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Different Efficacies (different + efficacy)
Selected AbstractsDonor Pretreatment with Tetrahydrobiopterin Saves Pancreatic Isografts from Ischemia Reperfusion Injury in a Mouse ModelAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010M. Maglione Depletion of the nitric oxide synthase cofactor tetrahydrobiopterin (H4B) during ischemia and reperfusion is associated with severe graft pancreatitis. Since clinically feasible approaches to prevent ischemia reperfusion injury (IRI) by H4B-substitution are missing we investigated its therapeutic potential in a murine pancreas transplantation model using different treatment regimens. Grafts were subjected to 16 h cold ischemia time (CIT) and different treatment regimens: no treatment, 160 ,M H4B to perfusion solution, H4B 50 mg/kg prior to reperfusion and H4B 50 mg/kg before recovery of organs. Nontransplanted animals served as controls. Recipient survival and endocrine graft function were assessed. Graft microcirculation was analyzed 2 h after reperfusion by intravital fluorescence microscopy. Parenchymal damage was assessed by histology and nitrotyrosine immunohistochemistry, H4B tissue levels by high pressure liquid chromatography (HPLC). Compared to nontransplanted controls prolonged CIT resulted in significant microcirculatory deterioration. Different efficacy according to route and timing of administration could be observed. Only donor pretreatment with H4B resulted in almost completely abrogated IRI-related damage showing graft microcirculation comparable to nontransplanted controls and restored intragraft H4B levels, resulting in significant reduction of parenchymal damage (p < 0.002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation. [source] The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptorsFEBS JOURNAL, Issue 7 2001Tiziana Bisogno It is not yet clear if the endocannabinoid 2-arachidonoylglycerol (2-AG) is transported into cells through the same membrane transporter mediating the uptake of the other endogenous cannabinoid, anandamide (N -arachidonoylethanolamine, AEA), and whether this process (a) is regulated by cells and (b) limits 2-AG pharmacological actions. We have studied simultaneously the facilitated transport of [14C]AEA and [3H]2-AG into rat C6 glioma cells and found uptake mechanisms with different efficacies but similar affinities for the two compounds (Km 11.0 ± 2.0 and 15.3 ± 3.1 µm, Bmax 1.70 ± 0.30 and 0.24 ± 0.04 nmol·min,1·mg protein,1, respectively). Despite these similar Km values, 2-AG inhibits [14C]AEA uptake by cells at concentrations (Ki = 30.1 ± 3.9 µm) significantly higher than those required to either 2-AG or AEA to inhibit [3H]2-AG uptake (Ki = 18.9 ± 1.8 and 20.5 ± 3.2 µm, respectively). Furthermore: (a) if C6 cells are incubated simultaneously with identical concentrations of [14C]AEA and [3H]2-AG, only the uptake of the latter compound is significantly decreased as compared to that observed with [3H]2-AG alone; (b) the uptake of [14C]AEA and [3H]2-AG by cells is inhibited with the same potency by AM404 (Ki = 7.5 ± 0.7 and 10.2 ± 1.7 µm, respectively) and linvanil (Ki = 9.5 ± 0.7 and 6.4 ± 1.2 µm, respectively), two inhibitors of the AEA membrane transporter; (c) nitric oxide (NO) donors enhance the uptake of both [14C]AEA and [3H]2-AG, thus suggesting that 2-AG action can be regulated through NO release; (d) AEA and 2-AG induce a weak release of NO that can be blocked by a CB1 cannabinoid receptor antagonist, and significantly enhanced in the presence of AM404 and linvanil, thus suggesting that transport into C6 cells limits the action of both endocannabinoids. [source] Sequential methods and group sequential designs for comparative clinical trialsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2003Véronique Sébille Abstract Comparative clinical trials are performed to assess whether a new treatment has superior efficacy than a placebo or a standard treatment (one-sided formulation) or whether two active treatments have different efficacies (two-sided formulation) in a given population. The reference approach is the single-stage design and the statistical test is performed after inclusion and evaluation of a predetermined sample size. In practice, the single-stage design is sometimes difficult to implement because of ethical concerns and/or economic reasons. Thus, specific early termination procedures have been developed to allow repeated statistical analyses to be performed on accumulating data and stop the trial as soon as the information is sufficient to conclude. Two main different approaches can be used. The first one is derived from strictly sequential methods and includes the sequential probability ratio test and the triangular test. The second one is derived from group sequential designs and includes Peto, Pocock, and O'Brien and Fleming methods, , and , spending functions, and one-parameter boundaries. We review all these methods and describe the bases on which they rely as well as their statistical properties. We also compare these methods and comment on their advantages and drawbacks. We present software packages which are available for the planning, monitoring and analysis of comparative clinical trials with these methods and discuss the practical problems encountered when using them. The latest versions of all these methods can offer substantial sample size reductions when compared with the single-stage design not only in the case of clear efficacy but also in the case of complete lack of efficacy of the new treatment. The software packages make their use quite simple. However, it has to be stressed that using these methods requires efficient logistics with real-time data monitoring and, apart from survival studies or long-term clinical trials with censored endpoints, is most appropriate when the endpoint is obtained quickly when compared with the recruitment rate. [source] Synaptic heterogeneity between mouse paracapsular intercalated neurons of the amygdalaTHE JOURNAL OF PHYSIOLOGY, Issue 1 2007Raffaella Geracitano GABAergic medial paracapsular intercalated (Imp) neurons of amygdala are thought of as playing a central role in fear learning and extinction. We report here that the synaptic network formed by these neurons exhibits distinct short-term plastic synaptic responses. The success rate of synaptic events evoked at a frequency range of 0.1,10 Hz varied dramatically between different connected cell pairs. Upon enhancing the frequency of stimulation, the success rate increased, decreased or remained constant, in a similar number of cell pairs. Such synaptic heterogeneity resulted in inhibition of the firing of the postsynaptic neurons with different efficacies. Moreover, we found that the different synaptic weights were mainly determined by diversity in presynaptic release probabilities rather than postsynaptic changes. Sequential paired recording experiments demonstrated that the same presynaptic neuron established the same type of synaptic connections with different postsynaptic neurons, suggesting the absence of target-cell specificity. Conversely, the same postsynaptic neuron was contacted by different types of synaptic connections formed by different presynaptic neurons. A detailed anatomical analysis of the recorded neurons revealed discrete and unexpected peculiarities in the dendritic and axonal patterns of different cell pairs. In contrast, several intrinsic electrophysiological responses were homogeneous among neurons, and synaptic failure counts were not affected by presynaptic cannabinoid 1 or GABAB receptors. We propose that the heterogeneous functional connectivity of Imp neurons, demonstrated by this study, is required to maintain the stability of firing patterns which is critical for the computational role of the amygdala in fear learning and extinction. [source] Current Evidence on the Unit Equivalence of Different Botulinum Neurotoxin A Formulations and Recommendations for Clinical Practice in DermatologyDERMATOLOGIC SURGERY, Issue 1 2009SYRUS KARSAI MD BACKGROUND The unit equivalence between the two main Botulinum neurotoxin A (BoNTA) preparations, Dysport (Ipsen Ltd., Slough, Berkshire, UK) and BOTOX (Allergan Inc., Irvine, CA), is a matter of discussion. The UK assay used to test Dysport is more sensitive than the U.S. assay used for BOTOX, resulting in a different efficacy per unit in both formulations. Ratios ranging from 6:1 to 1:1 can be found in the literature, but the more recently published literature suggests that 1 unit of BOTOX is equivalent to approximately 2 to 4 units of Dysport (ratio 2:1,4:1). OBJECTIVE Because the number of BoNTA treatments is constantly increasing, these differences warrant a systematic review of published evidence about the unit equivalence of UK and U.S. formulations. METHODS The review is based on a detailed literature research in all relevant databases (MEDLINE, PubMed, Cochrane Library, specialist textbooks). RESULTS The present review supports the recent assumption that dose ratios of less than 3:1 (e.g., 2.5:1 or even 2:1) between Dysport and BOTOX are probably more suitable. CONCLUSIONS The current evidence is still insufficient, and further investigation of lower dose ratios is recommended. [source] Comparison of broadband UVB, narrowband UVB, broadband UVA and UVA1 on activation of apoptotic pathways in human peripheral blood mononuclear cellsPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 1 2007Chanisada Tuchinda Background/purpose: Ultraviolet (UV) radiation is an important therapy for immune-mediated cutaneous diseases. Activation of early apoptotic pathways may play a role in the clinical effectiveness. Different UV wavelengths have different efficacy for various diseases, but it remains unclear whether the ability to induce apoptosis differs with respect to the wavelength, and whether they induce apoptosis through the same mechanism. The aim of this study is to analyze the effects of different UV wavelengths that are used clinically on normal human peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were treated with UV-light sources broadband UVB, narrowband UVB, broadband UVA and UVA1. Initiation of apoptosis was assessed by flow cytometry by staining,treated cells for activated caspases. Immunoblots were performed to measure for cleaved caspase-3, -8, -9, cytochrome c, Bcl 2-interacting domain and poly-(ADP ribose) polymerase cleavage. Results: We demonstrate that all the UV radiation sources induced caspase activation in a dose-and time-dependent manner. Components of both the extrinsic and intrinsic pathways of apoptosis were activated by all of the UV wavelengths tested, but differed in the level of energy needed for activation. Conclusion: The greater effectiveness of UVB on initiation of apoptotic pathway suggests that apoptosis may play a role in the clinical efficacy of UVB-responsive inflammatory cutaneous diseases. [source] Presentation modality effects in studying passages.APPLIED COGNITIVE PSYCHOLOGY, Issue 3 2003Are mental images always effective? The present research has tested the different efficacy of imagery-based and verbally-based strategies in the study of three passages presented orally or in written form. The first passage was a description rich in easily imagined details. The second was an abstract passage, easy to verbalize, but not to imagine. The third was the spatial description of a pathway which could be both imagined and verbalized. Experiment 1 compared participants who were instructed in the use of Imagery or verbal Rehearsal while in Experiment 2 participants had high or low imagery ability. A facilitating effect of oral presentation for Imagery and high-imagery ability groups and of written presentation for Rehearsal and low imagery-ability groups were hypothesized. Data confirmed this facilitating effect and showed that it was more evident for the easier-to-imagine passages. Results are discussed in a selective interference and working memory framework. Future implications and practical suggestions are given. Copyright © 2003 John Wiley & Sons, Ltd. [source] | ||||||||||