Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

A 10% increase in step rate improves running kinematics and clinical outcomes in runners with patellofemoral pain at 4 weeks and 3 months

Background: Aberrant frontal plane hip and pelvis kinematics have been frequently observed in runners with patellofemoral pain (PFP). Gait retaining interventions have been shown to improve running kinematics and may therefore be beneficial in runners with PFP. Purpose: the aim of this study was to investigate whether a 10% increase in running step rate influences frontal plane kinematics of the hip and pelvis, as well as clinical outcomes in runners with PFP. Study Design: Case Series Methods: Runners with PFP underwent a 3D gait analysis to confirm the presence of aberrant frontal plane hip and pelvis kinematics at baseline. Twelve participants with frontal plane hip and pelvis kinematics one standard deviation above a reference database, were invited to participate in the gait retraining intervention. Running kinematics along with clinical outcomes of pain and functional measures were recorded at baseline, 4 weeks following retraining and 3-months. Gait retraining consisted of a single session where step rate was increased by 10% using an audible metronome. Participants were asked to continue their normal running while self-monitoring their step rate using a global positioning system watch and audible metronome. Results: Following gait retraining significant improvements in running kinematics and clinical outcomes were observed at 4 week and 3-month follow up. Repeated measures ANOVA with post hoc Bonferroni (p <0.016) showed significant reductions in peak contralateral pelvic drop (Mean Difference [MD], 3.12⁰; 95% Confidence Interval [CI], 1.88⁰, 4.37⁰), hip adduction (MD, 3.99⁰; 95% CI, 2.01⁰, 5.96⁰) and knee flexion (MD, 4.09⁰; 95% CI, 0.04⁰, 8.15⁰), as well as significant increases in self-reported weekly running volume (MD, -13.78km; 95% CI, -22.93km, -4.62km) and longest run pain free (MD, -6.84km; 95% CI, -10.62km, -3.05km). Friedman test with post hoc Wilcoxon signed-rank showed significant improvements in Numerical Rating Scale for worst pain in the past week and Lower Extremity Functional Scale. Conclusion: A single session of gait retraining using a 10% increase in step rate results in significant improvements in running kinematics, pain and function in runners with PFP. These improvements were maintained at 3-month follow up. It is important to assess for aberrant running kinematics at baseline to ensure gait interventions are targeted appropriately. Clinical Relevance: Step rate modification is a simple method of gait retraining that can be easily integrated into clinical practice and running outside of a laboratory setting

Is there a pathological gait associated with common soft tissue running injuries?

Background: Previous research has demonstrated clear associations between specific running injuries and patterns of lower limb kinematics. However, there has been minimal research investigating whether the same kinematic patterns could underlie multiple different soft tissue running injuries. If they do, such kinematic patterns could be considered global contributors to running injury. Hypothesis: Injured runners will demonstrate differences in running kinematics when compared to injury free controls. These kinematic patterns will be consistent amongst injury subgroups. Study Design: Case- Control Study Methods: We studied 72 injured runners and 36 healthy controls. The injured group contained four subgroups of runners with either patellofemoral pain, iliotibial band syndrome, medial tibial stress syndrome or Achilles tendinopathy (n = 18 each). Three-dimensional running kinematics were compared between injured and healthy runners and then between the four injured subgroups. A logistic regression model was used to determine which parameters could be used to identify injured runners. Results: The injured runners demonstrated greater contralateral pelvic drop and forward trunk lean at mid-stance and a more extended knee and dorsiflexed ankle at initial contact. The subgroup ANOVA found these kinematic patterns were consistent across each of the four injury subgroups. Contralateral pelvic drop was found to be the most important variable predicting classification of participants as healthy/injured. Importantly, for every 1° increase in pelvic drop there was an 80% increase in the odds of being classified injured. Conclusion: This study identified a number of global kinematic contributors to common running injuries. In particular, we found injured runners to run with greater peak contralateral pelvic drop and trunk forward lean, as well as an extended knee and dorsiflexed ankle at initial contact. Contralateral pelvic drop appears to be the variable most strongly associated with common running related injuries. Clinical Relevance: The identified kinematic patterns may prove beneficial for clinicians when assessing for biomechanical contributors to running injuries

Effect of social media in improving knowledge among patients having fixed appliance orthodontic treatment: A single-center randomized controlled trial

Research has shown that orthodontic patients are more likely to retain information presented in an audiovisual format. However, there has been little research on the effectiveness of audiovisual information provided through different routes such as the Internet. This parallel-group randomized controlled trial assessed whether provision of audiovisual information on the YouTube (Google, San Bruno, Calif) Web site to orthodontic patients undergoing fixed appliance treatment results in improved patient knowledge when compared with conventional methods of information provision. The effects of sex and ethnicity were also investigated

Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis.

Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC.S-S Liau is in receipt of the MRC Clinician Scientist Fellowship. He is also funded by University of Cambridge Parke-Davis Fellowship, Royal Society of Medicine Ellison-Cliffe Fellowship, Dowager Countess Eleanor Peel Fellowship, HCA International Foundation Fellowship, European Society of Surgical Oncology Minor Fellowship, and MRC Centenary Early Career Award.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S074879831401097X#

Kinematic characteristics of male runners with a history of recurrent calf muscle strain injury

Background: Calf muscle strain injuries are a common running injury affecting male runners and are known to have high reoccurrence rates. Currently, limited evidence exists investigating factors associated with this injury with no previous study investigating the running kinematics of male runners with a history of repeat calf muscle strain injuries. Purpose: To investigate differences in running kinematics between runners with a history of recurrent calf muscle strain injury and injury free controls. Study Design: Case-control investigation Level of Evidence: 4 Methods: Stance phase kinematics were compared between 15 male runners with a history of calf muscle strain injury and 15 male control participants during treadmill running at 3.2m/s. Independent t-tests were used to compare differences in stance phase kinematic parameters between groups and effect sizes were calculated using Cohen’s d. Results: The group with a history of calf muscle strain injury demonstrated a significant 2.1⁰ and 3.1⁰ increase in contralateral pelvic drop and anterior pelvic tilt during mid stance. In addition, this group exhibited longer stance times and a more anterior tilted pelvis, flexed hip and a greater distance between the heel and centre of mass at initial contact. Large effect sizes, greater than 0.8, were observed for all differences. No significant differences were observed for ankle and knee joint kinematics between the groups. Conclusion: This is the first study to identify kinematic characteristics associated with recurrent calf muscle strain injury. While it is not possible to determine causality, the observed kinematic differences may contribute to recurrent nature of this injury. Specifically, it is possible that neuromuscular deficits of the hip and calf muscle complex may lead to increased strain on the calf complex. Rehabilitation interventions which focus on addressing pelvis and hip kinematics may reduce the demands placed upon the calf complex and could prove clinically effective

Sporormiella as a tool for detecting the presence of large herbivores in the Neotropics

The reliability of using the abundance of Sporormiella spores as a proxy for the presence and abundance of megaherbivores was tested in southern Brazil. Mud-water interface samples from nine lakes, in which cattle-use was categorized as high, medium, or low, were assayed for Sporormiella representation. The sampling design allowed an analysis of both the influence of the number of animals using the shoreline and the distance of the sampling site from the nearest shoreline. Sporormiella was found to be a reliable proxy for the presence of large livestock. The concentration and abundance of spores declined from the edge of the lake toward the center, with the strongest response being in sites with high livestock use. Consistent with prior studies in temperate regions, we find that Sporormiella spores are a useful proxy to study the extinction of Pleistocene megafauna or the arrival of European livestock in Neotropical landscapes