Citations

ABSTRACT More accurate techniques to estimate fracture risk could help reduce the burden of fractures in postmenopausal women. Although micro-finite element (µFE) simulations allow a direct assessment of bone mechanical performance, in this first clinical study we investigated whether the additional information obtained using geometrically and materially nonlinear µFE simulations allows a better discrimination between fracture cases and controls. We used patient data and high-resolution peripheral quantitative computed tomography (HRpQCT) measurements from our previous clinical study on fracture risk, which compared 100 postmenopausal women with a distal forearm fracture to 105 controls. Analyzing these data with the nonlinear µFE simulations, the odds ratio (OR) for the factor-of-risk (yield load divided by the expected fall load) was marginally higher (1.99; 95% confidence interval [CI], 1.41–2.77) than for the factor-of-risk computed from linear µFE (1.89; 95% CI, 1.37–2.69). The yield load and the energy absorbed up to the yield point as computed from nonlinear µFE were highly correlated with the initial stiffness (R2 = 0.97 and 0.94, respectively) and could therefore be derived from linear simulations with little loss in precision. However, yield deformation was not related to any other measurement performed and was itself a good predictor of fracture risk (OR, 1.89; 95% CI, 1.39–2.63). Moreover, a combined risk score integrating information on relative bone strength (yield load-based factor-of-risk), bone ductility (yield deformation), and the structural integrity of the bone under critical loads (cortical plastic volume) improved the separation of cases and controls by one-third (OR, 2.66; 95% CI, 1.84–4.02). We therefore conclude that nonlinear µFE simulations provide important additional information on the risk of distal forearm fractures not accessible from linear µFE nor from other techniques assessing bone microstructure, density, or mass. © 2013 American Society for Bone and Mineral Research.

Abstract Of the features that characterize glioblastoma, arguably none is more clinically relevant than the propensity of malignant glioma cells to aggressively invade into the surrounding normal brain tissue. These invasive cells render complete resection impossible, confer significant resistance to chemo- and radiation-therapy, and virtually assure tumor recurrence. Expression of TROY (TNFRSF19), a member of the TNF receptor superfamily, inversely correlates with patient survival and stimulates glioblastoma cell migration and invasion in vitro. In this study, we report that TROY is overexpressed in glioblastoma tumor specimens and TROY mRNA expression is increased in the invasive cell population in vivo. In addition, inappropriate expression of TROY in mouse astrocytes in vivo using glial-specific gene transfer in transgenic mice induces astrocyte migration within the brain, validating the importance of the TROY signaling cascade in glioblastoma cell migration and invasion. Knockdown of TROY expression in primary glioblastoma xenografts significantly prolonged survival in vivo. Moreover, TROY expression significantly increased resistance of glioblastoma cells to both IR- and TMZ-induced apoptosis via activation of Akt and NF-κB. Inhibition of either Akt or NF-κB activity suppressed the survival benefits of TROY signaling in response to TMZ treatment. These findings position aberrant expression and/or signaling by TROY as a contributor to the dispersion of glioblastoma cells and therapeutic resistance. Implications: Targeting of TROY may increase tumor vulnerability and improve therapeutic response in glioblastoma. Mol Cancer Res; 11(8); 865–74. ©2013 AACR.

Key PointsRadiation is appropriate primary therapy in approximately 25% of cases. Radiation provides long-term remissions in more than 50% of patients.

Objectives To assess the safety and efficacy of tadalafil once daily on lower urinary tract symptoms suggestive of clinical benign prostatic hyperplasia ( BPH‐LUTS ) in men without erectile dysfunction ( ED ). To compare these with effects in men with ED . Patients and Methods After a 4‐week washout period and 4‐week placebo run‐in period, 1089 men without ED ( n = 338) and with ED ( n = 751) were randomly assigned to placebo or tadalafil 5 mg once daily for 12 weeks in three global clinical studies with similar designs. In the pooled dataset, post hoc analyses of covariance assessed the impact and severity of BPH‐LUTS using the I nternational P rostate S ymptom S core ( IPSS ) and the BPH I mpact I ndex ( BII ) and IPSS quality‐of‐life ( IPSS ‐ QoL ) subscores. Safety was assessed using treatment‐emergent adverse events. The treatment‐by‐ ED ‐status interaction was used to assess efficacy differences between the with/without ED subgroups. Results Men without ED were similar in BPH‐LUTS severity/previous therapy to men with ED . Tadalafil significantly reduced BPH‐LUTS from baseline when compared with placebo in men without ED ( IPSS −5.4 vs −3.3, P < 0.01; IPSS voiding subscore −3.5 vs −2.0, P < 0.01; IPSS storage subscore −1.9 vs −1.3, P < 0.05). Tadalafil also significantly improved quality of life from baseline when compared with placebo in men without ED ( IPSS ‐ QoL −1.0 vs −0.7, BII −1.4 vs −1.0; both P < 0.05). Between‐ ED ‐subgroup interactions were not significant (all P > 0.68). Tadalafil was safe and well tolerated. Conclusion Tadalafil 5 mg once daily improved BPH‐LUTS in men without ED by a magnitude similar to that observed in men with ED . The adverse event profile in men without ED was consistent with that observed in men with ED .

To handle problems and trends in emergency department (ED) operations, designers and decision makers often simulate and evaluate various case-specific scenarios before testing them in a real-life environment. However, conceptualizing broad possible scenarios for ED operations prior to simulation operationalization is usually neglected. The authors developed a methodology that integrates design of simulation experiments (DSE) as follows: 1) From a literature survey, they culled generic factors whose varying levels determine possible scenarios; 2) the authors drew up a set of generic interactions among these generic factors; 3) a questionnaire was constructed to serve as an instrument to gather the relevant information from management staff about relevant factors, their levels and interactions for a specific ED. Questionnaire responses support a schematic conceptualization of scenarios that should be simulated for a specific ED. They illustrate the application of the authors’ methodology for conceptualization of ED simulation scenarios in two different EDs.

Background: Decreased hip range of motion (ROM) is a common finding in patients with femoroacetabular impingement (FAI). Purpose: To report the prevalence of decreased hip ROM in asymptomatic adolescent athletes and to correlate examination findings to signs of FAI on radiographs and magnetic resonance imaging (MRI). Study Design: Cross-sectional study (prevalence); Level of evidence, 3. Methods: A total of 226 adolescent athletes presenting for state-mandated preparticipation physical examinations were assessed. Hip internal rotation was measured with the participant supine and the hip flexed to 90°. All participants with ≤10° of internal rotation were invited to return for standard radiographs and MRI of both hips. An age-matched control group, with >10° of internal rotation, underwent MRI examination only. Twenty-six athletes (13 study and 13 control) returned for clinical and radiographic examinations. Results: Nineteen athletes (34 hips, 8%) were found to have <10° of internal rotation. Eight athletes (13 hips, 3%) also had a positive anterior impingement sign. Thirteen of 19 athletes participated in the radiographic portion of the study. Of these 13 participants, 4 had limited internal rotation unilaterally, leaving 22 hips in the study group. Eight of 13 participants (15 hips, 68%) had a cam-type deformity evident on plain radiographs, and 4 participants (7 hips, 32%) had a positive radiographic crossover sign. The average α angle measured from radial MRI sequences was 58.1° in the study group versus 44.3° in the control group ( P < .001). Fifteen hips (68%) in the study group had abnormal MRI findings within the acetabular labrum or cartilage compared with 10 of 26 hips (38%) in the control group (odds ratio, 3.4; P = .078). Conclusion: Eight percent of asymptomatic teenagers had limited internal rotation on examination; 68% of these had radiographic findings suggestive of FAI. More than two thirds of these participants had evidence of asymptomatic hip pathological lesions on MRI.

Abstract Epithelial cells at mucosal surfaces are integral components of innate and adaptive immunity. IL-25 is reportedly produced by epithelial cells and likely plays vital roles in regulating type-2 immune responses. However, little is known regarding the mechanisms that control production and extracellular releases of IL-25. We hypothesized that proteases from the multiple allergens may induce IL-25 production in airway epithelial cells. In this study, we found that IL-25 is constitutively produced and detectable in cytoplasm of resting normal human bronchial epithelial (NHBE) cells. When exposed to airborne allergens such as house dust mite (HDM), stored IL-25 was released rapidly to the extracellular space. IL-25 release was not accompanied by cell death, suggesting involvement of active secretory mechanism(s). HDM also enhanced IL-25 mRNA transcription, which was dependent on their protease activities. Furthermore, activation of NHBE cells with authentic proteases, such as trypsin and papain, or with a peptide agonist for protease-activated receptor 2 was sufficient to enhance IL-25 mRNA transcription and protein. Protease-driven increase in mRNA transcription and allergen-driven extracellular release of IL-25 protein was also observed in primary nasal epithelial cells from healthy individuals. These findings suggest that IL-25 production by airway epithelial cells is regulated by the transcription and protein release levels and that allergen proteases likely play pivotal roles in both biological processes.

Objective. To determine whether routine laboratory parameters are predictors of early mortality after acute ischemic stroke (AIS). Methods. The cohort consisted of 522 consecutive patients with AIS presenting to the emergency department (ED) at a tertiary referral center during a 27-month period, residing within the surrounding ten counties. Serum laboratory values were obtained for all patients and categorized according to whether the levels were low, normal, or high. These laboratory results were evaluated as potential predictors of 90-day mortality using Cox proportional hazards models. The associations were summarized by calculating risk ratios (RRs) and 95% confidence intervals (CI). Results. The presence of elevated white blood cell count (RR 2.2, 95% CI 1.5–3.4), low bicarbonate (RR 4.2, 95% CI 2.6–6.7), low calcium (RR 2.9, 95% CI 1.4–5.9), and high glucose (RR 1.3, 95% 1.1–1.6) were each univariately associated with significantly higher mortality within the first 90 days. Based on fitting a multivariate Cox regression model, elevated white blood cell count, low bicarbonate, and high glucose were each identified as being jointly associated with early mortality (). Conclusion. Early leukocytosis, acidosis, and hyperglycemia and hypocalcemia in AIS appear to be associated with early mortality. Whether addressing these factors will impact survival remains to be investigated.

Immigrants and refugees arrive to the United States healthier than the general population, but this advantage declines with increasing duration of residence. One factor contributing to this decline is suboptimal physical activity, but reasons for this are poorly understood. Persons from Somalia represent the largest African refugee population to the United States, yet little is known about perceptions of physical activity among Somali men. Somali members of a community-based participatory research partnership implemented three age-stratified focus groups and three semistructured interviews among 20 Somali men in Rochester, Minnesota. Team-based inductive analysis generated themes for barriers and facilitators to physical activity. Barriers to physical activity included less walking opportunities in the United States, embarrassment about exercise clothing and lack of familiarity with exercise equipment/modalities, fear of harassment, competing priorities, facility costs, transportation, and winter weather. Facilitators to physical activity included high knowledge about how to be active, success stories from others in their community as inspiration, and community cohesion. Findings may be used to derive interventions aimed to promote physical activity among Somali men in the United States.