Shifts in species interactions and farming contexts mediate net effects of birds in agroecosystems.

Some birds are viewed as pests and vectors of foodborne pathogens in farmlands, yet birds also benefit growers by consuming pests. While many growers seek to prevent birds from accessing their farms, few studies have attempted to quantify the net effects of bird services and disservices, let alone how net effects shift across farm management strategies. We quantified the net effect of birds on crop production across 20 California strawberry (Fragaria × ananassa) farms that varied in local management practices and landscape context. We surveyed farms for berry damage and bird droppings (as potential sources of pathogens) and implemented a large-scale exclusion experiment to quantify the impact of birds on production. We found that birds had only a slightly negative overall impact on strawberry production, reducing economic value by 3.6%. Direct bird damage and intraguild predation contributed equally to this net effect, underscoring the importance of indirect trophic interactions that may be less apparent to growers. In simple landscapes (e.g., low proportions of surrounding seminatural habitat), birds provided pest control in the interiors of farm fields, and costs from bird damage to crops peaked at field edges. In complex landscapes (e.g., high proportions of seminatural habitat), birds were more likely to disrupt pest control by feeding as intraguild predators. Nonetheless, seminatural habitat dampened bird services and disservices, and our models predicted that removing habitat around farm fields would increase costs from bird damage to crops by up to 76%. Fecal contamination of crops was extremely rare (0.01%). However, both fecal contamination and bird damage did increase on farms with higher densities of fencing and wires, where birds often perch. Our results demonstrate that maintaining seminatural habitat around farms may enhance bird diversity and mitigate bird damage without increasing food safety risks. We also show that the net effects of birds depend on farming context and vary in complex ways in relation to locations within a farm, local farm attributes, and the surrounding landscape. This context-specific variation must be considered in order to optimize the management of wild birds in agroecosystems.

The Orthopaedic Workforce Is Not as Diverse as the Population It Serves: Where Are the Minorities and the Women?: AOA Critical Issues Symposium.

The lack of sex and racial diversity of the physicians within the specialty of orthopaedic surgery was recognized decades ago, and formal steps to address these issues began in 1983 with the founding of the Ruth Jackson Orthopaedic Society and the J. Robert Gladden Orthopaedic Society. Despite the efforts of these organizations, the work of other interested groups, and the growing diversity in medical student demographics, physician diversity in orthopaedic surgery remains disproportionately poor relative to the populations that we serve as a specialty.

Social and Cultural Barriers: Understanding Musculoskeletal Health Literacy: AOA Critical Issues.

The Institute of Medicine considers limited health literacy a "silent epidemic," as approximately half of Americans lack the competencies necessary for making informed decisions regarding their health. Limited health literacy substantially impedes the effective dissemination and comprehension of relevant health information, and also complicates communication, compromises care, and leads to worse patient outcomes. Poor health, early death, and worse control of chronic conditions have also been associated with limited health literacy. Unfortunately, physicians often struggle to identify those with limited health literacy, which can have adverse effects on the physician-patient relationship. In this article, we discuss the meaning of health literacy,the risk factors for and consequences of limited health literacy, orthopaedic-specific implications and investigations, and the strategies orthopaedic surgeons can utilize to improve health literacy and communication.

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma.

Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and ß-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.

Alternative for carpal tunnel injection: palmar injection site (Rankin's zone).

This study investigates an alternative approach for steroid injection into the carpal canal through a palmar site and its exposure of vital wrist structures to potential injury. The Rankin's zone entry site is more distally located than conventional sites. This cadaveric study investigated 28 wrists from 26 cadavers. Red latex dye was injected as a localizing aid. Layered dissections were performed to localize the needle tip with respect to vital wrist structures. Calipers measured the distance from the needle to nerves. Twenty-three of the 28 injections using this approach demonstrated dye solely within the carpal tunnel. One median nerve was punctured. The mean distance from the median nerve was 5.76 ± 2.9 mm and 18.27 ± 5.27 mm from the palmar cutaneous branch. This study suggests that the Rankin's zone approach might be utilized with diminished frequency of neural puncture.

Walking the talk. Implementation of transitional care guidance in a UK paediatric and a neighbouring adult facility.

OBJECTIVES: To examine the quality of transitional care in a paediatric and adult hospital by investigating (i) adherence to national transition guidance and (ii) whether implementation is associated with better patient/carer experiences. METHODS: A cross-sectional study was conducted in a UK paediatric hospital (PH) and neighbouring adult hospital. Clinics completed a questionnaire to determine characteristics of their transitional care provision and invited patients aged 11-21 years and parents/carers to complete a questionnaire ('Mind the Gap') to assess their satisfaction. RESULTS: Twenty-three clinics participated. Fourteen (70%) reported delivering a transition programme, but only 5 (25%) indicated this was holistic (addressing medical, psychosocial and vocational issues). Participants included 457 young people and 330 parents, 71% and 88% respectively attending the PH. Ratings of current care were significantly lower than ratings of best care. These 'gap' scores were not excessive, although some participants were very dissatisfied. Better satisfaction was associated with attending clinics that provided transitional care, especially when defined as 'holistic' and youth-friendly. CONCLUSIONS: Transition programmes that adhere to current guidance are associated with better satisfaction, but variations in provision suggest barriers to implementation. Attention is required to how youth-friendly transitional care is defined with particular reference to the specific clinic model.

CTGF is a therapeutic target for metastatic melanoma.

Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.

In vitro human skin irritation test for evaluation of medical device extracts.

The aim of this study was to determine if the EpiDerm™ reconstructed human skin model (MatTek Corp.) could be an acceptable alternative to the ISO 10993-required rabbit skin irritation test for assessing medical device biocompatibility. Eleven medical device polymers were tested. Four extracts were prepared per polymer, two each with saline and sesame oil; half were spiked with two R-38 irritants, lactic acid for saline extracts and heptanoic acid for the sesame oil extracts. Tissue viability was assessed by MTT reduction and the proinflammatory response was assessed by IL-1α release. LOAELs of 2% for lactic acid in saline and 0.7% for heptanoic acid in sesame oil were determined. A cell viability reduction of >50% was indicative of skin irritation. Cells exposed to saline extracts spiked with 3.25% lactic acid had significantly reduced mean cell viabilities (12.6-17.2%). Cells exposed to sesame oil extracts spiked with 1.25% heptanoic acid also exhibited reduced mean cell viabilities (25.5%-41.7%). All spiked cells released substantial amounts of IL-1α (253.5-387.4pg/ml) signifying a proinflammatory response. These results indicate that the EpiDerm™ model may be a suitable in vitro replacement for the assessment of the irritation potential of medical device extracts.

[Prophylactic cranial irradiation in patients with extensive disease caused by small-cell lung cancer responsive to chemotherapy: fewer symptomatic brain metastases and improved survival]. / Profylactische schedelbestraling bij patiënten met uitgebreid kleincellig longcarcinoom dat reageert op chemotherapie: minder symptomatische hersenmetastasen en betere overleving.

OBJECTIVE: To determine the effect of prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to chemotherapy. DESIGN: Randomised, controlled clinical trial; phase III study (EORTC nr 08993-22993; www.clinicaltrials.gov, nr NCT00016211). METHOD: Patients aged 18-75 years with a functional status according to WHO < or = 2, and with ED-SCLC and any response to chemotherapy, were randomized to observation (standard care) or PCI. The primary endpoint was time to symptomatic brain metastases. If any pre-defined, key symptom suggesting brain metastases presented, a CT or MRI scan of the brain was performed. The size of the study (143 patients per arm) was determined to detect a hazard ratio (HR) of 0.44 at 80% power with 2-sided alpha = 0.05. RESULTS: The study accrued 286 patients. PCI decreased the risk of developing symptomatic brain metastases (HR = 0.27 (95% CI: 0.16-0.44; p < 0.001)). The cumulative incidence of developing brain metastases within 1 year was 40% in the control group (95% CI: 32-49) and 15% in the PCI group (95% CI: 8-21). PCI prolonged disease-free (HR = 0.76; 95% CI: 0.59-0.96, p = 0.02) and overall survival (HR = 0.68; 95% CI; 0.52-0.88, p = 0.003). The 1-year survival rate was 27% (95% CI: 19-36) for the PCI group versus 13% (95% CI: 8-20) for controls. Acute and late treatment toxicity was acceptable. These side effects did not significantly impact on quality of life. CONCLUSIONS: PCI significantly reduced the incidence of symptomatic brain metastases and prolonged both disease-free and overall survival and should be part of standard care in SCLC patients who respond to chemotherapy.

Rankin to focus on advocacy, unity, and diversity as president of AAOS.

In this issue of Orthopedics, Dr E. Anthony Rankin, new president of the American Academy of Orthopaedic Surgeons, discusses his role with the organization, his plans for the year, and his priorities in life.

The role of hypoxia-inducible factors in tumorigenesis.

Hypoxia-inducible factors (HIFs) are essential mediators of the cellular oxygen-signaling pathway. They are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-alpha) and a constitutive beta subunit (HIF-beta) that facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating the expression of genes that control glucose uptake, metabolism, angiogenesis, erythropoiesis, cell proliferation, and apoptosis. In most experimental models, the HIF pathway is a positive regulator of tumor growth as its inhibition often results in tumor suppression. In clinical samples, HIF is found elevated and correlates with poor patient prognosis in a variety of cancers. In summary, HIF regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy, making it a critical regulator of the malignant phenotype.

Weekly cisplatin with oral etoposide: a well-tolerated and highly effective regimen in relapsed ovarian cancer.

The optimal treatment of progressive ovarian cancer after first-line platinum-based therapy remains a challenge. We collected prospectively data on patients with relapsed or progressive ovarian cancer treated with weekly cisplatin and oral etoposide in our institution to evaluate the feasibility, efficacy, and toxicity of this regimen. Patients (n = 34) had stage IIIC/IV ovarian cancer, which was recurrent or progressive following previous treatment with carboplatin and a taxane. Cisplatin (50 mg/m(2)) was given days 1, 8, 15, 29, 36, and 43, with oral etoposide (50 mg daily) on days 1-15 and 29-43. Responders and those with stable disease then received oral etoposide (50 mg daily for 21 days of a 28-day cycle) until disease progression. The overall CA125 response rate was 88%. The overall radiological response rate was 57%: 78% in the platinum-sensitive group, 50% in the intermediate-sensitive group, and 46% in the platinum-resistant group. Treatment was well tolerated. Median survival in the overall group was 14 months: in the platinum-sensitive group 16.5 months, in the intermediate-sensitive group 11 months, and 10.5 months in the platinum-resistant group. We conclude that weekly cisplatin/etoposide, followed by maintenance oral etoposide, is an active and well-tolerated regimen in relapsed or progressive ovarian cancer, even in platinum-resistant patients.

First-into-man phase I and pharmacokinetic study of XR5944.14, a novel agent with a unique mechanism of action.

The bis-phenazine XR5944.14 is a novel cytotoxic agent which intercalates into DNA and inhibits transcription. The objectives of this study were to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR5944.14 when given at doses ranging from 3.6 to 36 mg m(-2) every 3 weeks to patients with advanced tumours. Twenty-seven patients were treated with a total of 77 cycles. Dose-limiting toxicities occurred at doses > or =24 mg m(-2). Oral mucositis was the most common DLT. Two patients developed acute renal failure possibly related to the study drug. Other less-severe toxicities were diarrhoea, nausea, vomiting and fatigue. Haematological toxicity was mild. One patient showed an objective partial response. Pharmacokinetic analysis was performed during the first cycle of treatment and plasma was assayed for XR5944.14 using a validated liquid chromatography tandem mass spectrometry. The systemic exposure of XR5944.14 increased more than proportionally with increasing dose, with inter-patient variability increasing from dose level 24 mg m(-2) onwards. The lack of correlation between toxicity and PK values makes it difficult to recommend a dose for further study in phase 2 trials. More work is needed to explain the inter- and intra-individual variation in PKs and pharmacodynamics.