Influence of gold nanoparticles on collagen fibril morphology quantified using transmission electron microscopy and image analysis

BACKGROUND: Development of implantable biosensors for disease detection is challenging because of poor biocompatibility of synthetic materials. A possible solution involves engineering interface materials that promote selfassembly and adhesion of autologous cells on sensor surfaces. Crosslinked type-I collagen is an acceptable material for developing engineered basement membranes. In this study, we used functionalized gold nanoparticles as the crosslinking agent. Functionalized nanoparticles provide sites for crosslinking collagen as well as sites to deliver signaling compounds that direct selfassembly and reduce inflammation. The goal of this study was to obtain a quantitative parameter to objectively determine the presence of crosslinks. METHODS: We analyzed TEM images of collagen fibrils by two methods: Run length analysis and topology analysis after medial axis transform. RESULTS: Run length analysis showed a significant reduction of the interfibril spaces in the presence of nanoparticles (change of 40%, P < 0.05), whereas the fibril thickness remained unchanged. In the topological network, the number of elements, number of branches and number of sides increased significantly in the presence of nanoparticles (P < 0.05). Other parameters, especially the number of loops showed only a minimal and nonsignificant change. We chose a ratiometric parameter of the number of branches normalized by the number of loops to achieve independence from gross fibril density. This parameter is lower by a factor of 2.8 in the presence of nanoparticles (P < 0.05). CONCLUSION: The numerical parameters presented herein allow not only to quantify fibril mesh complexity and crosslinking, but also to help quantitatively compare cell growth and adhesion on collagen matrices of different degree of crosslinking in further studies

Combined Oral Contraceptives in Women with Systemic Lupus Erythematosus

BACKGROUND Oral contraceptives are rarely prescribed for women with systemic lupus erythematosus, because of concern about potential negative side effects. In this double-blind, randomized, noninferiority trial, we prospectively evaluated the effect of oral contraceptives on lupus activity in premenopausal women with systemic lupus erythematosus. METHODS A total of 183 women with inactive (76 percent) or stable active (24 percent) systemic lupus erythematosus at 15 U.S. sites were randomly assigned to receive either oral contraceptives (triphasic ethinyl estradiol at a dose of 35 pgplus norethindrone at a dose of 0.5 to 1 mg for 12 cycles of 28 days each; 91 women) or placebo (92 women) and were evaluated atmonths 1,2,3,6,9, and 12. Subjects were excluded ifthey had moderate or high levels ofanticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. RESULTS The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P=0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P=0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial). CONCLUSIONS Our study indicates that oral contraceptives do not increase the risk of flare among women with systemic lupus erythematosus whose disease is stable

A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents

The Barents and Chukchi Seas: Comparison of two Arctic shelf ecosystems

This paper compares and contrasts the ecosystems of the Barents and Chukchi Seas. Despite their similarity in a number of features, the Barents Sea supports a vast biomass of commercially important fish, but the Chukchi does not. Here we examine a number of aspects of these two seas to ascertain how they are similar and how they differ. We then indentify processes and mechanisms that may be responsible for their similarities and differences.Both the Barents and Chukchi Seas are high latitude, seasonally ice covered, Arctic shelf-seas. Both have strongly advective regimes, and receive water from the south. Water entering the Barents comes from the deep, ice-free and "warm" Norwegian Sea, and contains not only heat, but also a rich supply of zooplankton that supports larval fish in spring. In contrast, Bering Sea water entering the Chukchi in spring and early summer is cold. In spring, this Bering Sea water is depleted of large, lipid-rich zooplankton, thus likely resulting in a relatively low availability of zooplankton for fish. Although primary production on average is similar in the two seas, fish biomass density is an order of magnitude greater in the Barents than in the Chukchi Sea. The Barents Sea supports immense fisheries, whereas the Chukchi Sea does not. The density of cetaceans in the Barents Sea is about double that in the Chukchi Sea, as is the density of nesting seabirds, whereas, the density of pinnipeds in the Chukchi is about double that in the Barents Sea. In the Chukchi Sea, export of carbon to the benthos and benthic biomass may be greater. We hypothesize that the difference in fish abundance in the two seas is driven by differences in the heat and plankton advected into them, and the amount of primary production consumed in the upper water column. However, we suggest that the critical difference between the Chukchi and Barents Seas is the pre-cooled water entering the Chukchi Sea from the south. This cold water, and the winter mixing of the Chukchi Sea as it becomes ice covered, result in water temperatures below the physiological limits of the commercially valuable fish that thrive in the southeastern Bering Sea. If climate change warms the Barents Sea, thereby increasing the open water area via reducing ice cover, productivity at most trophic levels is likely to increase. In the Chukchi, warming should also reduce sea ice cover, permitting a longer production season. However, the shallow northern Bering and Chukchi Seas are expected to continue to be ice-covered in winter, so water there will continue to be cold in winter and spring, and is likely to continue to be a barrier to the movement of temperate fish into the Chukchi Sea. Thus, it is unlikely that large populations of boreal fish species will become established in this Arctic marginal sea. © 2012 Elsevier B.V

Fluxes, Fins, and Feathers: Relationships Among the Bering, Chukchi, and Beaufort Seas in a Time of Climate Change

Ocean currents, water masses, and seasonal sea ice formation determine linkages among and barriers between the biotas of the Bering, Chukchi, and Beaufort Seas. The Bering Sea communicates with the Chukchi and Beaufort Seas via northward advection of water, nutrients, and plankton through Bering Strait. However, continuity of the ocean's physical properties is modulated by regional differences in heat, salt, and sea ice budgets, in particular, along the meridional gradient. Using summer density data from zooplankton, fish (bottom and surface trawl), and seabird surveys, we define three biogeographic provinces: the Eastern Bering Shelf Province (the eastern Bering Sea shelf south of Saint Lawrence Island), the Chirikov-Chukchi Province (the eastern Bering Sea shelf north of Saint Lawrence Island [Chirikov Basin] and Chukchi Sea), and the Beaufort Sea Province. Regional differences in summer distributions of biota largely reflect the underlying oceanography. Climate warming will reduce the duration and possibly the extent of seasonal ice cover in the Eastern Bering Shelf Province, but this warming may not lead to increased abundance of some subarctic species because seasonal ice cover and cold (< 2°C) bottom waters on the Bering shelf form a barrier to the northward migration of subarctic bottom fish species typical of the southeastern Bering Sea. While Arctic species that are dependent upon the summer extent of sea ice face an uncertain future, other Arctic species' resilience to a changing climate will be derived from waters that continue to freeze each winter