Processes of plasma protein N-homocysteinylation in multiple sclerosis.

BACKGROUND: Homocysteine thiolactone (HTL) is a cyclic thioester of homocysteine (Hcy) contributing to the toxicity of this amino acid. HTL spontaneously reacts with protein lysine residues leading to altered properties of target proteins and induction of immune response. HTL is hydrolyzed to Hcy by plasma enzyme, paraoxonase 1 (PON1). Although both Hcy and PON1 may be involved in the pathogenesis of multiple sclerosis (MS), protein modification by HTL in this disease has not been studied so far. Purpose/Aim: The aim of this study was to assess the level of Hcy, HTL and autoantibodies against N-homocysteinylated proteins as well as PON1 activity in patients with MS. METHODS: The studies were performed in 61 MS patients with relapsing-remitting (RR group, n = 25) and secondary-progressive type of MS (SP group, n = 36), and in healthy people (C - control group, n = 44). RESULTS: Homocysteine level was significantly higher in MS patients comparing to control group (C vs. RR p < 0.01; C vs. SP p < 0.05). The level of HTL tended to be higher in RR-MS in comparison to control group, but it did not reach the level of significance. The level of antibodies against N-homocysteinylated proteins did not differ significantly between studied groups. PON1 activity was significantly lower in SP type of MS (SP vs. C p < 0.05; SP vs. RR p < 0.05). CONCLUSIONS: Although plasma Hcy concentration is higher in MS patients and PON1 activity is reduced in the SP form, MS is associated with minor or no changes in protein-attached HTL and anti-homocysteinylated protein immune response.

Paraoxonase 1 activity in multiple sclerosis patients during mitoxantrone therapy.

OBJECTIVES: It has been implicated in many studies that reactive oxygen species play a role in the development of demyelination in multiple sclerosis (MS). Paraoxonase 1 (PON1) is an antioxidant enzyme that protects cell membranes against oxidative modification. Mitoxantrone is a cytotoxic drug approved for the treatment of MS with adverse effects associated potentially with an increased level of oxidative stress. The aim of this study was to assess the influence of mitoxantrone therapy on PON1 activity in patients with MS. METHODS: A studied group included 26 patients with secondary progressive MS, 16 women and 10 men. The blood was collected before the beginning of the therapy as well as after 6 and 12 months. Patients were receiving mitoxantrone every 12 weeks. Serum PON1 activity was assayed using two synthetic substrates: paraoxon and phenyl acetate. RESULTS: Paraoxonase 1 activity toward paraoxon and phenyl acetate and lipid profile did not change significantly in patients receiving mitoxantrone. CONCLUSIONS: Mitoxantrone therapy does not influence PON1 activity.

Total tau and S100b proteins in different types of multiple sclerosis and during immunosuppressive treatment with mitoxantrone.

PURPOSE: Brain-specific proteins are biochemical markers of neurodegeneration. The aim of this study was to estimate the role of biomarkers in neuronal and glial damage as a potent marker of efficiency of immunosuppressive treatment. MATERIAL AND METHODS: The levels of total Tau protein (tTau) and S100b protein were measured using the ELISA method in serum and cerebrospinal fluid (CSF) of 30 patients with RRMS, 24 patients with SPMS and 30 healthy subjects. Additionally, serum levels of tTau and S100b were assayed every 6 months during the 24-month mitoxantrone therapy. RESULTS: In CSF and serum of patients with MS, both tTau and S100b were increased compared to control group; however, no significant difference was found between respective MS types. In serum of mitoxantrone-treated patients, both proteins showed to decrease after 24 months, yet the difference was statistically significant only for S100b. CONCLUSIONS: CSF levels of tTau and S100b are elevated in patients with MS and can reflect an axonal and glial pathology. Measurement of serum concentrations of S100b may be useful for monitoring immunosuppressive therapy and may support clinical assessment. In contrast, tTau concentration did not prove to be a useful marker of mitoxantrone therapy.

CT volume/density ratio as the marker of ischaemic brain injury.

OBJECTIVES: We believe that the CT volume/density ratio (VDR) of infarcted area reflects the degree of brain tissue damage during ischaemic stroke (IS). PATIENTS AND METHODS: Forty six patients with IS were prospectively enrolled into the study. CT scan was performed on days 1 and 10 of hospitalization. S100BB serum level, gelatinase activities (MMP-2 and MMP-9) and neurological examination (NIHSS) were performed on days 1, 5 and 10 of IS. After 3 months, 42 patients were examined by functional disability scales: Barthel index (BI) and modified Rankin scale (mRS). RESULTS: The VDR of ischaemic focus correlated well with the average S100BB serum level, MMP-9 serum activity and NIHSS score. The weak but statistically significant relationships were noticed between the VDR vs BI and mRS estimated 3 months after stroke. CONCLUSION: VDR reflects well the damage ratio of brain tissue during IS. In addition, the study underlines the relationship between VDR vs patients' neurological status and disability after IS.

Impact of cladribine on soluble adhesion molecules in multiple sclerosis.

BACKGROUND: Soluble forms of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-Selectin play a role in the regulation of blood-brain barrier damage and represent markers of the clinical course of multiple sclerosis (MS) and magnetic resonance imaging activity. We determined sICAM, sVCAM and sE-Selectin concentrations in the cerebrospinal fluid (CSF) and serum of patients with remitting-relapsing multiple sclerosis before and after cladribine treatment as well as in a control group. METHODS: We examined 17 patients diagnosed according to McDonald's criteria. Thirteen healthy age-matched subjects served as controls. The ELISA method was used to measure sICAM-1, sVCAM-1 and sE-Selectin. RESULTS: The concentration of sICAM and sE-Selectin decreased in sera (difference between patients and controls was statistically significant, in the former P < 0.04, in the latter P < 0.0003) but not in the CSF of MS patients after cladribine treatment. CONCLUSIONS: The reduction in sICAM and sE-Selectin concentrations after cladribine treatment indicates an immuno-suppressive effect of the drug. The changes in levels of sICAM and sE-Selectin after cladribine treatment reflect disease activity and indicate a reduction in the inflammatory reaction.

Total-tau and phospho-tau(181Thr) in cerebrospinal fluid of neurologically intact population increase with age.

Tau protein is a microtubule-associated molecule playing a crucial role in maintenance of neuronal integrity and in many neurodegenerative processes; its pathology has become a hallmark feature at the tissue level. The aim of the study was to estimate total tau and phospho-tau (Thr181) concentrations in cerebrospinal fluid of healthy population. Cerebrospinal fluid samples were taken from 129 subjects (age 18-77 years) without known neurologic or psychiatric condition. Both total-tau and phospho-tau levels showed significant correlation with age, which was more pronounced in older population.

Paraoxonase 1 activity in different types of multiple sclerosis.

BACKGROUND: Paraoxonase 1 (PON1) is an antioxidant enzyme bound to plasma high-density lipoproteins and is also present in the brain. OBJECTIVE: The aim of this study was to estimate the activity of PON1 in patients with different types of MS. METHODS: The PON1 activity toward paraoxon and phenyl acetate and lipid profile was examined in 40 relapsing-remitting (RR) patients in relapse, in 42 RR patients in remission, in 55 progressive MS patients and in 40 healthy individuals. RESULTS: PON1 activity did not differ in MS patients compared to control group. PON1 activity in relapse was significantly lower in comparison to the other MS groups. Hypercholesterolemia was observed in MS patients. CONCLUSION: PON1 activity does not change in the course of stable and progressive type of MS and is decreased by the relapse of MS.

The CSF levels of total-tau and phosphotau in patients with relapsing-remitting multiple sclerosis.

Total-tau protein is considered the marker of axon damage whereas the abnormally phosphorylated tau forms are mainly associated with Alzheimer's disease. An increase in total-tau levels was observed in neurodegenerative diseases, including multiple sclerosis (MS). In order to find out whether the phosphorylated tau forms occur in MS patients and to evaluate their clinical significance, the levels of total-tau (t-tau) and tau phosphorylated at Thr 181 (p-tau) were determined in 60 MS patients (40 during relapse including 18 with the first relapse and 20 stable) and in 18 age-matched controls. The determinations were conducted in the cerebrospinal fluid (CSF) using the ELISA method. The levels of t-tau and p-tau were higher in MS patients than in controls; however, increased levels were not related to the clinical activity of the disease. In CSF of the patients with the first relapse the level of t-tau was significantly increased whilst the level of p-tau was not elevated.

Correlations between IL-4, IL-12 levels and CCL2, CCL5 levels in serum and cerebrospinal fluid of multiple sclerosis patients.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Both cytokines and chemokines have been implicated in the pathogenesis of MS. The aim of the study was to assess whether cytokine levels are correlated with chemokine levels during a different stage of relapsing-remitting MS (RR-MS). The study included 53 patients with RR-MS (20 subjects in stable stage and 18 patients with relapse). By ELISA method, the levels of the interleukin-4 (IL-4), interleukin-12 (IL-12), CCL2 and CCL-5 chemokines were measured both in serum and cerebrospinal fluid (CSF) of all patients. The serum IL-4 and IL-12 levels and CSF CCL5 level of patients with stable RR-MS were significantly different from the control level and the IL-12 levels were correlated with CCL5 levels in serum. During the relapse, a significant change in chemokine levels both in serum and CSF and IL-12 in CSF were noted, however no correlations were found between cytokines and chemokines.

The levels of chemokines CXCL8, CCL2 and CCL5 in multiple sclerosis patients are linked to the activity of the disease.

Chemokines are small cytokines with selective chemoattractant properties. They contribute to the T-cell-mediated pathogenesis of multiple sclerosis (MS). In order to ascertain whether different types and stage of disease correlate with a varying level of chemokines, the levels of CXCL8, CCL2 and CCL5 were measured in serum and the cerebrospinal fluid (CSF) of the MS patients. ELISA method was used to examine 56 patients with different types of MS alongside the 29 patients of the control group. The levels of CXCL8 and CCL2 in both groups were higher in CFS than in serum whilst the level of CCL5 measured higher in serum than in CSF. A significant rise in the levels of CXCL8 and CCL5 was observed during relapse, as against the level of CCL2 which was lower when compared with the control and other MS groups. No significant differences were observed in the levels of chemokines between the stable relapsing-remitting MS and progressive MS. The different levels of chemokines are linked to relapse of the disease. No separate, specific pattern of chemokine production dependent on the type of MS could be ascertained.

Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine.

OBJECTIVE: Chemokines are involved in the pathogenesis of multiple sclerosis. The aim of the study was to evaluate the effects of immunosuppressive therapy on production of two proinflammatory chemokines--interleukin-8 (IL-8) and RANTES (regulated on activation, normal T cell expressed and secreted). MATERIALS AND METHODS: Twenty-five patients with relapsing-remitting multiple sclerosis were treated with 2-chlorodeoxyadenosine (Cladribine), administered subcutaneously in 6 cycles repeated every 5 weeks. IL-8 and RANTES levels were measured by the enzyme-linked immunoassay (ELISA) method in serum and cerebrospinal fluid (CSF) before and after treatment. RESULTS: After Cladribine treatment the levels of IL-8 decreased significantly in CSF only, whereas the RANTES levels decreased significantly both in CSF and serum. CONCLUSION: Our results suggest that Cladribine therapy might modify the circulating level of RANTES.

Markers of inflammation in cerebral ischemia.

The study sought to determine whether cerebral ischemia is associated with inflammatory reactions indicated by an increase in levels of selected acute phase proteins (APP), C-reactive protein (CRP), fibrinogen, alpha-1 antitrypsin (AAT) and acidic alpha-1 glycoprotein (AGP). These proteins are thought to be markers of inflammatory reactions. We investigated 30 patients with acute cerebrovascular ischemia, 20 patients with transient ischemic attack, and 20 patients from a control group. Levels of CRP, AAT, AGP, and fibrinogen in blood sera were determined in all patients by kinetic turbidimetry. In the patients with cerebral infarct an increase was found in the levels of APP, which suggests that ischemic necrosis is associated with inflammatory reactions. All patients require active treatment of an inflammatory process that is associated with stroke.

[Tick-borne encephalitis versus multiple sclerosis: clinical and immunological aspects]. / Kleszczowe zapalenie mózgu a stwardnienie rozsiane--aspekty kliniczne i immunologiczne.

The condition of making the diagnosis of tick-borne encephalitis is the performance of serological investigation, quite apart from careful evaluation of medical history and clinical status of patient. Contemporary diagnostics of tick-borne encephalitis uses immuno-enzymatic test (ELISA), which enables detection of specific IgM antibodies (in initial phase of disease) or IgM and IgG antibodies (in the phase of the disease with neurological symptoms). The highest diagnostic value in the infection phase of disease has the demonstration of at least fourfold increase of viral antibodies level, measured in acute phase and 2 to 6 weeks after that. In case of multiple sclerosis, a laboratory test, specific for the illness, has not been established as yet. The basis for establishing the diagnosis is the clinical picture. Results of auxiliary examinations are used for the completion of clinical evaluation and for differential diagnosis. Seroepidemiological investigations were carried out in multiple sclerosis patients to estimate the level of antibodies against tick-borne encephalitis. The investigations indicated low level of IgG antibodies in patients' serum.

Biochemical markers of damage of the central nervous system in multiple sclerosis.

The examination of biochemical markers of the damage of the central nervous system may be the excellent complement of the neuroimaging methods. There are factors in the cerebrospinal fluid which indicate the damage of the precise structures of the CNS. In this paper there are described the main markers which are used in diagnostic multiple sclerosis: myelin basic protein (MBP) as a marker of demyelination of the white matter, neuron specific enolase (NSE) as a marker of neuronal damage, tau protein, 14-3-3 protein, neurofilament protein-subunit light (NFL) as markers of axonal damage and S-100 protein and glial fibrillary acidic protein as markers of astroglial damage.

A case of the Roussy-Levy syndrome family.

Roussy-Levy syndrome, also known as hereditary areflexic dystasia, is a very rare genetic neuromuscular disorder that typically becomes apparent during early childhood. The disorder is characterised by inherited gait ataxia, pes cavus and areflexia which are eventually associated with distal muscle atrophy, postural tremor and minor sensory loss. We report a family whose members in three generations (grandmother, mother, daughters) were showing these clinical signs of Roussy-Levy syndrome. All of these women have displayed gait ataxia, areflexia, pes cavus and sideways curvature of the spine (kyphoscoliosis).

[Differential diagnosis in multiple sclerosis: description of selected cases]. / Diagnostyka róznicowa stwardnienia rozsianego--omówienie na podstawie wybranych przypadków.

Multiple sclerosis (MS) should be differentiated with diseases causing disseminated lesions of central nervous system or imitating clinical course of MS. Clinical course and results of laboratory investigations also immunological tests should be taken into account in differential diagnosis of MS. We present four patients whose proper diagnoses were based on the immunological investigations.

Interleukin-6 concentration in serum and cerebrospinal fluid in multiple sclerosis patients.

INTRODUCTION: The aim of the investigation was to determine pleiotropic cytokine IL-6 concentrations in serum and CSF of MS patients, with regard to clinical circumstances. MATERIAL AND METHODS: The study covered 27 MS patients: 23-51 years old; in the 2-7 clinical stage according to Kurtzke's Scale; mean 3.6 +/- 1.8; disease duration time ranged between 2-22 years. Serum and CSF interleukin-6 were determined by the use of commercial ELISA kits. RESULTS: Increase of Il-6 in serum of MS patients was found (12.1 +/- 1.8 pg/ml) in comparison to the control group (6.6 +/- 4.5 pg/ml) (p = 0.03). Concentration of IL-6 in CSF of MS patients was 13.4 +/- 1.77 pg/ml and in the majority of patients it was higher than in the serum. The highest mean of IL-6 concentrations in serum and CSF have been found in patients at the longer disease duration time, although there were not statistically significant. We have found some degree of dependence between serum IL-6 concentration and the level of disability in Kurtzke's scale. CONCLUSIONS: IL-6 participation in the basic MS immune processes is confirmed by its elevated concentration in serum and CSF, its relation to disease severity with the more expressed rise in cerebrospinal fluid.