Relative Efficacies Research Articles

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

ObjectiveThe aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg.MethodsThis was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring.ResultsThe mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%).ConclusionCoadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

Determining the Relative Efficacy of Positive Allosteric Modulators of the GABAA Receptor: Design of a Screening Approach

Gamma amino butyric acid receptors (GABA) are major therapeutic targets for the development of drugs in neurological and psychiatric disorders. The new generation of GABAA modulators is targeting subtype selectivity and low/partial efficacy on the receptor to potentially overcome the adverse effects described for drugs with full agonist profile. We evaluated a screening approach to measure the relative efficacy of GABAA positive allosteric modulators (PAM) using automated patch clamp and fluorescence membrane potential assays. We determined that the use of an internal comparator (zolpidem), tested on each cell in parallel to the test compound, provides a reliable approach to measure and compare the relative efficacy of PAM ligands. Patch clamp recordings on recombinant GABAA receptors, using a multiple drug addition protocol, allows us to rank PAM ligands with different levels of efficacies. We observed that fluorescence membrane potential assays are not predictive of the relative efficacies of GABAA PAM ligands.

Coagulant Recovery from Water Treatment Residuals: A Review of Applicable Technologies

Conventional water treatment consumes large quantities of coagulant and produces even greater volumes of sludge. Coagulant recovery (CR) presents an opportunity to reduce both the sludge quantities and the costs they incur, by regenerating and purifying coagulant before reuse. Recovery and purification must satisfy stringent potable regulations for harmful contaminants, while remaining competitive with commercial coagulants. These challenges have restricted uptake and lead research towards lower-gain, lower-risk alternatives. This review documents the context in which CR must be considered, before comparing the relative efficacies and bottlenecks of potential technologies, expediting identification of the major knowledge gaps and future research requirements.

Does Dual-mobility Cup Geometry Affect Posterior Horizontal Dislocation Distance?

Dual-mobility acetabular cups have been marketed with the purported advantages of reduced dislocation rates and improvements in ROM; however, the relative efficacies of these designs in terms of changing joint stability via ROM and dislocation distance have not been thoroughly evaluated. In custom computer simulation studies, we addressed the following questions: (1) Do variations in component geometry across dual-mobility designs (anatomic, modular, and subhemispheric) affect the posterior horizontal dislocation distances? (2) How do these compare with the measurements obtained with standard hemispheric fixed bearings? (3) What is the effect of head size on posterior horizontal dislocation distances for dual-mobility and standard hemispheric fixed bearings? (4) What are the comparative differences in prosthetic impingement-free ROM between three modern dual-mobility components (anatomic, modular, and subhemispheric), and standard hemispheric fixed bearings? CT scans of an adult pelvis were imported into computer-aided design software to generate a dynamic three-dimensional model of the pelvis. Using this software, computer-aided design models of three dual-mobility designs (anatomic, modular, and subhemispheric) and standard hemispheric fixed bearings were implanted in the pelvic model and the posterior horizontal dislocation distances measured. Hip ROM simulator software was used to compare the prosthetic impingement-free ROMs of dual-mobility bearings with standard hemispheric fixed-bearing designs. Variations in component design had greater effect on posterior horizontal dislocation distance values than increases in head size in a specific design (p < 0.001). Anatomic and modular dual-mobility designs were found to have greater posterior horizontal dislocation distances than the subhemispheric dual-mobility and standard hemispheric fixed-bearing designs (p < 0.001). Increasing head sizes increased posterior horizontal dislocation distances across all designs (p < 0.001). The subhemispheric dual-mobility implant was found to have the greatest prosthetic impingement-free ROM among all prosthetic designs (p < 0.001; R(2) = 0.86). The posterior horizontal dislocation distances differ with the individual component geometries of dual-mobility designs, with the anatomic and modular designs showing higher posterior horizontal dislocation distances compared with subhemispheric dual-mobility and standard hemispheric fixed-bearing designs. Static, three-dimensional computerized simulation studies suggest differences that may influence the risk of dislocation among components with varying geometries, favoring anatomic and modular dual-mobility designs. Clinical studies are needed to confirm these observations.

Efficacy and safety of widely used treatments for macular oedema secondary to retinal vein occlusion: a systematic review

BackgroundMacular oedema secondary to retinal vein occlusion (RVO) can cause vision loss due to blockage of the central retinal vein (CRVO) or a branch retinal vein (BRVO). This systematic review assessed the efficacies of widely used treatments for macular oedema secondary to RVO and the feasibility of conducting indirect comparisons between these therapies.MethodsA systematic review was undertaken in November 2010, including a literature search for trials in medical databases and relevant websites. s, conference presentations and unpublished studies were considered. Studies were data-extracted and quality assessed by two independent researchers. Outcome measures included the mean change in best corrected visual acuity (BCVA) from baseline in the study eye and/or number of patients gaining at least 10 letters from baseline to 6 months or the nearest equivalent time point.ResultsFourteen unique randomized controlled trials (RCTs) were identified. Ranibizumab 0.5 mg produced greater improvements in BCVA at 6 months than sham in BRVO (mean difference 11.0 letters, 95% confidence interval [CI] 7.83, 14.17) and CRVO (mean difference 14.10 letters, 95% CI 10.51, 17.69) in two double-blind sham-controlled RCTs. Pooled data from two double-blind, sham-controlled RCTs showed that improvements in BCVA were also significantly better for dexamethasone intravitreal (IVT) implant 0.7 mg compared with sham in patients with BRVO or CRVO (mean difference 2.5 letters, 95% CI 0.7, 4.3); the difference was significant for BRVO alone, but not CRVO alone. A significantly greater proportion of patients with BRVO gained ≥15 letters with laser therapy vs. no treatment at 36 months in a large prospective RCT (odds ratio 3.16, 95% CI 1.25, 8.00), whereas no difference was observed at 9 months in a smaller study. Three studies reported no benefit for laser therapy in CRVO. No indirect comparisons with ranibizumab were feasible due to differences in study design and baseline characteristics.ConclusionsData from RCTs for ranibizumab and dexamethasone IVT demonstrate that both new agents constitute significant improvements over the previously widely accepted standard of care (laser therapy) for the treatment of BRVO and CRVO. However, head-to-head studies are needed to assess the relative efficacies of licensed therapies for RVO.

A Comparison of Evolutionary Computation Techniques for IIR Model Identification

System identification is a complex optimization problem which has recently attracted the attention in the field of science and engineering. In particular, the use of infinite impulse response (IIR) models for identification is preferred over their equivalent FIR (finite impulse response) models since the former yield more accurate models of physical plants for real world applications. However, IIR structures tend to produce multimodal error surfaces whose cost functions are significantly difficult to minimize. Evolutionary computation techniques (ECT) are used to estimate the solution to complex optimization problems. They are often designed to meet the requirements of particular problems because no single optimization algorithm can solve all problems competitively. Therefore, when new algorithms are proposed, their relative efficacies must be appropriately evaluated. Several comparisons among ECT have been reported in the literature. Nevertheless, they suffer from one limitation: their conclusions are based on the performance of popular evolutionary approaches over a set of synthetic functions with exact solutions and well-known behaviors, without considering the application context or including recent developments. This study presents the comparison of various evolutionary computation optimization techniques applied to IIR model identification. Results over several models are presented and statistically validated.

Long-term clinical outcomes of drug-eluting stents vs. bare-metal stents in Chinese geriatric patients.

Background & objectiveLittle is known about the relative efficacies of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and bare-metal stents (BMS) in elderly patients. The objective of this study was to evaluate the clinical outcome for geriatric patients who received either DES or BMS.MethodsFrom January 2002 to October 2005, 199 consecutive Chinese geriatric patients (≥ 75 years old) underwent PCI with coronary DES or BMS implantation at our institution. We analyzed the major clinical end points that included all-cause mortality, cardiovascular death, myocardial infarction, target lesion revascularization (TLR), stent thrombosis, and bleeding complications.ResultsThe three-year cumulative rates of all-cause mortality, cardiovascular death, and myocardial infarction were significantly lower in the DES group (6.3%, 3.6%, 5.4%) compared with the BMS group (16.2%, 11.5%, 14.9%; P < 0.05). No significant differences were found in the three-year cumulative rate for target lesion revascularization (6.3% vs. 4.6%, P = 0.61) or stent thrombosis (3.6% vs. 2.3%, P = 0.70). Likewise, there were no statistically significant differences in the cumulative rate for intracranial hemorrhage, or major and minor hemorrhage at three years.ConclusionsDES-based PCI was associated with a significant reduction in the three-year cumulative rate of all-cause mortality, cardiovascular death, and myocardial infarction compared with BMS, without increased risk of TLR, stent thrombosis, or bleeding complications at three years in this group of Chinese geriatric patients.

High Eradication Rates of Helicobacter pylori with Standard Triple Therapy in Rhode Island

Purpose: Most studies throughout the world have shown a decline in Helicobacter pylori (HP) eradication rates in the past decade. There is a paucity of recent U.S. data regarding real-life HP treatment success. We reviewed the relative efficacies of several commonly used treatment regimens within the Rhode Island population. Methods: All index cases of HP diagnosed via gastric biopsy, IgG serology, or fecal antigen at Rhode Island Hospital (RIH) during the year 2010 were identified, and demographic data on these patients were collected. The electronic medical records of those patients who followed up with the RIH Medical Primary Care Unit (MPCU), Gastroenterology Fellows Clinic (GIFC), or Faculty Practice (FP) were reviewed to determine whether and what type of treatment was given, and whether there was evidence of a test of cure (TOC) following any attempt at HP eradication. Finally, for those patients who were treated and had a TOC, eradication rates were calculated for each commonly used treatment regimen. Results: Four hundred ten unique index cases of HP were identified in the year 2010. Fifty-nine percent were female and 41% were male, with a median age of 53 years. Most cases were diagnosed via gastric biopsy (53%), followed by IgG serology (37%), and fecal antigen (10%). Of these 410 patients, 205 (50%) followed up in the MPCU, GIFC, or FP. Treatment was intentionally deferred in 17/205 (8%), while an attempt at eradication occurred in 188/205 (92%). Ten different treatment regimens were identified, although the majority of patients (72%) were treated with a form of “legacy” triple therapy with amoxicillin, clarithromycin, and a proton pump inhibitor (PPI) for 10-14 days. After treatment, a TOC was performed in 73/188 (39%) patients. The TOC was negative and eradication thereby confirmed in 63/73 (86%) cases. Most patients received legacy triple therapy for 10-14 days with a PPI, clarithromycin, and amoxicillin (metronidazole if penicillin allergic). For those patients with a TOC, eradication rates for all legacy triple therapy variants averaged 90%. Bismuth-based quadruple therapy was successful in 7/9 cases (78%). There was no statistically significant difference in cure rates between any of the examined treatment regimens. Conclusion: Within the Rhode Island population, traditional triple therapy remains an effective first-line regimen for HP eradication, with a cure rate of approximately 90%. There was no statistically significant difference in cure rates between any of the examined triple therapy variants or in comparison with other regimens.

Modelling flow and work hardening behaviour of cold worked Zr–2.5Nb pressure tube material in the temperature range of 30–600 ̊C

Under a postulated accident scenario of loss of cooling medium in an Indian Pressurised Heavy Water Reactor (IPHWR), temperature of the pressure tubes can rise and lead to large deformations. In order to investigate the modes of deformation of pressure tube – calandria tube assembly, material property data defining the flow behaviour over a temperature range from room temperature (RT) to 800̊C are needed. It is of practical importance to formulate mathematical equations to describe the stress–strain relationships of a material for a variety of reasons, such as the analysis of forming operations and the assessment of component's performance in service. A number of constitutive relations of empirical nature have been proposed and they have been found very suitable to describe the behaviour of a material. Although these relations are of empirical nature, various metallurgical factors appear to decide applicability of each of these relations. For example, grain size influences mainly the friction stress while the strain hardening is governed by dislocation density. In a recent work, tensile deformation behaviour of pressure tube material of IPHWR has been carried out over a range of temperature and strain rates (Dureja et al., 2011). It has been found that the strength parameters (yield and ultimate tensile strength) vary along the length of the tube with higher strength at the trailing end as compared to the leading end. This stems from cooling of the billet during the extrusion process which results in the variation of microstructure, texture and dislocation density from the leading to the trailing end. In addition, the variation in metallurgical parameters is also expected to influence the work hardening behaviour, which is known to control the plastic instability (related to uniform strain).In the present investigation, the tensile flow and work-hardening behaviour of a cold worked Zr–2.5Nb pressure tube material of IPHWRs has been studied over the temperature range of 30–600̊C. The stress strain data have been analysed in terms of stress–strain relations proposed by Hollomon (1945), Voce (1948) and Ramberg–Osgood (RO) (Ramberg and Osgood, 1943). The relative efficacies of these relations has been examined by fitting the appropriate equation to the experimentally obtained true stress–true strain data. The quality of fit of these empirical relations is quantified using square root of co-efficient of determination, i.e. R value (in %). The results have been discussed in terms of the correlation coefficient and in error in the estimation of UTS and uniform strain. Of the various relations employed, the Voce's relation has been found to describe the stress–strain behaviour most precisely up to 300̊C. Hollomon's relation describes the strain–stress behaviour of the material over the entire temperature range but with over-estimation of UTS. RO relation does not fit well in the initial stage but satisfactorily models the uniform elongation regime till UTS for temperatures up to 500̊C.

ChemInform Abstract: The Structural Basis of G‐Protein‐Coupled Receptor Signaling (Nobel Lecture).

AbstractReview: 51 refs.

Theoretical modeling of the urinary supersaturation of calcium salts in healthy individuals and kidney stone patients: Precursors, speciation and therapeutic protocols for decreasing its value

BackgroundSupersaturation (SS) of urinary salts has been extensively invoked for assessing the risk of renal stone formation, but precursors have often been ignored. Our objectives were to establish by computer modeling, which urinary components are essential for calculating reliable SS values, to investigate whether unique equilibrium processes occur in the urine of stone formers (SF) which might account for their higher SS levels relative to healthy controls (N), to determine the relative efficacies of three different, widely-used protocols for lowering urinary SS of calcium salts and to examine the influence of precursors. MethodsUrinary data from published studies were consolidated into three N–SF cohort pairs and were selected for modeling using the speciation program JESS. SS values of calcium oxalate monohydrate (COM) and its precursors calcium oxalate di- and tri-hydrate (COD, COT), as well as those of hydroxyapatite (HAP) and its precursors octacalcium phosphate (OCP) and brushite (Bru) were calculated. A pragmatic approach for the statistical analysis of the modeling outputs was developed and applied. ResultsThirteen urinary parameters were identified as being crucial for the accurate calculation of SS of calcium oxalate (CaOx) and calcium phosphate (CaP) salts. Chloride, sulfate and ammonium, or combinations thereof, have frequently been omitted from SS calculations, thereby giving erroneously high values for these parameters. Subtle differences occur in the urinary equilibrium processes of SF and N. SS (OCP) and SS (HAP) are more sensitive to dilution effects than the other urinary salts. Decreasing urinary Ca and decreasing Ox are equally efficacious in reducing SS of CaOx salts, and are marginally superior to increasing urinary volume. Decreasing urinary calcium and increasing urinary volume are equally efficacious in reducing SS of CaP salts. SS of precursors follow the Ostwald Lussac empirical rule and undergo the same changing trends in different urinary scenarios. ConclusionsResearchers are advised to include all of the 13 identified urinary parameters in their calculations of SS of Ca salts, in order to attain better accuracy. Differences in achieving speciation equilibria in N and SF contribute towards higher values of SS in SF, but in a minor way only. Increasing urinary volume is confirmed as the most realistically efficacious strategy for decreasing SS of urinary calcium salts. SS of HAP should be assigned equal importance to that of Bru in considering the stone-forming potential of urine. Precursors of CaOx and CaP salts should be taken into account when investigating stone forming mechanisms.

Network meta-analysis of the outcome ‘participant complete clearance’ in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review

The conclusions of pairwise meta-analyses of interventions for actinic keratosis (AK) are limited due to the lack of direct comparison between some interventions. Consequently, we performed a network meta-analysis for eight treatments [5-aminolaevulinic acid (ALA)-photodynamic therapy (PDT), cryotherapy, diclofenac 3% in 2·5% hyaluronic acid (DCF/HA), 5-fluorouracil (5-FU) 0·5% or 5·0%, imiquimod (IMI) 5%, ingenol mebutate (IMB) 0·015-0·05%, methyl aminolaevulinate (MAL)-PDT and placebo/vehicle (including placebo-PDT)] to determine their relative efficacies. As part of a prior Cochrane systematic review, different databases and grey literature were searched for randomized controlled trials up to April 2012. The inclusion criteria were parallel-group studies with nonimmunosuppressed participants: (i) reporting 'participant complete clearance' and (ii) comparing at least two of the interventions. Thirty-two publications met the criteria and they included the following number of individual or pooled studies (n) and total number of participants (N) for the different interventions: 5-FU 0·5% (n = 4, N = 169), 5-FU 5·0% (n = 2, N = 44), ALA-PDT (n = 6, N = 739), cryotherapy (n = 2, N = 174), DCF/HA (n = 5, N = 299), IMI (n = 14, N = 1411), IMB (n = 3, N = 560), MAL-PDT (n = 7, N = 557) and placebo (n = 32, N = 2520). Network analyses using a random-effects Bayesian model were carried out with the software ADDIS v1.16.1. The interventions were ranked as follows based on calculated probabilities and odd ratios: 5-FU > ALA-PDT ≈ IMI ≈ IMB ≈ MAL-PDT > cryotherapy > DCF/HA > placebo. This efficacy ranking was obtained based on the current available data on 'participant complete clearance' from randomized controlled trials and the analysis model used. However, several other factors should also be considered when prescribing a treatment for AK.

Comparative safety and efficacy of antithrombotics in the management of venous thromboembolism after knee or hip replacement surgery: focus on rivaroxaban

Routine thromboprophylaxis represents the current standard of care in the management of patients following total hip or knee replacement. Legacy agents used to address the issue of risk of venous thromboembolism present barriers to use, either by the need for monitoring and dose adjustment (warfarin) or the need for injection (low molecular weight heparins and fondaparinux), or pose a risk of upper gastrointestinal bleeding (acetylsalicylic acid and all antithrombotic agents). The introduction of new pharmacologic agents in recent years has sought to address the issues of not only efficacy, but also safety, ease of use, and patient compliance. New orally administered agents, ie, apixaban, dabigatran, and rivaroxaban, have demonstrated various degrees of efficacy over enoxaparin while preserving safety. Indirect comparisons of the relative efficacies of apixaban, dabigatran, and rivaroxaban have shown rivaroxaban to be more efficacious than dabigatran and apixaban in reducing symptomatic and total venous thromboembolism following total hip or knee replacement surgery. A pooled analysis of the four RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent deep vein thrombosis and pulmonary embolism) trials (two in total hip replacement and two in total knee replacement) demonstrated rivaroxaban to be the first and only antithrombotic agent ever to demonstrate superiority in reducing symptomatic venous thromboembolism and all-cause mortality compared with another antithrombotic agent (enoxaparin). New oral antithrombotic agents have demonstrated efficacy in prophylaxis against venous thromboembolism following total hip or knee replacement surgery while preserving safety, with increased ease of administration of thromboprophylaxis for both the patient and the physician, which may contribute to improved compliance.

Stents or surgery in coronary artery disease in 2013.

In addition to optimal medical therapy, some patients with coronary artery disease also require intervention on symptomatic and/or prognostic grounds. The debate over the relative efficacies of coronary artery bypass grafting (CABG) and stenting has recently been settled by the publication of the five-year outcomes of the SYNTAX and FREEDOM (in patients with diabetes) trials accompanied by supportive data from several large registries. There is also current evidence that stenting is still carried out in patients who would be better served by CABG, emphasizing the need for recommendations for intervention to be overseen by a multidisciplinary team rather than the individual practitioner.

Long-term treatment of somatostatin analog-refractory growth hormone-secreting pituitary tumors with pegvisomant alone or combined with long-acting somatostatin analogs: a retrospective analysis of clinical practice and outcomes

BackgroundPegvisomant (PEGV) is widely used, alone or with somatostatin analogs (SSA), for GH-secreting pituitary tumors poorly controlled by SSAs alone. No information is available on specific indications for or relative efficacies of PEGV?+?SSA versus PEGV monotherapy. Aim of our study was to characterize real-life clinical use of PEGV vs. PEGV?+?SSA for SSA-resistant acromegaly (patient selection, long-term outcomes, adverse event rates, doses required to achieve control).MethodsA retrospective analysis of data collected in 2005–2010 in five hospital-based endocrinology centers in Rome was performed. Sixty-two adult acromegaly patients treated ≥6 months with PEGV (Group 1, n?=?35) or PEGV?+?SSA (Group 2, n?=?27) after unsuccessful maximal-dose SSA monotherapy (≥12 months) were enroled. Groups were compared in terms of clinical/biochemical characteristics at diagnosis and before PEGV or PEGV?+?SSA was started (baseline) and end-of-follow-up outcomes (IGF-I levels, adverse event rates, final PEGV doses).ResultsGroup 2 showed higher IGF-I and GH levels and sleep apnea rates, higher rates residual tumor tissue at baseline, more substantial responses to SSA monotherapy and worse outcomes (IGF-I normalization rates, final IGF-I levels). Tumor growth and hepatotoxicity events were rare in both groups. Final daily PEGV doses were similar and significantly increased with treatment duration in both groups.ConclusionsPEGV and PEGV?+?SSA are safe, effective solutions for managing SSA-refractory acromegaly. PEGV?+?SSA tends to be used for more aggressive disease associated with detectable tumor tissue. With both regimens, ongoing monitoring of responses is important since PEGV doses needed to maintain IGF-I control are likely to increase over time.

Identifying efficient natural bioreductants for the preparation of graphene and graphene-metal nanoparticle hybrids with enhanced catalytic activity from graphite oxide

The implementation of green approaches towards the preparation of graphene and graphene-based materials with enhanced functionality from graphite oxide has been relatively little explored. Particularly, the use of bioreductants and the testing of their relative efficacies is an incipient area of research. Here, a pool of 20 environmentally friendly, natural antioxidants have been tested for their ability to reduce graphene oxide. These antioxidants were mostly vitamins, amino acids and organic acids. By establishing a protocol to systematically compare and optimize their performance, several new efficient bioreductants of graphene oxide have been identified, namely, pyridoxine and pyridoxamine (vitamin B6), riboflavin (vitamin B2), as well as the amino acids arginine, histidine and tryptophan. These biomolecules were used to prepare reduced graphene oxide–silver nanoparticle hybrids that displayed colloidal stability in water in the absence of additional dispersants. Particularly, hybrids prepared with pyridoxamine exhibited a combination of long-term colloidal stability and exceptionally high catalytic activity among silver nanoparticle-based catalysts in the reduction of p-nitrophenol with NaBH4. Thus, in addition to expanding substantially the number of green reductants available for graphene oxide reduction, the present results underline the idea that proper selection of bioreductant can be relevant to achieve graphene-based materials with improved performance.

Efficacy of Flowable Gel-type EDTA at Removing the Smear Layer and Inorganic Debris under Manual Dynamic Activation

IntroductionA flowable gel-type EDTA solution containing urea peroxide and polyacrylic acid was recently introduced into the endodontic market. However, its efficacy for removing the smear layer and inorganic debris remains unknown. This study was performed to investigate the relative efficacies of the flowable gel-type and liquid-type EDTA solutions for removal of the smear layer and inorganic debris. We also evaluated the effects of manual dynamic activation (MDA). MethodsWettability was evaluated by measuring the contact angle. The incidence of accidental extrusion of irrigant was determined. The effervescent effect was evaluated by mixing the solutions with sodium hypochlorite. The efficacies of the EDTA solutions at removing the smear layer and inorganic debris were evaluated by scanning electron microscopic examination. ResultsThe contact angles of the 2 EDTA solutions did not differ significantly throughout the experiment (P > .05). Accidental extrusion occurred 4 times for the liquid-type EDTA but never for the gel-type EDTA. The gel-type but not the liquid-type EDTA showed an effervescent effect. The EDTA/MDA treatment combinations did not produce significantly different smear layer scores (P > .05). However, the debris scores for the coronal and middle parts were significantly lower for the gel-type EDTA with MDA than for the liquid-type EDTA without MDA (P < .05). ConclusionsOur results suggest that the newly introduced gel-type EDTA might be an acceptable irrigant for removing the smear layer and inorganic debris present on the root canal wall.

Correlating efficacy and desensitization with GluK2 ligand-binding domain movements

Gating of AMPA- and kainate-selective ionotropic glutamate receptors can be defined in terms of ligand affinity, efficacy and the rate and extent of desensitization. Crucial insights into all three elements have come from structural studies of the ligand-binding domain (LBD). In particular, binding-cleft closure is associated with efficacy, whereas dissociation of the dimer formed by neighbouring LBDs is linked with desensitization. We have explored these relationships in the kainate-selective subunit GluK2 by studying the effects of mutating two residues (K531 and R775) that form key contacts within the LBD dimer interface, but whose truncation unexpectedly attenuates desensitization. One mutation (K531A) also switches the relative efficacies of glutamate and kainate. LBD crystal structures incorporating these mutations revealed several conformational changes that together explain their phenotypes. K531 truncation results in new dimer contacts, consistent with slower desensitization and sideways movement in the ligand-binding cleft correlating with efficacy. The tested mutants also disrupted anion binding; no chloride was detected in the dimer-interface site, including in R775A where absence of chloride was the only structural change evident. From this, we propose that the charge balance in the GluK2 LBD dimer interface maintains a degree of instability, necessary for rapid and complete desensitization.

The Pharmaco –, Population and Evolutionary Dynamics of Multi-drug Therapy: Experiments with S. aureus and E. coli and Computer Simulations

There are both pharmacodynamic and evolutionary reasons to use multiple rather than single antibiotics to treat bacterial infections; in combination antibiotics can be more effective in killing target bacteria as well as in preventing the emergence of resistance. Nevertheless, with few exceptions like tuberculosis, combination therapy is rarely used for bacterial infections. One reason for this is a relative dearth of the pharmaco-, population- and evolutionary dynamic information needed for the rational design of multi-drug treatment protocols. Here, we use in vitro pharmacodynamic experiments, mathematical models and computer simulations to explore the relative efficacies of different two-drug regimens in clearing bacterial infections and the conditions under which multi-drug therapy will prevent the ascent of resistance. We estimate the parameters and explore the fit of Hill functions to compare the pharmacodynamics of antibiotics of four different classes individually and in pairs during cidal experiments with pathogenic strains of Staphylococcus aureus and Escherichia coli. We also consider the relative efficacy of these antibiotics and antibiotic pairs in reducing the level of phenotypically resistant but genetically susceptible, persister, subpopulations. Our results provide compelling support for the proposition that the nature and form of the interactions between drugs of different classes, synergy, antagonism, suppression and additivity, has to be determined empirically and cannot be inferred from what is known about the pharmacodynamics or mode of action of these drugs individually. Monte Carlo simulations of within-host treatment incorporating these pharmacodynamic results and clinically relevant refuge subpopulations of bacteria indicate that: (i) the form of drug-drug interactions can profoundly affect the rate at which infections are cleared, (ii) two-drug therapy can prevent treatment failure even when bacteria resistant to single drugs are present at the onset of therapy, and (iii) this evolutionary virtue of two-drug therapy is manifest even when the antibiotics suppress each other's activity.

The role of the ß2‐adrenoceptor Gs pathway in the development of the asthma phenotype in murine models

Asthma is a chronic inflammatory disease of the airways. We have shown the requirement of the β2AR in the development of three main features of asthma in murine models. β2AR signal through various pathways including the canonical Gs and the β‐arrestin pathway. The objective of this study was to determine if formoterol and salmeterol, documented to have different relative intrinsic efficacies at the Gs pathway resulted in different asthma phenotypes. We used wild type (WT) and phenylethanolamine‐N‐methyltransferase null mice (PNMT−/−) mice. PNMT is responsible for converting norepinephrine into epinephrine and null mice have no detectable levels of epinephrine, the endogenous ligand for ß2AR. PNMT−/− mice were treated with formoterol and salmeterol 10μg/kg/day and 3μg/kg/day respectively, intraperitoneally twice daily at four treatment durations. Mice were phenotyped in an ovalbumin sensitized and challenged (Ova S/C) model. WT, but not PNMT−/− mice, had significant increases in inflammatory cells, mucus hyper‐secretion and airway hyper‐responsiveness. Ova S/C PNMT−/− mice, treated with formoterol and salmeterol significantly restored the asthma phenotype to the level seen in WT mice. Thus drugs with differing efficacies at the Gs pathway are equal at restoring the asthma phenotype, and suggest this pathway is not responsible for the requirement of ß2AR activation in development of the asthma phenotype.