Optimization of 3-D conformal radiation treatment plans.
Explore the source record for details and available documents.
Algorithms↗
Biomedical subjects
A Jackson
Publications and source records attributed to A Jackson.
Patterns of chronic adhesive arachnoiditis following Myodil myelography: the significance of spinal canal stenosis and previous surgery.
109 patients who had undergone Myodil myelography on at least one occasion were identified. The patterns of lumbar nerve root distribution in this group were examined using magnetic resonance imaging. The relationship between these patterns and the presence of spinal stenosis or previous surgery was investigated. Chronic adhesive arachnoiditic nerve root patterns were seen in 68 patients and were classified into three groups according to Delemarter et al. Central clumping of nerve roots (type 1) and complete opacification of the thecal sac (type 3), extending over at least one vertebral level, were significantly related to spinal stenosis at an adjacent level (p < 0.0001). Peripheral adhesion of nerve roots to the theca (type 2) was significantly related to previous surgery at the level of abnormality (p < 0.00005). Only a single case of arachnoiditic nerve root patterns was seen in the absence of stenosis or previous surgery. We conclude that chronic adhesive arachnoiditis is significantly related to previous Myodil myelography in the presence of spinal stenosis or previous surgery but that Myodil alone rarely produces these changes.
Adult↗
DNA sequencing of the MHC class II region and the chromosome 6 sequencing effort at the Sanger Centre.
The human Major Histocompatibility Complex (MHC) is located on the short arm of chromosome 6 (6p21.3) and spans about 4 Mb. According to different gene families the MHC is subdivided into a class I, class II and class III region and many of its gene products are associated with the immune system and the susceptibility to various diseases. To date, we have sequenced about 40% (400 kb) of the class II region between HLA-DP and HLA-DQ and a coordinated effort to sequence the entire MHC is well underway. Analysis of the sequence revealed several novel genes and provides new insights into the molecular organisation and evolution of the MHC. All our data are publicly available via the MHC database (MHCDB) which allows rapid access, retrieval and display in the context of other MHC associated data. MHCDB is online available at (http:(/)/www.hgmp.mrc.ac.uk/) and, together with all our sequences also via anonymous ftp (ftp.icnet.uk/icrf-public).
Animals↗
Organisation and functions of class II genes and molecules.
The class II region of the human MHC contains all of the known class II genes: as well as antigen processing components and only one gene not obviously associated with the immune system, RING3. As an approach to understanding linkage disequilibrium and recombination in relation to polymorphism of the region we are cloning and sequencing the class II region. To date, the sequence of the DP-DQ region has almost been completed (see Report by S. Beck). Several sets of genes implicated in the immune system, especially in antigen processing and presentation, are clustered together in the MHC: class I (HLA-A, B, C etc) class II (DR, DQ, DP, DN, DO, DM) LMP2 and 7, TAP1 and 2, TNF, C2, C4, Bf, Hsp70. This situation has provoked speculation that the MHC behaves as a gene cluster in which allelic products of polymorphic genes are maintained on a haplotype so as to co-ordinate T cell repertoire development and deployment. The high levels of linkage disequilibrium across the region are consistent with this idea. Functions of the genes in the MHC are being investigated as a step towards gaining insight into antigen processing and presentation as well as understanding MHC-disease associations. We are concentrating on the functions of the class II-related genes, DM and DN/DO as well as the TAP/LMP cluster.
ATP-Binding Cassette Transporters↗
Obesity in primary care patients in Kelantan, Malaysia: prevalence, and patients' knowledge and attitudes.
This study measured the body mass index (BMI), and assessed attitudes and knowledge about obesity, of 197 male and 217 female patients aged 20-59 years attending the primary care clinic of the university hospital in Kelantan, Malaysia. There was no significant difference between the mean BMI of males (23.7) and females (24.2). In the overweight group (BMI 25-29.9) were 60 men (30%) and 66 women (30%). In the obese group (BMI 30 and above) were 12 men (6%) and 22 women (10%). Both diabetes mellitus and hypertension were associated with significantly higher BMI's. Knowledge about obesity was lacking. Sixty-three (15%) failed to recognize that obesity is bad for health. When asked the causes of obesity, 88 (21%) failed to mention either diet or lack of exercise. "Being happy" was suggested as a cause by 32 (8%). When asked if certain foods would cause obesity if eaten in excess, 45 (11%) said "No" for fatty foods, and 164 (40%) said "No" for sweet foods. Concerning appearance, 30 (15%) men regarded an obese man as normal or even handsome, while 49 (23%) women regarded an obese woman as normal or beautiful. Obesity is common among our adult patients, and is associated with some of their common health problems. However, a substantial minority do not regard obesity as unhealthy, do not relate it to diet or lack of exercise, do not recognize important groups of fattening foods, and do not regard obesity as unattractive.
Adult↗
Organ-specific patterns of donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in lung, kidney, and liver transplant recipients.
Although their relative importance and interaction are unclear, donor antigen(Ag)*-specific hyporeactivity and allogeneic microchimerism have been associated with improved long-term graft outcome and a lower incidence of chronic rejection in solid organ transplant recipients. We have postulated that a critical level of donor antigen, for a critical time period, is necessary to develop and maintain donor antigen-specific hyporeactivity; both the level and the time may differ by organ transplanted. In our current study, we tested donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in liver and kidney recipients and compared these values with our previous findings in lung recipients. We tested 25 liver recipients at 12 to 29 months posttransplant: 10 (40%) had developed donor antigen-specific hyporeactivity; 5 (20%), peripheral blood allogeneic microchimerism. For all but 1 of the chimeric and hyporeactive recipients, the level of donor cells was very low (< 1:20,000). Five hyporeactive recipients and all 15 donor antigen-responsive recipients did not have detectable levels of peripheral blood microchimerism. No chronic rejection has developed in any of these recipients to date--however, a lower incidence of acute rejection was observed for those recipients with donor antigen-specific hyporeactivity (30% versus 60% without) or with peripheral blood allogeneic microchimerism (20% versus 55% without) (P = ns). These results differ from our previous findings in 19 lung recipients: at 12 to 18 months posttransplant, 35% of them had developed donor antigen-specific hyporeactivity; 47%, peripheral blood allogeneic microchimerism. All donor antigen-specific hyporeactivity recipients as well as some donor antigen-responsive recipients had peripheral blood allogeneic microchimerism. We expanded our current study to include 26 recipients and a quantitative estimate of the level of allogeneic microchimerism. We observed that the hyporesponsive recipients tended to have higher levels of donor cells in their peripheral blood (> 1:6,000) than did the responsive recipients. We previously reported that 22% of kidney recipients had developed donor antigen-specific hyporeactivity at 12 to 18 months posttransplant. In our current study of 33 kidney recipients, we observed peripheral blood allogeneic microchimerism in 7 (21%) at 12 to 18 months posttransplant. The level of donor cells was very low (approximately 1:75,000), with no correlation between donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism at the time point tested. These studies emphasize the organ-specific nature of the development of donor antigen-specific hyporeactivity and the persistence of peripheral blood allogeneic microchimerism. Donor antigen-specific hyporeactivity correlates with very low levels of donor cells in liver recipients, while a higher critical level of donor cells is important in lung recipients. Additional sequential early posttransplant studies are necessary to further define the possible interrelationship between donor antigen and the development and maintenance of donor antigen-specific hyporeactivity.
Antigen Presentation↗
The cysteine residue responsible for the release of fibroblast growth factor-1 residues in a domain independent of the domain for phosphatidylserine binding.
Fibroblast growth factor (FGF)-1 lacks a classical signal sequence to direct its secretion yet utilizes high affinity cell surface receptors to signal its heparin-dependent angiogenic and neurotrophic activities. We have previously reported that FGF-1 is released in response to temperature stress as a latent homodimer through a pathway that is potentiated by the Golgi inhibitor, brefeldin A (Jackson, A., Tarantini, F., Gamble, S., Friedman, S., and Maciag, T. (1995) J. Biol. Chem. 270, 33-36). In an attempt to further characterize this unconventional secretion mechanism, we sought to define the Cys residue(s) critical for FGF-1 dimer formation and release and to determine whether FGF-1 can associate with known phospholipid components of organelle or plasma membranes, which may be disturbed by brefeldin A. Utilizing FGF-1 Cys mutants, we were able to demonstrate that residue Cys30 is critical for FGF-1 release in response to heat shock. In addition, using solid phase phospholipid binding assays we demonstrate that FGF-1 is able to specifically associate with phosphatidylserine (PS). Heparin inhibits the association between FGF-1 and PS, and synthetic peptide competition assays suggest that the PS-binding domain of FGF-1 lies between residues 114 and 137. These observations indicate that FGF-1 may be able to associate with the PS component of organelle and/or plasma membranes and that the domains responsible for FGF-1 homodimer formation and PS binding are structurally distinct.
3T3 Cells↗
Analysis of clinical complication data for radiation hepatitis using a parallel architecture model.
PURPOSE: The detailed knowledge of dose volume distributions available from the three-dimensional (3D) conformal radiation treatment of tumors in the liver (reported elsewhere) offers new opportunities to quantify the effect of volume on the probability of producing radiation hepatitis. We aim to test a new parallel architecture model of normal tissue complication probability (NTCP) with these data. METHODS AND MATERIALS: Complication data and dose volume histograms from a total of 93 patients with normal liver function, treated on a prospective protocol with 3D conformal radiation therapy and intraarterial hepatic fluorodeoxyuridine, were analyzed with a new parallel architecture model. Patient treatment fell into six categories differing in doses delivered and volumes irradiated. By modeling the radiosensitivity of liver subunits, we are able to use dose volume histograms to calculate the fraction of the liver damaged in each patient. A complication results if this fraction exceeds the patient's functional reserve. To determine the patient distribution of functional reserves and the subunit radiosensitivity, the maximum likelihood method was used to fit the observed complication data. RESULTS: The parallel model fit the complication data well, although uncertainties on the functional reserve distribution and subunit radiosensitivity are highly correlated. CONCLUSION: The observed radiation hepatitis complications show a threshold effect that can be described well with a parallel architecture model. However, additional independent studies are required to better determine the parameters defining the functional reserve distribution and subunit radiosensitivity.
Hepatitis↗
The release of fibroblast growth factor-1 from NIH 3T3 cells in response to temperature involves the function of cysteine residues.
Fibroblast growth factor (FGF)-1 is released from NIH 3T3 cells in response to heat shock as a biologically inactive protein that is unable to bind heparin and requires activation by (NH4)2SO4 to generate a biologically active extracellular heparin-binding growth factor (Jackson, A., Friedman, S., Zhan, X., Engleka, K. A., Forough, R., and Maciag, T. (1992) Proc. Natl. Acad. Sci. USA 89, 10691-10695). To further study the mechanism of FGF-1 release in response to heat shock (42 degrees C), we examined the kinetics of FGF-1 release from FGF-1-transfected NIH 3T3 cells and observed that the cells require at least 1 h of exposure to heat shock conditions for the release of FGF-1. Interestingly, agents that interfere with the function of the endoplasmic reticulum-Golgi apparatus, exocytosis, and the multidrug resistance pathway (brefelden A, methylamine, and verapamil, respectively) do not inhibit the release of FGF-1 in response to temperature; rather, they exaggerate the release of FGF-1. Because immunoblot analysis of FGF-1 in the conditioned medium of heat-shocked NIH 3T3 cells revealed the presence of a minor band with an apparent molecular weight of a FGF-1 homodimer and because we have previously shown that FGF-1, but not FGF-2, is able to form a homodimer in response to chemical oxidation by CuCl2 (Engleka, K. A., and Maciag, T. (1992) J. Biol. Chem. 267, 11307-11315), we examined whether reducing agents would substitute for (NH4)2SO4 and activate extracellular FGF-1. Indeed, dithiothreitol and reduced glutathione are able to individually generate a FGF-1 monomer as a heparin-binding protein from the conditioned medium of heat-shocked NIH 3T3 cell transfectants. To confirm that cysteine residues are involved in the release of FGF-1 in response to temperature, we used mutagenesis to prepare a human FGF-1 Cys-free mutant in which Cys30, Cys97, and Cys131 were converted to serine. Analysis of the release of the FGF-1 Cys-free mutant in NIH 3T3 cells transfected with the FGF-1 Cys-free mutant demonstrated that the FGF-1 Cys-free mutant is not released into the conditioned medium in response to temperature. Interestingly, exposure of the NIH 3T3 cell FGF-1 Cys-free transfectants to brefelden A followed by heat shock also demonstrated the absence of the extracellular FGF-1 Cys-free mutant.(ABSTRACT TRUNCATED AT 400 WORDS)
3T3 Cells↗
Enlargement of the tensor intermuscularis muscle in Graves' ophthalmopathy. A computed tomographic and magnetic resonance imaging study.
OBJECTIVE: To determine whether the tensor intermuscularis muscle (TIM), which consists of muscle fibers in the superolateral intermuscular orbital septum, is involved in Graves' ophthalmopathy (GO). DESIGN: The computed tomographic (n = 24) and magnetic resonance imaging (n = 10) appearances of the TIM were retrospectively examined in 34 patients with known GO. The severity of GO was assessed by applying a scoring system from 0 to 3 (ie, normal [0], mild [1], moderate [2], and severe [3]) to each of the rectus muscles and superior oblique muscle. The severity of exophthalmos, enlargement of the superior ophthalmic vein, and displacement of the lacrimal gland were also recorded. RESULTS: The TIM appeared as thickening of the septum immediately behind the globe, and it was best seen on coronal magnetic resonance images. There was enlargement of the TIM in 19 of the 34 patients, and it was bilateral in 17. Enlargement was present only in patients with moderate or severe involvement of other muscles (muscle index, > 7/15), and it was significantly correlated with the muscle index (P < .05), exophthalmos (P < .05), enlargement of the superior ophthalmic vein (P < .005), and anterior displacement of the lacrimal gland (P < .01). Severe enlargement of the TIM was seen in only five of the 34 patients, and it showed a close correlation with the muscle index (P < .005), exophthalmos (P < .001), enlargement of the superior ophthalmic vein (P < .001), and anterior displacement of the lacrimal gland (P < .001). CONCLUSIONS: Enlargement of the TIM in GO can be identified on computed tomographic and magnetic resonance imaging scans. It is invariably associated with moderate or severe involvement of other extraocular muscles, and it correlates closely with other well-recognized imaging features of severe GO.
Adult↗
Plasticity in cultured carotid body chemoreceptors: environmental modulation of GAP-43 and neurofilament.
In this study we use dissociated cell cultures of the rat carotid body to investigate the adaptive capabilities of endogenous oxygen chemoreceptors, following chronic stimulation by various environmental factors. These oxygen chemoreceptors are catecholamine-containing glomus cells, which derive from the neural crest and resemble adrenal medullary chromaffin cells. Using double-label immunofluorescence, we found that chronic exposure of carotid body cultures to hypoxia (2% to 10% oxygen) caused a significant fraction of tyrosine hydroxylase-positive (TH+) glomus cells to acquire detectable immunoreactivity for growth-associated protein GAP-43. The effect was dose-dependent and peaked around an oxygen tension of 6%, where approximately 30% of glomus cells were GAP-43 positive. Treatment with agents that elevate intracellular cyclic adenosine monophosphate (cAMP) (i.e., dibutyryl cAMP or forskolin) also markedly stimulated GAP-43 expression. Since hypoxia is known to increase cAMP levels in glomus cells, it is possible that the effect of hypoxia on GAP-43 expression was mediated, at least in part, by a cAMP-dependent pathway. Unlike hypoxia, however, cAMP analogs also stimulated neurofilament (NF 68 or NF 160 kD) expression and neurite outgrowth in glomus cells, and these properties were enhanced by retinoic acid. Nerve growth factor, which promotes neuronal differentiation in related crest-derived endocrine cells, and dibutyryl cGMP were ineffective. Thus, it appears that postnatal glomus cells are plastic and can express neuronal traits in vitro. However, since hypoxia stimulated GAP-43 expression, without promoting neurite outgrowth, it appears that the two processes can be uncoupled. We suggest that stimulation of GAP-43 by hypoxia may be important for other physiological processes, e.g., enhancing neurotransmitter release or sensitization of G-protein-coupled receptor transduction.
Animals↗
A case of osteochondroma of the cervical spine.
Explore the source record for details and available documents.
Adult↗
Can the DRL 72s schedule selectively reveal antidepressant drug activity?
The effects of three antidepressants, desipramine (2.5-20 mg/kg) tranylcypromine (0.63-2.5 mg/kg) mianserin (1.25-10 mg/kg) and three non-antidepressants, chlordiazepoxide (CDP; 1.25-10 mg/kg) haloperidol (0.02-0.16 mg/kg) d-amphetamine (0.31-1.25 mg/kg) were evaluated in rats responding for water reinforcement under a DRL 72s schedule. The antidepressants all produced dose-related decreases in overall response rates, but no significant changes in reinforcement frequency. In contrast, the anxiolytic CDP did increase the number of reinforcers obtained. Haloperidol decreased both reinforcers and responses whilst d-amphetamine stimulated responding, thereby decreasing reinforcement frequency. An analysis of the modes of inter-response times (IRTs) revealed no significant shifts in the peaks of the IRT distributions for most of the drugs tested. Amphetamine, however, (0.31 and 0.63 mg/kg) decreased the modal values in correspondence with the shift to the left of the peak of responding caused by this compound. These results are discussed in the context of the use of the DRL 72s procedure as a screening test for antidepressant drugs.
Animals↗
State-dependent effects of atypical benzodiazepine-receptor agonists.
The state-dependent effect of the BZ-receptor agonist diazepam (1.25-10 mg/kg), the partial agonist FG 8205 (0.5-4.0 mg/kg) and the BZ1-receptor agonist zolpidem (0.25-2 mg/kg) were investigated in rats. During daily sessions, animals were trained to acquire FR10 lever pressing for food reinforcement whilst under the influence of the agonists, using an operant technique. Forty-eight hours after the final training session under drug, their performance of the FR10 was evaluated during a test session, carried out following vehicle administration only. Neither diazepam, nor FG 8205 impaired acquisition of the task. In the group treated with 2 mg/kg zolpidem, six out of eight rats failed to learn within 20 sessions, but the smaller doses were without effect on acquisition. When drug treatment was withdrawn, there was evidence that all three of the agonists tested produced state-dependency. This was apparent in the form of longer latencies to obtain reinforcement and decreased lever pressing rates. The significance of these findings are discussed in the context of the relationship between the state-dependent effects of BZ-receptor agonists and their other properties, and the receptor subtypes which might underly these effects.
Animals↗
Optimization of intensity-modulated 3D conformal treatment plans based on biological indices.
To overcome the limitations of the intensity modulation optimization techniques based on dose criteria, we introduce a method for optimizing intensity distributions in which we employ an objective function based on biological indices. The objective function also includes constraints on dose and dose-volume combinations to ensure that the results are consistent with the physician's judgement. We apply a variant of the steepest-descent method to optimize the objective function. The method is three-dimensional and incorporates scattered radiation in the optimization process using an iterative scheme employing the pencil beam convolution method. Previously we had shown that the inverse technique of obtaining optimum intensity distributions, for which the objectives are defined in terms of a desired uniform dose to the target volume and desired upper limits of dose to normal organs, produces satisfactory approximations of the desired dose distributions for prostate plans. However, for lung, the performance of this technique was considerably inferior. Our conclusion was that, in general, it is not sufficient to specify the objectives of optimization purely in terms of a desired pattern of dose and that the objectives should also incorporate biology, perhaps in the form of biological indices. We demonstrate that the biology-based approach produces lung plans that are superior to those produced when only dose-based objectives are used. For the treatment of prostate, the two methods produce comparable dose distributions.
Adenocarcinoma↗
Induction of c-fos in rat forebrain by pharmacological manipulation of 5-hydroxytryptamine levels.
The immunocytochemical localization of the immediate-early gene c-fos has been used to map sites of neuronal activity in the rat brain associated with 5-hydroxytryptamine function. Behavioural studies have shown that brain 5-hydroxytryptamine function is increased by treatment of animals with a combination of the 5-hydroxytryptamine precursor L-tryptophan (100 mg/kg) and the monoamine inhibitor tranylcypromine (20 mg/kg). We now report that such treatment induces a specific anatomical pattern of expression of c-fos in rat forebrain in many limbic, striatal and cortical areas which corresponds well with the distribution of 5-hydroxytryptamine-immunoreactive terminals. To investigate further the involvement of 5-hydroxytryptamine in this response, we pretreated animals with the tryptophan hydroxylase inhibitor p-chlorophenylalanine and observed the effects on Fos-like immunoreactivity after L-tryptophan and tranylcypromine challenge. Two-day pretreatment with p-chlorophenylalanine (300 mg/kg) prior to tranylcypromine and L-tryptophan resulted in a significant attenuation of Fos-like immunoreactivity in specific brain areas, including the piriform and frontal cortices, nucleus accumbens, caudate-putamen, paraventricular hypothalamus and paraventricular thalamic nucleus. A marked reduction of the hyperactivity syndrome was also seen, as has been reported in earlier studies. The results of this study suggest that the elevation in Fos-like immunoreactivity following treatment with tryptophan and a monoamine oxidase inhibitor is mainly due to increased 5-hydroxytryptamine synthesis and release. It is well known that 5-hydroxytryptamine mediates mood and affect, and this study indicates potential brain loci of action of serotonergic drugs.
Animals↗
The role of CT and MRI in the investigation of orbital roof fractures.
Explore the source record for details and available documents.
Adolescent↗