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.

Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFA and CoMSIA

CoMFA and CoMSIA analysis were utilized in this investigation to define the important interacting regions in paclitaxel/tubulin binding site and to develop selective paclitaxel-like active compounds. The starting geometry of paclitaxel analogs was taken from the crystal structure of docetaxel. A total of 28 derivatives of paclitaxel were divided into two groups—a training set comprising of 19 compounds and a test set comprising of nine compounds. They were constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided a good predictability (q2 = 0.699, r2 = 0.991, PC = 6, S.E.E. = 0.343 and F = 185.910). They showed the steric and electrostatic properties as the major interacting forces whilst the lipophilic property contribution was a minor factor for recognition forces of the binding site. These results were in agreement with the experimental data of the binding activities of these compounds. Five fields in CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor properties) were considered contributors in the ligand–receptor interactions. The results obtained from the CoMSIA studies were: q2 = 0.535, r2 = 0.983, PC = 5, S.E.E. = 0.452 and F = 127.884. The data obtained from both CoMFA and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin binding site. This intuitively suggested where the most significant anchoring points for binding affinity are located. This information could be used for the development of new compounds having paclitaxel-like activity with new chemical entities to overcome the existing pharmaceutical barriers and the economical problem associated with the synthesis of the paclitaxel analogs. These will boost the wide use of this useful class of compounds, i.e. in brain tumors as the most of the present active compounds have poor blood–brain barrier crossing ratios and also, various tubulin isotypes has shown resistance to taxanes and other antimitotic agents.

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.

Investigating in-domain data requirements for PLDA training

This paper analyzes the limitations upon the amount of in- domain (NIST SREs) data required for training a probabilistic linear discriminant analysis (PLDA) speaker verification system based on out-domain (Switchboard) total variability subspaces. By limiting the number of speakers, the number of sessions per speaker and the length of active speech per session available in the target domain for PLDA training, we investigated the relative effect of these three parameters on PLDA speaker verification performance in the NIST 2008 and NIST 2010 speaker recognition evaluation datasets. Experimental results indicate that while these parameters depend highly on each other, to beat out-domain PLDA training, more than 10 seconds of active speech should be available for at least 4 sessions/speaker for a minimum of 800 speakers. If further data is available, considerable improvement can be made over solely out-domain PLDA training.

Colonoscopy requirements of population screening for colorectal cancer in New Zealand

Aim: To estimate the colonoscopy burden of introducing population screening for colorectal cancer in New Zealand. Methods: Screening for colorectal cancer using biennial immunochemical faecal occult blood tests offered to people aged 50-74 years of age was modelled using population estimates from Statistics New Zealand for 2011-2031. Modelling to determine colonoscopy requirements was based on participation and test positivity rates from published results of screening programmes. Estimates of the number of procedures required for ongoing adenoma surveillance were calculated using screening literature results of adenoma yield, and New Zealand Guidelines for Adenoma Surveillance. Sensitivity analysis was undertaken on key parameters. Results: For a test positivity of 6.4%, biennial screening using immunochemical faecal occult blood testing with a 60% participation rate, would require 18,000 colonoscopies nationally, increasing to 28,000 by 2031. The majority of procedures are direct referrals from a positive FOBT, with surveillance colonoscopy numbers building over time. Conclusion: Colonoscopy requirements for immunochemical faecal occult blood based population screening for colorectal cancer are high. Significant expansion of services is required and careful management of surveillance procedures to ensure timely delivery of initial colonoscopies whilst maintaining symptomatic services. A model re-run informed by data from the screening pilot will allow improved estimates for the New Zealand setting.

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.

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.

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.

Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection

Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell-mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.

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.

A simple Bayesian decision-theoretic design for dose-finding trials

A flexible and simple Bayesian decision-theoretic design for dose-finding trials is proposed in this paper. In order to reduce the computational burden, we adopt a working model with conjugate priors, which is flexible to fit all monotonic dose-toxicity curves and produces analytic posterior distributions. We also discuss how to use a proper utility function to reflect the interest of the trial. Patients are allocated based on not only the utility function but also the chosen dose selection rule. The most popular dose selection rule is the one-step-look-ahead (OSLA), which selects the best-so-far dose. A more complicated rule, such as the two-step-look-ahead, is theoretically more efficient than the OSLA only when the required distributional assumptions are met, which is, however, often not the case in practice. We carried out extensive simulation studies to evaluate these two dose selection rules and found that OSLA was often more efficient than two-step-look-ahead under the proposed Bayesian structure. Moreover, our simulation results show that the proposed Bayesian method's performance is superior to several popular Bayesian methods and that the negative impact of prior misspecification can be managed in the design stage.

Decision-theoretic designs for dose-finding clinical trials with multiple outcomes

A decision-theoretic framework is proposed for designing sequential dose-finding trials with multiple outcomes. The optimal strategy is solvable theoretically via backward induction. However, for dose-finding studies involving k doses, the computational complexity is the same as the bandit problem with k-dependent arms, which is computationally prohibitive. We therefore provide two computationally compromised strategies, which is of practical interest as the computational complexity is greatly reduced: one is closely related to the continual reassessment method (CRM), and the other improves CRM and approximates to the optimal strategy better. In particular, we present the framework for phase I/II trials with multiple outcomes. Applications to a pediatric HIV trial and a cancer chemotherapy trial are given to illustrate the proposed approach. Simulation results for the two trials show that the computationally compromised strategy can perform well and appear to be ethical for allocating patients. The proposed framework can provide better approximation to the optimal strategy if more extensive computing is available.

Partial intervertebral fusion secures successful outcomes after thoracoscopic anterior scoliosis correction: A low-dose computed tomography study

Study Design Retrospective review of prospectively collected data. Objectives To analyze intervertebral (IV) fusion after thoracoscopic anterior spinal fusion (TASF) and explore the relationship between fusion scores and key clinical variables. Summary of Background Information TASF provides comparable correction with some advantages over posterior approaches but reported mechanical complications, and their relationship to non-union and graft material is unclear. Similarly, the optimal combination of graft type and implant stiffness for effecting successful radiologic union remains undetermined. Methods A subset of patients from a large single-center series who had TASF for progressive scoliosis underwent low-dose computed tomographic scans 2 years after surgery. The IV fusion mass in the disc space was assessed using the 4-point Sucato scale, where 1 indicates <50% and 4 indicates 100% bony fusion of the disc space. The effects of rod diameter, rod material, graft type, fusion level, and mechanical complications on fusion scores were assessed. Results Forty-three patients with right thoracic major curves (mean age 14.9 years) participated in the study. Mean fusion scores for patient subgroups ranged from 1.0 (IV levels with rod fractures) to 2.2 (4.5-mm rod with allograft), with scores tending to decrease with increasing rod size and stiffness. Graft type (autograft vs. allograft) did not affect fusion scores. Fusion scores were highest in the middle levels of the rod construct (mean 2.52), dropping off by 20% to 30% toward the upper and lower extremities of the rod. IV levels where a rod fractured had lower overall mean fusion scores compared to levels without a fracture. Mean total Scoliosis Research Society (SRS) questionnaire scores were 98.9 from a possible total of 120, indicating a good level of patient satisfaction. Conclusions Results suggest that 100% radiologic fusion of the entire disc space is not necessary for successful clinical outcomes following thoracoscopic anterior selective thoracic fusion.