Reply to 'Comment on 'A systematic review of the precision and accuracy of dose measurements in photon radiotherapy using polymer and Fricke MRI gel dosimetry''.
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Ferrous Compounds↗
Biomedical subjects
M A Smith
Publications and source records attributed to M A Smith.
Hydrogen-peroxide-induced toxicity of rat striatal neurones involves activation of a non-selective cation channel.
Striatal neurones are particularly vulnerable to hypoxia/ischaemia-induced damage, and free radicals are thought to be prime mediators of this neuronal destruction. It has been shown that hydrogen peroxide (H2O2), through the production of free radicals, induces rat insulinoma cell death by activation of a non-selective cation channel, which leads to irreversible cell depolarization and unregulated Ca2+ entry into the cell. In the study presented here, we demonstrate that a subpopulation of striatal neurones (medium spiny neurones) is depolarized by H2O2 through the production of free radicals. Cell-attached recordings from rat cultured striatal neurones demonstrate that exposure to H2O2 opens a large-conductance channel that is characterized by extremely long open times (seconds). Inside-out recordings show that cytoplasmically applied beta-nicotinamide adenine dinucleotide activates a channel with little voltage dependence, a linear current-voltage relationship and a single-channel conductance of between 70 and 90 pS. This channel is permeable to Na+, K+ and Ca2+ ions. Fura-2 imaging from cultured striatal neurones reveals that H2O2 exposure induces a biphasic intracellular Ca2+ increase in a subpopulation of neurones, the second, later phase resulting in Ca2+ overload. This later component of the Ca2+ response is dependent on the presence of extracellular Ca2+ and is independent of synaptic activity or voltage-gated Ca2+ channel opening. Consequently, this channel may be an important contributor to free radical-induced selective striatal neurone destruction. These results are remarkably similar to those observed for insulinoma cells and suggest that this family of non-selective cation channels has a widespread distribution in mammalian tissues.
Animals↗
Can FDG PET be used to successfully direct preoperative biopsy of soft tissue tumours?
Magnetic resonance imaging (MRI) has been the most useful tool in the anatomical definition of soft tissue sarcoma, although there remains the problem of defining the lesions as benign or malignant. The management of such lesions requires biopsy prior to surgical resection. If the most malignant area could be defined more accurately, then this area could be targeted for biopsy. Fluorodeoxyglucose positron emission tomography (FDG PET) has been found to be useful in identifying malignancy and variations in grade in soft tissue masses. The aim of this study was to assess the use of FDG PET scanning with or without co-registered MRI to indicate the most appropriate biopsy site. Twenty consecutive patients presented with soft tissue masses with clinical signs of malignancy. All patients underwent MRI and FDG PET scanning and the two images were co-registered. A biopsy site that was the most likely to be malignant was defined on the PET scan. All patients underwent an initial biopsy and then complete surgical resection of the mass. The histological results from the mass were compared with those from the biopsy specimen obtained from the site suggested by the PET scan. In malignant masses the biopsy site suggested by the FDG PET scan was found to be representative of the most malignant site on the whole mass histology. Benign lesions had low or no FDG uptake. In no case did the co-registered image add significantly to the appropriate biopsy site. FDG PET can be used to appropriately direct biopsy in soft tissue sarcoma and potentially may lead to computed tomography/MRI directed outpatient biopsy prior to definitive treatment.
Adult↗
Enhanced sensitivity to the antinociceptive effects of kappa opioids in naltrexone-treated rats: dose- and time-dependent effects.
The purpose of the present study was to examine sensitivity to the antinociceptive effects of kappa opioids during chronic treatment with the nonselective opioid antagonist naltrexone. In a warm-water tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from water maintained at 50 and 55 degrees C were recorded. Prior to chronic treatment, spiradoline, U50,488 and (-)-pentazocine produced dose-dependent increases in tail-withdrawal latencies at both 50 and 55 degrees C. Chronic treatment with 3.0 mg/kg naltrexone twice daily (b.i.d.) failed to alter sensitivity to the antinociceptive effects of spiradoline when tested 24 h following naltrexone administration. When the maintenance dose of naltrexone was increased to 30 mg/kg b.i.d., sensitivity to the effects of spiradoline was reduced when tested 24 h after naltrexone administration, but enhanced when tested 48 h after naltrexone administration. Enhanced sensitivity was also observed to the antinociceptive effects of U50,488 and (-)-pentazocine when tested 48 h after chronic treatment with 30 mg/kg naltrexone. After termination of chronic treatment, sensitivity to the antinociceptive effects of spiradoline, U50,488 and (-)-pentazocine returned to that originally observed prior to naltrexone treatment. These data indicate that chronic naltrexone treatment enhances sensitivity to the antinociceptive effects of kappa opioids, and that this effect is both dose and time dependent.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Cerebral perfusion in infants and neonates: preliminary results obtained using dynamic susceptibility contrast enhanced magnetic resonance imaging.
BACKGROUND: Previous studies have used the dynamic susceptibility contrast enhanced (DSCE) magnetic resonance (MR) imaging technique to measure cerebral perfusion in adults. OBJECTIVE: To assess the feasibility of the technique in a heterogeneous cohort of sick human infants and identify cerebral perfusion abnormalities. METHODS: Perfusion measurements were made by characterising the changing concentration of an injected bolus of contrast agent using a series of MR images acquired during the first pass of the contrast bolus. Qualitative values of relative cerebral blood flow (rCBF) were then calculated from these data on a pixel by pixel basis to generate parametric maps of perfusion. RESULTS: Images of perfusion were successfully calculated from 12 out of 27 neonates and infants, all with established cerebral pathology. Normal vascular anatomical structures such as the circle of Willis were identified within all calculated images. Values of rCBF were generally larger in grey matter than in white matter. In several patients, perfusion abnormalities resulted in structural abnormalities which were detected in conventional MR imaging at follow up. The acquisition of perfusion data was most difficult when the least mature brains were examined because of motion artefacts and a smaller head size with a lower level of rCBF than adults. CONCLUSIONS: This preliminary study shows that: (a) maps of rCBF can be acquired from neonates and infants; (b) characterisation of the bolus passage becomes progressively easier as the brain matures; (c) early abnormalities in cerebral perfusion may have negative prognostic implications; (d) the main difficulty when using the DSCE technique to study neonates relates to image artefacts resulting from bulk head motion.
Brain↗
An investigation of the MEK/ERK inhibitor U0126 in acute myeloid leukemia.
Blockade of mitogen-activated protein kinase kinase (MEK1/2), part of the extracellular signal-regulated kinase (ERK) or p44/42 mitogen-activated protein kinase (MAPK) pathway, has been shown in some instances to cause apoptosis in leukemic blast cells. This investigation examined the effect of the potent MEK/ERK inhibitor U0126 on apoptosis in acute myeloblastic leukemia (AML) cell lines, and acute leukemic and non-leukemic patient samples. The pro-apoptotic effect of the inhibitor varied across the five cell lines tested (KG1a, HEL, TF-1, MO7e, and THP-1) from highly significant induction of apoptosis to no apparent response. The pro-apoptotic effect of U0126 in the most sensitive cell line, KG1a, appeared to be related to its CD34 positivity. Three of five leukemic bone marrow samples showed considerable sensitivity to the inhibitor and a similar association with CD34 expression was evident. Interestingly, control marrow cells from six non-leukemic patients did not show a significant effect when exposed to U0126. These results suggest that this agent may offer a potential alternative to standard chemotherapy with a particular role in the most primitive types of leukemia, these often being the most resistant to standard chemotherapy.
Butadienes↗
X-ray contrast media induce aortic endothelial damage, which can be prevented with prior heparin treatment.
X-ray contrast media induce damage to the endothelial layer of vessels and initiate the formation of thrombosis, which is a complication for clinical diagnostic procedures. The future determination of the mechanisms, which underlie the damaging effect of X-ray contrast medium on vascular wall cells, especially vascular endothelium and possible prevention of this damage by vasoprotector, will result in a larger application in diagnostic procedures. The aim of the present study is to analyze the effect of X-ray contrast media (Verographin, Iodamid and Iodolipol) on the arterial endothelium morphology by using ultrastructural techniques (scanning and transmission electron microscopy, SEM and TEM respectively). Experiments have been carried out on New Zealand white rabbits (6 month old) and Wistar rats (6-8 month old) after a single injection of X-ray contrast media with and without prior heparin treatment. Control groups of animals were exposed to the same procedure but without X-ray contrast media injection and only received isotonic saline solution. The following time points were selected: 1, 6, 24, 72 h and 7 days. At the end of the experiments, animals were anesthetized by pentobarbital and then perfused with a balanced buffer for 1 min and followed by perfusion fixation with Karnovsky's fixative containing buffered solution of 2.5% paraformaldehyde and 2.5% glutaraldehyde (pH 7.36) at least 30 min. The aortic tissue was removed and immediately placed into a fresh portion of the same fixative. Aortic samples were then prepared for scanning and transmission electron microscopy (SEM and TEM respectively). Immediately after the injection of X-ray contrast media, the number of microvilli and blebs on the luminal surface of the endothelial cells (EC) significantly increased. Very often, nuclear portions of the EC sharply protruded into the vessel lumen. Clusters of spindle-shaped EC were seen throughout the endothelial monolayer. These changes persist through the 72-h period after X-ray contrast media injection. Moreover, the desquamation and denudation of the EC from the monolayer is often observed and this is accompanied by the presence of a microthrombus on the vessel surface. Seven days after the post-injection period, endothelial monolayers still show severe damage, which often coexists with the presence of a different sized microthrombus on the vessel surface. However, the degree of lesion formation in most areas is substantially decreased as compared to the early period of post-injection (24 and 72 h). Heparin treated group shows intact morphology similar to the control experimental groups (saline injected group). Infrequently, minimal morphological changes of the endothelium, such as increased number of microblebs and microvilli, were seen with heparin treatment. We conclude that the negative side effects of the X-ray contrast media can be eliminated by a single injection of heparin or other vasoprotector prior to the diagnostic procedure.
Animals↗
Evaluation of image quality in terahertz pulsed imaging using test objects.
As with other imaging modalities, the performance of terahertz (THz) imaging systems is limited by factors of spatial resolution, contrast and noise. The purpose of this paper is to introduce test objects and image analysis methods to evaluate and compare THz image quality in a quantitative and objective way, so that alternative terahertz imaging system configurations and acquisition techniques can be compared, and the range of image parameters can be assessed. Two test objects were designed and manufactured, one to determine the modulation transfer functions (MTF) and the other to derive image signal to noise ratio (SNR) at a range of contrasts. As expected the higher THz frequencies had larger MTFs, and better spatial resolution as determined by the spatial frequency at which the MTF dropped below the 20% threshold. Image SNR was compared for time domain and frequency domain image parameters and time delay based images consistently demonstrated higher SNR than intensity based parameters such as relative transmittance because the latter are more strongly affected by the sources of noise in the THz system such as laser fluctuations and detector shot noise.
Diagnostic Imaging↗
A systematic review of the precision and accuracy of dose measurements in photon radiotherapy using polymer and Fricke MRI gel dosimetry.
The purpose of this work is to undertake a critical appraisal of the evidence in the published literature concerning the basic parameters of accuracy and precision associated with the use of Fricke and polymer gels (in conjunction with MR imaging) as radiation dosimeters in photon radiotherapy, condensing and analysing the body of published information (to the end of April 2002). A systematic review was undertaken addressing specific issues of precision and accuracy asking defined questions of the published literature. Accuracy and precision in relation to gel dosimetry were defined. Information was obtained from published, peer-reviewed journals. A defined search strategy utilizing MeSH headings and keywords, with extensive use of cross-referencing, identified 115 references dealing with gel dosimetry. Exclusion criteria were used to select only data from publications which would give unequivocal evidence. For accuracy, results had to be compared with an ionization chamber as gold standard and all gel samples had to be manufactured in the same batch. For precision, in addition to gels being from the same batch, samples must all have been irradiated at the same time and scanned simultaneously (or within a short time frame). Many results were found demonstrating 'dose mapping' examples using gels. However, there were very few publications containing firm evidence of precision and accuracy. There was no evidence which fulfilled our criteria about accuracy or precision using Fricke gels. For polymer gels only one paper was found for accuracy (4% (Low et al 1999 Med. Phys. 26 1542-51)) and precision (1.7% (Baldock et al 1998 Phys. Med. Biol. 43695-702)); however, both were carried out at only one dose level. If the exclusion criteria were relaxed to include accuracy results comparing gel to a non gold standard dosimeter (e.g. TLD), results give a median accuracy of 10% (range 8-23.5%) for polymer gel (Cosgrove et al 2000 Phys. Med. Biol. 45 1195-210, De Deene et al 1998 Radiother: Oncol. 48 283-91, Farajollahi et al 2000 Br. J. Radiol. 72 1085-92, McJury et al 1999b Phys. Med. Biol. 44 2431-44, Murphy et al 2000b Phys. Med. Biol. 45 835-45, Oldham et al 2001 Med. Phys. 28 1436-45) and 5% for Fricke gel (Chan and Ayyangar 1995b Med. Phys. 22 1171-5). Evidence also points to accuracy worsening at lower dose levels for both gels. The precision data should be viewed with caution as repeated MR measurements were not performed with the same samples. The only precision data for Fricke gels was 1.5% (Johansson Back et al 1998 Phys. Med. Biol. 43 261-76), but for zero dose. In conclusion, despite the amount of published data, sparse research has been undertaken which provides clear evidence of the accuracy and precision for both gels. That which has been published has used higher doses than would be routine in radiotherapy. The basic radiation dosimeter qualities of accuracy and precision have yet to be fully quantified for polymer and Fricke gels at clinically relevant dose levels.
Ferrous Compounds↗
An introduction to medical imaging with coherent terahertz frequency radiation.
Methods have recently been developed that make use of electromagnetic radiation at terahertz (THz) frequencies, the region of the spectrum between millimetre wavelengths and the infrared, for imaging purposes. Radiation at these wavelengths is non-ionizing and subject to far less Rayleigh scatter than visible or infrared wavelengths, making it suitable for medical applications. This paper introduces THz pulsed imaging and discusses its potential for in vivo medical applications in comparison with existing modalities.
Alginates↗
Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy.
BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by a pure neurofibrillary tau pathology involving mainly basal ganglia and brainstem nuclei. In addition to a haplotype of the tau gene potentially favoring tau aggregation, lipoperoxidation has been shown to be associated with PSP tau pathology. OBJECTIVE: To analyze cdk5/p35 complex, a kinase that regulates neurite outgrowth, as a potential cellular mechanism underlying tau phosphorylation in brain tissues from PSP and control cases and comparatively in cerebral cortex from subjects with AD. METHODS: Cdk5/p35 protein levels and distribution were evaluated by immunoblotting and immunocytochemistry in brain regions from seven PSP, six AD, and seven control cases, with similar postmortem intervals. RESULTS: Total cdk5 protein levels were significantly increased by more than threefold in PSP tissue and were augmented in PSP neurons, codistributed with tau immunoreactivity. P35, the regulatory subunit of cdk5, was degraded by postmortem proteolysis to the same extent in PSP, AD, and control tissues. CONCLUSIONS: The proteolysis in vivo of p35, the regulatory subunit of the kinase, is not ascertainable because it is masked by its postmortem degradation. The study, however, indicates that in PSP, the alteration of cdk5 is different from that described in AD and suggests that the absence of amyloid beta protein deposition may account for the different pathways responsible for the same kinase activation.
Aged↗
Reactive oxygen: its sources and significance in Alzheimer disease.
Over the past decade, oxidative stress has been established as the earliest cytological feature of Alzheimer disease and an attractive therapeutic target. The major challenges now are establishing the source of the reactive oxygen and what oxidative stress tells us about the etiology of Alzheimer disease. These are complex issues since a variety of enzymatic and non-enzymatic processes are involved in reactive oxygen formation and damage to macromolecules. In this review, we consider disease mechanisms that show the greatest promise for future research.
Aged↗
The mitochondrial common deletion in Parkinson's disease and related movement disorders.
The mitochondrial 4977-bp common deletion has been reported in some studies to occur exclusively or with increased frequency in the midbrain of patients with Parkinson's disease (PD). Other studies could not confirm these results; rather, it was suggested that the mitochondrial common deletion is associated with aging in the midbrain and not PD. One possible explanation for these conflicting results is the difficulty in quantifying mitochondrial DNA deletions or mutations in the whole midbrain or substantia nigra (SN) while only a subset of midbrain neurons degenerate in PD. In addition, none of the studies has addressed the cell types with the common deletion within the midbrain. In this study we used in situ hybridization to detect the common deletion in sections of midbrain from patients with PD, multiple system atrophy-parkinsonian type (MSA-P), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), age-matched controls, and individuals of different ages. The results demonstrated that the mitochondrial common deletion accumulated primarily in neurons but not glia in both the SN and other midbrain regions. There was no significant difference in the number or distribution of neurons with the common deletion or the average of the mean densities (AMD) of staining with the common deletion in nigral neurons among patients with PD, MSA-P, PSP, DLB, or age-matched controls. In addition, there was no difference in the number or distribution of neurons with the common deletion in nigral neurons between any age group, although there was a tendency for the common deletion to increase in the non-nigral neurons in older patients. These data indicate that accumulation of the 4977-bp common deletion in mitochondrial DNA in midbrain occurred primarily in neurons, and by this cytological approach, it was not associated with nigral neurodegeneration in the common movement disorders or aging.
Adolescent↗
Role of the antioxidant ascorbate in hibernation and warming from hibernation.
Ground squirrels tolerate up to 90% reductions in cerebral blood flow during hibernation as well as rapid reperfusion upon periodic arousal from torpor without apparent neurological damage. Thus, hibernation is studied as a model of tolerance to cerebral ischemia and other types of brain injury. Metabolic suppression likely plays a primary adaptive role that allows hibernating species to tolerate dramatic fluctuations in blood flow. Several other aspects of hibernation physiology are also consistent with tolerance to ischemia and reperfusion suggesting that multiple neuroprotective adaptations may work in concert during hibernation. The purpose of the present work is to review evidence for enhanced antioxidant defense systems during hibernation, with a focus on ascorbate, and discuss potential roles of these antioxidants during hibernation. In concert with dramatic decreases in blood flow, nutrient and oxygen delivery, plasma concentrations of the antioxidant ascorbate [(Asc)p] increase 3-5-fold during hibernation. In contrast, during re-warming, [Asc]p declines at a relatively rapid rate that peaks at the time of maximal O(2) consumption. This peak in O(2) consumption also coincides with a brief rise in plasma urate concentration consistent with a surge in reactive oxygen species production. Overall, data suggest that elevated concentration of plasma ascorbate is poised for distribution to metabolically active tissues during the surge in oxidative metabolism that accompanies re-warming during hibernation. This pool of ascorbate, as well as increased expression of other antioxidant defense systems, may protect vulnerable tissues from oxidative stress during hibernation and re-warming from hibernation. Better understanding of the role of ascorbate in hibernation may guide use of ascorbate and other antioxidants in treatment of stroke, head trauma and neurodegenerative disease.
Animals↗
Clinical experience with the use of rhG-CSF in secondary autoimmune neutropenia.
This paper outlines the impact of granulocyte-colony stimulating factor (G-CSF) used as a single modality therapy in 17 patients with secondary autoimmune neutropenia (S-AIN) who had been treated a multiple number of times previously. Fifteen of these patients had demonstrable antineutrophil antibodies and two had cellular S-AIN with haemopoietic inhibitory T-cells present in the marrow. Prior to treatment, all had had problems with infection. All patients responded within 7 days of commencement of treatment. Provided G-CSF neutrophil counts were maintained above 1 x 109/l, no further infections occurred. This was achievable by using G-CSF administered as infrequently as once every 8 days. Eight of the 17 patients remained on G-CSF, although five switched to the glycosylated form because of side-effects. None have developed osteoporosis despite 47.29 patient years of total experience with G-CSF. In conclusion both glycosylated and nonglycosylated G-CSF can be used effectively in treating AIN on a long-term basis.
Adolescent↗
Possible involvement of ER chaperone Grp78 on reduced formation of amyloid-beta deposits.
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Alzheimer Disease↗
Possible protective mechanisms of heme oxygenase-1 in the brain.
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Alzheimer Disease↗
Functional imaging and the orthopaedic surgeon.
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Acute Disease↗