Search

Feline dysautonomia (FD) is a multiple system neuropathy of unknown aetiology. An apparently identical disease occurs in horses (equine grass sickness, EGS), dogs, rabbits, hares, sheep, alpacas and llamas. Horses with acute EGS have a marked reduction in plasma concentrations of the sulphur amino acids (SAA) cyst(e)ine and methionine, which may reflect exposure to a neurotoxic xenobiotic. The aim of this study was to determine whether FD cats have alterations in amino acid profiles similar to those of EGS horses. Amino acids were quantified in plasma/serum from 14 FD cats, 5 healthy in-contact cats which shared housing and diet with the FD cats, and 6 healthy control cats which were housed separately from FD cats and which received a different diet. The adequacy of amino acids in the cats' diet was assessed by determining the amino acid content of tinned and dry pelleted foods collected immediately after occurrences of FD. Compared with controls, FD cats had increased concentrations of many essential amino acids, with the exception of methionine which was significantly reduced, and reductions in most non-essential amino acids. In-contact cats also had inadequate methionine status. Artefactual loss of cysteine during analysis precluded assessment of the cyst(e)ine status. Food analysis indicated that the low methionine status was unlikely to be attributable to dietary inadequacy of methionine or cystine. Multi-mycotoxin screening identified low concentrations of several mycotoxins in dry food from all 3 premises. While this indicates fungal contamination of the food, none of these mycotoxins appears to induce the specific clinico-pathologic features which characterise FD and equivalent multiple system neuropathies in other species. Instead, we hypothesise that ingestion of another, as yet unidentified, dietary neurotoxic mycotoxin or xenobiotic, may cause both the characteristic disease pathology and the plasma SAA depletion.

Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

Background: Patellofemoral joint biomechanics contribute to anterior knee pain, instability, and dysfunction following total knee arthroplasty (TKA). Information about specific factors leading to anterior knee pain and dysfunction is currently limited. Changes in patellofemoral joint offset (PFO) refers to a mismatch between the preoperative and postoperative anteroposterior geometry of the patellofemoral joint. It remains unclear whether these changes lead to adverse outcomes in TKA., Methods: A retrospective radiographic review of 970 knees pre-TKA and post-TKA was completed to correlate the radiographic and clinical outcomes of changing the PFO using a posterior-stabilized single knee design with patellar resurfacing., Results: A total of 970 patients were reviewed. Postoperatively, the anterior femoral offset, anteroposterior femoral size, and anterior patellar offset were changed in 40%, 60%, and 71% of knees, respectively, compared to preoperative values. The Western Ontario and McMasters Osteoarthritis Index total score as well as subscale scores for pain and function were not significantly affected by an increase or decrease in PFO. Similarly, Knee Society Scores and range of motion were not significantly affected. Increased anterior patellar offset was, however, associated with increased postoperative patellar tilt. Postoperative patellar tilt was not correlated with adverse patient satisfaction scores or loss of range of motion., Conclusion: Changes in PFO (decreased, maintained, or increased) are common post-TKA and are not associated with a difference in clinical outcomes. Increases in anterior patellar offset led to increased patellar tilt, which was not associated with adverse patient satisfaction scores., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.

Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.

An open question in evolutionary biology is the relationship between standing variation for a trait and the variation that leads to interspecific divergence. By identifying loci underlying phenotypic variation in intra- and interspecific crosses we can determine the extent to which polymorphism and divergence are controlled by the same genomic regions. Sexual traits provide abundant examples of morphological and behavioral diversity within and among species, and here we leverage variation in the Drosophila sex comb to address this question. The sex comb is an array of modified bristles or 'teeth' present on the male forelegs of several Drosophilid species. Males use the comb to grasp females during copulation, and ablation experiments have shown that males lacking comb teeth typically fail to mate. We measured tooth number in >700 genotypes derived from a multiparental advanced-intercross population, mapping three moderate-effect loci contributing to trait heritability. Two quantitative trait loci (QTLs) coincide with previously identified intra- and interspecific sex comb QTL, but such overlap can be explained by chance alone, in part because of the broad swathes of the genome implicated by earlier, low-resolution QTL scans. Our mapped QTL regions encompass 70-124 genes, but do not include those genes known to be involved in developmental specification of the comb. Nonetheless, we identified plausible candidates within all QTL intervals, and used RNA interference to validate effects at four loci. Notably, TweedleS expression knockdown substantially reduces tooth number. The genes we highlight are strong candidates to harbor segregating, functional variants contributing to sex comb tooth number.

Background: In previous studies, 50%-70% of patients referred to orthopedic surgeons for total knee replacement (TKR) were not surgical candidates at the time of initial assessment. The purpose of our study was to identify and cross-validate patient self-reported predictors of suitability for TKR and to determine the clinical utility of a predictive model to guide the timing and appropriateness of referral to a surgeon., Methods: We assessed pre-consultation patient data as well as the surgeon's findings and post-consultation recommendations. We used multivariate logistic regression to detect self-reported items that could identify suitable surgical candidates., Results: Patients' willingness to undergo surgery, higher rating of pain, greater physical function, previous intra-articular injections and patient age were the factors predictive of patients being offered and electing to undergo TKR., Conclusion: The application of the model developed in our study would effectively reduce the proportion of nonsurgical referrals by 25%, while identifying the vast majority of surgical candidates (> 90%). Using patient-reported information, we can correctly predict the outcome of specialist consultation for TKR in 70% of cases. To reduce long waits for first consultation with a surgeon, it may be possible to use these items to educate and guide referring clinicians and patients to understand when specialist consultation is the next step in managing the patient with severe osteoarthritis of the knee.

Closely-related, and otherwise morphologically similar insect species frequently show striking divergence in the shape and/or size of male genital structures, a phenomenon thought to be driven by sexual selection. Comparative interspecific studies can help elucidate the evolutionary forces acting on genital structures to drive this rapid differentiation. However, genetic dissection of sexual trait divergence between species is frequently hampered by the difficulty generating interspecific recombinants. Intraspecific variation can be leveraged to investigate the genetics of rapidly-evolving sexual traits, and here we carry out a genetic analysis of variation in the posterior lobe within D. melanogaster. The lobe is a male-specific process emerging from the genital arch of D. melanogaster and three closely-related species, is essential for copulation, and shows radical divergence in form across species. There is also abundant variation within species in the shape and size of the lobe, and while this variation is considerably more subtle than that seen among species, it nonetheless provides the raw material for QTL mapping. We created an advanced intercross population from a pair of phenotypically-different inbred strains, and after phenotyping and genotyping-by-sequencing the recombinants, mapped several QTL contributing to various measures of lobe morphology. The additional generations of crossing over in our mapping population led to QTL intervals that are smaller than is typical for an F2 mapping design. The intervals we map overlap with a pair of lobe QTL we previously identified in an independent mapping cross, potentially suggesting a level of shared genetic control of trait variation. Our QTL additionally implicate a suite of genes that have been shown to contribute to the development of the posterior lobe. These loci are strong candidates to harbor naturally-segregating sites contributing to phenotypic variation within D. melanogaster, and may also be those contributing to divergence in lobe morphology between species., Competing Interests: The authors have declared that no competing interests exist.

Background: Considerable natural variation for lifespan exists within human and animal populations. Genetically dissecting this variation can elucidate the pathways and genes involved in aging, and help uncover the genetic mechanisms underlying risk for age-related diseases. Studying aging in model systems is attractive due to their relatively short lifespan, and the ability to carry out programmed crosses under environmentally-controlled conditions. Here we investigate the genetic architecture of lifespan using the Drosophila Synthetic Population Resource (DSPR), a multiparental advanced intercross mapping population., Results: We measured lifespan in females from 805 DSPR lines, mapping five QTL (Quantitative Trait Loci) that each contribute 4-5 % to among-line lifespan variation in the DSPR. Each of these QTL co-localizes with the position of at least one QTL mapped in 13 previous studies of lifespan variation in flies. However, given that these studies implicate >90 % of the genome in the control of lifespan, this level of overlap is unsurprising. DSPR QTL intervals harbor 11-155 protein-coding genes, and we used RNAseq on samples of young and old flies to help resolve pathways affecting lifespan, and identify potentially causative loci present within mapped QTL intervals. Broad age-related patterns of expression revealed by these data recapitulate results from previous work. For example, we see an increase in antimicrobial defense gene expression with age, and a decrease in expression of genes involved in the electron transport chain. Several genes within QTL intervals are highlighted by our RNAseq data, such as Relish, a critical immune response gene, that shows increased expression with age, and UQCR-14, a gene involved in mitochondrial electron transport, that has reduced expression in older flies., Conclusions: The five QTL we isolate collectively explain a considerable fraction of the genetic variation for female lifespan in the DSPR, and implicate modest numbers of genes. In several cases the candidate loci we highlight reside in biological pathways already implicated in the control of lifespan variation. Thus, our results provide further evidence that functional genetics tests targeting these genes will be fruitful, lead to the identification of natural sequence variants contributing to lifespan variation, and help uncover the mechanisms of aging.

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurodegeneration, and neuropathic pain, among others. As a result, ATX-LPA has become of significant interest within both the industrial and the academic communities. This review aims to provide a concise overview of the development of novel ATX inhibitors, including the disclosure of the first ATX clinical trial data.

Background: Wear in posterior-stabilized (PS) polyethylene tibial inserts depends on component position, limb alignment, and ligament balancing. Valgus-varus constrained (VVC) inserts are likely to be affected similarly. We aimed to compare wear characteristics of VVC and PS inserts and identify associated factors., Methods: This was a retrieval analysis (macroscopic and radiographic) of all 18 VVC liners collected from patients who underwent revision surgery from 1999 to 2011. These patients were matched to another group with PS inserts who underwent revision in the same time period., Results: There was significantly more damage in the posts of the VVC group (13.0 ± 5.0, compared to 4.7 ± 1.9 in the PS group; P < .001). Within the VVC group, the total damage score and cold flow damage were significantly higher with excessive joint line changes (≥5 mm; P = .01). The excessive joint line elevation was associated with rotational wear pattern of the post (P = .004). Damage scores were increased with femoral component malposition (P = .04), anterior tibial slope (P = .04), and tibial component malposition (P = .04)., Conclusion: Joint line elevation, femoral and tibial component malposition, and anterior tibial slope resulted in significantly more wear in the VVC inserts. Joint line elevation of >5 mm resulted in wear of the medial and lateral aspects of the post, femoral valgus resulted in cold flow wear of the anterior post, and tibial valgus and anterior slope resulted in wear of lateral aspect of the post., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In this article we describe a radically different industry-academia collaboration between the School of Chemistry, University of Nottingham, and GlaxoSmithKline (GSK), aiming to train students in research and give them an insight into medicinal chemistry as practiced in industry. The project concerns the discovery of potent and selective αvβ6 integrin antagonists to treat idiopathic pulmonary fibrosis; the synthetic chemistry is performed by a group of ten final-year undergraduates and the biological and physicochemical screening data are generated by GSK. The project planning, organisation and operation are discussed, together with some of the challenges and rewards of working with undergraduates., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: The purpose of the present study was to examine the long-term fixation of a cemented fixed-bearing polished titanium tibial baseplate (Genesis ll)., Patients and Methods: Patients enrolled in a previous two-year prospective trial (n = 35) were recalled at ten years. Available patients (n = 15) underwent radiostereometric analysis (RSA) imaging in a supine position using a conventional RSA protocol. Migration of the tibial component in all planes was compared between initial and ten-year follow-up. Outcome scores including the Knee Society Score, Western Ontario and McMaster Universities Arthritis Index, 12-item Short Form Health Survey, Forgotten Joint Score, and University of California, Los Angeles Activity Score were recorded., Results: At ten years, the mean migration of the tibial component was less than 0.1 mm and 0.1° in all planes relative to the post-operative RSA exam. Maximum total point movement increased with time (p = 0.002) from 0.23 mm (sd 0.18) at six weeks to 0.42 mm (sd 0.20) at ten years., Conclusion: The low level of tibial baseplate migration found in the present study correlates to the low rate of revision for this implant as reported in individual studies and in joint replacement registries., Take Home Message: Overall, the implant was found to be well fixed at ten years, supporting its continued clinical use and the predictive power of RSA for determining long-term fixation of implants. Cite this article: Bone Joint J 2016;98-B:616-21., (©2016 The British Editorial Society of Bone & Joint Surgery.)

We announce the draft genome sequence for Chromobacterium violaceum strain CV017, used as a model and tool to understand acyl-homoserine lactone-dependent quorum sensing. The assembly consists of 4,774,638-bp contained in 211 scaffolds., (Copyright © 2016 Wang et al.)

Background: Hard-on-hard bearings for total hip arthroplasty continue to warrant analysis even though crosslinked polyethylene is performing very well. Ceramic-on-metal (CoM) has low in vitro wear and did well in an early clinical trial. We report on a prospective, randomized, multicenter investigational device trial comparing CoM with metal-on-metal (MoM)., Questions/purposes: (1) Is there a difference in the number or type of revisions comparing CoM with MoM? (2) Are cobalt and chromium metal levels different for CoM and MoM THA?, Methods: Between August 2005 and October 2006, of 1015 patients screened, 390 patients were enrolled at 11 centers and randomized to 194 CoM and 196 MoM bearings. There was no difference in the preoperative patient demographics between the study groups. Mean followup was 50 months (range, 22-75 months). Seventy-two patients from two centers had metal level analysis., Results: With the numbers available, there was no difference in the proportion of patients undergoing revisions between the MoM and the CoM cohorts (MOM: 3% [six of 196]; COM: 1.5% [three of 194]; p = 0.50). Four MoM revisions were unrelated to the bearing surface. Two had bearing surface-related reoperations, one for an aseptic lymphocyte-dominated vasculitis-associated lesion and one for elevated metal levels with acetabular malposition. None of the CoM revisions were related to the bearing surface. The metal level analysis revealed that in contrast to the CoM, the MoM bearing group had increasing values of erythrocyte and serum cobalt from 1 to 5 years (CoM erythrocyte 0.45-0.55 ppb, p = 0.11 and CoM serum 0.88-0.85, p = 0.55, and MoM erythrocyte 0.32-0.51 ppb, p < 0.01 and MoM serum 0.65-1.01 ppb, p < 0.01). In addition, the MoM cobalt levels in erythrocytes and serum at 5 years were more variable than at 1 year (erythrocyte interquartile range [IQR], 0.26-0.44 to 0.31-1.21 ppb and serum IQR, 0.42-0.80 to 0.64-2.20 ppb, p < 0.02 for both)., Conclusions: Although both bearings performed well at short-term followup, the CoM bearing group had no wear-related revisions and maintained consistently low metal levels. The MoM cobalt elevations may be important considering recent reports of taper corrosion. This CoM bearing was approved by the FDA but withdrawn from the market because of low sales. If it were available, the authors would not use CoM until long-term data were available. The bearing would have to outperform crosslinked polyethylene because it is unlikely that CoM metal levels will return to normal., Level of Evidence: Level I, therapeutic study.

Background: Although it is understood that backside damage occurs in polyethylene acetabular liners, the effect of highly crosslinked polyethylene, which has completely replaced conventional polyethylene, has yet to be examined., Questions/purposes: The purpose of this study was to answer the following questions: (1) With conventional polyethylene (CPE), did the acetabular design make a difference in backside wear? (2) Is there a difference in backside damage between CPE and crosslinked polyethylene (XLPE) liners? (3) With XLPE, is the difference in backside wear between designs still present? (4) Is there any difference in backside damage in various zones on backside of individual liners?, Methods: This single-institution retrieval analysis involved visual damage scoring on the backside of 233 polyethylene liners implanted between 2002 and 2011. The liners were retrieved from either polished/dovetail cups (PD) or roughened/wire cups (RW) made by two different manufacturers. The inserts were divided into four groups: PD-CPE (n = 105), PD-XLPE (n = 16), RW-CPE (n = 99), and RW-XLPE (n = 13). Aseptic loosening and polyethylene wear were the predominant reasons for revision of CPE liners, whereas instability and infection were the common reasons for revision of XLPE liners. The time in situ (TIS) was shorter for the XLPE liners as compared with the CPE liners (PD-CPE: 8.5 years [SD 4.4]; RD-CPE: 9.5 [SD 4.8]; PD-CPE: 3.8 [SD 3.7]; RD-XLPE: 4.0 [SD 4.3]). The backside of each liner was divided into five zones and graded initially from a scale of 0 to 3 for seven different damage modes by one observer. There was substantial interobserver (kappa 0.769) and intraobserver (0.736) reliability on repeat scoring. To compare the effects of crosslinking, a subset of the conventional polyethylene liners was matched to the crosslinked liners based on TIS, resulting in 16 per group for the two PD types and 13 per group for the two RW types., Results: Total damage scores in the RW-CPE (19 ± 7) group were greater (p < 0.001) than the PD-CPE group (8 ± 4). Damage was reduced with XLPE (p = 0.02) only for the RW-XLPE (9 ± 9) versus RW-CPE-type sockets (4 ± 4). There was no difference (p = 0.16) between the RW-XLPE group and the PD-XLPE group. Damage scores in the peripheral zone of the locking mechanisms were higher for RW-CPE (4 ± 3) compared with PD-CPE (1.4 ± 1.0, p < 0.001) and RW-XLPE (1.3 ± 1.3, p = 0.02). Damage was greater (p < 0.001) within the superior zones (7 ± 4) compared with the inferior zones (3.0 ± 2.8) of all liners., Conclusions: The current study shows greater backside damage for CPE in the roughened, wire lock cups. XLPE was shown to be more resistant to backside damage for both socket designs., Clinical Relevance: Although the polished/dovetail cups seem to cause less backside damage in the CPE liners than roughened/wire cups, the use of XLPE liners has been shown to protect the liner from backside damage in either cup design. If an acetabular shell has a functional locking mechanism, surgeons should not worry about cup design when undertaking isolated liner revision using XLPE liners.

This study compared the damage scores and damage patterns in 19 tibial inserts from rotating hinge (RH) implants with 19 inserts from highly constrained (HC) implants. Each insert was divided into 16 damage zones and each zone was subjectively graded from a scale of 0-3 for seven different damage modes. The overall damage scores were comparable for the two groups (RH: 64.1 ± 15.4; HC: 66.1 ± 29.0; P = 0.59). The HC group, however, had greater post damage (compared to the post-hole of RH) while the RH group had greater backside damage. The pattern of damage was also different, with burnishing and cold flow being more common in HC group while pitting, scratching and embedded debris were more common in the RH group., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Obesity is a worldwide epidemic that has both economic and health implications of enormous consequence. The obese patients tend to have earlier symptoms related to osteoarthritis, more peri-operative medical problems, higher rates of infection and more technical difficulties intra-operatively following hip and knee arthroplasty. Nevertheless, these patients have good long-term clinical outcomes and implant survival rates and are often some of the most satisfied patients after joint arthroplasty. Therefore, obese patients should not be denied surgery based on their weight alone., (©2016 The British Editorial Society of Bone & Joint Surgery.)

Aims: The purpose of this study was to compare the long-term results of primary total hip arthroplasty (THA) in young patients using either a conventional (CPE) or a highly cross-linked (HXLPE) polyethylene liner in terms of functional outcome, incidence of osteolysis, radiological wear and rate of revision., Methods: We included all patients between the ages of 45 and 65 years who, between January 2000 and December 2001, had undergone a primary THA for osteoarthritis at our hospital using a CPE or HXLPE acetabular liner and a 28 mm cobalt-chrome femoral head. From a total of 160 patients, 158 (177 hips) were available for review (CPE 89; XLPE 88). The mean age, body mass index (BMI) and follow-up in each group were: CPE: 56.8 years (46 to 65); 30.7 kg/m(2) (19 to 58); 13.2 years (2.1 to 14.7) and HXLPE: 55.6 years (45 to 65); BMI: 30 kg/m(2) (18 to 51); 13.1 years (5.7 to 14.4)., Results: The mean Harris hip score (HHS) at final follow-up was 89.3 for the CPE group and 90.9 for the HXLPE group (p = 0.078). Osteolysis was present around 15 acetabular (17%) and 16 femoral (18%) components in the CPE hips compared with none (0%) in the HXLPE hips. The mean radiological linear wear of the CPE liners was 0.11 mm/year compared with 0.035 mm/year for the HXLPE liners (p = 0.006). The cumulative implant survival, with revision for polyethylene wear as the endpoint, was 86% (95% confidence interval 78 to 94) in the CPE group and 100% in the HXLPE group at 13 years (numbers at risk at 13 years - CPE: 65, XLPE: 61)., Discussion: This study shows that HXLPE liners are associated with significantly less osteolysis and a lower rate of revision THA than CPE liners at long-term follow-up., Take Home Message: The findings of this study highlight the clinical benefits of using HXLPE liners in THA and support the routine use of the material in order to improve implant longevity and to decrease the number of patients needing revision for aseptic osteolysis., (©2016 The British Editorial Society of Bone & Joint Surgery.)

This study investigated whether subluxation of articulating antibiotic spacers is associated with the bone defects found and constraint required when re-implanting the knee arthroplasty components. Staged revisions for infections of primary total knee arthroplasties between 2004 and 2012 were examined. Radiographic sagittal and coronal subluxations of 72 knees were measured prior to second stage revision. Coronal subluxation was found to be associated with increased requirement for constrained knee systems (P<0.035). Sagittal subluxation was associated with greater tibia bone defects (P<0.037). Careful surgical technique and monitoring of articulating spacers should be done to avoid subluxation after stage 1 revision. If subluxation of the articulating spacer is present, constrained revision knee systems as well as augments should be available at time of re-implantation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Formal homologation of sp(2)-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor.

Type 17 helper T-cell cytokines have been implicated in the pathogenesis of inflammatory bowel disease, a chronic condition affecting the gastrointestinal tract, but information regarding their contribution to pathology in different regions of the gut is lacking. By using a murine model of bacteria-induced typhlocolitis, we investigated the role of IL-17A, IL-17F, and IL-22 in cecal versus colonic inflammation. Cecal, but not colonic, pathology in C57BL/6 mice inoculated with Helicobacter hepaticus plus anti-IL-10 receptor (IL-10R) monoclonal antibody was exacerbated by co-administration of anti-IL-17A monoclonal antibody, suggesting a disease-protective role for IL-17A in the cecum. In contrast, anti-IL-17F had no effect on H. hepaticus-induced intestinal pathology. Neutralization of IL-22 prevented the development of colonic, but not cecal, inflammation in H. hepaticus-infected anti-IL-10R-treated mice, demonstrating a pathogenic role for IL-22 in the colon. Analysis of transcript levels revealed differential expression of IL-22R, IL-22 binding protein, and IL-23R between cecum and colon, a finding that may help explain why these tissues respond differently after anti-IL-22 treatment. Analysis of microarray data from healthy human intestine further revealed significant differences in cytokine receptor transcript levels (including IL-22RA1 and IL-23R) in distinct parts of the human gut. Together, our findings demonstrate that individual type 17 helper T-cell cytokines can have proinflammatory or anti-inflammatory effects in different regions of the intestine, an observation that may have implications for interventions against human inflammatory bowel disease., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to compare clinical outcomes of total knee arthroplasty (TKA) after manipulation under anaesthesia (MUA) for post-operative stiffness with a matched cohort of TKA patients who did not requre MUA. In total 72 patients (mean age 59.8 years, 42 to 83) who underwent MUA following TKA were identified from our prospective database and compared with a matched cohort of patients who had undergone TKA without subsequent MUA. Patients were evaluated for range of movement (ROM) and clinical outcome scores (Western Ontario and McMaster Universities Arthritis Index, Short-Form Health Survey, and Knee Society Clinical Rating System) at a mean follow-up of 36.4 months (12 to 120). MUA took place at a mean of nine weeks (5 to 18) after TKA. In patients who required MUA, mean flexion deformity improved from 10° (0° to 25°) to 4.4° (0° to 15°) (p < 0.001), and mean range of flexion improved from 79.8° (65° to 95°) to 116° (80° to 130°) (p < 0.001). There were no statistically significant differences in ROM or functional outcome scores at three months, one year, or two years between those who required MUA and those who did not. There were no complications associated with manipulation. At most recent follow-up, patients requiring MUA achieved equivalent ROM and clinical outcome scores when compared with a matched control group. While other studies have focused on ROM after manipulation, the current study adds to current literature by supplementing this with functional outcome scores., (©2015 The British Editorial Society of Bone & Joint Surgery.)

Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and characterize naturally-segregating polymorphisms that modulate toxicity. Here, we use the Drosophila Synthetic Population Resource (DSPR), a multiparent advanced intercross panel of recombinant inbred lines, to identify QTL (Quantitative Trait Loci) underlying xenobiotic resistance, and employ caffeine as a model toxic compound. Phenotyping over 1,700 genotypes led to the identification of ten QTL, each explaining 4.5-14.4% of the broad-sense heritability for caffeine resistance. Four QTL harbor members of the cytochrome P450 family of detoxification enzymes, which represent strong a priori candidate genes. The case is especially strong for Cyp12d1, with multiple lines of evidence indicating the gene causally impacts caffeine resistance. Cyp12d1 is implicated by QTL mapped in both panels of DSPR RILs, is significantly upregulated in the presence of caffeine, and RNAi knockdown robustly decreases caffeine tolerance. Furthermore, copy number variation at Cyp12d1 is strongly associated with phenotype in the DSPR, with a trend in the same direction observed in the DGRP (Drosophila Genetic Reference Panel). No additional plausible causative polymorphisms were observed in a full genomewide association study in the DGRP, or in analyses restricted to QTL regions mapped in the DSPR. Just as in human populations, replicating modest-effect, naturally-segregating causative variants in an association study framework in flies will likely require very large sample sizes.

To date, characterization of ancient oral (dental calculus) and gut (coprolite) microbiota has been primarily accomplished through a metataxonomic approach involving targeted amplification of one or more variable regions in the 16S rRNA gene. Specifically, the V3 region (E. coli 341-534) of this gene has been suggested as an excellent candidate for ancient DNA amplification and microbial community reconstruction. However, in practice this metataxonomic approach often produces highly skewed taxonomic frequency data. In this study, we use non-targeted (shotgun metagenomics) sequencing methods to better understand skewed microbial profiles observed in four ancient dental calculus specimens previously analyzed by amplicon sequencing. Through comparisons of microbial taxonomic counts from paired amplicon (V3 U341F/534R) and shotgun sequencing datasets, we demonstrate that extensive length polymorphisms in the V3 region are a consistent and major cause of differential amplification leading to taxonomic bias in ancient microbiome reconstructions based on amplicon sequencing. We conclude that systematic amplification bias confounds attempts to accurately reconstruct microbiome taxonomic profiles from 16S rRNA V3 amplicon data generated using universal primers. Because in silico analysis indicates that alternative 16S rRNA hypervariable regions will present similar challenges, we advocate for the use of a shotgun metagenomics approach in ancient microbiome reconstructions.

Current discussion exists whether to position a total knee arthroplasty (TKA) in slight undercorrection in varus osteoarthritis. The goal of this study was to analyse the effect of wear and lateral lift-off in primary TKA on coronal plane alignment and the implication to future constrained revision TKA. Seventy-six retrieved tibial inserts were analysed for the ratio of wear (RW), lateral lift-off and implications for future constrained revision surgery according to the coronal plane alignment. The RW significantly affects the coronal plane alignment in TKA. Progressive wear and lateral lift-off were seen with progressive varus alignment. However, there was no difference in constrained revision between mild varus and moderate varus aligned TKAs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Fibrosis, which leads to progressive loss of tissue function and eventual organ failure, has been estimated to contribute to ~45% of deaths in the developed world, and so new therapeutics to modulate fibrosis are urgently needed. Major advances in our understanding of the mechanisms underlying pathological fibrosis are supporting the search for such therapeutics, and the recent approval of two anti-fibrotic drugs for idiopathic pulmonary fibrosis has demonstrated the tractability of this area for drug discovery. This Review examines the pharmacology and structural information for small molecules being evaluated for lung, liver, kidney and skin fibrosis. In particular, we discuss the insights gained from the use of these pharmacological tools, and how these entities can inform, and probe, emerging insights into disease mechanisms, including the potential for future drug combinations.

Background: We present a case of multifocal infection involving the left total hip replacement and the right total knee replacement of a patient, further complicated by an infected non-union of a periprosthetic fracture of the right knee. This required the unique simultaneous management of both infection eradication and fracture stabilization in the knee., Methods: Both sites were treated with a two-stages procedure, including the novel use of a stemmed articulating spacer for the right knee. This spacer was made combining a retrograde humeral nail, coated with antibiotic-impregnated cement, and a pre-formed articulating cement spacer. The patient was able to weight-bear on this spacer., Results: The fracture went on to unite, and a second stage was performed with the use of stemmed prosthesis and augments. She remains infection free two years after the second stage operation., Conclusions: The use of a stemmed articulating knee spacer can facilitate infection eradication and fracture stabilization while preserving some motion and weight-bearing ability in the two-stages management of an infected periprosthetic fracture of the knee., Level of Evidence: Level V (Case report)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

327 proximal and 185 extensively coated femoral stems with mean 10-year follow-up were reviewed. Implant survivorship, clinical outcomes, and radiographic analyses were compared. Kaplan-Meier implant survivorship was 97.5% for the proximal, and 98.8% for the extensively coated stem for stem-only revisions at 10-years. The proximally coated stem outperformed on the PCS arm of the SF-12 (P = 0.04) and stiffness arm of the WOMAC (P = 0.03). Otherwise, all clinical outcomes were comparable. Thigh pain incidence was 12.5% and 5.3% for the extensive versus proximally coated groups, respectively (P = 0.007). Radiographic review identified more severe stress shielding (P < 0.001) in the extensively coated stems. This study supports the long-term clinical track record of total hip arthroplasty using two different cementless stem designs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We compared the 10-year survival rates and clinical outcomes of posterior cruciate-retaining (CR) versus posterior cruciate-substituting (CS) total knee arthroplasty (TKA), using the Genesis II knee system (Smith and Nephew, Memphis, TN). Our institutional database identified patients undergoing a primary knee with the Genesis II system between 1995 and 2000. These patients were followed for an average of 12.3years (range 10.2-14.4years). There were 143 (34.5%) CR and 271 (65.5%) CS implants. No significant difference in 10-year survivorship was noted between the two cohorts. The postoperative clinical scores (KSCRS, WOMAC, SF-12) and knee ROM were significantly better for the CS cohort. In this large, long-term, single-implant prospective study, CS performed better than CR in terms of clinical scores and range of motion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Highly crosslinked polyethylene (XLPE) is believed to demonstrate better wear resistance than conventional polyethylene (CPE) in total hip arthroplasty., Questions/purposes: The purpose of this study was to compare visual damage scores and micro-CT measurements of penetration, a surrogate for wear, between matched retrieved XLPE and CPE acetabular liners., Methods: Thirteen XLPE acetabular liners were matched in terms of implant design (all were of the same design), patient age, sex, liner dimensions, duration of implantation, and reason for revision to a group of CPE liners that were retrieved in the same time period. Penetration resulting from the combination of wear and creep in the two groups of liners was measured with micro-CT. Surface damage was scored by two blinded observers using a surface damage system that considers the seven common damage modes: pitting, scratching, burnishing, abrasions, impingement, embedded debris, and delamination, and wear patterns were documented., Results: There was no difference (p=0.32) in total damage score between the XLPE group (14±4) and the CPE group (15±5). However, there was three times greater penetration (odds ratio, 3.1; confidence interval, 2.3-5.1; p<0.001) in the CPE group (0.18±0.09 mm/year) than in the XLPE group (0.05±0.07 mm/year). There was less volumetric loss in XLPE (82±SD 134 mm3) versus the CPE group (350±SD 342 mm3; p=0.017)., Conclusions: XLPE liners undergo less penetration as a result of creep and wear than CPE liners based on quantitative measurements provided by micro-CT, which was not apparent using damage scoring alone. This demonstrates the use of three-dimensional imaging techniques such as micro-CT for quantifying wear in retrieval studies., Clinical Relevance: In this study, XLPE had less wear but similar damage scores than CPE, allaying concerns that the beneficial wear properties of XLPE might come with a tradeoff arising from the increased brittleness of that material.

Background: Porous metal acetabular augments have become widely used to fill bony defects in patients undergoing revision total hip arthroplasty. The objective of this study was to determine whether the currently offered size range of the augments is appropriate for surgical needs., Methods: We reviewed the cases of all patients at 1 centre with a porous revision shell, and when an augment was used we recorded the patient and implant characteristics., Results: We reviewed the cases of 281 patients, and augments were used in 24. Augment diameter was skewed toward the small end (p < 0.001), although thickness was not (p = 0.05); 21 of 24 augments were those with the smallest 3 diameters and thicknesses., Conclusion: Given the sizes used, the full range of inventory provided by the manufacturer may be unnecessary, as surgeons will likely attempt a larger shell before a larger augment.

The tandem ene/intramolecular Sakurai cyclisation (IMSC) reaction has been successfully applied to the synthesis of a range of C-glycosides, with key intermediates offering opportunities for functionalisation of the glycon moiety. To demonstrate the versatility of the approach to access the 2-deoxy-C-glycoside series, we synthesised diastereomerically pure C-glucoside and galactoside derivatives incorporating functionalised aromatic, heteroaromatic and bicyclic aromatic moieties, in addition to the C-homologue of (±)-β-2-deoxy-glucose 6-phosphate., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Prompt attention is typically required in managing intraoperative problems associated with total hip arthroplasty. There is often limited time for consultation or a review of the literature. The treating surgeon should be familiar with treatment options, favored treatment methods, and should be able to implement the most appropriate and optimal treatment for his or her patient. Common intraoperative complications associated with primary total hip arthroplasty include difficulty gaining sufficient exposure, problems with cup fixation, challenges with implant anteversion, intraoperative fracture of the femur, and difficulties with intraoperative limb length and hip instability.

Total knee arthroplasty is a common and immensely successful surgical procedure that reliably relieves pain and improves function. However, early revision rates and patient dissatisfaction are high suggesting that there is need for improvement through careful patient selection and education as well as attention to surgical technique. After ensuring that a patient is an appropriate candidate for the procedure, patient education is critical to ensure appropriate expectations. Careful preoperative planning and achieving appropriate alignment, sizing, and ligament balance are critical for optimal knee function. Careful attention to the cement technique is important for long-term implant fixation. With appropriate patient selection and careful surgical techniques, optimal patient outcomes will be achieved.

The integrin αvβ6 is a potential target for treatment of idiopathic pulmonary fibrosis (IPF). Equilibrium dialysis (ED) was investigated for its ability to report ligand binding in an αvβ6 inhibitor screening assay. As a preliminary experiment, an established peptidomimetic inhibitor of the integrin was dialyzed against αvβ6, and the fraction bound (f b) and percentage saturation determined by liquid chromatography-mass spectrometry (LC-MS) analysis. Quantitation of the inhibitor in the two chambers of the ED cartridge revealed an uneven distribution in the presence of αvβ6, corresponding to near saturation binding to the protein (93 ± 3%), while the control (without integrin) showed an equal partitioning of the inhibitor on either side of the dialysis membrane. A competitive ED assay with a 12 component mixture of antagonists was conducted, and the results compared with an established cell adhesion assay for quantifying αvβ6 inhibition of individual antagonists. Compounds clustered into three groupings: those with pIC 50 values between ca. 5.0 and 5.5, which possessed ED f b values indistinguishable from the controls, those with pIC 50s of 6.5 ± 0.2, which exhibited detectable integrin binding (f b 13-25%) in the ED assay, and a single compound of pIC 50 7.2 possessing an f b value of 38%. A good correlation between ED-derived f b and pIC 50 was observed despite the two assays utilizing quite different outputs. These results demonstrate that ED with LC-MS detection shows promise as a rapid αvβ6 integrin antagonist screening assay for mixtures of putative ligands.

Background: We previously demonstrated the feasibility and clinical effectiveness of a web-based assessment following total hip or total knee arthroplasty. The purpose of the present study was to conduct an economic evaluation to compare a web-based assessment with in-person follow-up., Methods: Patients who had undergone total joint arthroplasty at least twelve months previously were randomized to complete a web-based follow-up or visit the clinic for the usual follow-up. We recorded travel costs and time associated with each option. We followed patients for one year after the web-based or in-person follow-up evaluation and documented any resource use related to the joint arthroplasty. We conducted cost analyses from the health-care payer (Ontario Ministry of Health and Long-Term Care) and societal perspectives. All costs are presented in 2012 Canadian dollars., Results: A total of 229 patients (118 in the web-based group, 111 in the usual-care group) completed the study. The mean cost of the assessment from the societal perspective was $98 per patient for the web-based assessment and $162 per patient for the usual method of in-person follow-up. The cost for the web-based assessment was significantly lower from the societal perspective (mean difference, $-64; 95% confidence interval [CI], $-79 to $-48; p < 0.01) and also from the health-care payer perspective (mean difference, $-27; 95% CI, $-29 to $-25; p < 0.01)., Conclusions: The web-based follow-up assessment had a lower cost per patient compared with in-person follow-up from both societal and health-care payer perspectives., (Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.)

For most complex traits we have a poor understanding of the positions, phenotypic effects, and population frequencies of the underlying genetic variants contributing to their variation. Recently, several groups have developed multi-parent advanced intercross mapping panels in different model organisms in an attempt to improve our ability to characterize causative genetic variants. These panels are powerful and are particularly well suited to the dissection of phenotypic variation generated by rare alleles and loci segregating multiple functional alleles. We describe studies using one such panel, the Drosophila Synthetic Population Resource (DSPR), and the implications for our understanding of the genetic basis of complex traits. In particular, we note that many loci of large effect appear to be multiallelic. If multiallelism is a general rule, analytical approaches designed to identify multiallelic variants should be a priority for both genome-wide association studies (GWASs) and multi-parental panels., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvβ3, αvβ5, αvβ6, and αvβ8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvβ3 and αvβ5.

Published physicochemical descriptors of molecules that convey aromaticity-related character are reviewed in the context of drug design and discovery. Studies that have employed aromatic descriptors are discussed, and several descriptors are compared and contrasted.

Animals in nature are frequently challenged by toxic compounds, from those that occur naturally in plants as a defense against herbivory, to pesticides used to protect crops. On exposure to such xenobiotic substances, animals mount a transcriptional response, generating detoxification enzymes and transporters that metabolize and remove the toxin. Genetic variation in this response can lead to variation in the susceptibility of different genotypes to the toxic effects of a given xenobiotic. Here we use Drosophila melanogaster to dissect the genetic basis of larval resistance to nicotine, a common plant defense chemical and widely used addictive drug in humans. We identified quantitative trait loci (QTL) for the trait using the DSPR (Drosophila Synthetic Population Resource), a panel of multiparental advanced intercross lines. Mapped QTL collectively explain 68.4% of the broad-sense heritability for nicotine resistance. The two largest-effect loci-contributing 50.3 and 8.5% to the genetic variation-map to short regions encompassing members of classic detoxification gene families. The largest QTL resides over a cluster of ten UDP-glucuronosyltransferase (UGT) genes, while the next largest QTL harbors a pair of cytochrome P450 genes. Using RNAseq we measured gene expression in a pair of DSPR founders predicted to harbor different alleles at both QTL and showed that Ugt86Dd, Cyp28d1, and Cyp28d2 had significantly higher expression in the founder carrying the allele conferring greater resistance. These genes are very strong candidates to harbor causative, regulatory polymorphisms that explain a large fraction of the genetic variation in larval nicotine resistance in the DSPR., (Copyright © 2014 by the Genetics Society of America.)

The purpose of this study was to assess the feasibility, effectiveness and costs of a web-based follow-up compared to in-person assessment following primary total hip or total knee arthroplasty. Patients who were at least 12 months postoperative were randomized to follow-up method. We excluded patients who had revision surgery, osteolysis, complications or identified radiographic issues. 229 patients (118 Web, 111 in-person) completed the study. There were no patients who had an issue missed by the web-based follow-up. Patients in the web-based group travelled less (28.2km vs 103.7km, (P<0.01)), had lower associated costs ($10.45 vs $21.36, (P<0.01)) and took less time to complete (121.7min web vs 228.7min usual). Web-based follow-up is a feasible, clinically effective alternative with lower associated costs than in-person clinic assessment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Quantitative measurements of damage and wear in orthopaedic components retrieved from patients during revision surgery can provide valuable information. However, to perform these measurements there needs to be an estimate of the original, unworn geometry of the component, often requiring multiple scans of the various sizes of components that have been retrieved. The objective of this study was to determine whether the articular and backside surfaces could be independently segmented from a micro-CT reconstruction of a tibial insert, such that a tibial insert of one thickness could be used as a reference for a tibial insert of a different thickness., Methods: New tibial inserts of a single width but with six different thicknesses were obtained and scanned with micro-CT. An automated method was developed to computationally segment the articular and backside surfaces of the components. Variability between intact and extracted components was determined., Results: The deviations between the comparisons of the extracted surfaces (range, 0.0004 to 0.010 mm) were less (p<0.001) than the baseline deviation between the intact surfaces (range, 0.0002 to 0.053 mm)., Conclusions: An extracted surface from one insert thickness could be used to accurately represent the surface of an insert of a different thickness. This greatly enhances the feasibility of performing retrieval studies using micro-CT as a quantitative tool, by reducing the costs and time associated with acquiring, scanning, and reconstructing multiple reference tibial insert geometries., Clinical Relevance: This will add greater detail to studies of retrieved implants, to better establish how implants are functioning in vivo., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: A web-based followup assessment may be a feasible, cost-saving alternative of tracking patient outcomes after total joint arthroplasty. However, before implementing a web-based program, it is important to determine patient satisfaction levels with the new followup method. Satisfaction with the care received is becoming an increasingly important metric, and we do not know to what degree patients are satisfied with an approach to followup that does not involve an in-person visit with their surgeons., Questions/purposes: We determined (1) patient satisfaction and (2) patients' preferences for followup method (web-based or in-person) after total joint arthroplasty., Methods: We randomized patients who were at least 12 months after primary THA or TKA to complete a web-based followup or to have their appointment at the clinic. There were 410 eligible patients contacted for the study during the recruitment period. Of these, 256 agreed to participate, and a total of 229 patients completed the study (89% of those enrolled, 56% of those potentially eligible; 111 in the usual-care group, 118 in the web-based group). Their mean age was 69 years (range, 38-86 years). There was no crossover between groups. All 229 patients completed a satisfaction questionnaire at the time of their followup appointments. Patients in the web-based group also completed a satisfaction and preference questionnaire 1 year later. Only patients from the web-based group were asked to indicate preference as they had experienced the web-based and in-person followup methods. We used descriptive statistics to summarize the satisfaction questionnaires and compared results using Pearson's chi-square test., Results: Ninety-one patients (82.0%) in the usual-care group indicated that they were either extremely or very satisfied with the followup process compared with 90 patients (75.6%) who were in the web-based group (p < 0.01; odds ratio [OR] = 3.95; 95% CI, 1.79-8.76). Similarly, patients in the usual care group were more satisfied with the care they received from their surgeon, compared with patients in the web-based group (92.8% versus 73.9%; p < 0.01, OR = 1.37; 95% CI, 0.73-2.57). Forty-four percent of patients preferred the web-based method, 36% preferred the usual method, and 16% had no preference (p = 0.01)., Conclusions: Our results show moderate to high satisfaction levels with a web-based followup assessment. Patients who completed the usual method of in-person followup assessment reported greater satisfaction; however, the difference was small and may not outweigh the additional cost and time-saving benefits of the web-based followup method., Level of Evidence: Level I, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Staphylococcus aureus and Staphylococcus epidermidis cause dangerous and difficult to treat medical device-related infections through their ability to form biofilms. Extracellular poly-N-acetylglucosamine (PNAG) facilitates biofilm formation and is a vaccination target, yet details of its biosynthesis by the icaADBC gene products is limited. IcaC is the proposed transporter for PNAG export, however a comparison of the Ica proteins to homologous exo-polysaccharide synthases suggests that the common IcaAD protein components both synthesise and transport the PNAG. The limited distribution of icaC to the Staphylococcaceae and its membership of a family of membrane-bound acyltransferases, leads us to suggest that IcaC is responsible for the known O-succinylation of PNAG that occurs in staphylococci, identifying a potentially new therapeutic target specific for these bacteria., (Copyright © 2014. Published by Elsevier B.V.)

Modern genetic mapping is plagued by the "missing heritability" problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies.

The purpose of this study was to determine agreement between responses on electronic and paper versions of the WOMAC and SF-12(v2) questionnaires following total hip and total knee arthroplasty. Patients completed both electronic and paper questionnaires with a one week interval in-between. The order in which they completed the two versions was randomly assigned. A total of 53 patients completed the study, with a mean age of 69 years (range 50-90 years). The intraclass correlation coefficients (ICC) were high, indicating excellent agreement (WOMAC ICC = 0.96, 95% CI 0.94-0.98), SF-12 (PCS) ICC = 0.95, 95% CI 0.92-0.97; SF-12 (MCS) ICC = 0.92, 95%CI 0.86-0.95). Online data collection may be substituted for the traditional paper method with no significant effect on the criterion validity of the questionnaires., (© 2014.)

Using a published drug-likeness score based on the calculated physicochemical properties of marketed oral drugs (quantitative estimate of drug-likeness, QED) and published human data, high-scoring and low-scoring drugs were compared to determine how well the score correlated with their actual pharmaceutical and pharmacokinetic (PK) profiles in humans. Drugs with high QED scores exhibit higher absorption and bioavailability, are administered at lower doses and have fewer drug-drug interaction warnings, P-glycoprotein interactions and absorption issues due to a food effect. By contrast, the high-scoring drugs exhibit similar behaviour to low-scoring drugs with respect to free fraction in plasma, extent of gut-wall metabolism, first-pass hepatic extraction, elimination half-life, clearance, volume of distribution and frequency of dosing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)