Nanoprecipitation of polymeric nanoparticle micelles based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino)ethyl methacrylate (DPA), for intracellular delivery applications

Biodistribution of nanoparticle-based intracellular delivery systems is mediated primarily by particle size and physicochemical properties. As such, overcoming the rapid removal of these by the reticuloendothelial system remains a significant challenge. To date, a number of copolymer nanoparticle systems based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino)ethyl methacrylate (DPA), displaying biomimetic and pH responsive properties, have been published, however these have been predominately polymersome based, whilst micelle systems have remained relatively unexplored. This study utilised nanoprecipitation to investigate the effects of solvent and buffer choice upon micelle size and polydispersity, and found using methanol produced monodisperse micelles of circa 70 nm diameter, whilst ethanol produced polydisperse systems with nanoparticles of circa 128 nm diameter. The choice of aqueous buffer, dialysis of the systems, extended storage, and exposure to a wide temperature range (5–70 °C) had no significant effect on micelle size, and the systems were highly resistant to dilution, indicating excellent colloidal stability. Optimisation of the nanoprecipitation process, post precipitation, was investigated, and model drugs successfully loaded whilst maintaining system stability. Subsequent in vitro studies suggested that the micelles were of negligible cellular toxicity, and an apparent cellular uptake was observed via confocal laser scanning microscopy. This paper presents the first report of an optimised nanoprecipitation methodology for the formation of MPC–DPA nanoparticle micelles, and in doing so achieved monodisperse systems with the size and physicochemical characteristics seen as desirable for long circulating therapeutic delivery vehicles

The impact of cardiorespiratory fitness on classical cardiovascular disease risk factors in rheumatoid arthritis: a cross-sectional and longitudinal study

Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). Advanced measures of cardiorespiratory fitness (CRF) are associated with CVD risk factors. The present study aimed to examine whether CVD risk factors can predict clinic-based measures of CRF, using the Siconolfi step test and to determine if exercise can improve RA patients’ cardiovascular health. Sixty-five RA patients (46 females, age 58 ± 11 years) completed assessments of CRF, CVD risk factors, body composition and RA characteristics. Ten patients participated in a follow-up 8-week exercise intervention. CRF was low (22 ml kg−1 min−1) and associated with higher diastolic blood pressure (r = − 0.37, p = 0.002), higher global CVD risk (r = − 0.267, p = 0.031) and worse body composition profile (body fat, r = − 0.48, p < 0.001; waist, r = − 0.65, p < 0.001; hip, r = − 0.58, p < 0.001). Regular exercise significantly improved CRF (p = 0.021), lower body strength (p < 0.001), agility (p < 0.001), systolic blood pressure (p = 0.021), body fat (p = 0.018), waist circumference (p = 0.035), hip circumference (p = 0.016), disease activity (p = 0.002), disability (p = 0.007) and QoL (p = 0.004). Elevated diastolic blood pressure and worse body composition profile are strong predictors of clinic-based measures of CRF. CRF is an important determinant of CVD risk and warrants inclusion in the routine assessment of RA patients. Regular exercise can improve CRF and CVD risk factors without any exacerbation of disease activity and should be offered as part of routine care

An exploratory study to investigate the association between age, physical activity, femoral trochlear cartilage thickness and biomarkers of tissue metabolism in adult males

PURPOSE: To investigate the association between age, physical activity, femoral trochlear cartilage thickness and biomarkers of tissue metabolism in a cross-sectional sample of adult males. This study utilizes several emerging biomarkers that have been associated with early joint degenerative changes; serum COMP (cartilage oligomeric matrix protein), HA (hyaluronan) and lubricin. METHODS: Eighty-one males (age: mean (range): 43(18–70) years; body mass index: 25.2 (21.0–30.6) kg/m(2)) volunteered. Resting serum COMP, HA and lubricin concentrations were determined via commercially available enzyme-linked immunosorbent assay (ELISA) and femoral trochlear cartilage thickness via supra-patellar ultrasound imaging. Physical activity levels were assessed using questionnaires. Statistical analyses were performed using correlation and regression analyses. RESULTS: Age was correlated with lateral trochlear cartilage thickness (r = − 0.372; p  0.05). CONCLUSION: This study indicates that older age may be associated with thinner lateral trochlear cartilage and higher cartilage turnover. Being physically active may also be positive for lateral trochlear cartilage thickness. However, overall, both age and physical activity level only account for a small amount of the variability in cartilage thickness and serum biomarkers

A tale of two models: formal verification of KEMTLS via Tamarin

KEMTLS is a proposal for changing the TLS handshake to authenticate the handshake using long-term key encapsulation mechanism keys instead of signatures, motivated by trade-offs in the characteristics of post-quantum algorithms. Prior proofs of security of KEMTLS and its variant KEMTLS-PDK have been hand-written proofs in the reductionist model under computational assumptions. In this paper, we present computer-verified symbolic analyses of KEMTLS and KEMTLS-PDK using two distinct Tamarin models. In the first analysis, we adapt the detailed Tamarin model of TLS 1.3 by Cremers et al. (ACM CCS 2017), which closely follows the wire-format of the protocol specification, to KEMTLS(-PDK). We show that KEMTLS(-PDK) has equivalent security properties to the main handshake of TLS 1.3 proven in this model. We were able to fully automate this Tamarin proof, compared with the previous TLS 1.3 Tamarin model, which required a big manual proving effort; we also uncovered some inconsistencies in the previous model. In the second analysis, we present a novel Tamarin model of KEMTLS(-PDK), which closely follows the multi-stage key exchange security model from prior pen-and-paper proofs of KEMTLS(-PDK). The second approach is further away from the wire-format of the protocol specification but captures more subtleties in security definitions, like deniability and different levels of forward secrecy; it also identifies some flaws in the security claims from the pen-and-paper proofs. Our positive security results increase the confidence in the design of KEMTLS(-PDK). Moreover, viewing these models side-by-side allows us to comment on the trade-off in symbolic analysis between detail in protocol specification and granularity of security properties

ウィスコンシン ダイガク マディソンコウ ガ ジッシ シテイル ナンキョク ムジン キショウ カンソク (AWS) ケイカク ノ 2011-2012 ネン カキ ノ カツドウ

ウィスコンシン大学マディソン校で推進している南極無人気象観測計画(Antarctic Automatic Weather Station(AWS)program)の32 年目の観測が,2011/2012年の南半球夏期に完了した.無人気象観測網を利用して南極の気象と気候の研究が行われている.今シーズンはロス島周辺域,ロス棚氷,西南極,東南極にわたる領域で活動した.基本的に観測点のデータはアルゴス衛星を中継して配信されるが,今年はロス島周辺域の多くの観測点で,マクマード基地を中継して"Freewave modem"を通して配信された.各無人気象観測点報告には,現在設置されている測器と動作状況が含まれる.また,無人気象観測計画の全体像を,野外活動の実施状況に沿って示す.During the 2011-2012 austral summer, the Antarctic Automatic Weather Station (AWS) program at the University of Wisconsin?Madison completed its 32nd year of observations. Ongoing studies utilizing the network include topics in Antarctic meteorology and climate studies. This field season consisted of work throughout the Ross Island area, the Ross Ice Shelf, West Antarctica, and East Antarctica. Argos satellite transmissions are the primary method for relaying station data, but throughout this year, a number of stations in the Ross Island area have been converted to Freewave modems, with their data being relayed through McMurdo station. Each AWS station report contains information regarding the instrumentation currently installed and the work performed at each site. An overview of the AWS applications is included along with field work accomplished

Benefits of Exercise in Rheumatoid Arthritis

This paper aims to highlight the importance of exercise in patients with rheumatoid arthritis (RA) and to demonstrate the multitude of beneficial effects that properly designed exercise training has in this population. RA is a chronic, systemic, autoimmune disease characterised by decrements to joint health including joint pain and inflammation, fatigue, increased incidence and progression of cardiovascular disease, and accelerated loss of muscle mass, that is, “rheumatoid cachexia”. These factors contribute to functional limitation, disability, comorbidities, and reduced quality of life. Exercise training for RA patients has been shown to be efficacious in reversing cachexia and substantially improving function without exacerbating disease activity and is likely to reduce cardiovascular risk. Thus, all RA patients should be encouraged to include aerobic and resistance exercise training as part of routine care. Understanding the perceptions of RA patients and health professionals to exercise is key to patients initiating and adhering to effective exercise training