Community care and general practice. Focus should be put on barriers that hinder progress.
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Community Health Services↗
Biomedical subjects
S Webb
Publications and source records attributed to S Webb.
Endocardial cushion development and heart loop architecture in the trisomy 16 mouse.
Murine trisomy 16 (Ts16) is a model for Down's syndrome and has close to a 100% incidence of atrioventricular septal defects (AVSDs). These have been proposed to result from abnormal development of the endocardial cushions, but the mechanisms are unknown. We aim to identify the initial defects in Ts16 hearts, both to characterise the pathogenesis of AVSDs and as a first step in the search for molecular mechanisms. In 38 litters from an Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross, which was examined on days 10 and 11 of gestation, 28.4% of embryos were trisomic. Trisomic embryos were uniformly retarded compared to their normal litter mates, having on average 3.3 fewer somite pairs. All further comparisons were made between embryos of the same somitic stage. Twenty-one trisomic and 21 normal embryos of between 15 and 43 somites were serially sectioned, and stereomorphometric methods were used to reconstruct the volumes of the endocardial cushions and to count their number of mesenchymal cells. There were fewer cells in Ts16 superior and inferior cushions. In contrast, the volumes of trisomic cushions were significantly greater than normal. Thus, cell density was markedly lower in trisomic cushions. Importantly, the volumes of the cushions in trisomic embryos were already greater than normal at the 18 somite stage, prior to the invasion of cushions by mesenchymal cells. The architecture of Ts16 heart tubes in 15-25 somite embryos was subtly abnormal. This was reflected in the angle between the axis of the atrioventricular canal and the first pharyngeal cleft, which was significantly larger in trisomic hearts and showed a different relationship to somite stage when compared to normal embryos. These observations suggest that the primary cardiac defect in Ts16 mice may be localised to the myocardium, thus influencing the shape of the heart tube, with changes in the mesenchymal population of the endocardial cushions being later events. Whether AVSDs arise from one or both of these abnormalities remains to be established.
Animals↗
The structure of the mouse heart in late fetal stages.
Because of the opportunities for genetic manipulation, the mouse has become the major species for models of human disease. Recently, targeted and insertional mutations have induced many novel models of developmental abnormality, including several of congenital heart defects. Interpretation and use of such models requires a precise understanding of the similarities and differences between mouse and human in terms of cardiac development and structure. To this end, we have characterised the late fetal mouse heart using scanning electron microscopy and serial histological sections. Right atrial anatomy is dominated by the venous valves, which separate the orifices of the caval veins from the musculature of the primary atrium. Their structure and location suggest that the pulmonary vein is unlikely to develop from the venous sinus. The pectinated wall of the appendage serves to distinguish the morphologically right atrium, in that it runs around the atrioventricular junction, from the left atrium in which this vestibular region is smooth-walled. The persistence of the left superior caval vein draining to the right atrium, along with a solitary opening for the pulmonary vein in the left atrium, distinguishes the atrial anatomy of the mouse from that of the human. The flap valve of the oval foramen is extensive and represents the embryonic primary atrial septum. The superior rim of the foramen is an infolding of the atrial roof, as has been described in the human, showing that, contrary to orthodox opinion, there is no extensive formation of a secondary atrial septum. The region of the membranous septum seen in the human heart is a relatively thick structure in the late fetal mouse, and is located exclusively in an atrioventricular position. Unlike the human, there is little distinction between the apical trabeculations of the left and right ventricles of the mouse heart.
Animals↗
A comparison of pooled, fresh-frozen, and lyophilized sera as a matrix for enzyme proficiency testing: the experience of the Ontario Laboratory Proficiency Testing Program.
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Alkaline Phosphatase↗
A method to study the characteristics of 3D dose distributions created by superposition of many intensity-modulated beams delivered via a slit aperture with multiple absorbing vanes.
Highly conformal dose distributions can be created by the superposition of many radiation fields from different directions, each with its intensity spatially modulated by the method known as tomotherapy. At the planning stage, the intensity of radiation of each beam element (or bixel) is determined by working out the effect of superposing the radiation through all bixels with the elemental dose distribution specified as that from a single bixel with all its neighbours closed (the 'independent-vane' (IV) model). However, at treatment-delivery stage, neighbouring bixels may not be closed. Instead the slit beam is delivered with parts of the beam closed for different periods of time to create the intensity modulation. As a result, the 3D dose distribution actually delivered will differ from that determined at the planning stage if the elemental beams do not obey the superposition principle. The purpose of this paper is to present a method to investigate and quantify the relation between planned and delivered 3D dose distributions. Two modes of inverse planning have been performed: (i) with a fit to the measured elemental dose distribution and (ii) with a 'stretched fit' obeying the superposition principle as in the PEACOCK 3D planning system. The actual delivery has been modelled as a series of component deliveries (CDs). The algorithm for determining the component intensities and the appropriate collimation conditions is specified. The elemental beam from the NOMOS MIMiC collimator is too narrow to obey the superposition principle although it can be 'stretched' and fitted to a superposition function. Hence there are differences between the IV plans made using modes (i) and (ii) and the raw and the stretched elemental beam, and also differences with CD delivery. This study shows that the differences between IV and CD dose distributions are smaller for mode (ii) inverse planning than for mode (i), somewhat justifying the way planning is done within PEACOCK. Using a stretched elemental beam is a useful adjustment to improve the accuracy of inverse planning but the 3D dose distribution actually delivered will display characteristics of the collimation.
Humans↗
A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis.
Long TR and gadolinium enhanced spin echo brain MRI was performed weekly for three months in three patients with relapsing-remitting or secondary progressive multiple sclerosis. During the study, 38 new enhancing lesions were seen; 11 showed enhancement for less than four weeks, and two enhanced on only one scan. All 16 new lesions seen on long TR scans showed initial enhancement. When only every fourth (monthly) scan was analysed, a total of 33 new enhancing lesions were seen. Subject to confirmation in a larger cohort, the results suggest: (a) that blood brain barrier leakage is an invariable event in new lesion development in relapsing-remitting and secondary progressive multiple sclerosis; (b) the small increase in sensitivity of weekly scanning does not justify its use in preference to monthly scanning when monitoring treatments.
Adult↗
Overexpression of endothelin-1 and enhanced growth of pulmonary artery smooth muscle cells from fawn-hooded rats.
Increased production of endothelin-1 (ET-1) has been detected in lungs of fawn-hooded rats (FHR) with idiopathic pulmonary hypertension. Accelerated pulmonary artery (PA) smooth muscle cell (SMC) proliferation contributes to vascular remodeling in these rats. We hypothesized that PA SMC would be an important site of enhanced ET-1 expression in FHR lung, that these SMC would have increased growth compared with cells from a normotensive strain, and that this locally produced ET-1 would contribute to the increased growth of these cells. We found that isolated FHR PASMC overexpressed preproET-1 mRNA and produced more ET-1 peptide compared with cells from normotensive Sprague-Dawley control rats (SDR). PA SMC from FHR had increased growth compared with control cells under conditions of serum withdrawal (0.1%), submaximal serum stimulation (0.3%; a condition previously found to be required for detection of growth in response to the comitogen, ET-1), and maximal serum stimulation (10%). Enhanced growth of FHR PA SMC in the presence of 0.3% serum, but not under the other test conditions, was inhibited by the ETA receptor antagonist, BQ-123. In summary, PA SMC from rats with idiopathic pulmonary hypertension overproduce ET-1. This overproduction contributes to the enhanced growth of FHR PA SMC in the presence of 0.3% serum. These cells also possess other unique growth characteristics that are independent of ET-1. Together, these ET-1-dependent and -independent growth properties likely contribute to the hyperplasia of FHR PA SMC found in vivo.
Animals↗
A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction.
Quantifying the level of transgene expression necessary for phenotypic effect is an important consideration in designing somatic gene therapy protocols. A nonlinear relationship between phenotype and gene activity is predicted by control analysis for any autosomal recessive condition. The unaffected phenotype of heterozygotes for autosomal recessive disorders demonstrates that 50% of the normal level of gene expression is sufficient to prevent disease. By extension, an exaggerated and positive effect on the mutant phenotype is predicted to arise from only a small addition of normal transgene expression delivered by gene therapy. We tested this expectation directly by intercrossing mice carrying different Cftr alleles which modulate Cftr gene expression from 0 to 100%. We demonstrate that 5% of the normal level of Cftr gene expression results in a disproportionately large correction of the chloride ion transport defect (50% of normal) and essentially complete rescue of the intestinal disease (100% survival). It follows that even modest levels of transgene expression and only partial correction of CFTR channel activity may have a significant clinical impact.
Animals↗
Circulation of human hematopoietic cells in severe combined immunodeficient mice after Cl2MDP-liposome-mediated macrophage depletion.
Intravenous injection of dichloromethylene diphosphonate (Cl2MDP) encapsulated in liposomes results in specific elimination of macrophages in the spleen and liver of normal mice. Severe combined immunodeficient (SCID) mice were treated with Cl2MDP-liposomes followed by injection of human peripheral blood leukocytes. Control SCID mice had no detectable human cells within 72 hours as determined by fluorescence-activated cell sorting (FACS) analysis. However, Cl2MDP-liposome-treated animals maintained a large proportion (%) of human cells in peripheral blood and spleen for at least 12 days. Cl2MDP-liposome-injected SCID mice that had previously been implanted with human fetal thymus and liver showed a transient increase in human cell content in peripheral blood, and an accumulation of human cells specific to the white pulp of the spleen. These results indicate that murine mononuclear phagocytic cells may play an important role in the clearance of human cells injected intravenously or generated endogenously in SCID mice and that Cl2MDP-liposome-mediated macrophage depletion allows human hematopoietic cells to circulate and survive in SCID mice, thereby expanding the potential for studying human cellular processes in vivo.
Animals↗
A region of primer binding variation at the D6S265 locus associated with HLA-A25 and HLA-A26 antigens.
D6S265 is a polymorphic dinucleotide repeat, mapped within 70 kb centromeric of HLA-A, on chromosome 6p21.3. While genotyping families for genetic linkage analysis, allele non-amplification resulting in apparent non-Mendelian inheritance was observed at the D6S265 locus in 15 individuals, on chromosomes carrying the HLA-A25 and HLA-A26 antigens. The D6S265 locus was sequenced in a variant individual homozygous for allele non-amplification, and in a non-HLA-A25/-A26 individual, homozygous for D6S265 allele 1. Five base changes were identified in the reverse primer binding region of the variant individual, effectively preventing annealing of the 3' primer to the template.
Base Sequence↗
A comparison of conventional 'forward planning' with inverse planning for 3D conformal radiotherapy of the prostate.
A radiotherapy treatment plan optimisation algorithm has been applied to 48 prostate plans and the results compared with those of an experienced human planner. Twelve patients were used in the study, and 3-, 4-, 6- and 8-field plans (with standard coplanar beam angles for each plan type) were optimised by both the human planner and the optimisation algorithm. The human planner 'optimised' the plan by conventional forward planning techniques. The optimisation algorithm was based on fast simulated annealing using a cost-function designed to achieve a homogenous dose in the 'planning-target-volume' and to minimise the integral dose to the organs at risk. 'Importance factors' assigned to different regions of the patient provide a method for controlling the algorithm, and it was found that the same values gave good results for almost all plans. A study of the convergence of the algorithm is presented and optimal convergence parameters are determined. The plans were compared on the basis of both dose statistics and 'normal-tissue-complication-probability' (NTCP) and 'tumour-control-probability' (TCP). The results of the comparison study show that the optimisation algorithm yielded results that were at least as good as the human planner for all plan types, and on the whole slightly better. A study of the beam-weights chosen by the optimisation algorithm and the planner revealed differences that increased with the number of beams in the plan. The planner was found to make small perturbations about a conceived optimal beam-weight set. The optimisation algorithm showed much greater showed much greater variation, in response to individual patient geometry, frequently deselecting certain beams altogether from the plan. The algorithm is shown to be a useful tool for radiotherapy treatment planning. For simple (e.g., three-field) plans it was found to consistently achieve slightly higher TCP and lower NTCP values. For more complicated (e.g., eight-field) plans the optimisation also achieved slightly better results with generally less numbers of beams, unfavourable beams being deselected from the plan. Probably the greatest benefit is the reduced time taken by the optimisation to compute optimised beam-weights. This time always < or = 5 min; a factor of up to 20-times faster than the human planner.
Algorithms↗
The optimisation of wedge filters in radiotherapy of the prostate.
A treatment plan optimisation algorithm has been applied to 12 patients with early prostate cancer in order to determine the optimum beam-weights and wedge angles for a standard conformal three-field treatment technique. The optimisation algorithm was based on fast-stimulated-annealing using a cost function designed to achieve a uniform dose in the planning-target-volume (PTV) and to minimise the integral doses to the organs-at-risk. The algorithm has been applied to standard conformal three-field plans created by an experienced human planner, and run in three PLAN MODES: (1) where the wedge angles were fixed by the human planner and only the beam-weights were optimised; (2) where both the wedge angles and beam-weights were optimised; and (3) where both the wedge angles and beam-weights were optimised and a non-uniform dose was prescribed to the PTV. In the latter PLAN MODE, a uniform 100% dose was prescribed to all of the PTV except for that region that overlaps with the rectum where a lower (e.g., 90%) dose was prescribed. The resulting optimised plans have been compared with those of the human planner who found beam-weights by conventional forward planning techniques. Plans were compared on the basis of dose statistics, normal-tissue-complication-probability (NTCP) and tumour-control-probability (TCP). The results of the comparison showed that all three PLAN MODES produced plans with slightly higher TCP for the same rectal NTCP, than the human planner. The best results were observed for PLAN MODE 3, where an average increase in TCP of 0.73% (+/- 0.20, 95% confidence interval) was predicted by the biological models. This increase arises from a beneficial dose gradient which is produced across the tumour. Although the TCP gain is small it comes with no increase in treatment complexity, and could translate into increased cures given the large numbers of patients being referred. A study of the beam-weights and wedge angles chosen by the optimisation algorithm revealed significant inter-patient variability the implications of which are examined. Probably the most significant benefit of the algorithm is the time saved (about a factor of 10) in computing optimised beam-weights and wedge angles for this simple plan.
Algorithms↗
The experimental evaluation of a prototype rotating slat collimator for planar gamma camera imaging.
A collimator consisting of a series of parallel slats has been constructed and used in conjunction with a conventional gamma camera to collect one-dimensional projections of the radioisotope distribution being imaged. With the camera remaining stationary, the collimator was made to rotate continuously over the face of the detector and the projections acquired were used to reconstruct a planar image by the theory of computed tomography. The propagation of noise on image reconstruction was largely offset by the increased geometric efficiency that resulted from the enlarged solid angle of acceptance afforded by the slat collimator. For a uniform disc of activity the signal to noise ratio (SNR) at a point in an image reconstructed by convolution and backprojection is shown to be given by [formula:see text] and Q1(xi) is the one-dimensional filter function in Fourier space. Improved noise behaviour was observed for images acquired with the slat collimator compared to those acquired with a low-energy high-resolution (LEHR) collimator for small distributions of activity. Spatial resolution with the slat collimator was approximately equal to that obtained with an LEHR collimator and improved contrast was observed in images of small hot regions.
Biophysical Phenomena↗
The problem of isotropically orienting N converging vectors in space with application to radiotherapy planning.
This note presents the solutions to the problem of orienting N converging vectors with a common origin in space with maximal separation for N = 3,4,...,8. With a specific definition of maximal separation, an algorithm was developed and coded which iteratively converges to the solutions. It has been suggested that these orientations might be appropriate for photon beam directions in conformal radiotherapy. When N = 4, the solution is the previously proposed tetrad geometry. The solutions for other N are discussed.
Algorithms↗
Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss.
Proton magnetic resonance spectroscopy (MRS) and MRI were carried out in 11 patients with multiple sclerosis who had clinical evidence of severe cerebellar involvement, 11 multiple sclerosis patients (of similar age and disease duration) who had minimal or no signs of cerebellar disease, eight patients with autosomal dominant cerebellar ataxia (ADCA) and 11 healthy controls. In all subjects MRS was localized to cerebellar white matter (volumes of interest 3-6 ml). Apparent metabolite concentrations were calculated using the fully relaxed water spectrum as an internal standard of reference. The patients also underwent MRI to assess cerebellar volume and (in the two multiple sclerosis groups) lesion volume within the posterior fossa. Magnetic resonance spectroscopy from cerebellar white matter showed a highly significant reduction in the concentration of N-acetyl groups (NA) [which consists predominantly of N-acetylaspartate (NAA), a neuronal marker] in the multiple sclerosis group with cerebellar deficit compared with the multiple sclerosis group with minimal or no signs of cerebellar involvement, and healthy controls. Follow-up MRS performed in six of the multiple sclerosis patients 9 months later showed no change in the median NA concentration. The ADCA group showed a significant reduction of NA from a region of cerebellar white matter and also a reduction in the concentration of choline-containing compounds. The multiple sclerosis group with severe cerebellar deficit and the ADCA group both had significant cerebellar atrophy (suggesting nerve cell body and axon loss) compared with the multiple sclerosis patients with minimal or no signs of cerebellar deficit and healthy controls. The multiple sclerosis patients with cerebellar deficit had a significantly greater lesion volume in the posterior fossa, although the proportion of the spectroscopic voxel occupied by lesions was small, suggesting that axonal loss from normal appearing white matter also contributes to the observed reduction in NA. These results support the hypothesis that axonal loss is important in the development of persistent clinical disability in multiple sclerosis.
Adult↗
Magnetisation transfer ratios and transverse magnetisation decay curves in optic neuritis: correlation with clinical findings and electrophysiology.
Conventional MRI sequences do not permit the distinction between the different pathological characteristics (oedema, demyelination, gliosis, axonal loss) of the multiple sclerosis plaque. Magnetisation transfer imaging and transverse magnetisation decay curve (tMDC) analysis may be more specific. These techniques have been applied to the optic nerves in 20 patients with optic neuritis and the results correlated with clinical and visual evoked potential (VEP) findings. tMDC analysis failed to identify separate intracellular and extracellular water compartments within the optic nerve but gave a measure of transverse relaxation time (T2) without the confounding effects of CSF in the nerve sheath. Both T2 and magnetisation transfer ratio (MTR) were abnormal after an episode of optic neuritis. T2 did not correlate with visual function or with VEP latency or amplitude. There was a significant correlation between MTR reduction and prolongation of VEP latency: this increased latency may reflect an effect of myelin loss on MTR. Longer lesions were associated with worse visual outcome, implying that the overall extent of pathological involvement is likely to influence the degree of functional deficit.
Adult↗
Bronchoscopic insufflation of room air for the treatment of lobar atelectasis in mechanically ventilated patients.
Segmental and lobar pulmonary atelectasis is a common occurrence in mechanically ventilated patients. Standard therapy for atelectasis relies on positive pressure ventilation, positive and expiratory pressure (PEEP), tracheobronchial toilet and regular chest physiotherapy. Various adjuncts to physiotherapy such as bronchoscopic clearance of secretions have not proved to be of additional benefit. Bronchoscopic clearance of secretions followed by insufflation of room air at 30 cm H2O into the atelectatic segment was employed on ten occasions in mechanically ventilated patients. Rapid re-expansion of the collapsed segment or lobe occurred in seven out of the ten treatments.
APACHE↗