Opinion survey regarding pediatric orthopaedic trauma call and emergency trauma management

BACKGROUND: To determine the attitudes and practices of pediatric orthopaedic surgeons regarding on-call coverage and emergency fracture management. METHODS: A 32-question online survey was sent to all 597 active members of the Pediatric Orthopaedic Society of North America. There were 296 completed surveys, for a response rate of 49.6%. RESULTS: Of the respondents, 85.1% were male. The respondents ranged in age from 30 to older than 70 years, with 54% between 36 and 50 years of age, corresponding to an average of 15 years in practice. Seventy-seven percent of the respondents felt that taking trauma call is an integral aspect of being a pediatric orthopaedist. Of the respondents, 64.9% take call 1 to 9 times per month, 15.8% take 10 to 19 calls, 2.7% take 20 or more, and 16.6% take no call. The number of orthopaedists taking call per practice was fairly evenly distributed between 3 and 10. Call was shared equally in 32% of practices, and mandatory in 72%. Twenty-eight percent of the respondents were additionally compensated for taking calls, in amounts ranging from $100 to $2000 per night, with 1000 dollars the most common rate. One third of operative cases are done that night; one third, the next day; and one third, later in the week. Twenty-four percent of the respondents have dedicated operative block time on the day after the call. Forty-seven percent have a dedicated fracture clinic, of which 51% receive institutional support. CONCLUSIONS: Providing emergency trauma care for children is an integral aspect of pediatric orthopaedics. This survey provides information on the attitudes and strategies of practicing pediatric orthopaedic surgeons in the face of decreasing manpower and increasing demand for such services.     

Mammography as a screening tool for coronary artery disease

BACKGROUND: The leading cause of death in women over 40 y old is coronary artery disease (CAD) followed by cancer. This large retrospective study investigates the relationship between mammographic benign arterial calcifications (BAC) and a history of CAD to determine if mammography is a suitable screening tool for CAD. METHODS: To determine the incidence of BAC in our general screening population, we prospectively studied 1000 consecutive women undergoing screening mammography. We retrospectively identified a population of women with known CAD who had undergone screening mammography as our study group. These groups were compared according to age and the significance of BAC in each group was statistically evaluated using the Cochran-Mantel-Haenszel test and Cochran-Armitage test for trend. RESULTS: We prospectively evaluated the mammograms of 819 women with no history of diabetes or CAD. Eighty-six women had mammographic BAC for a baseline BAC incidence of 10.5%. We identified 395 women with CAD and 193 (49%) of these women had BAC. Vascular calcifications significantly increased with age (P < 0.0001) in both groups. Stratifying by age, women with CAD had a significant increase in BAC compared with women undergoing routine screening (P < 0.0001). The odds ratio of having CAD when BAC are present on screening mammography compared with having CAD when BAC are not present is 6.2 (95% confidence interval estimate 4.3-8.8). CONCLUSIONS: This preliminary study indicates that across age groups, the odds of having CAC are approximately 6.2 times greater if BAC are present compared with women without BAC indicating that mammography may be a useful screening tool for CAD.     

The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates

Toxicity is a leading cause of attrition at all stages of the drug development process. The majority of safety-related attrition occurs preclinically, suggesting that approaches to identify 'predictable' preclinical safety liabilities earlier in the drug development process could lead to the design and/or selection of better drug candidates that have increased probabilities of becoming marketed drugs. In this Review, we discuss how the early application of preclinical safety assessment--both new molecular technologies as well as more established approaches such as standard repeat-dose rodent toxicology studies--can identify predictable safety issues earlier in the testing paradigm. The earlier identification of dose-limiting toxicities will provide chemists and toxicologists the opportunity to characterize the dose-limiting toxicities, determine structure-toxicity relationships and minimize or circumvent adverse safety liabilities.     

Cell- and isoform-specific increases in arginase expression in acute silica-induced pulmonary inflammation

Arginase induction was reported in several inflammatory lung diseases, suggesting that this may be a common feature underlying the pathophysiology of such diseases. As little is known regarding arginase expression in silicosis, the induction and cellular localization of arginase were elucidated in lungs of Sprague-Dawley rats 24 h following exposure to varying doses of silica by intratracheal instillation. Arginase expression was evaluated by activity assay, quantification of arginase I and arginase II mRNA levels using real-time polymerase chain reaction (PCR), and immunohistochemistry. Analyses of cells and fluid obtained by bronchoalveolar lavage (BAL) showed that markers of pulmonary inflammation, tissue damage, activation of alveolar macrophages (AM) and NO production were significantly increased by all silica doses. Arginase activity was increased also in AMs isolated from BAL fluid of silica-treated rats. Silica produced two- and three-fold increases in arginase activity of whole lung at doses of 1 and 5 mg/100 g body weight, respectively. Levels of arginase I mRNA, but not of arginase II mRNA, were similarly elevated. In control lungs, arginase I immunoreactivity was observed only in AMs sparsely dispersed throughout the lung; no inducible nitric oxide synthase (iNOS) immunoreactivity was detected. In silica-treated lungs, arginase I and iNOS were co-expressed in most AMs that were abundantly clustered at inflammatory foci. The rapid induction of arginase I expression in inflammatory lung cells, similar to induction of arginase in other inflammatory lung diseases, implicates elevated arginase activity as a factor in the development of lung damage following exposure to silica.     

PGJ2 inhibition of LPS-induced inflammatory mediator expression from rat alveolar macrophages

Studies suggested that 15-deoxy-delta-(12,14)-prostaglandin J2 (PGJ2) may exert anti-inflammatory effects, including in the lung. Thus, in vitro studies were conducted to (1) investigate whether PGJ2 inhibited the production of inflammatory mediators from lipopolysaccharide (LPS)-exposed primary rat alveolar macrophages (AM), and (2) investigate possible mechanisms underlying PGJ2-mediated inhibition of inflammatory mediator production. These studies determined that PGJ2 inhibited LPS-induced nitric oxide (NO) production in a concentration- and time-dependent manner. PGJ2-mediated inhibition of NO, as well as of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2), was also determined to be dependent on the time of addition of PGJ2 relative to LPS, and suggested the PGJ2 inhibitory mechanism is an early event. PGJ2 was shown not to interfere with binding or internalization of LPS by AM, indicating this was not responsible for PGJ2 inhibitory effects. Another possible mechanism underlying PGJ2-mediated inhibition was via peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, biochemical studies suggested that PGJ2-mediated inhibition was not occurring through PPAR-gamma dependent mechanism, and molecular studies further established that both LPS and PGJ2 decrease PPAR-gamma mRNA expression. A third possible mechanism underlying PGJ2-mediated inhibition was by alteration of nuclear factor (NF)-kappaB. Molecular studies confirmed that LPS stimulated NF-kappaB mRNA expression, and PGJ2 reduced this stimulation, which is consistent with PGJ2 effect on LPS-induced production of NO, TNF-alpha and MIP-2. Thus, data in this study established that PGJ2 inhibited LPS-induced inflammatory mediator production in rat AM, and this inhibition is mediated, at least in part, by reducing the expression of NF-kappaB mRNA.     

Acute acrolein-induced cystitis in mice

OBJECTIVE: To develop a method of direct intravesical administration of acrolein and evaluate the severity of cystitis in response to increasing doses of acrolein in female C57BL/6N (C57) mice, with further studies to compare the severity of acute acrolein-induced cystitis among C57, C3H/HeJ (HeJ), and C3H/OuJ (OuJ) strains of mice, as chemical cystitis produced by the systemic administration of cyclophosphamide is thought to result from renal excretion of hepatic metabolites, particularly acrolein. MATERIALS AND METHODS: Doses of acrolein (0-1000 microg, 15 microL total volume) were instilled into the bladders of C57 female mice; the bladders were removed 4 or 24 h later, weighed, and processed for histology. Acrolein (6 or 10 microg; 15 microL) was instilled into the bladders of C57, HeJ and OuJ female mice, the bladders removed 4 or 24 h later, weighed, and processed for standard histology and immunohistochemical detection of uroplakin. RESULTS: Increasing doses of acrolein up to 100-200 microg caused a linear increase in bladder weight and greater histological evidence of inflammation. Doses of >200 microg caused submaximal increases in bladder weight, apparently due to structural damage of the bladder. Bladder weight and submucosal oedema were consistently greater in C57 and HeJ than OuJ mice. Treatment with acrolein caused loss of urothelium along with uroplakin in some areas of all bladder sections 4 h after treatment. Bladders from C57 mice had some loss of urothelium 24 h after instillation of 6 or 10 microg acrolein, but urothelium and uroplakin covered nearly all the surface of bladders of HeJ and OuJ mice 24 h after treatment. There were significantly more white blood cells in bladders from C57 or HeJ mice than in bladders from OuJ mice 24 h after an instillation of 6 or 10 microg acrolein. CONCLUSIONS: Intravesical instillation of acrolein produces dose-dependent cystitis in mice. OuJ mice appear relatively more resistant to irritant effects of intravesical acrolein than C57 or HeJ mice, and future studies will be directed at identifying genetic causes for these differences.     

Insulin-like growth factor-I receptor signaling blockade combined with radiation

Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.     

Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence

There is considerable interest in herbal therapies for cancer prevention but often with little scientific evidence to support their use. In this study, we examined epidemiological data regarding effects of commonly used herbal supplements on risk for ovarian cancer and sought supporting biological evidence. 4.2% of 721 controls compared to 1.6% of 668 cases regularly used Ginkgo biloba for an estimated relative risk (and 95% confidence interval) of 0.41 (0.20,0.84) (p=0.01); and the effect was most apparent in women with non-mucinous types of ovarian cancer, RR=0.33 (0.15,0.74) (p=0.007). In vitro experiments with normal and ovarian cancer cells showed that Ginkgo extract and its components, quercetin and ginkgolide A and B, have significant anti-proliferative effects ( approximately 40%) in serous ovarian cancer cells, but little effect in mucinous (RMUG-L) cells. For the ginkgolides, the inhibitory effect appeared to be cell cycle blockage at G0/G1 to S phase. This combined epidemiological and biological data provide supportive evidence for further studies of the chemopreventive or therapeutic effects of Ginkgo and ginkgolides on ovarian cancer.