The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude

Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well-defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3 °S), Brisbane (27.5 °S), Canberra (35.3 °S) and Hobart (42.8 °S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median=1.1, IQR: 0.5–2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r=0.23, p<0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r=0.50) and at high latitudes (Hobart, r=0.50; Canberra, r=0.39), to null or even slightly negative correlations, in summer (r=0.01) and at low latitudes (Townsville, r=-0.06; Brisbane, r=-0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances.

NSAM-derived total surface area vs. SMPS-derived "mobility equivalent" surface area for different environmentally relevant aerosols

The surface area of inhaled particles deposited in the alveolar region, as reported by the TSI nanoparticle surface area monitor (NSAM), was compared with the corresponding value estimated by a TSI scanning mobility particle sizer (SMPS) for a range of environmentally relevant aerosols, including petrol emissions, ETS, laser printer emissions, cooking emissions and ambient aerosols. The SMPS values were based on a mobility size distribution assuming spherical particles using the appropriate size-dependent alveolar-deposition factors provided by the ICRP. In most cases, the two instruments showed good linear agreement. With petrol emissions and ETS, the linearity extended to over 103 μm2 cm-3. With printer emissions, there was good linearity up to about 300 μm2 cm-3 while the NSAM increasingly overestimated the surface area at higher concentrations. The presence of a nucleation event in ambient air caused the NSAM to over-estimate the surface area by a factor of 2. We summarize these results and conclude that the maximum number concentration up to which the NSAM is accurate clearly depends on the type of aerosol being sampled and provide guidance for the use of the instrument.

Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with β-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.

Suitability of diodes for point dose measurements in IMRT/VMAT beams

This study investigated a potential source of inaccuracy for diode measurements in modulated beams; the effect of diode housing asymmetry on measurement results. The possible effects of diode housing asymmetry on the measurement of steep dose gradients were evaluated by measuring 5x5 cm2 beam profiles, with three cylindrical diodes and two commonly used ionization chambers, with each dosimeter positioned in a 3D scanning water tank with its stem perpendicular to the beam axis (horizontal) and parallel to the direction of scanning. The resulting profiles were used to compare the penumbrae measured with the diode stem pointing into (equivalent to a “stem-first” setup) and out of the field (equivalent to a “stem-last” setup) in order to evaluate the effects of dosimeter alignment and thereby identify the effects of dosimeter asymmetry. The stem-first and stem-last orientations resulted in differences of up to 0.2 mm in the measured 20-80% penumbra widths and differences of up to 0.4 mm in the off axis position of the 90% isodose. These differences, which are smaller than previously reported for older model dosimeters, were apparent in the profile results for both diodes and small volume ionization chambers. As an extension to this study, the practical use of all five dosimeters was exemplified by measuring point doses in IMRT test beams. These measurements showed good agreement (within 2%) between the diodes and the small volume ionization chamber, with all of these dosimeters being able to identify a region 3% under-dosage which was not identified by a larger volume (6 mm diameter) ionization chamber. The results of this work should help to remove some of the barriers to the use of diodes for modulated radiotherapy dosimetry in the future.

The dependence of computed tomography number to relative electron density conversion on phantom geometry and its impact on planned dose

A computed tomography number to relative electron density (CT-RED) calibration is performed when commissioning a radiotherapy CT scanner by imaging a calibration phantom with inserts of specified RED and recording the CT number displayed. In this work, CT-RED calibrations were generated using several commercially available phantoms to observe the effect of phantom geometry on conversion to electron density and, ultimately, the dose calculation in a treatment planning system. Using an anthropomorphic phantom as a gold standard, the CT number of a material was found to depend strongly on the amount and type of scattering material surrounding the volume of interest, with the largest variation observed for the highest density material tested, cortical bone. Cortical bone gave a maximum CT number difference of 1,110 when a cylindrical insert of diameter 28 mm scanned free in air was compared to that in the form of a 30 × 30 cm2 slab. The effect of using each CT-RED calibration on planned dose to a patient was quantified using a commercially available treatment planning system. When all calibrations were compared to the anthropomorphic calibration, the largest percentage dose difference was 4.2 % which occurred when the CT-RED calibration curve was acquired with heterogeneity inserts removed from the phantom and scanned free in air. The maximum dose difference observed between two dedicated CT-RED phantoms was ±2.1 %. A phantom that is to be used for CT-RED calibrations must have sufficient water equivalent scattering material surrounding the heterogeneous objects that are to be used for calibration.

LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion

Summary Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. © 2015 The Authors.

Synthesis and characterization of K2Ca5(SO4)6· H2O, the equivalent of görgeyite, a rare evaporite mineral

Görgeyite, K2Ca5(SO4)6··H2O, is a very rare monoclinic double salt found in evaporites related to the slightly more common mineral syngenite. At 1 atmosphere with increasing external temperature from 25 to 150 °C, the following succession of minerals was formed: first gypsum and K2O, followed at 100 °C by görgeyite. Changes in concentration at 150 °C due to evaporation resulted in the formation of syngenite and finally arcanite. Under hydrothermal conditions, the succession is syngenite at 50 °C, followed by görgyeite at 100 and 150 °C. Increasing the synthesis time at 100 °C and 1 atmosphere showed that initially gypsum was formed, later being replaced by görgeyite. Finally görgeyite was replaced by syngenite, indicating that görgeyite is a metastable phase under these conditions. Under hydrothermal conditions, syngenite plus a small amount of gypsum was formed, after two days being replaced by görgeyite. No further changes were observed with increasing time. Pure görgeyite showed elongated crystals approximately 500 to 1000 µ m in length. The infrared and Raman spectra are mainly showing the vibrational modes of the sulfate groups and the crystal water (structural water). Water is characterized by OH-stretching modes at 3526 and 3577 cm–1 , OH-bending modes at 1615 and 1647 cm–1 , and an OH-libration mode at 876 cm–1 . The sulfate 1 mode is weak in the infrared but showed strong bands at 1005 and 1013 cm–1 in the Raman spectrum. The 2 mode also showed strong bands in the Raman spectrum at 433, 440, 457, and 480 cm–1 . The 3 mode is characterized by a complex set of bands in both infrared and Raman spectra around 1150 cm–1 , whereas 4 is found at 650 cm–1.

Ex vivo investigation of novel wound healing therapies and development of a 3-D human skin equivalent wound model

It has previously been found that complexes comprised of vitronectin and growth factors (VN:GF) enhance keratinocyte protein synthesis and migration. More specifically, these complexes have been shown to significantly enhance the migration of dermal keratinocytes derived from human skin. In view of this, it was thought that these complexes may hold potential as a novel therapy for healing chronic wounds. However, there was no evidence indicating that the VN:GF complexes would retain their effect on keratinocytes in the presence of chronic wound fluid. The studies in this thesis demonstrate for the first time that the VN:GF complexes not only stimulate proliferation and migration of keratinocytes, but also these effects are maintained in the presence of chronic wound fluid in a 2-dimensional (2-D) cell culture model. Whilst the 2-D culture system provided insights into how the cells might respond to the VN:GF complexes, this investigative approach is not ideal as skin is a 3-dimensional (3-D) tissue. In view of this, a 3-D human skin equivalent (HSE) model, which reflects more closely the in vivo environment, was used to test the VN:GF complexes on epidermopoiesis. These studies revealed that the VN:GF complexes enable keratinocytes to migrate, proliferate and differentiate on a de-epidermalised dermis (DED), ultimately forming a fully stratified epidermis. In addition, fibroblasts were seeded on DED and shown to migrate into the DED in the presence of the VN:GF complexes and hyaluronic acid, another important biological factor in the wound healing cascade. This HSE model was then further developed to enable studies examining the potential of the VN:GF complexes in epidermal wound healing. Specifically, a reproducible partial-thickness HSE wound model was created in fully-defined media and monitored as it healed. In this situation, the VN:GF complexes were shown to significantly enhance keratinocyte migration and proliferation, as well as differentiation. This model was also subsequently utilized to assess the wound healing potential of a synthetic fibrin-like gel that had previously been demonstrated to bind growth factors. Of note, keratinocyte re-epitheliasation was shown to be markedly improved in the presence of this 3-D matrix, highlighting its future potential for use as a delivery vehicle for the VN:GF complexes. Furthermore, this synthetic fibrin-like gel was injected into a 4 mm diameter full-thickness wound created in the HSE, both keratinocytes and fibroblasts were shown to migrate into this gel, as revealed by immunofluorescence. Interestingly, keratinocyte migration into this matrix was found to be dependent upon the presence of the fibroblasts. Taken together, these data indicate that reproducible wounds, as created in the HSEs, provide a relevant ex vivo tool to assess potential wound healing therapies. Moreover, the models will decrease our reliance on animals for scientific experimentation. Additionally, it is clear that these models will significantly assist in the development of novel treatments, such as the VN:GF complexes and the synthetic fibrin-like gel described herein, ultimately facilitating their clinical trial in the treatment of chronic wounds.

Effects of inoculating dose on the kinetics of Chlamydia muridarum genital infection in female mice

Chlamydia trachomatis infections have been implicated in problems such as pelvic inflammatory disease and infertility in females. Although there are some studies examining the kinetics of ascending infection, there is limited information on the kinetics of pathology development and cellular infiltrate into the reproductive tissues in relation to the effects of inoculating dose, and a better understanding of these is needed. The murine model of female genital tract Chlamydia muridarum infection is frequently used as a model of human C. trachomatis reproductive tract infection. To investigate the kinetics of ascending genital infection and associated pathology development, female BALB/c mice were intravaginally infected with C. muridarum at doses ranging from 5102 to 2.6106 inclusion forming units. We found that the inoculating dose affects the course of infection and the ascension of bacteria, with the highest dose ascending rapidly to the oviducts. By comparison, the lowest dose resulted in the greatest bacterial load in the lower reproductive tract. Interestingly, we found that the dose did not significantly affect inflammatory cell infiltrate in the various regions. Overall, this data show the effects of infectious dose on the kinetics of ascending chlamydial infection and associated inflammatory infiltration in BALB/c mice.