Citations

In young adults, bone lost through osteoclast-mediated resorption is precisely replaced in both location and amount. Understanding how these two processes are coupled is crucial to advancing treatments for osteoporosis, a disease that progresses when the processes become uncoupled. We documented that osteoclasts secrete the mammalian integration 1 gene that is the homolog of Drosophila Wngless (Wnt) 10b, bone morphogenetic protein 6 (BMP6), and the chemokine sphingosin 1 phosphate (S1P) to promote mesenchymal cell mineralization in vitro. During bone resorption, TGF-β1 is released from the bone extracellular matrix and activated by osteoclasts. Thus, TGF-β1 levels are elevated during the resorption phase of bone turnover. We therefore investigated the influences of TGF-β1 on osteoclast-mediated support of mineralization. TGF-β1 increased osteoclast production of Wnt10b, but not BMP6 or S1P. Blocking Wnt10b activity with the Wnt signaling inhibitor Dickkoph-related protein 1 suppressed the ability of TGF-β–treated osteoclast-conditioned media to promote osteoblast mineralization. Examination of TGF-β signaling in osteoclasts revealed that induction of Wnt10b expression was dependent on Smad2/3 activation and independent from TGF-β1 stimulation of protein kinase B (AKT) or MAPK kinase. TGF-β1–treated osteoclast-conditioned media from cells with blocked Smad signaling exhibited a reduced ability to support mineralization, demonstrating the importance of Smad signaling in this response. Parallel cultures with suppressed TGF-β activation of AKT or MAPK kinase signaling retained their ability to elevate mineralization. These results demonstrate that TGF-β1 stimulates Wnt10b production in osteoclasts, which may enhance restoration of the bone lost during the resorptive phase of bone turnover.

Abstract Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2–driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B4 (LTB4) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase–deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-β in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB4 receptor (BLT-1−/− /I5/hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene–mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cys-leukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene–mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-β.

We previously developed and validated a vortexing-sonication technique for detection of biofilm bacteria on the surface of explanted prosthetic joints. Herein, we evaluated this technique for diagnosis of infected breast tissue expanders and used it to assess colonization of breast tissue expanders. From April 2008 to December 2011, we studied 328 breast tissue expanders at Mayo Clinic, Rochester, MN, USA. Of seven clinically infected breast tissue expanders, six (85.7%) had positive cultures, one of which grewPropionibacteriumspecies. Fifty-two of 321 breast tissue expanders (16.2%, 95% CI, 12.3–20.7%) without clinical evidence of infection also had positive cultures, 45 growingPropionibacteriumspecies and ten coagulase-negative staphylococci. While vortexing-sonication can detect clinically infected breast tissue expanders, 16 percent of breast tissue expanders appear to be asymptomatically colonized with normal skin flora, most commonly,Propionibacteriumspecies.

Background: Tibial tubercle–trochlear groove distance (TT-TG) is a commonly used measurement for surgical decision making in patients with patellofemoral malalignment and instability. This measurement has historically been performed utilizing axial computed tomography (CT). More recently, magnetic resonance imaging (MRI) has been proposed as an equivalent method, but this has not yet been fully validated. Purpose: To determine the reliability of TT-TG distance measurements on both MRI and CT and to determine whether the measurements are interchangeable with one another. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: All patients with patellar instability who underwent both CT and MRI of the knee from 2003 to 2011 were included (n = 59 knees in 54 patients). Two fellowship-trained musculoskeletal radiologists measured the TT-TG distances for each patient by CT and MRI in a randomized, blinded fashion. Interobserver reliability was calculated between radiologists for both imaging modalities, and intermethod reliability was calculated between the 2 imaging modalities. The results are reported using intraclass correlation coefficients (ICCs) and Bland-Altman analysis. Results: The 59 knees had a mean TT-TG distance of 16.9 mm (range, 8.3-25.8 mm) by CT and 14.7 mm (range, 1.5-25.1 mm) by MRI. Interobserver reliability between the radiologists was considered excellent for both CT and MRI (ICC = 0.777 and 0.843, respectively). When comparing CT to MRI, the ICC was considered only fair for each of the raters (0.532 and 0.539). Eleven patients (19%) had a TT-TG distance of ≥20 mm on CT preoperatively and underwent distal realignment by tibial tubercle osteotomy. In this surgical subgroup, the mean TT-TG distance was 22.5 mm (range, 19.8-25.8 mm) by CT and only 18.7 mm (range, 14.4-22.8 mm) by MRI for a mean difference of 3.80 mm ( P < .001). Conclusion: The TT-TG distance can be measured with excellent interrater reliability on both MRI and CT; however, the values derived from these 2 tests may not be interchangeable. This observation should be taken into consideration when MRI is used for surgical planning because MRI may underestimate the TT-TG distance when compared with CT.

Purpose Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Patients and Methods Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m 2 ) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Results Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m 2 for tablet and 160 mg/m 2 for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Conclusion Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Objective: To determine the temporal trends in diagnosis and management of pediatric overweight/obesity by primary care providers at a single medical center. Patients: Children 2 to 18 years old undergoing a general medical examination during 3 calendar years (2003, 2006, and 2009). The number of visits for general medical examination were 6390 in 2003, 6646 in 2006, and 7408 in 2009. Methods: We performed a retrospective review of the electronic medical records for weight related diagnostic and/or management terms and laboratory screening in children with body mass index at or greater than the 85th percentile (n = 1630 in 2003, 1495 in 2006, and 1730 in 2009). Results: There was a significant increase in the diagnosis of obesity among obese children seen in 2009 (53.3%) compared with 2006 (36%, P < .001) and 2003 (24.3%, P < .001). Weight-related counseling was documented in a higher proportion of obese children in 2009 (49.4%) compared with 2006 (34.8%) and 2003 (26.6%). There was a significant increase in counseling regarding screen time in 2009 compared with 2006. A significant increase in screening for nonalcoholic fatty liver disease was also noted (30.5% in 2009 vs 21.9% in 2006, P = .018). Conclusions: There has been steady improvement in the rates of obesity diagnosis and obesity-related counseling by primary care providers. However, continued efforts to increase awareness of these issues are needed as nearly half of obese children remained undiagnosed and recommended laboratory screening for obesity-related comorbidities was performed in only a third of obese children.