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Understanding differences between types of study design (SD) and level of evidence (LOE) are important when selecting research for presentation or publication and determining its potential clinical impact. The purpose of this study was to evaluate interobserver and intraobserver reliability when assigning LOE and SD as well as quantify the impact of a commonly used reference aid on these assessments.Thirty-six accepted abstracts from the Pediatric Orthopaedic Society of North America (POSNA) 2021 annual meeting were selected for this study. Thirteen reviewers from the POSNA Evidence-Based Practice Committee were asked to determine LOE and SD for each abstract, first without any assistance or resources. Four weeks later, abstracts were reviewed again with the guidance of the Journal of Bone and Joint Surgery (JBJS) LOE chart, which is adapted from the Oxford Centre for Evidence-Based Medicine. Interobserver and intraobserver reliability were calculated using Fleiss' kappa statistic (k). χ2 analysis was used to compare the rate of SD-LOE mismatch between the first and second round of reviews.Interobserver reliability for LOE improved slightly from fair (k=0.28) to moderate (k=0.43) with use of the JBJS chart. There was better agreement with increasing LOE, with the most frequent disagreement between levels 3 and 4. Interobserver reliability for SD was fair for both rounds 1 (k=0.29) and 2 (k=0.37). Similar to LOE, there was better agreement with stronger SD. Intraobserver reliability was widely variable for both LOE and SD (k=0.10 to 0.92 for both). When matching a selected SD to its associated LOE, the overall rate of correct concordance was 82% in round 1 and 92% in round 2 (P0.001).Interobserver reliability for LOE and SD was fair to moderate at best, even among experienced reviewers. Use of the JBJS/Oxford chart mildly improved agreement on LOE and resulted in less SD-LOE mismatch, but did not affect agreement on SD.Level II.

Carbon fiber reinforced polymers (CFRPs) are increasingly used in the aerospace industry because of their robust mechanical properties and strength to weight ratio. A significant drawback of CFRPs is their resistance to formability when drawing continuous CFRPs into complex shapes as it tends to bridge, resulting in various defects in the final product. However, CFRP made from Stretch Broken Carbon Fiber (SBCF) aims to solve this issue by demonstrating superior formability compared to conventional continuous CFRPs. To study and validate the performance of SBCF, a statistical design of the experiment was conducted using three different types of CFRPs in tow/tape form. Hexcel (Stamford, CT, USA) IM7-G continuous carbon fiber impregnated with Huntsman (The Woodlands, TX, USA) RDM 2019-053 resin system, Hexcel SBCF impregnated with RDM2019-053 resin, and Montana State University manufactured SBCF impregnated with Huntsman RDM 2019-053 resin were tested in a multitude of forming trials and the data were analyzed using a statistical model to evaluate the forming behavior of each fiber type. The results show that for continuous fiber CFRP tows forming, Fmax and Δmax do not show statistical significance based on temperature fluctuations; however, in SBCF CFRP tows forming, Fmax and Δmax is dominated by the temperature and geometry has a low statistical influence on the Fmax. The lower dependence on tool geometry at higher temperatures indicates possibly superior formability of MSU SBCF. Overall findings from this research help define practical testing methods to compare different CFRPs and provide a repeatable approach to creating a statistical model for measuring results from the formability trials.

Objectives Patient-reported outcomes (PRO) assessing health-related quality of life (HRQoL) are important outcome measures, especially in Legg-Calve-Perthes disease (LCPD) where symptoms (pain and limping), activity restrictions, and treatments vary depending on the stage of the disease. The purpose of this study was to investigate the validity of the Patient-reported Outcomes Measurement Information System (PROMIS) for measuring HRQoL of patients with LCPD in various stages of the disease. Methods This is a multicenter validity study. Patients with LCPD between 4 and 18 years old were included and classified into modified Waldenstrom stages of disease: Early (1 or 2A), Late (2B or 3), or Healed (4). Seven PROMIS domains were collected, including Pain Interference, Fatigue, Mobility, Depression, Anger, Anxiety, and Peer Relationships. Convergent, discriminant, and known group validity was determined. Results A total of 190 patients were included (mean age: 10.4±3.1 y). All 7 domains showed the worst scores in patients in the Early stage (known group validity). Within each domain, all domains positively correlated to each other (convergent validity). Patients who reported more anxiety, depression, and anger were associated with decreased mobility and increased fatigue and pain. Peer relationships had no to weak associations with other domains (discriminant validity). Conclusions PROMIS has construct validity in measuring the HRQoL of patients in different stages of LCPD, suggesting that PROMIS has potential to serve as a patient-reported outcome tool for this population. Level of evidence Diagnostic level III study.

Background Distal radius fractures (DRFs) are the most common pediatric orthopaedic fracture, of which 20% are displaced injuries. Displaced metaphyseal DRFs are often treated with sedated or anesthetized reduction. The necessity of reduction treatment of displaced fractures to achieve good clinical outcomes is unclear. The purpose of this investigation was to determine the treatment preferences for DRFs among pediatric orthopaedic surgeons and to determine whether they were uncertain enough in their decisions to randomize treatment. Methods Twenty-eight DRF scenarios in children aged 3 to 10 years were constructed in an electronic survey to represent a spectrum of age, angulation in sagittal and coronal planes, and displacement. The survey was disseminated to the full membership of the Pediatric Orthopaedic Society of North America (POSNA). Respondents could select either a treatment of (a) attempt anatomic reduction with sedation or (b) nonsedated immobilization. Respondents also denoted whether they would be willing to randomize the treatment of each injury scenario. Patient, fracture, and surgeon characteristics were analyzed to develop predictors of treatment recommendations and willingness to randomize treatment. Results A total of 319 surgeons responded (23% of POSNA membership). Respondents were a characteristic representation of POSNA membership (well distributed by years in practice, 78% academic, 91% whose work is >80% pediatrics, and 84% work with residents). Predictors of sedated reduction were complete displacement [odds ratio (OR), 9.23; 95% confidence interval (CI), 2.27-37.51; P=0.002] and coronal angulation (per 1-degree increase, OR, 1.09; 95% CI, 1.02-1.17; P=0.016), Willingness to randomize was inversely related to larger coronal plane angulation (per 1-degree increase, OR, 0.96; 95% CI, 0.93-0.99; P=0.01). A majority of surgeons were willing to randomize 7 of the 8 scenarios involving complete displacement and shortening, and >64% of surgeons were willing to randomize 5 of these 8 scenarios. Conclusions POSNA members recommend sedated reduction of DRFs primarily based on existence of complete displacement. Although most completely displaced DRFs would undergo reduction, most surgeons would be willing to randomize the treatment of these injuries. This suggests that most POSNA members do not know whether their recommended treatment for displaced DRFs is necessary or correct. This survey establishes the groundwork for a randomized, prospective trial comparing nonsedated immobilization with sedated/anesthetized reduction in the treatment of displaced pediatric DRFs. Levels of evidence Level II-survey study.

Stretch broken carbon fiber (SBCF) is generated by breaking individual filaments in carbon fiber tows at inherent flaws in tension in a continuous process. This process results in randomly broken, collimated fiber fragments. The shorter fiber length improves forming properties while retaining mechanical strength through shear load transfer. SBCF has the potential to take advantage of low-cost manufacturing processes like those used in sheet metal forming, resulting in ordersof- magnitude cost savings and enabling conversion to composite structures across the industry. Because uncured continuous carbon fiber composites do not exhibit significant plastic deformation, they cannot be readily adapted to many common sheet metal forming techniques. SBCF composites exhibit pseudo-plastic deformation, but this deformation is due to different mechanisms. To adapt the manufacturing processes for large and complex parts, new materials testing techniques are needed to quantify the forming behavior of SBCF at the meso-scale (tow and ply). This work’s primary objective is to develop predictive models for complex shape forming and large component characterization. Tests have been developed to characterize the behavior of SBCF tows under various forming conditions. Tow forming and laminate bulge testing allowed for experimental characterization of the SBCF response. Respectively, these tests focus on developing the load-displacement material response along with variation of the strain distribution. Using design of experiment (DOE) technique, the forming response to materials properties such as resin viscosity and mean fiber length have been related. For each test, a correlated Finite Element Analysis (FEA) model was developed, allowing for progression toward understanding a wider array of properties than experimentally.

We investigated if infants with a Barlow positive hip(s) have natural hip stabilization and can thus avoid Pavlik Harness (PH) treatment. We conducted a chart review for infants who presented within two weeks of life, had a Barlow positive hip, and were deferred treatment. Of the thirty infants, eighteen were treated with PH at 4-6 weeks or 12 weeks due to persistent dysplasia. Twelve infants avoided PH entirely. There were zero cases of PH failure. Parents can be counseled that deferring treatment until at least 4-6 weeks of age might avoid treatment altogether without an increased risk of harness failure.

Background Developmental dysplasia of the hip is effectively treated with a Pavlik harness (PH) within the first 6 months of life. Over 80% of unstable hips in the newborn period will naturally stabilize by 2 months of age. If there is no difference in the effectiveness of initiating PH treatment at 1 week compared with 4 weeks of age, waiting may allow the hips to naturally stabilize and avoid treatment. The purpose of this study is to evaluate whether the timing of PH implementation influences its effectiveness in the treatment of developmental dysplasia of the hip. Methods A retrospective review was conducted between 2004 and 2010. Patients were included if PH therapy was prescribed for hip instability or dislocation at or before 6 months of age. PH failure was defined as requiring any operative procedure for definitive management. Groups were divided based on the age at which the PH was initiated-group1= 60 days. Results A total of 176 children were included with 38 (21.6%) failing PH treatment. The mean age at PH initiation was 1.3 months (SD=1.3) in the successfully treated children and 1.4 months (SD=1.2) in the failures (P=0.77). There was no difference in the failure rates by age with group 1=19.1% (18/94), group 2=22.5% (9/40), and group 3=26.2% (11/42) (P=0.87). There was no statistical difference with respect to sex or breech positioning in the success or failure groups; however, there was a higher percentage of bilateral involvement in the failure group (P=0.04). Conclusions Patients who had PH initiation before 30 days of age were no more or less likely to fail than when PH was initiated after 30 days of age. Parents can be counseled that waiting until after 30 days of age is appropriate before PH implementation. By avoiding swaddling during this period, the hips may stabilize without treatment and allow for more parental-infant bonding before implementation of PH. Level of evidence Level III-therapeutic, case control study.

Cardiac fibrosis is an underlying cause of diastolic dysfunction, contributing to heart failure. Substance P (SP) activation of the neurokinin-1 receptor (NK-1R) contributes to cardiac fibrosis in hypertension. However, based on in vitro experiments, this does not appear to be via direct activation of cardiac fibroblasts. While numerous cells could mediate the fibrotic effects of SP, herein, we investigate mast cells (MC) as a mechanism mediating the fibrotic actions of SP, since MCs are known to play a role in cardiac fibrosis and respond to SP. Spontaneously hypertensive rats (SHR) were treated with the NK-1R antagonist L732138 (5 mg/kg/d) from 8 to 12 weeks of age. L732138 prevented increased MC maturation of resident immature MCs. NK-1R blockade also prevented increased cardiac MC maturation in angiotensin II-infused mice. MC-deficient mice were used to test the importance of MC NK-1Rs to MC activation. MC-deficient mice administered angiotensin II did not develop fibrosis; MC-deficient mice reconstituted with MCs did develop fibrosis. MC-deficient mice reconstituted with MCs lacking the NK-1R also developed fibrosis, indicating that NK-1Rs are not required for MC activation in this setting. In conclusion, the NK-1R causes MC maturation, however, other stimuli are required to activate MCs to cause fibrosis.

Purpose: Randomized controlled trials (RCTs) are considered the most rigorous type of clinical research. Pediatric orthopaedic surgery has historically lacked the infrastructure and administrative support to conduct high-quality multicenter studies. The IMPACCT (Infrastructure for Musculoskeletal Pediatric Acute Care Clinical Trials) consortium was formed as a resource to support the adoption of RCTs through a multicenter model to address questions in pediatric orthopedic surgery. The IMPACCT Consensus Conference was organized to determine which topics to prioritize for RCTs and obtain the buy-in of surgeons for future multicenter RCTs on these topics. …

Objective Adequate resources are required to rapidly diagnose and treat pediatric musculoskeletal infection (MSKI). The workload MSKI consults contribute to pediatric orthopaedic services is unknown as prior epidemiologic studies are variable and negative work-ups are not included in national discharge databases. The hypothesis was tested that MSKI consults constitute a substantial volume of total consultations for pediatric orthopaedic services across the United States. Study design Eighteen institutions from the Children's ORthopaedic Trauma and Infection Consortium for Evidence-based Study (CORTICES) group retrospectively reviewed a minimum of 1 year of hospital data, reporting the total number of surgeons, total consultations, and MSKI-related consultations. Consultations were classified by the location of consultation (emergency department or inpatient). Culture positivity rate and pathogens were also reported. Results 87,449 total orthopaedic consultations and 7,814 MSKI-related consultations performed by 229 pediatric orthopaedic surgeons were reviewed. There was an average of 13 orthopaedic surgeons per site each performing an average of 154 consultations per year. On average, 9% of consultations were MSKI related and 37% of these consults yielded positive cultures. Finally, a weak inverse monotonic relationship was noted between percent culture positivity and percent of total orthopedic consults for MSKI. Conclusion At large, academic pediatric tertiary care centers, pediatric orthopaedic services consult on an average of ~3,000 'rule-out' MSKI cases annually. These patients account for nearly 1 in 10 orthopaedic consultations, of which 1 in 3 are culture positive. Considering that 2 in 3 consultations were culture negative, estimating resources required for pediatric orthopaedic consult services to work up and treat children based on culture positive administrative discharge data underestimates clinical need. Finally, ascertainment bias must be considered when comparing differences in culture rates from different institution's pediatric orthopaedics services, given the variability in when orthopaedic physicians become involved in a MSKI workup.

Fiber reinforced polymer composites are often used as a replacement for metal alloys because of the superior strength to weight ratio. However, a major drawback of these materials is the lack of formability caused by the low strain to failure ratio that does not allow the material to follow tooling contours into deep drawn shapes or tight radii. Composite materials have a multiscale hierarchical structure where micro and meso scale effects (fiber and tow scales) contribute to the macro structural response (laminate scale). In particular, during forming, different deformation occurs simultaneously at every scale. Currently, the amount of quantifiable and comparable forming data for both continuous and discontinuous fiber reinforced polymer composites, including a multi-scale understanding of the deformation response, is limited because of the lack of a testing system. This article proposes a novel test method and an apparatus called “the forming fixture” for testing the tow formability of fiber reinforced polymer composites by determining the required load to form an uncured resin impregnated fiber tow sample into a stretch drawn profile. Test results from forming of Hexcel (Stamford, CT) IM7-G continuous carbon fiber impregnated with Huntsman (The Woodlands, TX) RDM 2019-053 resin system, in the temperature range of 21°C–121°C, are discussed to demonstrate the use of the proposed apparatus including representative data. Results showed consistency and repeatability, validating the reliability of the novel method. The test aided in defining the forming behavior of the material in real time both visually (e.g. sample failure location) and as forming load versus displacement curves. A novel forming metrics, relating the maximum drawing depth with no failure and the maximum forming load, is defined to compare and select different fiber and resin formulations. Widespread adoption of the forming fixture will reduce reliance on a “trial and error” approach during the the forming process.

Investigation into the role of vitamin D in fractures in the pediatric population has been limited despite estimates that as many as 70% of American children have inadequate vitamin D levels (measured as 25-hydroxyvitamin D, 25(OH)D). The purpose of this study was to evaluate vitamin D’s role in pediatric fracture risk by comparing 25(OH)D between fractured and nonfractured cohorts. A 12-month prospective case-control study was completed in children aged 2 to 14 years in an urban, academic hospital. Sixty fractured children requiring conscious sedation or general anesthesia for management were compared with 60 nonfractured controls. All participants and their guardians were surveyed for low bone density risk factors, and total serum 25(OH)D was measured. Statistical analysis was completed using Student t tests, χ2 tests, analysis of variance, and logistic regression models. After controlling for age and daily sun exposure, lower total serum 25(OH)D was associated with higher fracture risk (odds ratio=0.94; 95% confidence interval, 0.90-0.99; P=0.023). In the fractured cohort, 6 (10%) patients were deficient (25(OH)D

INTRODUCTION AND OBJECTIVES:Urinary incontinence is more common in older people, especially women. Androgen receptors are found throughout the pelvic floor and lower urinary tract. At menopause, women experience a decline in testosterone. However, the relationship between available testosterone in the blood and urinary incontinence in older women is not understood. Our objective was to determine if serum free testosterone levels were associated with urinary leakage in older women in a population-based cohort of aging.METHODS:The study population consisted of 3,075 healthy and well-functioning white and black men and women aged 70 to 79 years participating in the Health, Aging and Body Composition Study. Serum free and total testosterone were measured at the same time urinary health questionnaires were administered. Urinary incontinence was defined as self-reported daily urinary leakage. Data were first split by gender and then grouped by self-reported urinary leakage. A one-way ANOVA was performed, for ea...

Continuous carbon fibers are premium reinforcing material for aerospace composites. The challenge with continuous carbon fibers is their difficulty to form deep drawn parts requiring intricate manufacturing techniques that increase manufacturing time, cost and material waste. Stretch broken carbon fiber (SBCF), is a form of aligned discontinuous fiber, has been proposed as an alternative to overcome this challenge. SBCF provide flexibility to form complex shapes while maintaining comparable strength and stiffness. This study compared the tensile behavior of sized continuous fiber and SBCF tows at seven different gauge lengths and two temperatures (24 °C and 100 °C). Materials included Hexcel IM7-G continuous carbon fiber and Hexcel IM7-GP SBCF. The results of this study show that SBCF demonstrate decreased tensile loads when tested at elevated temperatures compared to continuous fibers. The maximum load capacity of SBCF tow increases as gauge length decreases. The load bearing capacity of heated SBCF tow is linked to fiber continuity. These findings suggest superior forming properties of SBCF as compared with continuous fiber tow.

INTRODUCTION AND OBJECTIVE:Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) has significant unmet medical needs including the lack of an objective laboratory test, such as a urine based biomark...

Background Enhancing the safety, quality, and value of care provided is a point of emphasis for modern health care systems. We performed a review of recent literature to highlight those efforts relevant to pediatric musculoskeletal care. Methods We searched the PubMed database for all papers related to quality improvement, patient safety, and/or value in pediatric orthopaedics published from October 1, 2012 to October 31, 2017, yielding 193 papers. Results A total of 36 papers were selected for review based upon new findings. Papers were selected based on significant contributions in the following categories: casting safety, antibiotic stewardship/infection prevention, perioperative care pathways, blood conservation, venous thromboembolic disease prevention, and imaging safety/appropriateness. Conclusions There have been numerous advances in safety, quality, and value in pediatric orthopaedic care. Quality improvement efforts emphasizing provider education and safety monitoring can lead to a decrease in cast-related complications. Perioperative care pathways and bundles are associated with a decrease risk of surgical site infection and decreased length of stay in pediatric spinal deformity surgery. Increased scrutiny has been placed on the value of routine follow-up radiographs in pediatric fracture and spinal deformity care. Level of evidence Level 4-literature review.

PURPOSE: Instillation of novel contrast mixture (NCM) was recently shown to improve the contrast resolution of rat bladder wall with high contrast-to-noise ratio (CNR). Here, the clinical safety and the feasibility of NCM-enhanced MRI to achieve artifact-free visualization of human bladder wall suitable for quantitative measurement of the magnetic resonance (MR) longitudinal relaxation time (T1) was assessed. METHODS: Six female subjects [two controls and two with Hunner-type interstitial cystitis IC and two with non-Hunner-type IC] consented for MRI at 3 T before and after instillation of NCM [4 mM gadobutrol and 5 mM ferumoxytol in 50 mL of sterile water for injection]. Single breath-hold fast MR acquisition in large readout bandwidth for 5-mm-thick single slice with variable flip angle was applied to minimize the motion and chemical shift artifacts in measurements of bladder wall thickness (BWT), CNR and T1 from 20 pixels. RESULTS: NCM instillation in subjects did not evoke pain or discomfort. Fourfold increase in bladder wall CNR (*p < 0.02) and pixel size of 0.35 mm with minimal influence of artifacts allowed accurate determination of bladder wall thinning ~ 0.46 mm from 50 mL NCM (*p < 0.05). Pre-contrast bladder wall T1 of 1544 ± 34.2 ms was shortened to 860.09 ± 13.95 ms in Hunner-type IC (*p < 0.0001) relative to only 1257.42 ± 20.59 and 1258.16 ± 6.16 ms in non-Hunner-type IC and controls, respectively. CONCLUSION: Findings demonstrate the safety and feasibility of NCM-enhanced MRI to achieve artifact-free differential contrast and spatial resolution of human bladder wall, which is suitable for measuring BWT and pixel-wise measurement of T1 in post-contrast setting.

Nuclear factor erythroid-2–related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload–induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction –induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction.

We primarily determined whether the small animal radiation research platform could create a rat radiation cystitis model via targeted bladder irradiation (phase I). The response to treating early phase radiation cystitis in rats with transurethral catheter instillation of liposomal tacrolimus was also examined (phase II).In phase I 16 adult female Sprague Dawley® rats were used. Metabolic urination patterns were analyzed before and after exposure to 20, 30 or 40 Gy radiation. In phase II irradiated rats were randomly assigned to receive a single instillation of saline or liposomal tacrolimus.The 40 Gy radiation dose induced statistically significant reductions in the intermicturition interval compared to the lower radiation doses. By approximately 20 minutes 40 Gy radiation caused a significant decrease in the mean intermicturition interval (p0.0001). Histological analysis revealed degenerative epithelial changes and urothelial swelling with evidence of pseudocarcinomatous epithelial hyperplasia. Therefore, 40 Gy were chosen for the phase II efficacy study. There was no measurable change in total voided urine volume after irradiation, or after liposomal tacrolimus or saline instillation. Liposomal tacrolimus significantly increased the post-irradiation intermicturition interval by approximately 30 minutes back to baseline (p0.001).The radiation cystitis rat model showed a dose dependent decrease in the intermicturition interval without inducing short-term skin or gastrointestinal damage. This study demonstrates that liposomal tacrolimus may be a promising new intravesical therapy for the rare, serious condition of radiation cystitis.

Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart.

Ethnopharmacological relevance: American ginseng is capable of ameliorating cardiac dysfunction and activating Nrf2, a master regulator of antioxidant defense, in the heart. This study was designed to isolate compounds from American ginseng and to determine those responsible for the Nrf2-mediated resolution of inflamed macrophage-induced cardiomyocyte hypertrophy. Materials and methods: A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. A bioassay-based fractionization of American ginseng was performed to identify the putative substances which could activate Nrf2-mediated suppression of pro-inflammatory cytokine expression in macrophages and macrophage-mediated pro-hypertrophic growth in cardiomyocytes. Results: A hexane fraction of an anti-inflammatory crude extract of American ginseng was found to be most effective in suppressing the inflammatory responses in macrophages. Preparative, reverse-phase HPLC and a comparative analysis by analytical scale LC–UV/MS revealed the hexane fraction contains predominantly C17 polyacetylenes and linolenic acid. Panaxynol, one of the major polyacetylenes, was found to be a potent Nrf2 activator. Panaxynol posttranscriptionally activated Nrf2 by inhibiting Kelch-like ECH-associated protein (Keap) 1-mediated degradation without affecting the binding of Keap1 and Nrf2. Moreover, panaxynol suppressed a selected set of cytokine expression via the activation of Nrf2 while minimally regulating nuclear factor-kappa B (NF-κB)-mediated cytokine expression in macrophages. It also dramatically inhibited the inflamed macrophage-mediated cardiomyocyte death and hypertrophy by activating Nrf2 in macrophages. Conclusions: These results demonstrate that American ginseng-derived panaxynol is a specific Nrf2 activator and panaxynol-activated Nrf2 signaling is at least partly responsible for American ginseng-induced health benefit in the heart.

Background: The absence of a reliable classification system for Legg-Calve-Perthes disease has contributed to difficulty in establishing consistent management strategies and in interpreting outcome studies. The purpose of this study was to assess interobserver and intraobserver reliability of the modified Waldenstrom classification system among a large and diverse group of pediatric orthopaedic surgeons. Methods: Twenty surgeons independently completed the first two rounds of staging: two assessments of forty deidentified radiographs of patients with Legg-Calve-Perthes disease in various stages. Ten of the twenty surgeons completed another two rounds of staging after the addition of a second pair of radiographs in sequence. Kappa values were calculated within and between each of the rounds. Results: Interobserver kappa values for the classification for surveys 1, 2, 3, and 4 were 0.81, 0.82, 0.76, and 0.80, respectively (with 0.61 to 0.80 considered substantial agreement and 0.81 to 1.0, nearly perfect agreement). Intraobserver agreement for the classification was an average of 0.88 (range, 0.77 to 0.96) between surveys 1 and 2 and an average of 0.87 (range, 0.81 to 0.94) between surveys 3 and 4. Conclusions: The modified Waldenstrom classification system for staging of Legg-Calve-Perthes disease demonstrated substantial to almost perfect agreement between and within observers across multiple rounds of study. In doing so, the results of this study provide a foundation for future validation studies, in which the classification stage will be associated with clinical outcomes.

The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NF-kB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLD’s expression, function and regulation with emerging reports on its role in cardiovascular disease.

Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload–induced adverse cardiac remodeling by inhibiting mast cell (MC) chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized (OVX) rats. Three days before creating the constriction, additional groups of OVX rats began receiving 17β-estradiol, a chymase inhibitor, or a MC stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, MC density and degranulation, and myocardial and plasma chymase levels were assessed 18 days postsurgery. Aortic constriction resulted in ventricular hypertrophy in intact and OVX groups, whereas collagen volume fraction was increased only in OVX rats. Chymase protein content was increased by aortic constriction in the intact and OVX groups, with the magnitude of the increase being greater in OVX rats. MC density and degranulation, plasma chymase levels, and myocardial active transforming growth factor-β1 levels were increased by aortic constriction only in OVX rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, MC density and degranulation, plasma chymase, and myocardial active transforming growth factor-β1, as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction–induced ventricular hypertrophy and collagen volume fraction in the OVX rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects, except for the reduction of chymase content. We conclude that the estrogen-inhibited release of MC chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.

Atherosclerosis is a leading cause of disability and death worldwide. Research into the disease has led to many compelling hypotheses regarding the pathophysiology of atherosclerotic lesion formation and the resulting complications such as myocardial infarction and stroke. Herbal medicine has been widely used in China as well as other Asian countries for the treatment of cardiovascular diseases for hundreds of years; however, the mechanisms of action of Chinese herbal medicine in the prevention and treatment of atherosclerosis have not been well studied. In this review, we briefly describe the mechanisms of atherogenesis and then summarize the research that has been performed in recent years regarding the effectiveness and mechanisms of antiatherogenic Chinese herbal compounds in an attempt to build a bridge between traditional Chinese medicine and cellular and molecular cardiovascular medicine.

Here, we tested whether combined contrast-enhanced magnetic resonance imaging (CCE-MRI), using a mixture of gadolinium- and iron oxide-based contrast agents, can segment the bladder wall from the bladder lumen. CCE-MRI relies on the differences in particle size and contrast mechanisms of two agents for improved image contrast. Under isoflurane anesthesia, T1-weighted imaging of adult female Sprague-Dawley rat bladder was performed using standard turbospin echo sequences at 7 Tesla, before and after transurethral instillation of 0.3 ml of single-contrast MRI or CCE-MRI composed of 0.4–64 mM of gadolinium chelate (Gd-DTPA/Gadavist) and 5 mM ferumoxytol. Bladder wall contrast was assessed in the control group exposed to saline and in the bladder injury group exposed to 0.5 ml of protamine sulfate (10 mg/ml) for 30 min. CCE-MRI following instillation of 0.4–4 mM Gd-DTPA and 5 mM ferumoxytol mixture achieved segmentation between the bladder lumen and bladder wall. Hyperintensity in the bladder wall combined with hypointensity in the lumen is consistent with the increased diffusion of the dissolved Gd-DTPA and simultaneous localization of the larger nanoparticles of ferumoxytol in the lumen. The normalized hyperintense signal in the bladder wall increased from 0.46 ± 0.07 in control group to 0.73 ± 0.14 in the protamine sulfate-exposed group ( P < 0.0001). CCE-MRI following instillation of contrast mixture identifies bladder wall changes likely associated with bladder injury with improved image contrast.

Ischemia/reperfusion results in tissue damage, a rapid increase in cytokines and chemokines and inflammatory cell infiltration. Herein we investigated the ability of a selective TLR2/4 antagonist, Sparstolonin B (SsnB), to protect rat cultured left ventricular tissue (LV) slices from hypoxic injury by inhibiting the myocardial inflammatory response independent of inflammatory cell infiltration.Media Lactate dehydrogenase (LDH) levels were measured to reflect hypoxia-induced cytotoxicity and cell injury with and without SsnB. Incubation with SsnB (15 and 30 μM) significantly reduced by 20 and 40%, respectively, the amount of LDH released from the hypoxic LV slices. TUNEL staining showed that SsnB significantly attenuated the levels of hypoxia-induced apoptotic cells from 61.5 ± 4.0 to 27.0 ± 2.1 (15 μM SsnB) and 23.5 ± 2.2 (30 μM SsnB) cells/unit area. Similarly, the Periodic Acid-Schiff (PAS) staining of ischemic areas in untreated hypoxic LV slices was increased 17 fold from 0.26± 0.09 to 4.41 ± 0.43%, while in hypoxic slices incubated with 15 and 30 μM of SsnB, the PAS positive ischemic areas were increased by only 6.4 fold to 1.66 ± 0.39% and 3.8 fold to 1.00 ± 0.22%, respectively. Rt-PCR confirmed that MCP1 and IL-6 expression during hypoxia was elevated by 2 and 4 fold, respectively, while their up-regulation was significantly inhibited (i.e.,0.7 fold increase) by SsnB.The selective TLR2/4 antagonist, Sparstolonin B, can substantially protect LV myocardium via its ability to inhibit injury resulting from hypoxic myocardial-generated inflammation. Accordingly SsnB has potential as a therapeutic agent for the attenuation of myocardial ischemia-reperfusion injury.

Background: Tibial spine fractures, although relatively rare, account for a substantial proportion of pediatric knee injuries with effusions and can have significant complications. Meyers and McKeever type II fractures are displaced anteriorly with an intact posterior hinge. Whether this subtype of pediatric tibial spine fracture should be treated operatively or nonoperatively remains controversial. Surgical delay is associated with an increased risk of arthrofibrosis; thus, prompt treatment decision making is imperative. Purpose: To assess for variability among pediatric orthopaedic surgeons when treating pediatric type II tibial spine fractures. Study Design: Cross-sectional study. Methods: A discrete choice experiment was conducted to determine the patient and injury attributes that influence the management choice. A convenience sample of 20 pediatric orthopaedic surgeons reviewed 40 case vignettes, including physis-blinded radiographs displaying displaced fractures and a description of the patient’s sex, age, mechanism of injury, and predominant sport. Surgeons were asked whether they would treat the fracture operatively or nonoperatively. A mixed-effects model was then used to determine the patient attributes most likely to influence the surgeon’s decision, as well as surgeon training background, years in practice, and risk-taking behavior. Results: The majority of respondents selected operative treatment for 85% of the presented cases. The degree of fracture displacement was the only attribute significantly associated with treatment choice ( P < .001). Surgeons were 28% more likely to treat the fracture operatively with each additional millimeter of displacement of fracture fragment. Over 64% of surgeons chose to treat operatively when the fracture fragment was displaced by ≥3.5 mm. Significant variation in surgeon’s propensity for operative treatment of this fracture was observed ( P = .01). Surgeon training, years in practice, and risk-taking scores were not associated with the respondent’s preference for surgical treatment. Conclusion: There was substantial variation among pediatric orthopaedic surgeons when treating type II tibial spine fractures. The decision to operate was based on the degree of fracture displacement. Identifying current treatment preferences among surgeons given different patient factors can highlight current variation in practice patterns and direct efforts toward promoting the most optimal treatment strategies for controversial type II tibial spine fractures.

Myocardial ischemia–reperfusion (MIR) injury is characterized by a rapid increase in cytokines and chemokines and an infiltration of inflammatory cells. Toll-like receptors (TLRs) 2 and 4 mediate these inflammatory responses. Herein we investigated the ability of Sparstolonin B (SsnB), a new selective TLR2/4 antagonist, to inhibit the TLR2/4-mediated inflammatory responses during cardiomyocyte hypoxia–reoxygenation injury as well as the responsible mechanisms. Lactate dehydrogenase (LDH) assay was performed to measure the cytotoxicity of SsnB on H9c2 cardiomyocytes. Quantitative real-time PCR (qRT-PCR) confirmed that TLR2 and TLR4 expression was elevated during hypoxia–reoxygenation, and that their up-regulation in cardiomyocytes was significantly inhibited by SsnB ( P

Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to reform bladder smooth muscle, vasculature, and promote peripheral nerve tissue growth when using autologous populations of cells. Within the context of this study, we demonstrate the role of two specific populations of bone marrow (BM) stem/progenitor cells used in combination with a synthetic elastomeric scaffold that provides a unique and alternative means to current bladder regeneration approaches. In vitro differentiation, gene expression, and proliferation are similar among donor mesenchymal stem cells (MSCs), whereas poly(1,8-octanediol-cocitrate) scaffolds seeded with SB BM MSCs perform analogously to control counterparts with regard to bladder smooth muscle wall formation in vivo. SB CD34 + hematopoietic stem/progenitor cells cotransplanted with donor-matched MSCs cause a dramatic increase in tissue vascularization as well as an induction of peripheral nerve growth in grafted areas compared with samples not seeded with hematopoietic stem/progenitor cells. Finally, MSC/CD34 + grafts provided the impetus for rapid urothelium regeneration. Data suggest that autologous BM stem/progenitor cells may be used as alternate, nonpathogenic cell sources for SB patient-specific bladder tissue regeneration in lieu of current enterocystoplasty procedures and have implications for other bladder regenerative therapies.

This review is focused on gender differences in cardiac remodeling secondary to sustained increases in cardiac volume (VO) and generated pressure (PO). Estrogen has been shown to favorably alter the course of VO-induced remodeling. That is, the VO-induced increased extracellular matrix proteolytic activity and mast cell degranulation responsible for the adverse cardiac remodeling in males and ovariectomized rodents do not occur in intact premenopausal females. While less is known regarding the mechanisms responsible for female cardioprotection in PO-induced stress, gender differences in remodeling have been reported indicating the ability of premenopausal females to adequately compensate. In view of the fact that, in male mice with PO, mast cells have been shown to play a role in the adverse remodeling suggests favorable estrogen modification of mast cell phenotype may also be responsible for cardioprotection in females with PO. Thus, while evidence is accumulating regarding premenopausal females being cardioprotected, there remains the need for in-depth studies to identify critical downstream molecular targets that are under the regulation of estrogen and relevant to cardiac remodeling. Such studies would result in the development of therapy which provides cardioprotection while avoiding the adverse effects of systemic estrogen delivery.

Bladder drug delivery via catheter instillation is a widely used treatment for recurrence of superficial bladder cancer. Intravesical instillation of liposomal botulinum toxin has recently shown promise in the treatment of overactive bladder and interstitial cystitis/bladder pain syndrome, and studies of liposomal tacrolimus instillations show promise in the treatment of hemorrhagic cystitis. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core that can encapsulate hydrophilic and hydrophobic drug molecules to be delivered to cells via endocytosis. This review will present new developments on instillations of liposomes and liposome-encapsulated drugs into the urinary bladder for treating lower urinary tract dysfunction.

Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-α in male hearts secondary to sustained volume overload. These elevated levels of TNF-α are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats ( n = 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula + Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (≥2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-α, which was downregulated by estrogen, and the TNF-α receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the β1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes.

Substance P and neurokinin A (NKA) are sensory nerve neuropeptides encoded by the TAC1 gene. Substance P is a mast cell secretagogue and mast cells are known to play a role in adverse myocardial remodelling. Therefore, we wondered whether substance P and/or NKA modulates myocardial remodelling via a mast cell-mediated mechanism.Volume overload was induced by aortocaval fistula in TAC1(-/-) mice and their respective wild types. Left ventricular internal diameter of wild-type (WT) fistulas increased by 31.9%; this was prevented in TAC1(-/-) mice (4.2%). Matrix metalloproteinase (MMP) activity was significantly increased in WT fistula mice and was prevented in TAC1(-/-) mice. Myocardial collagen volume fraction was decreased in WT fistula mice; this collagen degradation was not observed in the TAC1(-/-) group. There were no significant differences between any groups in tumour necrosis factor (TNF)-α or cell death. Cardiac mast cells were isolated from rat hearts and stimulated with substance P or NKA. We found that these cells degranulated only to substance P, via the neurokinin-1 receptor. To determine the effect of substance P on mast cells in vivo, volume overload was created in Sprague-Dawley rats treated with the NK-1 receptor antagonist L732138 (5 mg/kg/day) for a period of 3 days. L732138 prevented: (i) increases in cardiac mast cell density; (ii) increased myocardial TNF-α; and (iii) collagen degradation.Our studies suggest that substance P may be important in mediating adverse myocardial remodelling secondary to volume overload by activating cardiac mast cells, leading to increased TNF-α and MMP activation with subsequent degradation of the extracellular matrix.

The mast cell product, tryptase, has recently been implicated in fibrosis in the hypertensive heart. Tryptase has been shown to mediate non-cardiac fibroblast function via activation of protease activated receptor-2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal-regulated kinase1/2. Therefore, we hypothesized that this pathway may be a mechanism leading to fibrosis in the hypertensive heart. Isolated adult cardiac fibroblasts were treated with tryptase, which induced activation of extracellular signal-regulated kinase1/2 via protease activated receptor-2. Blockade of protease activated receptor-2 with FSLLRY (10 μM) and inhibition of the extracellular signal-regulated kinase pathway with PD98059 (10 μM) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. p38 mitogen activated protein kinase and stress-activated protein/c-Jun N-terminal kinase were not activated by tryptase. Cardiac fibroblasts isolated from spontaneously hypertensive rats showed this same pattern of activation and treatment of spontaneously hypertensive rats with FSLLRY prevented fibrosis in these animals indicating the in vivo applicability of the cultured fibroblast findings. Also, tryptase induced a myofibroblastic phenotype indicated by elevations in α smooth muscle actin and ED-A fibronectin. Thus, the results from this study demonstrate the importance of tryptase for inducing a cardiac myofibroblastic phenotype, ultimately leading to the development of cardiac fibrosis through the activation of the extracellular signal-regulated kinase pathway. Specifically, tryptase causes cardiac fibroblasts to increase collagen synthesis via a mechanism involving activation of protease activated receptor-2 and subsequent induction of extracellular signal-regulated kinase signaling.

Aims Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to be a negative regulator of maladaptive cardiac remodelling and dysfunction; however, a potential of the Nrf2-mediated cardiac protection in diverse pathological settings remains to be determined. This study was aimed to explore the role of Nrf2 in angiotensin II (Ang II)-induced cardiac hypertrophy. Methods and results Littermate wild-type (WT) and Nrf2 knockout (Nrf2−/−) mice were administered Ang II via osmotic mini-pumps for 2 weeks to induce cardiac hypertrophy. Elevation of blood pressure by the continuous Ang II infusion was comparable between WT and Nrf2−/− mice. Relative to WT mice, however, Nrf2−/− mice exhibited exaggerated myocardial oxidative stress with an impaired induction of a group of antioxidant genes and increased cardiac hypertrophy in response to the sustained Ang II stimulation. In cultured cardiomyocytes, adenoviral overexpression of Nrf2 shRNA enhanced Ang II-induced reactive oxygen species (ROS) production and protein synthesis, whereas adenoviral overexpression of Nrf2 exerted opposite effects. Moreover, Nrf2 deficiency exacerbated Ang II-induced down-regulation of p27kip1 expression in the heart via a mechanism of post-transcriptional regulation. In contrast, adenoviral overexpression of Nrf2 increased p27kip1 protein but not mRNA expression and reversed Ang II-induced down-regulation of p27kip1 protein expression in cultured cardiomyocytes by suppressing ROS formation. Finally, the enhancement of Ang II-induced hypertrophic growth due to the Nrf2 deficiency was negated by overexpressing p27kip1 in cultured cardiomyocytes. Conclusion The Nrf2-p27kip1 pathway serves as a novel negative feedback mechanism in Ang II-induced pathogenesis of cardiac hypertrophy, independent of changes in blood pressure.

Case We describe a patient who was diagnosed with developmental hip dislocation at 21 months of age despite having had normal ultrasonography findings at 5 weeks of age. Conclusion This case report provides evidence that late developmental hip dislocation can occur despite normal clinical and sonographic findings early in life, and that it is difficult to know the cause of developmental hip dislocation when it presents late.