Properties of small molecular drug loading and diffusion in a fluorinated PEG hydrogel studied by ^1H molecular diffusion NMR and ^(19)F spin diffusion NMR

R_f-PEG (fluoroalkyl double-ended poly(ethylene glycol)) hydrogel is potentially useful as a drug delivery depot due to its advanced properties of sol–gel two-phase coexistence and low surface erosion. In this study, ^1H molecular diffusion nuclear magnetic resonance (NMR) and ^(19)F spin diffusion NMR were used to probe the drug loading and diffusion properties of the R_f-PEG hydrogel for small anticancer drugs, 5-fluorouracil (FU) and its hydrophobic analog, 1,3-dimethyl-5-fluorouracil (DMFU). It was found that FU has a larger apparent diffusion coefficient than that of DMFU, and the diffusion of the latter was more hindered. The result of ^(19)F spin diffusion NMR for the corresponding freeze-dried samples indicates that a larger portion of DMFU resided in the R_f core/IPDU intermediate-layer region (where IPDU refers to isophorone diurethane, as a linker to interconnect the R_f group and the PEG chain) than that of FU while the opposite is true in the PEG–water phase. To understand the experimental data, a diffusion model was proposed to include: (1) hindered diffusion of the drug molecules in the R_f core/IPDU-intermediate-layer region; (2) relatively free diffusion of the drug molecules in the PEG-water phase (or region); and (3) diffusive exchange of the probe molecules between the above two regions. This study also shows that molecular diffusion NMR combined with spin diffusion NMR is useful in studying the drug loading and diffusion properties in hydrogels for the purpose of drug delivery applications

The unexplained success of stentplasty vasospasm treatment

Background Cerebral vasospasm (CVS) following subarachnoid hemorrhage occurs in up to 70% of patients. Recently, stents have been used to successfully treat CVS. This implies that the force required to expand spastic vessels and resolve vasospasm is lower than previously thought. Objective We develop a mechanistic model of the spastic arterial wall to provide insight into CVS and predict the forces required to treat it. Material and Methods The arterial wall is modelled as a cylindrical membrane using a constrained mixture theory that accounts for the mechanical roles of elastin, collagen and vascular smooth muscle cells (VSMC). We model the pressure diameter curve prior to CVS and predict how it changes following CVS. We propose a stretch-based damage criterion for VSMC and evaluate if several commercially available stents are able to resolve vasospasm. Results The model predicts that dilatation of VSMCs beyond a threshold of mechanical failure is sufficient to resolve CVS without damage to the underlying extracellular matrix. Consistent with recent clinical observations, our model predicts that existing stents have the potential to provide sufficient outward force to successfully treat CVS and that success will be dependent on an appropriate match between stent and vessel. Conclusion Mathematical models of CVS can provide insights into biological mechanisms and explore treatment approaches. Improved understanding of the underlying mechanistic processes governing CVS and its mechanical treatment may assist in the development of dedicated stents

Large head metal-on-metal cementless total hip arthroplasty versus 28mm metal-on-polyethylene cementless total hip arthroplasty: design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis of the hip is successfully treated by total hip arthroplasty with metal-on-polyethylene articulation. Polyethylene wear debris can however lead to osteolysis, aseptic loosening and failure of the implant. Large head metal-on-metal total hip arthroplasty may overcome polyethylene wear induced prosthetic failure, but can increase systemic cobalt and chromium ion concentrations. The objective of this study is to compare two cementless total hip arthroplasties: a conventional 28 mm metal-on-polyethylene articulation and a large head metal-on-metal articulation. We hypothesize that the latter arthroplasties show less bone density loss and higher serum metal ion concentrations. We expect equal functional scores, greater range of motion, fewer dislocations, fewer periprosthetic radiolucencies and increased prosthetic survival with the metal-on-metal articulation.</p> <p>Methods</p> <p>A randomized controlled trial will be conducted. Patients to be included suffer from non-inflammatory degenerative joint disease of the hip, are aged between 18 and 80 and are admitted for primary cementless unilateral total hip arthroplasty. Patients in the metal-on-metal group will receive a cementless titanium alloy acetabular component with a cobalt-chromium liner and a cobalt-chromium femoral head varying from 38 to 60 mm. Patients in the metal-on-polyethylene group will receive a cementless titanium alloy acetabular component with a polyethylene liner and a 28 mm cobalt-chromium femoral head. We will assess acetabular bone mineral density by dual energy x-ray absorptiometry (DEXA), serum ion concentrations of cobalt, chromium and titanium, self reported functional status (Oxford hip score), physician reported functional status and range of motion (Harris hip score), number of dislocations and prosthetic survival. Measurements will take place preoperatively, perioperatively, and postoperatively (6 weeks, 1 year, 5 years and 10 years).</p> <p>Discussion</p> <p>Superior results of large head metal-on-metal total hip arthroplasty over conventional hip arthroplasty have been put forward by experts, case series and the industry, but to our knowledge there is no randomized controlled evidence.</p> <p>Conclusion</p> <p>This randomized controlled study has been designed to test whether large head metal-on-metal cementless total hip arthroplasty leads to less periprosthetic bone density loss and higher serum metal ion concentrations compared to 28 mm metal-on-polyethylene cementless total hip arthroplasty.</p> <p>Trial registration</p> <p>Netherlands Trial Registry NTR1399</p

Evaluation of the Finnish National Biodiversity Action Plan 1997-2005

The results of the evaluation of the Finnish National Biodiversity Action Plan 1997-2005 indicate clear changes towards better consideration of biodiversity in the routines and policies of many sectors of the administration and economy. There are many indications that actors across society have recognized the need to safeguard biodiversity and have begun to adjust their practices accordingly. Several concrete measures have been undertaken in forests, agricultural habitats and in other habitats significantly affected by human activities. Biodiversity research has expanded significantly and the knowledge of Finland´s biological diversity has increased. In general, the Action Plan has supported public discussion of the need to safeguard biodiversity and this discussion has resulted in more positive attitudes towards nature conservation.So far, however, the implemented measures have not been sufficiently numerous or efficient to stop the depletion of original biological diversity. Many habitats remain far from their original state. More species will become endangered in the immediate future unless more effective and far-reaching measuresare taken. The objective of the EU to halt the decline of biodiversity by 2010 will not be achieved given the current development. Although the deterioration in biodiversity may have slowed down in several cases, many economic activities continue to have a negative impact on biodiversity. The scale of these activities is normally greater than that of the measures taken to manage and restore biodiversity.The evaluation focused on detecting changes in the administration of key sectors, analysing the recent development of biodiversity and observing interlinkages between these two. The analysis of administrative measures was based on interviews and on examining policy documents, reports and other relevant literature. The analysis covered changes in the administration of nature conservation, forestry,  agriculture, land use and regional and development cooperation. The analysis of the development of biodiversity was based on employing 75 pressure, state, impact and response indicators. There were 5 to 15 indicators for each of the nine major habitat types of Finland.Three separate case studies were made to provide further insights into some key issues: 1) A GISanalysis was made of the development of land use patterns in North Karelia and south-west Finland between 1990 and 2000, 2) two scenarios on the development of forest structure in North Karelia until 2050 were developed using a special MELA-model and 3) the cost-effectiveness of the agri-environmental support scheme was examined by comparing different land allocation choices and their effects on biodiversity on an average farm in southern Finland. The evaluation also paid special attention to the role of research in safeguarding biodiversity and reflected Finnish experiences against an international background

Direct targets of the transcription factors ABA-Insensitive(ABI)4 and ABI5 reveal synergistic action by ABI4 and several bZIP ABA response factors

The plant hormone abscisic acid (ABA) is a key regulator of seed development. In addition to promoting seed maturation, ABA inhibits seed germination and seedling growth. Many components involved in ABA response have been identified, including the transcription factors ABA insensitive (ABI)4 and ABI5. The genes encoding these factors are expressed predominantly in developing and mature seeds, and are positive regulators of ABA mediated inhibition of seed germination and growth. The direct effects of ABI4 and ABI5 in ABA response remain largely undefined. To address this question, plants over-expressing ABI4 or ABI5 were used to allow identification of direct transcriptional targets. Ectopically expressed ABI4 and ABI5 conferred ABA-dependent induction of slightly over 100 genes in 11 day old plants. In addition to effector genes involved in seed maturation and reserve storage, several signaling proteins and transcription factors were identified as targets of ABI4 and/or ABI5. Although only 12% of the ABA- and ABI-dependent transcriptional targets were induced by both ABI factors in 11 day old plants, 40% of those normally expressed in seeds had reduced transcript levels in both abi4 and abi5 mutants. Surprisingly, many of the ABI4 transcriptional targets do not contain the previously characterized ABI4 binding motifs, the CE1 or S box, in their promoters, but some of these interact with ABI4 in electrophoretic mobility shift assays, suggesting that sequence recognition by ABI4 may be more flexible than known canonical sequences. Yeast one-hybrid assays demonstrated synergistic action of ABI4 with ABI5 or related bZIP factors in regulating these promoters, and mutant analyses showed that ABI4 and these bZIPs share some functions in plants