Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection.Malaria vaccines based on the 19-kDa region of merozoite surface protein 1  were most prevalent during three consecutive years and in all age groups with overall prevalences of 46%  and 36% (95% CI 34%–39%), respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%–18%). Multiplicity of infection based on MSP-119 was higher at the beginning of the transmission season and in the oldest individuals (aged ≥11 y). Three MSP-119 haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-119 polymorphisms in consecutive infections implicate three polymorphisms  as being particularly important in determining allele specificity of anti-MSP-119 immunity.Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-119 haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial site. If immunity elicited by an MSP-1-based vaccine is allele-specific, a vaccine based on either the FVO or FUP strain might have better initial efficacy at this site. This study, to our knowledge the largest of its kind to date, provides molecular information needed to interpret population responses to MSP-1-based vaccines and suggests that certain MSP-119 polymorphisms may be relevant to cross-protective immunity.Parasites with MSP-1 Christopher Plowe and colleagues surveyed local malaria parasites for genetic diversity in MSP-1, a candidate vaccine antigen. These data are needed to interpret population responses to MSP-1-based vaccines during trials planned at this site. Plasmodium falciparum, which is transmitted to humans through the bites of infected mosquitoes. These insects inject a form of the parasite known as sporozoites into people that replicates inside liver cells without causing symptoms. Four to five days later, merozoites (another form of the parasite) are released from the liver cells and invade red blood cells. Here, they replicate 10-fold before bursting out and infecting other red blood cells. This massive increase in parasite burden causes malaria's flu-like symptoms. If untreated, it also causes anemia (a red blood cell deficit) and damages the brain and other organs where parasitized red blood cells sequester. Malaria can be treated with antimalarial drugs and partly prevented by reducing the chances of being bitten by an infected mosquito. In addition, researchers are developing vaccines designed to reduce the global burden of malaria. These contain individual malaria antigens (proteins from the parasite that stimulate an immune response) that should, when injected into people, prime the immune system so that it can rapidly control malaria infections.Malaria, a tropical parasitic disease, kills about one million people—mainly children—every year. Most of these deaths are caused by 19, which is included in a vaccine currently being tested in Mali, West Africa. Although most of the MSP-119 sequence is conserved, it contains six strain-specific polymorphisms (genetic variations); the candidate vaccine contains MSP-119 from the 3D7 strain of P. falciparum.The development of an effective malaria vaccine is not easy, in part because people can be simultaneously infected with several parasite strains. These often carry different variants  of the genes encoding antigens, which means that the actual parasite proteins might differ from the ones used for vaccination. If this is the case, the immune response generated by the vaccine might be less effective or even ineffective. An ideal vaccine would therefore stimulate an immune response that recognizes all these strain-specific antigens. However, little is known about their distribution in parasite populations in malarial regions, or about how this distribution changes over time (its dynamics). This information is needed to aid vaccine design and development. In this study, the researchers have investigated the distribution and dynamics of genetic variants of a merozoite antigen called MSP-119 sequence in more than 1,300 malaria infections in 100 Malian children. They compared the frequencies of 14 MSP-119 haplotypes (sets of polymorphisms at the six variant sites) over three years, in three age groups, and in consecutive infections within individuals. They found that the frequency of individual MSP-119 haplotypes fluctuated in their study population but that those found in P. falciparum FVO and FUP strains were always the commonest, each being present in about 40% of the infections. By contrast, the P. falciparum 3D7 MSP-119 haplotype was present in only 16% of the infections. They also found that mixed infections were more common at the start of each malaria season and in older individuals. In addition, individuals who were infected repeatedly by parasites from different strains (with different MSP-119 variants) seemed to get sick with malaria more often than those infected multiple times by the same strain. The differences might, therefore, be important in determining the specificity of the immune response to MSP-119.The researchers used rapid DNA sequencing (pyrosequencing) to examine the MSP-119 have a different form of MSP-119. Although early results from field trials suggest that the 3D7-derived vaccine provides some protection against the more common FVO and FUP strains, the immunity stimulated by the vaccine might be mainly allele specific. If this turns out to be the case, these results suggest that a FVO- or FUP-derived vaccine might be more effective in Mali than the 3D7-derived vaccine, though not necessarily elsewhere. More generally, these results show the importance of determining the genetics of pathogen populations before starting vaccine trials. Without this information, a vaccine's ability to prevent infections with specific parasite strains cannot be determined accurately and potentially useful vaccines might be abandoned if they are tested in inappropriate populations. Importantly, baseline information of this sort will also allow vaccine developers to detect any vaccine-induced changes in the pathogen population that might affect the long-term efficacy of their vaccines.These findings indicate that most parasites that cause malaria at the Malian test site for the malaria vaccine that contains 3D7-specific MSP-1http://dx.doi.org/10.1371/journal.pmed.0040093.Please access these Web sites via the online version of this summary at PLoS MedicinePerspective by Colin Sutherland discusses variation in malaria antigens as a challenge in vaccine developmentA related malaria program of the University of Maryland Center for Vaccine Development performs research on many aspects of malariaThe Malaria Vaccine InitiativeInformation on malaria and the development of vaccines is available from the World Health Organization provides links to general information on malaria plus some specific information on malaria vaccine developmentThe malaria and on vaccinationMedlinePlus encyclopedia has entries on US Centers for Disease Control and Prevention provides information for patients and professionals on malariaUS National Institute of Allergy and Infectious Diseases has information on malaria, including research into vaccines Plasmodium falciparum, which is responsible for most malaria mortality. Reducing the malaria burden will require the coordinated use of several strategies, including combination antimalarial therapies, insecticide-treated nets and, potentially, malaria vaccines ) currently being targeted for vaccines [19 diversity suggest that a change in amino acid at specific residues may be more important than having any particular haplotype, it will be important to examine the association between MSP-119 haplotypes and clinical malaria in other endemic regions and in the context of genome-wide analyses to determine whether these three haplotypes are inherently less virulent (or are linked to important virulence factors) or whether these associations are an artifact of the haplotype dynamics at this particular site.This study also demonstrated a reduced frequency of three specific MSP-1vaccines . This as19 polymorphisms may be most relevant to cross-protective immunity and thus informs vaccine design. If immunity elicited by such a vaccine is allele specific, a vaccine derived from either the FVO or FUP strain might have better initial efficacy in settings where these MSP-119 haplotypes predominate and haplotypes corresponding to the leading vaccine strain, 3D7, are less frequent. Given the polymorphic nature of vaccine antigens for P. falciparum and other genetically diverse pathogens, it is important to monitor pathogen populations before, during, and after introduction of vaccines to determine vaccine efficacy at the molecular level and to detect potential vaccine-induced changes in the pathogen population that could compromise vaccine efficacy.This molecular epidemiology study provides information needed to accurately measure and interpret population responses to an MSP-1-based malaria vaccine in clinical trials of vaccine efficacy. It also provides insight into which MSP-1msp-1 from the 3D7 strain of P. falciparum was published with the P. falciparum genome sequence and can be found under GenBank (http://www.ncbi.nlm.nih.gov/) accession number XM_001352134.The sequence of


Previous evaluations of the cost-effectiveness of the cyclooxygenase-2 selective inhibitor celecoxib  have produced conflicting results. The recent controversy over the cardiovascular (CV) risks of rofecoxib and other coxibs has renewed interest in the economic profile of celecoxib, the only coxib now available in the United States. The objective of our study was to evaluate the long-term cost-effectiveness of celecoxib compared with nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in a population of 60-year-old osteoarthritis (OA) patients with average risks of upper gastrointestinal (UGI) complications who require chronic daily NSAID therapy.We used decision analysis based on data from the literature to evaluate cost-effectiveness from a modified societal perspective over patients' lifetimes, with outcomes expressed as incremental costs per quality-adjusted life-year (QALY) gained. Sensitivity tests were performed to evaluate the impacts of advancing age, CV thromboembolic event risk, different analytic horizons and alternate treatment strategies after UGI adverse events.Our main findings were: 1) the base model incremental cost-effectiveness ratio (ICER) for celecoxib versus nsNSAIDs was $31,097 per QALY; 2) the ICER per QALY was $19,309 for a model in which UGI ulcer and ulcer complication event risks increased with advancing age; 3) the ICER per QALY was $17,120 in sensitivity analyses combining serious CV thromboembolic event  risks with base model assumptions.Our model suggests that chronic celecoxib is cost-effective versus nsNSAIDs in a population of 60-year-old OA patients with average risks of UGI events. Nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) are widely used to treat acute and chronic pain, including the symptoms of osteoarthritis (OA). The most clinically important adverse events associated with nsNSAID use, ulcer perforations, obstructions, and bleeds (collectively POBs), can be life-threatening and constitute a major public health problem with a large cost to society -3. UncomThe cyclooxygenase-2 selective inhibitor celecoxib reduces the risks of nsNSAID-induced gastropathy without compromising clinical efficacy. However, evaluations of the cost-effectiveness of celecoxib have produced conflicting results owing mainly to differences in model structures, populations at risk, probabilities, cost-effectiveness indicators, and relative drug prices across countries.The objective of our study was to evaluate the cost-effectiveness of the long-term use of celecoxib compared with nsNSAIDs in a population of 60-year-old OA patients with average risks of upper gastrointestinal (UGI) complications who require chronic daily NSAID therapy. We assume that acetaminophen is contraindicated or otherwise inferior to NSAID therapy in these patients. Ours is the only coxib evaluation that uses UGI ulcer probabilities from a population comprised only of OA patients, and accounts for reductions in the prices of celecoxib and over-the-counter (OTC) omeprazole after loss of patent protection. Although there have been other lifetime coxib models, only ours extrapolates probabilities and models health states based on long-term evidence from the literature and evaluates celecoxib independently -13. In sCost-effectiveness analysis is used to compare celecoxib  at 200 mg/d, the recommended OA dose, with a combination of diclofenac at 100 mg/d and naproxen at 1000 mg/d. The target population is 60-year-old patients with moderate to severe OA requiring chronic daily NSAIDs. The outcomes of the model are incremental costs per quality-adjusted life-year (QALY) gained from reductions in symptomatic peptic ulcers, perforations, obstructions, bleeding ulcers (collectively PUBs), and nonulcer dyspepsia. CV thromboembolic events and efficacy in relieving OA symptoms are excluded in the base model on the assumption that there are no differences in these outcomes between celecoxib and nsNSAIDs -17.The structure of the model used in this study is presented in Figure A lifetime analytic horizon is used because many OA sufferers are long-term NSAID users, with high cumulative risks of gastropathy, and some adverse events in the model affect health states for extended periods . Our socWe assume that all members of the celecoxib and nsNSAID treatment groups are aged 60 years at the outset and all die in the base model at age 81 years, except those with an adverse gastrointestinal (GI) event resulting in premature death before the end of the 21-year lifetime horizon .We conducted literature searches to obtain representative clinical adverse event rates and information on the long-term courses of health states after adverse events. We sought UGI adverse event rates for patients using the doses of celecoxib and nsNSAIDs recommended for OA patients. Celecoxib is more commonly used for the treatment of the symptoms of OA rather than rheumatoid arthritis. Our search strategies are outlined in more detail in Appendix I.Our probabilities for POBs and peptic ulcers are based on event rates in the Successive Celecoxib Efficacy and Safety Study-1 (SUCCESS), the only celecoxib clinical trial that was conducted in a population of OA patients and that used POBs and PUBs as end points . This 12The model's POB probabilities per 100 patient-years are 0.8 for nsNSAIDs and 0.1 for celecoxib, representing a crude relative risk reduction (RRR) for celecoxib of 0.875 . This RRThe base model extrapolates these probabilities over 21 years to calculate POB cumulative incidence rates of 15.5% for the naproxen-diclofenac combination and 2.1% for celecoxib, and respective peptic ulcer rates of 22.4% and 17.3% , nausea, diarrhea, heartburn, constipation, and flatulence, are relevant to economic evaluations because they diminish patients' quality of life and result in increased treatment costs. However, we model only for dyspepsia-like symptoms (including nausea), mainly due to data limitations.Our clinical probabilities for dyspepsia-like symptoms of 12.0%  for an nsNSAID and 7.8%  for celecoxib 200 mg/d are based on moderate to severe dyspepsia, abdominal pain, or nausea event rates in a pooled analysis of trials in arthritis patients  for only 2 of the variables when ranged over the values in Tables Univariate analysis of the sensitivity of the ICER to proportional changes in economic and clinical variables identified the following important variables listed in declining order of their impact on the ICER, along with their threshold values and the proportional changes in each required to attain threshold: celecoxib cost per pill, $3.72 (+41%) and 21-year probabilities of nsNSAID dyspepsia, 0.0743 (-38%); nsNSAID peptic ulcer, 0.126 (-44%); nsNSAID POB, 0.061 (-61%); and celecoxib dyspepsia, 0.1295 (+66%). Hence, the results are robust for all but very large proportional changes.In addition to the above sensitivity analysis for uncertainty, we assessed variants of the base model in which: 1) risks of PUBs increase with age; 2) the length of the analytic horizon is varied; 3) treatment regimens are altered after adverse events; and 4) different serious CV thromboembolic risks are assumed.Advanced age is a well-documented risk factor for PUBs ,31,66-70The ICER declined to $19,309 when age-related increases in PUB risks were factored into the base-model assumptions Table . The cumThe ICER declined 74.9% from $124,100 for a 1-year model to $31,097 for the 21-year model without age risks Table . In the The base model switched patients initially taking celecoxib or an nsNSAID to regimens of celecoxib plus a proton pump inhibitor (PPI) after dyspepsia or a PUB, an approach that is clinically reasonable given the elevated risks of PUBs and perhaps death after such events. In sensitivity analysis, we also assessed 4 alternate secondary strategies to determine whether the ICER for celecoxib versus an nsNSAID would remain below $60,000 per QALY for other possible postevent treatment regimens.Helicobacter pylori eradication therapy, as necessary; 2) all patients continue on celecoxib or their nsNSAID and commence PPI cotherapy for the rest of their lives after PUBs; 3) all nsNSAID patients switch to celecoxib plus PPI and celecoxib patients add a PPI for the rest of their lives post-PUB, but nonulcer dyspepsia patients continue on their original treatment regime; and 4) all nsNSAID patients add a PPI after PUBs with all other treatments unchanged after events.The 4 alternate treatment strategies were: 1) all patients continue on their original treatment regimen, after undergoing temporary courses of PPI healing therapy for PUBs and Celecoxib is cost-effective at the sub-$60,000 per QALY level for models incorporating each of the 4 post event treatment regimens Table  37,50,7-77. ClinWe also tested an alternate assumption that our SUCCESS POB probabilities were too high for constant-risk extrapolation in our model owing to depletion of susceptibles, the theory that risks are higher in the first few months of NSAID use. The ICER in the base case rose to $40,841 per QALY in a base case model with a 30% reduction in POB risks. The ICER further rose to $45,955 per QALY when we extended the 30% reduction to peptic ulcer probabilities and POBs.Our serious CV thromboembolic event , stroke, CV death) costs, and disutilities take into account the impact of the initial event and of subsequent effects, as described in more detail in Appendix II.Our probabilities of such events are based on a meta-analysis of serious CV thromboembolic risk that found event rates of 1.01 per 100 patient-years in celecoxib patients and 1.23 per 100 patient-years in nsNSAID users, with a RR of 0.86  . The ICEWe conducted a cost-effectiveness analysis of long-term celecoxib use compared with nsNSAID use in OA patients. Some of our key assumptions, not adequately addressed in previous models, include a more realistic analytic horizon for UGI adverse events in OA patients with extrapolation and health states based on long-term evidence from the literature, prescription drug prices influenced by termination of patent protection, and ulcer probabilities derived from an OA population.Our base-case celecoxib ICER of $31,097 per QALY suggests cost-effectiveness for 60-year-old OA patients with average baseline UGI risks, 7.1% of whom were taking aspirin for cardioprophylaxis. The ICER declines to $19,309 when account is taken of the increase in PUB risks with advancing age. The ICER, including risks of serious CV thromboembolic events, is $17,120 for a model without age-related risks, and ICERs ranged from $38,807 to $46,192 per QALY in sensitivity analysis with alternate post adverse event treatment strategies.Our model suggests that the use of short analytic horizons to evaluate long-term celecoxib therapy in OA patients results in biased findings ,78,79. TPrevious coxib evaluations do not appear to have accounted for the patent expiration of celecoxib in 2013 or that of omeprazole in 2002, although PPIs are important drivers of costs in some models and the current OTC price represents a reduction of more than 75% in the United States.Our main results are based on regimens of daily nsNSAIDs, whereas intermittent therapy provides adequate relief of OA symptoms for some users of chronic nsNSAIDs in the community. Additionally, some candidates for continuous nsNSAID therapy may interrupt treatment periodically as a strategy to lower MI and stroke risks, even though they suffer disutilities from symptom relief foregone during washout periods. Published coxib evaluations have assumed continuous nsNSAID use because evidence-based probabilities for intermittent treatment regimens are unavailable and myriad patterns of intermittent use are possible .We assessed frequent but intermittent nsNSAID use, which we defined as a minimum of 104 days of therapy per year or approximately 2 days per week for 52 weeks. Our celecoxib versus nsNSAID ICERs were $43,000 per QALY or lower depending on the assumed behavior of UGI risks during intermittent use, number of therapy days, and other factors. Hence, our model's results are not contingent on a restrictive assumption of continuous use.Six evaluations from Europe, Asia, and Canada suggest a favorable economic profile for celecoxib ,81-85. HConversely, an influential American study evaluating a celecoxib-rofecoxib hybrid and a Canadian study comparing celecoxib with ibuprofen and diclofenac produced base-case ICERs far outside ranges considered to be cost-effective, although both found that coxibs might be cost-effective in high-risk populations ,37. ThesDifferences in assumptions and model parameters created most of the inconsistencies between the results of the American study by Spiegel and coauthors and our findings. Our model used the SUCCESS trial results as the basis for the key celecoxib and nsNSAID ulcer probabilities, whereas Spiegel used those for a coxib hybrid with predominant weightings from rofecoxib trials and CLASS, with its supratherapeutic doses of celecoxib. More important, Spiegel's results were driven by an assumption that the annual new patient incidence of PUBs would decrease by 35% per year over its entire 21-year analytic horizon. This pivotal assumption was based on a special-case comparison of the POB incidence rates of nsNSAID patients in the first 6 months and the remaining observational period of the CLASS trial . Under tThe data in our review of coxib and nsNSAID trials ranging in duration from 1 to 3 years support the generalization that PUB and POB risks are constant in long clinical trials ,31,96,97The use of ulcer event rates from the longer-term CLASS trial is 1 reason for the inconsistency of Maetzel and colleagues' Canadian model with our results ,80. The Probabilities obtained from the SUCCESS trial and our modeling decisions tend to be conservative. Relevant decisions include the assumed independence of PUB risks and age in the base model and the exclusion of indirect costs. The doses used in the SUCCESS trial tended to favor nsNSAIDs: one half the celecoxib patients received double the dose recommended for OA patients, whereas the 100-mg daily diclofenac dose was less than the maximum dose approved for OA patients in participating countries ,23,103. The results of our model cannot necessarily be generalized to all populations of OA patients. Furthermore, our results are contingent both on the validity of the short-term probabilities in the model and of our approach to extrapolating them over a 21-year period. Although extrapolation is commonly employed in, and generally recommended for, cost-effectiveness analyses of pharmaceuticals, it engenders uncertainties that increase with the length of the period .According to 3 competing theories, CV thromboembolic risks may be associated with individual NSAIDs, coxibs as a class, or all nonaspirin NSAIDs as a class. Incremental cost-effectiveness analysis as employed in this article deals only with differences in risks between nsNSAIDs and celecoxib.One limitation of the clinical trials in which celecoxib versus nsNSAID CV thromboembolic events have been studied to date, including those in the meta-analysis we used to account for possible differences in CV risks, is that none were originally designed for the primary purpose of assessing differences in these events between treatment groups and they tend to be underpowered for this purpose. Furthermore, the follow-up periods in most of the clinical trials in the meta-analysis that we used were shorter than one year in duration. However, longer observational studies of CV risk are consistent with a similarity of celecoxib and nsNSAID risks, even though they often employ MI end points, which generally favor nsNSAIDs in clinical trials -121. CurOur model suggests that the long-term use of celecoxib is cost-effective versus nsNSAIDs in a population of 60-year-old OA patients with average risks of UGI events.This study was supported by Pfizer Inc, New York, USA. Dale Rublee is a full-time employee of Pfizer Inc. He holds stock options in Pfizer. Michael Loyd & Associates Ltd has consulting agreements with Pfizer Inc for this study and a related study. He owns Pfizer stock. Philip Jacobs received honoraria from Pfizer Inc and Michael Loyd & Associates Ltd.All authors contributed to the design, conduct and analysis of the study, modeling decisions, and the preparation of the manuscript. All authors read and approved the final manuscript.To obtain clinical probabilities for symptomatic ulcers and POBs, we searched PUBMED for all clinical trials comparing celecoxib versus nsNSAIDs at recommended doses for the treatment of OA patients with symptomatic peptic ulcers or ulcer complications as end points. Key words used in the search were "clinical trial" or "RCT" ; "osteoarthritis"; "celecoxib," "ulcer," "hemorrhage," "haemorrhage," "bleed," "bleeding," "perforation," "POB," "PUB", or "PUD" (peptic ulcer disease). We reviewed the resultant abstracts, obtained the full articles as warranted, and reviewed article references. SUCCESS was the only clinical trial with the required end points that exclusively involved OA patients. The SUCCESS trial partially fulfilled our dosage objective, but one half of the celecoxib patients received double the 200-mg daily dose recommended for OA patients.Articles were identified on 2 other clinical trials with some relevance, but both included OA and rheumatoid arthritis patients and also proved to be inferior matches in other respects ,23. We eWe also searched for observational studies that most closely matched our criteria, given the dearth of relevant celecoxib clinical trial data to compare with SUCCESS probabilities. We wanted insights into adverse event rates in the community, and POB or PUB rates over longer periods. Two case control studies involving celecoxib were identified, one with average-risk patients and another with high-risk patients ,122. OnlFor clinical probabilities of dyspepsia, we sought articles on clinical trials involving OA patients and comparing nsNSAIDs and celecoxib at doses normally used in OA patients, with relatively comprehensive definitions of dyspepsia, including related UGI symptoms, but excluding heartburn as a dominant symptom. Our search used key words "clinical trial" or "RCT," "dyspepsia," "abdominal pain," "UGI discomfort" or "NUD," "celecoxib," "NSAIDs," and "arthritis." We identified 3 articles, but the article based on CLASS was eliminated because supratherapeutic doses of celecoxib were used ,34,35.Various other searches were conducted including systematic searches on PubMed for all articles on the risks and courses of dyspepsia, peptic ulcers, POBs, strokes and MIs over extended periods. The objectives were to determine, based on the best available evidence, how to model the period prevalence rates, annual incidence rates, and durations of events over our analytic horizon, which extends far beyond the durations of clinical trials. We searched the literature systematically and manually for multivariate analyses of the risk factors for peptic ulcers and POBs, focusing especially on analyses with age as a continuous variable or with multiple categorical age interval variables. We also systematically reviewed other analyses powered to provide breakdowns of RRs by age.The searches for UGI events were last conducted in January 2005.Health sector costs for first MIs or strokes included initial hospitalizations, ongoing maintenance costs, and forecasted excess costs of future care ,123-130.The pre-publication history for this paper can be accessed here:


The purpose of this study was to determine the intraosseous torsional shear strength of an osseointegrated oral implant using 3-D finite element (FE) stress analysis implemented by ® hollow screw dental implant in a patient was subjected to torque failure test using a custom-made strain-gauged manual torque wrench connected to a data acquisition system. The 3-D FE model of the implant and peri-implant circumstances was constructed. The in vivo strain data was converted to torque units (N.cm) to involve in loading definition of FE analysis. Upon processing of the FE analysis, the shear stress of peri-implant bone was evaluated to assume torsional shear stress strength of the bone-implant interface.A Ø 3.5 mm × 12 mm ITIin vivo torque failure test yielded 5952 μstrains at custom-made manual torque wrench level and conversion of the strain data resulted in 750 N.cm. FE revealed that highest shear stress value in the trabecular bone, 121 MPa, was located at the first intimate contact with implant. Trabecular bone in contact with external surface of hollow implant body participated shear stress distribution, but not the bone resting inside of the hollow.The The torsional strength of hollow-screw implants is basically provided by the marginal bone and the hollow part has negligible effect on interfacial shear strength. Following the introduction of osseointegrated oral implants to rehabilate functional and esthetic consequences related to the loss of teeth and associated hard and soft tissues, a variety of criteria have been placed to evaluate short- and long-term implant success -3. DespiMarginal bone loss to a certain level, particularly within the first year of function, is accepted as a physiologic reaction. Nevertheless, peri-implantitis and functional- or over-loading seem to be role-mates in progressive bone loss beyond the clinically-accepted limits, and likely result in failure of the bone-implant interface. Although various treatment modalities -7 have bper se coined as osseointegration [in vivo experiments of temporary implants [in vivo mechanical experimental tests of smaller diameter temporary implants with machined surface do not represent the actual bone-implant interface strength. In order to improve current knowledge on the mechanical properties of the interface, the purpose of this biomechanical study was to quantify failure torque of an osseointegrated implant with severe bone loss and involve the in vivo data in finite element (FE) analysis to define torsional shear strength at yield.Due to the prerequisite of direct bone implant contact egration , a greategration  or in viimplants . However® hollow screw dental implant  was present in place of tooth # 46 without any restoration  [A 62 year-old male patient applied for treatment of extensive breakdown of implant and teeth supported fixed prostheses that have been in functioning for 8 years both in maxillary and mandibular partially edentulous arches. In the maxilla, one-piece acrylic veneered fixed prosthesis was present on teeth # 13 and # 27, and implants were placed at #14, # 21, # 23 and # 26. In the mandible, the roots of the teeth # 35 and # 47 were present, and a Ø 3.5 mm × 12 mm ITITorque failure of the existing bone-implant interface was tested using a custom-made strain gauged manual torque wrench . During Torque = K x εK is the calibration constant and ε is the strain-gauge reading. Then, torque failure output was implemented in definition of loading conditions of the simulation of in vivo experimental circumstances using finite element stress analysis.where in vivo experimental circumstances were simulated using finite element stress analysis to get more information about the biomechanical properties of the bone-implant interface. In this regard, 2-D model of the Ø 3.5 mm × 12 mm ITI® hollow screw dental implant (Institut Straumann) and the solid abutment (Institut Straumann) were constructed in one-piece using pre-processor, MSC.Marc Metat 2005 . Helical continuity in threads of the implant body was not considered in modelling, but as symmetrical rings [0 axial rotating of planar model using MSC.Marc Metat 2005 (MSC. Software Corporation). A fully-bonded interface was defined for the implant body in the bone simulant. Eight-node isoparametric hexahedral elements were used in 3-D FE model conversion and resulted in 27.300 and 31.500 elements in implant-abutment and bone, respectively  on the occlusal surface of the abutment was selected and retained. All other nodes resting on the occlusal surface and their degree of freedom (dof) were connected to centrally retained node using RBE 2 link (MSC.Software Corporation). Then the rotational torque force was applied onto the centrally-retained node along the implant axis , was used for processing the rotational torque force application. All materials were assumed to be homogenous, isotropic and linearly elastic with Young's modulus and Poisson's ratio for implant-abutment complex 110,000 MPa and 0.35, respectively, and trabecular bone 1850 MPa and 0.3, respectively. In addition, no further definition was considered to define bone-implant contact due to lack of validated data concerning absolute shear bond strength of bone-implant interface. Scalar results of shear stress in trabecular bone representative were evaluated using post-processor, MSC.MarcMetat 2005 (MSC. Software Corporation).The al rings . The impvely Fig . The calaxis Fig . Rotatioin vivo torque failure test of bone-implant interface, implant spinning was not evident, but at the moment of failure, bleeding from the peri-implant sulcus and partial loss of torque resistance of the implant was observed. The in vivo torque failure test yielded 5952 μstrains, as determined from the computer software. Conversion of in vivo strain data to torque units revealed that the torque failure of the bone-implant interface occurred at 750 N.cm.During As a sequel of finite element analysis, high shear stress values were recorded circumferentially at the first intimate contact of trabecular bone with implant surface. Torsional shear stresses at first contact with trabecular bone and consecutive two thread tips in descending order to implant apical, and were 121 MPa, 109 MPa, and 97 MPa, respectively Fig  and 5b. ex vivo torque failure studies to test bone-implant interface are abundant [in vivo data. Advanced peri-implantitis place an argument regarding validity of osseointegration. In addition to lack of peri-implant radiolucency, acute infection with suppuration and mobility was not associated clinically for the implant tested. Therefore, the clinical/radiologic status of the implant, as suggested within a recent consensus report [Following intraosseous placement, achievement and maintenance of direct bone-implant contact is of utmost importance for optimum long-term functioning of oral implants. One of the major concerns regarding mechanical integration of implants is the interfacial strength between the bone and the implant. Therefore, evaluation of shear strength of bone-implant interface with pushout and pullout experiments are required to test mechanical competence of orthopedic and oral implants. In essence, the rationale behind the common use of uniaxial testing is the relative simplicity in the experimental procedures . If the abundant -19. In aabundant -22. Owinabundant  carried abundant  of 2 nons report , rendereIn the present study, evaluation of the shear stress state of peri-implant bone revealed that trabecular bone within hollow part of the implant body did not contribute to interfacial shear strength. This finding is very important clinically, as the one of the rationale behind fabricating such hollow-screw implants was to increase bone-implant contact and improve the biomechanical performance of these implants. The very low magnitude stresses within the hollow part, in comparison with the higher stresses in the outer aspect demonstrate that it is the surface of the implant, particularly the marginal bone region that bears the failure load. Indeed, highest shear stress, which likely indicates the location of "start to debonding", was observed at the first intimate contact of trabecular with the implant surface. This, in part, may also explain why time-dependent bone resorption takes in the marginal bone region, although higher loads and stresses occur in the apical part of loaded implants. It is also very interesting to note that the screw threads resist torsional load to a great extent, as low magnitude stresses were observed on the implant body between the threads. This also implies that the design of threads, particularly at the collar region of implants is crucial , should The author(s) declare that they have no competing interests.


The suggestion that the ketonaemic response to fasting may be altered in the tumour-bearing state was investigated by studying the metabolism of fasted C57/BL6j mice bearing transplanted B16 melanomas. Ketone body (D-3-hydroxybutyrate and acetoacetate) concentrations in the blood of the tumour-bearing mice were significantly increased after a 24 h fast compared to control mice with identical dietary histories. Hepatic glycogen levels were lower at the start of the fasting period in the tumour-bearing mice as were the fat stores. The loss of adipose tissue during the fasting period was greater in the tumour-bearing mice. After 48 h of fasting, the ketonaemia was significantly lower in the tumour-bearing mice compared to the appropriate controls. Two distinct metabolic states are indicated in these fasted tumour-bearing mice, one characterised by accelerated ketonaemia, and a later, near terminal stage, where fat deposits are markedly depleted and ketonaemia is decreased.


The contribution of family circumstance to physical activity and television viewing has not been widely investigated in pre-adolescents, and available information is inconsistent. This study examines whether television viewing and objectively measured physical activity vary by different indicators of family circumstance.Data from the 2001 Children's Leisure Activity Study and the 2002/3 Health, Eating and Play Study, involving Australian children in Grades Prep (mean age 6y) and 5–6 (mean age 11y), were combined. Children wore accelerometers for six consecutive 24 hour periods. Average min/day in low-intensity activity (1.0–1.9 METs) and moderate-to-vigorous-intensity activity (≥3 METs) were calculated. Parents reported children's television viewing and family circumstance. Linear regression analyses were conducted separately for young girls, young boys, older girls and older boys.Complete data were available for 2458 children. Parental education and, to a lesser extent, employment level were inversely associated with television viewing. Children in single-parent families, those whose fathers were not in paid employment, and those without siblings tended to spend more time in low-intensity activity than their peers. Children with siblings spent more time in moderate-to-vigorous-intensity activity; associations were stronger for girls. Maternal education was positively associated with moderate-to-vigorous-intensity activity for younger children. Maternal employment was positively associated with moderate-to-vigorous-intensity activity for older children. Multivariable models did not demonstrate a cumulative explanatory effect.Individual measures of family circumstance were differentially associated with television, low-intensity activity and moderate-to-vigorous-intensity activity and associations were often not consistent across age-by-gender groups. Interventions may need to be tailored accordingly. Regular physical activity is associated with improved physical and psychosocial well-being in children ,2, whileThe family is a potentially important source of influence on children's physical activity and television viewing . HoweverThere is inconsistent evidence for an association between SES, the most commonly investigated aspect of family circumstance, and the physical activity of preadolescent children. A 1999 review  of studiOther indicators of family circumstance have been less widely investigated and have produced conflicting results for physical activity but more consistent results for television viewing. Multiple studies report no association between number of parents in the home and children's physical activity ,18,21,24Available information on associations between children's physical activity and family circumstance in the pre-adolescent age group is inconsistent. Most studies have considered single indicators of family circumstance, making it difficult to compare different aspects of family circumstance across studies with different samples and methodologies. Current evidence is further limited by subjective measurement of physical activity. This study aims to examine whether television viewing and objectively measured physical activity vary by different indicators of family circumstance in pre-adolescent children.st, 3rd and 5th quintile; 2nd and 4th quintile schools were excluded) were selected to provide a cross-section of SES; a total of 24  schools agreed to participate.Data were combined from two cross-sectional studies, both assessing family circumstance, television viewing and objectively-measured physical activity in independent samples: 2001 Children's Leisure Activities Study (Study 1) and 2002/2003 Health, Eating and Play Study (Study 2). Both used stratified random sampling with probability proportional to size  to select schools in Melbourne, Australia with more than 200 students. Study 1 selected 19 government schools in high (n = 10) and low (n = 9) SES areas. Study 2 classified government and Catholic schools into SES quintiles using Australian Bureau of Statistics Socio-Economic Indexes for Areas Index of Relative Socio-Economic Disadvantage . ThirteeDue to constraints on the number of schools able to be included in the study, it was not possible to sample schools from all SES quintiles, however the SES of individual families included is likely to have spanned all SES quintiles. For both studies, all children in Grade Prep (mean age 6y) were invited to participate. All Grade 5–6 children (mean age 11y) attending Study 1 schools and 15 of the 24 Study 2 schools were invited to participate . The 15 schools from which Grade 5 and 6 children were included were spread across the low, middle and high SES groups.Studies received ethics approval from the University Ethics Committee and appropriate education authorities. Under existing ethical guidelines it was necessary to seek active consent from parents for each child's participation and no information could be accessed regarding characteristics of non-respondents.Children wore the Manufacturing Technology Inc accelerometer Model 7164 (formerly CSA) on their right hip for six consecutive 24-hour periods except when bathing, swimming and sleeping. It measures intensity, frequency and duration of movement, and is a valid predictor of children's heart rate and energy expenditure . AccelerMovement count thresholds, based on age-specific energy expenditure prediction equations , were apParents reported children's usual television viewing time (including videos and DVDs) via self-completed questionnaire. In Study 1 parents reported total hours and minutes their child spends watching television on Monday-Friday and Saturday-Sunday during a typical week. Estimates were summed then divided by seven to generate average viewing time (min/day). In Study 2 parents reported the time their child spends watching television on a usual weekday and usual weekend day. Weekday estimates were multiplied by five and weekend day estimates were multiplied by two, the totals were summed and divided by seven to generate average viewing time (min/day).Parents also provided family circumstance information including highest level of education and current employment status of the respondent and co-carer, marital status, number of parents in the home and number of children in the family. Parents in Study 2 also reported average daily hours of paid employment for themselves and the co-carer. Based on gender, respondent and co-carer information was converted to maternal and paternal information.survey commands with svyset, psu(school) and cluster(school) options in Stata). As children's physical activity differs by age and gender,. Unlike television viewing, objectively measured sedentary time comprised a range of sedentary behaviors, many of which may be non-discretionary, occurring outside the home, and thus less likely to be influenced by family circumstance.These findings are based on cross-sectional data, therefore causality can not be inferred. While the modest response rate might be considered a limitation, participants spanned a broad range of sociodemographic and family circumstance backgrounds. The strengths of the study include the objective measurement of physical activity and a large sample enabling stratification by age and gender. However, it should be noted that where the number of children in a single family circumstance category was low (eg. children with unemployed fathers), estimates should be interpreted with caution.Our findings that individual measures of family circumstance were differentially associated with varying intensities of activity and that associations differed across the age-by-gender groups may help explain conflicting findings reported in the literature . This stThe author(s) declare that they have no competing interests.KH carried out the statistical analyses and drafted the paper. DC was involved in the design and conduct of both studies and contributed to the drafting of the paper. JS was involved in the design and conduct of both studies and contributed to the drafting of the paper. All authors read and approved the final manuscript.


The event-related brain response mismatch negativity (MMN) registers changes in auditory stimulation with temporal lobe sources reflecting short-term echoic memory and frontal sources a deviance-induced switch in processing. Impairment, controversially present at the onset of schizophrenia, develops rapidly and can remain independent of clinical improvement. We examined the characteristics of the scalp-recorded MMN and related these to tests of short-term memory and set-shifting. We assessed whether the equivalent dipole sources are affected already at illness-onset in adolescence and how these features differ after a 14-year course following an adolescent onset. The strength, latency, orientation and location of frontal and temporal lobe sources of MMN activity early and late in the course of adolescent-onset schizophrenia are analysed and illustrated.MMN, a measure of auditory change-detection, was elicited by short deviant tones in a 3-tone oddball-presentation and recorded from 32 scalp electrodes. Four dipole sources were placed following hypothesis-led calculations using brain electrical source analysis on brain atlas and MR-images. A short neuropsychological test battery was administered. We compared 28 adolescent patients with a first episode of schizophrenia and 18 patients 14 years after diagnosis in adolescence with two age-matched control groups from the community .MMN peaked earlier in the younger than the older subjects. The amplitude was reduced in patients, especially the younger group, and was here associated with negative symptoms and slow set-shifting. In first-episode patients the temporal lobe sources were more ventral than in controls, while the left cingular and right inferior-mid frontal sources were more caudal. In the older patients the left temporal locus remained ventral , the right temporal locus extended more antero-laterally (illness progression), and the right frontal source moved antero-laterally .From the start of the illness there were differences in the dipole-model between healthy and patient groups. Separate characteristics of the sources of the activity differences showed an improvement, stasis or deterioration with illness-duration. The precise nature of the changes in the sources of MMN activity and their relationship to selective information processing and storage depend on the specific psychopathology and heterogeneous course of the illness. The detection of a change in ongoing ambient auditory stimulation is an important preliminary requirement for the conscious organisation of an adaptive response to a significant event. The unusual sound could be an unexpected tone in a well-known piece of music, or the telephone ringing during a conversation. The change is detected automatically, but the altered behaviour requires controlled information processing beyond detection. The brain's response on detecting deviance is registered by an event-related potential (ERP) called mismatch negativity (MMN). This is recorded by subtracting the ERPs after a series of similar stimuli from that elicited by the unexpected tone. The procedure requires no task, and is thus well-suited for study in patients with schizophrenia. But what parts of the brain generate MMN activity and what mechanisms are involved?Sources of neuronal activity have been reported for the auditory cortices and the frontal lobe ,2. The fA reduced MMN is widely reported in patients with schizophrenia with or without antipsychotic medication -23. In cInitial studies of MMN sources with magnetoencephalography MEG: ,34) and  and 34])In this current report two groups of patients were selected to examine the hypotheses of there being impaired frontal sources and a progressive deterioration with course in schizophrenia. Patients were either experiencing their first episode as adolescents, or had been diagnosed initially in adolescence 14 years before. (It has been suggested that an onset in adolescence can lead to a severer course of illness .) We souThe study protocol was reviewed and approved by both the board of the University of Essen Psychiatry Clinics and the Ethics Committee of the Faculty of Medicine according to the criteria of the Declaration of Helsinki 00-2-1357-Y). After the procedures had been described all subjects and care-givers gave written informed consent. A first-episode of DSM-IV schizophrenia was diagnosed in 28 adolescent inpatients (early-onset: EOS) on the basis of a clinical interview and hospital records first on the ward and then by research group personnel. This was confirmed 6 months later to exclude affective, schizoaffective and schizophreniform psychoses. Eighteen outpatients who had their first break as adolescents in our clinic on average 14.4y before  were also recruited: 11 showed a partial remission (CGI 3–5), and 7 a chronic course or no remission (CGI 6–8). They had a mean of 4.6 hospitalizations (range 1–12). Of 34 patients contacted, 9 declined and 7 were too ill: participants did not differ on mean age, gender, illness-severity or social function . Patient357-Y. AfAn auditory oddball sequence  was presented over 1600 trials. There was a pseudorandom sequence of standards , frequency deviants  and duration deviants  with each deviant preceded by at least one standard . During 4 blocks of 200 trials (passive auditory condition) subjects performed a simple visual red/green circle discrimination on a PC . Responses to the green target alternated between hands between blocks. Tone detection is not suppressed during various concurrent visual processes , nonetheAn EEG was recorded  from 31 tin electrodes  in an electrode cap  with impedance <5 kΩ. A vertical EOG was recorded from the supra-orbital ridge of the right eye and a horizontal EOG from the outer canthus of the right and left eye to monitor blink-and eye-movements for rejection of artefacts (>50 μV) in EOG leads. Electrodes were referenced to linked-earlobes and the average-reference recomputed offline. A band-pass filter was set at 0.1–100 Hz. Data were digitised with 16-bit resolution, sampled at 500 Hz and stored on a hard disk. Records were epoched separately for each tone type with 100 ms prestimulus baseline and linear detrended. A 30 Hz low-pass filter (24 dB/octave) was used offline.group) using data from 29 electrodes. The 135–165 and 165–195 ms windows covering the MMN peak (factor window), where inspection showed there to be potential group differences ) and 4 coronal rows . This reduced the degrees of freedom that were also adjusted with the Greenhouse-Geisser epsilon. The MMN in the active condition as well as the latency were analysed by ANOVAs using the same factors (for the latter excluding the factor window). Where significant main effects or interactions involved more than two factor levels, additional ANOVAs were carried out to test simple effects. The influence of antipsychotic medication was examined with ANOVA and Spearman correlations in the EOS group. Exploratory correlations were sought for 3 sets of MMN measures  with the CGI sum scores, the main clusters of SANS/SAPS symptoms, and neuropsychological measures of processes putatively related to MMN measures [P < .05 and type-1 corrected correlations at P < .002.The MMN waveform was derived by subtracting the ERP to standard tones from those elicited by the duration-deviant. Peaks were sought automatically from 90 to 225 ms after stimulus-onset. The MMN was averaged across blocks for each group and the mean amplitude was computed in successive 30 ms windows from average-refenced data (105–135–165–195–225 ms) for the active and passive condition, respectively. An initial repeated-measures analysis of variance (ANOVA) was carried out for 4 subject groups (between subject factor l-making),53. TrenBrain electrical source analysis (BESA) using a four-shell head-model  was usedTo calculate statistical differences between groups, the individual solutions were re-calculated for each subject. Waveforms were high-  and low-pass filtered . Data were discarded if a criterion of RV<4% was not reached. This reflects the decreased signal-to-noise ratio of an individual's waveform. Two C-EOS, 6 EOS, 3 C-14Y, and 5 S-14Y subjects were removed . Dipole-locations were compared between groups with a MANOVA including the 4-level factor dipole as well as the between-subject factor group. The x, y, and z-coordinates of each dipole  and the 3,79 = 5.8, P < .01). Slow reaction times were confirmed for S-14Y patients in the auditory task . Here both patient groups made fewer hits than their comparison groups  in the 135–165 ms window . The reduction in the older patients vs. their controls attained trend significance , but it should be noted that the older controls had a smaller MMN than the younger controls . The MMN amplitudes did not differ between patient groups, and thus provide no evidence for a deterioration nor an improvement between onset (EOS) and later stages of the illness (S-14Y).Initial analyses with 29 electrodes showed group differences for MMN amplitude . MMN amplitudes in the frontal and fronto-central rows did not differ but were larger than in the other rows . Further MMN amplitudes were largest at the midline electrodes . However, the topography did vary with the time window . The MMN was broadly distributed in the 135–165 ms window : but in the 165–195 ms window the midline MMN amplitude was larger than on the left or right side .The ANOVA using mean amplitudes in two consecutive time windows confirmed the fronto-centrally pronounced MMN topography . Simple effects confirmed differences between the EOS group and their adolescent controls  as well as between the adolescent and the adult control groups . Effects were specific to time window and row . The group effect was pronounced in the 135–165 ms interval  and reduced to a trend in the 165–195 ms window . At 135–165 ms tests of simple effects revealed differences between EOS patients and their controls at all but the centro-parietal row . Differences between the control groups were most pronounced at the frontal and fronto-central row . When compared to their adult controls the S-14Y group showed a smaller MMN amplitude only at the frontal row .Most importantly, the 4 subject groups differed significantly from each other . Especially the S-14Y group showed an increased MMN latency, both, when compared to their adult controls  and to the younger patient group . MMN amplitude tended to decrease more in the second window (165–195 ms) with dose of antipsychotic medication . In other words there was a modest tendency for medication to sharpen the shape of the MMN waveform around its peak latency.An ANOVA comparing MMN amplitudes in 15 EOS patients with and 13 without medication was not significant  differed significantly between the groups . Potentially reflecting post-adolescent maturation the left temporal source was more lateral (10 mm) and ventral (12 mm) in the older vs. the younger controls , while on the right it was more medial (9 mm) and ventral . The frontal source in the older controls was more posterior in the left cingulate (12 mm), and on the right it was more anterior (10 mm) and medial (13 mm) vs. the younger controls .Source locations calculated from the 12,30 = 15.4, P < .001). The left temporal source was more lateral (8 mm), and that on the right was 15 mm more ventral . This is reminiscent of the adult control loci, but 11 mm more rostral. In the EOS patients the left cingulate source lay 15 mm more posterior, and the right frontal source 18 mm more medial than in the C-EOS group . These changes lay on different dimensions from those described between young patients and controls. Differences between older and younger patients that could reflect maturation or illness progression were evident . The left temporal source was markedly more ventral (18 mm) and the right temporal source slightly more lateral (7 mm) in the older patients . In contrast to the temporal source, the left frontal locus was 13 mm more dorsal and the right frontal locus 10 mm more rostral in the older than the younger patients . But ANOVA showed there were interactions with location rather than group. The right frontal source was always the weakest . Likewise the slightly later dipole-latencies in patients were not significant . This is attributable to the variation recorded (SD 19–31 ms). However across groups mean latencies were longer for the right frontal source  illustrating a bottom up sequence for activation. Finally although the dipole-orientation for the whole group solutions clearly differed between groups . An interaction of group × window indicated that a significant reduction of MMN amplitude in the EOS vs. C-EOS group was delayed to the 165–195 ms window . Differences for EOS vs. S-14Y  and C-EOS vs. C-15Y  were retained for the 135–165 ms window. But comparisons between the older subjects were non-significant.Group differences similar to those in the passive condition, were found with attention to the auditory modality . Peak-dipole activity in the older subjects also fitted well the 60 ms envelope around the peak .P = .002) and mastoid sites . In both patient groups associations of MMN with symptoms were restricted to 3 clusters. In EOS patients reduced MMN at the mastoids related to anergia  and flat affect . Quite separately in S-14Y patients there were indications that hallucinations related to decreased MMN at frontal sites , while, unexpectedly, increased amplitudes at the mastoids related to anergia ratings .Correlations were sought between MMN amplitude at Fz and the mastoids with the CGI and the 9 clusters of SANS/SAPS symptom ratings. EOS but not S-14Y patients showed decreasing amplitude with increasing CGI severity at frontal  is of interest in view of trends in both older groups for an association of trails performance with temporal lobe dipole-moments in the left hemisphere .Correlations for MMN amplitude with z-scores for trail-making measures of set-switching and digit-span measures of working memory were explored. Trails B-A scores were unrelated to MMN amplitude in healthy adolescents, but were negatively related to MMN amplitude at both mastoid sites in both time windows in EOS patients . No correlations were evident in the older groups. There were no relationships to dipole-moments in the young subjects. But an association with the left cingular dipole in healthy adults . In contrast in EOS patients the correlations tended in the opposite direction at mastoid sites  and FCz . These measures were not correlated in the older subjects. There was no evidence of an association of MMN characteristics with other indicators of short-term memory . Isolated relationships with dipole-moments could not be distinguished from chance.Surprisingly, in the C-EOS group digit-span scores correlated negatively with left and right mastoid MMN amplitudes in both time windows . The unexpected decrease of MMN amplitude in healthy adults compared to adolescent controls (from 2.1 to 1.5 μV) underlies the attenuated statistical difference between adult healthy and patient groups  was reduced in teenagers experiencing their first break of schizophrenia, compared to age-matched controls . The desee also ,23,44.In all subjects MMN was calculated as reflecting bilateral source-activity in the temporal lobes and the left cingulate gyrus followed by the right inferior-mid frontal cortex in a bottom-up sequence. These source locations, originally described in Jemel et al.  have beevs. healthy 17-year-olds. In these controls this likely reflects developmental white-matter expansion and grey-matter density increases [In young first-episode patients sources in both the left and right auditory cortices appeared more to the left, and in the right hemisphere more ventral than in healthy teenagers. These are the same directions of change observed for the more caudally located sources in healthy 30- ncreases ,61 that ncreases . The supncreases ,64 that ncreases .In the older patients the left temporal source was more ventral than in controls or either group of young subjects. Indeed, their right temporal source changed in association with illness progression, being more anterolateral than in either the EOS or the C-14Y groups.The reductions of MMN amplitude (significant), smaller dipole moments in the temporal lobe and slightly longer latencies (both non-significant) in adolescent patients are very similar to alterations reported for first-episode and adult patients ,66. TherFrontal MMN sources varied more between groups on the rostrocaudal axis rather than on the lateral axis, as seen for sources in the temporal lobe. In the young patients the right frontal source was more caudo-medial than in their controls, but with similar lateral coordinates to the older controls. The dipoles were more rostrally located in younger and older controls. This more caudal locus in the patients is consistent with data for the frequency-deviant MMN  and was Possibly also reflecting the illness and its duration the left cingular source in the S-14Y group was more medial than the controls, and more dorsal than in the young patients. But like the younger patients the cingular source was more caudally located than in the controls. It is intriguing that the left cingular source in young patients was more medio-caudally located than in the young healthy controls, but in a similar locus to the older controls. This result has some similarity with the results for the other dipoles (above). But it differs from changes we reported for the detection of frequency-deviants , where tStudies of normal subjects demonstrate that temporal lobe contributions to MMN represent the short-term memory templates for standard tones against which deviants can be contrasted. Frontal sources, active after deviant detection, initiate a switch to controlled processing to allow the significance for response to be assessed ,7. The cTrail-making abilities to switch between sets are associated with prefrontal function . ExploraImaging studies show that digit-span measures of working memory rely on recruiting activity in a network that includes the right dorsolateral prefrontal and anterior cingulate cortices . DespiteIt is remarkable that the associations for SANS/SAPS symptom-clusters with frontal and mastoid MMN were largely restricted to negative symptoms of anergia and positive hallucinations. The former was associated with reduced mastoid MMN in the EOS group, as reported elsewhere for duration-deviant MMN in the right hemisphere . In the Sources of MMN activity in the frontal, cingulate and temporal cortices have been proposed without detailed localization ,2,84. DeIn summary, superimposed on the post-adolescent brain expansion manifest on the lateral axis in the temporal lobes and rostro-caudally in the frontal lobes, separate anomalies of structural-functional relationships develop along these 2 axes in psychotic patients. We propose that in the temporal lobes a ventro-lateral migration of the MMN sources occurs secondarily to ventricle expansion. In the frontal lobes the lack of a rostral migration of MMN sources reflects delayed post-adolescent development of prefrontal regions in psychotic patients. An MMN impairment was marked in association with symptoms of withdrawal  and a lack of cognitive flexibility .Scalp records of MMN show a modest recovery of change-detection between the EOS and S-14Y groups. However, in both the younger and in the older patients dipole moments and latencies were diffusely weaker and delayed compared to controls. These results may reflect a modicum of adaptive plasticity. The significant movement of the centres of activity giving rise to the MMN dipoles may reflect this as plasticity, expansion or migration of these functional centres. Alternatively the changed locations may represent a progressive illness-dependent impairment requiring adaptation elsewhere in central nervous function.BESA, Brain electrical source activity; CGI, Clinical global impression inventory; DSM, Diagnostic and statistical manual (of the American Psychiatric Association); EOS, Early-onset schizophrenia; ERP, Event-related potential; MEG, magnetoencephalography; MMN, Mismatch Negativity; MR(I), magnetic resonance (imaging); RV, Residual variance; SAPS/SANS. Scale for the assessment of positive/negative symptoms; SCID, Structured clinical interview for DSM schizophrenia; SD, Standard deviation;The author(s) declare that they have no competing interests.NWW carried out most of the recordings, and their analysis, and contributed to drafting the manuscript; SAJ assisted NWW with the recordings and contributed to the analysis. LBO carried out some early recordings and analyses. RDO conceived planned and organised the study, ran the initial recordings and drafted most of the MS. JS and BR were involved in recruitment, diagnosis and neuropsychological testing and initial analyses of these data. All authors read and approved the draft manuscript.The pre-publication history for this paper can be accessed here:


N170 effects associated with visual words may be related to perceptual expertise effects that have been demonstrated for faces and other extensively studied classes of visual stimuli. Although face and other object expertise effects are typically bilateral or right-lateralized, the spatial topography of reading-related N170 effects are often left-lateralized, providing potential insights into the unique aspects of reading-related perceptual expertise.Extending previous research in German , we use A sample-by-sample permutation test computed on word versus symbol ERP topographies revealed differences during two time windows corresponding to the N170 and P300 components. Topographic centroid analysis of the word and symbol N170 demonstrated significant differences in both left-right as well as inferior-superior dimensions. Words elicited larger N170 negativities than symbols at inferior occipito-temporal channels, with the maximal effect over left inferior regions often unsampled in conventional electrode montages. Further contrasts produced inferior-superior topographic effects for the pseudoword-symbol comparison and left-lateralized topographic effects for the word-pseudoword comparison.Fast specialized perception related to reading experience produces an N170 modulation detectable across different EEG systems and different languages. Characterization of such effects may be improved by sampling with greater spatial frequency recordings that sample inferior regions. Unlike in German, reading-related expertise effects in English produced only partial generalization in N170 responses to novel pseudowords. The topographic inferior-superior N170 differences may reflect general perceptual expertise for orthographic strings, as it was found for words and pseudowords across both languages. The topographic left-right N170 difference between words and pseudowords was only found in English, and may suggest that ambiguity in pronunciating novel pseudowords due to inconsistency in spelling-to-sound mapping influences early stages of letter string processing. These two topographic effects generalized to a different degree to pseudowords in the present study, suggesting that the two effects may be associated with different functional properties of reading-related expertise.The inferior-superior modulation of the N170 word-symbol difference fully generalized to pseudowords in the present study. The same inferior-superior effect was also found for the word-symbol and pseudoword-symbol contrast in the Zurich study with participants speaking a different language ,3.Such speculation regarding various forms of expertise, however, requires additional investigation, as studies on face or object expertise have not analyzed topographic effects beyond lateralization -6. It reEarlier findings suggested that the main characteristic feature of reading-related N170 specialization lies in its left-lateralized topography ,8, contrEnglish and German differ in the degree of orthographic depth, which is deep in English and shallow in German. Orthographic depth refers to the level of consistency whith which spelling maps onto word sounds (feedforward consistency) and word sounds map onto spelling (feedbackward consistency). In the case of pseudoword reading, the former plays an important role. Due to inconsistency in spelling-to-sound mapping in English, the pronunciation of pseudowords is much more ambiguous in English than in German. Thus the left-lateralized topographic N170 effect may specifically relate to processes involved in mapping letters onto word sounds. Mapping consistency has been demonstrated to be a central factor modulating the rise of automaticity in information processing . The lacSuch an interpretation also fits with the lack of N170 word-pseudoword differences in earlier studies in Finnish and French ,16. WherOne study in English also did not find N170 differences between words and pseudowords, but the participants performed a lexical task that encouraged deeper language processing of the pseudowords, which is in agreement with the automaticity hypothesis .Another study in English found larger N170 amplitudes for irregular pseudowords than for words, which may suggest that the irregularity of the pseudowords led to an enhancement of the N170 similar to findings for consonant strings ,15. The Different levels of engagement in orthographic-to-phonological processing might also explain the variable left-lateralization of N170 related to reading in the literature ,12. ThusEvidence for language-specific effects on pseudoword processing also comes from a PET study with English and Italian subjects. During explicit and implicit pseudoword processing, left posterior inferior temporal regions were more activated in English subjects, whereas in Italian subjects left superior temporal regions were more activated . These rCombined hemodynamic and electrophysiological studies can also help localize the sources of the reading-related N170 specialization. Studies combining fMRI with MEG  and EEG The notion of the Visual Word Form Area was first inspired by neuropsychological observations of "pure" alexia, or letter by letter reading, characterized by an inability to read entire words, typically following damage to left-inferior-temporal regions with a maximal probability over fusiform gyrus . In conThe present study provides further evidence that there are rapid perceptual processes in the brain that are specialized for reading. The N170 topography is a robust neurophysiological marker for this specialization showing more inferior and left-lateralized negativity for words compared to symbols. The results extend this general finding via a dense array and extended inferior coverage, demonstrating that the maximal negative effect is more inferior than reported previously. Further characterization of the N170 response in the current study suggests that reading-related perceptual expertise in the N170 can be characterized by at least two topographic effects which generalize to novel word forms to different degrees. The inferior-superior topographic effect in the N170 fully generalized to novel word forms, and may reflect expertise for letters or well-ordered letter strings. Unlike in German, the left-lateralized topographic effect in the N170 did not generalize to novel word forms in English. Inference from language differences between English and German suggests that the left-lateralized topographic effect in reading-related N170 specialization may reflect spelling-to-sound conversion, which might be less automaticly engaged in pseudoword processing in English due to more ambiguous pronunciation of novel word forms.The data of 15 right-handed, native English speakers (19 to 29 years old) are presented. All subjects had normal or corrected-to-normal vision and their word reading and pseudoword decoding abilities  were witTo investigate rapid specialization for print, we used a paradigm that was used in an earlier study in Zurich, Switzerland . The maiThe 129 channel ERPs were recorded using a geodesic sensor net  with a C on non-normalized (raw) ERP maps was computed for each time point. TANOVA on raw maps detects all systematic amplitude differences between two maps running a nonparametric randomization test [To assess differential processing of word and symbol strings, a Topographic Analysis of Variance  of the averaged word and symbol GFP grandmeans, as in . GFP andFor the behavioral analysis two repeated measure ANOVAs were computed for accuracy and reaction time with the "condition" factor (words vs. pseudowords vs. symbols).3D: three-dimensionalANOVA: Analysis of VarianceEEG: ElectroencephalographyERP: Event-related potentialGFP: Global Field PowerTANOVA: Topographic Analysis of VarianceUM, DB, and BDM designed the study and the data analysis strategy. UM and BDM shared the elaboration of the paper. UM was responsible for data collection and data analysis.


N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37°C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an  Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that leads to the destruction of diarthrodial joints. Many consider it to be an autoimmune disorder, although the exact cause is unknown. The primary target of the inflammatory process is synovial tissue. The inflamed synovium invades and destroys articular bone and cartilage, leading to significant pain and disability -3.Currently, there is no cure for RA. The most commonly used medications for treatment and management of the disease include nonsteroidal anti-inflammatory drugs, glucocorticoids (GCs), and disease-modifying anti-rheumatic drugs, including the so-called biologic agents that target tumour necrosis factor-alpha and interleukin-1 . There iAlthough progress has been made in understanding the molecular mechanisms and identification of novel therapeutic targets for RA, challenges still remain. Most of the available therapies for RA do not have tissue specificity. Therefore, to reach effective drug concentrations in affected joint tissues, high systemic doses of the therapeutic agent must often be administered, which may lead to significant adverse systemic and extra-articular side effects. Reductions in drug doses may attenuate toxicity but may lead to reduced therapeutic efficacy. To overcome this limitation, approaches that specifically target agents to affected joints offer unique promise.N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers in an adjuvant-induced arthritis (AIA) rat model  10/30)  with phosphate-buffered saline (pH 7.3) as the eluent. The average molecular weights of the polymers were calculated using calibrations with poly(HPMA). UV spectra of all tested compounds were obtained on a Cary 400 Bio UV-Vis spectrometer . 1H NMR spectra of all synthesized compounds were recorded on a Varian Unity 500-MHz NMR spectrometer . The solvent peak was used for reference . Mass spectra of all synthesized compounds were obtained using a Finnigan LCQ DECA mass spectrometer  interfaced to an electrospray ionization (ESI) source.The weight average molecular weight  using N,N'-dicyclohexylcarbodiimide (DCC) as the coupling agent. After removal of the resulting dicyclohexylurea and the extra DCC, the Boc (tert-butoxycarbonyl) protection in the resulting conjugate was removed by trifluroacetic acid treatment for 2 hours. The resulting polymer was precipitated, dialyzed, and lyophilized to obtain the HPMA copolymer-hydrazide conjugate ([-NHNH2] = 4 × 10-4 mol/g). This copolymer (0.75 g) was mixed with an excess of Dex  in N,N-dimethylformamide (1 ml), and one drop of acetic acid was added to catalyze the reaction. It was stirred overnight at room temperature and then purified on an LH-20 column (×2) to remove the unreacted low molecular weight compounds.P-Dex was synthesized with the following exemplary procedure Figure . HPMA  removal of the solvent, the isolated samples were dissolved in acetonitrile/water  for high-performance liquid chromatography (HPLC) analysis. An Agilent 1100 HPLC system  with a quaternary pump (with degasser), an autosampler, a fluorescence detector, and a diode-array-based UV detector was used for the Dex-release study.P-Dex (1.8 mg/ml) was dissolved in acetate buffer  or phosphate buffer  and incubated at three different temperatures . At selected time intervals, the conjugate solution (300 μl) was withdrawn and extracted with ethyl acetate (3 × 400 μl). After Speed Vac18  was used for the analysis with acetonitrile/water = 1/1 as the mobile phase. Its flow rate was set constant at 0.5 mL/min. The UV detection wavelength was at 240 nm. The sample injection volume was 10 μL for all evaluation. A linear external Dex calibration curve was established in the range of 1 to 150 μg. The calibration was performed with the analysis of each batch of Dex sample. The analysis of each sample was repeated three times. The resulting mean value was converted to the percentage of Dex released.A reverse phase CM. tuberculosis H37Ra (1 mg) and LA (5 mg) were mixed in paraffin oil (100 μl), sonicated, and injected subcutaneously into the base of the tail [Principles of Laboratory Animal Care .Male Lewis rats 175 to 200 g) were obtained from Charles River Laboratories, Inc.  and allowed to acclimate for at least 1 week. To induce arthritis, 0 g were Rats with established arthritis were selected and randomly assigned into three groups (six or seven rats per group). A fourth healthy, untreated group (seven rats) was included as control. On the 13th day after arthritis induction, P-Dex  was injected intravenously into one group of the RA rats. An equivalent total dose of water-soluble free Dex (sodium phosphate) was divided into four aliquots and administered in separate intravenous injections to the second group of rats on days 13, 14, 15, and 16. Saline was similarly given to a third group of rats (controls). The changes in ankle size and body weight during the treatment were monitored.On day 22, all animals were euthanized and joint tissues were collected. The bone mineral densities (BMDs) of the ankle region  and the whole femur and lumbar vertebral bodies (fourth and fifth) were measured by peripheral dual x-ray absorptiometry (pDXA). The tissues were fixed in phosphate-buffered formalin for 2 days, and the intact ankle regions were then dehydrated in ascending concentrations of ethanol and embedded undecalcified in methyl methacrylate. Sections of the entire joint were cut with a low-speed saw using diamond-wafering blades. The sections were mounted on plastic slides and ground to approximately 50 μm in thickness, and the surface was stained using a Giemsa stain modified for plastic sections . The ankp value of less than 0.05.The differences between the groups were first tested by a one-way analysis of variance followed by a Fisher's predicted least-square difference test to determine the significance of individual group comparisons. Differences were considered to be significant at a w of the conjugate was 73 kDa with a polydispersity index of 1.4 and this material was selected for use in the treatment study of the rats. Given that no difference in Mw was observed for P-Dex and its precursor, the possibility that both carbonyl groups in Dex would react with hydrazide and cause cross-linking of the polymer was minimal.After overnight polymer-analogue reaction between the pendent hydrazide and Dex , the conjugate was purified twice using an LH-20 column. A subsequent FPLC analysis of the conjugate indicated that there was no detectable free Dex in the purified copolymer conjugate. The remaining hydrazide in the conjugate was determined using the TNBS  assay  and compin vitro release study, another batch of P-Dex was synthesized with the Dex content determined to be 106 mg/g polymer conjugate by the TNBS assay and by HPLC after full hydrolysis. As shown in Figure For the At 13 days after arthritis induction, the ankle size of most of the AIA rats reached a plateau (data not shown). At this time, the hind legs of the affected animals were less mobile and the animals had reduced body weights. Some inflammation was also observed in the front limbs, but it was not as severe as the inflammation observed in the hind limbs. The intravenous administration of free Dex or P-Dex on day 13 led to a rapid suppression of the inflammation. The ankle sizes of both treatment groups were greatly reduced by day 14. Though not quantified, the animals were more mobile and active after the Dex or P-Dex treatments. The effects of P-Dex on the suppression of observable inflammation and mobility and activity lasted for the duration of the entire study (euthanasia on day 22). This was unlike the animals given four daily injections of Dex, in which the inflammation and decreased mobility rapidly returned after the cessation of the Dex injections. By the end of the study on day 22, the animals that had been treated with Dex were indistinguishable from those in the untreated control group.The measurements of BMD of the ankle region, whole femur, and lumbar vertebral bodies (fourth and fifth) of all animals at the end of the study, as determined by pDXA, are presented in Figure The percentages of endosteal cancellous bone surfaces undergoing active bone resorption (resorption surface) with the different treatment groups are presented in Figure Representative histological sections of AIA rats' ankle joints from all treatment groups are shown in Figure Colloidal drug delivery systems, including water-soluble polymers, have been used extensively to improve the safety and efficacy of chemotherapeutic treatment for solid tumors ,11. The PEGylated liposome systems have been used with some success to deliver GCs for the treatment of inflammatory arthritis . As a naIn this proof-of-principle study, we selected Dex as the model compound to be conjugated to the delivery system. Dex, a synthetic GC, is a very potent anti-inflammatory drug that exhibits a rapid therapeutic response. Dex and other GCs are often used in the early phases of RA treatment to relieve symptoms. It has also been reported that these agents can modify the disease progression in patients with RA . HoweverThe first challenge for this study was how to conjugate Dex to HPMA copolymer. In a previous report, Dex was conjugated to PVP via its hydroxyl group . HoweverPolymer-analogue reactions were used to conjugate Dex to the HPMA copolymer Figure . As the in vivo Dex release may be accelerated due to the presence of various proteins that bind hydrophobic drugs.To validate the pH sensitivity of P-Dex, the conjugate was incubated at three different pH levels in isotonic buffers. As can be seen in Figure It is of interest to see that both the free Dex and the P-Dex groups showed immediate relief of inflammation after administration. Because drug-polymer conjugates are not easily recognized by their receptors, their therapeutic activity depends mainly on the amount of free drug released from the conjugate. It usually takes longer for non-targeted polymer-drug conjugates, such as P-Dex, to be endocytosed and incorporated into the lysosomes where the acidic environment would act to release the Dex . The freA previous MRI study suggested that polymeric drug carriers such as HPMA copolymers might be retained in the arthritic joint for at least 1 to 2 days. They were gradually cleared through the urinary tract. However, this cannot explain the observed long-lasting (>9 days) therapeutic effect of P-Dex. One potential explanation is that during its residence in the synovial tissue, colloidal drug carriers  may be endocytosed by cells such as macrophages . SimilarThe ankle joints, compared with other joints, were most affected by the induced arthritis as determined in a previous MRI study and in the present study by histopathology. The advantages of using P-Dex compared with free Dex were also most evident in the ankle joints. The BMD was significantly greater, whereas the relative perimeter of cancellous bone surfaces undergoing active osteoclastic bone resorption was significantly less in the joints from animals treated with one injection of P-Dex compared with four injections of free Dex. In the bones of the ankle joint, the BMD of the P-Dex group was not significantly different from that in healthy controls, indicating that the P-Dex was more effective than free Dex in slowing the bone loss during the disease progression. These differences were not as apparent, however, in the lumbar vertebra and the femur, where both the P-Dex and Dex groups had a greater BMD than the untreated group, but the values were not significantly different from each other. As noted above, the joints in the femur (knee joint) and the lumbar vertebra  did not have the same level of inflammation observed in the ankle joints.Osteoclasts are the cells that resorb bone and are responsible for the bony destruction that accompanies the inflammatory process in RA. The daily treatments with Dex suppressed osteoclastic bone resorption in the ankle bones of the AIA rats compared with the untreated AIA rats, consistent with previous observation. However, osteoclastic bone resorption was further suppressed and was significantly less in the animals given P-Dex compared with free Dex treatment. The fact that the P-Dex was given 9 days prior to the end of the study and that the BMD was preserved in this region indicates that the P-Dex treatment had a sustained effect on limiting osteoclastic bone resorption. There was also less joint destruction in the P-Dex-treated animals compared with those treated with free Dex as confirmed by histological analyses. Further studies will be required to establish time- and dose-related effects of the polymer delivery system on bone and joint metabolism.In this study, the histology was used to substantiate the efficacy of the treatment with respect to preservation of articular bone structure. pDXA was also used to offer a sensitive measurement of ankle BMD change during the treatment. In future investigations, we will consider using additional imaging modalities such as microcomputed tomography to provide more useful information regarding the preservation of articular bone morphology with this new treatment strategy.The experiments presented here were not designed for rigorous evaluation of systemic side effects of GC therapy. It would be anticipated that, due to its unique design, this delivery system (which may be viewed as a macromolecular prodrug) would have less systemic toxicity. To activate the prodrug, two conditions must be met: (a) a pathological condition  that would allow local enrichment of the prodrug and (b) an acidic environment  that would trigger the release of active Dex from the polymer carrier. Because healthy tissues and organs would lack at least one of these conditions, it would be predicted that this therapy might also reduce the systemic side effects of GC therapy. Exploration of proper animal models is under way to confirm this hypothesis.A novel HPMA copolymer-Dex conjugate was designed, synthesized, and tested in an animal model of inflammatory arthritis. The hydrazone bond linking Dex to HPMA copolymer side chains was demonstrated to be cleavable under an acidic pH. When administered systemically, P-Dex proved to offer superior and longer-lasting anti-inflammatory effects compared with free Dex, consistent with its selective accumulation, retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. Greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. This initial study demonstrates that this novel copolymer system may offer therapeutic advantage for the delivery, retention, and release of drugs in the treatment of RA and related forms of inflammatory arthritis.tert-butoxycarbonyl; Boc-NHNH2 = carbazic acid tert-butyl ester; DCC = N,N'-dicyclohexylcarbodiimide; Dex = dexamethasone; EPR = enhanced permeability and retention; FPLC = fast protein liquid chromatography; GC = glucocorticoid; HPLC = high-performance liquid chromatography; HPMA = N-(2-hydroxypropyl)methacrylamide; LA = N, N-dioctadecyl-N', N'-bis(2-hydroxyethyl)propanediamine; MA-Gly-Gly-OH = N-methacryloylglycylglycine; MRI = magnetic resonance imaging; Mw = weight average molecular weight; NMR = nuclear magnetic resonance; P-Dex = N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugate; pDXA = peripheral dual x-ray absorptiometry; PVP = polyvinylpyrrolidone; RA = rheumatoid arthritis; SEC = size exclusion chromatography; SF = synovial fluid; TNBS = 2,4,6-trinitrobenzenesulfonic acid.AIA = adjuvant-induced arthritis; BMD = bone mineral density; Boc = DW and SCM are inventors named in a patent application partially related to the content of this manuscript. University of Utah holds the full rights to this patent application. DW and SCM have not received any financial benefit related to this patent application. All other authors declare that they have no competing interests.in vitro evaluation of P-Dex. BA participated in the histology study. SXW participated in the synthesis and in vitro evaluation of P-Dex. SRG participated in the design of the treatment study, data evaluation, and the preparation of the manuscript. All authors read and approved the final manuscript.DW conceptualized the treatment strategy, designed and synthesized the P-Dex conjugate, and prepared the manuscript. SCM participated in the design of the treatment study, carried out the histology study and data analysis, and participated in the preparation of the manuscript. X-ML participated in the synthesis, characterization, and