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S J Karlik

Publications and source records attributed to S J Karlik.

At least 19 recordsLinked to original sources
PubMed2005

Spontaneous remyelination following prolonged inhibition of alpha4 integrin in chronic EAE.

Inhibition of alpha(4)beta(1) integrin blocks immune cell influx into the CNS providing benefit to patients with multiple sclerosis and in animal model systems. We have used this mechanism to examine whether the presence of inflammatory cells suppresses spontaneous myelin repair in experimental autoimmune encephalomyelitis. We observed (1) 87% of plaques showed remyelination after 40 days of treatment; (2) myelin repair occurred in half of the total lesion area; (3) half of the animals regained motor function. There was no significant repair or gain of motor function in vehicle-treated animals. Therefore, prolonged inhibition of CNS inflammation, in the absence of targeted myelin repair, facilitates mechanisms of spontaneous remyelination.

Animals↗
PubMed2005

Resolution-dependent estimates of multiple sclerosis lesion loads.

BACKGROUND: Changes in brain lesion loads assessed with magnetic resonance imaging obtained at 1.5 Telsa (T) are used as a measure of disease evolution in natural history studies and treatment trials of multiple sclerosis. METHODS: A comparison was made between the total lesion volume and individual lesions observed on 1.5 T images and on high-resolution 4 T images. Lesions were quantified using a computer-assisted segmentation tool. RESULTS: There was a 46% increase in the total number of lesions detected with 4 T versus 1.5 T imaging (p < 0.005). The 4 T also showed a 60% increase in total lesion volume when compared with the 1.5 T (p < 0.005). In several instances, the 1.5 T scans showed individual lesions that coalesced into larger areas of abnormality in the 4 T scans. The relationship between individual lesion volumes was linear (slope 1.231) showing that the lesion volume observed at 4 T increased with the size of the lesion detected at 1.5 T. The 4 T voxels were less than one quarter the size of those used at 1.5 T and there were no consistent differences between their signal-to-noise ratios. CONCLUSIONS: The increase in signal strength that accompanied the increase in field strength compensated for the loss in signal amplitude produced by the use of smaller voxels. This enabled the acquisition of images with improved resolution, resulting in increased lesion detection at 4 T and larger lesion volumes.

Adult↗
PubMed2005

Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of alpha4 integrin.

PURPOSE: To determine the efficacy of a small molecule inhibitor of alpha4 integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE). MATERIALS AND METHODS: EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization. Animals received either saline (n = 12), anti-alpha4 integrin antibody (AN100226m; n = 12) or CT301 (n = 12). T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for cerebral inflammation and gadolinium enhancement. T1-weighted images were further analyzed to quantify this enhancement as a measure of blood-brain barrier integrity. Dissected CNS was evaluated for inflammation and demyelination. RESULTS: CT301 successfully reversed two clinical indicators of disease over the course of the treatment period. These animals showed decreased T2-weighted abnormalities, as well as a reduction in gadolinium leakage on T1-weighted images. Meningeal and perivascular inflammation was decreased by anti-alpha4 integrin treatments. CONCLUSION: CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in multiple sclerosis (MS).

Acute Disease↗
PubMed2003

VEGF and vascular changes in chronic neuroinflammation.

A vascular component has long been associated with the pathological changes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). Despite the codependence of angiogenesis and many chronic inflammatory disorders, only circumstantial evidence is available to support the existence of angiogenesis in MS or EAE. To determine if angiogenesis occurs in conjunction with clinical and pathological signs of CNS inflammatory disease we evaluated temporal and spatial blood vessel counts, VEGF immunoreactivity, and histopathological changes in the spinal cord of guinea pigs with chronic-progressive (CP)-EAE (day 0-90 post-immunization, n=64) and controls (n=17). The number of vessels per section increased in infiltrated and demyelinated lesions by day 15 post-immunization and remained significantly higher than controls throughout the course of the disease. The number of vessels correlated with both clinical and pathological scores for inflammation, infiltration and demyelination. Vascular endothelial growth factor (VEGF) expression increased during acute disease peaking at day 26, which was the transition from the acute-inflammatory to chronic-demyelinating phase, before gradually returning to baseline levels. These observations implicate angiogenesis as a component of chronic neuroinflammation and demyelination and may suggest alternative therapeutic strategies for multiple sclerosis.

Animals↗
PubMed2002

Prolonged reversal of chronic experimental allergic encephalomyelitis using a small molecule inhibitor of alpha4 integrin.

CNS leukocytic invasion in experimental allergic encephalomyelitis (EAE) depends on alpha4beta1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interactions. A small molecule inhibitor of alpha4beta1 integrin (CT301) was administered to guinea pigs in the chronic phase (>d40) of EAE for 10, 20, 30 or 40 days. CT301 elicited a rapid, significant improvement in the clinical and pathological scores that was maintained throughout the treatment period. A progressive loss of cells in the spinal cord of treated animals confirmed the resolution of inflammation associated with clinical recovery. Therefore, prolonged inhibition of alpha4beta1 integrin caused a sustained reversal of disease pathology in chronic EAE and may be similarly useful in MS.

Animals↗
PubMed2000

Magnetization transfer and multicomponent T2 relaxation measurements with histopathologic correlation in an experimental model of MS.

Magnetization transfer and multicomponent T2 imaging techniques were implemented to study guinea pig in vivo. A chronic-progressive model of experimental allergic encephalomyelitis (EAE) was produced, and the inflammatory component of the disease was manipulated using antibodies against integrin. The magnetization transfer ratio (MTR) and T2 relaxation properties were measured in normal-appearing white matter (NAWM) with histological comparisons. Significant reductions in both the mean MTR and the myelin water percentage were measured in NAWM of EAE guinea pig brain. However, the MTR and myelin water percentage appear to measure different aspects of pathology in NAWM in EAE. Reductions in the MTR were prevented or reversed with suppression of inflammation. However, modulation of inflammatory activity was not reflected in the measurement of the myelin water percentage. Since the amount of myelin is not expected to vary with inflammatory-related changes, these observations support our hypothesis that the MTR is sensitive to physiological changes to myelin induced by inflammation, while the short T2 component is a more specific indicator of myelin content in tissue. Pathologic features other than demyelination may be important in the determination of the MTR.

Animals↗
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

In vivo measurements of multi-component T2 relaxation behaviour in guinea pig brain.

Multi-echo Carr-Purcell-Meiboom-Gill (CPMG) imaging sequences were implemented on 1.5 T and 4.0 T imaging systems to test their ability to measure in vivo multi-component T2 relaxation behavior in normal guinea pig brain. The known dependence of accurate T2 measurements on the signal-to-noise ratio (SNR) was explored in vivo by comparing T2 decay data obtained using three methods to increase SNR (improved RF coil design, signal averaging and increased magnetic field strength). Good agreement between T2 values of nickel-doped agarose phantoms was found between imaging and spectroscopic methods. T2 values were determined for gray matter (GM) and white matter (WM) locations from images of guinea pig brain in vivo. T2 measurements of GM were found to be monoexponential at both field strengths. The mean T2 times for GM were 71 ms at 1.5 T, and 53 ms at 4.0T. The highest average SNR was achieved using an improved RF coil at 4.0T. In this case, two peaks were extracted in WM, a "short" T2 peak at approximately 6 ms, and a "medium" T2 peak at approximately 48 ms. T2 values in GM and the major component of WM were significantly decreased at 4.0T compared to 1.5 T. The improved SNR attained with this optimized imaging protocol at 4.0T has allowed for the first time extraction of the myelin-sensitive T2 component of WM in animal brain in vivo.

Animals↗
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↗