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Background and Purpose. Although physical therapy techniques are used to alleviate pain and stiffness in joint injuries, whether these methods are capable of affecting bone is unknown. For example, can these techniques potentially influence bone formation or resorption? To begin exploring this possibility, this study investigated the ability of 4 manual techniques to generate levels of compressive strains that presumably can stimulate bone metabolism. Subjects. Six 3,4 metacarpals from three 3-year-old Merino ewes were used. Methods. A rosette strain gauge was implanted onto the dorsomedial cortex of each ovine 3,4 metacarpal. Four different manual procedures were applied on 2 occasions on each metacarpal in vivo and ex vivo. Mean peak principal compressive strains were calculated for each technique. Results. Levered bending produced greater mean peak compressive strains than almost all other manual procedures tested in vivo or ex vivo. Conclusion and Discussion. Manual levered bending created levels of compressive strain similar in magnitude to those created by mechanical devices used in previous animal experiments to induce new bone formation (osteogenesis). This animal model appears to be suitable for investigating the effects of manually applied procedures on bone and may establish whether manual techniques can stimulate bone formation. [ABSTRACT FROM AUTHOR]

Alcohols are among the most abundant chemical feedstocks, yet they remain vastly underutilized as coupling partners in transition metal catalysis. Herein, we describe a copper metallaphotoredox manifold for the open shell deoxygenative coupling of alcohols with N -nucleophiles to forge C( sp 3 )-N bonds, a linkage of high value in pharmaceutical agents that is challenging to access via conventional cross-coupling techniques. N -heterocyclic carbene (NHC)-mediated conversion of alcohols into the corresponding alkyl radicals followed by copper-catalyzed C-N coupling renders this platform successful for a broad range of structurally unbiased alcohols and 18 classes of N -nucleophiles.

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

During zygotic mitosis in many species, forces generated at the cell cortex are required for the separation and migration of paternally provided centrosomes, pronuclear migration, segregation of genetic material, and cell division. Furthermore, in some species, force-generating interactions between spindle microtubules and the cortex position the mitotic spindle asymmetrically within the zygote, an essential step in asymmetric cell division. Understanding the mechanical and molecular mechanisms of microtubule-dependent force generation and therefore asymmetric cell division requires identification of individual cortical force-generating units in vivo . There is no current method for identifying individual force-generating units with high spatiotemporal resolution. Here, we present a method to determine both the location and the relative number of microtubule-dependent cortical force-generating units using single-molecule imaging of fluorescently labeled dynein. Dynein behavior is modeled to classify trajectories of cortically bound dynein according to whether they are interacting with a microtubule. The categorization strategy recapitulates well-known force asymmetries in C. elegans zygote mitosis. To evaluate the robustness of categorization, we used RNAi to deplete the tubulin subunit TBA-2. As predicted, this treatment reduced the number of trajectories categorized as engaged with a microtubule. Our technique will be a valuable tool to define the molecular mechanisms of dynein cortical force generation and its regulation as well as other instances wherein anchored motors interact with biopolymers (e.g., actin, tubulin, DNA)., Competing Interests: The authors declare no competing interests., (© 2023.)

Background: We report the radiological and functional outcomes at five years in patients with severe osteoarthritis of the glenohumeral joint and a Walch type B glenoid who have undergone stemless anatomic total shoulder replacement. Methods: A retrospective analysis of case notes, computed tomography scans and plain radiographs of patients undergoing anatomic total shoulder replacement for primary glenohumeral osteoarthritis were performed. Patients were grouped by the severity of their osteoarthritis using the modified Walch classification, glenoid retroversion and posterior humeral head subluxation. An evaluation was made using modern planning software. Functional outcomes were assessed using the American shoulder and elbow surgeons score, shoulder pain and disability index and visual analogue scale. Annual Lazarus scores were reviewed as regard to glenoid loosening. Results: Thirty patients were reviewed at 5 years. Analysis of all patient-reported outcome measures demonstrated significant improvement at 5-year review, American shoulder and elbow surgeons ( p  = <0.0001), shoulder pain and disability index ( p  = 0.0001), visual analogue scale ( p  = 0.0001). Radiological associations between Walch scores and Lazarus scores were not statistically significant ( p  = 0.1251) at 5 years. There were no associations between features of glenohumeral osteoarthritis and patient-reported outcome measures. Discussion: The severity of osteoarthritis did not show any association with glenoid component survivorship or with patient-reported outcome measures at 5 years review. Level of evidence: IV., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SB has a consultancy agreement with Mathys Ltd Bettlach, Switzerland, and Stryker Medical, Australia. JC receives funds for data collection, entry and storage through her department of Monash University from Mathys Bettlach, Switzerland, Mathys Australia, and Stryker Medical, Australia., (© The Author(s) 2021.)

Evaluating novel compounds for neuroprotective effects in animal models of traumatic brain injury (TBI) is a protracted, labor-intensive and costly effort. However, the present lack of effective treatment options for TBI, despite decades of research, shows the critical need for alternative methods for screening new drug candidates with neuroprotective properties. Because natural products have been a leading source of new therapeutic agents for human diseases, we used an in vitro model of stretch injury to rapidly assess pro-survival effects of three bioactive compounds, two isolated from natural products (clovanemagnolol [CM], vinaxanthone [VX]) and the third, a dietary compound (pterostilbene [PT]) found in blueberries. The stretch injury experiments were not used to validate drug efficacy in a comprehensive manner but used primarily, as proof-of-principle, to demonstrate that the neuroprotective potential of each bioactive agent can be quickly assessed in an immortalized hippocampal cell line in lieu of comprehensive testing in animal models of TBI. To gain mechanistic insights into potential molecular mechanisms of neuroprotective effects, we performed a pathway-specific PCR array analysis of the effects of CM on the rat hippocampus and microRNA sequencing analysis of the effects of VX and PT on cultured hippocampal progenitor neurons. We show that the neuroprotective properties of these natural compounds are associated with altered expression of several genes or microRNAs that have functional roles in neurodegeneration or cell survival. Our approach could help in quickly assessing multiple natural products for neuroprotective properties and expedite the process of new drug discovery for TBI therapeutics., Competing Interests: The authors have declared that no competing interests exist.

Background: We assessed distal humeral column preservation effects on clinical, radiographic and patient reported outcomes following distal humerus hemiarthroplasty for acute unreconstructable fractures., Methods: Thirty-seven consecutive patients (mean age, 75; range, 29-93 years) with an average follow-up of 61 months (range, 24-105 months) after distal humerus hemiarthroplasty using a triceps preserving approach were studied. QuickDASH and Oxford Elbow Score assessed patient reported outcomes. Clinical and radiographic assessments comprised range of motion, grip strength, instability, implant loosening, chondral wear, heterotopic ossification and condylar union., Results: Average QuickDASH was 14.9 (range, 0-63) and Oxford Elbow Score 40.35 (range, 25-48). Mean flexion arc was 108°, extension deficit 17° and pronosupination arc 155°. Average operative sided grip strength was 31.05 kg versus 31.13 kg contralaterally. Column preservation had no statistically significant effect on QuickDASH ( p  = 0.75), Oxford Elbow Score ( p  = 0.78), flexion-extension ( p  = 0.87), pronosupination ( p  = 0.78) or grip strength ( p  = 0.87). No progressive radiographic loosening or symptomatic chondral wear occurred. All fixed columns united. Three cases of immediate post-operative laxity fully resolved on elbow mobilisation. Four post-operative complications required further surgery: one ulnar neuropathy, one heterotopic ossification, one wound breakdown and one traumatic dislocation., Conclusion: Medium-term outcome of distal humerus hemiarthroplasty for acute unreconstructable distal humeral fractures is reliable irrespective of condylar preservation., Competing Interests: Declaration of Conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2020 The British Elbow & Shoulder Society.)

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer's disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18 F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18 F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18 F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18 F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Although confessions related to abusive head trauma (AHT) are reported, no detailed analysis exists. Therefore, we systematically reviewed studies of AHT confessions and examined the details, including country of origin, mechanisms and perpetrators' characteristics [PUBLISHER - THE PRECEDING UNDERLINED TEXT IS FOR THE MARGIN]. Employing 36 search terms across three search engines, we searched Medline and CINAHL from 1963 to 2018. All relevant studies underwent two independent reviews and data extraction. Descriptive statistics were used to characterise the sample; chi square and Fisher's exact tests were used to assess differences in demographic and clinical characteristics. Of 6759 identified studies, 157 full texts were reviewed and 55 articles from 15 countries spanning four continents were included. Included articles contained 434 confessions. The mechanisms of abuse included shaking alone (64.1%), impact alone (17.1%), shaking plus impact (18.0%) and other (0.9%). There was no statistically significant difference in the percentage of confessions reporting shaking alone when comparing continents: North America (64.0%), Europe (64.2%) and Oceania (60.0%; P =.92), or when comparing circumstances in which the confession was obtained: medical evaluation (74.6%) vs police or judicial investigations (63.4%; P =.11). Of 119 cases with identified perpetrators, 67.2 per cent were cases with males alone. Confessions reveal striking similarities in the mechanism of AHT (predominantly shaking) and occur across the globe.

Background: We report functional outcomes at six years in patients with varying degrees of fatty infiltration and atrophy of the rotator cuff muscles who have undergone anatomic total shoulder replacement., Methods: A retrospective analysis of case notes and magnetic resonance imaging scans of patients undergoing total shoulder replacement for primary glenohumeral arthritis was performed. Patients were grouped based upon their pre-operative magnetic resonance imaging findings for fatty infiltration, muscle area and tendinopathy. Post-operative functional outcomes were assessed using the Oxford Shoulder Score and Quick Disabilities of the Arm, Shoulder and Hand score. Post-operative measurements were made for active shoulder movements., Results: Thirty-two patients were reviewed at a mean of 67 months following surgery. All patients demonstrated fatty infiltration on their pre-operative magnetic resonance imaging scan. Muscle atrophy was shown in 22 patients and 12 had tendinopathy. Multiple regression analysis showed no correlation between the Oxford Shoulder Score (p = 0.443), the Quick Disabilities of the Arm, Shoulder and Hand score (p = 0.419), forward flexion (p = 0.170), external rotation (p = 0.755) and any of the pre-operative independent variables., Discussion: The degree of fatty infiltration, muscle atrophy and tendinopathy of the rotator cuff muscle on pre-operative magnetic resonance imaging scanning is not associated with functional outcome score or functional movement at medium-term follow-up following total shoulder replacement., Level of Evidence: IV., (© 2018 The British Elbow & Shoulder Society.)

Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.

Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin's stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species' body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use.

Investigation into the biological function of 5-benzylidene-4-oxazolidinones revealed dose-dependent inhibition of biofilm formation in Methicillin-resistant S. aureus (MRSA). This structurally unusual class of small molecules inhibit up to 89% of biofilm formation with IC 50 values as low as 0.78 μM, and disperse pre-formed biofilms with IC 50 values as low as 4.7 μM. Together, these results suggest that 4-oxazolidinones represent new chemotypes to enable the study of bacterial biofilms with small molecule chemical probes.

Fibroin proteins isolated from the cocoons of certain silk-producing insects have been widely investigated as biomaterials for tissue engineering applications. In this study, fibroins were isolated from cocoons of domesticated Bombyx mori (BM) and wild Antheraea pernyi (AP) silkworms following a degumming process. The object of this study was to obtain an assessment on certain properties of these fibroins in order that a concept might be had regarding the feasibility of using their blends as biomaterials. Membranes, 10-20 μm thick, which are water-insoluble, flexible and transparent, were prepared from pure fibroins and from their blends, and subjected to water vapor annealing in vacuum, with the aim of providing materials sufficiently strong for manipulation. The resulting materials were characterized by electrophoretic analysis and infrared spectrometry. The tensile properties of the membranes were measured and correlated with the results of infrared analysis. At low concentrations of any of the two fibroins, the mechanical characteristics of the membranes appeared to be adequate for surgical manipulation, as the modulus and strength surpassed those of BM silk fibroin alone. It was noticed that high concentrations of AP silk fibroin led to a significant reduction in the elasticity of membranes., Competing Interests: Compliances with ethical standards Conflict of interest The authors declare that there is no conflict of interest of a scientific or commercial nature. The authors have no relevant affiliations or financial support from any organization that might have a financial interest in the subject matter.

In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans. The bioavailability and lymphatic transport of free MPA and total MPA related materials were examined following oral administration of the parent drug (MPA) and the prodrug (2-MPA-TG) to both thoracic lymph duct cannulated and intact (noncannulated) greyhound dogs. The enrichment of free MPA in lymph nodes and lymph-derived lymphocytes was also determined to examine the efficiency of drug targeting to potential sites of action within the lymph. Via biochemical integration into a series of site-specific metabolic processes, the prodrug markedly increased (288-fold) lymphatic transport of total MPA related material (present as re-esterified 2-MPA-TG) when compared to the parent MPA and the extent of lymphatic transport was significantly greater in the dog (36.4% of the dose recovered in lymph) when compared to the previous data in the rat (13.4% of the dose). Conversion from 2-MPA-TG derivatives to parent MPA occurred in vivo, resulting in a marked increase in MPA concentrations in lymph nodes (5-6-fold) and lymph lymphocytes (21-fold), when compared to animals administered the parent drug. In conclusion, the data demonstrate that the TG prodrug of MPA facilitates efficient delivery of MPA to the lymphatic system in dogs and suggest that the TG prodrug strategy may more effectively facilitate targeted delivery in large animals than in rats.

Expanded polytetrafluoroethylene (ePTFE) vascular conduits with less than or equal to 6 mm internal diameter typically occlude due to a combination of thrombus formation and neointimal hyperplasia. We hypothesized that by layering the polymerized elastin precursor, human tropoelastin, in the synthetic vessel lumen we could mimic the internal elastic lamina and so maintain low thrombogenicity while significantly reducing smooth muscle cell proliferation. The luminal surfaces of ePTFE conduits were activated with plasma immersion ion implantation (PIII) treatment to facilitate covalent attachment of tropoelastin. Multilayered tropoelastin vessels (2TE) enhanced endothelial cell attachment and proliferation in vitro and were superior to materials lacking the protein. In an ovine carotid interposition model of graft compatibility, partially tropoelastin coated vessels (1TE) thrombosed at a greater rate than control ePTFE, but 2TE maintained the same patency as controls. 2TE showed a significant reduction in neointimal area down to 9.7 ± 5.2% ( p < 0.05) in contrast to 32.3 ± 3.9% for ePTFE alone. This reduction was due to a halving of the number of smooth muscle cells present and a corresponding reduction in their proliferation. 2TE, but not 1TE, enhanced the vascular compatibility of these materials: while both tropoelastin presentations increased in vitro endothelialization, only 2TE displayed the dual benefits of maintained hemocompatibility and simultaneously suppressed neointimal hyperplasia in vivo. We conclude that 2TE surface modification provides a significant improvement over ePTFE vascular conduits in a pilot large animal model study and presents an attractive path toward clinical applications for reduced diameter vessels.

This study reports major complications in a large cohort of dogs following tibial tuberosity advancement using either a fork-based or a screw-based implant system. Four hundred thirty-eight stifles were included in the study and major complications occurred in 51 stifles. Explanatory variables evaluated included implant type and body weight. No variables evaluated were associated with major complications.

Choking is one of the alternative explanations of abusive head trauma in children that have been offered in courtroom testimony and in the media. Most of these explanations - including choking - are not scientifically supported. This article highlights four points. (1) The origins of choking as an explanation for intracranial and retinal hemorrhages are speculative. (2) Choking has been used in high profile court testimony as an explanation for the death of a child thought to have been abused. (3) A case report that proposes choking as an alternative explanation for the death of a child diagnosed with abusive head trauma includes omissions and misrepresentations of facts. (4) There was a decision by the editor of the journal that published the case report that it was not necessary to include all the facts of the case; moreover, the editor indicated that facts are not required when presenting an alternative explanation. The use of scientifically unsupported alternative explanations for abusive head trauma based on inaccurate and biased information constitutes further victimization of the abused child and represents a travesty of justice., (Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Bombyx mori silk fibroin membranes provide a potential delivery vehicle for both cells and extracellular matrix (ECM) components into diseased or injured tissues. We have previously demonstrated the feasibility of growing retinal pigment epithelial cells (RPE) on fibroin membranes with the view to repairing the retina of patients afflicted with age-related macular degeneration (AMD). The goal of the present study was to investigate the feasibility of incorporating the ECM component elastin, in the form of human recombinant tropoelastin, into these same membranes. Two basic strategies were explored: (1) membranes prepared from blended solutions of fibroin and tropoelastin; and (2) layered constructs prepared from sequentially cast solutions of fibroin, tropoelastin, and fibroin. Optimal conditions for RPE attachment were achieved using a tropoelastin-fibroin blend ratio of 10 to 90 parts by weight. Retention of tropoelastin within the blend and layered constructs was confirmed by immunolabelling and Fourier-transform infrared spectroscopy (FTIR). In the layered constructs, the bulk of tropoelastin was apparently absorbed into the initially cast fibroin layer. Blend membranes displayed higher elastic modulus, percentage elongation, and tensile strength (p < 0.01) when compared to the layered constructs. RPE cell response to fibroin membranes was not affected by the presence of tropoelastin. These findings support the potential use of fibroin membranes for the co-delivery of RPE cells and tropoelastin.

A silk protein, fibroin, was isolated from the cocoons of the domesticated silkworm (Bombyx mori) and cast into membranes to serve as freestanding templates for tissue-engineered corneal cell constructs to be used in ocular surface reconstruction. In this study, we sought to enhance the attachment and proliferation of corneal epithelial cells by increasing the permeability of the fibroin membranes and the topographic roughness of their surface. By mixing the fibroin solution with poly(ethylene glycol) (PEG) of molecular weight 300 Da, membranes were produced with increased permeability and with topographic patterns generated on their surface. In order to enhance their mechanical stability, some PEG-treated membranes were also crosslinked with genipin. The resulting membranes were thoroughly characterized and compared to the non-treated membranes. The PEG-treated membranes were similar in tensile strength to the non-treated ones, but their elastic modulus was higher and elongation lower, indicating enhanced rigidity. The crosslinking with genipin did not induce a significant improvement in mechanical properties. In cultures of a human-derived corneal epithelial cell line (HCE-T), the PEG treatment of the substratum did not improve the attachment of cells and it enhanced only slightly the cell proliferation in the longer term. Likewise, primary cultures of human limbal epithelial cells grew equally well on both non-treated and PEG-treated membranes, and the stratification of cultures was consistently improved in the presence of an underlying culture of irradiated 3T3 feeder cells, irrespectively of PEG-treatment. Nevertheless, the cultures grown on the PEG-treated membranes in the presence of feeder cells did display a higher nuclear-to-cytoplasmic ratio suggesting a more proliferative phenotype. We concluded that while the treatment with PEG had a significant effect on some structural properties of the B. mori silk fibroin (BMSF) membranes, there were minimal gains in the performance of these materials as a substratum for corneal epithelial cell growth. The reduced mechanical stability of freestanding PEG-treated membranes makes them a less viable choice than the non-treated membranes.

Allyl sulphides are reactive substrates in ruthenium-catalysed olefin metathesis reactions, provided each substrate is matched with a suitable catalyst. A profile of catalyst activity is described, along with the first demonstration of allyl sulphides as traceless promoters in relayed ring-closing metathesis reactions.

Objective: To conduct a test of noninferiority for CardioCel (Admedus, Brisbane, Australia), a chemically engineered bovine pericardium over autologous pericardium treated intraoperatively with glutaraldehyde in a chronic juvenile sheep model of pulmonary valve (PV) and mitral valve (MV) reconstruction., Methods: We replaced the posterior leaflet of the MV and of 1 PV cusp with patches in ewes aged 10 months. There were 2 groups: CardioCel (n = 6) and control (n = 4). All valves were competent. Echocardiography was performed before euthanasia. The collected data were function, macroscopy, histology, and calcium contents. The primary end points were thickening and calcium content., Results: All animals survived until sacrifice after 7 months. The valves had normal echo. The macroscopic aspect of the valves was excellent. Examination of the slides for both groups revealed a continuous endothelium on both sides of the patch and a layer of new collagen developed on both sides between patch and endothelium and interstitial cells and smooth muscle cell in these layers. The patch had not thickened but the 2 layers of new collagen for the PV showed a median thickening of 37% in the CardioCel group and 111% in the control group (P = .01), and for the MV a thickening of 108% and 251%, respectively, was seen (P = .01). The median calcium content in the PV was 0.24 μg/mg (range, 0.19-0.30) in the CardioCel group versus 0.34 μg/mg (range, 0.24-0.62) in controls (P = .20). In the MV it was 0.46 μg/mg (range, 0.30-1.0) in the CardioCel group and 0.47 μg/mg (range, 0.29-1.9) in controls (P = 1.0)., Conclusions: In this growing lamb model the CardioCel patch allowed accurate valve repair at both systemic and pulmonary pressure. The mechanical properties of CardioCel after 7 months were preserved with a more controlled healing than the treated autologous pericardium and without calcification., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

The present study investigated the use of lipid based drug delivery systems to enhance the oral bioavailability of the CETP inhibitors CP-532,623 and torcetrapib. A series of self-emulsifying lipid based drug delivery systems (SEDDS) were assembled and examined using an in vitro lipid digestion model to evaluate patterns of drug precipitation under simulated intestinal conditions. Drug exposure after oral administration of the same formulations was subsequently assessed in beagle dogs. CP-532,623 was maintained in a solubilised state during dispersion of most formulations in simulated intestinal fluid, however, solubilisation capacity was reduced to various degrees upon in vitro digestion. Administration of SEDDS formulations to beagle dogs resulted in moderate differences in plasma AUC when compared to the differences in solubilisation observed in vitro. Similar trends were observed for torcetrapib. In all cases, however, in vivo exposure of CP-532,623 was greatly enhanced by administration in lipid based drug delivery systems when compared to a powder formulation. Some correlation between in vitro solubilisation and in vivo drug exposure (AUC) was evident; however, this was not linear. The data suggest that for highly lipophilic drugs such as CP-532,623 in vitro digestion data may be a conservative in vitro indicator of utility and that good exposure may be evident even for formulations that result in significant drug precipitation during in vitro digestion., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol., Methods: Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations. Changes to lipolytic enzyme activity and intestinal bile salt concentration were evaluated using in vitro lipolysis., Results: Drug exposure increased linearly with dose in younger animals. In older animals, bioavailability increased with increasing dose to a tipping point, beyond which bioavailability reduced (consistent with initiation of precipitation). No differences in hepatic function were apparent across cohorts. Changes to enzyme concentrations in lipolysis studies had little impact on drug precipitation/solubilisation. In contrast, higher bile salt concentrations better supported supersaturation at higher drug loads., Conclusions: Differences in animal cohort can have a significant impact on drug absorption from lipid based formulation. For danazol, bioavailability was enhanced under some circumstances in older animals. In vitro experiments suggest that this was unlikely to reflect changes to metabolism or lipolysis, but might be explained by increases in luminal bile salt/phospholipid concentrations in older animals.

The Suzuki-Miyaura cross-coupling reaction is a foundation stone of modern organic synthesis, as evidenced by its widespread use in the preparation of pharmaceuticals, agrochemicals, polymers, and other functional materials. With the prevalence of this venerable reaction in industrial synthesis, it is prudent to ensure its application adheres to the tenets of green chemistry. The introduction of cross-coupling catalysts that are active in sustainable solvents is therefore an important endeavor. In this report, a melamine-palladium complex is introduced as a versatile catalyst for the Suzuki-Miyaura cross-coupling reaction. This catalyst is soluble and active in both water and the renewable organic solvent ethyl lactate. The melamine-palladium catalyst can also be cross-linked by reaction with formaldehyde to generate an insoluble polymeric catalyst that can be recovered after the cross-coupling. The melamine-palladium system is inexpensive, easy to handle, bench-stable, and effective in catalysis in the presence of a variety of impurities (high cross-coupling yields were obtained in reactions run in unfiltered river water to illustrate this final point). Additionally, investigations reported herein revealed an intriguing relationship between catalytic efficiency and the base employed in the cross-coupling reaction. Implications for the mechanism of transmetalation in aqueous Suzuki-Miyaura cross-coupling reaction are discussed.

Understanding the nature of mixed surfactant self-assembly on the surface of organoclays is an important step toward optimizing their performance in polymer nanocomposites and for other potential applications, where selective surface interactions are crucial. In segmented thermoplastic polyurethane nanocomposite systems, dual-modified organoclays have shown significantly better performance compared to their single-modified counterparts. Until now, we had not fully characterized the physical chemistry of these dual-modified layered silicates, but had hypothesized that the enhanced composite performance arises due to some degree of nanoscale phase separation on the nanofiller surface, which enables enhanced compatibilization and more specific and inclusive interactions with the nanoscale hard and soft domains in these thermoplastic elastomers. This work examines the organization of quaternary alkyl ammonium compounds on the surface of Lucentite SWN using X-ray diffraction (XRD), thermogravimetric analysis (TGA), attenuated total reflectance Fourier-transfer infrared (ATR FT-IR), (13)C cross-polarization (CP)/magic angle spinning (MAS) nuclear magnetic resonance (NMR), and small-angle neutron scattering (SANS). When used in combination with choline, dimethyldioctadecylammonium (DMDO) was observed to self-assemble into discontinuous hydrophobic domains. The inner part of these hydrophobic domains was essentially unaffected by the choline (CC); however, surfactant intermixing was observed either at the periphery or throughout the choline-rich phase surrounding those domains., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have prepared a number of silicone-based thermoplastic polyurethane (TPU) nanocomposites and demonstrated an enhancement of in vitro biostability against metal-ion-induced oxidation for potential use in long-term implantable medical devices. Organoclays based on both low-aspect-ratio hectorites and high-aspect-ratio fluoromicas were evaluated after being dual-modified with two quaternary alkyl ammonium salts with differing degrees of polarity. The resultant nanocomposites were tested for in vitro biostability using physiologically relevant oxidizing conditions. Subsequently, the effects of oxidative treatment on the surface degradation and bulk mechanical integrity of the nanocomposites were investigated and compared with the parent TPUs to identify nanocomposites with the most desirable features for long-term implantation. Here, we demonstrate that the low-aspect-ratio organohectorite was delaminated and well dispersed in the nanocomposites. Importantly, these factors gave rise to the enhanced oxidative stability. In addition, the mechanical properties of all nanocomposites were less adversely affected by the oxidative treatment compared to their parent TPUs. These results suggest the potential for improved mechanical integrity and biostability when suitable dual modified organoclays are incorporated in a silicone-based TPU., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

A woman in her late 70s presented to the acute general surgical take with a 3-day history of worsening right leg pain and swelling. She had undergone right revision total hip arthroplasty 20 months previously and reported chronic postoperative right thigh pain attributed to a femoral deep venous thrombosis for which she had been warfarinised. On examination, Grey Turner's sign (bruising of the flanks indicating retroperitoneal haemorrhage) was present, as well as a large tender mass in the right iliac fossa and pitting oedema throughout the right lower limb. Urgent CT scan with intravenous contrast revealed a right retroperitoneal haematoma secondary to a right acetabular screw protruding into the right external iliac vein. The patient was successfully managed with warfarin reversal and surgical removal of the relevant acetabular screw. At 2-month follow-up, the patient's symptoms continue to resolve.

This study is the first to demonstrate in canines the ability of silica-lipid hybrid (SLH) microparticles to enhance the bioavailability and efficacy of a poorly water-soluble drug after oral administration. Spray-dried SLH microparticles comprising Capmul MCM (mono-diglycerides of C8/C12 fatty acids) and silica nanoparticles (Aerosil® 380) were shown to significantly enhance the fasted state oral bioavailability of celecoxib (CEL) (6.5 fold, relative to an aqueous suspension and more than 2-fold higher relative to the fed state) after oral administration to beagle dogs. Comparable bioavailability was observed between the SLH microparticle formulation and a conventional Capmul lipid solution, however, plasma concentrations were observed to be higher (Cmax, 1.1±0.06 vs. 0.8±0.03μg/mL) (p≤0.05) with the SLH microparticle system. The enhanced bioavailability of CEL observed with the SLH microparticles was reflected in a subsequent efficacy study conducted in an adjuvant-induced arthritis model in the rat. Reduced clinical and histological severity was observed at a dose of 3mg/kg/day, with the progression of arthritic symptoms and tissue damage reduced to a similar degree to that of a higher dose administered at 5mg/kg/day and prepared in an aqueous suspension., The enhanced bioavailability and improved efficacy observed with the SLH microparticles were attributed to the maintenance of CEL in a solubilised form during digestion of the lipid vehicle. We hypothesise that the presence of silica in the formulation may have contributed to the prevention of drug precipitation in the intestinal lumen by providing an alternative binding site for CEL to adsorb to prior to re-solubilisation and absorption. The study highlights the potential utility of novel SLH microparticle formulations as stable dry powders that possess the properties of a lipid-based formulation for the enhanced delivery and efficacy of poorly water-soluble drugs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We have compared the effects of different sterilization techniques on the properties of Bombyx mori silk fibroin thin films with the view to subsequent use for corneal tissue engineering. The transparency, tensile properties, corneal epithelial cell attachment and degradation of the films were used to evaluate the suitability of certain sterilization techniques including gamma-irradiation (in air or nitrogen), steam treatment and immersion in aqueous ethanol. The investigations showed that gamma-irradiation, performed either in air or in a nitrogen atmosphere, did not significantly alter the properties of films. The films sterilized by gamma-irradiation or by immersion in ethanol had a transparency greater than 98% and tensile properties comparable to human cornea and amniotic membrane, the materials of choice in the reconstruction of ocular surface. Although steam-sterilization produced stronger, stiffer films, they were less transparent, and cell attachment was affected by the variable topography of these films. It was concluded that gamma-irradiation should be considered to be the most suitable method for the sterilization of silk fibroin films, however, the treatment with ethanol is also an acceptable method., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Knee dislocation is an uncommon but serious injury that has traditionally been associated with high velocity injuries such as motor vehicle accidents. More recently, individual cases of obese individuals sustaining knee dislocation from a low velocity mechanism have been noted. Associated injuries of knee dislocation are common and include popliteal vessel damage requiring surgical repair and injuries to the peroneal nerve. Prompt diagnosis and reduction is essential to reduce the risk of these complications., Objectives: We aim to highlight the importance of prompt diagnosis and management of obese patients presenting with knee pain after a seemingly innocuous injury who may have a knee dislocation., Cases: We present a series of four cases of dislocation of the knee that have presented to our hospital over the course of 1 year. Each was sustained by a morbidly obese female of body mass index range 35-41, age range 33-52 years, experiencing a simple mechanical fall from standing. Magnetic resonance image scanning revealed multiple knee ligament rupture in all four cases. One case had peroneal nerve palsy., Conclusion: This is the first series of such injuries that we are aware of and highlights a potential future increase in incidence of these major injuries as body mass in society increases, placing more strain on health care resources. Practitioners in the Emergency Department need to be aware that serious injury can be present in morbidly obese patients that have sustained no more than a fall from standing height. Prompt investigation and management is essential., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S(M)DIGEST). The ability of the formulation to maintain solubilization in vitro decreased as the S(M) of the formulation increased. PPI significantly increased supersaturation stabilization and precipitation was inhibited where S(M)DISP < 3.5 and S(M)DIGEST < 4. In the presence of polymer, some degree of supersaturation was maintained up to S(M)DIGEST ∼ 8. Differentiation in the ability of SEDDS to maintain drug solubilization stems from the ability to stabilize supersaturation and for MC SEDDS, utilization of lower drug loads, higher surfactant levels (balanced against increases in S(M)DISP), lower cosolvent and the addition of PPI enhanced formulation performance. In vivo studies confirmed the ability of PPI to promote drug exposure at moderate drug loads (40% of saturated solubility in the formulation). At higher drug loads (80% saturation) and in lipid-free SEDDS, this effect was lost, suggesting that the ability of PPIs to stabilize supersaturation in vitro may, under some circumstances, overestimate utility in vivo.