Axonal damage, demyelination and inflammation of the central nervous system are the major pathological features of multiple sclerosis (MS). MS is thought to be due to an abnormal T cell mediated immune response. Oxidative stress plays an important role in the advancement of MS. The reduced glutathione (GSH) has very important role in the management of oxidative stress. In our experiment we used Experimental autoimmune encephalomyelitis (EAE) animal model that mimic human MS and tested the effect of Thymoquinone (TQ) a constituent of oil of Nigella Sativa also known as black seed. Thirty female mice strain C57BL/6J between 6 to 12 weeks of age were placed into 3 groups of 10 and MOG was used subcutaneously (s.c) to induce EAE. Group A, the control group. Group B, received MOG (s.c) and TQ intraperiotoneally (i.p) from day 1 till day 50. Group C, received MOG (s.c) and TQ (i.p) was given on the appearance of first sign and symptoms of Chronic relapsing EAE (CR-EAE). All Mice were examined daily for behavioral deficits and all euthanized and sacrificed on day 50. In this study we found mice belonging to group C (EAE with TQ treatment after the appearance of chronic symptoms) were observed to have the highest mean clinical scores in both the acute and chronic phases of EAE with symptom reduction following the TQ injections. Group B (which received daily TQ injections) had decreased symptoms compared to Group A and C. Glutathione level dropped significantly in the control group (p < 0.05) and increased (p > 0.05) in groups B and C mice who received TQ injections. We also noted that EAE clinical signs correlated well with the extent of perivascular lymphocyte infiltrate compared with normal histology following TQ injections. Our results indicate that TQ, due to its anti-oxidant effects is almost 80% preventive and 50% curative in CR-EAE. These results could assist further studies on the mechanism of the action of TQ in CR-EAE and on the possibility of treating the chronic- relapsing phase of human multiple sclerosis. It seems within the realm of possibility that TQ may be as, if not more, therapeutically efficacious as interferon â and glatiramer acetate.

No description available.

Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / "December 2006" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

Background: Pain is frequently reported by people with multiple sclerosis (MS). It has been associated with decreased quality of life, psychiatric morbidity, interference with day to day activities, and frequent healthcare attendance. It has been reported by people with multiple sclerosis to be one of their most important symptoms, and available treatments are limited in their effectiveness. Despite this, our understanding of the epidemiology and mechanisms of pain in people with MS are limited. Our understanding of the interactions of central nervous system mechanisms and pain states overall is growing. However, the application of this knowledge to MS is incomplete. Previous studies have shown that the descending pain modulatory system (DPMS) is an endogenous network of cortical and subcortical brain structures which act to limit, or accentuate, an individual’s perception of pain, via descending brainstem pathways. Associated clinical measures include depression, anxiety, and cognitive flexibility. Our understanding of the function or dysfunction of this system in MS is limited. We do not know if the MS disease process may adversely affect the structure or function of the DPMS. Hypothesis: In people with neuropathic limb pain in relapsing remitting MS (RRMS), compared to people with RRMS who do not have pain, there will be disruption of the endogenous descending pain modulatory system. This will manifest as impaired descending inhibition of pain. Aims and Methods Establishing the background using systematic reviews: The first aim of this thesis was to establish the prevalence, natural history and associations of pain (and pain syndromes) occurring in people with MS. The second aim was to explore existing knowledge of how the MS disease process may contribute to pain states, using a systematic review of neuroimaging studies. Prospective clinical study: A case-control study of 47 people with RRMS was then carried out. 31 of these had neuropathic pain in the limbs, and 16 did not have pain. Using targeted assessments, function of the descending pain modulatory system was assessed in the following ways: First: Detailed clinical, behavioural and neuropsychological assessment, focussing on cognitive, behavioural and affective features known to be closely related to the DPMS. Second: MRI imaging of brain structure, focussing on the volume and location of MS lesions, as well as the volume of key grey-matter structures involved in the DPMS. Third: Resting state functional MRI imaging of the brain, focussing on functional connectivity between the rostral anterior cingulate cortex and two other key DPMS structures (dorsolateral prefrontal cortex, and periaqueductal gray). Results: Systematic reviews: Meta-analysis of existing prospective studies confirmed that pain is very common in MS, affecting about 63% of people with MS on average (95%CI between 55 and 70%). Many different types of pain contribute to this overall estimate. No significant associations with disease course or stage emerged. Several neuroimaging studies have assessed people with MS-associated pain using MRI. These studies were often small, and with associated methodological issues. It is likely that location of MS lesions is implicated in aetiology of pain syndromes in some cases, though our overall knowledge is limited. Prospective study: In a prospective study, people with and without pain were matched for age and gender. Furthermore, groups were balanced for a range of other variables. The pain group more frequently received gabapentinoid medications. The presence of pain was significantly associated with increased scores for depression, fatigue and catastrophising, as well as with specific impairments at neuropsychological assessment, including cognitive flexibility. Many of these impairments are directly relevant to existing models of the DPMS. Overall volume of MS lesions was not different in people with pain, though lesions were more likely to occur in the brainstem. Some alterations of grey-matter volumes in people with pain which mirrored studies of pain disorders outside MS were found, but these did not involve structures key to the DPMS. Affected structures included trigeminothalamic nucleus (relative volume increase in pain group), posterior cingulate cortex and parahippocampal gyrus (volume decrease in pain group). Functional connectivity of the rostral anterior cingulate cortex to the periaqueductal grey matter, a key structure in the descending modulation of pain, was stronger in the group without pain. Conversely, functional connectivity to the dorsolateral prefrontal cortex, repeatedly implicated in the DPMS and thought to be involved in cognitive evaluation and flexibility, was stronger in the pain group. MS lesion volume appeared to account for some of this difference in a multivariate analysis. Limitations: Key limitations of this work include cross-sectional design, small sample size, and number of statistical comparisons carried out. Conclusions: Systematic reviews examined the prevalence, natural history and associations of pain in MS, as well as examining existing neuroimaging studies which investigated how the MS disease process could contribute to pain states. A prospective study found evidence of both emotional/affective and cognitive dysfunctions relevant to the hypothesis of dysfunction in the DPMS. Higher likelihood of MS lesions in the brainstem could be relevant to DPMS function. Separately, there were structural grey-matter volume alterations reflecting those found in many pain studies outside MS. Importantly, however, these did not affect key DPMS structures. Resting state functional MRI however demonstrated altered connectivity of core DPMS structures, which may be partly mediated by MS lesion volume. Functional connectivity findings could be consistent with the hypothesis of impaired descending pain inhibition, in people with relapsing remitting MS affected by neuropathic limb pain.

No description available.

Objective: To evaluate the 5-year real-world benefit–risk profile of fingolimod in patients with relapsing–remitting MS (RRMS) in Germany. Methods: Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional realworld study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively. Results: At the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with ‘no change’ in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%). Conclusions: PANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term realworld treatment of patients with RRMS.

No description available.

Infectious diseases such as malaria and relapsing fever borreliosis (RF), cause severe human mortality and morbidity in developing countries. Malaria, caused by Plasmodium spp. parasites, is estimated by the World Health Organization to cause 1.5-2.7 million deaths annually. RF, caused by Borrelia spirochetes, has the highest prevalence described for any bacterial disease in Africa, with infection outcomes ranging from asymptomatic to fatal. RF borreliosis manifests in humans as a recurring fever and with other symptoms very similar to those of malaria. RF borreliosis has been regarded as a transient infection of the blood. However, B. duttonii exploits the brain as an immunoprivileged site escaping the host immune response while spirochetes in the blood are cleared. To investigate whether residual bacteria are dormant or actively dividing, mice with residual brain infection were administered ceftriaxone, a β-lactam antibiotic interfering with cell wall synthesis. Hence, it only affects actively dividing bacteria. Ceftriaxone eradicated brain RF infection in all treated mice, demonstrating that the bacteria are actively multiplying rather than in a dormant state. The findings support the therapeutic use of ceftriaxone for RF neuroborreliosis since penetration into cerebrospinal fluid is greater for ceftriaxone than for the often recommended doxycycline. The clinical features of malaria and RF are similar and diagnosis is further complicated by the frequently occurring concomitant malaria-RF infections. Therefore, we established a mouse model to study the pathogenesis and immunological response to Plasmodium/Borrelia mixed infection. Interestingly, malaria was suppressed in the co-infected animals whereas spirochete numbers were elevated 21-fold. The immune response in the concomitantly infected mice was polarized towards malaria leaving the spirochetes unharmed. Mice with co-infections also exhibited severe anemia and internal damages, probably attributed to escalating spirochete numbers. A secondary malaria infection reactivated the residual brain RF infection in 60% of the mice. This highlights the importance of co-infections as diagnostic pitfalls as well as the need for novel treatment strategies. Currently there is no commercial malaria vaccine and increasing drug resistance presents an urgent need for new malaria chemotherapeutics. Blood-stage malaria parasites are rapidly growing with high metabolic and biosynthetic activity, making them highly sensitive to limitations in polyamine supply. Disrupting polyamine synthesis in vivo with trans-4-methylcyclohexylamine (4MCHA) eradicated the malaria infection gradually, resulting in protective immunity. This leads the way for further biochemical and pharmacological development of the polyamine inhibitor 4MCHA and similar compounds as antimalarial drugs

The peripheral naive CD4 T cell pool is homeostatically regulated through a balance of thymic production, delivery of survival signals and homeostatic proliferation. CD4 recent thymic emigrants (RTEs) have a high T cell receptor excision circle (TREC) content and express high levels of CD31. We report premature thymic involution in RRMS, initiated by reduced numbers of naive CD4 T cells and various naive CD4 T cell subsets in peripheral blood. Further, CXCR4, a receptor involved in emigration from the thymus, and CD127 and Bcl-2 (survival signals) are upregulated in various naive CD4 T cell subsets in RRMS. As a compensatory process, naive CD4 T cells undergo homeostatic proliferation. This proliferation is a form of peripheral positive selection through self-MHC/self-antigen interaction and thus can contribute to the expansion of autoreactive T cells and predispose to development of RRMS.

Host cell attachment by pathogenic bacteria can play very different roles in the course of infection. The pathogenic spirochetes Borrelia hermsii and Borrelia burgdorferi sensu lato which cause relapsing fever and Lyme disease, respectively, are transmitted by the bite of infected ticks. After transmission, these spirochetes can cause systemic infection. Relapsing fever spirochetes remain largely in the bloodstream causing febrile episodes, while Lyme disease will often colonize a variety of tissues, such as the heart, joint and nervous system, resulting in a chronic multisystemic disorder. Borrelia species have the ability to bind to various cell types, a process which plays a crucial role in pathogenesis and may influence spirochetal clearance from the bloodstream. Colonization of multiple tissues and cell types is likely promoted by the ability to bind to components found in target tissues, and many B. burgdorferi adhesins have been shown to promote attachment to a wide variety of cells and extracellular matrix components. Different Lyme disease strains have been shown to preferentially colonize certain tissues, although the basis of this tissue tropism is not well understood. In this study we found that among different Lyme disease strains, allelic variation of the adhesin DbpA contributes to variation in its in vitro binding activities raising the possibility that this variation contributes to tissue tropism in vivo. In studying B. hermsii infection, we found evidence by both histological and fluorescence in situ hybridization (FISH) analysis of tissues that indicated that red blood cells were removed by tissue resident macrophages in infected mice. Spirochetes in the spleen and liver were often visualized associated with RBCs, lending support to the hypothesis that direct interaction of B. hermsii spirochetes with RBCs leads to clearance of bacteria from the bloodstream. Our findings indicate that host cell attachment play a key role in the establishment of Lyme disease infection, and in contrast contributes to the clearance of relapsing fever infection.