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Background: The U.S. Food and Drug Administration has requested post-market surveillance data, including data on metal ion levels, regarding metal-on-metal total hip arthroplasty. We performed a prospective, randomized study of metal ion levels in erythrocytes, serum, and whole blood at five years after 28 and 36-mm metal-on-metal and 28-mm metal-on-polyethylene total hip arthroplasty., Methods: One hundred and five enrolled patients were randomized equally to the three bearing surface options and were blinded with regard to their treatment group. Metal ion measurements and clinical evaluations were performed at regular intervals., Results: Cobalt and chromium ion levels in all blood sample types at the five-year time point were significantly lower in the metal-on-polyethylene group than in each of the two metal-on-metal groups (p < 0.001) with the exception of chromium in erythrocytes (p = 0.194). Cobalt in serum (p = 0.029) and erythrocytes (p = 0.002) showed significant increases from two to five years in the 36-mm metal-on-metal group; similar increases were not seen in the 28-mm metal-on-metal group. At five years, five patients in the 36-mm metal-on-metal group and none in the 28-mm metal-on-metal group had cobalt or chromium levels of >7 ppb. Correlations among levels in serum, erythrocyte, and whole blood were stronger for cobalt than for chromium. One patient in the 36-mm metal-on-metal group underwent revision because of an adverse local tissue reaction., Conclusions: The 36-mm metal-on-metal bearing underperformed the 28-mm metal-on-metal bearing with respect to metal ion levels. The authors are closely following all patients treated with metal-on-metal total hip arthroplasty.

This was a retrieval analysis of 83 PS inserts to assess the effect of limb alignment, implant position and joint line position on the pattern of wear in posterior stabilized (PS) tibial inserts. The total damage score was significantly higher in knees with postoperative varus alignment more than 3° (P = 0.03). The total damage score to the post was significantly more in knees with joint line elevation more than 5 mm (9.7 ± 3.9, compared to 6.5 ± 3.7 in knees with less joint line elevation) (P = 0.05). Limb malalignment and joint line elevation resulted in more damage in PS inserts. An external rotation subluxation damage pattern was found in joint line elevation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Numerous steps are required to successfully complete a revision total knee arthroplasty. A review of the technical details of each step will be helpful to arthroplasty surgeons, along with a discussion of reoperative planning, complex surgical exposure techniques, component removal, and the choice of prosthetic components. A review of common difficult issues, including bone loss, ligamentous instability, and management of the extensor mechanism, will also aid in achieving a successful revision total knee arthroplasty.

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The purpose of this study was to determine the fate of the remaining hip(s) and knee(s) following an initial total hip or knee arthroplasty in 5352 patients with idiopathic osteoarthritis who were followed for a minimum ten years (mean 17.8 ± 5.7 years). Following an initial primary TKA, 46.0% of patients had a contralateral TKA, 2.3% had an ipsilateral THA and 1.3% had a contralateral THA. Following an initial primary THA, 30.5% of patients had a contralateral THA, 6.8% had an ipsilateral TKA and 2.9% had a contralateral TKA. Cox regression analysis demonstrated that BMI was the sole risk factor for a second THA, but both age less than sixty years and a higher BMI were significant factors for patients requiring an additional primary TKA., (Copyright © 2013. Published by Elsevier Inc.)

Total hip replacement (THR) is a very common procedure undertaken in up to 285 000 Americans each year. Patient satisfaction with THR is very high, with improvements in general health, quality of life, and function while at the same time very cost effective. Although the majority of patients have a high degree of satisfaction with their THR, 27% experience some discomfort, and up to 6% experience severe chronic pain. Although it can be difficult to diagnose the cause of the pain in these patients, this clinical issue should be approached systematically and thoroughly. A detailed history and clinical examination can often provide the correct diagnosis and guide the appropriate selection of investigations, which will then serve to confirm the clinical diagnosis made.

Here we present computational machinery to efficiently and accurately identify transposable element (TE) insertions in 146 next-generation sequenced inbred strains of Drosophila melanogaster. The panel of lines we use in our study is composed of strains from a pair of genetic mapping resources: the Drosophila Genetic Reference Panel (DGRP) and the Drosophila Synthetic Population Resource (DSPR). We identified 23,087 TE insertions in these lines, of which 83.3% are found in only one line. There are marked differences in the distribution of elements over the genome, with TEs found at higher densities on the X chromosome, and in regions of low recombination. We also identified many more TEs per base pair of intronic sequence and fewer TEs per base pair of exonic sequence than expected if TEs are located at random locations in the euchromatic genome. There was substantial variation in TE load across genes. For example, the paralogs derailed and derailed-2 show a significant difference in the number of TE insertions, potentially reflecting differences in the selection acting on these loci. When considering TE families, we find a very weak effect of gene family size on TE insertions per gene, indicating that as gene family size increases the number of TE insertions in a given gene within that family also increases. TEs are known to be associated with certain phenotypes, and our data will allow investigators using the DGRP and DSPR to assess the functional role of TE insertions in complex trait variation more generally. Notably, because most TEs are very rare and often private to a single line, causative TEs resulting in phenotypic differences among individuals may typically fail to replicate across mapping panels since individual elements are unlikely to segregate in both panels. Our data suggest that "burden tests" that test for the effect of TEs as a class may be more fruitful.

A total of 6275 consecutive TKA patients were divided into three groups based on their age: <55, 55-70 and >70 years. There was a statistically significant difference in the change in WOMAC score (32 vs 31 vs 26, P<0.001) and Knee Society Score (78.9 vs 76.0 vs 69.0, P<0.001) favoring the younger populations. However, the revision rate was higher in the younger patients with a Kaplan-Meier survivorship at 5 years of 95.5%, 97.2% and 98.1% and at 10 years of 92.2%, 95.9% and 97.6%. Infection was the most frequent cause for failure in all groups although aseptic loosening and instability accounted for the increased revision rate in the younger patients. Younger patients may experience slightly better clinical outcomes following TKA but lower survivorship, when compared to older patient populations., (© 2013 Elsevier Inc. All rights reserved.)

A soft-tissue defect over an infected total knee replacement (TKR) presents a difficult technical problem that can be treated with a gastrocnemius flap, which is rotated over the defect during the first-stage of a revision procedure. This facilitates wound healing and the safe introduction of a prosthesis at the second stage. We describe the outcome at a mean follow-up of 4.5 years (1 to 10) in 24 patients with an infected TKR who underwent this procedure. A total of 22 (92%) eventually obtained a satisfactory result. The mean Knee Society score improved from 53 pre-operatively to 103 at the latest follow-up (p < 0.001). The mean Western Ontario and McMaster Universities osteoarthritis index and Short-Form 12 score also improved significantly (p < 0.001). This form of treatment can be used reliably and safely to treat many of these complex cases where control of infection, retention of the components and acceptable functional recovery are the primary goals.

The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors.

To perform wear measurements on retrieved joint replacement implants, a reference geometry of the implant's original state is required. Since implants are rarely individually scanned before implantation, a different, new implant of the same kind and size is frequently used. However, due to manufacturing variability, errors may be introduced into these measurements, as the dimensions between the retrieved and reference components may not be exactly the same. The hypothesis of this study was that new polyethylene tibial inserts from different manufacturing lots would demonstrate greater variability than those from the same lot. In total, 12 new tibial inserts of the same model and size were obtained, 5 from the same lot and the remainder from different lots. The geometry of each tibial insert was obtained using microcomputed tomography. Measurements of tibial insert volume, thickness, and three-dimensional surface deviations were obtained and compared between tibial inserts from the same and different manufacturing lots. Greater variability was found for the tibial inserts from different manufacturing lots for all types of measurements, including a fourfold difference in volume variability (p < 0.001) and a maximum of 0.21 mm difference in thickness (p < 0.001). Investigators should be aware of this potential confounding error and take steps to minimize it, such as by averaging together the geometries of multiple new components from different manufacturing lots for use as the reference geometry.

Objective: Little is known about the relationships among pain, function, psychological variables like perceived helplessness and emotional health, and patient satisfaction in people with revision knee replacement surgery. We hypothesized that pain and function would have a direct association with satisfaction as well as an indirect association through patient perceptions of helplessness and emotional health., Design: This longitudinal study included 145 participants undergoing revision knee replacement surgery. Demographic data and expectation of benefit from surgery were recorded prior to surgery. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Arthritis Helplessness Scale (AHS) and the Mental Component Scale (MCS) of the SF-36 (emotional health) were collected prior to and 2 years post-surgery. Satisfaction was recorded 2 years post-surgery. Regression analyses were conducted to test for mediation effects of helplessness and MCS., Results: Participants were on average 69 years old and 54% were women. Participants were satisfied with the results of the surgery (mean ± standard deviation (SD) = 70.42 ± 31.46). Less pain and functional disability were associated with increased patient satisfaction and, the effect of pain or function was also mediated through helplessness whereby more pain and disability were associated with perceptions of helplessness and helplessness was associated with lower satisfaction. MCS did not mediate the relationship of pain and function with satisfaction., Conclusion: Helplessness plays an important role in understanding patient satisfaction. Interventions aimed at improving patient outcome should target not only pain and function but also should address strategies to support people in managing following knee revision surgery to maximize satisfaction with outcome., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to examine the complications and outcomes of total hip replacement (THR) in super-obese patients (body mass index (BMI) > 50 kg/m(2)) compared with class I obese (BMI 30 to 34.9 kg/m(2)) and normal-weight patients (BMI 18.5 to 24.9 kg/m(2)), as defined by the World Health Organization. A total of 39 THRs were performed in 30 super-obese patients with a mean age of 53 years (31 to 72), who were followed for a mean of 4.2 years (2.0 to 11.7). This group was matched with two cohorts of normal-weight and class I obese patients, each comprising 39 THRs in 39 patients. Statistical analysis was performed to determine differences among these groups with respect to complications and satisfaction based on the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, the Harris hip score (HHS) and the Short-Form (SF)-12 questionnaire. Super-obese patients experienced significantly longer hospital stays and higher rates of major complications and readmissions than normal-weight and class I obese patients. Although super-obese patients demonstrated reduced pre-operative and post-operative satisfaction scores, there was no significant difference in improvement, or change in the score, with respect to HHS or the WOMAC osteoarthritis index. Super-obese patients obtain similar satisfaction outcomes as class I obese and normal-weight patients with respect to improvement in their scores. However, they experience a significant increase in length of hospital stay and major complication and readmission rates.

Background: Directed cell migration is a fundamental process in normal development and in tumor metastasis. In C. elegans the MAB-5/Hox transcription factor is a determinant of posterior migration of the Q neuroblast descendants. In this work, mab-5 transcriptional targets that control Q descendant migration are identified by comparing RNA-seq profiles in wild type and mab-5 mutant backgrounds., Results: Transcriptome profiling is a widely-used and potent tool to identify genes involved in developmental and pathological processes, and is most informative when RNA can be isolated from individual cell or tissue types. Cell-specific RNA samples can be difficult to obtain from invertebrate model organisms such as Drosophila and C. elegans. Here we test the utility of combining a whole organism RNA-seq approach with mab-5 loss and gain-of-function mutants and functional validation using RNAi to identify genes regulated by MAB-5 to control Q descendant migration. We identified 22 genes whose expression was controlled by mab-5 and that controlled Q descendant migration. Genes regulated by mab-5 were enriched for secreted and transmembrane molecules involved in basement membrane interaction and modification, and some affected Q descendant migration., Conclusions: Our results indicate that a whole-organism RNA-seq approach, when combined with mutant analysis and functional validation, can be a powerful method to identify genes involved in a specific developmental process, in this case Q descendant posterior migration. These genes could act either autonomously in the Q cells, or non-autonomously in other cells that express MAB-5. The identities of the genes regulated by MAB-5 indicate that MAB-5 acts by modifying interactions with the basement membrane, resulting in posterior versus anterior migration.

Background: High flexion (HF) implants were introduced to increase ROM and patient satisfaction, but design changes to the implant potentially have deleterious effects on polyethylene wear. It is unclear whether the HF implants affect wear., Questions/purposes: We therefore examined whether the design changes between HF and posterior-stabilized (PS) tibial inserts would affect overall damage or damage on their articular surface, backside, and tibial post and whether flexion angle achieved related to damage., Methods: We matched 20 retrieved HF inserts to 20 retrieved PS inserts from the same implant system on the basis of duration of implantation, body mass index, and age. Inserts were divided into 16 zones and a microscopic analysis of surface damage was carried out. Five inserts were scanned using micro-CT to further quantify instances of severe post notching. We determined overall damage with a scoring system., Results: We found greater backside and post damage in the HF group but no difference in the articular surface or overall damage scores. Backside and post damage scores correlated to flexion angle in the HF group. There was no flexion/damage correlation in the PS group. Notch depths around the post in both groups ranged from 0.6 to 1.9 mm., Conclusions: HF inserts are more susceptible to post damage, possibly as a result of higher contact stresses from greater flexion. The increased backside damage was unexpected because the two groups have the same tibial component, locking mechanism, and sterilization method., Clinical Relevance: The introduction of a highly crosslinked HF insert will require close scrutiny as a result of the potential for post damage demonstrated in this series.

Obesity is an epidemic across both the developed and developing nations that is possibly the most important current public health factor affecting the morbidity and mortality of the global population. Obese patients have the potential to pose several challenges for arthroplasty surgeons from the standpoint of the influence obesity has on osteoarthritic symptoms, their peri-operative medical management, the increased intra-operative technical demands on the surgeon, the intra- and post-operative complications, the long term outcomes of total hip and knee arthroplasty. Also, there is no consensus on the role the arthroplasty surgeon should have in facilitating weight loss for these patients, nor whether obesity should affect the access to arthroplasty procedures.

This conversation represents an attempt by several arthroplasty surgeons to critique several abstracts presented over the last year as well as to use them as a jumping off point for trying to figure out where they fit in into our current understanding of multiple issues in modern hip and knee arthroplasty.

Previous literature suggested highly cross-linked acetabular liners demonstrated notching patterns that may be a point of crack origin and rim failure. We examined (1) whether notching patterns and rim cracks existed and demonstrated similar morphological properties in retrieved highly cross-linked and non-cross-linked liners and (2) whether the dimensions of these notches correlated with their duration of implantation. We retrieved a series of 14 identical liners out to an average of 2.03 years. Liners were microscopically examined and then scanned using microcomputed tomography. All liners demonstrated identical notching patterns. Microcomputed tomographic scans demonstrated no signs of crack initiation or rim failure but were able to accurately quantify the notch dimensions. The notching patterns were likely caused by liner-cup micromotion and are better characterized as creep deformation because they did not progress markedly over longer durations of implantation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Periprosthetic joint infection has been the leading cause of failure following TKA surgery. The gold standard for infection control has been a two-staged revision TKA. There have been few reports on mid- to long-term survivorship, functional outcomes, and fate of patients with a failed two-stage revision TKA., Questions/purposes: Therefore, we determined (1) the mid-term survivorship of two-stage revision TKA, (2) the function of patients in whom infection was controlled, and (3) the outcome of patients with a failed two-stage revision due to recurrent infection., Methods: We retrospectively reviewed 239 patients who underwent 253 two-stage revision TKAs for periprosthetic infection. There were 239 patients (253 knees), 104 men and 135 women, with a mean age of 70 ± 10 years at the time of two-stage revision and a mean BMI of 31.53 ± 6.74 kg/m2. During followup, we obtained WOMAC and The Knee Society Clinical Rating Scores and radiographs. The minimum followup was 1 year (median, 4 years; range, 1-17 years)., Results: Thirty-three patients experienced a failed two-staged TKA. Sixteen patients experienced failure due to recurrent sepsis. There were 17 failures for aseptic causes., Conclusion: The overall infection-free survivorship for two-stage revision TKA was 85% at 5 years and 78% at 10 years., Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Purpose: The ability to accurately measure joint kinematics is an important tool in studying both normal joint function and pathologies associated with injury and disease. The purpose of this study is to evaluate the efficacy, accuracy, precision, and clinical safety of measuring 3D joint motion using a conventional flat-panel radiography system prior to its application in an in vivo study., Methods: An automated, image-based tracking algorithm was implemented to measure the three-dimensional pose of a sparse object from a two-dimensional radiographic projection. The algorithm was tested to determine its efficiency and failure rate, defined as the number of image frames where automated tracking failed, or required user intervention. The accuracy and precision of measuring three-dimensional motion were assessed using a robotic controlled, tibiofemoral knee phantom programmed to mimic a subject with a total knee replacement performing a stair ascent activity. Accuracy was assessed by comparing the measurements of the single-plane radiographic tracking technique to those of an optical tracking system, and quantified by the measurement discrepancy between the two systems using the Bland-Altman technique. Precision was assessed through a series of repeated measurements of the tibiofemoral kinematics, and was quantified using the across-trial deviations of the repeated kinematic measurements. The safety of the imaging procedure was assessed by measuring the effective dose of ionizing radiation associated with the x-ray exposures, and analyzing its relative risk to a human subject., Results: The automated tracking algorithm displayed a failure rate of 2% and achieved an average computational throughput of 8 image frames/s. Mean differences between the radiographic and optical measurements for translations and rotations were less than 0.08 mm and 0.07° in-plane, and 0.24 mm and 0.6° out-of-plane. The repeatability of kinematics measurements performed using the radiographic tracking technique was better than ±0.09 mm and 0.12° in-plane, and ±0.70 mm and ±0.07° out-of-plane. The effective dose associated with the imaging protocol used was 15 μSv for 10 s of radiographic cine acquisition., Conclusions: This study demonstrates the ability to accurately measure knee-joint kinematics using a single-plane radiographic measurement technique. The measurement technique can be easily implemented at most clinical centers equipped with a modern-day radiographic x-ray system. The dose of ionizing radiation associated with the image acquisition represents a minimal risk to any subjects undergoing the examination.

The herpes simplex virus 1 (HSV-1) strain McKrae is highly virulent compared to other wild-type strains of HSV-1. To help us better understand the genetic determinants that lead to differences in the pathogenicity of McKrae and other HSV-1 strains, we sequenced its genome. Comparing the sequence of McKrae's genome to that of strain 17 revealed that the genomes differ by at least 752 single nucleotide polymorphisms (SNPs) and 86 insertion/deletion events (indels). Although the majority of these polymorphisms reside in noncoding regions, 241 SNPs and 10 indels alter the protein-coding sequences of 58 open reading frames. Some of these variations are expected to contribute to the pathogenic phenotype of McKrae.

Adverse biological reactions causing failures of metal-on-metal (MoM) hip arthroplasty can be local or systemic. Both dose-dependent cytotoxicity of wear debris leading to subsequent necrosis of periprosthetic soft tissues and adaptive immunity may play an important role in pathogenesis in susceptible patients. There appears to be a spectrum of clinical presentations of adverse soft tissue reactions, reflecting a complex interplay of implant, surgical, and patient factors. A systematic treatment approach is helpful in optimizing evidence-based management of MoM patients. Although specialized tests such as metal ion levels are a useful diagnostic tool for evaluating MoM hip arthroplasty patients, overreliance on any single investigative tool in clinical decision-making process should be avoided. Future research focusing on diagnostic tools for detecting adverse periprosthetic soft tissue necrosis as well as optimization of MoM bearings and modular connections to further diminish wear and corrosion is warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

2-Deoxy-C-nucleosides are a subcategory of C-nucleosides that has not been explored extensively, largely because the synthesis is less facile. Flexible synthetic procedures giving access to 2-deoxy-C-nucleosides are therefore of interest. To exemplify the versatility and highlight the limitations of a synthetic route recently developed to that effect, the first synthesis of 2-deoxy benzamide riboside is reported. Biological properties of this novel C-nucleoside are also discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Symbiotic nitrogen recycling enables animals to thrive on nitrogen-poor diets and environments. It traditionally refers to the utilization of animal waste nitrogen by symbiotic micro-organisms to synthesize essential amino acids (EAAs), which are translocated back to the animal host. We applied metabolic modelling and complementary metabolite profiling to investigate nitrogen recycling in the symbiosis between the pea aphid and the intracellular bacterium Buchnera, which synthesizes EAAs. The results differ from traditional notions of nitrogen recycling in two important respects. First, aphid waste ammonia is recycled predominantly by the host cell (bacteriocyte) and not Buchnera. Host cell recycling is mediated by shared biosynthetic pathways for four EAAs, in which aphid transaminases incorporate ammonia-derived nitrogen into carbon skeletons synthesized by Buchnera to generate EAAs. Second, the ammonia substrate for nitrogen recycling is derived from bacteriocyte metabolism, such that the symbiosis is not a sink for nitrogenous waste from other aphid organs. Host cell-mediated nitrogen recycling may be general among insect symbioses with shared EAA biosynthetic pathways generated by the loss of symbiont genes mediating terminal reactions in EAA synthesis.

The purpose of this prospective study was to evaluate the minimum 10-year outcomes and survivorship of the Reflection shell with a polished inner surface and an improved locking mechanism. Three hundred sixty-three total hip replacements with a mean follow-up of 11.6 years (range, 10.0-15.1) were evaluated. The mean Harris Hip and WOMAC scores at last follow-up were 87 and 77, respectively. Four cups were revised: 2 for infection and 2 for aseptic loosening. Thirteen cases underwent liner exchange for wear. Radiographic review of remaining cups identified 8.8% with identifiable peri-acetabular osteolysis and no cases of loosening. The overall 10- and 15-year Kaplan-Meier survivorship was 94% and 90% for the total hip arthroplasty system while the survivorship of the shell remained 99.4% at 15 years., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Retrieved knee implants were examined to investigate the influence of patient and implant related factors on backside damage. Fifty-two implants of three different models were examined that all had cemented tibial trays without screw holes. A semi-quantitative grading system supplied backside damage scores (BDS) for each polyethylene (PE) tibial insert. Evidence was obtained to support the use of a constraining partial-peripheral locking mechanism and polished tibial tray surface (particularly for male patients) to reduce backside damage. Overall, male patients in the present study were associated with higher body mass and higher BDS compared with female patients. Furthermore, PE inserts sterilized by gamma-in-air had higher BDS than PE inserts sterilized in inert environments (gas-plasma or ethylene-oxide). Also, the proximal surfaces of tibial trays that had been grit-blasted showed embedded particles that may have increased backside damage. While none of these overall findings was unexpected, the present study provided detailed supporting analysis based on data from clinical retrievals, which may further support the use of a polished tibial tray combined with partial-peripheral locking mechanism to reduce BDS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Genetic dissection of complex, polygenic trait variation is a key goal of medical and evolutionary genetics. Attempts to identify genetic variants underlying complex traits have been plagued by low mapping resolution in traditional linkage studies, and an inability to identify variants that cumulatively explain the bulk of standing genetic variation in genome-wide association studies (GWAS). Thus, much of the heritability remains unexplained for most complex traits. Here we describe a novel, freely available resource for the Drosophila community consisting of two sets of recombinant inbred lines (RILs), each derived from an advanced generation cross between a different set of eight highly inbred, completely resequenced founders. The Drosophila Synthetic Population Resource (DSPR) has been designed to combine the high mapping resolution offered by multiple generations of recombination, with the high statistical power afforded by a linkage-based design. Here, we detail the properties of the mapping panel of >1600 genotyped RILs, and provide an empirical demonstration of the utility of the approach by genetically dissecting alcohol dehydrogenase (ADH) enzyme activity. We confirm that a large fraction of the variation in this classic quantitative trait is due to allelic variation at the Adh locus, and additionally identify several previously unknown modest-effect trans-acting QTL (quantitative trait loci). Using a unique property of multiparental linkage mapping designs, for each QTL we highlight a relatively small set of candidate causative variants for follow-up work. The DSPR represents an important step toward the ultimate goal of a complete understanding of the genetics of complex traits in the Drosophila model system.

The Drosophila Synthetic Population Resource (DSPR) is a newly developed multifounder advanced intercross panel consisting of >1600 recombinant inbred lines (RILs) designed for the genetic dissection of complex traits. Here, we describe the inference of the underlying mosaic founder structure for the full set of RILs from a dense set of semicodominant restriction-site-associated DNA (RAD) markers and use simulations to explore how variation in marker density and sequencing coverage affects inference. For a given sequencing effort, marker density is more important than sequence coverage per marker in terms of the amount of genetic information we can infer. We also assessed the power of the DSPR by assigning genotypes at a hidden QTL to each RIL on the basis of the inferred founder state and simulating phenotypes for different experimental designs, different genetic architectures, different sample sizes, and QTL of varying effect sizes. We found the DSPR has both high power (e.g., 84% power to detect a 5% QTL) and high mapping resolution (e.g., ∼1.5 cM for a 5% QTL).

Introduction: Malaria causes a huge humanitarian and economic burden. Parasite resistance to established and recently launched anti-malarials is a major issue which, when combined with a malaria eradication agenda, means there is a considerable need for new small molecule anti-malarials. Catalyzed by a recent surge in funding for malaria drug discovery and development, there is an increasing number of compounds in the malaria pipeline., Areas Covered: This review covers patents published in English between January 2010 and June 2011, which feature small molecules for the treatment of malaria. Approximately 50 series of compounds are described. Patents covering clinical applications, diagnosis kits or vaccines are not included, nor patents where the principle disease focus is not malaria., Expert Opinion: There is considerable activity in the field of small molecules for malaria which is likely to continue. The ultimate goal is to identify novel drugs to support the malaria eradication agenda. This requires safe and efficacious compounds, from novel chemotypes, which rapidly kill parasites and which are readily synthesized from cheap starting materials. In addition, compounds which have activity in the liver stages or in transmission blocking may be prioritized for development over analogs related to established anti-malarial series targeting the asexual blood stages of the parasite.

Calf serum lubricants consisting of various polypeptide constituent fractions are routinely used in knee wear simulators as part of the standardized test protocol. Three calf sera (bovine, new-born and alpha) were diluted as per the recommendation of ISO 14243-3 and used in displacement-controlled knee wear simulators to investigate their effects on polyethylene wear. Biochemical analyses included measuring total polypeptide degradation, electrophoretic profiles and low-molecular weight polypeptide concentrations to elucidate their involvement in the wear process. The effects of the various calf sera constituent fractions on microbial growth were also explored. The polyethylene wear rates and the results from the biochemical analyses for the three calf serum lubricants were all found to be statistically significantly different from each other. The lubricant derived from the alpha-calf serum was closest in constituent fractions to human synovial fluid. It also showed the lowest polyethylene wear rate (14.38 +/- 0.85 mm3/million cycles) and the lowest amount of polypeptide degradation (7.77 +/- 3.87%). Furthermore, the alpha-calf serum lubricant was associated with the least amount of change in the electrophoretic profile, the least change in low-molecular weight polypeptide concentration, and the lowest microbial growth in the presence of sodium azide (a microbial inhibitor conventionally used in implant wear testing). Replacing sodium azide with a broad spectrum antibiotic-antimycotic eradicated the microbial growth. Some speculation was entertained regarding the effect of alpha-calf serum on colloid-mediated boundary lubrication. Based on the results, it was recommended that ISO 14243-3 be modified to include guidelines on calf serum constituent fractions that would favour using alpha-calf serum in order to improve the fidelity of the simulation in knee implant wear testing.

Herpes simplex virus type 1 (HSV-1) strain KOS has been extensively used in many studies to examine HSV-1 replication, gene expression, and pathogenesis. Notably, strain KOS is known to be less pathogenic than the first sequenced genome of HSV-1, strain 17. To understand the genotypic differences between KOS and other phenotypically distinct strains of HSV-1, we sequenced the viral genome of strain KOS. When comparing strain KOS to strain 17, there are at least 1,024 small nucleotide polymorphisms (SNPs) and 172 insertions/deletions (indels). The polymorphisms observed in the KOS genome will likely provide insights into the genes, their protein products, and the cis elements that regulate the biology of this HSV-1 strain.

The treatment goals of Vancouver type B2 periprosthetic femoral fractures in elderly patients with a limited life expectancy are early weight bearing without compromising the fracture healing. Thirty-one patients with a mean age of 82 years were treated with a long cemented stem with additional allograft or plate fixation, followed by immediate full weight bearing. Seven major complications occurred within the first 3 months postoperatively. Forty-three percent of patients had died within the first year with their implant in place. Sixteen patients had survived more than 1 year. None of the implants had to be revised at a mean follow-up of 46 months. The results of this series suggest that this technique can provide acceptable results and offers the advantages of reduced cost and early weight bearing., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Pain management is a major concern for patients contemplating total knee replacement surgery and is one of the leading causes of dissatisfaction after knee replacement. Substantial progress has been made over the past several years in improving pain control after total knee replacement using multimodal pain control, preemptive analgesia, and periarticular injections.

Purpose: The C57BL/6ByJ and BALB/cByJ inbred strains of mice are, respectively, susceptible and resistant to oxygen-induced retinopathy (OIR). The purpose of this work was to investigate the genetic control of the retinal avascular area in mouse OIR using a mapping cross., Methods: The central retinal avascular area was measured on postnatal day 16 (P16) in C57BL/6ByJ, BALB/cByJ, 101 (C57BL/6ByJ x BALB/cByJ)F₂, and 116 (BALB/cByJ x C57BL/6ByJ)F₂ mice that had been subjected to the OIR protocol. A genome-wide scan was performed of selected albino and non-albino mice to determine quantitative trait loci associated with weight and avascular area., Results: C57BL/6ByJ mice had significantly larger avascular areas than BALB/cByJ ones. Albino mice of the F₂ generation had smaller avascular areas than the non-albino mice. Genotyping was performed at 856 informative single nucleotide polymorphisms approximately evenly distributed across the genome from each of 85 selected F₂ mice. Weight, sex, and the paternal grandmother were found to act as additive covariates associated with the avascular area on P16; mapping analyses that used a model incorporating these covariates found a quantitative trait locus on chromosome 7 related to avascular area. Mapping analyses that used a model that did not incorporate covariates found a quantitative trait locus on chromosome 9 related to avascular area. A quantitative trait locus for bodyweight on P16 was mapped to chromosome 5., Conclusions: The retinal avascular area in the mouse OIR model is under genetic control. Revascularization in OIR is related to the weight, strain of paternal grandmother, sex, and albinism. Our data support the existence of a quantitative trait locus on chromosome 5 that influences weight after exposure to hyperoxia, as well as quantitative trait loci on chromosomes 7 and 9 that modify susceptibility to OIR.

Medial opening wedge high tibial osteotomy is a popular treatment option for medial compartment osteoarthritis of the knee. One of the proposed advantages is easier conversion to a total knee replacement compared to lateral closing wedge osteotomies, although there are few studies to support this. We reviewed the technical considerations in 36 knees in which conversion of a medial opening wedge osteotomy to total knee arthroplasty was performed, and contrasted these to previously reported studies of knee arthroplasty after closing lateral wedge or dome osteotomies. The clinical results in 33 patients (34 knees) with minimum 2 year follow-up (mean 3.4 years, range 2 to 8 years) were compared to a control group of 1315 knee arthroplasties performed without prior tibial osteotomy. Total knee arthroplasty after a medial opening wedge osteotomy is relatively straightforward, although we encountered patella baja in 27% of cases, and an increased posterior tibial slope of over 15° in 21%. There was a lower Knee Society score and a lower pain score (more pain) in the study group compared to the control group. While technically straightforward in most cases, knee arthroplasty following medial opening wedge osteotomy in this study group yielded inferior clinical results compared to a group of knee arthroplasties performed without prior tibial osteotomy., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The purpose of this prospective study was to evaluate the outcomes and survivorship of a trispiked, sintered bead-coated titanium shell with a polished inner surface, no screw holes, and an improved locking mechanism. A total of 506 total hip arthroplasties with a minimum 5-year follow-up were available for review at a mean of 7 years (range, 5-11 years). Three sockets (0.6%) were revised for reasons other than aseptic loosening, and 14 (2.8%) polyethylene liners were exchanged. There was no difference in revision rate between non-cross-linked and highly cross-linked liners (P = .4). There were no cases of radiographic loosening. Retroacetabular osteolysis was identified in 2%. The overall 5-year and 10-year Kaplan-Meier survivorship was 97.5% and 97.4%, respectively, whereas survivorship of the shell was 99.8%., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The observation that male genitalia diverge more rapidly than other morphological traits during evolution is taxonomically widespread and likely due to some form of sexual selection. One way to elucidate the evolutionary forces acting on these traits is to detail the genetic architecture of variation both within and between species, a program of research that is considerably more tractable in a model system. Drosophila melanogaster and its sibling species, D. simulans, D. mauritiana, and D. sechellia, are morphologically distinguishable only by the shape of the posterior lobe, a male-specific elaboration of the genital arch. We extend earlier studies identifying quantitative trait loci (QTL) responsible for lobe divergence across species and report the first genetic dissection of lobe shape variation within a species. Using an advanced intercross mapping design, we identify three autosomal QTL contributing to the difference in lobe shape between a pair of D. melanogaster inbred lines. The QTL each contribute 4.6-10.7% to shape variation, and two show a significant epistatic interaction. Interestingly, these intraspecific QTL map to the same locations as interspecific lobe QTL, implying some shared genetic control of the trait within and between species. As a first step toward a mechanistic understanding of natural lobe shape variation, we find an association between our QTL data and a set of genes that show sex-biased expression in the developing genital imaginal disc (the precursor of the adult genitalia). These genes are good candidates to harbor naturally segregating polymorphisms contributing to posterior lobe shape.

The literature supports the routine use of a tourniquet during total knee arthroplasty (TKA). With tourniquet use, there is decreased intraoperative blood loss with subsequent improved visibility and a bloodless surgical field. This facilitates efficiency with the potential for decreased operating time. Increased operating time has been associated with an increase in the incidence of infection after TKA. Opponents of routine tourniquet use cite rare or theoretical concerns. Multiple authors have concluded that the incidence of deep vein thrombosis is not related to using a tourniquet. The rare events of muscle dysfunction or nerve injury are transient. Peripheral vascular disease, in which patients have no palpable distal pulses, should be considered a possible contraindication to the use of a tourniquet during TKA. If tourniquet time and pressure are respected during TKA, we believe the benefits outweigh the perceived and theoretical concerns., (Copyright 2011, SLACK Incorporated.)

Total hip arthroplasty (THA) is an effective intervention for the treatment of arthrosis with excellent survivorship. Nonetheless, dislocation and osteolysis remain significant complications. A dual-mobility acetabular component has been advocated to improve stability and wear. Stability is imparted by increasing the effective femoral head size, which allows a larger range of motion (ROM) before neck-socket impingement occurs. Increasing ROM, however, introduces an additional problem of bony impingement of the trochanter against the pelvis. Consequently, there is little improvement in ROM for heads >36 to 40 mm. A 0.4% incidence of instability at the larger articulation has been reported in primary THA using the dual-mobility liner, which is equivalent to reports for conventional THA. The dual-mobility liner has introduced the unique complication of intraprosthetic dislocation, where the femoral head dissociates at the smaller articulation as a result of polyethylene wear. An incidence of intraprosthetic dislocation of 3.6% has been reported, which far exceeds dislocation of conventional arthroplasty. The dual-mobility liner is a monoblock acetabular component without the capacity for augmented bony fixation. Inability to achieve primary stability has been reported as high as 18% and therefore its usefulness in revision THA is questionable. Proponents of the dual-mobility liner cite improved wear characteristics over conventional THA; however, few studies support this proposition. Retrieval studies have reported that the dual-mobility liner does not avoid wear or osteolysis. Theoretically, it is inconceivable that wear would be diminished with an additional articulation with a huge surface area, where the differential hardness has been reversed to a soft-on-hard bearing., (Copyright 2011, SLACK Incorporated.)

Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparum in vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.

A six-station displacement-controlled knee simulator with separately controlled left (L) and right (R) banks (three wear implants per bank) was commissioned for a total of three million cycles (Mc) following ISO 14243-3. A commissioning protocol was applied to compare the polyethylene wear among the six wear stations by exchanging the implants between wear stations. Changes in lubricant characteristics during wear testing, such as polypeptide degradation, low-molecular-weight polypeptide concentration, and possible microbial contamination were also assessed. The total mean wear rate for the implants was 23.60 +/- 1.96 mm3/Mc and this was of a similar magnitude to the mean wear rate for the same implant tested under similar conditions by DePuy Orthopaedics Inc. (Warsaw, IN). Repeated run-in wear was observed when the implants were exchanged between wear stations, suggesting that implants should be subjected to the same wear station throughout the duration of a wear test. The total polypeptide degradation for the implants measured 30.53 +/- 3.96 percent; the low-molecular-weight polypeptide concentration of the "used" lubricant for implants (0.131 +/- 0.012 g/L) was 3.3 times greater than the mean polypeptide concentration of the fresh, "unused" lubricant (0.039 +/- 0.004 g/L). This increase in low-molecular weight polypeptide concentration was suggested to be attributable to protein shear in the articulation of the implant, the circulation of the lubricant, and some proteolytic activity. Sodium azide was ineffective in maintaining a sterile environment for wear testing as a single, highly motile Gram-negative micro-organism was identified in the lubricant from wear tests.

An efficient chemical synthesis of 5a-carba-α-D-mannose and its enzymatic elaboration to 5a-carba-α-D-mannose-6-phosphate, using yeast hexokinase, is described., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The pervasive influence of resident microorganisms on the phenotype of their hosts is exemplified by the intracellular bacterium Buchnera aphidicola, which provides its aphid partner with essential amino acids (EAAs). We investigated variation in the dietary requirement for EAAs among four pea aphid (Acyrthosiphon pisum) clones. Buchnera-derived nitrogen contributed to the synthesis of all EAAs for which aphid clones required a dietary supply, and to none of the EAAs for which all four clones had no dietary requirement, suggesting that low total dietary nitrogen may select for reduced synthesis of certain EAAs in some aphid clones. The sequenced Buchnera genomes showed that the EAA nutritional phenotype (i.e. the profile of dietary EAAs required by the aphid) cannot be attributed to sequence variation of Buchnera genes coding EAA biosynthetic enzymes. Metabolic modelling by flux balance analysis demonstrated that EAA output from Buchnera can be determined precisely by the flux of host metabolic precursors to Buchnera. Specifically, the four EAA nutritional phenotypes could be reproduced by metabolic models with unique profiles of host inputs, dominated by variation in supply of aspartate, homocysteine and glutamate. This suggests that the nutritional phenotype of the symbiosis is determined principally by host metabolism and transporter genes that regulate nutrient supply to Buchnera. Intraspecific variation in the nutritional phenotype of symbioses is expected to mediate partitioning of plant resources among aphid genotypes, potentially promoting the genetic subdivision of aphid populations. In this way, microbial symbioses may play an important role in the evolutionary diversification of phytophagous insects., (© 2011 Blackwell Publishing Ltd.)

A three-step one pot reaction/purification protocol was developed to facilitate rapid access to benzimidazole-based nucleosides, for which benzoylated benzimidazoribosyl nucleosides incorporating boronic esters were key reaction intermediates.

Fluid adsorption and the associated mass gain behaviour in tibial inserts of total knee replacements was investigated in polyethylene (PE) manufactured from extruded GUR 1050 resin. Repeatedly removing the PE inserts from the soak fluid for gravimetric assessment (including cleaning, desiccation, and weighing) increased the mass gain. Soaking PE inserts for 46 days or 92 days seemed to give about the same mass gain. PE inserts that were soaked at 37 degrees C gained more mass than PE inserts soaked at room-temperature. Gas-plasma sterilized PE inserts gained less mass than gamma-in-air sterilized PE inserts. No statistically significant differences were detected in mass gain between PE inserts that were of 10mm and 14mm thickness. The mass gain of PE inserts was higher in protein-rich soak fluid compared with low-ion distilled water. Prior to knee simulator wear testing, tibial PE inserts should be conditioned in the same medium and under the same test conditions (gravimetric assessment frequency, fluid protein content, and fluid temperature). This approach would help improve the accuracy and precision of the gravimetrically determined PE wear rate during knee simulator wear testing.

Two self-aligning mobile bearing knee replacements (SAL-1) with gamma-in-nitrogen sterilized polyethylene inserts were revised due to instability after 6.3 years and after 14.2 years in vivo in two patients. The predominant damage features were burnishing, cracking, and delamination and were observed on the proximal bearing surface of the retrieved polyethylene inserts. This suggested an association with sub-surface fatigue, perhaps initiated by in vivo oxidative degradation which was confirmed by developing a sub-surface white band in one insert. The damage features observed on the distal bearing surface of the polyethylene inserts suggested both an adhesive wear mechanism and an abrasive wear mechanism. The titanium-nitrite coated, titanium-alloy tibial tray was severely worn in one case and possibly contributed to third-body abrasive wear at the distal surface interface. We suggest to carefully follow-up patients who received this type of mobile bearing knee system., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology., (Copyright © 2011 Elsevier Ltd. All rights reserved.)