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Biomedical subjects

S J Karlik

Publications and source records attributed to S J Karlik.

At least 19 recordsLinked to original sources
PubMed1999

Correlation between MRI and clinico-pathological manifestations in Lewis rats protected from experimental allergic encephalomyelitis by acylated synthetic peptide of myelin basic protein.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system which constitutes an accepted animal model for multiple sclerosis (MS). The disease can take an acute or chronic form depending on the injection route, animal strain and nature of the disease-inducing antigen administered. The neuroinflammation associated with the acute form can be detected with T2-weighted, T1-weighted and diffusion MRI, and blood-brain barrier changes can be investigated with Gd-DTPA-enhanced T1-weighted imaging, similar to that of MS patients. A synthetic peptide of myelin basic protein (MBP) encephalitogenic for the Lewis rat (MBP 68-86) was acylated by the attachment of a palmitoyl residue (PAL68-86), and was shown to confer almost complete protection against EAE, when administered to rats before and after an encephalitogenic challenge. In this study, treatment of Lewis rats with PAL68-86 prevented the appearance of clinical signs (p < 0.0001) after challenge with the native peptide (p68-86) in complete Freund's adjuvant (CFA), and reduced considerably the MRI and histopathological signs of the disease (p < 0.0001). Measurement of the gadolinium leakage due to neuroinflammation revealed a significant decrease in permeability from 4.09 +/- 2.1 to 2.95 +/- 1.79% pixels > mean + 2 SD (p = 0.011). Therefore, quantitative MRI measurements correlate very well with the reduced cellular infiltration in the CNS and the absence of clinical signs in the EAE-protected animal.

Acylation↗
PubMed1999

Reduced visual evoked responses in multiple sclerosis patients with optic neuritis: comparison of functional magnetic resonance imaging and visual evoked potentials.

The limited application of functional magnetic resonance imaging (fMRI) for investigations of multiple sclerosis (MS) patients has already shown that deficits of the motor, cognitive and visual systems may be identified by differences in the patterns of activation in response to a suitable stimulus. In MS patients with unilateral optic neuritis, the area of activation in the primary visual cortex, measured by fMRI techniques, is dramatically reduced in response to stimulation of the affected eye. The latency of the major positive component of the visual evoked potential (VEP) recorded upon stimulation of the affected eye is significantly increased in these patients, as compared to the unaffected eye and normal volunteers. We have found a correlation between the neural response measured using fMRI and the latency of the VEP. fMRI signal responses have the potential to provide more detailed topographic information relating to functional deficits in MS.

Evoked Potentials, Visual↗
PubMed1998

Apoptotic cells are present in the CNS throughout acute and chronic-progressive EAE in the absence of clinical recovery.

Experimental allergic encephalomyelitis (EAE) is an autoimmune, demyelinating disorder of the central nervous system induced in susceptible animals as a model for the human disease multiple sclerosis. Antibodies against the leukocyte adhesion molecule alpha4 integrin have been shown to prevent and reverse acute and chronic EAE of the guinea pig. The results presented in this paper implicate apoptosis as the mechanism of reversal of EAE following treatment with anti-alpha4 integrin antibody. Apoptotic cells were observed in the central nervous system (CNS) throughout chronic-progressive EAE of the guinea pig in the absence of clinical recovery. Many of the apoptotic cells were identified as T cells using immunohistochemistry. Similarly, apoptotic cells were present in the CNS of animals during anti-alpha4 integrin-mediated recovery from acute and chronic disease. Therefore, anti-alpha4 integrin-mediated recovery from EAE is due to the prevention of the influx of new inflammatory cells into the CNS that are required to replace those undergoing apoptosis.

Acute Disease↗
PubMed1998

Radiology residents' research in Canada: status of infrastructure.

OBJECTIVE: To survey all Canadian radiology residency training programs concerning their programs in research and critical inquiry, in order to assess the status of the research infrastructure for residents. METHODS: A questionnaire was developed through consensus among the radiology research directors in Canadian training programs. RESULTS: Fourteen of the 16 universities have a research and critical inquiry program, although there is considerable variation in the components and structure of the programs. Many programs do not have personnel, funds or written guidelines for their operation. Didactic aspects of research, such as biostatistics, ethics and quality assurance, are widely taught and thought to be important. Similarly, there is widespread agreement on which methods qualify for research projects, such as departmental audits or retrospective chart reviews. However, except for requiring a presentation at a research day, very few residency programs view research work as essential to the completion of training. The commitment to research programs is strong, as evidenced by the time devoted by residents and mentors and the funds made available for presentations. CONCLUSION: This survey provides information to assist in the development of individual programs and national guidelines for radiology residency programs in critical inquiry and research.

Canada↗
PubMed1997

Genetically regulated response to intravesical bacillus Calmette Guerin immunotherapy of orthotopic murine bladder tumor.

PURPOSE: Genetically regulated host response to intravesical Bacillus Calmette Guerin (BCG) immunotherapy was assessed using the murine bladder tumor MM45T in Bcgr and Bcgs inbred congenic strains of mice. MATERIALS AND METHODS: Tumor detection and monitoring of treatment response to BCG was carried out using magnetic resonance imaging (MRI) of BALB/c (Bcgs allele) and BALB/c. CD2 (CD2) (Bcgr allele) mice implanted orthotopically with MM45T tumor cells. Intravesical BCG instillation (3 doses per week for 3 weeks) was used as prophylaxis against tumor implantation in both Bcgr and Bcgs strains and as definitive treatment against MRI-confirmed established tumors. Tumors implanted in both strains of untreated mice served as controls. Intravesical injection of BCG was also performed in established heterotopic subcutaneous tumors in both strains. Immunologic response in all groups was assessed by flow cytometric analysis of the bladder irrigation fluid cell composition, measuring CD4+ (helper/inducer) and CD8+ (cytotoxic/ suppressor) cell subsets. RESULTS: Intralesional injection of BCG into established heterotopic tumors showed growth inhibition in the Bcgs strain but not in the Bcgr strain. Intravesical BCG treatment against established orthotopic tumors showed significant tumor regression in the Bcgs strain compared to control but there was no effect in the Bcgr strain. CONCLUSION: The differential anti-tumor activity of BCG in the Bcgs and Bcgr congenic murine strains supports the notion that Bcg gene-controlled responsiveness to BCG innoculation determines, at least partially, the host response to immunotherapy. These results have potential clinical significance in patient selection for intravesical therapy for bladder cancer.

Adjuvants, Immunologic↗
PubMed1996

Mycobacterium cell wall: an alternative to intravesical bacillus Calmette Guerin (BCG) therapy in orthotopic murine bladder cancer.

PURPOSE: The antitumor effect of intravesical mycobacterium cell wall (MCW) therapy on orthotopic and heterotopic bladder tumors in the mouse was assessed with magnetic resonance imaging (MRI). MATERIALS AND METHODS: The live bacillus Calmette Guerin (BCG) organism was replaced with a cell wall extract derived from the outer capsule of Mycobacterium phlei. This alternative form of intravesical therapy was used with the aim of reducing the toxicity associated with the live mycobacterium organism without compromising efficacy. Response to multiple doses of intravesical MCW and BCG was assessed in mice with established MBT-2 tumors after transurethral tumor implantation. RESULTS: Serial MRI of BCG-treated mice revealed significant tumor regression. The MR images correlated well with the corresponding histology of the whole mount bladder sections. Treatment with MCW also resulted in significant inhibition of tumor growth compared with control untreated animals (p < 0.05) although the antitumor effect was less pronounced than that of live BCG. Treatment was well tolerated in the MCW group with no apparent ill effects. Flow cytometric (FCM) analysis of bladder washings with phenotype-specific monoclonal antibodies revealed predominantly a CD3+ T cell infiltrate in the control and BCG-treated as well as the MCW-treated mice. The CD4+ (helper/inducer) subset of T cells predominated over the CD8+ (suppressor/cytotoxic) subset in both the BCG- and MCW-treated animals, and the CD4+/CD8+ ratio in both of the treated groups differed significantly from that of the control untreated groups. CONCLUSION: Intravesical MCW appears to invoke a similar inflammatory response in the mouse bladder mucosa as the live BCG organism and retains an antitumor action. It deserves further evaluation as a potential antitumor agent against bladder cancer. A Phase II clinical trial is now underway.

Adjuvants, Immunologic↗
PubMed1996

The variability of manual and computer assisted quantification of multiple sclerosis lesion volumes.

The high resolution and excellent soft tissue contrast of Magnetic Resonance Imaging (MRI) have enabled direct, noninvasive visualization of Multiple Sclerosis (MS) lesions in vivo. This has allowed the quantification of changes in the appearance of lesions in MR exams to be used as a measure of disease state. Nevertheless, accurate quantification techniques are subject to inter- and intra-operator variability, which may hinder monitoring of disease progression. We have developed a computer program to assist an experienced operator in the quantification of MS lesions in standard spin-echo MR exams. The accuracy of assisted and manual quantification under known conditions was studied using exams of a test phantom, while inter- and intra-operator reliability and variability were studied using exams of a MS patient. Results from the phantom study show that accuracy is improved by assisted quantification. The patient exam results indicate that assisted quantification reduced inter-operator variability from 0.34 to 0.17 cm3, and reduced intra-operator variability from 0.23 to 0.15 cm3. In addition, the minimum significant change between two successive measurements of lesion volume by the same operator was 0.64 cm3 for manual quantification and 0.42 cm3 for assisted quantification. For two different operators making successive measurements, the minimum significant change was 0.94 cm3 for manual quantification, but only 0.47 cm3 for assisted quantification. Finally, the number of lesions to be monitored for an average change in volume at a given power and significance level was reduced by a factor of 2-4 by assisted quantification. These results suggest that assisted quantification may have practical applications in clinical trials, especially those that are large, multicenter, or extended over time, and therefore require lesion measurements by one or more operators.

Analysis of Variance↗
PubMed1996

Quantification of multiple sclerosis lesion volumes in 1.5 and 0.5 T anisotropically filtered and unfiltered MR exams.

Recently, guidelines for the use of MRI in the monitoring of MS have recommended the use of imaging systems with mid-field (0.5-1.0 T) or high-field (greater than 1.0 T) strengths. Higher field strengths provide many advantages, including increased signal-to-noise ratios (SNR). SNR also may be increased by post-processing algorithms that reduce noise. In this paper we evaluate the impact on operator variability of (a) lesion quantification in high-field (1.5 T) versus mid-field (0.5 T) exams; and (b) an anisotropic diffusion filter algorithm that reduces image noise without blurring or moving object boundaries. Inter- and intra-operator reliability and variability were studied using repeated quantification of lesions in 1.5 and 0.5 T filtered and unfiltered MR exams of a MS patient. Results indicate that inter-operator variability in 1.5 T unfiltered exams was 0.34 cm3 and was significantly larger than that in 1.5 T filtered (0.27 cm3), 0.5 T unfiltered (0.26 cm3), and 0.5 T filtered (0.24 cm3) exams. Similarly, intra-operator variability in 1.5 T unfiltered exams was 0.23 cm3 and was significantly larger than that in 1.5 T filtered (0.19 cm3), 0.5 T unfiltered (0.19 cm3), and 0.5 T filtered (0.18 cm3) exams. In addition, the minimum significant change between two successive measurements of lesion volume by the same operator, was 0.64 cm3 in 1.5 T unfiltered exams, but 0.53 cm3 or less in other exams. For two different operators making successive measurements, the minimum significant change was 0.94 cm3 in 1.5 T unfiltered exams, but only 0.75 cm3 or less in other exams. Finally, the number of lesions to be monitored for an average change in volume at a given power and significance level was greater by 30%-60% for quantification in 1.5 T unfiltered exams. These results suggest that inter- and intra-operator variability are reduced by anisotropic filtering, and by quantification in 0.5 T exams. Reduced operator variabilities may result from higher detail signal-to-noise ratios (dSNRs) in 0.5 T and filtered exams.

Analysis of Variance↗
PubMed1996

Comparison of tirilazad mesylate (U-74006F) and methylprednisolone sodium succinate treatments in experimental allergic encephalomyelitis in the guinea pig.

The effects of the non-glucocorticoid 21-aminosteroid, tirilazad mesylate (U-74006F), on MRI and clinical findings in guinea pigs with experimental allergic encephalomyelitis were compared to treatment with methylprednisolone sodium succinate (MPSS). A dose response experiment for U-74006F was performed 1, 3 and 10 mg/kg/day i.p. on day 0-12 after immunization. Additionally, the 3 mg/kg/day i.p. dose was extended to 24 and 35 days. MPSS was given in three different protocols at doses ranging from 0.8 to 3.2 mg/kg/day. Abnormalities in T2-weighted images were assessed as measures of edema and inflammation and gadolinium-DTPA enhanced T1-weighted images were used to determine blood-brain barrier integrity. U-74006F improved the clinical status at doses of 3 and 10 mg/kg. For example, maximum clinical score was halved at 10 mg/ kg/day (P < 0.01). The presence of gadolinium-DTPA in the parenchyma was also decreased at 3 and 10 mg/kg/day U-74006F although maximum MRI scores were decreased only in the 10 mg/kg U-74006F group. Clinical disease suppression seen with 3 mg/kg treatment on days 0-12 reverted to control at > 24 days of dosing. MPSS treatment considerably worsened the clinical outcome of EAE. Mean clinical scores for vehicle and the highest MPSS dose were 0.94 +/- 0.66 versus 2.64 +/- 1.49 (P < 0.05). The combination of decreased T2-weighted abnormalities, clinical signs and gadolinium-DTPA permeation in the U-74006F treated animals suggested protection of the blood-brain barrier without the severe glucocorticoid effects associated with steroid therapy.

Acute Disease↗
PubMed1995

A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis.

In experimental allergic encephalomyelitis (EAE), circulating leukocytes enter the central nervous system (CNS) producing inflammation, myelin damage and paralysis. Prevention of leukocyte infiltration by an antibody against alpha 4 integrin suppressed clinical and pathological features of EAE in the guinea pig. Rapid clearance of leukocytes from the CNS and reversal of clinical findings were observed when anti-alpha 4 treatment was administered during active disease. Clinical improvement was accompanied by a marked decrease in abnormal pathological findings, including demyelination. Therefore anti-alpha 4 is an effective treatment of EAE and may be similarly useful in the treatment of autoimmune diseases such as multiple sclerosis.

Animals↗
PubMed1993

Gadolinium-DTPA enhanced MRI demonstrates uterine vascular changes associated with artificially induced decidualization and ovoimplantation in rats.

Gadolinium-DTPA enhanced magnetic resonance (MR) imaging has been used to demonstrate uterine vascular changes during ovoimplantation and artificially induced decidualization in rats. Evans blue dye and Gd-DTPA were injected i.v. into rats 10 h after unilateral decidualization was induced by injection of sesame oil into the lumen of one uterine horn. Animals were killed various times later and uteri were removed, T1-weighted proton imaging was performed, and mean image intensities for stimulated and control uterine horns were calculated by computer-assisted image analysis. Macroscopic bluing confined to stimulated horns was apparent 5 min after tracer injection and increased in intensity until the experiment was terminated at 320 min. Analysis of MR images showed that mean image intensity of control horns did not change significantly at any time after injection of the Gd-DTPA and Evans blue whereas mean image intensity of stimulated horns increased significantly by 5 min after injection, peaked at 20 min, and returned to values not different from controls by 320 min. T1-weighted images of day 6 pregnant rats injected with Gd-DTPA and Evans blue revealed patterns of image enhancement that matched those of macroscopic bluing. Uterine concentrations of radioactivity after injection of 153Gd-DTPA indicated that increased extracellular fluid volume (ECFV) produces the image enhancement of stimulated horns since the tracer permeates the extracellular fluid of both horns. Gd-DTPA-enhanced MR imaging of uteri after deciduogenic stimulation revealed significant image enhancement for stimulated horns at both 9 and 27 h after stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Gadolinium enhancement in acute and chronic-progressive experimental allergic encephalomyelitis in the guinea pig.

Magnetic resonance imaging detects blood-brain barrier disruption after gadolinium-DTPA enhancement of central nervous system lesions of multiple sclerosis. Experimental allergic encephalomyelitis has many clinical and pathological features in common with multiple sclerosis including alterations in the integrity of the blood-brain barrier. We have compared T2-weighted cranial MR images with Gd-DTPA dimeglumine-enhanced T1-weighted images of myelin basic protein-induced acute (Days 8-42 postimmunization) and central nervous system-induced chronic-progressive (Days 70-95 postimmunization) forms of experimental allergic encephalomyelitis in the guinea pig. Although animals from both groups had abnormal T2-weighted images, only the myelin basic protein-acute-EAE animals (Days 14-24 postimmunization) showed enhancement on postcontrast MR studies. The different responses of the acute and chronic diseases may result from different immunogens, severity of disease, or different permeability of the blood-brain barrier. Therefore, gadolinium-DTPA-enhanced, T1-weighted MR images distinguish acutely active and chronic inflammatory lesions in experimental allergic encephalomyelitis.

Animals↗
PubMed1993

Baseline consideration of liposomal contrast agent. CNS transport by macrophages in experimental allergic encephalomyelitis.

The purpose of this study was to investigate a specialized liposomal contrast agent for magnetic resonance imaging (MRI), as part of a program to examine infiltrating immune cells in lesions of experimental allergic encephalomyelitis (EAE). A potent investigational liposomal contrast agent, phosphatidylethanolamine-DTPA-gadolinium, was chosen which has been shown to remain tightly liposomal-associated, with long persistence in vivo. Europium (Eu3+), a fluorescent paramagnetic metal, was also utilized in these experiments in place of gadolinium. This material is avidly taken up by monocytes in vivo. Thirty-four animals received some form of liposomal material either before or during the opening of the blood-brain barrier (BBB). Twenty-seven Hartley guinea pigs were inoculated for EAE with homogenized brain and Complete Freunds Adjuvant (CFA) and seven control animals received CFA alone. Eighty-two percent of the experimental animals exhibited degeneration of the BBB with inflammation and edema in the brain, while all control animals had normal brain scans. T1-weighted MRI, performed to detect the presence of liposomal contrast material in experimental animals, was not different from untreated animals. Fluorescent microscopy revealed no characteristic changes associated with Eu3+ presence in the brains of treated or control animals. Therefore, it would seem that insufficient material crosses the disrupted BBB, either in free form or subsequent to macrophage ingestion, to be detected by MRI or fluorescent microscopic examination.

Animals↗
PubMed1993

Stability studies on chemoembolization mixtures. Dialysis studies of doxorubicin and lipiodol with Avitene, Gelfoam, and Angiostat.

RATIONALE AND OBJECTIVES: Chemoembolization, using a combination of embolic and chemotherapeutic agents, appears to be an effective treatment for hepatocellular carcinoma. Although the postulated mechanism of effectiveness hinges on a prolonged drug delivery, increasing evidence suggests that embolization mixtures are not stable. The objective of this study was to investigate examples of these mixtures. METHODS: Dialysis techniques have been used to examine the pharmacokinetic properties of chemoembolization mixtures that contain doxorubicin, Lipiodol (Guerbet Products, Montreal, Quebec), and the embolizing agents Avitene (Alcon Laboratories Inc., Fort Worth, Texas), Gelfoam (Upjohn, Kalamazoo, MI), and Angiostat (Regional Therapeutic Inc., Pacific Palisades, CA). RESULTS: Lipiodol, Gelfoam, and Avitene, when combined with doxorubicin, had only a small effect on the diffusion of the drug when compared with the diffusion curve of doxorubicin alone. Gelfoam or Avitene produced a thrombus-like consistency when added to a doxorubicin/Lipiodol combination, and an additional decrease in the doxorubicin appearance rate was observed. However, after 6 hours, doxorubicin levels for these mixtures reached control values observed in 3 hours. Angiostat without Lipiodol produced a profound concentration-dependent decrease in the diffusion of doxorubicin. After 9 hours, only 23% of the doxorubicin had been released. CONCLUSION: The strong complexing ability of the embolic agent Angiostat may enable it to be a carrier for doxorubicin and surpass other mixtures currently employed for transcatheter chemoembolization.

Antineoplastic Agents↗
PubMed1993

An open-trial evaluation of mitoxantrone in the treatment of progressive MS.

We treated 13 patients with progressive MS with mitoxantrone. All patients received a standard IV dose of mitoxantrone (8 mg/m2) every 3 weeks for a total of seven infusions, with dosage adjustments depending on the hematologic profile at the nadir. The treatment was well tolerated, with the most common side effect being mild nausea. Four of seven women developed transient secondary amenorrhea. The postenrollment clinical behavior of these patients was generally more favorable than during the 18 months prior to enrollment (only three of 13 patients developed an increase in the Expanded Disability Status Scale of more than 0.5 points), suggesting a possible treatment effect, but comparison with two historical control groups (both the active and placebo groups from the Canadian Cooperative Trial of Cyclophosphamide and Plasma Exchange) does not suggest that mitoxantrone was efficacious. Eight of 12 patients had evidence of MRI activity on 13 of 29 follow-up visits. This small, open-labeled pilot study did not provide strong support for proceeding with a randomized, controlled trial of this dosage regimen of mitoxantrone in patients with progressive MS.

Adult↗
PubMed1993

Producing picture-perfect posters.

Scientific posters form an integral part of many radiology meetings. They provide the opportunity for interested parties to read the material at an individualized pace, to study the images in detail, and to return to the exhibit numerous times. Although the content of the poster is undoubtedly its most important component, the visual presentation of the material can enhance or detract from the clarity of the message. With the wide availability of sophisticated computer programs for desktop publishing (DTP), one can now create the poster on a computer monitor with full control of the form as well as the content. This process will result in a professional-appearing poster, yet still allow the author the opportunity to make innumerable revisions, as the poster is visualized in detail on the computer monitor before printing. Furthermore, this process is less expensive than the traditional method of typesetting individual sections separately and mounting them on cardboard for display. The purpose of this article is to present our approach to poster production using commercially available DTP computer programs.

Computer Graphics↗
PubMed1993

Reduction of sunburn damage to skin by topical application of vitamin E acetate following exposure to ultraviolet B radiation: effect of delaying application or of reducing concentration of vitamin E acetate applied.

The skin of the skh-1 mouse after ultraviolet B (280-320 nm, UVB) irradiation shows the pathological changes typical of sunburn damage: spongiosis (edematous spaces) around some cells, necrosis of keratinocytes, giving rise to sunburn cells, inflammatory infiltration of polymorphonuclear leucocytes, etc. In our previous study, these were accompanied by erythema, increased skin sensitivity, and edematous swelling. The topical application of tocopherol acetate (TA) immediately after the UVB exposure decreased these changes. In this paper, multiple measurements of the skin thickness were made at different locations along the magnetic resonance imaging (MRI) cross-sectional image of the skin. This permits effects to be quantified with (if desired) the contralateral half of the back serving as an internal control, either exposed (positive control) or unexposed (negative control). Topical application of TA resulted in an increase in the concentration of free tocopherol in the skin. No qualitative differences in ultrastructural appearance of the UVB-irradiated, TA-treated skin could be discerned by careful examination. In vivo high resolution video microscopy of blood flow in venules of the irradiated mouse ear revealed a large (tenfold) but not statistically significant decrease in stationary lymphocytes adhering to the venule walls. The delaying of the application of TA up to 8 hours after the termination of UVB irradiation still offered statistically significant protection as did immediate application of 5% TA in diluent Myritol 318 (Delios S, Henkel).

Administration, Topical↗