Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis.

Development of pharmacotherapies that promote remyelination is a high priority for multiple sclerosis (MS), due to their potential for neuroprotection and restoration of function through repair of demyelinated lesions. A novel preparation of clean-surfaced, faceted gold nanocrystals demonstrated robust remyelinating activity in response to demyelinating agents in both chronic cuprizone and acute lysolecithin rodent animal models. Furthermore, oral delivery of gold nanocrystals improved motor functions of cuprizone-treated mice in both open field and kinematic gait studies. Gold nanocrystal treatment of oligodendrocyte precursor cells in culture resulted in oligodendrocyte maturation and expression of myelin differentiation markers. Additional in vitro data demonstrated that these gold nanocrystals act via a novel energy metabolism pathway involving the enhancement of key indicators of aerobic glycolysis. In response to gold nanocrystals, co-cultured central nervous system cells exhibited elevated levels of the redox coenzyme nicotine adenine dinucleotide (NAD+), elevated total intracellular ATP levels, and elevated extracellular lactate levels, along with upregulation of myelin-synthesis related genes, collectively resulting in functional myelin generation. Based on these preclinical studies, clean-surfaced, faceted gold nanocrystals represent a novel remyelinating therapeutic for multiple sclerosis.

Effects of an aqueous extract of North American ginseng on MOG(35-55)-induced EAE in mice.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which the release of reactive oxygen species by infiltrating immune cells contributes to demyelination. American ginseng ( Panax quinquefolius ) is a natural health product with numerous beneficial properties, including anti-inflammatory and anti-oxidant effects. The purpose of this study was to determine whether ginseng could influence the course of the disease experimental autoimmune encephalomyelitis (EAE), an animal model of MS. C57BL/6J mice were immunized with MOG((35-55)) peptide to induce EAE. After clinical disease appeared, mice received either oral doses of an aqueous extract of ginseng (150 mg/kg body mass), or the vehicle. Clinical symptoms were recorded, and spinal cord tissue samples were analyzed for pathological signs of disease. The aqueous extract of ginseng significantly decreased (i) clinical signs of EAE, (ii) levels of circulating TNF-α, and (iii) central nervous system immunoreactive iNOS and demyelination scores, without a change in other neuropathological measures. This study shows that an aqueous extract of ginseng may be able to attenuate certain signs of EAE, suggesting that it may be a useful adjuvant therapy for MS.

Targeting vascular changes in lesions in multiple sclerosis and experimental autoimmune encephalomyelitis.

What is the origin of the complex vascular changes that exist in the CNS lesions of Multiple Sclerosis (MS)? From the beginning of the study of the pathological changes in MS in the 19th century, lesions were seen to be associated with veins. On a microscopic level, there have been numerous pathological changes to these vessels including altered structure and permeability, fibrinolysis, iron-related alterations and collagen deposition. Vascular changes in inflammatory conditions outside the CNS are well documented and we hypothesize that angiogenesis (the generation of new blood vessels from existing) is an integral process of lesion development and spread in MS. We demonstrated similar vascular abnormalities in MS and in the animal model, EAE. We measured the increase in angiogenesis-related genes in EAE and review herein the effectiveness of chemical inhibitors of angiogenesis (SU5416, thalidomide and several derivatives). We postulate that interference with angiogenesis provides a suitable non-immunological target for investigation in MS.

Thalidomide derivatives for the treatment of neuroinflammation.

The precise mechanism-of-action of thalidomide remains uncertain and might differ between diseases and under different clinical condition. With implications in the treatment of a variety of inflammatory and autoimmune diseases, as well as for use as an anticancer agent, alone or in combination with established therapeutics, it is clear that thalidomide and its derivatives deserve further scrutiny. In particular, thalidomide was shown to be effective in a mouse model of multiple sclerosis (MS), an autoimmune inflammatory disorder, called experimental autoimmune encephalomyelitis (EAE). Herein, we describe the synthesis and preliminary biological evaluation of new macromolecular prodrugs of thalidomide bearing an aminoalkyl group on the phthalimide ring. The effectiveness of these compounds to limit EAE was investigated, and it was shown that, at 100 mg kg⁻¹ thalidomide-equivalent dose, they abrogated the clinical and pathological features of EAE.

Quantitative assessment of the superior sagittal sinus on unenhanced computed tomography.

PURPOSE: To determine the relationship between hemoglobin levels and attenuation measurements of the superior sagittal sinus (SSS) on unenhanced computed tomography (UECT). Secondly, to determine if SSS attenuation values are normally distributed such that measurements below and above certain thresholds are suggestive of pathology, such as anemia or acute venous thrombosis respectively. METHODS: Institutional review board approval was obtained for retrospective review of adult patients having both an UECT head examination and a complete blood count within 24 h of the scan. A cohort of 151 consecutive patients formed the study sample (76 males and 75 females, 17-91 years of age with a mean of 61). The dorsal aspect of the SSS was divided into upper, middle and lower segments. Using freehand and circle region of interest (ROI) techniques, a total of six attenuation measurements were obtained from each patient. Next, statistical analyses were preformed to assess the correlation between Hgb levels and attenuation values, and distribution curves were plotted to assess the normal range of SSS attenuation measurements. RESULTS: There is a moderate, yet statistically significant (p<0.001), correlation between Hgb levels and attenuation values in upper, middle and lower segments of the SSS (r=0.487, 0.497 and 0.533 respectively). Based on the calculated mean, median and mode, the attenuation values are normally distributed. When using the freehand ROI technique, the mean value is 50 Hounsfield Units (HU) with a standard deviation (SD) of 7.5. Attenuation values less than 2 SDs (35 HU) are highly suggestive of anemia (specificity and PPV=100%). CONCLUSION: There is a moderate, yet statistically significant, correlation between Hgb levels and attenuation of the SSS on UECT. Furthermore, attenuation measurements of the SSS are normally distributed with a mean of 50 HU and a SD of 7.5. Therefore, quantitative assessment of the SSS may prove useful in the clinical practice of a radiologist; namely, in the diagnosis of anemia and acute venous thrombosis.

Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application.

The present work deals with the synthesis of a new series of thalidomide derivatives for therapeutic applications. These compounds were evaluated in vitro on a human endothelial cell line EA.hy926 for their antiproliferative potential and in vivo on an experimental animal multiple sclerosis model called EAE as angiogenesis inhibitors. The preliminary results obtained on EAE assays seem to validate that anti-angiogenesis compounds could be promising tools for the treatment of MS.

Iron-oxide labeling of hematogenous macrophages in a model of experimental autoimmune encephalomyelitis and the contribution to signal loss in fast imaging employing steady state acquisition (FIESTA) images.

PURPOSE: To determine the contribution of blood-derived macrophages to the signal loss observed in MR images of inflammatory lesions in experimental autoimmune encephalomyelitis (EAE). MATERIALS AND METHODS: A relapsing-remitting form of EAE was induced in transgenic mice that express enhanced green fluorescent protein (EGFP) specifically in hematopoietic cells of the myelomonocytic lineage. Animals were injected with Feridex, a superparamagnetic iron oxide (SPIO) nanoparticle, 24 hours prior to in vivo MRI. MRI was performed using a 1.5T whole-body scanner; a high-performance, custom-built gradient coil insert; and a 3D steady-state free precession (SSFP) imaging pulse sequence. Comparisons were made between MR images and corresponding anti-GFP and Perl's Prussian blue (PPB)-stained brain sections. RESULTS: MR images revealed the presence of discrete regions of signal loss throughout the brains of EAE animals that were administered Feridex. Histological staining showed that regions of signal loss on MR images corresponded anatomically with regions of PPB- and GFP-positive cells. CONCLUSION: This experiment provides the first direct evidence that macrophages of hematogenous origin are labeled with SPIO after intravenous administration of Feridex, and contribute to the regions of signal loss detected in MR images of EAE brain.

MRI and multinuclear MR spectroscopy of 3,200-year-old Egyptian mummy brain.

OBJECTIVE: Our objective was to present the MR and MR spectroscopy imaging findings of a 3,200-year-old preserved brain from an Egyptian mummy. MATERIALS AND METHODS: In this work, the morphology of the intact specimen was examined by MRI at 1.5 T. Chemistry of the intact specimens was studied by proton spectroscopy at 1.5 T and sodium nuclear MR (NMR) spectroscopy at 4.0 T. Biopsies from the temporal lobes were analyzed by proton and phosphorus NMR spectroscopy (14 T) or rehydrated and stained for paleohistologic study. RESULTS: MRI showed a heterogeneous brain with convolutions, gyri, and air pockets. Paleohistology showed a uniform, disorganized cerebral substance with numerous eosinophilic structures and argentophilic granules. Spectroscopic studies identified bound sodium ions in the specimen and phosphate and free fatty acids in extracts. CONCLUSION: MR techniques are a nondestructive method for the analysis of adipocere observed in a preserved mummy's brain.

Pathology-guided MR analysis of acute and chronic experimental allergic encephalomyelitis spinal cord lesions at 1.5T.

PURPOSE: To directly correlate spinal cord pathology of guinea pigs with experimental allergic encephalomyelitis (EAE) to the MRI data obtained at 1.5T. MATERIALS AND METHODS: Spinal cords from EAE animals were imaged in vivo with the following MRI sequences: T2-FSE, PD-FSE, fluid-attenuated inversion recovery (FLAIR)-FSE, T2-CSE, T1-CSE, T1-CSE + gadolinium-DTPA (Gd-DTPA), PD-CSE, and short-tau inversion recovery (STIR)-FSE. The spinal cords were removed and the lesions with specific pathological compositions were identified by histological analysis. Regions of interest (ROIs) were drawn on the corresponding MR images, and signal-to-noise ratios (SNRs) were measured for each MR sequence and compared with controls. RESULTS: The receiver operating characteristic (ROC) analysis of STIR-FSE and PD-CSE was able to differentiate tissue that contained cellular infiltrates with a high degree of accuracy. The SNRs of T2-FSE, STIR-FSE, T2-CSE, PD-CSE, and T1-CSE + Gd-DTPA were elevated in lesions that contained cellular infiltrates alone, whereas the SNRs of PD-CSE and T1-CSE + Gd-DTPA were reduced in demyelinated lesions that also contained inflammation. CONCLUSION: The SNR difference between the two lesion groups suggests that the combination of STIR-FSE, PD-CSE, and T1-CSE + Gd-DTPA sequences may be useful for differentiating inflammatory lesions containing demyelination from lesions with inflammation alone.

In vivo 4.0-T magnetic resonance investigation of spinal cord inflammation, demyelination, and axonal damage in chronic-progressive experimental allergic encephalomyelitis.

PURPOSE: To image and dissect the lumbar spinal cord of guinea pigs with chronic-progressive experimental allergic encephalomyelitis (CP-EAE) and directly correlate the pathology to the magnetic resonance (MR) image data obtained at 4 T and determine if these MR contrasts can accurately differentiate a specific type of pathology from control tissue. MATERIALS AND METHODS: The amount of inflammation, demyelination, and axonal pathology were quantified in the whole cord cross sections. The signal intensities (SIs) for 228 individual regions of interest (ROIs) (normal-appearing white matter (NAWM) and tissue containing inflammation with or without demyelination) were measured directly from the corresponding area on the MR images. RESULTS: Conventional MR contrast SIs and magnetization transfer ratio (MTR) were related to the degree of demyelination and presence of inflammation. MTR and proton density-weighted (PDw) SIs were both moderately related to axonal density. The SIs for NAWM and in lesions containing both cellular infiltrates and demyelination in all conventional MR contrast images were also increased, whereas the MTR was decreased when compared to control tissue. CONCLUSION: The SIs from the conventional MR contrasts and MTR at 4 T were sensitive to the presence of disease within CP-EAE spinal cord, but were not specific to the underlying pathology.

Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon?

Characteristic pathological features of multiple sclerosis (MS) include inflammation, demyelination and axonal and oligodendrocyte loss. In addition, lesions can also have a significant vascular component. In this review, morphological, biochemical and radiological evidence is presented suggesting angiogenesis as a potential focus for investigation in MS. We hypothesize that angiogenesis plays a significant role in the MS lesion, perpetuating disease progression. Thus, treatment strategies that inhibit angiogenesis may decrease clinical and pathological signs of disease. Several approaches for testing this hypothesis are outlined.

The cost of angiography procedures: OHIP gets a bargain.

OBJECTIVE: To determine the costs for 1000 randomized interventional angiographic procedures. METHODS: An 9-page paper form was used to manually record the consumables, technologist time, room occupancy time and recovery room time for 80 different procedures collected over a 2-year period. The average cost for expendables per procedure was calculated for procedures that occurred 5 or more times. RESULTS: Of the 1000 procedures surveyed, there were 20 that had 10 or more occurrences, 9 that occurred 5-9 times and 51 that occurred less than 5 times, of which 32 had only a single occurrence. The total expendables used were $514,008. The total examination time was 1158 hours. The total technologist time was 2493 hours, and the total recovery room time was 1806 hours. Examples of the average cost per procedure are: cerebral angiogram (n = 249), avg. cost $441.24, and transvenous liver biopsy (n = 30), avg. cost $642.89. The coefficient of variation for procedure costs ranged from 15% to 139%. There were no correlations of technician time or procedure technical cost with the date of scan, indicating that there was no systematic increase or decrease in costs over the survey period. There were moderate correlations of the technical cost of a procedure with technologist time (Pearson r = 0.69) and the duration of a procedure (Pearson r = 0.73). The technical costs of interventional procedures were significantly underfunded; the reimbursement from the Ontario Hospital Insurance Plan was $278,446, or 54% of the actual costs. Fourteen procedures were reimbursed at below 50% of their costs. CONCLUSION: This shortfall in funding has serious consequences for the types and numbers of procedures that are possible in radiology departments. Funds must be diverted from other places to prevent serious rationing of these services.