bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential treatment effect on measures of neurologic exam, functional impairment and patient self-report in multiple sclerosis
Authors: Hoogervorst E LJ , Kalkers N F , van Winsen L ML , Uitdehaag B MJ , Polman C H
Published: January 2007

Objective: To determine the relative sensitivity of the Expanded Disability Status Scale (EDSS), the newly developed MS Functional Composite (MSFC) and the Guy's Neurological Disability Scale (GNDS) to changes in the neurological condition of Multiple Sclerosis (MS) patients induced by treatment with intravenous methylprednisolone (IV-MP). Methods: Sixty MS patients were treated with IV-MP. On the first day of treatment patients were trained for the three domains of the MSFC; on the second day baseline data were obtained for all measurements. Follow-up data were obtained 6-8 weeks after IV-MP treatment. Results: Significant changes were found for both EDSS and GNDS. Remarkably, the improvements on the GNDS were mainly due to changes in the subcategories cognition, speech, fatigue and `others'. No significant change was found for the MSFC. Forty-seven patients reported a subjective improvement in their condition. Twenty-one patients showed a significant improvement in the EDSS, 28 patients showed a significant improvement in the GNDS and a very small number of significant changes were found on the MSFC (actual number depending on the definition of the reference population). Conclusion: The observations in this study show that the relative sensitivity to change in acute or subacute deterioration in MS patients, is low for the MSFC and high for the GNDS. It is obvious from this study that such a treatment can have a differential effect on measurements of functional impairment, rating of neurologic examination and patient self-report.
Cerebrospinal fluid markers in multiple sclerosis: an overview
Authors: Massaro A R , Tonali P
Published: January 2007

Cerebrospinal fluid (CSF), with its protein markers, is a formidable material for investigating the relationships among the various cell types involved during the initial phase of plaque formation, or, successively, in the remyelination process. Its analysis may give definite help in better focusing on therapeutic objectives and therapeutic tools. Therefore, the possible use of CSF MBP, S-100, GFAP, N-CAM, NGF, and CNTF in pathogenetic studies and in clinical follow-up is critically reviewed. The need for correct interpretation of the data, for uniformity and reliability of the analytical methods, and for easy access to them is stressed. CSF examination and MRI should not be considered as alternative tools, or in competition, but should be used together, to take the maximum advantage of their individual possibilities.
Multiple Sclerosis: IL-2 and sIL-2R levels in cerebrospinal fluid and serum. Review of literature and critical analysis of ELISA pitfalls
Authors: Sivieri S , Ferrarini A M , Gallo P
Published: January 2007

The presence of interleukin-2 (IL-2) and soluble IL-2 receptors (sIL-2R) in the serum and cerebrospinal fluid (CSF) of patients suffering from multiple sclerosis (MS) has been extensively investigated. These studies, however, have produced conflicting results. The only significant finding concerns the frequent detection of increased sIL-2R levels in the serum in patients with relapsing-remitting MS (RRMS), especially after a short interval of time from the last relapse. Whether this finding can be used for clinical purposes requires further investigation. A standardization of the ELISA methods used to detect cytokines in biological fluids is urgently needed. Increased serum and/or CSF levels of IL-2 and sIL-2R strongly confirm a CD4+Th1 activation.
Myelin basic protein in cerebrospinal fluid and other body fluids
Authors: Whitaker John N
Published: January 2007

Myelin basic protein (MBP) or a fragment thereof may enter cerebrospinal fluid (CSF) and other body fluids in an etiologically nonspecific fashion to provide information about the status of central nervous system (CNS) myelin damage. MBP immunochemically detected is referred to as MBP-like material (MBPLM). The clinical utility of the assay for MBPLM in CSF is to document the presence, continuation, or resolution of CNS myelin injury. The analysis of CSF for MBPLM is subject to many variables, among which are the antisera and the form of the assay utilized. The dominant epitope of CSF MBPLM is in the decapeptide of 80-89 from the intact MBP molecule of 170 residues. Normally, CSF has no detected MBPLM. Following an acute relapse of MS, MBPLM rises quickly in the range of ng/ml and rapidly declines and disappears. The presence of MBPLM in CSF in chronic and progressive phases of the disease is unusual, but it may sometimes be detected in low levels, depending on the assay used for detection. The level of CSF MBPLM is related to both the mass of CNS myelin damage and how recently it occurred. The level of CSF MBPLM rarely is elevated in optic neuritis. The level of CSF MBPLM is unrelated to CSF protein level, level of IgG, presence of oligoclonal bands or pleocytosis. CSF MBPLM has the potential of serving as a marker of therapeutic effectiveness in MS and does have predictive value for response to glucocorticoids given for worsening of disease. The detection of MBPLM in body fluids other than CSF would be of great value because of the resulting improved feasibility for objectively monitoring the natural history of MS and response to therapy. Studies on blood have yet to produce a valid assay of MBPLM. Urinary MBPLM, though different in its features from that in CSF, may provide a correlate, not with acute demyelination in MS as is the case for CSF, but with progression of disease.
Cerebrospinal fluid and serum nitric oxide metabolites in patients with multiple sclerosis
Authors: Giovannoni G
Published: January 2007

Nitric oxide is hypothesised to play a role in the immunopathogenesis of multiple sclerosis. Raised cerebrospinal fluid and serum levels of the nitric oxide metabolites nitrate and nitrite have been described in patients with multiple sclerosis. Cerebrospinal fluid and serum nitrate and nitrite were measured in patients with multiple sclerosis, inflammatory and non-inflammatory neurological diseases, and correlated with the albumin quotient, an index of blood-brain-barrier dysfunction. Patients undergoing diagnostic lumbar and vene puncture were prospectively recruited, clinical data were obtained from the hospital records, and the CSF and serum nitrate and nitrite levels were measured by the nitrate reductase and Griess reaction methods. Nitrate and nitrite, were raised in the CSF and serum of patients with multiple sclerosis and other inflammatory neurological diseases compared to patients with non-inflammatory neurological disorders (median nitrate and nitrite: cerebrospinal fluid=10.3 μM vs 15.4 μMvs 6.6 μM, P50.001, and serum=49.0 μM vs 46.4 μM vs 38.8 μM, P=0.02, respectively). CSF nitrate and nitrite levels correlated with the albumin quotient (n=59, r=0.42, P50.001). This study provides further evidence for a role of nitric oxide in the immunopathogenesis of multiple sclerosis and supports a role for nitric oxide as a possible mediator of inflammatory blood-brain-barrier dysfunction.
Identification of peptides binding to IgG in the CSF of Multiple Sclerosis patients
Authors: Cortese I , Capone S , Tafi R , Grimaldi L ME , Nicosia A , Cortese R
Published: January 2007

Phage displayed random peptide libraries were screened in order to identify phagotopes reacting with the IgG present in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. Six families of phagotopes each composed of different isolates were identified. These phagotopes were used as reagents, to characterise IgG present in the CSF of MS patients. The following results were obtained: (a) CSF antibodies from different patients display different specificities; (b) anti-phagotope antibodies are also present in the serum of MS patients; (c) Anti-phagotope antibodies are equally frequent in the serum of MS patients and of healthy individuals; (d) some of the anti-phagotope antibodies are enriched in the CSF of MS patients. These data show that the natural antigen(s) recognised by CSF antibodies is rather common in the general population. By using the selected phagotopes as immunogens in rabbits, we have derived large quantities of anti-phagotope antisera which can provide for useful tools toward the identification of the natural antigen(s) recognised by MS CSF antibodies.
JC virus excreted by multiple sclerosis patients and paired controls from Hungary
Authors: Stoner Gerald L. , Agostini Hansjürgen T. , Ryschkewitsch Caroline F. , Komoly Samuel
Published: January 2007

JC virus (JCV), a human polyomavirus, is the agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV exists in four main genotypes in the USA. Type 1, including subtypes Type 1A and Type 1B, makes up about 64% of strains in the USA and is thought to be of European origin. Type 2 is found in Asia, and Type 3 in Africa. A fourth type is found only in the USA. In general, these genotypes differ in 1-2.5% of their DNA sequence. Thirty MS patients and 30 paired controls from Budapest were studied. The clinical course of MS was mainly secondary progressive, and patients were stable at the time of testing. Most of the controls were relatives of the probands: a spouse, parent, or child. Overall, 25 of 60 (42%) of the urines tested positive for JCV by PCR. These included 13 of 30 MS patients, and 12 of 30 controls. Genotyping in the VP1 gene showed all 25 JCV strains to be Type 1. Among the MS patients, seven were Type 1A and six were Type 1B. Among the controls, nine were Type 1A and three were Type 1B. In five pairs of MS patients and controls, both were positive for JCV by PCR. Two of these were husband/wife pairs of which one pair was matched for subtype (both Type 1A), and the other was not. Two of them were mother/daughter pairs, and both were matched for subtype (both Type 1B). These findings demonstrate that JCV Type 1 predominates among Hungarians, and suggest that parent/child pairs can be used to trace JCV transmission within the MS family.
Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions
Authors: Mews I , Bergmann M , Bunkowski S , Gullotta F , Brück W
Published: January 2007

Oligodendrocyte and axon pathology was studied in 11 autopsy cases of clinically silent multiple sclerosis. A total of 54 lesions, either demyelinated or late remyelinated, were distributed through the whole brain and spinal cord with 39% of the lesions located in periventricular areas. Determination of axon density revealed an average reduction of 64% and 59% in demyelinated and remyelinated lesions with an extreme variation between different plaques and cases. Oligodendrocytes were identified by immunocytochemistry for myelin oligodendrocyte glycoprotein (MOG) and in situ hybridization for proteolipid protein (PLP) mRNA. Oligodendrocytes were almost completely lost in demyelinated lesions; remyelinated lesions revealed preservation of a considerable number of oligodendrocytes within the lesions. At the border between plaques and the periplaque white matter, similar oligodendrocyte numbers as in remyelinated lesions were found. Different factors including lesion site, axonal preservation and remyelination may thus contribute to the clinical nonappearance of multiple sclerosis lesions.
Immunomodulating functions of recombinant ovine interferon tau: potential for therapy in mulitple sclerosis and autoimmune disorders
Authors: Khan O A , Jiang H , Subramaniam P S , Johnson H M , Dhib-Jalbut S S
Published: January 2007

The interferons (IFN) are a family of complex proteins possessing antiviral, antiproliferative, and immunomodulatory activities. Two type 1 recombinant human IFN have been recently approved for the treatment of multiple sclerosis (MS). However, use of high dose type 1 IFN treatment in MS patients has been limited by dose-related toxicity. Ovine IFNt is a unique type 1 interferon discovered for its role in the animal reproductive cycle. It differs from other type 1 IFNs in that it is remarkably less toxic even at high concentrations, is able to cross species barriers, and is not inducible by viral infection. Ovine IFNt has been shown to be very effective in the treatment of animal models of MS. In this study, we examined the toxicity of OvIFNt on human T-cells at high doses and its immunregulatory properties at equivalent doses. Our experiments confirmed the remarkably non-toxic nature of OvIFNt on human cells at high concentrations as well as immunomodulating properties consistent with other type 1 IFNs including an antilymphoproliferative effect and inhibition of IFNg-induced HLA class II expression. These results suggest that OvIFNt could be developed into a potentially less toxic therapeutic option for immune-mediated disorders including MS.
Monocyte activation in multiple sclerosis
Authors: Reder Anthony T , Genc Kursad , Byskosh Paul V , Porrini Anna Maria
Published: January 2007

Monocytes, macrophages, and microglia have a central role in the CNS inflammation of MS. Monocytes are important in the earliest events in MS. Peripheral blood monocytes secrete prostaglandins before MS attacks. During clinical activity monocyte activation markers increase and IL-1 and TNF-a levels are elevated. Other monocyte products such as IL-10 reduce inflammation. IL-10 mRNA in MNC is increased during stable disease. Manipulation of monokine secretion and expression of monocyte surface proteins are reasonable approaches for immune therapy of MS.
Cytokines in multiple sclerosis: pro-inflammation or pro-remyelination?
Authors: Sharief M K
Published: January 2007

The targets of the inflammatory response in multiple sclerosis (MS) are myelin and the myelin producing cells, oligodendrocytes. The infiltration of activated immune cells and recruitment of endogenous glia lead to the destruction of myelin and oligodendrocytes, a process that is compounded by the release of cytokines by infiltrating cells. Recent evidence suggests that key cytokines that are responsible for the destruction of myelin may also mediate the process of remyelination and repair. It appears that both inflammatory and repair processes are governed by the temporal and spatial relation of cytokines to their targets.
Serum soluble intercellular adhesion molecule-1 in MS: relation to clinical and Gd-MRI activity and to rIFNβ-1b treatment
Authors: Trojano M , Avolio C , Ruggieri M , Defazio G , Giuliani F , Paolicelli D , Livrea P
Published: January 2007

The validity of serum sICAM-1 levels to assess Multiple Sclerosis (MS) activity was evaluated in 49 untreated definite relapsing-remitting (RR) patients. sICAM-1 levels were significantly (P = 0.0009) higher in the `clinically active' group (No 22) than in the `clinically inactive' (No 27), whereas no different values were found between patients with Gd-enhancing lesions at MRI (Gd-positive) (No 32) and patients without such lesions (Gd-negative) (No 17) independently of their clinical activity. Among the `clinically active' MS, the Gd-positive (No 16) subgroup showed significant (P50.05) lower sICAM-1 levels when compared to the Gd-negative (No 6) subgroup, but higher (P = 0.009) than those of the `clinically inactive Gd-positive' (No 16) patients. The sICAM-1 levels did not differ between the two `clinically inactive' subgroups Gd-positive (No 16) and Gd-negative (No 11). Finally the clinically active Gd-negative (No 6) showed sICAM-1 levels higher (P = 0.002) than the clinically inactive Gd-negative (No 11). The specificity of high serum sICAM-1 levels (above M+2 s.d. of control values) to assess the disease activity in MS resulted higher (100%) using clinical than Gd-MRI activity (76%) as gold standard. The changes induced by 1 year recombinant Interferon-b-1b (rIFNb-1b) treatment on sICAM- 1 serum levels were also longitudinally investigated in 36 of the 49 RR MS. sICAM-1 levels at baseline significantly increased in the first 2 months (baseline vs 1st month P50.0001 and 1st vs 2nd month P=0.02), persisted at high levels without any significant change after 3 months, showed a temporary decrease at 6 months, then significantly increased again at 9 and 12 months. Fourteen patients experienced relapses, with a total of 20 relapses, during the whole treatment duration. The mean relapse/rate and the frequency of patients with Gd-positive MRI scans resulted significantly higher in the first semester compared to the second semester of treatment. This study adds further insights into the validity of serum sICAM-1 to assess disease activity in MS and on the immunomodulatory properties of rIFNβ-1b.
A unique population of circulating autoantibodies promotes central nervous system remyelination
Authors: Asakura K , Rodriguez M
Published: January 2007

In previous studies we demonstrated that the humoral immune response directed against unique central nervous system (CNS) antigens enhanced CNS remyelination in the Theiler's virus experimental model of multiple sclerosis (MS). To expand on this observation, a mouse IgMk monoclonal antibody (mAb) which enhances CNS remyelination, was raised against normal mouse spinal cord homogenate. Characterization of this mAb revealed that it is polyreactive towards variety of intracellular antigens but also reacts to an unidentified surface antigen on oligodendrocytes. The mAb is encoded by germline immunoglobulin genes without somatic mutations consistent with the observation that it is a natural autoantibody. Recently we generated another mouse IgMk mAb raised against normal spinal cord homogenate, which also promotes CNS remyelination. Further characterization revealed that both mAbs which promote remyelination have similar binding characteristics. Conventionally Abs which recognize normal CNS components, especially oligodendrocytes or myelin, have been considered to be a disease marker or be involved in the pathogenesis of MS. However, we have identified a unique population of circulating autoantibodies which are beneficial for myelin repair. Therefore this observation indicates the need to reevaluate autoantibody production against myelin components in CSF and blood as markers of disease activity versus repair in MS.
A gene therapy approach to treat demyelinating diseases using nonreplicative herpetic vectors engineered to produce cytokines
Authors: Martino G , Furlan R , Galbiati F , Poliani P L , Bergami A , Grimaldi L ME , Adorini L , Comi G
Published: January 2007

A successful gene therapy approach in organ-specific autoimmune diseases, such as multiple sclerosis (MS), encompasses the inhibition of the autoreactive T cells or the modification of the target organ cells by the introduction of exogenous `protective' genes. In MS, an autoimmune disease of the central nervous system (CNS), the inciting autoantigen is still unknown and therefore the isolation of autoreactive T cells may only be inferential. At present, gene therapy approaches in MS should therefore aim to the modification of the target organ. Possible candidate genes to be transferred within the CNS of MS patients are those coding for anti-inflammatory cytokines (i.e. interleukin-4, interleukin-10, transforming growth factor b) which have been shown to ameliorate demyelinating diseases at least in experimental models. However, a limiting factor for this therapy is the difficulty to reach the CNS. A gene therapy approach using viral vectors able to infect post-mitotic cells, such as those present within the CNS, without inducing toxic reactions, may overcome this limitation. We propose to use non-replicative herpetic vectors, which represent a viable gene-transfer alternative to the classical retroviral and adenoviral vectors. Key advantages are their size, able to accommodate multiple foreign genes, and their ability to infect post-mitotic cells such as those present within the CNS. We first transferred a gene coding for interleukin-4 within the CNS of mice undergoing experimental allergic encephalomyelitis, an animal model for MS, using non-replicative Herpes Simplex Virus type 1- derived vectors. We found that this approach ameliorates the disease course and delays the disease onset. The establishment of this technique to deliver anti-inflammatory cytokines within the CNS using herpetic vectors should clarify the role of individual cytokines in the demyelinating process and allow assessment of whether gene therapy using herpetic vectors is a feasible and safe approach to treat human demyelinating disorders.
Neurophysiological and cognitive markers of disease evolution in multiple sclerosis
Authors: Comi G , Martinelli V , Locatelli T , Leocani L , Medaglini S
Published: January 2007

Both evoked potentials and cognitive tests may provide useful information which cannot be derived from the clinical observation. For this reason, there have been some attempts to use EPs in monitoring the natural history of the disease and in assessing the efficacy of therapeutic trials. However, no conclusion can be derived from the few available data. Although MRI is more sensitive than EPs in revealing new lesions in brain, cerebellum and brainstem, EPs are more sensitive in revealing optic nerve and spinal cord lesions. Moreover, the poor relationship between brain MRI abnormalities and disability has raised the possibility that cognitive evaluation may be an additional sensitive marker of brain involvement over time. Since the gold standard for the assessment of disease activity is uncertain, it is therefore advisable that frequent MRI, EPs and cognitive assessment may integrate clinical outcomes measured by conventional scales, both in the study of the natural disease course and in monitoring clinical trials.
Body fluid markers to monitor multiple sclerosis: the assays and the challenges
Authors: Laman J D , Thompson E J , Kappos L
Published: January 2007

The need for reliable markers of disease activity in multiple sclerosis (MS) to better guide basic research, diagnosis, treatment, and monitoring of therapy is well-recognized. A recent European Charcot Foundation Symposium (Body fluid markers for course and activity of disease in multiple sclerosis (Madrid, Spain, October 2-4, 1997) organized by the European Charcot Foundation and the Fundación Española de Esclerosis Múltiple (the Spanish Multiple Sclerosis Foundation) brought together experts in the field to review the state of the art for the technology measuring markers in body fluids. An array of different approaches was presented to measure a wide diversity of classic and novel marker molecules, including cytokines, adhesion molecules, myelin compounds, and free antibody light chains, in either blood, urine, or cerebrospinal fluid. Here, recent progress in these approaches is assessed in the context of distinct pathophysiological stages of the disease, the requirements which such molecules and assays should ideally meet, and the practical and conceptual challenges which they face. Recommendations for further improvements are described.
The effect of cross-talk on MRI lesion numbers and volumes in multiple sclerosis using conventional and turbo spin-echo
Authors: Filippi Massimo , Yousry Tarek A , Rocca Maria A , Pereira Clodoaldo , Alkadhi Hatem , Comi Giancarlo
Published: January 2007

We measured and compared lesion numbers and volumes present on brain magnetic resonance imaging (MRI) scans of patients with multiple sclerosis (MS) acquired with contiguous (scheme A) and interleaved (scheme B) slice acquisition, to evaluate whether there was a gain in sensitivity using the second pattern of acquisition and whether this counterbalanced the doubled acquisition time. Conventional spin-echo (CSE) sequences were performed for eight patient and turbo spin-echo (TSE) sequences for ten. Acquisition scheme B detected 3.8% more lesions than acquisition scheme A (the increase was 3. 1% for CSE and 4.5% for TSE). These differences were not statistically significant. No significant difference in lesion numbers was found when different lesion locations were also considered. Lesion volumes were significantly higher when scheme B was used (P= 0.024). This was due to higher lesion volumes on TSE images (P= 0.006), especially on even-numbered slices (P= 0.008). Inter-slice cross-talk has a negligible effect on lesion numbers and volume estimates in MS for CSE sequence, whilst it cannot be neglected when TSE sequences are used to measure MS lesion volume.
Cerebrospinal fluid measures of disease activity in patients with multiple sclerosis
Authors: Sellebjerg Finn , Christiansen Michael , Nielsen Peter Michael , Frederiksen Jette L
Published: January 2007

The potential of magnetic resonance imaging to serve as a surrogate marker of disease activity in patients with multiple sclerosis (MS) is increasingly recognised. In contrast, the use of cerebrospinal fluid analysis has received less attention. We analysed the correlation between clinical data and cerebrospinal fluid parameters in 75 patients with acute optic neuritis (ON) as a possible first symptom of MS, as a symptom of clinically definite MS, and in patients with an attack of MS other than ON. The samples were obtained within 30 days from the onset of an exacerbation. The concentration of myelin basic protein (MBP) in cerebrospinal fluid was significantly correlated with the visual acuity in patients with ON and the Kurtzke EDSS score in patients with MS. The concentration of MBP in CSF also correlated positively with the CSF leukocyte count, intrathecal IgG synthesis, and the CSF-serum albumin concentration quotient. The concentration of MBP in CSF correlated negatively with intrathecal IgA synthesis. The results support the use of the concentration of MBP in CSF as a surrogate marker of disease activity during acute exacerbations of MS; the data also link the presence of MBP in CSF to neuroimmunological parameters.
Assessing relapses in treatment trials of relapsing and remitting multiple sclerosis: can we do better?
Authors: Liu C , Blumhardt L D
Published: January 2007

Published Phase III immunomodulatory treatment trials in relapsing and remitting multiple sclerosis have demonstrated a modest decline in attack rates, but only a minor effect on disability. As genuine disability progression is difficult to ascertain in relatively short studies with the conventional rating scales available, the acquisition and analysis of relapse data are critical. However, there are as yet unresolved questions related to the latter. We will first discuss the problems associated with relapse definitions by trial investigators, the paucity of the data collected (especially on the magnitude and duration of exacerbations) and statistical issues in their analysis. We will then suggest practical points for obtaining more accurate information on relapses and evaluating them meaningfully. While there is still general consensus among neurologists that primary endpoints for therapeutic trials should be clinical, improvements for future protocols are essential.
Pathological laughing and crying in multiple sclerosis: a preliminary report suggesting a role for the prefrontal cortex
Authors: Feinstein A , O'Connor P , Gray T , Feinstein K
Published: January 2007

As part of a wide ranging study investigating the prevalence, demographic and disease related characteristics of pathological laughing and crying (PLC) in multiple sclerosis (MS), a putative role for the prefrontal cortex was also explored. Eleven multiple sclerosis (MS) patients with carefully defined PLC were compared to a control group of 13 MS patients without PLC on various cognitive indices known to be sensitive to frontal lobe dysfunction. Although the two groups did not differ with respect to age, sex, physical disability, disease course, duration of MS, years of education, premorbid IQ, and depression, the PLC group performed more poorly on the Stroop test and a measure of verbal fluency. They also showed a trend to make more total errors on the Wisconsin Card Sort Test. The relevance of these findings to the pathogenesis of PLC is discussed, in particular whether the syndrome is, in part, mediated by dysfunction of the prefrontal cortex.
Relationship between tumour necrosis factor-alpha (TNFα) production and a specific multiple sclerosis (MS) associated TNF gene haplotype
Authors: Armstrong M A , McDonnell G V , Graham C A , Kirk C W , Droogan A G , Hawkins S A
Published: January 2007

Objective: To determine if monocyte TNFa production from patients homozygous for a specific MS associated TNF gene haplotype is different from that produced in patients either heterozygous for, or without this haplotype. Background: The balance between pro- and anti-inflammatory cytokines is important in the clinical outcome of inflammatory reactions. Levels of TNFa, a pro-inflammatory cytokine, is raised in MS as well as being found in acute and chronic MS lesions. A previous population based study in Northern Ireland with polymorphisms spanning the TNF gene region identified a conserved MS associated haplotype in relation to three markers (130: 118: 127 TNF d: a: b) for which 19 MS patients were homozygous. Methods: Venous blood collected in EDTA to give a concentration of 1073 M was drawn from 16 patients with the conserved MS associated haplotype, 19 patients heterozygous for the haplotype and 17 patients without the haplotype. Mononuclear cells were separated and cultured by standard techniques and levels of TNFa and of TNF binding proteins I and II were determined by commercial enzyme-linked immunosorbent assays. Results: There were no significant differences in TNFa production in the 3 h (P=0.28) or 24 h cultures (P=0.18) or following stimulation with interferon-g (P=0.17) between the group positive for the conserved haplotype and the group negative for this haplotype. There was also no significant difference when compared to the heterozygote group. No association was found between the MS associated haplotype and levels of either TNF binding protein. A greater proportion of patients with the conserved haplotype had a benign clinical course (P=0.06). Conclusion: We conclude that whilst a trend exists, we have found no significant association between peripheral TNFa production and a specific MS associated TNF haplotype in this population. Paradoxically this haplotype may also predict a more favourable clinical course.
Prognostic factors for survival in multiple sclerosis
Authors: Lević Z M , Dujmović I , Pekmezović T , Jarebinski M , Marinković J , Stojsavljević N , Drulović J
Published: January 2007

In a hospital-based study of 119 patients with definite multiple sclerosis, demographic and clinical factors were analysed with respect to their validity in assessing the long-term prognosis. Over a mean follow-up of 21.7 years, the following factors negatively influenced the prognosis by the univariate analysis: male sex, age at onset over 25, pyramidal involvement or spasticity at onset, 53 functional systems affected at onset or after 5 years, incomplete first remission, length of the first remission 41 year, 45 attacks in the first 10 years, secondary or primary-progressive disease, time to reach secondary progression over 5 years and time to reach EDSS 6 over 7 years. The multivariate model showed that in patients with relapsing-remitting disease, 5 years after onset, pyramidal involvement at onset and shorter time to reach EDSS 6 predicted poor outcome, while after 10 years, higher age at onset and incomplete first remission indicated poor prognosis. Ten years after onset, the predictors of poor outcome in the secondary-progressive group were shorter time to reach EDSS 6 or secondary progression and higher EDSS, while in the primary-progressive group those variables were spasticity or higher number of functional systems affected at onset, and higher EDSS after 5 and 10 years.
A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis
Authors: Rostami A M , Sater R A , Bird S J , Galetta S , Farber R E , Kamoun M , Silberberg D H , Grossman R I , Pfohl D
Published: January 2007

Extracorporeal photopheresis is a safe therapy for cutaneous T-cell lymphoma and may have efficacy in certain autoimmune disorders. We performed a randomized, double-blinded, placebo-controlled trial of monthly photopheresis therapy in 16 patients with clinically definite multiple sclerosis (MS). All patients had progressed during the preceding year with entry Expanded Disability Status Scale (EDSS) scores between 3.0 and 7.0. Patients received photopheresis or sham therapy for 1 year and were followed for an additional 6 to 12 months. Patients were clinically evaluated by three disability scales: (1) EDSS; (2) Ambulation index and (3) Scripp's quantitative neurologic assessment. No serious side effects occurred in either group. There were no differences between the photopheresis and sham therapy groups by the disability measures. Additionally, there were no differences in progression of MRI plaque burden or evoked potential latencies. In this limited study, photopheresis was found to be safe but did not significantly alter the course of chronic progressive MS.
MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS)
Authors: Barkhof Frederik
Published: January 2007

Magnetic resonance (MR) imaging is very sensitive in showing disseminated MS lesions. Subclinical MR progression occurs frequently, explaining why MR is now used to monitor treatment, even without measurable consequences, of new MR lesions to the patient at this moment. In the light of this clinico-radiological paradox, the significance of MR in MS is discussed, particularly in relation with the expanded disability status scale (EDSS). Gadolinium-enhancing lesions correlate with the occurrence of relapses, CSF myelin breakdown products and, in patients with relapsingremitting disease, with higher EDSS. However, the predictive value of the frequency of enhancement for changes in EDSS is only weak. For conventional T2-weighted MR imaging, the cross-sectional correlation with EDSS varies between 0.15 and 0.60, and is limited mainly by the inherent lack of tissues specificity of T2-weighted images. Both T1 black holes and magnetisation transfer (MT) parameters show a better correlation with EDSS; it should be noted that lesions in which those abnormalities are found go through an initial phase of enhancement as well. For T1 black holes, a correlation up to 0.81 has been reported for SP patients. Post-mortem studies show that black holes and low MT ratios are in vivo markers of axonal loss. Preliminary data indicate that progressive atrophy also correlates with progression on the EDSS scale. More should be learned about the fate of new MR lesion with regards to development of axonal loss, which at present is difficult to predict in the enhancing stage. The existence of escape mechanisms, including remyelination, make a simple correlation with EDSS extremely unlikely, and perhaps not even desirable. Nevertheless, while the clinical effect of a given new lesion may be difficult to ascertain, the absence of (new) MR lesions is prognostically favourable, as will be the degree to which new lesions are prevented by treatment.
Bimonthly cranial MRI activity following an isolated monosymptomatic demyelinating syndrome: potential outcome measures for future multiple sclerosis `prevention' trials
Authors: Kinkel R P , Simon J H , Baron B
Published: January 2007

Patients with characteristic white matter lesions on MR imaging are at increased risk for the subsequent development of clinically definite MS (CDMS) following an isolated, monosymptomatic demyelinating syndrome (IMDS). These MR positive first-onset patients are thus candidates for MS prevention trials. Seven consecutive patients with IMDS and two or more periventricular and/or oval lesions on MR imaging were enrolled into a prospective trial based on serial T2-weighted and enhanced MR imaging at two month intervals for 12-15 months. Forty-seven new enhancing lesions were detected with triple dose MR contrast compared to 31 lesions using the standard dose. Four of the seven patients accounted for 98% of all enhancing lesions in this study, while the remaining three patients showed little MRI or clinical disease activity. New T2 lesion counts correlated strongly with enhanced lesion counts (r=0.82-0.98). We detected 49 new T2-hyperintense (T2) lesions based on short-interval (2 monthly) follow-up, and 31 new T2-lesions comparing exit and entry examinations. These results suggest several potential MR-based strategies for evaluating first onset patients in a phase III MS prevention trial. Since these patients have a small average T2-lesion load, it is quite easy to visually detect new T2 lesions. As a result, at a bimonthly study interval, T2-weighted lesion analysis is an effective measure of cumulative disease activity, provided high-resolution T2-weighted imaging studies are acquired to quantitate new T2-lesions. Enhanced lesion activity remains an important measure of blood-brain-barrier breakdown and may predict short term MRI and clinical disease activity in IMDS patients.
Cytokine analysis in multiple sclerosis by competitive RT - PCR: A decreased expression of IL-10 and an increased expression of TNF-α in chronic progression
Authors: Huang Wen-Xin , Huang Ping , Link Hans , Hillert Jan
Published: January 2007

Multiple sclerosis (MS) is an inflammatory, demyelinating disease that is specific to the central nervous system. Cytokines are thought to be key mediators of the autoimmune attack against central nervous system myelin in MS. To investigate the involvement of cytokines in MS, the mRNA levels of interferon gamma (IFN-g), tumor necrosis factor alpha (TNF-a), interleukin-4 (IL-4) and interleukin-10 (IL-10) in peripheral blood mononuclear cells without stimulation in vitro were quantified by a competitive reverse transcription polymerase chain reaction technique. The level of IL-10 specific mRNA was significantly decreased in 47 MS patients compared with 42 healthy controls (P50.0001). TNF-a was significantly increased in MS patients compared with healthy controls (P=0.014), especially in the patients with chronic progressive MS (P=0.0003). Thus we conclude that there are significant in vivo alterations in cytokine gene expression in the periphery in MS.
Multiple sclerosis is associated with enhanced B cell responses to the ganglioside GD I a
Authors: Matá Sabrina , Lolli Francesco , Söderström Mats , Pinto Francesco , Link Hans
Published: January 2007

The occurrence and role of autoantibodies to gangliosides and other lipid-containing components of the central nervous system in Multiple Sclerosis (MS) are unsettled Using sensitive ELISAs, we measured IgG and JgM antibody titers and absorbances to the three major gangliosides GDIa, GD l b and GM, and to sulfatides, cardiolipin and myelin proteins in paired serum and cerebrospinal fluid (CSF) from patients with untreated MS, optic neuritis (ON), acute aseptic meningo-encephalitis (AM) and other neurological diseases (OND). Twenty-three per cent of 30 MS (P < 0.04) and 18% of 32 ON patient (P <0.05) presented elevated IgG antibody titers to GD) a in serum compared to 9% of patient with OND. Six (40%) of the patient with malignant MS had elevated serum IgG antibody titers to GD) a compared to one (6%) of th e patient with benign MS (P <0.04). In CSF, elevated IgG antibody titers to GDIa were measured in 13% of MS and 20% of ON patient compared to 4% of patient with OND (P < 0.03 and P < 0.02, respectively). The augmented IgG response to GD) a in serum also separated MS from Guillain-Barr6 syndrome. Compared to OND increased JgM absorbances to sulfatides and cardiolipin were observed in CSF of patient with MS, but also in AM. Elevated IgG antibody titers to myelin proteins were found more often in MS patient' serum and MS, ON and AM patient' CSF compared to OND. The data implicate that among the multitude of enhanced B-cell responses occurring in MS and ON, that directed to GD I a is common and more discriminative, and should be evaluated in future MS treatment studies.
Circulator boot therapy alters the natural history of ischemic limb ulceration
Authors: Vella Adrian , Carlson Lori A , Blier Bill , Felty Cindy , Kuiper James D , Rooke Thom W
Published: January 2007

Despite numerous advances in interventional radiology and vascular surgery, the clinician continues to be confronted with inoperable vascular disease. Previous studies have shown that ulceration associated with a transcutaneous oxygen pressure (tcPO2)of,20 mmHg is refractory to all attempts at healing. External pneumatic compression for the treatment of peripheral vascular disease has been available for several years, although there is a relative paucity of data regarding its role in clinical practice as well as its efficacy. The objective of this study was to examine the experience with circulator boot therapy in the treatment of ischemic ulcers in the absence of osteomyelitis, and specifically to determine whether such therapy can be of benefit in ischemic limb ulceration associated with a tcPO2 of,20 mmHg. A retrospective chart review was undertaken of all patients with a lower limb ulcer who, in the absence of osteomyelitis, underwent circulator boot therapy at the Gonda Vascular Center. A total of 98 patients was identified. Two patients died within 1 month of commencing therapy and were not included in further analysis. The tcPO2 data were unavailable in five patients. Outcome in the patient population was classified as favorable if (1) healing was achieved, (2) the ulcer decreased in size, or (3) the affected limb improved sufficiently to allow successful revascularization. An unfavorable outcome was one where a major amputation was performed or where the ulcer increased in size. Out of a total of 29 patients with a tcPO2,20 mmHg at the area of ulceration, 19 had a favorable outcome following circulator boot therapy. Of the remaining 62 patients with a tcPO2 .20 mmHg, 54 had a favorable outcome. Circulator boot therapy is associated with improved outcomes in limb ulceration due to peripheral vascular disease. Complete ulcer healing as well as preservation of the affected limb can be achieved in most cases.
Pulmonary embolism and intracardiac thrombi - individual therapeutic procedures
Authors: Brodmann Marianne , Stark Gerhard , Pabst Edmund , Lueger Andreas , Pilger Ernst
Published: January 2007

Mobile right heart thrombus is a severe but rare presentation of thromboembolic disease and usually coexists with an already massive pulmonary embolism (PE). But looking at the literature there is no clear consensus on therapeutic management. We therefore tried to find possible therapeutic guidelines and to evalute an optimal diagnostic procedure looking at three patients who presented at our department with mobile right heart thrombbus in the last year. The first patient with a small (diameter = 1 cm) thrombus in the right ventricle and peripheral pulmonary embolism underwent successful thrombolytic therapy without any complications. Patients II and III showed large intracardiac masses, in patient III extending into the superior vena cava, with central PE. These two patients underwent pulmonary arteriotomy. The diagnostic line in each case was transthoracal echocardiography followed by a helix lung CT scan. Only patients with small intracardiac thrombi and thrombotic masses in the peripheral pulmonary arteries but with hemodynamically significant PE should be treated with thrombolytic agents.
Insights into the molecular pathogenesis of atherosclerosis and therapeutic strategies using gene transfer
Authors: Hiltunen Mikko O , Turunen Mikko P , Laitinen Marja , Ylä-Herttuala Seppo
Published: January 2007

Gene therapy for the treatment of atherosclerosis and related diseases has shown its potential in animal models and in the first human trials. Gene transfer to the vascular system can be performed both via intravascular and extravascular periadventitial routes. Intravascular gene transfer can be done with several types of catheters under fluoroscopic control. Extra-vascular gene transfer, on the other hand, provides a well-targeted gene delivery route available during vascular surgery. It can be done with direct injection or by using perivascular cuffs or surgical collagen sheets. Ex vivo gene delivery via transfected smooth muscle cells or endothelial cells might be useful for the production of secreted therapeutic compounds. Gene transfer to the liver has been used for the treatment of hyperlipidemia. The first clinical trials for the induction of therapeutic angiogenesis in ischemic myocardium or peripheral muscles with VEGF or FGF gene transfer are under way and preliminary results are promising. VEGF has also been used for the prevention of postangioplasty restenosis because of its capability to induce endothelial repair and production of NO and prostacyclin. However, further basic research is needed to fully understand the pathophysiological mechanisms involved in conditions related to atherosclerosis. Also, further development of gene transfer vectors and gene delivery techniques will improve the efficacy and safety of human gene therapy.
Long-term benefit of thrombolytic therapy in patients with pulmonary embolism
Authors: Sharma GVRK , Folland Edward D , McIntyre Kevin M , Sasahara Arthur A
Published: January 2007

A total of 23 of the 40 patients who had angiographically proven pulmonary embolism and who had initially been randomized to an IV infusion of heparin ( n = 11) or a thrombolytic agent (urokinase or streptokinase, n = 12) were restudied after a mean follow-up of 7.4 years to measure the right-sided pressures and to evaluate their response to exercise during supine bicycle ergometry. Results showed that, at rest, the pulmonary artery (PA) mean pressure and the pulmonary vascular resistance (PVR) were significantly higher in the heparin group compared with the thrombolytic group (22 vs. 17 mmHg, p < 0.05, and 351 vs. 171 dynes s-1 cm-5, p < 0.02, respectively). During exercise both parameters rose to a significantly higher level in the heparin group (from rest to exercise, PA: 22-32 mmHg, p < 0.01; PVR: 351-437 dynes s-1 cm-5, p < 0.01, respectively), but not in the thrombolytic group (rest to exercise, PA: 17-19 mmHg, p = NS; PVR: 171-179 dynes s-1 cm-5, p = NS). It is concluded that thrombolytic therapy preserves the normal hemodynamic response to exercise in the long term and may prevent recurrences of venous thromboembolism and the development of pulmonary hypertension.
Local drug delivery: an emerging approach in the treatment of restenosis
Authors: Ettenson David S , Edelman Elazer R
Published: January 2007

Very limited success has been demonstrated with systemic pharmacological treatment to reduce the incidence of restenosis following angioplasty in patients. The lack of success of many of the pharmacotherapeutic agents in reducing the restenosis rates post-angioplasty and following stent implementation is believed to arise from inadequate concentrations of the agents at the lesion site. This has led to the development of various local delivery devices that would ideally deliver and retain adequate amounts of drug to the vessel wall for sufficient periods of time to ensure a therapeutic effect without inducing further injury or compromising blood flow. Local dosing would avoid systemic toxicity, and the use of modified balloon catheters or coated stents might enable percutaneous approaches.