No description available.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

Approximately half of Multiple Sclerosis (MS) patients experience cognitive deficits. Accessing neuropsychological assessment can be challenging due to the considerable time, expense, and expertise required for test administration. Computerized cognitive testing has been proposed as an alternative. The objective was to validate a computer generated cognitive screen for MS patients. Ninety-nine MS patients and 98 healthy controls completed the computerized battery consisting of the Stroop, Symbol Digit Modalities Test (C-SDMT), Paced Auditory Serial Addition Test (PVSAT-2, PVSAT-4), and simple and choice reaction time tests. The Minimal Assessment of Cognitive Function in MS (MACFIMS) was used to define cognitive impairment in the MS sample. A combination of the C-SDMT, PVSAT-2, PVSAT-4 had a sensitivity of 83.3% and specificity of 87.7% in detecting cognitive impairment. Each measure had good test-retest reliability (p < 0.001). High sensitivity and specificity, and brevity emphasize the usefulness of the computerized cognitive screen in busy MS clinics.

Approximately half of Multiple Sclerosis (MS) patients experience cognitive deficits. Accessing neuropsychological assessment can be challenging due to the considerable time, expense, and expertise required for test administration. Computerized cognitive testing has been proposed as an alternative. The objective was to validate a computer generated cognitive screen for MS patients. Ninety-nine MS patients and 98 healthy controls completed the computerized battery consisting of the Stroop, Symbol Digit Modalities Test (C-SDMT), Paced Auditory Serial Addition Test (PVSAT-2, PVSAT-4), and simple and choice reaction time tests. The Minimal Assessment of Cognitive Function in MS (MACFIMS) was used to define cognitive impairment in the MS sample. A combination of the C-SDMT, PVSAT-2, PVSAT-4 had a sensitivity of 83.3% and specificity of 87.7% in detecting cognitive impairment. Each measure had good test-retest reliability (p < 0.001). High sensitivity and specificity, and brevity emphasize the usefulness of the computerized cognitive screen in busy MS clinics.

Intravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however, its mechanism of action remains elusive. Our results demonstrate a novel finding wherein IVIg treatment induces a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and that the liver is the organ of increased IL-11 transcription. Furthermore, we show that IL-11Rα knockout mice, although initially protected, become resistant to protection by IVIg during experimental autoimmune encephalomyelitis (EAE) and develop disease with a similar incidence and severity as control-treated IL-11Rα-/- mice. The inability of IVIg to prevent EAE in IL-11Rα-/- mice correlated with a failure of this agent to decrease IL-17 production by myelin-reactive T-cells in the draining lymph nodes. Finally, we show that IL-11 can directly inhibit IL-17 production by lymph node cells in culture. Together, these results implicate IL-11 as an important immune effector of IVIg in the amelioration of EAE.

Disease maps are geographical maps that display local estimates of disease risk. When the disease is rare, crude risk estimates can be highly variable, leading to extreme estimates in areas with low population density. Bayesian hierarchical models are commonly used to stabilize the disease map, making them more easily interpretable. By exploiting assumptions about the correlation structure in space and time, the statistical model stabilizes the map by shrinking unstable, extreme risk estimates to the risks in surrounding areas (local spatial smoothing) or to the risks at contiguous time points (temporal smoothing). Extreme estimates that are based on smaller populations are subject to a greater degree of shrinkage, particularly when the risks in adjacent areas or at contiguous time points do not support the extreme value and are more stable themselves. / A common goal in disease mapping studies is to identify areas of elevated risk. The objective of this thesis is to compare the accuracy of several fully Bayesian hierarchical models in discriminating between high-risk and background-risk areas. These models differ according to the various spatial, temporal and space-time interaction terms that are included in the model, which can greatly affect the smoothing of the risk estimates. This was accomplished with simulations based on the cervical cancer rate of Kentucky and at-risk person-years of the state of Kentucky's 120 counties from 1995 to 2002. High-risk areas were 'planted' in the generated maps that otherwise had background relative risks of one. The various disease mapping models were applied and their accuracy in correctly identifying high- and background-risk areas was compared by means of Receiver Operating Characteristic curve methodology. Using data on Multiple Sclerosis (MS) on the island of Sardinia, Italy we apply the more successful models to identify areas of elevated MS risk.

520 L $$aIn the CNS, myelination of axons is essential for the rapid conduction of impulses down the nerve. In demyelinated or failing axons however, conduction is less efficient and requires more energy. The principal function of mitochondria is to provide energy for the axon but in doing so they generate most of the intra-axonal reactive oxygen species (ROS). Therefore and increased energy requirement will promote an increased production of ROS which could lead to significant damage to essential DNA, proteins and lipids and could eventually damage the axon. This thesis investigates the mitochondrial involvement in axonal pathology in the CNS diseases, multiple sclerosis (MS), autosomal dominant optic atrophy (ADOA) and tosomal dominant optic atrophy with cataract (ADOAC).

No description available.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.