Validation of a personalized ligament-constraining discrete element framework for computing ankle joint contact mechanics.

BACKGROUND AND OBJECTIVE: Computer simulations of joint contact mechanics have great merit to improve our current understanding of articular ankle pathology. Owed to its computational simplicity, discrete element analysis (DEA) is an encouraging alternative to finite element analysis (FEA). However, previous DEA models lack subject-specific anatomy and may oversimplify the biomechanics of the ankle. The objective of this study was to develop and validate a personalized DEA framework that permits movement of the fibula and incorporates personalized cartilage thickness as well as ligamentous constraints. METHODS: A linear and non-linear DEA framework, representing cartilage as compressive springs, was established, verified, and validated. Three-dimensional (3D) bony ankle models were constructed from cadaveric lower limb CT scans imaged during application of weight (85 kg) and/or torque (10 Nm). These 3D models were used to generate cartilage thickness and ligament insertion sites based on a previously validated statistical shape model. Ligaments were modelled as non-linear tension-only springs. Validation of contact stress prediction was performed using a simple, axially constrained tibiotalar DEA model against an equivalent FEA model. Validation of ligamentous constraints compared the final position of the ankle mortise to that of the cadaver after application of torque and sequential ligament sectioning. Finally, a combined ligamentous-constraining DEA model was validated for predicted contact stress against an equivalent ligament-constraining FEA model. RESULTS: The linear and non-linear DEA model reproduced a mean articular contact stress within 0.36 MPa and 0.39 MPa of the FEA calculated stress, respectively. With respect to the ligamentous validation, the DEA ligament-balancing algorithm could reproduce the position of the distal fibula within the ankle mortise to within 0.97 mm of the experimental observed distal fibula. When combining the ligament-constraining and contact stress algorithm, DEA was able to reproduce a mean articular contact stress to within 0.50 MPa of the FEA calculated contact stress. CONCLUSION: The DEA framework presented herein offers a computationally efficient alternative to FEA for the prediction of contact stress in the ankle joint, manifesting its potential to enhance the mechanical understanding of articular ankle pathologies on both a patient-specific and population-wide level. The novelty of this model lies in its personalized nature, inclusion of the distal tibiofibular joint and the use of non-linear ligament balancing to maintain the physiological ankle joint articulation.

Multidimensional redox potential/pKa coupling in multicopper oxidases from molecular dynamics: implications for the proton transfer mechanism.

Bilirubin oxidases (BOD) are metalloenzymes that catalyze the conversion of O2 and bilirubin to biliverdin and water in the metabolism of chlorophyll and porphyrin. In this work we have used the CpHMD method to analyze the effects of the different oxidation states on the BOD trinuclear cluster (TNC). Our results demonstrate that there is a link between the different oxidation states of copper ions and the protonation capacity of nearby titratable residues. Each configuration affects pKa differently, creating proton gradients within the enzyme that act in an extremely orderly manner. This order is closely linked to the catalytic mechanism and leads us to the conclusion of the entry of the O2 molecule and its reduction in water molecules is associated with the probability of the release of protons from nearby acid groups. With this information, we deduce that under the initial reaction conditions the acidic side chains of nearby residues can be protonated; this allows the enzyme to reduce the activation energy of the reaction by coupling the proton transfer to oxidation state changes in the metallic center.

Genetic Algorithms Applied to Thermodynamic Rational Design of Mimetic Antibodies Based on the GB1 Domain of Streptococcal Protein G: An Atomistic Simulation Study.

The development of mimetic antibodies (MA) capable of combining the high affinity and selectivity of antibodies with the small size of the peptides has enormous potential for applications in current biotechnology. In this work, we demonstrate that in silico MA design is possible through genetic algorithms (GA) developed from shell scripts capable of combining software commonly used for atomistic simulation. Our results demonstrate that, using the GB1 domain of the streptococcal G protein as a model, it is possible to optimize the molecular recognition capacity of a large MA population in a few generations. In the first case, GA was able to generate 10 MA with binding free energy (BFE) less than the vascular endothelial cell growth factor conjugated with the fms-type tyrosine kinase receptor. In the second case, it generated 13 MA with BFE less than that of the hepatitis C-E2 viral envelope conjugate with the antibody. Through the GA developed in this work, we demonstrate the use of a new protocol, capable of guiding experimental methods for the design of bioactive peptides that can assist in the development of new therapeutic molecules.

Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors.

Checkpoint inhibitor (CPI) therapy has vastly improved long-term outcomes in metastatic malignant melanoma (MMM). Therapy takes the form of monoclonal antibody infusions that target immune cell checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1/programmed death ligand 1 (PD1/PDL1). Cutaneous immune-related adverse effects (IrAEs) are frequent in patients with MMM treated with CPIs. Our aim was to review the clinical presentations of cutaneous IrAEs associated with CPI therapy in adult patients with MMM. We carried out a literature review of clinical trials, case series and case reports of patients with melanoma and those with other cancers treated with anti-CTLA4, anti-PD1/PDL1, or a combination of these therapies. Diverse clinical presentations of cutaneous IrAEs are recognized. Anti-CTLA4 therapy has a higher associated rate of cutaneous IrAEs than anti-PD1/PDL1 therapies. Low-grade cutaneous IrAEs are common and are usually managed supportively while continuing CPI therapy. Delayed presentations arising after established use of CPIs can make therapy-associated cutaneous IrAEs difficult to distinguish from coincidental dermatological disease. Vitiligo-like depigmentation is a good prognostic indicator of outcome in patients with melanoma. Life-threatening adverse events including toxic epidermal necrolysis are rare. The identification of predictive biomarkers that highlight patients at risk of life-threatening IrAEs remains an unmet need. The involvement of dermatologists in the multidisciplinary assessment of cutaneous IrAEs is increasingly pertinent in the management and care of CPI-treated patients with melanoma.

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-ß1.

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-ß1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-ß1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-ßRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-ß1 than healthy control CD4+ T cells [reduced TGF-ß-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-ß1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis.

OBJECTIVES: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. METHODS: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. RESULTS: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. CONCLUSION: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable. TRIAL REGISTRATION NUMBER: NCT01352858.

Patient-specific chondrolabral contact mechanics in patients with acetabular dysplasia following treatment with peri-acetabular osteotomy.

OBJECTIVE: Using a validated, patient-specific finite element (FE) modeling protocol, we evaluated cartilage and labrum (i.e., chondrolabral) mechanics before and after peri-acetabular osteotomy (PAO) to provide insight into the ability of this procedure to improve mechanics in dysplastic hips. DESIGN: Five patients with acetabular dysplasia were recruited in this case-controlled, prospective study. Models, which included anatomy for bone, cartilage, and labrum, were generated from computed tomography (CT) arthrography scans acquired before and after PAO. Cartilage and labrum contact stress and contact area were quantified overall and regionally. Load supported by the labrum, expressed as a percentage of the total hip force, was analyzed. RESULTS: Percent cartilage contact area increased post-operatively overall, medially, and superiorly. Peak acetabular contact stress decreased overall, laterally, anteriorly, and superiorly. Average contact stress decreased overall, laterally, anteriorly, and posteriorly. Only average contact stress on the superior labrum and peak labrum stress overall decreased. Load supported by the labrum did not change significantly. CONCLUSIONS: PAO was efficacious at medializing cartilage contact and reducing cartilage contact stresses, and therefore may minimize deleterious loading to focal cartilage lesions, subchondral cysts, and cartilage delaminations often observed in the lateral acetabulum of dysplastic hips. However, the excessively prominent, hypertrophied labrum of dysplastic hips remains in contact with the femoral head, which continues to load the labrum following PAO. The clinical ramifications of continued labral loading following PAO are not known. However, it is plausible that failure to reduce the load experienced by the labrum could result in end-stage hip OA following PAO.

Total ankle replacement in patients with von Willebrand disease: mid-term results of 18 procedures.

von Willebrand disease (VWD) is a recognized cause of secondary ankle osteoarthritis (OA). Few studies have examined orthopaedic complications and outcomes in VWD patients treated for end-stage ankle OA with total ankle replacement (TAR). To determine the clinical presentation, intraoperative and postoperative complications and evaluate the mid-term outcome in VWD patients treated with TAR. Eighteen patients with VWD with mean age 47.3 years (range = 34.0-68.7) were treated for end-stage ankle OA with TAR. The mean duration of follow-up was 7.5 years (range = 2.9-13.2). Intraoperative and perioperative complications were recorded. Component stability was assessed with weight-bearing radiographs. Clinical evaluation included range of motion (ROM) tests using a goniometer and under fluoroscopy using a lateral view. Clinical outcomes were analysed by a visual analogue scale, the American Orthopaedic Foot and Ankle Society hindfoot score and Short Form (36) Health Survey (SF-36) health survey. One patient sustained an intraoperative medial malleolar fracture. In two patients delayed wound healing was observed. Two secondary major surgeries were performed. Pain level decreased from 8.2 ± 0.9 (range = 7-10) preoperatively to 1.1 ± 1.2 (range = 0-4) postoperatively. Significant functional improvement including ROM was observed. All categories of SF-36 score showed significant improvement in quality of life. Mid-term results of TAR in patients with VWD are encouraging. The total rate of intraoperative and postoperative complications was 33.3%. However, longer term outcomes are necessary to fully understand the clinical benefit of TAR in patients with VWD.

Computed tomography arthrography with traction in the human hip for three-dimensional reconstruction of cartilage and the acetabular labrum.

AIM: To develop and demonstrate the efficacy of a computed tomography arthrography (CTA) protocol for the hip that enables accurate three-dimensional reconstructions of cartilage and excellent visualization of the acetabular labrum. MATERIALS AND METHODS: Ninety-three subjects were imaged (104 scans); 68 subjects with abnormal anatomy, 11 patients after periacetabular osteotomy surgery, and 25 subjects with normal anatomy. Fifteen to 25 ml of contrast agent diluted with lidocaine was injected using a lateral oblique approach. A Hare traction splint applied traction during CT. The association between traction force and intra-articular joint space was assessed qualitatively under fluoroscopy. Cartilage geometry was reconstructed from the CTA images for 30 subjects; the maximum joint space under traction was measured. RESULTS: Using the Hare traction splint, the intra-articular space and boundaries of cartilage could be clearly delineated throughout the joint; the acetabular labrum was also visible. Dysplastic hips required less traction (∼5 kg) than normal and retroverted hips required (>10 kg) to separate the cartilage. An increase in traction force produced a corresponding widening of the intra-articular joint space. Under traction, the maximum width of the intra-articular joint space during CT ranged from 0.98-6.7 mm (2.46 ± 1.16 mm). CONCLUSIONS: When applied to subjects with normal and abnormal hip anatomy, the CTA protocol presented yields clear delineation of the cartilage and the acetabular labrum. Use of a Hare traction splint provides a simple, cost-effective method to widen the intra-articular joint space during CT, and provides flexibility to vary the traction as required.

Interest and informational preferences regarding genomic testing for modest increases in colorectal cancer risk.

BACKGROUND/AIMS: This study explored the interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer. METHODS: Surveys were conducted on 272 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhal's Common Sense Model of Self-Regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with interest in SNP testing and preferences for receiving genomic risk communications. RESULTS: Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials (69.5%), oncologists (54.8%), primary-care physicians (58.4%), and the web (58.1%). Overall, persons who were unmarried (p = 0.029), younger (p = 0.003) and with greater cancer-related fear (p = 0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer-related fear was associated with the interest in predictive genomic testing in the intervention group (p = 0.017), but not the control group. CONCLUSIONS: Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups and those with greater cancer fear.

Patient-specific analysis of cartilage and labrum mechanics in human hips with acetabular dysplasia.

BACKGROUND: Acetabular dysplasia is a major predisposing factor for development of hip osteoarthritis (OA), and may result from alterations to chondrolabral loading. Subject-specific finite element (FE) modeling can be used to evaluate chondrolabral mechanics in the dysplastic hip, thereby providing insight into mechanics that precede OA. OBJECTIVE: To evaluate chondrolabral contact mechanics and congruency in dysplastic hips and normal hips using a validated approach to subject-specific FE modeling. METHODS: FE models of ten subjects with normal acetabula and ten subjects with dysplasia were constructed using a previously validated protocol. Labrum load support, and labrum and acetabular cartilage contact stress and contact area were compared between groups. Local congruency was determined at the articular surface for two simulated activities. RESULTS: The labrum in dysplastic hips supported 2.8-4.0 times more of the load transferred across the joint than in normal hips. Dysplastic hips did not have significantly different congruency in the primary load-bearing regions than normal hips, but were less congruent in some unloaded regions. Normal hips had larger cartilage contact stress than dysplastic hips in the few regions that had significant differences. CONCLUSIONS: The labrum in dysplastic hips has a far more significant role in hip mechanics than it does in normal hips. The dysplastic hip is neither less congruent than the normal hip, nor subjected to elevated cartilage contact stresses. This study supports the concept of an outside-in pathogenesis of OA in dysplastic hips and that the labrum in dysplastic hips should be preserved during surgery.

Predictors of antenatal alcohol use among Australian women: a prospective cohort study.

OBJECTIVE: To identify predictors of antenatal alcohol consumption among women who usually consume alcohol. DESIGN: Prospective cohort study. SETTING: Australian Longitudinal Study on Women's Health (ALSWH). POPULATION OR SAMPLE: A total of 1969 women sampled from the ALSWH 1973-78 cohort. METHODS: Women were included if they were pregnant in 2000, 2003, 2006 or 2009. The relationship between antenatal alcohol consumption and sociodemographics, reproductive health, mental health, physical health, health behaviours, alcohol guidelines and healthcare factors was investigated using a multivariate logistic regression model. MAIN OUTCOME MEASURES: Alcohol use during pregnancy. RESULTS: Most (82.0%) women continued to drink alcohol during pregnancy. Women were more likely to drink alcohol during pregnancy if they had consumed alcohol on a weekly basis before pregnancy (odds ratio [OR] 1.47; 95% confidence interval [95% CI] 1.13-1.90), binge drank before pregnancy (OR 2.28; 95% CI 1.76-2.94), or if they were pregnant while alcohol guidelines recommended low alcohol versus abstinence (OR 1.60; 95% CI 1.26-2.03). Drinking during pregnancy was less likely if women had a Health Care Card (OR 0.63; 95% CI 0.45-0.88) or if they had ever had fertility problems (OR 0.64; 95% CI 0.48-0.86). CONCLUSIONS: Most Australian women who drank alcohol continued to do so during pregnancy. Prepregnancy alcohol consumption was one of the main predictors of antenatal alcohol use. Alcohol guidelines, fertility problems and Health Care Card status also impacted antenatal alcohol consumption.

Finite element predictions of cartilage contact mechanics in hips with retroverted acetabula.

BACKGROUND: A contributory factor to hip osteoarthritis (OA) is abnormal cartilage mechanics. Acetabular retroversion, a version deformity of the acetabulum, has been postulated to cause OA via decreased posterior contact area and increased posterior contact stress. Although cartilage mechanics cannot be measured directly in vivo to evaluate the causes of OA, they can be predicted using finite element (FE) modeling. OBJECTIVE: The objective of this study was to compare cartilage contact mechanics between hips with normal and retroverted acetabula using subject-specific FE modeling. METHODS: Twenty subjects were recruited and imaged: 10 with normal acetabula and 10 with retroverted acetabula. FE models were constructed using a validated protocol. Walking, stair ascent, stair descent and rising from a chair were simulated. Acetabular cartilage contact stress and contact area were compared between groups. RESULTS: Retroverted acetabula had superomedial cartilage contact patterns, while normal acetabula had widely distributed cartilage contact patterns. In the posterolateral acetabulum, average contact stress and contact area during walking and stair descent were 2.6-7.6 times larger in normal than retroverted acetabula (P ≤ 0.017). Conversely, in the superomedial acetabulum, peak contact stress during walking was 1.2-1.6 times larger in retroverted than normal acetabula (P ≤ 0.044). Further differences varied by region and activity. CONCLUSIONS: This study demonstrated superomedial contact patterns in retroverted acetabula vs widely distributed contact patterns in normal acetabula. Smaller posterolateral contact stress in retroverted acetabula than in normal acetabula suggests that increased posterior contact stress alone may not be the link between retroversion and OA.

Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease.

Interleukin (IL)-17 is pivotal in orchestrating the activity of neutrophils. Neutrophilic inflammation is the dominant pathology in cystic fibrosis (CF) lung disease. We investigated IL-17 protein expression in the lower airway in CF, its cellular immunolocalisation and the effects of IL-17 on CF primary bronchial epithelial cells. Immunohistochemistry was performed on explanted CF lungs and compared with the non-suppurative condition pulmonary hypertension (PH). Airway lavages and epithelial cultures were generated from explanted CF lungs. Immunoreactivity for IL-17 was significantly increased in the lower airway epithelium in CF (median 14.1%) compared with PH (2.95%, p=0.0001). The number of cells staining positive for IL-17 in the lower airway mucosa was also increased (64 cells·mm(-1) compared with 9 cells·mm(-1) basement membrane, p=0.0005) and included both neutrophils in addition to mononuclear cells. IL-17 was detectable in airway lavages from explanted CF lungs. Treatment of epithelial cultures with IL-17 increased production of IL-8, IL-6 and granulocyte macrophage colony-stimulating factor. In conclusion, immunoreactive IL-17 is raised in the lower airway of people with CF and localises to both neutrophils and mononuclear cells. IL-17 increases production of pro-neutrophilic mediators by CF epithelial cells, suggesting potential for a positive feedback element in airway inflammation.

Validation of computational models in biomechanics.

The topics of verification and validation have increasingly been discussed in the field of computational biomechanics, and many recent articles have applied these concepts in an attempt to build credibility for models of complex biological systems. Verification and validation are evolving techniques that, if used improperly, can lead to false conclusions about a system under study. In basic science, these erroneous conclusions may lead to failure of a subsequent hypothesis, but they can have more profound effects if the model is designed to predict patient outcomes. While several authors have reviewed verification and validation as they pertain to traditional solid and fluid mechanics, it is the intent of this paper to present them in the context of computational biomechanics. Specifically, the task of model validation will be discussed, with a focus on current techniques. It is hoped that this review will encourage investigators to engage and adopt the verification and validation process in an effort to increase peer acceptance of computational biomechanics models.

Racial/ethnic differences in the use of surgery for ovarian cancer in the United States.

PURPOSE: This study provides an assessment of patterns of both hysterectomy and other surgeries among ovarian cancer patients in the United States according to race/ethnicity. METHODS: Analyses are based on data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, 2002 through 2006. RESULTS: About 75% of ovarian cancer patients received surgery, with most undergoing unilateral or bilateral (salpingo-) oophorectomy with omentectomy or debulking (cytoreductive surgery). Black and Hispanic patients were significantly less likely to receive surgery after adjusting for age, marital status, and tumor stage and grade at diagnosis. Among cases aged 15-44 with localized disease, 35% selected fertility-conservative management. The percentage receiving fertility-conservative management fell from 57% in ages 15-29 to 12% in ages 40-44. There was no significant difference among women of childbearing age across racial/ethnic classifications in their use of fertility-conservative management. Among the 88% of patients aged 45 years or older at diagnosis, treatment with surgery was generally high: 90% for ages 45-59, 81% for ages 60-69, 68% for ages 70-79, and 38% for ages 80 and older. CONCLUSION: Black and Hispanic patients are less likely to receive surgery, but in women of childbearing age with locally staged disease there is no difference among racial/ethnic groups in fertility-conservative management.

Seasonal changes in suppressive capacity of CD4+ CD25+ T cells from patients with hayfever are allergen-specific and may result in part from expansion of effector T cells among the CD25+ population.

BACKGROUND: Suppression of allergen-stimulated peripheral blood CD4(+) CD25(-) effector T cells by CD4(+) CD25(+) regulatory T cells obtained from subjects with allergic rhinoconjunctivitis is reduced during the pollen season when compared with out of season. OBJECTIVE: We examined possible explanations for this effect of seasonal pollen exposure on suppression of allergen responses. METHODS: CD4(+) CD25(-) and CD4(+) CD25(+) T cells were isolated from blood obtained from 44 volunteers with allergic rhinoconjunctivitis during and out of the UK grass pollen season. Co-cultures were performed with grass pollen extract and house dust mite (HDM) to examine allergen specificity. The frequency of IL-5 and IL-10 producing cells was determined by ELISPOT and the expression of T cell activation markers and the CD25(+) regulatory T cell-associated transcription factor Foxp3 were examined. Lactic acid stripping of IgE was used to determine IgE dependence of T cell responses. RESULTS: The seasonal reduction in suppression by CD4(+) CD25(+) T cells was confirmed and was shown to be allergen specific because suppression of HDM-stimulated cultures was not affected significantly. The CD4(+) CD25(+) population contained IL-5 and IL-10 producing cells but increases in their frequencies with seasonal pollen exposure were not significant. Both activation marker and Foxp3 expression increased during the pollen season. IgE stripping reduced CD4(+) and CD4(+) CD25(-) T cell responses to allergen, but had no effect on suppression by CD4(+) CD25(+) T cells. CONCLUSION: The seasonal reduction in suppression of grass pollen-stimulated effector T cells by CD4(+) CD25(+) T cells is allergen specific and cannot be explained by increased IgE-facilitated allergen presentation. We suggest that changes in the proportion of effector to regulatory T cells among the CD25(+) population isolated may partially explain these findings, and that trafficking to the site of allergic disease may reduce allergen-specific regulatory T cell numbers in peripheral blood.