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Biomedical subjects

S Webb

Publications and source records attributed to S Webb.

At least 181 records · Page 10Linked to original sources
PubMed1996

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↗
PubMed1996

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

The optimization and inherent limitations of 3D conformal radiotherapy treatment plans of the prostate.

This paper describes the applications of an inverse planning optimization algorithm to the real clinical problem of prostate cancer. The algorithm has been designed to compute optimized beam-weights taking full account of three-dimensional spatial information of dose inside the patient. The algorithm is based on fast simulated annealing, utilizing a cost-function containing both linear and quadratic terms. The linear part of the cost function allows for the implementation of "short-cuts" in the cost-function computation, which reduces the calculation time by a factor of about 30. It has been applied to compute optimized beam-weights for a three-field and a seven-field prostate treatment plan. It is shown for the three-field plan that the optimization algorithm can reproduce, and even slightly improve on, the results of an experienced human planner. For the seven-field plan, the human planner experienced difficulty finding beam-weights that gave an acceptable dose distribution. It is shown that the optimization algorithm can achieve good results in this case. The outcome of the optimization of the seven-field plan prompted an investigation into the best results that could be achieved by an "ideal" conformal radiotherapy technique. The results of this investigation are presented and it is shown that the limiting factor for conformal therapy of the prostate is the size of the overlap volume between the planning target volume (PTV) and the rectum. Finally, the efficiency and accuracy of fast simulated annealing is compared with that of classical simulated annealing. The former was found to be at least 10 times faster for the problem studied.

Algorithms↗
PubMed1995

MR magnetization transfer measurements in temporal lobe epilepsy: a preliminary study.

MR magnetization transfer ratio was measured in both hippocampi of three patients with temporal lobe epilepsy, and in two control subjects. The magnetization transfer ratio in each section was significantly lower on the affected side than on the contralateral side and in control subjects. Magnetization transfer ratio measurements are relatively fast and precise, this preliminary study shows that they may provide useful presurgical information.

Adult↗
PubMed1994

Engraftment of human hematopoietic precursor cells with secondary transfer potential in SCID-hu mice.

Human fetal bone fragments implanted subcutaneously in immunodeficient (SCID) mice maintain active human hematopoiesis. In this study, we show that this human hematopoietic microenvironment supports the engraftment and differentiation of HLA-mismatched, CD34+ primitive hematopoietic progenitor cells isolated from fetal and adult human bone marrow (BM). The BM CD34+ cells were depleted of CD2, CD14, CD15, CD16, glycophorin A, and CD19 lineage-committed cells (CD34+Lin-). Donor cell engraftment was manifested by the presence of B (CD19+) and myeloid (CD33+) cells of donor HLA phenotype. Successful engraftment was observed as early as 4 weeks after fetal BM donor cell injection and sustained for at least 12 weeks, with engraftment success rates of 100% (11/11 grafts) and 92% (11/12 grafts) at 8 and 12 weeks, respectively. Mixed BM chimerism of donor and endogenous cells was consistently observed in SCID-hu bones successfully engrafted with HLA-mismatched CD34+Lin- donor cells. Preconditioning of the SCID-hu bone with a single dose of sublethal (350 rad) whole body irradiation (WBI) immediately before cell injection enhanced the repopulation of the bone grafts with donor cells and, in some instances, resulted in complete repopulation. After WBI, as few as 500 fetal bone marrow CD34+Lin- cells injected in the human bone grafts resulted in donor-derived hematopoiesis. Donor progenitor cells recovered from the SCID-hu bone grafts 8 weeks postinjection had the capacity to repopulate secondary groups of HLA-disparate fetal human bones in SCID-hu mice with B and myeloid cells as well as CD34+ cells in some recipients. In addition, these cells repopulated fetal human thymus fragments in SCID mice with donor thymocytes including immature CD4+CD8+ and mature CD4+CD8- as well as CD4-CD8+ subsets. These results indicate that the fetal human bone implants of SCID-hu mice can support the maintenance of a cell population that has both multilineage potential and repopulating potential for periods of time as long as 16 weeks. The SCID-hu bone model consistently supported the engraftment of both fetal and adult CD34+Lin- cells without the administration of exogenous human cytokines to these animals. This model is currently being used to permit the isolation and characterization of candidate human hematopoietic stem cells (HSCs) and provide important information critical for human HSC therapy in humans.

Animals↗
PubMed1994

Human fetal bone marrow early progenitors for T, B, and myeloid cells are found exclusively in the population expressing high levels of CD34.

Experimentation on human stem cells is hampered by the relative paucity of this population and by the lack of assays identifying multilineage differentiation, particularly along the lymphoid lineages. In our current study, phenotypic analysis of low-density fetal bone marrow cells showed two distinct populations of CD34+ cells: those expressing a high density of CD34 antigen on their surface (CD34hi) and those expressing an intermediate level of CD34 antigen (CD34lo). Multiple tissues were used to characterize the in vitro and in vivo potential of these subsets and showed that only CD34hi cells support long-term B lymphopoiesis and myelopoiesis in vitro and mediate T, B, and myeloid repopulation of human tissues implanted into SCID mice. CD34lo cells repeatedly failed to provide long-term hematopoietic activity in vivo or in vitro. These results indicate that a simple fractionation based on well-defined CD34 antigen levels can be used to reproducibly isolate cells highly enriched for in vivo long-term repopulating activity and for multipotent progenitors, including T- and B-cell precursors. Additionally, given the limited variability in the results and the high correlation between in vitro and in vivo hematopoietic potential, we propose that the CD34hi population contains virtually all of the stem cell activity in fetal bone marrow and therefore is the population of choice for future studies in hematopoietic stem cell development and gene therapy.

Animals↗
PubMed1994

Generation of T cells from cytokine-mobilized peripheral blood and adult bone marrow CD34+ cells.

The present study compared the T-cell progenitor content of CD34+ lineage (Lin)- cells isolated from normal adult bone marrow (ABM) and mobilized peripheral blood (MPB). Both cell populations were found to differentiate into T cells when injected into human fetal thymi implanted into severe combined immunodeficient mice. Cytokine-MPB cells were less efficient than ABM cells in engrafting in the fetal human thymus, although both gave rise to thymocytes with identical phenotypes based on the analysis of CD1a, CD3, CD4, and CD8 expression. Thymocytes derived from adult CD34+ Lin- cells were capable of fully differentiating into mature CD3+ T cells expressing either the T-cell receptor (TCR) gamma delta or the TCR alpha beta (the later associated with CD4 or CD8), showing that the T-cell progenies of adult CD34+ cells were polyclonal and functional. Our data indicate that human MPB CD34+ cells are qualitatively identical to their BM counterparts, and demonstrate the existence of T-lymphoid progenitor cell activity in MPB.

Adult↗
PubMed1994

Dr Know.

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Communication↗