening of a stent strut into a side branch could permit the stenting, at least partly, of the side branch ostium. This resulted in the provocative concept of "stenting both branches with a single stent." Therefore, a simple approach is currently implemented in the majority of cases: stenting of the main branch with provisional stenting of the side branch, The technique consists of inserting a guidewire in each coronary branch. A stent is then positioned in the main branch with a wire being "jailed" in the side branch. The wires are then exchanged, starting with the main branch wire that is passed through the stent struts into the side branch. After opening the stent struts in the side branch, kissing balloon inflation is performed. A second stent is deployed in the side branch in the presence of suboptimal results only. Over the last 2 years, this technique has been associated with a 98% angiographic success rate in both branches. Two stents are used in 30%,35% of cases and final kissing balloon inflation is performed in > 95% of cases. The in-hospital major adverse cardiac events (MACE) rate is around 5% and 7-month target vessel revascularization (TVR) is 13%. Several stents specifically designed for coronary bifurcation lesions are currently being investigated. The objective is to simplify the approach for all users. In the near future, the use of drug-eluting stents should reduce the risk of restenosis. [source] A Rational Approach to the Use of Tracheotomy in Surgery of the Anterior Skull BaseTHE LARYNGOSCOPE, Issue 2 2008FRCS(C), Yadranko Ducic MD Abstract Objective: To offer an algorithm for airway management in anterior skull base surgery. Methods: This is a retrospective review of 109 patients undergoing major anterior skull base surgery from a single senior surgeon's experience from September 1997 to May 2006. Results: We report only one (1%) postoperative mortality in this series and only seven major complications in six patients, including two cases of stroke, one case of cerebrospinal fluid (CSF) leak, and four cases of delayed osteoradionecrosis. No patients in this series developed tension pneumocephalus. The total major complication rate is 6%. Fifty-one (47%) patients received prophylactic tracheotomy, and 58 (53%) patients did not receive prophylactic tracheotomy. Eighty-eight (81%) patients received anterior skull base reconstruction with local flaps. Six (5.5%) patients required primary reconstruction with a free flap. Conclusion: We attribute the very low rate of major complications in this series and, in particular, no cases of tension pneumocephalus and rarity of CSF leaks primarily to prophylactic tracheotomy in selected patients and to a reconstructive strategy that emphasizes use of local vascularized tissue to reconstruct the anterior skull base. [source] Sentinel Lymph Node Biopsy: A Rational Approach for Staging T2N0 Oral Cancer,THE LARYNGOSCOPE, Issue 12 2005Nestor Rigual MD Abstract Objectives/Hypothesis: For oral cancer patients, the presence of neck nodal metastases is the most important disease prognosticator. However, a significant proportion of clinically N0 patients harbor occult microscopic nodal metastasis. Our objective was to determine the feasibility and accuracy of sentinel node biopsy (SNB) in the staging of T2N0 oral carcinoma patients. Study Design: Prospective analysis. Methods: Twenty patients with previously untreated N0 oral cavity squamous cell carcinoma were studied. Each patient had an SNB performed using preoperative technetium sulfur colloid lymphoscintigraphy, intraoperative gamma probe guidance, and intraoperative peritumoral injection of 1% isosulfan blue. All patients underwent neck dissection. The sentinel lymph nodes (SLNs) were sectioned in 2- to 3-mm intervals, formalin fixed, and sectioned at three levels. The non-SLNs were sectioned in a routine manner for histologic examination. Results: SLNs were identified in all patients (100%) and accurately predicted the pathologic nodal status in 18 of 20 patients (90%). Tumor was found exclusively in the SLNs in six patients (30%). Two patients had positive SLNs at multiple neck levels. Two patients had a negative SLN and a positive non-SLN (false-negative findings). Occult nodal metastases were present in 60% of the cohort. Conclusions: SNB is a technically feasible and accurate procedure for staging the neck in oral carcinoma patients. However, SNB accuracy is lower for floor of the mouth lesions. The rate of occult nodal metastases identified in this cohort is higher than previously reported in the literature. These results suggest that SNB warrants further multi-institutional studies. [source] A Rational Approach to the Ionothermal Synthesis of an AlPO4 Molecular Sieve with an LTA-Type Framework,ANGEWANDTE CHEMIE, Issue 27 2010Gesunde Struktur: Bei der Synthese eines AlPO4 -LTA-Zeoliths in ionischen Flüssigkeiten fungieren 1-Benzyl-3-methylimidazolium-, Tetramethylammonium- und Fluoridionen als Strukturbildner für die ,-Käfige, Sodalith-Käfige und würfelförmigen Baueinheiten (siehe Bild; C,grau, N,blau, O,rot, Al und P,pink, F grün). Selektives Entfernen der 1-Benzyl-3-methylimidazolium-Ionen ergab ein stabiles AlPO4 -LTA-Molekularsieb. [source] Rational approaches to the neurobiologic study of youth at risk for bipolar disorder and suicideBIPOLAR DISORDERS, Issue 5p2 2006M Elizabeth Sublette Objectives:, The aims of this paper are to provide an overview of neuroimaging findings specific to bipolar disorder and suicide, and to consider rational approaches to the design of future in vivo studies in youth at risk. Methods:, Neuroimaging and related neurobiological literature pertaining to bipolar disorder and suicide in adult and pediatric samples was reviewed in a non-quantitative manner. Results:, Specific structural and functional brain findings in bipolar disorder are described, where possible in the context of relevant current neurobiological theories of etiology. Diagnostic and prognostic implications are discussed. Conclusions:, The simultaneous use of complementary neurobiological approaches may be a powerful way of identifying and validating factors reliably associated with bipolar disorder and suicide. A profile of neurobiological markers with which to screen for bipolar disorder and suicide risk may provide for earlier and more accurate diagnosis, perhaps even in the pre- or subsyndromal stages in high-risk youth. [source] Navigating toward Fetal and Maternal Health: The Challenge of Treating Epilepsy in PregnancyEPILEPSIA, Issue 10 2004Torbjörn Tomson Summary:, A rational approach to the treatment of women of childbearing potential with epilepsy has been hampered by the lack of conclusive data on the comparative teratogenic potential of different antiepileptic drugs (AEDs). Although, several cohort studies on birth defects associated with AED use during pregnancy have been published, these have generally failed to demonstrate differences in malformation rates between AEDs, probably mainly due to insufficient power. In particular, pregnancies with new generation AEDs have been too few. In recent years, pregnancy registries have been introduced to overcome this problem,EURAP (an international collaboration), the North American, and the U.K. AED and pregnancy registries are observational studies that prospectively assess pregnancy outcome after AED exposure using slightly different methods. Each has enlisted 3,5,000 pregnancies in women with epilepsy, and the North American and the U.K. have released preliminary observations. Thus the U.K. registry reported a higher malformation rate with valproate, 5.9% (4.3,8.2%; 95% CI), than with carbamazepine, 2.3% (1.4,3.7%), and lamotrigine, 2.1% (1.0,4.0%). Most of the more recent cohort studies have also identified a nonsignificant trend toward a higher teratogenicity with valproate. These signals need to be interpreted with some caution since none of the studies to date have fully assessed the impact of possible confounders, such as type of epilepsy, family history of birth defects, etc. However, with increasing number of pregnancies it should be possible in the near future for the pregnancy registries to take such confounding factors into account and thus make more reliable assessments of the causal relationship between exposure to specific AEDs and teratogenic risks. While awaiting more conclusive results, it appears reasonable to be cautious in prescribing valproate to women considering to become pregnant if other suitable treatment alternatives, and with less teratogenic potential, are available. Any attempt to change treatment should, however, be accomplished well before conception. The importance of maintained seizure control must also be kept in mind, and the woman who needs valproate to control her seizures should not be discouraged from pregnancy, provided that counseling at the best of available knowledge is given. [source] Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence ReviewedEPILEPSIA, Issue 11 2000Charles L. P. Deckers Summary: Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Results: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. Conclusions: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy. [source] Rational Combination Therapy in Refractory MigraineHEADACHE, Issue 6 2008B. Lee Peterlin DO Refractory migraine (RM) headaches pose important treatment challenges to the patients who live with them and the clinicians who try to treat them. Defined based on the lack of response to acute, preventive, and nonpharmacologic treatment, RM is often treated with a combination of treatments. Although combination therapy for RM has not been systematically studied in randomized trials, clinical experience suggests that a rational approach to RM treatment, utilizing a combination of treatments, may be effective where monotherapy has failed. In this article we briefly identify patient populations appropriate for more aggressive migraine prevention with combination therapy. We then discuss modifiable risk factors and comorbidities in migraine and then focus on the use of rational combination therapy, as well as the duration migraine preventatives should be considered for use. Future research is needed to evaluate the full potential of rational combination treatment as a strategy for treating and ultimately preventing RM. [source] Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastomaHISTOPATHOLOGY, Issue 5 2007D Ribatti Aims:, Previous studies have shown that increased vascularity is associated with tumour progression in human neuroblastoma (NB). The involvement of erythropoietin (Epo) in tumour angiogenesis has also been reported. The aim of this study was to correlate microvascular density and Epo/Epo-receptor (EpoR) expression in endothelial and tumour cells to the clinical stage of NB. Methods and results:, Specimens of NB obtained from 20 patients were investigated immunohistochemically by using anti-CD31, anti-Epo and anti-EpoR antibodies. The extent of angiogenesis was found to be up-regulated in advanced disease. In keeping with this observation, Epo/EpoR expression in tumour and endothelial cells, respectively, was also highly correlated with the extent of angiogenesis and higher clinical stage. Conclusions:, The correlation of Epo/EpoR expression with angiogenesis and tumour progression suggests the presence of a loop in the Epo,EpoR system. Epo is secreted by tumour cells and affects vascular endothelial cells via its receptor, promoting tumour angiogenesis in a paracrine manner. Data suggest that Epo represents an important mediator in NB angiogenesis. Understanding the mechanisms of NB angiogenesis provides the basis for a rational approach to the development of antiangiogenic therapy in patients affected by NB. [source] Crinkling Ultralong Nanotubes: Crinkling Ultralong Carbon Nanotubes into Serpentines by a Controlled Landing Process (Adv. Mater.ADVANCED MATERIALS, Issue 41 200941/2009) A rational approach to crinkling ultralong CNTs into serpentine geometries by controlling their landing on a quartz substrate is demonstrated by Jin Zhang and co-workers on p. 4158. Using this method, the length, density, and number of parallel CNT segments in the serpentine CNTs were significantly increased. When incorporated into ultrahigh-current devices, the performance of the devices could be improved by increasing the number of parallel segments in the serpentine CNT arrays. [source] Aldehyde-Amine Chemistry Enables Modulated Biosealants with Tissue-Specific AdhesionADVANCED MATERIALS, Issue 32-33 2009Natalie Artzi The interfacial regions between PEG: dextran-based adhesive sealant and excised rat heart, lung, liver, and duodenum tissues exhibit three distinct domains; target tissue (red and blue), bulk material (green), and an adhesive regime interposed between the two. The variation in adhesive regime morphology when applied to different tissues provides a rational approach for the engineering of application-specific surgical sealants. [source] A rational approach to mass matrix diagonalization in two-dimensional elastodynamicsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 15 2004E. A. Paraskevopoulos Abstract A variationally consistent methodology is presented, which yields diagonal mass matrices in two-dimensional elastodynamic problems. The proposed approach avoids ad hoc procedures and applies to arbitrary quadrilateral and triangular finite elements. As a starting point, a modified variational principle in elastodynamics is used. The time derivatives of displacements, the velocities, and the momentum type variables are assumed as independent variables and are approximated using piecewise linear or constant functions and combinations of piecewise constant polynomials and Dirac distributions. It is proved that the proposed methodology ensures consistency and stability. Copyright © 2004 John Wiley & Sons, Ltd. [source] Strategies for developing multi-epitope, subunit-based, chemically synthesized anti-malarial vaccinesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5b 2008M. E. Patarroyo ,,Introduction ,,P. falciparum invasion of RBCs ,,Merozoite proteins involved in invading erythrocytes ,,Erythrocyte proteins involved in merozoite invasion ,,The state of current worldwide anti-malarial vaccine approaches ,,A rational approach towards developing subunit-based synthetic vaccines ,,The immune response elicited by conserved HABPs ,,Structural analysis of native and modified HABPs ,,Secondary structure analysis ,,Native and modified HABP 3D structure explains some immunological phenomena ,,Supporting the haplotype , and allele-conscious TCR concept ,,Modified HABPs' 3D structure revealed a fit into HLA molecules ,,Conclusion Abstract An anti-malarial vaccine against the extremely lethal Plasmodium falciparum is desperately needed. Peptides from this parasite's proteins involved in invasion and having high red blood cell-binding ability were identified; these conserved peptides were not immun genic or protection-inducing when used for immunizing Aotus monkeys. Modifying some critical binding residues in these high-activi binding peptides' (HABPs') attachment to red blood cells (RBC) allowed them to induce immunogenicity and protection against expermental challenge and acquire the ability to bind to specific HLA-DRp1* alleles. These modified HABPs adopted certain characterist structural configurations as determined by circular dichroism (CD) and 1H nuclear magnetic resonance (NMR) associated with certain HLA-DR,1* haplotype binding activities and characteristics, such as a 2-Å-distance difference between amino acids fitting into HLA-DRp1 Pockets 1 to 9, residues participating in binding to HLA-DR pockets and residues making contact with the TCR, suggesting haplotyp and allele-conscious TCR. This has been demonstrated in HLA-DR-like genotyped monkeys and provides the basis for designing high effective, subunit-based, multi-antigen, multi-stage, synthetic vaccines, for immediate human use, malaria being one of them. [source] Mechanistic understanding of the fermentative L -glutamic acid overproduction by Corynebacterium glutamicum through combined metabolic flux profiling and transmembrane transport characteristicsJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 12 2004Theodora Tryfona Abstract Since the 1950s when Micrococcus glutamicus later renamed Corynebacterium glutamicum was discovered, the production of amino acids by fermentative methods has become an important aspect of industrial microbiology. Numerous studies to understand and improve the metabolic conditions leading to amino acid overproduction have been carried out. Most amino acids are currently produced by use of mutants that contain combinations of auxotrophic and regulatory mutations. L -Glutamic acid is the amino acid produced in the greatest quantities (106 tonnes per year) and Corynebacteria are central to its industrial production. However, further improvements to strain performance are difficult to obtain by empirical optimization and a more rational approach is required. The use of metabolic flux analysis provides valuable information regarding bottlenecks in the formation of desired metabolites. Such techniques have found application in elucidating flux control, provided insight into metabolic network function and developed methods to amplify or redirect fluxes in engineered bioprocesses. Hence, branch points in biosynthesis, precursor supply in fuelling reactions and export of metabolites can be manipulated, resulting in high glutamic acid overproduction by Corynebacterium glutamicum fermentations. In this review, in addition to reviewing the state of play in metabolic flux analysis for glutamate overproduction, the metabolic pathways involved in the production of L -glutamic acid, the mechanisms mediating its efflux and secretion as well as their manipulation to achieve higher glutamate production, are discussed. The link between metabolic flux and transmembrane transport of glutamic acid are also considered. Copyright © 2004 Society of Chemical Industry [source] Pathologic interactions in pulpal and periodontal tissuesJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2002M. Zehnder Abstract Both endodontic and periodontal disease are caused by a mixed anaerobic infection. The pathways for the spread of bacteria between pulpal and periodontal tissues have been discussed with controversy. This article is an attempt to provide a rational approach to the perio-endo/endo-perio question based on a review of the relevant literature. In the light of evidence, clinical concepts for the diagnosis and treatment of lesions involving both periodontal and pulpal tissues are discussed. Zusammenfassung Pathologische Interaktionen bei pulpalen und parodontalen Geweben Sowohl die endodontalen als auch parodontalen Erkrankungen sind durch eine gemischte anaerobe Infektion verursacht. Die pathogenetischen Muster für die Ausbreitung der Bakterien zwischen pulpalen und parodontalen Geweben sind kontrovers diskutiert worden. Dieser Artikel ist ein Versuch für einen rationalen Ansatz zu den paro-endo bzw. endo-paro Fragen, basierend auf einer Übersicht der relevanten Literatur. Im Blick der Evidence werden die klinischen Konzepte für die Diagnose und Therapie der Läsionen, die sowohl parodontale als auch pulpale Gewebe einbeziehen, diskutiert. Résumé Interactions pathologiques entre les tissus pulpaires et parodontaux. Les maladies endodontiques et parodontales sont toutes deux causes par une infection mixte anaérobique. Les voies de dissémination des bactéries entre les tissus pulpaires et parodontaux ont été discutée avec controverse. Cet article est une tentative d'apporter une approche rationnelle à la question paro-endo/endo-paro à partir d'une revue critique de la littérature appropriée. A la lumière des preuves, des concepts cliniques pour le diagnostic et le traitement des lésions impliquant à la fois les tissus parodontaux et pulpaires sont discutés. [source] Rational determination of charge distributions for free energy calculationsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 4 2003Christophe Chipot Abstract Point charges derived from RHF/6-31G* electrostatic potentials are attractive because they tend to exaggerate the polarity of solvated molecules, thereby compensating in an average fashion missing induction effects. In the context of free energy calculations, wherein the molecule is transferred from a polar environment to a nonpolar one, we propose a more rational approach based on a self-consistent reaction field computation at a higher level of theory, supplemented by an estimation of the corresponding distortion energy to account for the change of polarity of the surroundings. Application of this method to the test cases acetamide, acetic acid, methyl acetate and phenol, using multinanosecond molecular dynamics/"umbrella sampling" simulations, yields consistent hydration free energies in reasonably good agreement with experiment. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 409,415, 2003 [source] Stenting of Bifurcation Lesions: A Rational ApproachJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 6 2001FSCAI, THIERRY LEFÈVRE M.D. The occurrence of stenosis in or next to coronary bifurcations is relatively frequent and generally underestimated. In our experience, such lesions account for 15%,18% of all percutaneous coronary intervention > (PCI). The main reasons for this are (1) the coronary arteries are like the branches of a tree with many ramifications and (2) because of axial plaque redistribution, especially after stent implantation, PCI of lesions located next to a coronary bifurcation almost inevitably cause plaque shifting in the side branches. PCI treatment of coronary bifurcation lesions remains challenging. Balloon dilatation treatment used to be associated with less than satisfactory immediate results, a high complication rate, and an unacceptable restenosis rate. The kissing balloon technique resulted in improved, though suboptimal, outcomes. Several approaches were then suggested, like rotative or directional atherectomy, but these techniques did not translate into significantly enhanced results. With the advent of second generation stents, in 1996, the authors decided to set up an observational study on coronary bifurcation stenting combined with a bench test of the various stents available. Over the last 5 years, techniques, strategies, and stent design have improved. As a result, the authors have been able to define a rational approach to coronary bifurcation stenting. This bench study analyzed the behavior of stents and allowed stents to be discarded that are not compatible with the treatment of coronary bifurcations. Most importantly, this study revealed that stent deformation due to the opening of a strut is a constant phenomenon that must be corrected by kissing balloon inflation. Moreover, it was observed that the opening of a stent strut into a side branch could permit the stenting, at least partly, of the side branch ostium. This resulted in the provocative concept of "stenting both branches with a single stent." Therefore, a simple approach is currently implemented in the majority of cases: stenting of the main branch with provisional stenting of the side branch, The technique consists of inserting a guidewire in each coronary branch. A stent is then positioned in the main branch with a wire being "jailed" in the side branch. The wires are then exchanged, starting with the main branch wire that is passed through the stent struts into the side branch. After opening the stent struts in the side branch, kissing balloon inflation is performed. A second stent is deployed in the side branch in the presence of suboptimal results only. Over the last 2 years, this technique has been associated with a 98% angiographic success rate in both branches. Two stents are used in 30%,35% of cases and final kissing balloon inflation is performed in > 95% of cases. The in-hospital major adverse cardiac events (MACE) rate is around 5% and 7-month target vessel revascularization (TVR) is 13%. Several stents specifically designed for coronary bifurcation lesions are currently being investigated. The objective is to simplify the approach for all users. In the near future, the use of drug-eluting stents should reduce the risk of restenosis. [source] Rationality and Its Symbols: Signalling Effects and Subjectification in Management Consulting*JOURNAL OF MANAGEMENT STUDIES, Issue 8 2004Thomas Armbrüster abstract In service sectors such as management consulting, it is very difficult to measure the impact or success of a service even after it has been delivered. In these markets of goods between experience and credence, symbolic value is helpful and necessary to complement quality perceptions. The leading management consulting firms, in particular, do not only deliver data-driven analyses but also represent and symbolize the rational approach to business issues. This article looks at the role of personnel selection in the context of quality symbolization. It argues that the predominant tool for personnel selection in the consulting sector, the case study, accounts for both a signalling effect of rationality to the business environment and a subjectification of consulting staff to the consulting culture and rationality beliefs. The case is made that, rather than leading to a valid selection of high-performance personnel, the process of personnel selection has latent effects, which nonetheless contribute to the consulting industry's success. [source] Differential apoptotic response of J774 macrophages to alumina and ultra-high-molecular-weight polyethylene particlesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2002Alain Petit We recently identified apoptosis in in vitro wear particle-stimulated macrophages. The recent explosion of interest in apoptosis lies in the fact that it is under positive and negative regulation through evolutionary conserved biochemical pathways. It may also be possible to modulate macrophage apoptosis in the treatment of periprosthetic osteolysis. The purpose of this study was to compare the macrophage response to identically sized particles of alumina ceramic (Al2O3) and ultra-high-molecular-weight polyethylene (UHMWPE) in terms of TNF-, release and induction of apoptosis. J774 mouse macrophages were incubated for 0,24 h in the presence of Al2O3 and UHMWPE particles. TNF-, release was measured by ELISA; Poly(ADP-ribose)polymerase (PARP) and caspase-3 expression was analyzed by Western blot; DNA fragmentation (DNA laddering) was visualized on agarose gel containing ethidium bromide. Al2O3 particles induced TNF-, release after 4 h incubation with concentrations reaching 483 and 800 pg/ml after 24 h with 125 and 250 particles/macrophage, respectively (control = 161 pg/ml) (P < 0.05 vs. control). The same concentrations of UHMWPE particles induced a much larger and significant TNF-, release after only 1 h incubation, increasing up to 6250 pg/ml after 24 h (P < 0.05 vs. control). Western blot analysis demonstrated that the active caspase-3 fragment (17 kDa) and the proteolytic PARP fragment (85 kDa) were expressed after 2 h incubation with 125 and 250 Al2O3 particles/macrophage. The active caspase-3 and the PARP fragment had lower expression and appeared after a longer incubation time (8 h) with 125 and 250 UHMWPE particles/macrophage. Finally, DNA fragmentation (DNA laddering) was observed after 16 h with 125 and 250 particles of Al2O3 per macrophage whereas no laddering was induced by UHMWPE particles even after 24 h incubation. This study shows that although both Al2O3 and UHMWPE particles induce TNF-, release, this stimulation was much greater (8,10 times higher) with UHMWPE than A12O3 (P < 0.05 vs. control). As well, the induction of apoptosis, as measured by activation of caspase-3, PARP cleavage and DNA laddering, is different for these two particles, being faster and more important with Al2O3 than UHMWPE. We hypothesize that the ability of Al2O3 to induce macrophage apoptosis may explain the lower TNF-, release observed with these particles and explain the differences seen in osteolysis patterns of ceramic,ceramic (CC) vs. metal,polyethylene (Mpe) articulations. In conclusion, apoptosis may be a major internal mechanism to decrease macrophage activity and may be a desired therapeutic endpoint. The identification of an apoptosis-related pathway in the macrophage response to ceramic particles provides crucial data for a rational approach in the treatment and/or prevention of periprosthetic osteolysis. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Quality-by-Design (QbD): An integrated process analytical technology (PAT) approach for real-time monitoring and mapping the state of a pharmaceutical coprecipitation process,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2010Huiquan Wu Abstract In this work, an integrated PAT approach was developed for monitoring a pharmaceutical (naproxen) and a polymer (eudragit) coprecipitation process: real-time in-line near-infrared (NIR) absorbance monitoring, real-time on-line turbidity monitoring, and in situ crystal size monitoring. The data and information obtained through these three monitoring techniques confirmed the observation of the onsets of three distinct stages: incubation, nucleation, and crystal growth. The process trajectory constructed based on results of applying principal component analysis (PCA) to either process NIR spectra data or process turbidity profile, clearly demonstrated that various distinguishable process events, including incubation, nucleation, and crystal growth, could be accurately tracked and differentiated. These findings were further supported by process knowledge and information, such as process design, process sequence, thermodynamic and mass-transfer analysis. Therefore, this work provides a case study that illustrated a rational approach to develop a science-based and knowledge-based process monitoring strategy, which is essential for establishing both a suitable process control strategy and an operational process space for a pharmaceutical unit operation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1516,1534, 2010 [source] Engineering of pharmaceutical materials: An industrial perspectiveJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2008Kwok Chow Abstract Crystal engineering provides a rational approach to solving formulation, processing and product performance problems. This review discusses how the concept of crystal engineering can be judiciously utilized to manipulate the solid-state properties of drugs and excipients for successful pharmaceutical formulation and process development. Existing and emerging manufacturing as well as co-processing technologies being applied in the pharmaceutical industry are also presented together with selected examples of crystal form design, crystal form selection and crystal modifications for illustration purposes. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 2855,2877, 2008 [source] Emesis in dogs: a reviewJOURNAL OF SMALL ANIMAL PRACTICE, Issue 1 2010C. Elwood Emesis is a common presenting sign in small animal practice. It requires a rational approach to management that is based upon a sound understanding of pathophysiology combined with logical decision making. This review, which assesses the weight of available evidence, outlines the physiology of the vomiting reflex, causes of emesis, the consequences of emesis and the approach to clinical management of the vomiting dog. The applicability of diagnostic testing modalities and the merit of traditional approaches to management, such as dietary changes, are discussed. The role and usefulness of both traditional and novel anti-emetic drugs is examined, including in specific circumstances such as following cytotoxic drug treatment. The review also examines areas in which common clinical practice is not necessarily supported by objective evidence and, as such, highlights questions worthy of further clinical research. [source] A rational approach to internal mammary node biopsy in the era of lymphatic mapping for breast cancerJOURNAL OF SURGICAL ONCOLOGY, Issue 1 2002Kenneth A. Kern MD First page of article [source] Cloning and paratope analysis of an antibody fragment, a rational approach for the design of a PAI-1 inhibitorJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2004K. Verbeke Summary., This study reports the cloning, characterization and paratope analysis of the plasminogen activator inhibitor-1 (PAI-1) neutralizing single-chain variable fragment 56A7C10 (scFv-56A7C10). ScFv-56A7C10-wt exhibits a similar affinity (KA = 1.01 ± 0.3 × 109 m,1) and PAI-1 inhibitory capacity (90 ± 6% PAI-1 inhibition at a 16-fold molar excess and IC50 = 44 ± 14 ng mL,1) as MA-56A7C10 (KA = 1.43 ± 0.4 × 109 m,1, 90 ± 2% PAI-1 inhibition at a 16-fold molar excess and IC50 = 122 ± 26 ng mL,1). Subsequently, alanine scanning of the six complementarity determining regions (CDRs) was performed and the scFv-56A7C10-mutants (n = 26) were analyzed for their PAI-1 binding and PAI-1 inhibitory properties. Mutation of the residues Y32 and V33 in the CDR1 of the heavy chain (HCDR1) and the residues R98, H99, W100 or F100a (HCDR3) resulted in reduced PAI-1 inhibitory capacities (IC50 , 418 ng mL,1), confirmed by reduced affinities (14-, 17-, 7-, 9- and 16-fold reduced, respectively, vs. scFv-56A7C10-wt). In the light chain, mutation of the residues W50 (LCDR2), H91, Y92, D93, or W96 (LCDR3) resulted in reduced PAI-1 inhibitory properties (IC50 , 160 ng mL,1) and decreased affinities (i.e. 4-, 9-, 3-, 3- and 2-fold reduced affinity, respectively, vs. scFv-56A7C10-wt). Furthermore, an overlapping peptide scan confirmed the importance of the HCDR3 region. These data, combined with a three-dimensional model of scFv-56A7C10, reveal the molecular and structural properties of the paratope and contribute to the rational design of PAI-1 neutralizing compounds. [source] What is the real gain after liver transplantation?LIVER TRANSPLANTATION, Issue S2 2009James Neuberger Key Points 1. For most liver allograft recipients, both the quality and length of life are greatly improved after transplantation. However, neither the quality of life nor the length of life in the survivors returns to that seen in age-matched and sex-matched normal subjects. 2. The gain in survival after transplantation can be estimated by a comparison of the actual outcome after transplantation and the predicted survival in the absence of transplantation. 3. The reduction in graft and patient survival, in comparison with a normal age-matched and sex-matched population, is determined by several factors: short-term survival is affected by the patient's condition pre-transplant and the quality of the graft, and for longer term survival, recurrent disease accounts for most of the differences seen between different indications. Some of the causes of premature death (such as infection, de novo malignancy, and cardiovascular and cerebrovascular disease) that are increased in the liver allograft recipient may be reduced by improved management with more aggressive surveillance and treatment. 4. The aims of selection and allocation vary in different health care systems: transparency, objectivity, equity of access, justice, mortality awaiting transplantation, utility, and transplant benefit are all important but often competing demands. Understanding the associated increase in survival will allow for a rational approach to this complex area. Liver Transpl 15:S1,S5, 2009. © 2009 AASLD. [source] Medication-induced mitochondrial damage and diseaseMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 7 2008John Neustadt Abstract Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis. Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have stain medications, analgesics such as acetaminophen, and many others. While targeted nutrient therapies using antioxidants or their prescursors (e. g., N -acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge. The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects. [source] Protein Kinase Target Discovery From Genome-Wide Messenger RNA Expression ProfilingMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 4 2010Avi Ma'ayan Abstract Genome-wide messenger RNA profiling provides a snapshot of the global state of the cell under different experimental conditions such as diseased versus normal cellular states. However, because measurements are in the form of quantitative changes in messenger RNA levels, such experimental data does not provide direct understanding of the regulatory molecular mechanisms responsible for the observed changes. Identifying potential cell signaling regulatory mechanisms responsible for changes in gene expression under different experimental conditions or in different tissues has been the focus of many computational systems biology studies. Most popular approaches include promoter analysis, gene ontology, or pathway enrichment analysis, as well as reverse engineering of networks from messenger RNA expression data. Here we present a rational approach for identifying and ranking protein kinases that are likely responsible for observed changes in gene expression. By combining promoter analysis; data from various chromatin immunoprecipitation studies such as chromatin immunoprecipitation sequencing, chromatin immunoprecipitation coupled with paired-end ditag, and chromatin immunoprecipitation-on-chip; protein-protein interactions; and kinase-protein phosphorylation reactions collected from the literature, we can identify and rank candidate protein kinases for knock-down, or other types of functional validations, based on genome-wide changes in gene expression. We describe how protein kinase candidate identification and ranking can be made robust by cross-validation with phosphoproteomics data as well as through a literature-based text-mining approach. In conclusion, data integration can produce robust candidate rankings for understanding cell regulation through identification of protein kinases responsible for gene expression changes, and thus rapidly advancing drug target discovery and unraveling drug mechanisms of action. Mt Sinai J Med 77:345,349, 2010. © 2010 Mount Sinai School of Medicine [source] Stem cells in craniofacial and dental tissue engineeringORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 2 2005MV Risbud Abstract Authors ,, Risbud MV, Shapiro IM Mesenchymal stem cells (MSC) have been identified in a variety of adult tissues as a population of pluripotential self-renewing cells. Based on their adherence and colony forming properties, a small number of MSC can be isolated from most mesenchymal tissues as well as bone marrow. In the presence of one or more growth factors, these cells commit to lineages that lead to the formation of bone, cartilage, muscle, tendon and adipose tissue; recent studies indicate that stem cells for cementum, dentine and the periodontal ligament also exist. All of these cells can be expanded in vitro, and, embedded in a scaffold, inserted into defects to promote healing and tissue replacement. Increased understanding of the molecular mechanism directing lineage specification and morphogenesis is providing a rational approach for the regeneration of craniofacial tissues and oral structures. [source] Investor Psychology and Asset PricingTHE JOURNAL OF FINANCE, Issue 4 2001David Hirshleifer The basic paradigm of asset pricing is in vibrant flux. The purely rational approach is being subsumed by a broader approach based upon the psychology of investors. In this approach, security expected returns are determined by both risk and misvaluation. This survey sketches a framework for understanding decision biases, evaluates the a priori arguments and the capital market evidence bearing on the importance of investor psychology for security prices, and reviews recent models. [source] A rational approach to heavy-atom derivative screeningACTA CRYSTALLOGRAPHICA SECTION D, Issue 4 2010M. Gordon Joyce Despite the development in recent times of a range of techniques for phasing macromolecules, the conventional heavy-atom derivatization method still plays a significant role in protein structure determination. However, this method has become less popular in modern high-throughput oriented crystallography, mostly owing to its trial-and-error nature, which often results in lengthy empirical searches requiring large numbers of well diffracting crystals. In addition, the phasing power of heavy-atom derivatives is often compromised by lack of isomorphism or even loss of diffraction. In order to overcome the difficulties associated with the `classical' heavy-atom derivatization procedure, an attempt has been made to develop a rational crystal-free heavy-atom derivative-screening method and a quick-soak derivatization procedure which allows heavy-atom compound identification. The method includes three basic steps: (i) the selection of likely reactive compounds for a given protein and specific crystallization conditions based on pre-defined heavy-atom compound reactivity profiles, (ii) screening of the chosen heavy-atom compounds for their ability to form protein adducts using mass spectrometry and (iii) derivatization of crystals with selected heavy-metal compounds using the quick-soak method to maximize diffraction quality and minimize non-isomorphism. Overall, this system streamlines the process of heavy-atom compound identification and minimizes the problem of non-isomorphism in phasing. [source] | ||||||||||||||||||||||||||||||||||||||||