An audit of current practice and management of metastatic spinal cord compression at a regional cancer centre.

Metastatic spinal cord compression (MSCC) is an oncological emergency requiring prompt recognition and management to preserve neurological function and mobility. We performed an audit to assess current practice of MSCC against current best practice as outlined by NICE. Our retrospective audit identified 10 patients from January to December 2009 with confirmed MSCC. The most common primary tumours were prostate 3 (30%), breast 3 (30%) and lung 2 (20%). Pain was the main presenting symptom 9 (90%), followed by weakness 7 (70%) and sensory changes 1 (10%). 5 (50%) had MRI within 24 hours and only 6 (60%) underwent full MRI scan. 8 (80%) had corticosteroids before MRI scan. 6 (60%) received radiotherapy within 24 hours. Only 4 (40%) were referred to orthopaedics and none of these patients had been recommended surgery. Up 14 days following radiological confirmation of MSCC, the number of patients who were unable to walk increased by 20%. Only 5 (50%) were discharged during this period of study. Our audit reported a number of variances in management compared to NICE guideline. These can be improved by following a'fast track' referral pathway and regular education for junior doctors and primary care doctors.

A missense mutation in the transcription factor Foxo3a causes teratomas and oocyte abnormalities in mice.

An N-ethyl-N-nitrosourea random mutation screen was used to identify recessive modifiers of gene silencing in the mouse using an epigenetically sensitive reporter transgene. One of the mutant lines, MommeR1, was identified as a suppressor of variegation and it showed female-specific age-associated infertility in homozygotes. Linkage analysis identified a region on chromosome 10, containing the Foxo3a gene, previously shown to play a critical role in female gametogenesis. Foxo3a is a transcription factor with roles in cell cycle control, apoptosis, neural and hematopoietic cell differentiation, and DNA repair. Sequencing of the Foxo3a gene in MommeR1 mice revealed a point mutation that causes an amino acid substitution in the highly conserved Forkhead DNA-binding domain. In vitro transcription assays showed that the point mutation causes loss of FOXO3a transactivation activity. Compound heterozygotes made with Foxo3a-null mice (carrying the targeted deletion of exon 2) displayed complementation with respect to both the activation of the reporter transgene and defects in folliculogenesis similar to those seen in MommeR1 homozygotes, supporting the conclusion that this is the causative mutation. Approximately one in six female MommeR1 homozygotes develop teratomas, a phenotype not reported in Foxo3a-null mice. Ovulated oocytes from MommeR1 homozygotes display a number of abnormalities. The MommeR1 mice provide a novel platform to investigate teratocarcinogenesis and link Foxo3a with parthenogenesis and ovarian cancer. The finding of Foxo3a as a modifier of epigenetic reprogramming is discussed.

3D in silico modeling of the human respiratory system for inhaled drug delivery and imaging analysis.

The efficacies of inhaled pharmacologic drugs could be improved if drugs could be targeted to appropriate sites within the human respiratory system. The spatial deposition patterns of particles can now be detected with a high degree of resolution using advanced techniques of imaging (e.g., SPECT). However, the effectiveness of such laboratory regimens has been limited by the inability to clearly identify airway composition within images. Therefore, we have developed a theoretical protocol to map airways within human lungs that is designed to be used in a complementary manner with laboratory investigations. The in silico model has two components: a mathematical model based on concepts of topology; and, a computer algorithm which tracks the millions of constituent lung airways. The in silico model produces 3D lung structures that are anatomically correct and can be customized to each patient. We have applied the protocol to a SPECT study where the interiors of lungs were partitioned into a series of ten nested shells. Airway composition in the respective shells provides a heretofore unavailable quantification of scintigraphy images. The protocol can be employed in a practical manner in the medical arena to aid in the interpretation of SPECT images, and to provide a platform for the design of human subject tests.

Simulation of realistic abnormal SPECT brain perfusion images: application in semi-quantitative analysis.

Simulation is useful in the validation of functional image analysis methods, particularly when considering the number of analysis techniques currently available lacking thorough validation. Problems exist with current simulation methods due to long run times or unrealistic results making it problematic to generate complete datasets. A method is presented for simulating known abnormalities within normal brain SPECT images using a measured point spread function (PSF), and incorporating a stereotactic atlas of the brain for anatomical positioning. This allows for the simulation of realistic images through the use of prior information regarding disease progression. SPECT images of cerebral perfusion have been generated consisting of a control database and a group of simulated abnormal subjects that are to be used in a UK audit of analysis methods. The abnormality is defined in the stereotactic space, then transformed to the individual subject space, convolved with a measured PSF and removed from the normal subject image. The dataset was analysed using SPM99 (Wellcome Department of Imaging Neuroscience, University College, London) and the MarsBaR volume of interest (VOI) analysis toolbox. The results were evaluated by comparison with the known ground truth. The analysis showed improvement when using a smoothing kernel equal to system resolution over the slightly larger kernel used routinely. Significant correlation was found between effective volume of a simulated abnormality and the detected size using SPM99. Improvements in VOI analysis sensitivity were found when using the region median over the region mean. The method and dataset provide an efficient methodology for use in the comparison and cross validation of semi-quantitative analysis methods in brain SPECT, and allow the optimization of analysis parameters.

betaA- and betaC-activin, follistatin, activin receptor mRNA and betaC-activin peptide expression during rat liver regeneration.

The mRNA expression of two activin growth factor subunits (betaA- and betaC-activin), activin receptor subunits (ActRIIA, ActRIIB) and the activin-binding protein follistatin, and peptide expression of betaA-activin and betaC-activin subunits, were examined in regenerating rat liver after partial hepatectomy (PHx). Liver samples were collected from adult, male Sprague-Dawley rats, 12-240 h (n=3-5 rats per time point) after PHx or from sham-operated controls at the same time points. Hepatocyte mitosis and apoptosis were assessed histologically and by in situ cell death detection. RT and PCR were used to assess relative gene expression. betaA- and betaC-activin peptide immunoreactivity was assessed in liver and serum samples by western blotting, whereas cellular expression was investigated by immunohistochemistry, using specific monoclonal antibodies. betaA- and betaC-activin mRNA dropped to < 50% of sham control values 12 h after PHx and remained at this level until 168 h post-PHx, when betaA-activin expression increased to three times sham control values and betaC-activin mRNA returned to pre-PHx levels. A peak in follistatin expression was observed 24-48 h post-PHx, coincident with an increase in hepatocyte mitosis. No changes were observed in ActRIIA mRNA, whereas ActRIIB expression paralleled that of betaA-activin mRNA. betaC-activin immunoreactive homo- and heterodimers were observed in regenerating liver and serum. Mitotic hepatocytes frequently contained betaC-activin immunoreactivity, whereas apoptotic hepatocytes were often immunoreactive for betaA-activin. We conclude that betaA- and betaC-activin subunit proteins are autocrine growth regulators in regenerating liver and when expressed independently lead to hepatocyte apoptosis or mitosis in a subset of hepatocytes.

Proliferating cell nuclear antigen immunoreactivity in the ovarian surface epithelium of mice of varying ages and total lifetime ovulation number following ovulation.

Everytime an oocyte is released at ovulation, the ovarian surface epithelium (OSE) is ruptured and must be restored by epithelial cell proliferation. Ovulation site closure was studied in mice of various ages along with total lifetime ovulation number to investigate the known association of these factors with the risk of epithelial ovarian cancer. Ovaries from Swiss Webster mice were collected at various time points postovulation from 3-mo virgin animals (estimated median total lifetime ovulation number, 92; n = 40 mice), 8-mo virgin animals subject to incessant ovulation (estimated median total lifetime ovulation number, 652; n = 15 mice), and 12-mo breeders (estimated median total lifetime ovulation number, 208; n = 35 mice). Diameters of ovulation sites were estimated by scanning electron microscopy. No differences were found in the rate of ovulation site closure between the groups. Sections of ovaries were analyzed using immunohistochemistry for proliferating cell nuclear antigen (PCNA). The highest density of immunoreactive cells was observed in all animal groups in the cuboidal cells around the rupture site the day after ovulation. Despite the similarity in ovulation site closure rates between groups, the total number of OSE cells that were positive for PCNA in both the 8- and 12-mo animals was significantly reduced, so the number of stained cells appeared to be insufficient to cover the ovulation site. These data suggest that other mechanisms, such as proliferation of the extraovarian mesothelium, may play a role in the re-epithelialization of the ovary.

A comparison of planar scintigraphy and SPECT measurement of total lung deposition of inhaled aerosol.

Planar gamma camera imaging of inhaled aerosol deposition is extensively used to assess the total deposition in the lung. However, validation of the measurements is not straightforward, as gold standard measurements of lung activity against which to compare are not readily available. Quantitative SPECT imaging provides an alternative method for comparison. Four different methods for planar image quantification are compared. Two attenuation correction techniques, thickness measurement and transmission measurement, have been combined with two scatter correction techniques, reduced attenuation coefficient and line-source scatter function convolution subtraction. Each technique has been applied to 10 studies of aerosol deposition of a fine aerosol (mass median aerodynamic diameter 1.8 microm) and 10 studies using a coarse aerosol (mass median aerodynamic diameter 6.5 microm). The total activity in the right lung for each measurement has been compared to the value determined from SPECT imaging on the same subjects. When the thickness measurement and transmission techniques were applied with scatter compensation using a reduced attenuation coefficient, activity was systematically overestimated by 5% in both cases. The corresponding random errors (coefficient of variation) were 8.6% and 6.6%. Separate scatter correction reduced these systemic errors significantly to -1.5% and 2.7%, respectively. The random errors were not affected. All techniques provided assessment of total lung activity with an accuracy and precision that differed by less than 10% compared to the SPECT values. Planar gamma camera imaging provides a good method of assessing total lung deposition of inhaled aerosol.

Alzheimer's disease: differences in technetium-99m HMPAO SPECT scan findings between early onset and late onset dementia.

OBJECTIVE: To compare the HMPAO SPECT cerebral perfusion patterns in early and late onset Alzheimer's disease. METHODS: Twenty patients with early onset disease (<65 years) and 44 patients with late onset disease (>65 years) were studied. All patients fulfilled NINCDS-ADRDA clinical criteria and had details of disease severity and length of history at the time of imaging. Technetium-99m HMPAO SPECT brain scans were acquired on a multi-detector gammacamera and analysed visually and with statistical parametric mapping (SPM99). RESULTS: Patients with early onset disease had significantly greater posterior cortical association area involvement whereas those with late onset disease had significantly greater medial temporal hypoperfusion. These findings were unchanged after controlling for disease severity and length of illness. DISCUSSION: These functional imaging findings of the differences between early and late onset Alzheimer's disease are supported by published findings that include histopathological and clinical evidence; namely late onset patients tend to present with the characteristic involvement of the medial temporal lobes producing marked memory loss whereas early onset patients present with predominant posterior cortical association area involvement. These age related findings should be borne in mind when clinically diagnosing, and interpreting functional brain imaging studies in, patients with suspected Alzheimer's disease.

Measurement of cerebral perfusion volume and 99mTc-HMPAO uptake using SPECT in controls and patients with Alzheimer's disease.

Methods for quantifying the changes in brain function observed in single photon emission computed tomography (SPECT) using hexamethylenepropylene amine oxime (HMPAO) for patients with Alzheimer's disease have the potential of improving the diagnostic accuracy of the procedure and its ability to monitor response to treatment. The absolute percentage uptake of HMPAO and the cerebral perfusion volume (CPV) of the brain were assessed using SPECT in 26 patients with mild to moderate Alzheimer's disease (AD) and 24 control subjects. A subset of 15 control subjects, which was age-matched to the AD patients, was selected to allow fair statistical comparison of parameters between groups. The percentage of brain volume with reduced perfusion (R) and a volume loss index (VLI), given by /CPV, were also calculated. Eight of the control subjects were studied on a second occasion after a mean period of 6 months. There was no significant difference in percentage uptake between controls and AD patients, the mean value being 5.8%. Cerebral perfusion volume in controls was found to depend on sex (mean value in males and females being 1327 ml and 1222 ml, respectively) and on age. The volume loss index corrected for age and sex provided good discrimination between controls and AD subjects giving a sensitivity and specificity of 81% and 96%, respectively. The repeatability coefficient, the 95% confidence limit for the difference between repeat measurements, on controls was 67 ml (5%). The measurement of cerebral perfusion volume and related indices may be of value in identifying patients with early Alzheimer's disease and in following their response to treatment.

Changes in the mouse ovarian surface epithelium with age and ovulation number.

The cell biology of ovarian surface epithelium (OSE) was studied in mice of varying age and lifetime total ovulation number (OV#), to determine the relative importance of these factors in control of OSE proliferation and development of invaginations and cysts. Ovaries from Swiss Webster mice (total OV# median: range [n mice]) were collected at 4 weeks of age (prepubertal; 0[9]), from 3-month virgins (113: 11-235 [55]), from 12-month old breeders (217: 97-386 [21]) and from 8-month virgin mice, housed in split cages alongside a male, to induce continuous oestrous cycles (629: 456-908 [16]). Scanning electron microscopy revealed cuboidal and squamous cells in OSE from all ages. Higher total OV# markedly increased the rate of OSE invagination and layering. Histology showed the incidence of cysts, which had the appearance of benign serous cystadenomata, increased with age rather than total OV#.

UK audit of single photon emission computed tomography reconstruction software using software generated phantoms.

The purpose of this study was to undertake an audit of the quantitative characteristics of single photon emission computed tomography software using projection data from an analytically generated software phantom and a measured line source. The phantom consisted of three structures. A uniformly filled cylinder, a series of cylindrical rods of various diameters in a background activity with a rod to background ratio of 2:1 and lastly, a set of three concentric rings of activity in the ratio 1:0:1. The phantom contained no added statistical noise. No attenuation was imposed on the data. The phantom was generated analytically and projections were distributed at six different count densities. A single set of projections from a thin line source was also distributed. These data were distributed to centres throughout the UK. Centres were asked to reconstruct the data using a 'ramp only' reconstruction with no additional smoothing function applied. Data were requested for mean and standard deviation in the uniform cylinder, the maximum counts for each cylindrical rod and the mean counts in regions placed within the concentric rings. For the measured line source, centres were asked to measure the full width at half maximum and peak pixel counts for a profile through the reconstructed line. Results from 115 systems were obtained from 100 centres throughout the UK. These provided data from 12 software providers, 11 of these being commercial companies. Data were compared with the known input values and histograms of the distribution of results obtained. Significant differences in quantitative parameters were noted for the different input count densities as well as between suppliers and revisions of software from single suppliers.

Study of the three-dimensional geometry of the central conducting airways in man using computed tomographic (CT) images.

Clinical research on the deposition of inhaled substances (e.g. inhaled medications, airborne contaminants, fumes) in the lungs necessitates anatomical models of the airways. Current conducting airway models lack three-dimensional (3D) reality as little information is available in the literature on the distribution of the airways in space. This is a limitation to the assessment or predictions of the particle deposition in relation to the subject's anatomy. Detailed information on the full topology and morphology of the airways is thus required to model the airway tree realistically. This paper presents the length, diameter, gravity, coronal and sagittal angles that together describe completely the airways in 3D space. The angle at which the airways branch out from their parent (branching angle) and the rotation angle between successive bifurcation planes are also included. These data are from the study of two sets of airways computed tomography (CT) images. One CT scan was performed on a human tracheobronchial tree cast and the other on a healthy male volunteer. The airways in the first nine generations of the cast and in the first six conducting generations of the volunteer were measured using a computer-based algorithm. The data contribute to the knowledge of the lung anatomy. In particular, the spatial structure of the airways is shown to be strongly defined by the central airways with clear angular lobar patterns. Such patterns tend to disappear with a mean gravity, coronal and sagittal angles of 90 degrees in each generation higher than 13-15. The mean branching angle per generation appears independent of the lobe to which the airways belong. Non-planar geometry at bifurcation is observed with the mean (+/- SD) bifurcation plane rotation angle of 79 +/- 410 (n = 229). This angle appears constant over the generations studied. The data are useful for improving the 3D realism of the conducting airway structure modelling as well as for studying aerosol deposition, flow and biological significance of non-planar airway trees using analytical and computational flow dynamics modelling.

Pulmonary clearance rate of two chemically different forms of inhaled pertechnetate.

Attempts to image the pulmonary deposition site of radiolabeled aerosols delivered by dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs) using single photon emission computed tomography (SPECT) have been limited by the rapid pulmonary clearance of radiolabel. To determine whether aqueous solubility of the radiolabel is a significant factor, the pulmonary clearance rates of two chemically different forms of 99mTc were calculated. A dry powder formulation of terbutaline sulphate was radiolabeled for inhalation by Turbuhaler (AstraZeneca) using the water-soluble salt sodium pertechnetate and the water-insoluble salt tetraphenylarsonium pertechnetate. A pilot study was conducted during which two control subjects each inhaled the two radiolabeled aerosols on separate days. Intrasubject clearance rates for the two species were very similar. It was therefore concluded that water insolubility of the pertechnetate salt alone was not enough to extend the lung residency time of the radiolabel.

UK audit and analysis of quantitative parameters obtained from gamma camera renography.

The purpose of this study was to perform an audit of quantitative values obtained from gamma camera renography in the UK. Ten patient image sequences representing normal and pathological renal function were obtained from archived studies and distributed to hospitals in the UK. Hospitals were asked to measure five parameters: relative function, renogram time-to-peak (left and right), and whole kidney mean transit time (left and right). Details of methodology, software used and operator experience were requested. This allowed the influence of operational factors on variations in reported values to be examined. A total of 180 responses from 81 hospitals were received. Values reported for the parameters, together with other details supplied, were entered into Excel and SPSS for statistical analysis. Histograms representing the distribution of values were produced for each parameter. The largest variations were found for mean transit time and occasionally for time-to-peak. The effect of factors was assessed using nonparametric statistical tests applied independently to each renogram. For all the parameters, the hospital, UK region, supplier, computer and software version influenced variations in the reported values. Algorithm and site of background region were influencing factors for relative function, the background subtraction method influenced time-to-peak, and curve smoothing influenced mean transit time.

Measures of transgender behavior.

Using factor analysis, we sought to identify the components of transgenderism. Subjects were 455 transvestites and 61 male-to-female transsexuals, all biological males. A 70-item questionnaire was used, along with other structured questions concerning preferred and usual sex partners. Five factors were identified and interpreted: Transgender Identity, Role, Sexual Arousal, Androallure, and Pleasure. These factors represent the most salient dimensions of transgenderism. All five-factor Means for transvestites and transsexuals differ. An examination of overlap of group distributions for each factor showed such overlap to range from only 6% for Identity to 46% for both Androallure and Pleasure. Factor intercorrelations for the obliquely rotated factors ranged from -.37 to .27. While transvestites and transsexuals have different lifestyles, their transgender cognition and behavior seem constructed upon different combinations of the same variables. A second-order analysis of these five factors yielded two factors: Sexual Arousal loaded highest on the first factor (.91), and for the second the highest loading variable was Androallure (.57). Each of these highlights the primary importance of sexual arousal in transgender cognition and behavior. Studying possible age effects, we found that the younger versus older transvestite groups had significantly different scale Means for Androallure and Pleasure; there were no age differences between older and younger transsexuals on any of the five scales. Six percent of transvestites reported a male as their usual sex partner; 25% of the transsexuals reported a female as their usual sex partner. For each group, one-third indicated their usual sex practice was without any partner, while only 5% said they preferred this practice. We propose that the five variables identified offer a comprehensive approach to the description of individual differences in transgender experience and expression.

Evaluation of the accuracy and precision of lung aerosol deposition measurements from single-photon emission computed tomography using simulation.

Single-photon emission computed tomography (SPECT) imaging is being increasingly used to assess inhaled aerosol deposition. This study uses simulation to evaluate the errors involved in such measurements and to compare them with those from conventional planar imaging. SPECT images of known theoretical distributions of radioaerosol in the lung have been simulated using lung models derived from magnetic resonance studies in human subjects. Total lung activity was evaluated from the simulated images. A spherical transform of the lung distributions was performed, and the absolute penetration index (PI) and a relative value expressed as a fraction of that in a simulated ventilation image were calculated. All parameters were compared with the true value used in the simulation, and the errors were assessed. An iterative method was used to correct for the partial volume effect, and its effectiveness in improving errors was evaluated. The errors were compared with those of planar imaging. The precision of measurements was significantly better for SPECT than planar imaging (2.8 vs 6.3% for total lung activity, 6 vs 20% for PI, and 3 vs 6% for relative PI). The method of correcting for the influence of the partial volume effect significantly improved the accuracy of PI evaluation without affecting precision. SPECT is capable of accurate and precise measurements of aerosol distribution in the lung, which are improved compared with those measured by conventional planar imaging. A technique for correcting the SPECT data for the influence of the partial volume effect has been described. Simulation is demonstrated as a valuable method of technique evaluation and comparison.

Lung models: strengths and limitations.

The most widely used particle dosimetry models are those proposed by the National Council on Radiation Protection, International Commission for Radiological Protection, and the Netherlands National Institute of Public Health and the Environment (the RIVM model). Those models have inherent problems that may be regarded as serious drawbacks: for example, they are not physiologically realistic. They ignore the presence and commensurate effects of naturally occurring structural elements of lungs (eg, cartilaginous rings, carinal ridges), which have been demonstrated to affect the motion of inhaled air. Most importantly, the surface structures have been shown to influence the trajectories of inhaled particles transported by air streams. Thus, the model presented herein by Martonen et al may be perhaps the most appropriate for human lung dosimetry. In its present form, the model's major "strengths" are that it could be used for diverse purposes in medical research and practice, including: to target the delivery of drugs for diseases of the respiratory tract (eg, cystic fibrosis, asthma, bronchogenic carcinoma); to selectively deposit drugs for systemic distribution (eg, insulin); to design clinical studies; to interpret scintigraphy data from human subject exposures; to determine laboratory conditions for animal testing (ie, extrapolation modeling); and to aid in aerosolized drug delivery to children (pediatric medicine). Based on our research, we have found very good agreement between the predictions of our model and the experimental data of Heyder et al, and therefore advocate its use in the clinical arena. In closing, we would note that for the simulations reported herein the data entered into our computer program were the actual conditions of the Heyder et al experiments. However, the deposition model is more versatile and can simulate many aerosol therapy scenarios. For example, the core model has many computer subroutines that can be enlisted to simulate the effects of aerosol polydispersity, aerosol hygroscopicity, patient ventilation, patient lung morphology, patient age, and patient airway disease.

A comparison of performance of three gamma camera systems for positron emission tomography.

The development of coincidence positron imaging using a gamma camera should significantly increase PET utilization. This study has compared the performance of three such systems with each other and with an equivalent single photon emission computed tomography (SPECT) measurement. A Carlson phantom, which consisted of a 20 cm diameter cylinder containing areas of uniform activity, hot lesions, cold lesions and orthogonal alternate hot and cold lines, was filled with an activity of 18F chosen to try and best exploit each camera and imaged for a fixed time (27 min). The image quality of 9 mm thick slices in each section of the phantom was compared visually. Several image quality parameters were also compared including line source resolution and noise equivalent count rate. There were considerable differences in PET image quality between the three cameras but all were at least as good as the SPECT image. The full width at half maximum (FWHM) resolution of all systems was similar (approximately 4.5 mm) but the maximum noise equivalent count rates in a 20 cm cylinder were significantly different (6.3, 2.6 and 1.6 kcps) (where cps is counts per second) and correlated with the phantom image quality.

Human lung morphology models for particle deposition studies.

Knowledge of human lung morphology is of paramount importance in calculating deposition patterns of inhaled particulate matter (PM) to be used in the definition of ambient air quality standards. Due to the inherently complex nature of the branching structure of the airway network, practical assumptions must be made for modeling purposes. The most commonly used mathematical models reported in the literature that describe PM deposition use Weibel's model A morphology. This assumes the airways of the lung to be a symmetric, dichotomously branching system. However, computer simulations of this model, when compared to scintigraphy images, have shown it to lack physiological realism (Martonen et al., 1994a). Therefore, a more physiologically realistic model of the lung is needed to improve the current PM dosimetry models. Herein, a morphological model is presented that is based on laboratory data from planar gamma camera and single-photon emission computed tomography (SPECT) images. Key elements of this model include: The parenchymal wall of the lung is defined in mathematical terms, the whole lung is divided into distinct left and right components, a set of branching angles is derived from experimental measurements, and the branching network is confined within the discrete left and right components (i.e., there is no overlapping of airways). In future work, this new, more physiologically realistic morphological model can be used to calculate PM deposition patterns for risk assessment protocols.