Biomedical subjects

C Baldock

Publications and source records attributed to C Baldock.

At least 37 records · Page 2Linked to original sources

PubMed2002

Attenuation of diagnostic energy photons by polymer gel dosimeters.

Post-irradiation changes in the linear attenuation coefficient, mu, of polymer gel dosimeters give rise to a change which can be measured with x-ray computed tomography. Polymer gel dosimeters were manufactured consisting of 3% (by weight) acrylamide and 3% N,N'-methylene-bis-acrylamide comonomers dissolved in aqueous gelatin (5% gelatin by total weight and 89% de-ionized distilled water). Mu was measured in a collimated radiation beam of photons from an 241Am source. Density, rho, of polymer gel dosimeters was measured using volumetric flasks with capillary stoppers. The measured post-irradiation data of mu was plotted against the data of rho for different batches, and linear least squares fits gave r2 values of 0.99605 and 0.99953, with P values of less than 0.001. This confirms that the post-irradiation change in mu is proportional to that of rho. The change in rho implies a change in volume regardless of the evaluation modality of the polymer gel dosimeter.

Dose-Response Relationship, Radiation↗

PubMed2002

A basic study of some normoxic polymer gel dosimeters.

Polymer gel dosimeters offer a wide range of potential applications in the three-dimensional verification of complex dose distribution such as in intensity-modulated radiotherapy (IMRT). Until now, however, polymer gel dosimeters have not been widely used in the clinic. One of the reasons is that they are difficult to manufacture. As the polymerization in polymer gels is inhibited by oxygen, all free oxygen has to be removed from the gels. For several years this was achieved by bubbling nitrogen through the gel solutions and by filling the phantoms in a glove box that is perfused with nitrogen. Recently another gel formulation was proposed in which oxygen is bound in a metallo-organic complex thus removing the problem of oxygen inhibition. The proposed gel consists of methacrylic acid, gelatin, ascorbic acid, hydroquinone and copper(II)sulphate and is given the acronym MAGIC gel dosimeter. These gels are fabricated under normal atmospheric conditions and are therefore called 'normoxic' gel dosimeters. In this study, a chemical analysis on the MAGIC gel was performed. The composition of the gel was varied and its radiation response was evaluated. The role of different chemicals and the reaction kinetics are discussed. It was found that ascorbic acid alone was able to bind the oxygen and can thus be used as an anti-oxidant in a polymer gel dosimeter. It was also found that the anti-oxidants N-acetyl-cysteine and tetrakis(hydroxymethyl)phosphonium were effective in scavenging the oxygen. However, the rate of oxygen scavenging is dependent on the anti-oxidant and its concentration with tetrakis(hydroxymethyl)phosphonium being the most reactive anti-oxidants. Potentiometric oxygen measurements in solution provide an easy way to get a first impression on the rate of oxygen scavenging. It is shown that cupper(II)sulphate operates as a catalyst in the oxidation of ascorbic acid. We, therefore, propose some new normoxic gel formulations that have a less complicated chemical formulation than the MAGIC gel.

Acetylcysteine↗

PubMed2002

Optimization of multiple spin-echo sequences for 3D polymer gel dosimetry.

The overall performance of polymer gel dosimeters for three-dimensional radiation dosimetry is determined by the temporal and spatial stability of the gels, dose sensitivity and image quality with respect to both systematic and stochastic deviations. The dose resolution (D(p)delta) is determined by the dose sensitivity and the signal-to-noise ratio (SNR) in the dose images. The dose sensitivity can be altered by changing the chemical composition of the polymer gel. The SNR is determined by the scanner and the imaging sequence. In the dose verification of conformal radiotherapy treatments the chosen number of slices may reach a number of 10-20. For these experiments, to obtain a sufficient SNR within a reasonable measurement time using a certain MR scanner, the imaging sequence should be optimized. A few other studies have emphasized the importance of optimizing the imaging sequence with respect to dose resolution (D(p)delta) or SNR but do not give quantitative values for the optimal sequence parameters for scanning a polymer gel dosimeter in three dimensions. In this paper, it is proved that a multiple spin-echo sequence is preferable to a single spin-echo sequence. It is also shown that when using a multiple spin-echo sequence it is not the inter-echo time that should be optimized but the number of echoes. An algebraical expression is derived for the dose resolution in terms of sequence parameters. A mathematical formalism and look-up tables are provided that can be used to optimize both a single and a slice-selective multiple spin-echo sequence to acquire a set of dose images at various locations. The use of the optimization protocol is illustrated by some examples. The optimization protocol enables the user to derive the optimal sequence parameters to acquire a set of dose maps obtained by quantitative T2 imaging for each polymer gel dosimeter within the shortest time possible.

Acrylic Resins↗

PubMed2002

Dose-response stability and integrity of the dose distribution of various polymer gel dosimeters.

In this study the stability of different polymer gel dosimeters is investigated. Further to a previous chemical stability study on a (6%T, 50%C) PAG gel, the change in slope and intercept of the linear part of the R2-dose plot is recorded with time for different gel formulations. In addition to this R2-dose-response stability study, the dose edge of a half-blocked field was recorded with time. Three different PAG type polymer gels, a hydroxyethyl acrylate (HEA) gel and two different normoxic polymer gels were investigated. In the PAG type polymer gels, the relative concentration of gelatin and comonomers was varied in order to study the influence of the different components, that constitute the dosimeter, on the stability. It is shown that the R2-dose-response stability is largely determined by the chemical composition of the gel dosimeters. All the PAG gel dosimeters and the normoxic gel dosimeters are found to preserve the integrity of the dose distribution up to 22 days after irradiation. The half-life of the change in dose sensitivity of a MAGIC gel is found to be 18 h compared to 5.7 h for a (6%T, 50%C) PAG gel. A maximum relative decrease in dose sensitivity of 21% was noted for the MAGIC gel compared to an increase of 50% for a (6%T, 50%C) PAG gel. A loss of integrity of the dose distribution was found in the HEA gel.

Acrylic Resins↗

PubMed2002

Magnetization transfer imaging for polymer gel dosimetry.

Off-resonance RF pre-saturation was used to obtain contrast in MRI images of polymer gel dosimeters irradiated to doses up to 50 Gy. Two different polymer gel dosimeters composed of 2-hydroxyethyl-acrylate or methacrylic acid monomers mixed with N, N'-methylene-bisacrylamide (BIS), dispersed in an aqueous gelatin matrix were evaluated. Radiation-induced polymerization of the co-monomers generates a fast-relaxing insoluble polymer. Saturation of the polymer using off-resonance Gaussian RF pulses prior to a spin-echo readout with a short echo time leads to contrast that is dependent on the absorbed dose. This contrast is attributed to magnetization transfer (MT) between free water and the polymer, and direct saturation of water was found to be negligible under the prevailing experimental conditions. The usefulness of MT imaging was assessed by computing the dose resolution obtained with this technique. We found a low value of dose resolution over a wide range of doses could be obtained with a single experiment. This is an advantage over multiple spin echo (MSE) experiments using a single echo spacing where an optimal dose resolution is achieved over only very limited ranges of doses. The results suggest MT imaging protocols may be developed into a useful tool for polymer gel dosimetry.

Dose-Response Relationship, Radiation↗

PubMed2002

Investigation of the NMR relaxation rate dose-response of a ceric sulphate dosimeter.

The relationship between the radiation absorbed dose and the NMR longitudinal and transversal relaxation rates, R1 and R2, respectively, of a ceric sulphate dosimeter was examined. By adding copper sulphate, the R1 and R2 dose-responses were found to be linear up to 60 kGy with dose sensitivities of 13 x 10(-6) and 15 x 10(-6) s(-1) Gy(-1) , respectively. There is thus the potential for a three-dimensional ceric dosimeter for high dose applications, provided a suitable gelling substance is used.

Magnetic Resonance Spectroscopy↗

PubMed2001

Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization.

The ability of the cornea to transmit light while being mechanically resilient is directly attributable to the formation of an extracellular matrix containing orthogonal sheets of collagen fibrils. The detailed structure of the fibrils and how this structure underpins the mechanical properties and organization of the cornea is understood poorly. In this study, we used automated electron tomography to study the three-dimensional organization of molecules in corneal collagen fibrils. The reconstructions show that the collagen molecules in the 36-nm diameter collagen fibrils are organized into microfibrils (approximately 4-nm diameter) that are tilted by approximately 15 degrees to the fibril long axis in a right-handed helix. An unexpected finding was that the microfibrils exhibit a constant-tilt angle independent of radial position within the fibril. This feature suggests that microfibrils in concentric layers are not always parallel to each other and cannot retain the same neighbors between layers. Analysis of the lateral structure shows that the microfibrils exhibit regions of order and disorder within the 67-nm axial repeat of collagen fibrils. Furthermore, the microfibrils are ordered at three specific regions of the axial repeat of collagen fibrils that correspond to the N- and C-telopeptides and the d-band of the gap zone. The reconstructions also show macromolecules binding to the fibril surface at sites that correspond precisely to where the microfibrils are most orderly.

Animals↗

PubMed2001

A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase.

Enoyl acyl carrier protein (ACP) reductase catalyses the last reductive step of fatty acid biosynthesis, reducing the enoyl group of a growing fatty acid chain attached to ACP to its acyl product using NAD(P)H as the cofactor. This enzyme is the target for the diazaborine class of antibacterial agents, the biocide triclosan, and one of the targets for the front-line anti-tuberculosis drug isoniazid. The structures of complexes of Escherichia coli enoyl-ACP reductase (ENR) from crystals grown in the presence of NAD+ and a family of diazaborine compounds have been determined. Analysis of the structures has revealed that a mobile loop in the structure of the binary complex with NAD+ becomes ordered on binding diazaborine/NAD+ but displays a different conformation in the two subunits of the asymmetric unit. The work presented here reveals how, for one of the ordered conformations adopted by the mobile loop, the mode of diazaborine binding correlates well with the activity profiles of the diazaborine family. Additionally, diazaborine binding provides insights into the pocket on the enzyme surface occupied by the growing fatty acid chain.

Binding Sites↗

PubMed2001

Mutation of the gene encoding fibrillin-2 results in syndactyly in mice.

Fibrillins are large, cysteine-rich glycoproteins that form microfibrils and play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin-2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in the autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres. MFS is characterized by cardiovascular, skeletal and ocular abnormalities, and CCA by long, thin, flexed digits, crumpled ears and mild joint contractures. Although mutations arise throughout FBN1, those clustering within exons 24-32 are associated with the most severe form of MFS, so-called neonatal MFS. All the mutations described in CCA occur in the "neonatal region" of FBN2. Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibrils are mainly engaged in tissue homeostasis rather than elastic matrix assembly. In the current investigation, we have analysed the classical mouse mutant shaker-with-syndactylism using a positional candidate approach and demonstrated that loss-of-function mutations outside the "neonatal region" of Fbn2 cause syndactyly in mice. These results suggest that phenotypes distinct from CCA may result in man as a consequence of mutations outside the "neonatal region" of FBN2.

Amino Acid Sequence↗

PubMed2001

The supramolecular organization of fibrillin-rich microfibrils.

We propose a new model for the alignment of fibrillin molecules within fibrillin microfibrils. Automated electron tomography was used to generate three-dimensional microfibril reconstructions to 18.6-A resolution, which revealed many new organizational details of untensioned microfibrils, including heart-shaped beads from which two arms emerge, and interbead diameter variation. Antibody epitope mapping of untensioned microfibrils revealed the juxtaposition of epitopes at the COOH terminus and near the proline-rich region, and of two internal epitopes that would be 42-nm apart in unfolded molecules, which infers intramolecular folding. Colloidal gold binds microfibrils in the absence of antibody. Comparison of colloidal gold and antibody binding sites in untensioned microfibrils and those extended in vitro, and immunofluorescence studies of fibrillin deposition in cell layers, indicate conformation changes and intramolecular folding. Mass mapping shows that, in solution, microfibrils with periodicities of <70 and >140 nm are stable, but periodicities of approximately 100 nm are rare. Microfibrils comprise two in-register filaments with a longitudinal symmetry axis, with eight fibrillin molecules in cross section. We present a model of fibrillin alignment that fits all the data and indicates that microfibril extensibility follows conformation-dependent maturation from an initial head-to-tail alignment to a stable approximately one-third staggered arrangement.

Amino Acid Sequence↗

PubMed2001

Simple methods for the correction of T2 maps of phantoms.

Two simple methodologies for correcting the errors in T2 maps for phantom measurements are presented; they both give accurate MRI maps with a low coefficient of variation (CV). The rate correction method is based on an equation relating the true T2 (T2,t) and that determined experimentally (T2,exp) for homogenous phantoms. The response matrix method is a phenomenological analysis of the difference between T2,exp and T2,t, from which correction factors are computed for a range of T2 values and for every pixel of an image. The factors were obtained from phantoms filled with a homogeneous gelatin gel and having different T2,t values. The CV in homogeneous phantom measurements were reduced from 2.5-4.0% to approximately 0.6-2.0% for T2,t values ranging from 180-600 ms. Examples are shown for the correction of T2 maps of phantoms filled with polymer dosimeter gel irradiated with photon beams from a linear accelerator. The methodologies presented can easily be implemented on a clinical MRI scanner.

Humans↗

PubMed2001

Experimental determination of the diffusion coefficient in two-dimensions in ferrous sulphate gels using the finite element method.

A novel two-dimensional finite element method for modelling the diffusion which occurs in Fricke or ferrous sulphate type radiation dosimetry gels is presented. In most of the previous work, the diffusion coefficient has been estimated using simple one-dimensional models. This work presents a two-dimensional model which enables the diffusion coefficient to be determined in a much wider range of experimental situations. The model includes the provision for the determination of a drift parameter. To demonstrate the technique comparative diffusion measurements between ferrous sulphate radiation dosimetry gels, with and without xylenol orange chelating agent and carbohydrate additives have been undertaken. Diffusion coefficients of 9.7 +/- 0.4, 13.3 +/- 0.6 and 9.5 +/- 0.8 10(-3) cm2h-1 were determined for ferrous sulphate radiation dosimetry gels with and without xylenol orange and with xylenol orange and sucrose additives respectively.

Chelating Agents↗

PubMed2001

Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly.

Fibrillin-rich microfibrils are a unique class of extensible connective tissue macromolecules. Their critical contribution to the establishment and maintenance of diverse extracellular matrices was underlined by the linkage of their principal structural component fibrillin to Marfan syndrome, a heritable connective tissue disorder with pleiotropic manifestations. Microscopy and preparative techniques have contributed substantially to the understanding of microfibril structure and function. The supramolecular organisation of microfibrillar assemblies in tissues has been examined by tissue sectioning and X-ray diffraction methods. Published findings are discussed and new information reported on the organisation of microfibrils in the ciliary zonular fibrils by environmental scanning electron microscopy. This review summarises microscopy and X-ray diffraction studies that are informing current understanding of the ultrastructure of fibrillin-rich microfibrils.

Ectopia Lentis↗

PubMed2001

Dose resolution optimization of polymer gel dosimeters using different monomers.

Polymer gel dosimeters of different formulations were manufactured from different monomers of acrylamide, acrylic acid, methacrylic acid, 1-vinyl-2-pyrrolidinone, 2-hydroxyethyl methacrylate and 2-hydroxyethyl acrylate. Gelatin and agarose were used as the gelling agents and N,N'-methylene-bis-acrylamide was used as a co-monomer in each polymer gel dosimeter. The T2 dependence of each dosimeter was analysed using a model of fast exchange of magnetization. The influence of the half-dose and the apparent T2 of the polymer-proton pool on the dose resolution (Dpdelta) were examined. Comparisons are made with the commonly employed R2-dose sensitivity. Differences exist suggesting that experiments reported in the literature using what were thought to be more optimal dosimeters may not actually be so. Based on Dpdelta of each formulation, conclusions are drawn on the optimal formulation required for a specific range of absorbed doses. In addition, information about the extent of polymerization of the monomers used along with some characteristics of the polymer network formed are reported. The influence of the concentration of monomers and gelling agent was subsequently evaluated using a model of fast exchange of magnetization. Based on these calculations, further improvement in Dpdelta can be expected.

Acrylamide↗

PubMed2001

Modelling of post-irradiation events in polymer gel dosimeters.

The nuclear magnetic resonance (NMR) spin-spin relaxation time (T2) is related to the radiation-dependent concentration of polymer formed in polymer gel dosimeters manufactured from monomers in an aqueous gelatin matrix. Changes in T2 with time post-irradiation have been reported in the literature but their nature is not fully understood. We investigated those changes with time after irradiation using FT-Raman spectroscopy and the precise determination of T2 at high magnetic field in a polymer gel dosimeter. A model of fast exchange of magnetization taking into account ongoing gelation and strengthening of the gelatin matrix as well as the polymerization of the monomers with time is presented. Published data on the changes of T2 in gelatin gels as a function of post-manufacture time are used and fitted closely by the model presented. The same set of parameters characterizing the variations of T2 in gelatin gels and the increasing concentration of polymer determined from FT-Raman spectroscopy are used successfully in the modelling of irradiated polymer gel dosimeters. Minimal variations in T2 in an irradiated PAG dosimeter are observed after 13 h.

Acrylic Resins↗

PubMed2001

An experimental study of the dose response of polymer gel dosimeters imaged with x-ray computed tomography.

Changes in the linear attenuation coefficient of polymer gel dosimeters post-irradiation enable the imaging of dose distributions by x-ray computed tomography (CT). Various compositions of polymer gel dosimeters manufactured from acrylamide (AA), and N,N'-methylene-bis-acrylamide (BIS) comonomers and gelatin or agarose gelling agents were investigated. This work shows that increasing the comonomer concentration increases the CT-dose sensitivity of the polymer gel dosimeter. This can be further increased by replacing gelatin with agarose. Varying the gelatin concentration however does not significantly change the CT-dose sensitivity. Among the compositions studied, dose resolution (D(delta)95%) was found to be optimal for polymer gel dosimeters comprising 5% gelatin, 3% AA, 3% BIS and 89% water.

Acrylamide↗

PubMed2001

The relationship between radiation-induced chemical processes and transverse relaxation times in polymer gel dosimeters.

The effects of ionizing radiation in different compositions of polymer gel dosimeters are investigated using FT-Raman spectroscopy and NMR T2 relaxation times. The dosimeters are manufactured from different concentrations of comonomers (acrylamide and N,N'-methylene-bis-acrylamide) dispersed in different concentrations of an aqueous gelatin matrix. Results are analysed using a model of fast exchange of magnetization between three proton pools. The fraction of protons in each pool is determined using the known chemical composition of the dosimeter and FT-Raman spectroscopy. Based on these results, the physical and chemical processes in interplay in the dosimeters are examined in view of their effect on the changes in T2. The precipitation of growing macroradicals and the scavenging of free radicals by gelatin are used to explain the rate of polymerization. The model describes the changes in T2 as a function of the absorbed dose up to 50 Gy for the different compositions. This is expected to aid the theoretical design of new, more efficient dosimeters, since it was demonstrated that the optimum dosimeter (i.e, with the lowest dose resolution) must have a range of relaxation times which match the range of T2 values which can be determined with the lowest uncertainty using an MRI scanner.

Dose-Response Relationship, Radiation↗

PubMed2000

The role of the C1 and C2 a-domains in type VI collagen assembly.

Constructs of each of the three chains of type VI collagen were generated and examined in an in vitro transcription/translation assay supplemented with semipermeabilized cells. Each of the constructs when used in the in vitro system was shown to be glycosylated and to undergo intracellular assembly, the extent of which was determined by the nature of the C-terminal globular domains. All three chains containing the C1 domain formed monomers; however, the C2 domain was required for dimer and tetramer formation. In the case of the full-length alpha2(VI) chain, monomers, dimers, and tetramers formed in a time-dependent manner. Although the splice variant alpha2(VI)C2a could form monomers, it was unable to form dimers and tetramers. Similar results to the alpha2(VI) chain were found for the full-length alpha1(VI) chain, although assembly was at a slower rate. In the case of the alpha3(VI) chain containing both C1 and C2 domains only monomers were observed. Addition of the C3, C4, and C5 did not change this pattern. Homology modeling suggested that a 10-amino acid insertion in the C2 domain of the alpha3(VI) chain may interfere with dimer formation. A near full-length construct of the alpha3(VI) chain only formed monomers but was shown to facilitate tetramer formation in cotranslation experiments.

Alternative Splicing↗