Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis

We report the case of an infant with Sturge-Weber syndrome whose regional cerebral blood flow (rCBF) showed an increase and a subsequent decrease. As compared with simultaneous CT and MR findings, we speculate that the transient increase in rCBF reflects the neuronal reaction to hypoxia caused by congestion.     

Increased HLA-DQ2-affinity of a synthetic gliadin peptide by acid-induced deamidation of glutamine residues

Presentation of antigenic gliadin peptides by the HLA-DQ2 molecule is considered as a key event in celiac disease pathogenesis. Chemical deamidation of the side chains of glutamine residues might have a strong influence on gliadin peptide binding to the DQ2 molecule. Glutamine deamidation of A-gliadin peptide (45-56) under acidic conditions corresponding to the gastric environment was studied using RP-HPLC, Edman degradation, capillary electrophoresis and electrospray mass spectrometry. Deamidation resulted in peptides with increased DQ2-affinities as assessed in a cell-free binding assay.     

Neuroimaging in multiple sclerosis

Neuroimaging in multiple sclerosis is now dominated by MR imaging. This article will focus primarily on conventional MR imaging studies in multiple sclerosis, but will also discuss briefly some of the more recent advances related to MR imaging. Fast spin-echo imaging, fluid attenuated inversion recovery MR studies, three-dimensional volumetric studies, magnetization transfer, and magnetic resonance spectroscopy as it applies to multiple sclerosis are examined.     

Prognosis in multiple sclerosis

Prognosis of the natural course of multiple sclerosis is most often measured on Kurtzke's "expanded disability status scale" (EDSS), a non-linear scale over 20 steps, heavily weighted on mobility. Optic neuritis and sensory disturbances as initial symptoms, lower age at onset of the disease, female sex and a longer interval between relapses are indicators of a more favorable prognosis. As a rule, disability as measured on this scale 5 years after onset corresponds to 3/4 of the disability status after 15 years. The number of relapses diminishes naturally over the course of the disease. Presence and extent of lesions on the initial MRI of the brain in clinically isolated syndromes are valuable predictors of dissemination of the disease process over the following 5-10 years. New therapies (e.g. interferon beta 1b and 1a, copolymer 1) reduce relapse frequency by 1/3 and diminish the extent of pathological lesions in brain MRI, but fail to show (as yet) significant influence on disability.     

A synthetic peptide ligase

The preparation of synthetic molecules showing the remarkable efficiencies characteristic of natural biopolymer catalysts remains a formidable challenge for chemical biology. Although significant advances have been made in the understanding of protein structure and function, the de novo construction of such systems remains elusive. Re-engineered natural enzymes and catalytic antibodies, possessing tailored binding pockets with appropriately positioned functional groups, have been successful in catalysing a number of chemical transformations, sometimes with impressive efficiencies. But efforts to produce wholly synthetic catalytic peptides have typically resulted in compounds with questionable structural stability, let alone reactivity. Here we describe a 33-residue synthetic peptide, based on the coiled-coil structural motif, which efficiently catalyses the condensation of two shorter peptide fragments with high sequence- and diastereoselectivity. Depending on the substrates used, we observe rate enhancements of tenfold to 4,100-fold over the background, with catalytic efficiencies in excess of 10(4). These results augur well for the rational design of functional peptides.     

Childhood multiple sclerosis

Multiple sclerosis begins before the age of 17 years in 0.4 to 0.5% of the cases, but the diagnosis is exceptionally made before the age of 10 years. Female predominance is more marked in early onset multiple sclerosis. The general features of the disease (clinical expression, progression, prognostic) and the findings of complementary explorations are comparable with those found when the disease begins in adulthood although acute onset and signs of brain stem involvement have been reported. The diagnosis must be made with prudence, especially when progression is slow from the beginning. An analysis of the influence of infective environmental factors and puberty has not provided new insight. Corticosteroids can be used in case of flare-ups. Management requires a multidisciplinary approach to maintain appropriate educational activities.     

Antigen specificity of antihistone antibodies in systemic sclerosis

OBJECTIVES: The aim of the study was to determine the prevalence and clinical significance of antibodies to individual histone components in systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (lSSc; n = 42) and diffuse cutaneous SSc (dSSc; n = 28) were examined for IgG and/or IgM antibodies to individual histone components and complexes by enzyme linked immunosorbent assay (ELISA). RESULTS: The level of IgG antibody to total histones was significantly higher in lSSc and dSSc than in normal controls. The level of IgM antibody to total histones was significantly higher in lSSc, but not in dSSc, than in normal controls. IgG antibody to total histones tended to be increased in dSSc when compared with that in lSSc. On the other hand, IgM antibody to total histones tended to be increased in lSSc when compared with that in dSSc. Although SSc showed various antihistone specificities, H2B, H2A-H2B, (H2A-H2B)-dsDNA were main antigens recognised by IgG antibodies in both lSSc and dSSc. Although IgM antibodies to H2B and H2A-H2B were also detected in both lSSc and dSSc, serum samples from lSSc patients exhibited highest IgM reactivity with H1. CONCLUSION: SSc may be included among conditions in which heterogeneous antihistone antibodies are produced. IgM antibodies to the most accessible histone H1 may be related to mild clinical features (lSSc) and IgG antibodies to the inner core molecules of native histone such as H2B or complexes including H2B may be associated with severe clinical features (dSSc) in Ssc.     

Genetics of multiple sclerosis

The cause of MS is unknown. There is considerable circumstantial evidence that MS is a complex trait, probably autoimmune in nature, and is determined by both genetic and environmental factors. At present, it must be acknowledged, however, that our understanding of the pathogenesis of MS is minimal. Very little is known about the genes determining disease susceptibility and perhaps even less is understood about environmental factors that influence penetrance or the geographic distribution. This lack of knowledge results neither from lack of effort nor from a shortage of fertile imaginations. Almost every imaginable hypothesis has, in the past, found some support. The intractability of the problem could well result from its complexity, because answers to testable hypotheses are commonly negative or ambiguous. Today, the opportunity exists for researchers to provide such answers because of recent major developments. The first development is the recognition that MS research requires a relatively large pool of well-ascertained, carefully diagnosed, and longitudinally well-characterized MS patients. The last two developments are the identification and successful application of statistical and molecular genetic techniques carrying sufficient power to allow the exploration of complex traits such as MS.     

DNA binding specificity and transactivation properties of SREBP-2 bound to multiple sites on the human apoA-II promoter

DNase I footprinting of the apoA-II promoter using sterol regulatory element binding protein-2 [(SREBP-2 (1-458)] expressed in bacteria identified four protected regions, designated AIIAB (-64 to -48), AIICD (-178 to -154), AIIDE (-352 to -332) and AIIK (-760 to -743), which bind SREBP-2 and contain either palindromic or direct repeat motifs. Potassium permanganate and dimethyl sulfate interference experiments using the AIIAB region as probe showed that the nucleotides of a decameric palindromic repeat RTCAMVTGMY and two 5' T residues participate in DNA-protein interactions. SREBP-2 transactivated the intact (-911/+29) apoA-II promoter 1.7-fold and truncated apoA-II promoter segments which contain one, two or three SREBP-2 sites 11- to 17-fold in HepG2 cells. Transactivation of a promoter construct containing the binding site AIIAB and the apoA-II enhancer, which includes the binding site AIIK, was abolished by mutations in element AIIAB. An SREBP-2 mutant defective in DNA binding caused a dose-dependent repression of the apoA-II promoter activity. Repression was also caused by an SREBP-2 mutant which lacks the N-terminal activation domain (residues 1-93) but binds normally to its cognate sites. In contrast, a double SREBP-2 mutant which lacks both the DNA binding and the activation domains has no effect on the apoA-II promoter activity. Overall, the findings suggest that SREBP-2 can transactivate the apoA-II promoter by binding to multiple sites. Furthermore, the repression caused by the DNA binding deficient mutants results from squelching of positive activator(s) which appear to recognize the activation domain of SREBP-2.     

Mitoxantrone immunotherapy in multiple sclerosis

We compared the effects of postural changes on intraocular pressure, systemic blood pressure, and pupil size with and without induced mydriasis in 15 chronic chagasic patients and 20 healthy age-matched controls. The chagasic patients showed a marked fall in intraocular pressure on rising. However, systemic systolic blood pressure changes and pupil size in patients did not differ from those measured in controls. Our findings may be explained by an alteration in the autonomic ocular system that regulates homeostasis of ocular pressure and the probable existence of a baroreceptor arc-reflex that restores the equilibrium of sudden changes in the intraocular pressure.     

Genetic factors in multiple sclerosis

OBJECTIVE: To evaluate the role of candidate genes in the susceptibility to multiple sclerosis (MS) and describe the role of T-cell receptor (TCR) gene rearrangements in the MS brain lesion in identifying a major target of the immune response in this disease. DATA SOURCES: MEDLINE, bibliography review of published data, and unpublished studies. STUDY SELECTION: Published studies using novel molecular approaches to analyze the role of the major histocompatibility complex (MHC) and TCR gene complexes, as well as other candidate genes, in susceptibility to MS. We analyze epigenetic events involving TCR genes in individuals with MS and describe recent clinical trials in which immunotherapy has been attempted. DATA SYNTHESIS: Consistent with a polygenic model for disease predisposition, MHC and TCR gene associations with MS are relatively weak. Despite intensive research, no other putative "MS genes" have been firmly established. The analysis of TCR rearrangements in the brain lesion has helped to identify a major target of the immune response in MS. CONCLUSION: Understanding the genetic basis for autoimmune demyelination will offer new possibilities for the treatment of this illness.     

Paroxysmal itching in multiple sclerosis

In three women with multiple sclerosis, paroxysmal attacks of itching occurred. There were several similarities between these attacks and other types of paroxysmal phenomena previously described in multiple sclerosis. The attacks were brief, but usually lasted several minutes, they started and ended abruptly, and recurred several times a day. The were controlled effectively by carbamazepine. It is suggested that paroxysmal itching is caused by transversely spreading ephaptic activation of axons within a partially demyelinated lesion in pain-conducting fibre tracts in the central nervous system.     

Glycosaminoglycan specificity of a heparin-binding peptide

Glycosaminoglycans are complex sulfated polysaccharides with a diverse range of biological functions. Three glycosaminoglycan standards--chondroitin sulfate, dermatan sulfate and heparin--were characterized during this study. The interaction of the heparin binding site of protein C inhibitor, represented by the peptide sequence 264-283, in solution with the above glycosaminoglycan standards was studied. Circular dichroism spectroscopy was used to determine the dominant secondary structure induced in the peptide upon binding the relevant glycosaminoglycans. The various glycosaminoglycans induced different secondary structures. The level of induced secondary structure by dermatan sulfate and heparin was approximately twice that induced by chondroitin sulfate. For chondroitin sulfate and heparin, alpha-helix was the dominant ordered secondary structure, whereas for dermatan sulfate the beta-strand conformation dominated. The order of secondary structure induction of the protein C inhibitor peptide by the glycosaminoglycans paralleled the reported biological activities of these glycosaminoglycans for mediation of the biological activity in the intact protein. The strength of the interaction of dermatan sulfate and heparin with the protein C inhibitor peptide was measured by determining the concentration of salt required to inhibit 50% of the interaction. The values determined were 0.1 and 0.3 M salt for dermatan sulfate and heparin, respectively. These results show that different glycosaminoglycans can support different secondary structures in the protein C inhibitor peptide.     

The pathogenesis of multiple sclerosis. Cytotoxic antibodies against myelin sheath tissue in multiple sclerosis

Cytotoxic antibodies to myelin can be demonstrated by the method of 51Cr-release from chick erythrocytes coated with myelin basic protein. The cytotoxic antibody is inactivated by heating to 56 degrees C and needs complement in order to exert its action. The antibody was determined as IgM and IgG. It has relative specifity and shows cross-reaction with other basic proteins. The cytotoxic antibody was found in only 8% of healthy persons. Patients with multiple sclerosis were positive in 87% of the cases and in acute cases in 94%. In other neurological diseases cytotoxic antibody was present in 64%. The occurrence of cytotoxic antibody to myelin protein is not specific for a particular neurological disorder, especially not for multiple sclerosis. Cytotoxic antibodies arise as a secondary phenomenon, they are not the cause of the disease involved. They appear to be suitable, however, to determine, in association with cellular immunological reactions against myelin which may be regarded as the "primary" immunological processes, the demyelination process in the multiple sclerosis focus.     

Changes in neurotransmitters in multiple sclerosis

PURPOSE: The aim of this study was to identify the route of administration of 5-FU with the greatest pharmacological advantage in a rat model using non-invasive in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. METHODS: 5-FU (50 mg/kg) was administered to anesthetized Wistar rats cannulated into the hepatic artery, portal vein or tail vein and 11 NMR spectra were acquired from the liver region to 60.5 min every 5.5 min. RESULTS: With systemic i.v. (tail vein) infusion, the 19F-NMR signal for 5-FU from the liver region peaked in the first spectrum (0-5.5 min), and then gradually decreased. The signal for the 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) gradually increased to the sixth spectrum (0-33.0 min) and then plateaued. Following portal vein infusion the intensity of the first 5-FU spectrum was twice as high as that following i.v. infusion, but the intensity decreased and the FBAL signal increased gradually in the sixth spectrum as systemic i.v. infusion. In contrast, the intensity of the 5-FU signal following hepatic artery infusion was the same as that following portal vein infusion in the first spectrum, and maintained a strong intensity to the final spectrum (60.5 min). The FBAL signal was detected from the second spectrum following hepatic artery infusion, but its intensity was significantly weaker than that following i.v. or portal vein infusion. CONCLUSIONS: Hepatic arterial infusion resulted in the active form of 5-FU being present for a longer time and its degradation in the liver being suppressed compared with the results following portal vein infusion. This catabolic advantage of hepatic arterial infusion could lead to a more potent anti-tumor activity against liver metastases, but could also lead to significant host toxicity including biliary toxicity. We recommend that the dose/schedule of 5-FU administered via the hepatic artery should be adjusted carefully.     

Genetic epidemiology of multiple sclerosis

Random Amplified Polymorphic DNA (RAPD) analysis is a new technology of molecular marking which has proved very powerful in detecting genetic diversity at the level of population. The genomic DNAs used in our experiment were extracted from fresh leaves taken from 59 individuals sampled from three natural populations in Yan An, Shanxi Province. Through more than 2,000 PCRs, deep-going RAPD analysis was carried out on DNA samples from 49 individuals. The percentage of polymorphic RAPD loci found in these three populations were respectively 27.2%, 18.6% and 5.4%; the average genetic distances within population, 0.055, 0.036 and 0.008; the average genetic distances between populations (I-II), (I-III) and (II-III), 0.105, 0.096 and 0.060. The genetic diversity of A. brachypus within and between populations was found, for the first time, to be rather poor, thus revealing innate factors as the cause contributing to its endangered status. In addition, our work also provides basic materials for elucidating the underlying cause of its endangerment and for its protection biology.     

Disease markers in acute multiple sclerosis

Three serum components that are known to become elevated during inflammation and tissue destruction, C-reactive protein, C3 proactivator, and orosomucoid, which are acute phase reactants, and serum lgM were measured in patients with multiple sclerosis (MS) hospitalized with acute exacerbations. Significantly elevated levels of one or more of these serum components were found in 12 of 13 patients with clinically active MS. Serial studies in two patients revealed that clinical improvement was accompanied by a decline in the serum levels of these factors. These findings suggest that measurement of these serum proteins may be of value in assessing progress of disease activity in MS patients.