Estimation of inhaled ultrafine particle surface area dose for urban environments

There is considerable scientific interest in personal exposure to ultrafine particles. Owing to their small size, these particles are able to penetrate deep into the lungs, where they may cause adverse respiratory, pulmonary and cardiovascular health effects. This article presents Bayesian hierarchical models for estimating and comparing inhaled particle surface area in the lung.

The Wzy O-antigen polymerase of Yersinia pseudotuberculosis O:2a has a dependence on the Wzz chain-length determinant for efficient polymerization

Lipopolysaccharide is a major immunogenic structure for the pathogen Yersinia pseudotuberculosis, which contains the O-specific polysaccharide (OPS) that is presented on the cell surface. The OPS contains many repeats of the oligosaccharide O-unit and exhibits a preferred modal chain length that has been shown to be crucial for cell protection in Yersinia. It is well established that the Wzz protein determines the preferred chain length of the OPS, and in its absence, the polymerization of O units by the Wzy polymerase is uncontrolled. However, for Y. pseudotuberculosis, a wzz mutation has never been described. In this study, we examine the effect of Wzz loss in Y. pseudotuberculosis serotype O:2a and compare the lipopolysaccharide chain-length profile to that of Escherichia coli serotype O111. In the absence of Wzz, the lipopolysaccharides of the two species showed significant differences in Wzy polymerization. Yersinia pseudotuberculosis O:2a exhibited only OPS with very short chain lengths, which is atypical of wzz-mutant phenotypes that have been observed for other species. We hypothesise that the Wzy polymerase of Y. pseudotuberculosis O:2a has a unique default activity in the absence of the Wzz, revealing the requirement of Wzz to drive O-unit polymerization to greater lengths.

Enhanced cortisol suppression following administration of low-dose dexamethasone in first-episode psychosis patients

OBJECTIVE Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis and hyper-activity of this system have been described in patients with psychosis. Conversely, some psychiatric disorders such as post-traumatic stress disorder (PTSD) are characterised by HPA hypo-activity, which could be related to prior exposure to trauma. This study examined the cortisol response to the administration of low-dose dexamethasone in first-episode psychosis (FEP) patients and its relationship to childhood trauma. METHOD The low-dose (0.25 mg) Dexamethasone Suppression Test (DST) was performed in 21 neuroleptic-naive or minimally treated FEP patients and 20 healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. RESULTS FEP patients reported significantly higher rates of childhood trauma compared to controls (p = 0.001) and exhibited lower basal (a.m.) cortisol (p = 0.04) and an increased rate of cortisol hyper-suppression following dexamethasone administration compared to controls (33% (7/21) vs 5% (1/20), respectively; p = 0.04). There were no significant group differences in mean cortisol decline or percent cortisol suppression following the 0.25 mg DST. This study shows for the first time that a subset of patients experiencing their first episode of psychosis display enhanced cortisol suppression. CONCLUSIONS These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored.

Inhaled particle surface area dose: Stationary vs personal monitoring

The aim of this paper is to determine the suitability of solely stationary measurements for exposure assessment and management applications. For this purpose, quantified inhaled particle surface area (IPSA) doses using both stationary and personal particle exposure monitors were evaluated and compared.

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 MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS. © 2015 Field et al.

Morphometric analysis of the thoracic intervertebral foramen osseous anatomy in adolescent idiopathic scoliosis using low dose computerized tomography

Introduction. The dimensions of the thoracic intervertebral foramen in adolescent idiopathic scoliosis (AIS) have not previously been quantified. During posterior approach scoliosis correction surgery pedicle screws may occasionally breach into the foramen. Better understanding of the dimensions of the foramen may be useful in surgical planning. This study describes a reproducible method for measurement of the thoracic foramen in AIS using computerized tomography (CT). Methods. In 23 pre-operative female patients with Lenke 1 type AIS with right side convexity major curves confined to the thoracic spine the foraminal height (FH), foraminal width (FW), pedicle to superior articular process distance (P-SAP) and cross sectional foraminal area (FA) were measured using multiplanar reconstructed CT. Measurements were made at entrance, midpoint and exit of the thoracic foramina from T1/T2 to T11/T12. Results were correlated with potential dependent variables of major curve Cobb Angle measured on X-ray and CT, Age, Weight, Lenke classification subtype, Risser Grade and number of spinal levels in the major curve. Results. The FH, FW, P-SAP and FA dimensions and ratios are all significantly larger on the convexity of the major curve and maximal at or close to the apex. Mean thoracic foraminal dimensions change in a predictable manner relative to position on the major thoracic curve. There was no significant correlation with the measured foraminal dimensions or ratios and the potential dependent variables. The average ratio of convexity to concavity dimensions at the apex foramina for entrance, midpoint and exit respectively are FH (1.50, 1.38, 1.25), FW (1.28, 1.30, 0.98), FA (2.06, 1.84, 1.32), P-SAP (1.61, 1.47, 1.30). Conclusion. Foraminal dimensions of the thoracic spine are significantly affected by AIS. Foraminal dimensions have a predictable convexity to concavity ratio relative to the proximity to the major curve apex. Surgeons should be aware of these anatomical differences during scoliosis correction surgery.

Using low dose computerized tomography to morphometrically analyse the thoracic intervertebral foramen osseous anatomy in adolescent idiopathic scoliosis

INTRODUCTION The dimensions of the thoracic intervertebral foramen in adolescent idiopathic scoliosis (AIS) have not previously been quantified. During posterior approach scoliosis correction surgery pedicle screws may occasionally breach into the foramen. Better understanding of the dimensions of the foramen may be useful in surgical planning. This study describes a reproducible method for measurement of the thoracic foramen in AIS using computerized tomography (CT). METHODS In 23 pre-operative female patients with Lenke 1 type AIS with right side convexity major curves confined to the thoracic spine the foraminal height (FH), foraminal width (FW), pedicle to superior articular process distance (P-SAP) and cross sectional foraminal area (FA) were measured using multiplanar reconstructed CT. Measurements were made at entrance, midpoint and exit of the thoracic foramina from T1/T2 to T11/T12. Results were correlated with potential dependent variables of major curve Cobb Angle measured on X-ray and CT, Age, Weight, Lenke classification subtype, Risser Grade and number of spinal levels in the major curve. RESULTS The FH, FW, P-SAP and FA dimensions and ratios are all significantly larger on the convexity of the major curve and maximal at or close to the apex. Mean thoracic foraminal dimensions change in a predictable manner relative to position on the major thoracic curve. There was no significant correlation with the measured foraminal dimensions or ratios and the potential dependent variables. The average ratio of convexity to concavity dimensions at the apex foramina for entrance, midpoint and exit respectively are FH (1.50, 1.38, 1.25), FW (1.28, 1.30, 0.98), FA (2.06, 1.84, 1.32), P-SAP (1.61, 1.47, 1.30). CONCLUSION Foraminal dimensions of the thoracic spine are significantly affected by AIS. Foraminal dimensions have a predictable convexity to concavity ratio relative to the proximity to the major curve apex. Surgeons should be aware of these anatomical differences during scoliosis correction surgery.

IgE-Associated IGHV Genes from Venom and Peanut Allergic Individuals Lack Mutational Evidence of Antigen Selection

Antigen selection of B cells within the germinal center reaction generally leads to the accumulation of replacement mutations in the complementarity-determining regions (CDRs) of immunoglobulin genes. Studies of mutations in IgE-associated VDJ gene sequences have cast doubt on the role of antigen selection in the evolution of the human IgE response, and it may be that selection for high affinity antibodies is a feature of some but not all allergic diseases. The severity of IgE-mediated anaphylaxis is such that it could result from higher affinity IgE antibodies. We therefore investigated IGHV mutations in IgE-associated sequences derived from ten individuals with a history of anaphylactic reactions to bee or wasp venom or peanut allergens. IgG sequences, which more certainly experience antigen selection, served as a control dataset. A total of 6025 unique IgE and 5396 unique IgG sequences were generated using high throughput 454 pyrosequencing. The proportion of replacement mutations seen in the CDRs of the IgG dataset was significantly higher than that of the IgE dataset, and the IgE sequences showed little evidence of antigen selection. To exclude the possibility that 454 errors had compromised analysis, rigorous filtering of the datasets led to datasets of 90 core IgE sequences and 411 IgG sequences. These sequences were present as both forward and reverse reads, and so were most unlikely to include sequencing errors. The filtered datasets confirmed that antigen selection plays a greater role in the evolution of IgG sequences than of IgE sequences derived from the study participants.

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven

Background: IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses. Objectives: To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy. Methods: Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced. Results: The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts. Conclusion: In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.

Vaccination of koalas (Phascolarctos cinereus) with a recombinant chlamydial major outer membrane protein adjuvanted with poly I:C, a host defense peptide and polyphosphazine, elicits strong and long lasting cellular and humoral immune responses

Chlamydial infections are wide spread in koalas across their range and a solution to this debilitating disease has been sought for over a decade. Antibiotics are the currently accepted therapeutic measure, but are not an effective treatment due to the asymptomatic nature of some infections and a low efficacy rate. Thus, a vaccine would be an ideal way to address this infectious disease threat in the wild. Previous vaccine trials have used a three-dose regimen; however this is very difficult to apply in the field as it would require multiple capture events, which are stressful and invasive processes for the koala. In addition, it requires skilled koala handlers and a significant monetary investment. To overcome these challenges, in this study we utilized a polyphosphazine based poly I:C and a host defense peptide adjuvant combined with recombinant chlamydial major outer membrane protein (rMOMP) antigen to induce long lasting (54 weeks) cellular and humoral immunity in female koalas with a novel single immunizing dose. Immunized koalas produced a strong IgG response in plasma, as well as at mucosal sites. Moreover, they showed high levels of C. pecorum specific neutralizing antibodies in the plasma as well as vaginal and conjunctival secretions. Lastly, Chlamydia-specific lymphocyte proliferation responses were produced against both whole chlamydial elementary bodies and rMOMP protein, over the 12-month period. The results of this study suggest that a single dose rMOMP vaccine incorporating a poly I:C, host defense peptide and polyphosphazine adjuvant is able to stimulate both arms of the immune system in koalas, thereby providing an alternative to antibiotic treatment and/or a three-dose vaccine regime.

Ultrasound attenuation computed tomography assessment of PAGAT gel dose

Ultrasound has been previously investigated as an alternative readout method for irradiated polymer gel dosimeters, with authors reporting varying dose responses. We extend previous work utilizing a new computed tomography ultrasound scanner comprising of two identical 5 MHz, 128-element linear-array ultrasound transducers, co-axially aligned and submerged in water as a coupling agent, with rotational of the gel dosimeter between the transducers facilitated by a robotic arm. We have investigated the dose-dependence of both ultrasound bulk attenuation and broadband ultrasound attenuation (BUA) for the PAGAT gel dosimeter. The ultrasound bulk attenuation dose sensitivity was found to be 1.46  ±  0.04 dB m −1 Gy −1, being in agreement with previously published results for PAG and MAGIC gels. BUA was also found to be dose dependent and was measured to be 0.024  ±  0.003 dB MHz −1 Gy −1; the advantage of BUA being its insensitivity to frequency-independent attenuation mechanisms including reflection and refraction, thereby minimizing image reconstruction artefacts.

Low-dose curcumin stimulates proliferation, migration and phagocytic activity of olfactory ensheathing cells

One of the promising strategies for neural repair therapies is the transplantation of olfactory ensheathing cells (OECs) which are the glial cells of the olfactory system. We evaluated the effects of curcumin on the behaviour of mouse OECs to determine if it could be of use to further enhance the therapeutic potential of OECs. Curcumin, a natural polyphenol compound found in the spice turmeric, is known for its anti-cancer properties at doses over 10 µM, and often at 50 µM, and it exerts its effects on cancer cells in part by activation of MAP kinases. In contrast, we found that low-dose curcumin (0.5 µM) applied to OECs strikingly modulated the dynamic morphology, increased the rate of migration by up to 4-fold, and promoted significant proliferation of the OECs. Most dramatically, low-dose curcumin stimulated a 10-fold increase in the phagocytic activity of OECs. All of these potently stimulated behavioural characteristics of OECs are favourable for neural repair therapies. Importantly, low-dose curcumin gave a transient activation of p38 kinases, which is in contrast to the high dose curcumin effects on cancer cells in which these MAP kinases tend to undergo prolonged activation. Low-dose curcumin mediated effects on OECs demonstrate cell-type specific stimulation of p38 and ERK kinases. These results constitute the first evidence that low-dose curcumin can modulate the behaviour of olfactory glia into a phenotype potentially more favourable for neural repair and thereby improve the therapeutic use of OECs for neural repair therapies

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.