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Biomedical subjects

H C Roberts

Publications and source records attributed to H C Roberts.

At least 19 recordsLinked to original sources
PubMed2001

Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT II trial.

OBJECTIVE: To analyze the frequency, clinical characteristics, and predictors of symptomatic intracerebral hemorrhage (ICH) after intraarterial (IA) thrombolysis with recombinant pro-urokinase (r-proUK) in acute ischemic stroke. METHOD: The authors conducted an exploratory analysis of symptomatic ICH from a randomized, controlled clinical trial of IA thrombolysis with r-proUK for patients with angiographically documented occlusion of the middle cerebral artery within 6 hours from stroke onset. Patients (n = 180) were randomized in a ratio of 2:1 to either 9 mg IA r-proUK over 120 minutes plus IV fixed-dose heparin or IV fixed-dose heparin alone. As opposed to intention to treat, this analysis was based on "treatment received" and includes 110 patients given r-proUK and 64 who did not receive any thrombolytic agent. The remaining six patients received out-of-protocol urokinase and were excluded from analysis. The authors analyzed centrally adjudicated ICH with associated neurologic deterioration (increase in NIH Stroke Scale [NIHSS] score of > or =4 points) within 36 hours of treatment initiation. RESULTS: Symptomatic ICH occurred in 12 of 110 patients (10.9%) treated with r-proUK and in two of 64 (3.1%) receiving heparin alone. ICH symptoms in r-proUK-treated patients occurred at a mean of 10.2 +/- 7.4 hours after the start of treatment. Mortality after symptomatic ICH was 83% (10/12 patients). Only blood glucose was significantly associated with symptomatic ICH in r-proUK-treated patients based on univariate analyses of 24 variables: patients with baseline glucose >200 mg/dL experienced a 36% risk of symptomatic ICH compared with 9% for those with < or =200 mg/dL (p = 0.022; relative risk, 4.2; 95% CI, 1.04 to 11.7). CONCLUSIONS: Symptomatic ICH after IA thrombolysis with r-proUK for acute ischemic stroke occurs early after treatment and has high mortality. The risk of symptomatic ICH may be increased in patients with a blood glucose >200 mg/dL at stroke onset.

Acute Disease↗
PubMed2001

Correlation of microvascular permeability derived from dynamic contrast-enhanced MR imaging with histologic grade and tumor labeling index: a study in human brain tumors.

RATIONALE AND OBJECTIVES: Dynamic contrast material-enhanced magnetic resonance (MR) imaging may be used to quantify fractional blood volume (fBV) and microvascular permeability in human brain tumors. Hypothesis is that these measurements correlate with tumor histologic grade and immunohistologically assessed mitotic activity. MATERIALS AND METHODS: Thirty-eight patients with newly diagnosed gliomas underwent MR imaging consisting of dynamic three-dimensional spoiled gradient-recalled acquisition in the steady state image sets following bolus injections of a single dose of gadodiamide. Signal intensity changes in blood and tissue were kinetically analyzed, yielding estimates of fBV and microvascular permeability (k). Tumor specimens were graded with the World Health Organization-II four-point grading score. MIB-1 immunohistochemical labeling (anti-Ki-67 monoclonal antibody) was performed in 22 patients to evaluate mitotic activity. RESULTS: Histologic study revealed nine grade 2, 14 grade 3, and 15 grade 4 tumors. fBV ranged from 0.4% to 24%, k from -0.4 to 31.4 mL/100 cm3 x min, and MIB-1 labeling indexes from 1.7% to 42.8%. Correlation to the tumor grade was highest for permeability (r = 0.73), followed by the MIB-1 index (r = 0.63), and fBV (r = 0.48). Correlation between k and MIB-1 index was strong (r = 0.84). There was no statistically significant difference between the fBV of any of the groups. Despite some overlap between the permeability values of specific tumors from different grades, differences were statistically significant. The MIB-1 index was significantly different between grades 3 and 4 but not between grades 2 and 3. CONCLUSION: Dynamic contrast-enhanced MR imaging allows noninvasive determination of tumor fBV and microvascular permeability k. k is more reliable than the MIB-1 labeling index for differentiating grade 2 from grade 3 tumors.

Brain↗
PubMed2000

Neuroimaging: do we really need new contrast agents for MRI?

The use of exogenous contrast media in magnetic resonance imaging of the brain has brought dramatic improvement in the sensitivity of detection and delineation of pathological structures, such as primary and metastatic brain tumors, inflammation and ischemia. Disruption of the blood brain barrier leads to accumulation of the intravenously injected contrast material in the extravascular space, leading to signal enhancement. Magnetic resonance angiography benefits from T(1)-shortening effects of contrast agent, improving small vessel depiction and providing vascular visualization even in situations of slow flow. High speed dynamic MRI after bolus injection of contrast media allows tracer kinetic modeling of cerebral perfusion. Progressive enhancement over serial post-contrast imaging allows modeling of vascular permeability and thus quantitative estimation of the severity of blood brain barrier disruption. With such an array of capabilities and ever improving technical abilities, it seems that the role of contrast agents in MR neuroimaging is established and the development of new agents may be superfluous. However, new agents are being developed with prolonged intravascular residence times, and with in-vivo binding of ever-increasing specificity. Intravascular, or blood pool, agents are likely to benefit magnetic resonance angiography of the carotid and cerebral vessels; future agents may allow the visualization of therapeutic drug delivery, the monitoring of, for example, gene expression, and the imaging evaluation of treatment efficacy. So while there is a substantial body of work that can be performed with currently available contrast agents, especially in conjunction with optimized image acquisition strategies, post processing, and mathematical analysis, there are still unrealized opportunities for novel contrast agent introduction, particularly those exploiting biological specificity. This article reviews the current use of contrast media in magnetic resonance neuroimaging, discusses some of the developing strategies for new applications of imaging with these agents and finally offers some views and indications for contrast agents currently under development, as well as some speculation on unsolved problems in neuroimaging, and opportunities for novel contrast agents.

Angiography↗
PubMed2000

Mode of action of cyclosporin A against Hymenolepis microstoma (Cestoda): relationship between cyclophilin binding and drug-induced damage.

Cyclosporin A (CsA) is a widely investigated experimental anti-parasitic drug whose mode of action remains unresolved. The immunosuppressive action of CsA depends on the drug binding to the intracellular receptor cyclophilin (CyP). This study investigates whether complexing of CsA with parasite CyP is equally essential for its anthelmintic action. The correlation between initial cyclosporin-induced damage in vitro and drug binding to parasite CyP has been examined. CsA and the analogues B-5-49, CsH and CsA-acetate all induced similar damage to the tapeworm Hymenolepis microstoma in vitro in incubations between 2 h and 4 days. The initial foci of drug damage were the parasite surface and mitochondria in the syncytium. In a competitive binding assay only B-5-49 displaced [H3]-CsA from either crude parasite cytosolic CyP or affinity-purified CyP while CsH and CsA-acetate had no effect. These data suggest strongly that cyclosporins act on the surfaces of helminth parasites but that drug action does not involve complex formation with CyP. An alternative drug-binding site must therefore be identified which may lead to the rational design of novel anthelminitic drugs.

Animals↗
PubMed2000

Dynamic CT perfusion to assess the effect of carotid revascularization in chronic cerebral ischemia.

We present the case of a female patient who was studied with dynamic contrast-enhanced CT perfusion before and after carotid revascularization. Before treatment, there was decreased perfusion in the ipsilateral insula, which was shown to be resolved on the scan obtained 1 day after treatment, indicating the technical success of the revascularization. In the ipsilateral basal ganglia, there was delayed contrast agent clearance from the tissue, which was attributed to vasodilation; after revascularization, there remained a subtle stenotic effect. The observed changes in the dynamic CT perfusion study suggest that this technique may be a useful tool in the evaluation of patients with asymmetrical cerebral blood flow.

Aged↗
PubMed2000

Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging may be used to quantify tissue fractional blood volume (fBV) and microvascular permeability. We tested this technique in patients with brain tumors to assess whether these measurements correlate with tumor histologic grade. METHODS: Twenty-two patients with newly diagnosed gliomas underwent MR imaging followed by surgery. Imaging consisted of one pre- and six dynamic postcontrast 3D spoiled gradient-recalled acquisition in the steady state data sets after administration of a single dose (0.1 mmol/kg) of contrast material. Signal intensity changes in blood and tissue were kinetically analyzed using a bidirectional two-compartment model, yielding estimates of fBV (mL/cm3) and microvascular permeability (mL/100 cm3 per minute). Stained tumor specimens were scored on a four-point scale (1 = low grade, 4 = high grade). RESULTS: Histologic examination revealed one grade 1, eight grade 2, seven grade 3, and six grade 4 tumors. fBV values ranged from 0.5% to 13.7%. Permeability values ranged from -0.4 to 18.8, with a strong correlation (r = 0.83) to tumor grade. Despite some overlap between the permeability values of specific tumors from different grades, differences in the mean were statistically significant. There was a weak correlation (r = 0.39) between estimated fBV and tumor grade, and no statistically significant difference among fBV values in any of the groups. CONCLUSION: This relatively simple method of analysis provides quantitative estimates of fBV and microvascular permeability in human brain tumors, with the permeability being predictive of pathologic grade. The technique can be easily implemented on clinical scanners and may prove useful in the assessment of tumor biology and in therapeutic trials.

Adult↗
PubMed2000

Quantification and reproducibility of tracking cortical extent of activation by use of functional MR imaging and magnetoencephalography.

BACKGROUND AND PURPOSE: Functional MR imaging and magnetoencephalography are commonly used to study normal cortical sensory and cognitive processing as well as a variety of disease states. The usefulness of these techniques is dependent on the reproducibility and sensitivity to change of derived measures of brain function. The purpose of this study was to compare the efficacy of functional MR imaging and magnetoencephalography as measures of the extent of cortical activity in response to a graded stimulus. METHODS: Five participants underwent functional MR imaging and magnetoencephalography involving stimulation of one, two, three, and four digits of the left hand. Measurements of activation were repeated three times per participant. The cortical extent of activation was assessed for functional MR imaging by observing the number of "activated" pixels and the "amount of activation": the product of the number of activated pixels and the mean signal change. Activation was quantified for magnetoencephalography as the magnitude of the evoked magnetic field peak and as the strength of the modeled current source, Q. RESULTS: For functional MR imaging, the number of activated pixels tended to increase with the increasing number of stimulated digits. High intra- and interparticipant variability (66% and 85% variation, respectively) did not, however, allow statistical resolution of this trend. The amount of activation was similarly variable (interparticipant, 89%). Magnetoencephalography was more robust regarding quantification. The evoked field amplitude varied linearly with the number of digits stimulated; intra- and interparticipant variability was 18% and 41%, respectively, permitting resolution of significant differences between any combination of stimulated digits, except two versus three (P < .05). CONCLUSION: Although functional MR imaging and magnetoencephalography show measurable evoked responses with somatosensory stimulation, in this study, functional MR imaging did not permit robust quantification of increasing cortical areas of activation.

Cerebral Cortex↗
PubMed1999

The size and fiber composition of the anterior commissure with respect to gender and schizophrenia.

BACKGROUND: In light of evidence for deviations in asymmetry and alterations in the anatomy of the corpus callosum in schizophrenia, this study examined the anterior commissure in post mortem brains (n = 14 female control patients, 15 male control patients, 11 female schizophrenic patients, 15 male schizophrenic patients). METHODS: Measures were made of the cross-sectional area of the anterior commissure in the midsagittal plane. In addition, the fiber density and fiber number were measured in a subset of cases (n = 10 female control subjects, 10 male control subjects, 8 female schizophrenic patients, 9 male schizophrenic patients), using the Palmgren silver stain and stereological methods. RESULTS: In control subjects, fiber numbers were greater (p = .024) in women than men. In schizophrenia, the cross-sectional area was unaffected, but for fiber density there was a significant gender x diagnosis interaction (p = .026), corresponding to a reduction in female, but not male patients with schizophrenia. CONCLUSIONS: The reduction in density of fibers in the anterior commissure is consistent with an alteration of interhemispheric connectivity in schizophrenia, but the restriction of the finding to women emphasizes the relevance of gender to understanding the nature of the hemispheric interaction.

Age Distribution↗
PubMed1999

MRI of acute myocardial ischemia: comparing a new contrast agent, Gd-DTPA-24-cascade-polymer, with Gd-DTPA.

A new macromolecular contrast agent, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)-24-cascade-polymer, was compared with Gd-DTPA for time-dependent delineation of acute myocardial ischemia. Acute myocardial ischemia was produced in 12 rats by occluding the anterior branch of the left coronary artery for 20-40 minutes. Dynamic spin-echo magnetic resonance imaging (MRI) was performed for 30 minutes after injection of Gd-DTPA (n = 6) or the cascade polymer (n = 6) using equimolar doses (0.1 mmol of Gd/kg). The contrast agent-induced changes in signal intensity (deltaSI) in normal and ischemic myocardium were observed. In normal myocardium, both contrast agents caused a sharp increase in deltaSI, followed by a decline to baseline values over the 30-minute period. Enhancement in the ischemic myocardium was attenuated. Gd-DTPA showed greater deltaSI in ischemic myocardium than the cascade polymer, which gave rise to virtually no enhancement. Significant differences (P<0.05) in signal enhancement between normal and ischemic myocardium persisted for only 6 minutes using Gd-DTPA but for 18 minutes with the cascade polymer. Use of Gd-DTPA-24-cascade-polymer extends the temporal window of dynamic contrast-enhanced MRI for the differentiation of ischemic and normal myocardium. Identification of the ischemic zone is easier with the cascade polymer, which demonstrates virtually no signal enhancement in this territory.

Animals↗
PubMed1999

Parasite-induced anorexia: leptin, insulin and corticosterone responses to infection with the nematode, Nippostrongylus brasiliensis.

The nematode parasite, Nippostrongylus brasiliensis, induces a biphasic anorexia in its rat host. The mechanisms, underlying this anorexia and its possible advantages to the host or parasite are unknown. We have investigated the effect of acute (12-24 h) and chronic (2-17 days) infections on plasma concentrations of leptin, insulin and corticosterone, and on hypothalamic expression of neuropeptide Y, galanin and corticotrophin-releasing factor genes. Plasma leptin was elevated in infected rats relative to uninfected ad libitum-fed controls and pair-fed controls in 12 h infections initiated at dark onset and in infections of 2 days' duration. At other times prior to parasite expulsion, plasma leptin in infected and pair-fed rats was lower than that of uninfected ad libitum-fed controls, reflecting the existing state of negative energy balance. Elevated plasma leptin concentrations in infected rats at day 2 post-infection were accompanied by reduced neuropeptide Y gene expression in the hypothalamic arcuate nucleus compared with both ad libitum control and pair-fed animals, and by lowered corticotrophin-releasing factor gene expression in the paraventricular nucleus relative to pair-feds. Twelve hour infections were characterized by a substantial increase in plasma corticosterone that was independent of reduced food intake, and in 12 h infections initiated at dark onset, where plasma leptin was elevated, there was also increased plasma insulin concentration in infected rats. In longer infections, differences between the groups in plasma insulin and corticosterone concentration were only observed at day 4 post-infection. In summary, perturbations to leptin, insulin and corticosterone signals early in infection may have a causative role and might feed back onto hypothalamic gene expression, whereas subsequent changes in these parameters are more likely to be secondary to negative energy balance.

Animals↗
PubMed1999

Mucosal mast cell responses and release of mast cell protease-I in infections of mice with Hymenolepis diminuta and H. microstoma: modulation by cyclosporin A.

The dynamics of intestinal mucosal mast cells and the major mucosal mast cell protease were followed during the course of laboratory infections of mice with Hymenolepis diminuta and H. microstoma. The effects of the drug cyclosporin A (CsA), which is both immunosuppressive and selectively anthelmintic depending upon dose regime, were determined. In H. diminuta infections worm expulsion occurred around day 9 and coincided with peak mastocytosis and peak mMCP-I concentrations in tissues and serum. Immunosuppressive treatment with CsA prevented worm expulsion, permitting some individuals to reach maturity, and abrogated mast cell proliferation and mMCP-I production and release. By contrast, H. microstoma infections persisted for 64 days in spite of a considerable mastocyosis in both intestine and bile duct tissues accompanied by a high level of mMCP-I in tissues and serum. A subimmunosuppressive regime of CsA had only limited effects on worms and mast cell numbers and activity. Together these data shed light on the variable mast cell response to gastrointestinal infections and on the potential significance of parasite location in evasion of mast cell action. Use of CsA reveals the contributions of both T cell-dependent mechanisms, including mast cell proliferation and activation, and T cell-independent events in regulating intestinal helminth infections.

Animals↗
PubMed1997

[Macromolecular contrast media for MR mammography. A new approach to characterizing breast tumors].

The value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of "blood-pool"-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed.

Breast↗
PubMed1997

Characterization of calcineurin from Hymenolepis microstoma and H. diminuta and its interaction with cyclosporin A.

The drug cyclosporin A (CsA) exerts its immunosuppressive action by binding to the cytosolic protein, cyclophilin (CyP) and, as a complex, binding to and inhibiting the calcium/calmodulin-dependent serine threonine phosphatase, calcineurin. It is unknown whether a similar mode of action occurs during the drug's antiparasite activity. Calmodulin-binding proteins from the helminth parasites Hymenolepis microstoma and H. diminuta were purified by affinity chromatography, yielding single polypeptide bands of 60000 M(r), according to SDS-PAGE. These proteins were tested for calcineurin activity by the dephosphorylation of the RII peptide (part of the catalytic subunit of cAMP-dependent protein kinase). Both proteins were calcium- and calmodulin-dependent and were inhibited by mammalian cyclophilin complexed with cyclosporin A (IC50 values of 0.75 microgram CyP for H. microstoma and 0.90 microgram CyP for H. diminuta). However, neither of the parasite calcineurins was inhibited by H. microstoma cyclophilin/CsA. These data suggest the anthelmintic mode of action of CsA in these helminth models does not involve the inhibition of a signal transduction pathway requiring interaction with calcineurin.

Amino Acid Isomerases↗
PubMed1997

[The algorithm of imaging diagnostics of pulmonary embolism: is it time for a new definition?].

Acute pulmonary embolism (PE) is an increasing and underdiagnosed cause of mortality and morbidity in hospitalised patients: pulmonary hypertension based on chronic pulmonary embolism is an uncommon, but severe and surgically curable complication. Since clinical signs might be silent or unspecific, both acute and chronic PE require imaging methods for diagnosis and treatment planning. Chest radiographic findings are usually non-specific. Scintigraphy provides a high sensitivity for PE, but lacks anatomic resolution and sufficient specificity. Pulmonary angiography, albeit accurate, is an invasive procedure associated with low but still not negligible morbidity and mortality. Hence, non-invasive methods offer advantages. Spiral CT, for example, is most reliable in the diagnosis of acute and chronic PE: Such fast CT techniques provide a non-invasive means to detect and differentiate acute emboli and organised thrombi, as well as perfusion abnormalities and other concomitant findings. MRI offers both morphological and functional information on lung perfusion and right heart function, but its image quality still needs improvement to be comparable with CT. Thus, while MRI must still be tested in clinical studies. CT is recommended as a screening method in acute and chronic pulmonary embolism.

Algorithms↗