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This study examined whether treatment with the specific thromboxane (TX) A2 receptor antagonist GR32191 B would result in an improvement in peripheral haemodynamics during and after cardiopulmonary bypass (CPB) in anaesthetized dogs compared with animals given either saline (control) or aspirin. Following thoracotomy, heparinization and aortic cannulation, and 35 minutes before CPB, dogs received intravenously either G R32191 B (15 microgram/kg/min), saline (50 ml bolus) or aspirin (225 mg bolus) (n = 6 per group). Cardiac output (dye dilution), femoral artery blood flow (electromagnetic flowmeter), gastrocnemius muscle tissue perfusion (133Xe clearance), retinal blood flow (fluorescein angiography), and thromboxane biosynthesis (urinary excretion rates of TXB2 and the metabolite 2,3-dinor-TXB2) were measured before, during and after a standard 90 minute period of CPB at 2.4 l/min/m2 and 28 degrees C. The aspirin-treated group manifested an eightfold reduction in TXB2 excretion compared with controls, indicating a decrease in TXA2 biosynthesis. There were few haemodynamic differences between the groups, though the aspirin-treated group had better maintained muscle tissue perfusion post-CPB and significantly fewer retinal microcirculatory occlusions than GR32191 B-treated animals. We conclude that specific TXA2 receptor antagonism provides no significant improvement in peripheral haemodynamics; rather aspirin provides a modest haemodynamic benefit. [ABSTRACT FROM AUTHOR]

Imaging of radiolabeled aerosols provides useful in vivo data on both the initial site of deposition and its subsequent transport by mucociliary clearance and epithelial permeability. Single Photon Emission Computed Tomography (SPECT) uses a gamma camera with multiple rotating heads to produce three-dimensional (3D) images of inhaled radioaerosol labeled with technetium-99m. This enables total lung deposition and its 3D regional distribution to be quantified. Aligned 3D images of lung structure allow deposition data to be related to lung anatomy. Mucociliary clearance or epithelial permeability can be assessed from a time series of SPECT aerosol images. SPECT is slightly superior to planar imaging for measuring total lung deposition. However, it is more complex to use, and for studies where total lung deposition is the endpoint, planar imaging is recommended. However, SPECT has been shown to be clearly superior to planar imaging for assessing regional distribution of aerosol and is the method of choice for this purpose. It therefore has applications in studying the influence of regional deposition on clinical effectiveness and also in validating computer models of deposition. The inability to directly radiolabel drug molecules with 99m Tc is a clear disadvantage of SPECT and limits its potential use for pharmacokinetic studies. SPECT provides a wealth of data on aerosol deposition, which has been relatively underused at present. Optimal methods of analyzing and interpreting the data need to be developed. SPECT can also, in principle, provide detailed information of mucociliary clearance and has the potential to significantly improve knowledge of this process and hence clarify the role of clearance as a biomarker.

Background: Mucociliary clearance (MCC) rate from the lung has been shown to be reduced in chronic obstructive pulmonary disease (COPD). This study investigates the value of regional clearance measurements in assessing MCC in mild-to-moderate disease. Methods: Measurement of lung MCC using planar gamma camera imaging was performed in three groups: (i) healthy nonsmoking controls (NSCs) ( n  = 9), (ii) smoking controls (SCs) who were current smokers with normal lung function ( n  = 10), and (iii) current smokers with mild-to-moderate COPD and bronchitis ( n  = 15). The mean (±standard deviation) forced expiratory volumes at 1 second (FEV1) for the three groups were 109 (± 18), 94 (± 5), and 78 (± 12), respectively. After inhalation of a technetium-99m labeled aerosol, planar imaging was performed over 4 hours and then at 24 hours. Both lung clearance and tracheobronchial clearance (TBC) (normalized to 24 hours clearance) were calculated for inner and outer lung zones. Inner zone clearance was corrected for input from the outer zone. A novel parameter, the bronchial airways clearance index (BACI), which combined clearance data from both zones, was also evaluated. Regional results were compared with whole lung clearance in the same subjects. Results: Corrected inner zone clearance at 3 hours was not reduced compared with NSC in either SCs or COPD. Outer zone clearance was higher in COPD than in the other groups. Corrected inner zone TBC showed significant reductions in SC and COPD compared with NSC. BACI was significantly reduced in COPD compared with NSC and also correlated with FEV1. The mean BACI for SC was also reduced compared with NSC, but the distribution of results was bimodal, with a significant proportion of subjects having values in the NSC range. Conclusions: Regional MCC demonstrated differences between NSCs, SCs, and subjects with mild-to-moderate COPD, which were not apparent with whole lung measurements.

Background: Mucociliary clearance (MCC) rate from the lung has been shown to be reduced in chronic obstructive pulmonary disease (COPD). This study compared the use of change in penetration index (PI) with conventional whole lung clearance in assessing MCC in mild-to-moderate disease. Methods: Measurement of lung MCC using planar gamma camera imaging was performed in three groups: (1) healthy nonsmoking controls ( n  = 9), (2) smoking controls who were current smokers with normal lung function ( n  = 10), and (3) current smokers with mild-to-moderate COPD and bronchitis ( n  = 15). The mean (±standard deviation) forced expiratory volume at 1 second (FEV 1 ) for the three groups was 109 (±18), 94 (±5), and 78 (±12), respectively. Following inhalation of a technetium-99m labeled aerosol, planar imaging was performed over 4 hours and then at 24 hours. Total lung clearance and tracheobronchial clearance (TBC; normalized to 24-hour clearance) were calculated. A novel parameter, the normalized change in PI (NOCHIP), was also evaluated. PI is the ratio of counts between outer and inner lung zones normalized to lung volume. Results: More aerosol was deposited in central airways in COPD compared to nonsmoking controls, using 24-hour clearance measurements ( p  < 0.001). Smoking controls had intermediate values. The optimal endpoint for MCC assessment was chosen to be 3 hours, when intersubject variability was minimal, while preserving a measure of early clearance. There was no statistical difference between the three groups in mean total lung clearance, or TBC, at 3 hours. NOCHIP at 3 hours was reduced significantly, compared to nonsmoking controls, in both smoking controls ( p  = 0.007) and COPD ( p  < 0.0001). It also correlated with FEV 1 ( p  = 0.003). A higher proportion of smoking control subjects had NOCHIP values in the nonsmoking control range than in the COPD group. Conclusions: NOCHIP was a more sensitive measure of MCC than whole lung clearance and TBC in mild-to-moderate COPD.

Background: Measurement errors occurring during glomerular filtration rate (GFR) studies propagate to an error in the calculated GFR. Previous work has modelled measurement errors for slope-intercept (SI-GFR), single-sample (SS-GFR) and slope-only (SO-GFR) methods. In this study, we have extended these models. The primary aims were to (i) compare measurement errors in two-sample SI-GFR, three-sample SI-GFR, SS-GFR and SO-GFR, and (ii) determine the sensitivity of GFR to errors arising from different measurements., Patients and Methods: This study expanded on previous models of GFR measurement error incorporating biological data from 786 patients and realistic measurement errors. GFR median absolute error and the coefficient of variation (CV) were calculated for each method. A sensitivity analysis was carried out for individual measurement errors., Results: The median absolute error ranged between 1.2 and 2.3 ml/min/1.73 m, lowest for SS-GFR (4 h) and highest for SO-GFR. At higher rates of clearance, CV was less than 5% for all methods. CV increased rapidly when GFR decreased below a threshold ranging between 34 and 56 ml/min/1.73 m, lowest for three-point SI-GFR and highest for SO-GFR. SI-GFR and SS-GFR are most sensitive to injected activity quantification, but less sensitive to other measurement errors., Conclusion: Measurement errors are probably insignificant relative to biological variation for GFR of more than 60 ml/min/1.73 m, but become significant irrespective of biological variation at lower GFR, particularly in serial studies when GFR less than 25 ml/min/1.73 m. Limits of precision recommended in the 2018 British Nuclear Medicine Society guideline are appropriate for once-off GFR measurement, whereas slightly more stringent limits are proposed for serial studies.

Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap between scientific research aimed at predicting, controlling, and measuring ADD and the clinical use of inhaled aerosols is the considerable challenge of obtaining, in a single study, accurate information describing the optimal lung regions to be targeted, the effectiveness of targeting determined from ADD, and some measure of the drug's effectiveness. Other identified gaps were the language and methodology barriers that exist among disciplines, along with the significant regulatory hurdles that need to be overcome for novel drugs and/or therapies to reach the marketplace and benefit the patient. Despite these gaps, much progress has been made in recent years to improve clinical efficacy of inhaled drugs. Also, the recent efforts by many funding agencies and industry to support multidisciplinary networks including basic science researchers, R&D scientists, and clinicians will go a long way to further reduce the gap between science and clinical efficacy.

Objective: Glomerular filtration rate (GFR) is frequently assessed using the slope-intercept method by fitting a single exponential to plasma samples obtained 2-5 h after injection. The body surface area (BSA)-corrected one-pool clearance (CO,BSA) overestimates true GFR (CT,BSA) because it fails to sample the full plasma curve, and values of CT,BSA are usually estimated from CO,BSA using the Brøchner-Mortensen (BM) equation. An improved equation, CT,BSA=CO,BSA/(1+fBSA×CO,BSA), with fBSA a fixed constant, was proposed by Fleming, but subsequently Jødal and Brøchner-Mortensen (JBM) reported that fBSA varies with BSA. We report data for a large group of individuals who underwent GFR investigations with sampling of the full plasma curve. The aims were to validate the JBM equation with independent data and assess whether replacing the BM equation with a BSA-dependent correction based on Fleming's equation can increase the accuracy of the slope-intercept method., Methods: Plasma data were analysed for 142 children and adults aged 0.6-56 years who underwent technetium-99m-diethylenetriaminepentaacetic acid GFR investigations with blood samples taken between 5 min and 8 h after injection. Values of CO,BSA were calculated using the 2, 3 and 4 h data. Values of CT,BSA were calculated by integrating the plasma curve between 5 min and 4 h and extrapolating the terminal exponential. Individual values of fBSA were calculated using the relationship fBSA=1/CT,BSA-1/CO,BSA. Nonlinear regression was used to fit the function fBSA=f1×BSA and find the best-fit values for f1 and n. Scatter and Bland-Altman plots were drawn comparing the various formulae for correcting slope-intercept GFR., Results: The trend for fBSA to decrease with increasing BSA was highly significant (Spearman's test: RS=-0.31; P=0.0002). When the data were fitted by nonlinear regression, the best-fit values (95% confidence interval) of the model parameters were n=-0.13 (from -0.21 to -0.04) and f1=0.00191 (from 0.00183 to 0.00200)., Conclusion: The results confirm that fBSA varies with BSA and provide independent values of the parameters f1 and n. Differences from GFRs calculated using the original JBM equation were small and not clinically significant. The BM equation also performed well for CT,BSA less than 125 ml/min/1.73 m. However, there was a small number of children with CT,BSA greater than 150 ml/min/1.73 m for whom the JBM formula provided more accurate estimates of true GFR than did the BM equation.

Background: In this second UK audit of quantitative parameters obtained from renography, phantom simulations were used in cases in which the 'true' values could be estimated, allowing the accuracy of the parameters measured to be assessed., Materials and Methods: A renal physical phantom was used to generate a set of three phantom simulations (six kidney functions) acquired on three different gamma camera systems. A total of nine phantom simulations and three real patient studies were distributed to UK hospitals participating in the audit. Centres were asked to provide results for the following parameters: relative function and time-to-peak (whole kidney and cortical region). As with previous audits, a questionnaire collated information on methodology. Errors were assessed as the root mean square deviation from the true value., Results: Sixty-one centres responded to the audit, with some hospitals providing multiple sets of results. Twenty-one centres provided a complete set of parameter measurements. Relative function and time-to-peak showed a reasonable degree of accuracy and precision in most UK centres. The overall average root mean squared deviation of the results for (i) the time-to-peak measurement for the whole kidney and (ii) the relative function measurement from the true value was 7.7 and 4.5%, respectively. These results showed a measure of consistency in the relative function and time-to-peak that was similar to the results reported in a previous renogram audit by our group., Conclusion: Analysis of audit data suggests a reasonable degree of accuracy in the quantification of renography function using relative function and time-to-peak measurements. However, it is reasonable to conclude that the objectives of the audit could not be fully realized because of the limitations of the mechanical phantom in providing true values for renal parameters.

Background and Aim: Assessment of volume of distribution (VD) and half-life (T1/2) values during glomerular filtration rate (GFR) investigations is a useful quality control check. The aim of this study was to derive reference data for VD and T1/2 and also to provide reference data for GFR from studies performed using Tc-diethylenetriaminepentaacetic acid (Tc-DTPA)., Methods: This was a retrospective study of 126 healthy potential kidney donors (age range 18-59 years). The GFR was evaluated from Tc-DTPA plasma clearance using the 2004 British Nuclear Medicine Society guidelines. The association between VD and body surface area (BSA) was assessed. T1/2 was correlated with age and GFR. The correlation between the Brochner-Mortensen-corrected GFR (BM-GFRCorr) and age was evaluated., Results: The uncorrected VD value (l) was 10.1×BSA±40.6% (P<0.01). The corrected VD value (l) was 8.19×BSA±34.4% (P<0.01). In individuals under the age of 40 years, the mean T1/2 was 95.0 min±36.2%. In individuals aged 40 years and above, the T1/2 increased at a rate of 0.49 min/year (P=0.04); the T1/2 (min) was 9480×(1/BM-GFRCorr)±35.1% (P<0.01). In individuals younger than 40 years of age, the correlation between BM-GFRCorr and age was not statistically significant (P=0.45), and the mean GFR was 108 ml/min/1.73 m±27.5%. In individuals aged 40 years and above, the BM-GFRCorr was 170-(1.55×age) ml/min/1.73 m±36.7% (P<0.001)., Conclusion: Well-defined reference data for VD and T1/2 can be used for quality control checks in GFR investigations. In addition to these, reference data for GFR using Tc-DTPA have been defined. This will enhance the interpretation of adult Tc-DTPA GFR measurements.

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.

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.

Background: The conceptual model of the lung describes the spatial distribution of the air volume of each airway generation within the lung. It is a generic model that can be used as a powerful tool in interpreting images of aerosol deposition. The model divides the lung volume into 10 concentric shells, and specifies the volume of each airway generation in each shell based on a statistical analysis of morphometric data available in the literature. In this study, an updated version of the conceptual model, called the Hybrid Conceptual Model (HCM), is introduced. This model incorporates individual morphometric data from upper bronchial airways (generations 0-5) available from High Resolution Computed Tomography (HRCT)., Methods: The HCM has been tested on one 27-year-old healthy male volunteer, on which magnetic resonance imaging (MRI) and HRCT scans of the thorax have been performed. Four major changes have been introduced in the HCM; (1) the incorporation of in vivo data, (2) a better distribution of airway volume within each shell, (3) the adoption of more accurate morphometric assumptions, and (4) the incorporation of the spatial definition of the segmental divisions of the lung., Results and Conclusions: The resulting model was shown to compare very well to past literature models with respect to airway volume per generation and mean airway position within the lung. It can be concluded that the HCM can be used to describe the spatial location of different airway generations of the lung with good spatial and quantitative accuracy. This represents a further step toward the personalization of the conceptual model to an individual subject.

Exopolysaccharides, either succinoglycan or galactoglucan, are essential for the establishment of the symbiosis between Sinorhizobium meliloti and Medicago sativa (alfalfa). The ExoS/ChvI two-component regulatory system is known as a regulator of succinoglycan production but the genes that are directly regulated by ChvI have not been determined. Difficulty isolating exoS and chvI null mutants has prompted the suggestion that these genes are essential for S. meliloti viability. We have successfully isolated exoS and chvI null mutants using a merodiploid-facilitated strategy. We present evidence that the S. meliloti ExoS/ChvI two-component regulatory system is essential for symbiosis with alfalfa. Phenotypic analyses of exoS and chvI null mutant strains demonstrate that ExoS/ChvI controls both succinoglycan and galactoglucan production and is required for growth on over 21 different carbon sources. These new findings suggest that the ExoS/ChvI regulatory targets might not be the exo genes that are specific for succinoglycan biosynthesis but rather genes that have common influence on both succinoglycan and galactoglucan production. Other studied alpha-proteobacteria ExoS/ChvI orthologues are required for the bacteria to invade or persist in host cells and thus we present more evidence that this two-component regulatory system is essential for alpha-proteobacterial host interaction.

Objective: Simulated data from the recent Institute of Physics and Engineering in Medicine audit of quantitative cerebral perfusion were used to optimize the parameters of eigenimage analysis, a method for computer-aided detection., Methods: Twenty normal images provided by the audit were registered to the International Consortium for Brain Mapping 452 template using HERMES multimodality software and normalized to total counts. Six normal atlases were formed using the mean image and from zero to five eigenimages. Eight patient images, with computer-simulated lesions at known positions, were similarly registered and normalized. For each atlas, z-score images were formed for each patient. Thresholds of z0 = 2-5 in intervals of 0.5 were applied to the z-score images to form binary images of normal and abnormal voxels. A lesion was defined as a connected group of abnormal voxels with a minimum size of 1 ml. Lesions were assigned to one of 12 regions defined by the template. For eight patients, this gave 96 regions, 19 of which were known to contain an abnormality. Receiver-operating characteristic analysis was performed for the regions using z0 as a variable threshold., Results: For the receiver-operating characteristic analysis, an optimal area under the curve of approximately 0.90 was found using either one or three eigenimages, whereas good results (sensitivity = 0.75%; specificity = 90%) were obtained for a threshold of z0 approximately equal to 3. When the number of images in the normal dataset was considered, a meta-analysis showed consistency with other studies., Conclusion: Eigenimage analysis was shown to give good diagnostic accuracy for cerebral perfusion images based on objective evaluation using simulated images.

Opioid binding protein/cell adhesion molecule-like gene (OPCML) is frequently inactivated in epithelial ovarian cancer, but the role of this membrane protein in normal reproductive function is unclear. The ovarian surface epithelium (OSE) is thought to be the cell of origin of most epithelial ovarian cancers, some of which arise after transformation of OSE cells lining ovarian inclusion cysts, formed during ovulation. We used immunohistochemistry, immunoblotting and quantitative RT-PCR (qRT-PCR) to investigate OPCML expression in the uteri and ovaries of cycling 3-month CD-1 mice, as well as in ovaries from older mice containing inclusion cysts derived from rete ovarii tubules. Immunoblotting showed OPCML bands in uterine, but not whole ovarian or muscle extracts. Strong OPCML immunoreactivity was observed in oviduct, rete ovarii and uterus, whereas in ovary more immunoreactivity was seen in granulosa cells than OSE. No staining was observed in OSE around ovulation sites, where OSE cells divide to cover the site. OPCML immunoreactivity was also weaker in more dysplastic cells lining large ovarian inclusion cysts, compared with normal rete ovarii. No significant changes in Opcml mRNA expression were observed in whole ovarian and uterine extracts at different stages of the cycle. We conclude that murine OPCML is more consistently expressed in cells lining the uterus, oviduct and rete ovarii than in ovary and is not expressed in OSE associated with ovulation sites. This observation supports the hypothesis that a proportion of epithelial ovarian cancers arise from ductal cells and other epithelia of the secondary Mullerian system, rather than the OSE.

Tumours arising in BRCA1 mutation carriers have a characteristic phenotype, the molecular and cellular basis of which is unknown. To address the hypothesis that this phenotype reflects a role for BRCA1 in either in the basal or the stem cell compartments of the mammary epithelia, we have targeted its disruption to K14 and K6a expressing cells of the mouse. Unlike MMTV and WAP driven conditional knockout models of Brca1, these two models did not result in any observable changes in the mammary gland. Our results suggest that BRCA1-associated tumours arise either in K14 and K6a negative basal cells of the mammary gland, or possibly from transdifferentiation of luminal epithelia.

Objectives: Inconsistency in the intercentre measurement of whole kidney mean transit time (MTT) has been reported in a previously published UK audit. The main objectives of this study were to identify a probable value of MTT for each kidney in the UK audit data and to find likely reasons for the reported variations., Methods: Datasets of MTT values were obtained by an independent review of the audit data by four experienced practitioners of deconvolution techniques. The deconvolution techniques used included the matrix method, a constrained least squares method as well as a residence time technique. The datasets were compared using t-test, linear regression, and mean difference analysis., Results: Twelve of a total of 13 datasets showed nonsignificant differences using a paired t-test (P>0.05). For each kidney (x), a collective mean and standard deviation, Mx and SDx, respectively, were calculated from these 12 datasets and a probable range was defined as Mx+/-3SDx. Average SDx/Mx was 3.6% (range 1.5-7.7%). For five kidneys, Mx exceeded the median of the audit results by 3.5-15.3 SDx (P<0.001)., Conclusion: Probable ranges for whole kidney MTT have been estimated with good precision. Underestimation of the area under the plateau of the renal retention function as well as overestimation of the plateau height might have contributed to an underestimation of MTT apparent in some audit results. Visual display of both the renal retention function and the reconvolution curve are suggested as simple quality control measures for analysis software.

Objective: To investigate the consistency of glomerular filtration rate (GFR) calculation from plasma sampling in the UK., Methods: Ten patients' data sets from plasma sampling measurements of GFR were distributed throughout the UK. The data included count rates from four samples taken between 2 and 4 h after injection, a diluted sample of injected dose for standardisation, the patient's height, weight, age and sex. Participants were asked to use the routine method to calculate GFR and express the results in absolute terms (i.e. in millilitres/minute) and normalized for body surface area (ml/min/1.73 m2). Supplementary data were also requested relating to workload, method used and normal range. Intercentre variability was assessed by calculating the root median square (RMedS) deviation of each GFR from the median for that data set. Centres using a particular analysis method were grouped together and the RMedS deviation of each result from the median for that group and that data set was calculated. The influence of using normalized data and number of samples was also studied., Results: Seventy-nine returns were received. For the normalized data, the overall RMedS variability was 5.8 ml/min/1.73 m2. This decreased significantly to 0.6 ml/min/1.73 m2 when results were grouped by analysis method. Results were similar for non-normalized data. A small but significant decrease in error with the number of samples was observed., Conclusion: Considerable variability in GFR values obtained at different centres in the UK for a given set of data was observed. Nearly all this variability was due to different methods of analysis. If methodology were standardized then intercentre variability in GFR analysis could be reduced dramatically. Radionuclide techniques are confirmed as being the method of choice if an accurate value of GFR is required.

An analytical algorithm has been recently described for converting planar scintigraphic images of aerosol distributions in the lungs to an equivalent three-dimensional (3D) representation. The recovery of the volumetric information has opened up to planar imaging the possibility of measuring aerosol deposition per airway generation. This paper investigates the accuracy and precision of the generation analysis achievable with planar imaging using simulation. Typical generation parameters--such as the bronchial and conducting airway deposition fractions (BADF and CADF)--have been derived. The accuracy of the technique has been measured by the coefficient of variation (COV) of the estimates from the known values used in the simulation. The results have also been compared to those obtained from 3D imaging (single photon emission computed tomography or SPECT). Finally, the technique has been applied to two aerosol studies conducted on a healthy volunteer, to demonstrate its implementation on clinical data. The accuracy of the BADF and CADF estimates from planar imaging were 42% and 41%, respectively; the corresponding values from SPECT were 32% and 22%. In conclusion, approximate estimates of airway distribution parameters can be derived from planar imaging. However, the errors are significantly higher than with SPECT.

Objective: To assess the utility of the appearances of occipital lobe perfusion on HMPAO SPECT in the diagnosis of dementia with Lewy bodies (DLB) using the 123I-FP-CIT findings as the diagnostic 'gold standard'., Methods: Eighty-four consecutive patients underwent both HMPAO SPECT and 123I-FP-CIT as part of their routine investigations for suspected DLB., Results: Thirty-nine of the 84 FP-CIT scans were abnormal indicating a prevalence of 44% of patients with DLB in this series. In those patients classified as DLB, 28% of HMPAO SPECT scans demonstrated occipital hypoperfusion. In those patients with a dementia other than DLB 31% of patients demonstrated occipital hypoperfusion (P=0.8)., Conclusion: Occipital lobe hypoperfusion as demonstrated by HMPAO SPECT in patients with suspected Lewy body dementia does not appear to be able to either rule in, or rule out, the diagnosis of DLB.

Background: Female CD-1/Swiss Webster mice subjected to incessant ovulation for 8 months and 12-month breeder mice both developed ovarian inclusion cysts similar to serous cystadenomas. The majority of cysts appeared to be dilated rete ovarii tubules, but high ovulation number resulted in more cortical inclusion cysts. We hypothesized that comparison of inclusion cyst pathology in animals of the same age, but with differences in total lifetime ovulation number, might allow us to determine distinguishing characteristics of the two types of cyst., Methods: Ovaries from breeder mice (BR) or females subjected to incessant ovulation (IO) were compared at 6-, 9- and 12-months of age. Ovaries were serially sectioned and cysts characterized with regard to location and histology, E-cadherin immunoreactivity and rates of BrdU incorporation., Results: Inclusion cysts developed with age in BR and IO ovaries. The majority of cysts were connected to the ovarian hilus. Two cortical inclusion cysts were observed in ten IO ovaries and one in ten BR ovaries. Low or no E-cadherin immuno-staining was seen in the OSE of all mice studied. Conversely, strong membrane immuno-staining was observed in rete ovarii epithelial cells. Variable E-cadherin immunoreactivity was seen in cells of hilar inclusion cysts, with strong staining observed in cuboidal ciliated cells and little or no staining in flat epithelial cells. Two of the three cortical cysts contained papillae, which showed E-cadherin immuno-staining at the edge of cells. However hilar and cortical cysts were not distinguishable by morphology, cell type or E-cadherin immunoreactivity. BrdU incorporation in cyst cells (1.4% [95% CI: 1.0 to 2.1]) was greater than in OSE (0.7% [95% CI: 0.4 to 1.2]) and very few BrdU-labeled cells were observed in rete ovarii at any age. Incessant ovulation significantly increased BrdU incorporation in OSE of older animals., Conclusion: These experiments confirm ovarian inclusion cysts develop with age in the CD-1 mouse strain, irrespective of total ovulation burden. We conclude longer periods of incessant ovulation do not lead to significant changes in inclusion cyst formation or steroidogenesis in CD-1 mice and inclusion cyst type can not be distinguished by morphology, cell proliferation rate or E-cadherin immunoreactivity.

Background: Although Tc-dimercaptosuccinic acid (DMSA) scans are routinely used to quantify relative renal function, no quantification method is universally adopted. Audits using real patient data indicate reasonable consistency but, as the true relative function is unknown, accuracy cannot be assessed. The aim was to simulate realistic DMSA images that can be used to assess accuracy., Methods: Anatomical models were created from computed tomography (CT) scans of a patient who had also undergone DMSA imaging. Organs that take up DMSA were outlined on CT and each assigned an activity concentration (with renal cortex and medulla modelled separately). The simulated images were visually compared to the patient's clinical images and subtracted to identify differences. Iteration was used on the posterior image to find the organ activities that produced the most realistic simulated image. The optimal activity distribution was then used to also simulate an anterior image. To assess the simulations, the percentage difference was calculated between the counts in each kidney on the real and simulated images., Results: Visually, the clinical and simulated images appear similar and the subtracted images indicate only small differences. The percentage difference in kidney counts between the images was less than 1% for both kidneys on the posterior image and less than 5% on the anterior image. The cortex and medulla activity concentrations were approximately equal., Conclusion: A technique for realistic simulation of DMSA images has been devised and should prove useful for evaluating image analysis software.

Objectives: Glomerular filtration rate (GFR) is commonly assessed by plasma sampling using the slope-intercept technique. This method assumes a single exponential approximation to the plasma curve. To obtain an accurate estimate of GFR it is necessary to correct the slope-intercept value for the approximation. This is commonly done using the Brochner-Mortensen equation. This has been validated for normal and abnormally low GFRs, but there has been some suggestion that it may underestimate supra-normal GFR. This paper investigates this suggestion and aims to produce a new equation based on compartmental analysis, which should extrapolate the correction to higher values of GFR., Methods: Compartmental analysis was used to produce the complete expression of the relationship between true GFR and slope-intercept GFR. A simplified analytical equation was then derived. The performance of the new equation was compared to the Brochner-Mortensen and Chantler equations using the true GFR as reference., Results: The new analytical equation had minimal systematic error compared to true GFR up to 250 ml x min(-1) per 1.73 m(2). The Brochner-Mortensen equation was shown to underestimate high values of GFR. The error increased with GFR with a 10% underestimation at 180 ml x min(-1) per 1.73 m(2). The Chantler equation gave a systematic overestimate of GFR. The error increased with GFR with a 30% overestimate at 180 ml x min(-1) per 1.73 m(2)., Conclusions: The new equation described in this paper gave considerably improved correction for the single exponential approximation at high GFR compared to previously described equations.

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., (2006 Wiley-Liss, Inc. and the American Pharmacists Association)

The objective of the study was to identify factors related to the number of solution-focused brief therapy sessions required to solve adolescents' problems. The study was conducted at the foster care and health care institutions. The sample consisted of 73 adolescents (41% of males, 59% of females), aged 12 to 18 years, who achieved high level of therapeutic progress during solution-focused brief therapy. Respondents from foster care institutions made up 47% and from health care institutions--53%. The study design included: (1) an initial evaluation, where adolescents' psychosocial adjustment and personality traits were evaluated as well as information on demographic characteristics and type of referral for therapy was collected; (2) solution-focused brief therapy was carried out. In the first session, information on the type and severity of the problem presented for the therapy and motivation to solve the problem was collected; (3) the effectiveness of solution-focused brief therapy was evaluated. Standardized interview for the evaluation of psychosocial adjustment of adolescents was used to evaluate the difficulties of adolescents' psychosocial functioning. Eysenck Personality Questionnaire was administered to evaluate adolescents' personality traits. Therapist's evaluation of improvement was used to evaluate the effectiveness of solution-focused brief therapy. The analysis of results showed that 60.3% of adolescents needed two to three solution-focused brief therapy sessions to solve their problems. Lower number of sessions needed to achieve a solution was related to lower level of psychoticism, lower level of subjectively evaluated problem severity, and living with parents (as the opposite of living in foster care institutions). Ordinal regression analysis revealed that living with parents, self-referral to the therapy, lower level of subjectively evaluated problem severity, and higher self-confidence were significant predictors of lower number of sessions needed to achieve solution.

Purpose: A technique is described for accurate quantification of the specific binding ratio (SBR) in [(123)I]FP-CIT SPECT brain images., Methods: Using a region of interest (ROI) approach, the SBR is derived from a measure of total striatal counts that takes into account the partial volume effect. Operator intervention is limited to the placement of the striatal ROIs, a task facilitated by the use of geometrical template regions. The definition of the image for the analysis is automated and includes transaxial slices within a "slab" approximately 44 mm thick centred on the highest striatal signal. The reference region is automatically defined from the non-specific uptake in the whole brain enclosed in the slab, with exclusion of the striatal region. A retrospective study consisting of 25 normal and 30 abnormal scans-classified by the clinical diagnosis reached with the scan support-was carried out to assess intra- and inter-operator variability of the technique and its clinical usefulness. Three operators repeated the quantification twice and the variability was measured by the coefficient of variation (COV)., Results: The COVs for intra- and inter-operator variability were 3% and 4% respectively. A cutoff approximately 4.5 was identified that separated normal and abnormal groups with a sensitivity, specificity and diagnostic concordance of 97%, 92% and 95% respectively., Conclusion: The proposed technique provides a reproducible and sensitive index. It is hoped that its independence from the partial volume effect will improve consistency in quantitative measurements between centres with different imaging devices and analysis software.

An analytical algorithm is described for converting planar scintigraphic images of aerosol distributions in the lungs to an equivalent three-dimensional (3D) representation. The recovery of volumetric information should benefit regional quantification. The technique has been validated using simulated planar images of eleven known aerosol distributions in ten realistic lungs. Global and regional 3D parameters, such as the total activity deposition (A), the penetration index (PI) and the relative penetration index (rPI), were quantified on the planar images and on their 3D representation. Random and systematic errors of the estimation were measured. Finally, the performance of planar imaging was compared with that of single-photon emission computed tomography (SPECT). SPECT images were simulated for the same aerosol distributions in the same subjects and quantified for A, PI, and rPI. The systematic errors in A, PI and rPI obtained from planar imaging were 8.9%, 64.8%, and 54.1%, respectively, using the two-dimensional (2D) analysis; they improved significantly to 4.4%, 19.0%, and 25.5% with the 3D analysis (p < 0.01). The corresponding values for SPECT were 5.2%, 9.8%, and 15.7%, significantly better for PI and rPI (p < 0.01). The random errors of A were similar for all techniques being about 5%; those of PI and rPI measurements were significantly higher for planar imaging (

Three-dimensional (3D) radionuclide imaging provides detailed information on the distribution of inhaled aerosol material within the body. Analysis of the data can provide estimates of the deposition per airway generation. Information on regional distribution of deposited aerosol can also be obtained from 24-hour clearance measurements. In this study, a nebulizer was used to deliver a radiolabeled aerosol to nine human subjects. Single photon emission computed tomography (SPECT) has been used to assess the distribution of aerosol deposition per airway generation. The deposition pattern was also estimated using measurements of the aerosol remaining in the lung 24 h after inhalation. The error in the SPECT value was assessed by simulation and that in the 24-h clearance value by repeat analysis. The mean fraction of lung deposition in the conducting airway (CADF) from SPECT was 0.21. The corresponding 24-h clearance value was 0.23. These values were not significantly different. There was a weak but non-significant correlation between the SPECT and 24-h measurements (r = 0.49). The standard error of the difference was 0.11. The corresponding errors on the SPECT and 24-h clearance measurements were 0.04 and 0.05, respectively. There was no systematic difference between the values of conducting airways deposition obtained from 24-h measurements and SPECT. However, there were random differences on individual subjects, which were larger than the estimated measurement errors.