Imaging microvascular structure with contrast enhanced MRI.
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Contrast Media↗
Biomedical subjects
A Jackson
Publications and source records attributed to A Jackson.
Simultaneous mapping of blood volume and endothelial permeability surface area product in gliomas using iterative analysis of first-pass dynamic contrast enhanced MRI data.
We describe a novel method for the calculation of endothelial permeability surface area product from dynamic contrast enhanced MRI. The technique uses iterative estimation to automatically decompose tissue residue function into intravascular and extravascular components, which are subsequently used to generate tumour blood volume, which is equal to relative cerebral blood volume calculated from T(1) weighted images and corrected for contamination by contrast agent leakage (rCBV(T1)(corrected), and endothelial permeability (k(fp)) maps. The technique was assessed in patients with cerebral glioma (n=5) by examining the reproducibility of endothelial permeability and rCBV(T1)(corrected) between two separate examinations conducted with a 2-day interval. The technique produces maps of endothelial permeability that appear to be free of any contribution from intravascular contrast agent. Maps of rCBV(T1)(corrected) show close correlation with maps of blood volume calculated from independently acquired dynamic susceptibility weighted MRI examinations, with no evidence of residual permeability effects. The results were highly reproducible with strong intra-class correlation between the two examinations for mean values and for 97.5 percentiles of endothelial permeability and rCBV(T1)(corrected). The excellent reproducibility of this technique and the ability to calculate endothelial permeability and rCBV(T1)(corrected) values from rapidly acquired data sets offer considerable advantages over conventional approaches and support the use of this methodology for therapeutic monitoring or trials of novel therapeutic agents.
Aged↗
Reproducibility of quantitative dynamic contrast-enhanced MRI in newly presenting glioma.
We have investigated the reproducibility of dynamic contrast enhanced imaging techniques in nine patients with cerebral glioma. Patients were imaged twice with a 2 day interval between scans. Maps were produced of the time taken to achieve 90% enhancement (T90), the maximal intensity change per time interval ratio (MITR), the volume transfer coefficient between plasma and the extravascular extracellular space (K(trans)) and the extravascular extracellular contrast distribution volume, v(e). Measurements of K(trans) greater than 1.2 min(-1) were used to exclude pixels where first pass perfusion effects dominated the measurement. Measures of the test-retest coefficient of variation (CoV) and intraclass correlation coefficients were used to assess reproducibility for measurements from a volume of interest containing enhancing tissue from the whole tumour. MITR showed poor reproducibility (mean CoV 17.9%, 95% confidence limits for group comparisons 20.2%). T90 showed good reproducibility (mean CoV 7.1%, 95% confidence limits for group comparisons 5.2%). Calculated values of K(trans) and v(e) also showed good reproducibility (mean CoV 7.7% and 6.2% respectively, 95% confidence limits for group comparisons 6.2% and 4.8%, respectively). We conclude that the measurements of K(trans) and v(e) derived from pharmacokinetic analysis are sufficiently reproducible to support their use as a biological markers in therapeutic trials.
Aged↗
Rhythm generation in monkey motor cortex explored using pyramidal tract stimulation.
We investigated whether stimulation of the pyramidal tract (PT) could reset the phase of 15-30 Hz beta oscillations observed in the macaque motor cortex. We recorded local field potentials (LFPs) and multiple single-unit activity from two conscious macaque monkeys performing a precision grip task. EMG activity was also recorded from the second animal. Single PT stimuli were delivered during the hold period of the task, when oscillations in the LFP were most prominent. Stimulus-triggered averaging of the LFP showed a phase-locked oscillatory response to PT stimulation. Frequency domain analysis revealed two components within the response: a 15-30 Hz component, which represented resetting of on-going beta rhythms, and a lower frequency 10 Hz response. Only the higher frequency could be observed in the EMG activity, at stronger stimulus intensities than were required for resetting the cortical rhythm. Stimulation of the PT during movement elicited a greatly reduced oscillatory response. Analysis of single-unit discharge confirmed that PT stimulation was capable of resetting periodic activity in motor cortex. The firing patterns of pyramidal tract neurones (PTNs) and unidentified neurones exhibited successive cycles of suppression and facilitation, time locked to the stimulus. We conclude that PTN activity directly influences the generation of the 15-30 Hz rhythm. These PTNs facilitate EMG activity in upper limb muscles, contributing to corticomuscular coherence at this same frequency. Since the earliest oscillatory effect observed following stimulation was a suppression of firing, we speculate that inhibitory feedback may be the key mechanism generating such oscillations in the motor cortex.
Algorithms↗
Breath-hold perfusion and permeability mapping of hepatic malignancies using magnetic resonance imaging and a first-pass leakage profile model.
We have applied a novel pharmacokinetic model of the distribution of contrast media to dynamic contrast-enhanced MRI data from patients with hepatic neoplasms. The model uses data collected during the passage of a bolus of contrast medium and allows breath-hold image acquisition. The aims of the study were to investigate the feasibility of permeability mapping using the first pass technique and breath-hold acquisitions, and to examine the reproducibility of the technique and the effect of the liver's dual vascular supply on the assumptions of the model. Imaging was performed in 14 patients with hepatic neoplasms. Dynamic data clearly demonstrated differences in the timing and shape of the contrast medium concentration-time course curve in the systemic arterial and portal venous systems. Mapping of the arrival time (T(0)) of contrast medium allowed identification of tissue supplied by the hepatic arteries and portal vein. Hepatic tumours all showed typical hepatic arterial enhancement. Repeated measurements of endothelial permeability surface area product (k(fp)) and relative blood volume (rBV), performed in five patients, showed excellent reproducibility with variance ratios (V(r)) of 0.134 and 0.113, respectively. Measurement of enhancing tumour volume was also highly reproducible (V(r) = 0.096) and this was further improved by the use of T(0) maps to identify pixels supplied by the hepatic artery (V(r) = 0.026). Estimates of k(fp) and rBV in normal hepatic tissue supplied by the portal vein were highly inaccurate and these pixels were identified by use of the T(0) parameter and excluded from the analysis. In conclusion, dynamic MRI contrast enhancement combined with a pharmacokinetic model of the distribution of contrast media in the first pass allows us to produce highly reproducible parametric maps of k(fp) and rBV from hepatic tumours that are supplied by the hepatic arterial system using breath-hold acquisitions.
Adenocarcinoma↗
Behavior of osteoblast, adipocyte, and myoblast markers in genome-wide expression analysis of mouse calvaria primary osteoblasts in vitro.
Several genes, such as alkaline phosphatase, osteocalcin, and Cbfa1/Osf2, are known to be regulated during osteoblastic differentiation and are commonly used as "osteoblast markers" for in vitro or in vivo studies. The number of these genes is very limited, however, and it is of major interest to identify new genes that are activated or repressed during the process of osteoblast differentiation and bone formation as well as to extend the available information on gene families relevant to this particular differentiation pathway. To identify such genes, we have implemented a genome-wide analysis by determining changes in expression levels of 27,000 genes during in vitro differentiation of primary osteoblasts isolated from mouse calvaria. This study focuses on the description of the analytical and filtering process applied; on the transcriptional analysis of well-established "bone," "adipocyte," and "muscle" pathway markers; and on a description of the regulation profiles for genes recently described in the Skeletal Gene Database. We also demonstrate that new array technologies constitute reliable and powerful tools to monitor the transcription of genes involved in osteoblastic differentiation, allowing a more integrated vision of the biological pathways regulated during osteoblast commitment, differentiation, and function.
Adipocytes↗
Diagnostic value of high signal abnormalities on T2 weighted MRI in the differentiation of Alzheimer's, frontotemporal and vascular dementias.
OBJECTIVE: The occurrence of high signal abnormalities on T2 weighted images is strongly age related. The diagnostic value of these changes in a younger population with dementia is not currently known. We studied the potential of high signal changes on magnetic resonance imaging (MRI) in differentiating Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) in younger patients. METHODS: High signal abnormalities were rated, using a previously validated scale, from hard copies of T2 weighted axial images of 102 patients with AD (n=49), VaD (n=31), FTD (n=22) (mean ages 63-65 years). RESULTS: High signal abnormalities were widespread across AD, VaD and FTD. Although they were most frequent and most severe in the VaD group only lacunes and grade III deep white matter hyperintensities (DWMH) were specific for these patients. CONCLUSIONS: High signal changes on T2 weighted images on MRI are common across degenerative (AD and FTD) and vascular dementias. Although lacunes and grade III DWMH are specific for VaD, the low sensitivities (sensitivities: for lacunes, 0.32; for grade III DWMH, 0.16) limit their use as diagnostic markers for VaD. High signal changes on MRI should be interpreted with caution in dementias. Their presence, even in younger patients, should not deter one from diagnosing AD or FTD.
Aged↗
Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease, frontotemporal dementia and vascular dementia.
OBJECTIVES: Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) are the three most common causes of young onset dementias. Most neuroimaging studies of these disorders have involved comparisons with normal controls. The aims of this study were to examine the clinical diagnostic value of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) (in combination and in isolation) in the differentiation of one form of dementia from another from amongst a group of AD, FTD and VaD. METHODS: T1 weighted MRI images and 99mTc-HMPAO SPECT images were obtained from consecutive patients with FTD (n=21), AD (n=23) and VaD (n=20) and rated visually by experienced neuroradiologists and nuclear medicine physicians. RESULTS: Asymmetrical atrophy was seen only in FTD. Frontotemporal dementia patients were the most atrophic whereas severe atrophy was rarely observed in VaD. Severe frontal atrophy (unilaterally or bilaterally) and/or asymmetrical atrophy on MRI is highly diagnostic (sensitivity 0.71, specificity 0.93, LR 10.24) of FTD from within a group of FTD and non-FTD (AD, VaD) patients. Mild or severe parietal atrophy with severe reduction in parietal regional cerebral blood flow on SPECT is diagnostic (sensitivity 0.71, specificity 0.76, LR 3.02) of AD from within a group of AD and non-AD (VaD, FTD) patients. CONCLUSION: Anatomical (MRI) and functional (SPECT) imaging provide different information and a combination of these modalities improves diagnostic specificity.
Aged↗
Child care decisions: parental choice or chance?
AIM: A study of the context of child care decision making by inner city and suburban mothers, using parents to help develop and administer a semi-structured questionnaire. METHODS: A total of 131 mothers were interviewed (73 inner city and 58 suburban) at home. RESULTS: Inner city mothers were more likely to bottle feed, smoke and adopt risky infant sleeping positions, for example the settee. Virtually all babies (98%) were fully vaccinated and placed prone (95%) to sleep at night. Inner city mothers smoked (71%) despite the known health risks and continued postnatally (55%), mainly as a means of relieving stress. In total, 30% of inner city mothers wanted to breast feed; 19% had succeeded to 6-8 weeks postnatally. Bottle feeding helped both mother and baby to have uninterrupted nights of sleep. Suburban mothers (59%) succeeded in breast feeding, with others choosing bottle feeding mostly because of returning to work. The average weekly alcohol consumption, 32 units inner city and 15 units suburban, was taken in weekend binges by inner city parents, but in daily small amounts by suburban mothers. CONCLUSIONS: The well-being of the baby was the prime concern of all mothers, irrespective of social background. However, inner city mothers made rational decisions to smoke and bottle feed to reduce the impact of stress and allow the mother much needed respite for the good of the entire family.
Adult↗
Predictors of outcome of mammography in the National Health Service Breast Screening Programme.
BACKGROUND: Little is known about the factors influencing the risk of recall for assessment, invasive diagnostic procedures, and early rescreening after screening mammography. METHODS: From June 1996 to March 1998 women attending screening at 10 National Health Service Breast Screening Programme (NHSBSP) centres completed a self administered questionnaire and were followed up for their screening outcome. RESULTS: 1969 (3.3%) out of 60 443 women aged 50-64 who had never used hormone replacement therapy (HRT) were recalled for assessment but were not diagnosed with breast cancer (defined here as false positive recall). After adjustment for the variation between centres, false positive recall was decreased significantly among women who were likely to have had a previous NHSBSP mammogram (odds ratio (OR) 0.49, 95% confidence interval (95% CI) 0.38 to 0.63 for likely versus unlikely), who were postmenopausal (OR 0.65, 95% CI 0.56 to 0.76 for postmenopausal v premenopausal) and increased significantly for women reporting previous breast surgery (OR 1.64, 95% CI 1.42 to 1.89). Although false positive recall decreased significantly with parity and increasing body mass index, these effects were not large and no significant variation was found with age, education, family history of breast cancer, oral contraceptive use, sterilisation, exercise, smoking, or alcohol consumption. Altogether 655 (1.1%) women had an invasive diagnostic procedure; no personal characteristics were predictive of this outcome, 286(0.5%) were referred for early rescreening, and this was increased significantly by nulliparity and a family history of breast cancer. INTERPRETATION: Premenopausal women, those without a previous NHSBSP mammogram, and women with previous breast surgery have an increased risk of false positive recall by the NHSBSP.
Age Factors↗
Human microdialysis.
Microdialysis has been used extensively in animal studies for decades and in human pharmacokinetic studies for about 10 years. Microdialysis is based on the passive diffusion of a compound along its concentration gradient from the tissue through the membrane into the dialysate. Microdialysis samples from the interstitial space which is a defined, anatomical compartment; there is no net loss of body fluid; the sample is "purified" and no enzymatic degradation takes place because proteins do not pass through the probe membrane into the dialysate; microdialysis data relate to the intact molecule; time resolution is high compared to biopsy and skin blister techniques; radioabelling or induction of a magnetic response is not needed; microdialysis is also an alternative method to determine protein binding of a compound in vivo; microdialysis can readily be set up in clinical research units without expensive infrastructure. Microdialysis has been used to measure tissue concentrations of endogenous compounds and to investigate the tissue penetration of drugs in a variety of tissues in humans in vivo in both healthy volunteers and patients. Microdialysis data have also been used in PK-PD modelling and to obtain concentration-response relationships locally in tissues in vivo. There are also studies combining microdialysis with imaging techniques, e.g. PET. Microdialysis data may be used in early studies to select the appropriate compound, to optimise dosing regimens and to investigate the kinetic and dynamic consequences in the tissues of drug-drug and drug-disease interactions. Microdialysis can also be used in late phase studies to provide tissue concentration data in support of therapeutic efficacy trials or to create a niche for an already marketed drug. FDA and CPMP documents emphasise the value and importance of human tissue drug concentration data and support the use of microdialysis in humans to obtain such information. Microdialysis can satisfy regulatory requirements by providing data on drug concentrations in a well-defined anatomical tissue compartment at or close to the effect target site. Microdialysis is a versatile technique because of its multifaceted utility, low cost, ease of use, adaptability to different types of compounds and its feasibility for a number of organs and tissues. Equipment and probes for use in various organs have been commercially available for years.
Animals↗
The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.
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Carotid Stenosis↗
Inhibition of lordosis behavior by intrahypothalamic infusion of a protein kinase G antagonist.
Previous experiments demonstrated that intracerebroventricular infusion of the protein kinase G inhibitor KT5823 inhibits lordosis behavior in hormone-treated female rats. Present studies show that KT5823 attenuates lordosis in a dose-dependent manner when infused bilaterally into the ventromedial hypothalamus. Thus, activation of protein kinase G in the ventromedial hypothalamus is necessary for the expression of hormone-dependent lordosis behavior in female rats.
Alkaloids↗
Fitting tumor control probability models to biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer: pitfalls in deducing radiobiologic parameters for tumors from clinical data.
PURPOSE: The goal of tumor control probability (TCP) models is to predict local control for inhomogeneous dose distributions. All existing fits of TCP models to clinical data have utilized summaries of dose distributions (e.g., prescription dose). Ideally, model fits should be based on dose distributions in the tumor, but usually only dose-volume histograms (DVH) of the planning target volume (PTV) are available. We fit TCP models to biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer using either a dose distribution summary or the full DVH in the PTV. We discuss differences in the radiobiologic parameters and dose-response curves and demonstrate pitfalls in interpreting the results. METHODS AND MATERIAL: Two mechanistic TCP models were fit with a maximum likelihood technique to biopsy outcome from 103 prostate patients treated at Memorial Sloan-Kettering Cancer Center. Fits were performed separately for different patient subgroups defined by tumor-related prognostic factors. Fits were based both on full DVHs, denoted TCP(DVH(calc)), and, alternatively, assuming a homogeneous PTV dose given by the mean dose (Dmean) of each DVH, denoted TCP(Dmean(calc)). Dose distributions for these patients were very homogeneous with any cold spots located on the periphery of the PTV. These cold spots were uncorrelated with biopsy outcome, likely because the low-dose regions may not contain tumor cells. Therefore, fits of TCP models that are potentially sensitive to cold spots (e.g., TCP(DVH(calc))) likely give biologic parameters that diminish this sensitivity. In light of this, we examined differences in fitted clonogenic cell number, N(C), or density, rho(C), surviving fraction after 2 Gy, SF(2), or radiosensitivity, alpha, and their standard deviations in the population, sigma(SF(2)) and sigma(alpha), resulting from fits based on TCP(DVH(calc)) and TCP(Dmean(calc)). Dose-response curves for homogeneous irradiation (characterized by TCD(50), the dose for a TCP of 50%) and differences in TCP predictions calculated from the DVH using alternatively derived parameters were evaluated. RESULTS: Fits of TCP(Dmean(calc)) are better (i.e., have larger likelihood) than fits of TCP(DVH(calc)). For TCP(Dmean(calc)) fits, matching values of SF(2) and sigma(SF(2)) (or alpha and sigma(alpha)) exist for all N(C) (rho(C)) above a threshold that give fits of equal quality, with no maximum in likelihood. In contrast, TCP(DVH(calc)) fits have maximum likelihood for high SF(2) (low alpha) values that minimize effects of cold spots. Consequently, small N(C) (rho(C)) values are obtained to match the observed control rate. For example, for patients in low-, intermediate-, and high-risk groups, optimum values of SF(2) and N(C) are 0.771 and 3.3 x 10(3), 0.736 and 2.2 x 10(4), and 0.776 and 1.0 x 10(4), respectively. The TCD(50) of dose-response curves for intermediate-risk patients is 2.6 Gy lower using TCP(DVH(calc)) parameters (TCD(50) = 67.8 Gy) than for TCP(Dmean(calc)) parameters (TCD(50) = 70.4 Gy). TCP predictions calculated from the DVH using risk group-dependent TCP(Dmean(calc)) parameters are up to 53% lower than corresponding calculations with TCP(DVH(calc)) parameters. CONCLUSION: For our data, TCP parameters derived from DVHs likely do not reflect true radiobiologic parameters in the tumor, but are a consequence of the reduced importance of low-dose regions at the periphery of the PTV. Deriving radiobiologic parameters from TCP(Dmean(calc)) fits is not possible unless one parameter is already known. TCP predictions using TCP(DVH(calc)) and TCP(Dmean(calc)) parameters may differ substantially, requiring consistency in the derivation and application of model parameters. The proper derivation of radiobiologic parameters from clinical data requires both substantial dose inhomogeneities and understanding of how these coincide with tumor location.
Adenocarcinoma↗
Temporal and spatial profiling of the modification of an electroactive polymeric interface using neutron reflectivity.
Electropolymerized films of the functionalized pyrrole, pentafluorophenyl-3-(pyrrol-1-yl)propionate (PFP), were reacted with a solution-phase nucleophile, ferrocene ethylamine. This reaction was chosen as a model representative of a postdeposition modification of the polymer membrane's properties. For the first time, a nondestructive method for direct chemical analysis of the reaction profile within the electrodeposited polymer membrane after nucleophilic substitution is presented. This was achieved through the application of in situ neutron reflectivity with supplementary analytical information concerning the film's chemical composition obtained from XPS, FT-IR, and electrochemical measurements. The results presented illustrate how, for a partially reacted film resulting from a short reaction time, the extent of reaction with ferrocene ethylamine is not homogeneous throughout the thickness of the film, but occurs predominantly at the polymer/solution interface. We show that the progress of the reaction within the polymer film is limited by the transport of reacting species in the dense regions of the membrane that are furthest from the solution interface. The data do not fit an alternative model in which there is spatially homogeneous progression of the reaction front throughout the bulk of the thin film polymer. Guided by the neutron reflectivity measurements, suitable modifications were made to the electrodeposition method to prepare films whose architecture resulted in faster rates of reaction.
Journal Article↗
Motor control: forcing neurons to change.
New research shows that the properties of cells in motor cortex change during learning of new tasks, shedding new light on the neural basis of motor adaptation.
Adaptation, Physiological↗
Estrogen-derived steroidal metal complexes: agents for cellular delivery of metal centers to estrogen receptor-positive cells.
Targeted cellular delivery of drugs to specific tissues is an important goal in biomedical chemistry. Achieving this requires harnessing and applying molecular-level recognition events prevalent in (or specific to) the desired tissue type. Tissues rich in estrogen receptors (ERs), which include many types of breast cancer, accumulate molecules that have high binding affinities for these receptors. Therefore, molecules that (i) bind to the ER, (ii) have favorable cellular transport properties, and (iii) contain a second functionality (such as a center that may be used for diagnostic imaging or medical therapy) are exciting synthetic targets in the field of drug delivery. To this end, we have prepared a range of metallo-estrogens based on 17alpha-ethynylestradiol and examined their binding to the ER both as isolated receptor and in whole cell assays (ER positive MCF-7 cells). Estrogens functionalized with metal binding units are prepared by palladium-catalyzed cross-coupling reactions and a wide range of metal centers introduced readily. All the compounds prepared and tested exhibit effective binding to the estrogen receptor and are delivered across the cell membrane into MCF-7 cells. In the whole cell assays, despite their monocationic nature, the palladium and platinum complexes prepared exhibit similar (and even enhanced) receptor binding affinities compared to their corresponding neutral free ligands. It is unprecedented for a higher ER binding affinity to be observed for a cationic complex than for its metal-free ligand.
Biological Transport↗
Ammonium extraction method for ion chromatographic measurements of disc drive components.
The analysis of ionic micro-contamination is of growing importance in the disc drive industry. Through the use of ion chromatography, cleanliness of drive components can be assessed. An objective to improve quantification of highly reactive inorganic ions that exist within the drive environment was implemented. This paper presents a new extraction technique used to determine low levels of ammonium, by microbore ion chromatography. Various chemical compounds within adhesive formulations can be a source of extractable ammonium. By combining this new extraction method with ion chromatography, the percentage of different chemical compounds within adhesive formulations was correlated to the level of extractable ammonium observed.
Chromatography, Liquid↗