Polymorphisms in the coagulation factor VII gene and risk of primary intracerebral hemorrhage

Data concerning genetic factors that may influence the risk of primary intracerebral hemorrhage (PICH) are scarce. One previous study, indicated that the carriers of the (-323)Ins allele of the coagulation factor VII (FVII) have an increased risk of PICH. Another recent study, tested the effect of apolipoprotein E. We analyzed, whether the (-401)G → T polymorphism, which is in linkage disequilibrium (LD) with the 10-bp Ins/Del polymorphism at position (-323), or the (-402)G → A polymorphisms of the FVII gene are associated with an increased risk for PICH. We performed a small case–control study in 85 patients with PICH and in 85 healthy control subjects. To each patient a control was individually matched for age, gender, and hypertension. We did not find any significant differences in allele frequencies for the A allele of the FVII (-402)G → A polymorphism (0.25 vs. 0.25; P  = 0.900, OR = 1, ns.) nor for the T Allele of the FVII (-401)G → T polymorphism (0.09 vs. 0.12; P  = 0.480, OR = 1.38, ns.). The analysis of haplotype distributions did not reveal significant differences. Our results do not support the hypothesis that the investigated polymorphisms in the FVII gene are significantly associated with the risk for PICH.     

Intrathecal IgG synthesis: marker of progression in multiple sclerosis patients

OBJECTIVES: We study the power of IgG synthesis value as a marker of disease activity in multiple sclerosis (MS). MATERIAL AND METHODS: Link index was calculated in 202 MS patients. Time between first, second and third attack and progression index (PI) were compared in patient with normal (NLI) high (HL) or very high Link index (VHLI). RESULTS: Secondary progressive (SP) patients had a higher LI than relapsing-remitting (RR) and primary progressive (PP) courses (1.10 +/- 0.5 for SP vs 0.86 +/- 0.5 for RR and 0.81 +/- 0.5 for PP, P=0.01 and 0.03, respectively). Having a HLI in MS RR and SP patients has no time effect in the development of the second and third attack. PI was higher in patients with VHIL (0.67 +/- 0.7) vs patients with NLI (0.42 +/- 0.4, P=0.008) and with HLI (0.39 +/- 0.3, P=0.001). CONCLUSIONS: This study confirmed that LI is a good marker of subsequent progression of MS.     

多发性硬化患者病情演变与血浆和脑脊液趋化因子CXCL10水平的相关性

目的 观察急性期多发性硬化(MS)患者血浆和脑脊液中趋化因子CXCL10水平的动态变化规律及其与临床神经功能障碍的相关性,探讨其对疾病活动性的判定价值.方法 收集急性期MS患者、缓解期MS患者及健康对照各53例,神经系统非炎性疾病(NIND)32例,采用酶联免疫吸附试验法检测血浆和脑脊液中CXCL10水平,并进行扩展残疾状况评分量表(EDSS)评分.结果 (1)与急性期初期相比,急性期MS组患者第2、4周血浆CXCL10水平[(601±365)、(575±297)pg/ml]明显升高(t=-2.898、-2.651,P=0.001、0.003);第4周脑脊液中CXCL10水平[(1807±803)pg/ml]与急性期初期比较差异无统计学意义.(2)急性期初期MS组血浆CXCL10水平明显高于缓解期MS组[(287±118)pg/ml,t=3.555,P=0.001]和健康对照组[(248±130)pg/ml,t=4.895,P=0.000].(3)急性期MS组脑脊液CXCL10水平[(1774±604)pg/ml]明显高于NIND组[(122±114)pg/ml,t=15.192,P=0.000].(4)急性期MS组患者血浆与脑脊液中CXCL10水平间存在相关性(r=0.792,P=0.001);脑脊液CXCL10水平与同期EDSS评分之间存在相关性(r=0.526,P=0.002).结论 (1)MS患者血浆中CXCL10水平对判断疾病活动性有一定的参考价值.(2)急性期MS患者血浆CXCL10水平能在一定程度上反映其在脑脊液中的水平.(3)检测急性期MS患者脑脊液CXCL10水平对判断临床功能障碍程度有一定的参考价值.

Abstract：

Objective To investigate the evolution of CXCL10 in blood plasma and cerebrospinal fluid (CSF) during relapses of multiple sclerosis (MS),and the correlation between these and the clinical neurological dysfunction.Methods Fifty-three patients with definite MS during relapsing state (relapsing MS group) diagnosed by the McDonald criteria;fifty-three patients with definite MS during remitting state ( remitting MS group);thirty-two patients with non-inflammatory neurologic disease ( NIND group) and fiftythree healthy controls (NC group) were enrolled in the study.Each patient clinical status was evaluated with the Expanded Disability Status Scale ( EDSS).Plasma and CSF levels were analyzed by enzyme-linked immunoassay.Results ( 1 ) The CXCL10 level in plasma in relapsing MS group elevated significantly between the 2nd ( (601 ± 365 ) pg/ml,t = - 2.898,P = 0.001) and the 4th ( (575 ± 297 ) pg/ml,t = -2.651,P=0.003) week after relapsing;GXL10 in CSF (n =32) did not changed significantly in the 4th week after relapsing( (1807 ±803) pg/ml).(2) The CXCL10 level in plasma in relapsing MS group were significantly higher than that in the healthy control group ((248±130) pg/ml,(=4.895,P=0.000) and remitting MS group ((287 ±118) pg/ml,t = 3.555,P = 0.001 ).( 3 ) The CXCL10 level in CSF in relapsing MS group (( 1774 ± 604) pg/ml) was significantly higher than that in NIND group ( ( 122 ± 114) pg/ml,t= 15.192,P =0.000).(4) The CXCL10 level in plasma in relapsing MS group had correlation with that in CSF (r=0.792,P=0.001).The CXCL10 level in CSF in relapsing MS group had correlation with EDSS scores (r = 0.526,P = 0.002 ).Conclusions The CXCL10 level in plasma might be implemented as a paraclinical marker of disease activity in MS.The CXCL10 level in plasma of MS may be relevant to that in CSF.The CXCL10 level in CSF of MS may indicate the clinical neurological dysfunction.     

Relationship of urinary myelin basic protein-like material with cranial magnetic resonance imaging in advanced multiple sclerosis

BACKGROUND: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS). OBJECTIVE: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status. DESIGN AND METHODS: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging. RESULTS: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138). CONCLUSIONS: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.     

Selected issues of immunomodulating treatment in multiple sclerosis

Placebo-controlled or open trials of immunomodulating drugs shed more light upon pivotal clinical issues in relapsing-remitting and secondary progressive multiple sclerosis (RR MS, SP MS). Extension over 4 years of IFN beta-1b, IFN beta-1a s.c. and glatiramer acetate trials provided modest clinical benefit in RR MS patients. After 4-8 years of treatment an annual relapse rate decreased (0.20-0.57) and proportion of progression free RR MS patients increased significantly (56-65%). The percentages of SP MS patients without relapses increased markedly in EUSPMS, IMPACT, NASMPS and SPECTRIMS trials to 36-63. However, the treatments did not slow progression in two latter clinical investigations (p=ns). In most non-responders to IFN beta the second-line immunomodulating drugs brought about clinical improvement. About half of MS patients showed one year or longer adherence to the first immunomodulating drug and nearly one fifth benefited from the change of this drug to another immunotherapeutic agent.     

Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.

It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)-12 (p40 and p35), tumor necrosis factor-alpha, interferon-gamma, and IL-10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing-remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL-12p40 and decreased levels of IL-10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL-12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL-12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL-12p40 mRNA. In RR MS, IL-10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL-10 mRNA levels constitutively, suggesting that IL-10 plays an important role in the control of disease progression.     

The association of V249I and T280M fractalkine receptor haplotypes with disease course of multiple sclerosis

We investigated the association of CX3CR1 genotypes/haplotypes with MS and performed the prediction analysis of protein sequence variants' effects on CX3CL1/CX3CR1 interaction. We found no association of CX3CR1 with MS susceptibility. Frequency of I(249)T(280) haplotype was significantly lower in SP compared to RR patients (RR>10 years, OR=0.30, 95%CI=0.11-0.79, p=0.01; OR=0.53, 95%CI=0.18-1.56, p=0.2, in SP<10 years vs. RR>10 years). Prediction analysis showed that I249 T280 protein variant would significantly affect CX3CL1/CX3CR1 interaction. Our results suggest that CX3CR1 I???T??? haplotype could have protective effect for switch to SP MS. Further research is warranted to validate and replicate currently observed results.     

Influence of CCR5 delta32 polymorphism on multiple sclerosis susceptibility and disease course

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). We carried out an allelic association study using a deletion polymorphism in the coding region of the CCR5 gene in 331 relapsing-remitting (RR) and secondary progressive (SP) MS patients, 108 primary progressive (PP) MS patients and 230 healthy controls. Of the 331 RR and SPMS patients, 172 were recruited from specialist clinics and 159 from a population survey. Disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS) and used to calculate a progression index for each patient (defined as EDSS divided by duration of disease). No significant difference in distribution of the CCR5 delta32 allele was observed between the 331 RR/SPMS patients and controls, between the 108 PPMS patients and controls or between the PPMS and RR/SPMS groups. Furthermore, no differences in rate of disease progression were detected between carriers and noncarriers of the delta32 allele. In the population-based group of RR/SPMS patients, carriage of the CCR5 delta32 polymorphism was associated with a lower age at disease onset (mean age 26.562 versus 31.065 years, P = 0.003). However, no significant differences in age of onset were present in the PPMS group or in a second RRMS population. These results suggest that the CCR5 delta32 polymorphism is not a major determinant of susceptibility to develop MS in the population under study, and conflict with a previously reported association between CCR5 delta32 carriage and a better prognosis.     

Differential patterns of memory performance in relapsing, remitting and secondary progressive multiple sclerosis

BACKGROUND: Memory dysfunction is common in multiple sclerosis (MS). A retrieval failure has been reported as the primary cause for the memory deficits, although some studies also described a faulty acquisition. AIMS: The aim of the study was to examine memory function in relapsing remitting (RR) and secondary progressive (SP) MS patients, analyze the patterns of performance and to investigate whether disease course influences this performance. DESIGN AND SETTINGS: Case-control prospective study conducted in a clinical setting. MATERIALS AND METHODS: Fifty-five RR, 23 SP MS patients and 80 normal subjects were evaluated with a comprehensive neuropsychological battery. Memory was assessed with tasks from the Signoret memory battery. Attention and executive function were also assessed. STATISTICAL ANALYSIS: Univariate analysis of variance, Mann-Whitney U-test, multivariate logistic regression and Chi-square test were used as appropriate. RESULTS: MS patients performed significantly worse than controls on almost all measures of memory (P < 0,001). MS subgroups differed in tasks of delayed recall (logical memory- P =0,019; wordlist delayed recall, P < 0,001), semantic cued recall (P < 0,001), recognition trials (P =0,006) rate of forgetting (P < 0,001) and confabulation and intrusion errors (P =0,004). CONCLUSIONS: Memory is consistently impaired in MS patients and disease course differentially affects the pattern of performance. SP patients show greater difficulties and a more pervasive pattern of dysfunction than RR patients. Delayed recall was the most affected memory measure and performance on this task discriminates between RR and SP MS patients. Relapsing remitting patients performed within the mildly impaired range while SP patients showed a moderate to severe impairment.     

The relationship of brain and cervical cord volume to disability in clinical subtypes of multiple sclerosis: a three-dimensional MRI study

OBJECTIVES: Brain and cervical cord volume is a potentially valuable index marker of irreversible pathological processes in multiple sclerosis (MS). Volume in both brain and cervical cord regions in the same patients has only been investigated in a small number of subjects. We aimed at measuring volume in different parts of the central nervous system, and its relationship with clinical measures, in relapsing-remitting (RR) and secondary progressive (SP) MS patients. MATERIAL AND METHODS: Conventional dual echo and three-dimensional (3-D) magnetization prepared rapid acquisition gradient echo imaging was performed on 97 (49 RR and 48 SP) MS patients, and on 31 age- and gender-matched healthy controls. The volumes of the supratentorial brain, lateral ventricles, brainstem, cerebellum and upper cervical cord (UCC) were determined on 3-D magnetic resonance imaging. RESULTS: RR MS patients had significantly smaller supratentorial brain (P=0.002) and larger lateral ventricles (P=0.047) compared with controls, but no differences were found for cerebellum, brainstem and UCC volumes. Significantly smaller supratentorial brain (P<0.0001), cerebellum (P=0.007), brainstem (P=0.0004) and UCC (P<0.0001) volumes, and larger lateral ventricles (P<0.0001) were observed in SP MS patients than in controls. In RR MS, T2-lesion volume correlated with supratentorial (r=-0.46, P=0.0009), lateral ventricular (r=0.65, P<0.0001), cerebellar (r=-0.42, P=0.003) and brainstem (r=-0.35, P=0.01) volumes, but not with UCC volume (r=-0.18, P=0.22). In SP MS, apart from lateral ventricular volume (r=0.52, P=0.0002), none of the estimated structural volumes correlated with T2-lesion volume. The UCC volume correlated with brainstem volume in both RR MS (r=0.35, P=0.016) and SP MS (r=0.38, P=0.007). Multiple regression analysis showed that supratentorial brain volume in RR group, and UCC volume in SP group, were single significant contributors (P=0.01 and 0.04, respectively) to the Expanded Disability Status Scale of all factors entered into the regression model. CONCLUSION: Atrophy is confined to the supratentorial compartment early in the disease course corresponding to the RR stage, but becomes more pronounced in the brain and cervical spinal cord in the SP phase. The estimate of cervical cord volume for SP MS is relevant to functional disability and may be helpful in monitoring MS evolution in the progressive form of disease.     

Melatonin pathway genes are associated with progressive subtypes and disability status in multiple sclerosis among Finnish patients

In this study we investigated the relationship between melatonin pathway and multiple sclerosis (MS) in a high-risk Finnish population by studying the single nucleotide polymorphisms (SNPs) in the genes coding for critical enzymes and receptors involved in the melatonin pathway. A total of 590 subjects (193 MS patients and 397 healthy controls) were genotyped for seven SNPs in four genes including tryptophan hydroxylases (TPH)1 and 2, arylalkylamine N-acetyltransferase (AANAT) and melatonin receptor 1B (MTNR1B). An overrepresentation of T allele carriers of a functional polymorphism (G-703T, rs4570625) in the promoter region of TPH2 gene was observed in the progressive MS subtypes. The haplotype rs4570625-rs10506645TT of TPH2 gene was associated with the risk of severe disability in primary progressive MS (PPMS), while haplotype rs4570625-rs10506645TC appeared to be protective against disability in secondary progressive MS (SPMS). In the MTNR1B gene, the haplotype rs10830963-rs4753426GC was associated with the risk of SPMS, whereas another haplotype rs10830963-rs4753426GT showed an association with the risk of PPMS. These data showing the association of polymorphisms in the TPH2 and MTNR1B genes with the progressive subtypes of MS and disability suggest dysregulation in melatonin pathway. Melatonin pathway seems to be involved in disease progression, and therefore its potential effects in overcoming MS-related neurodegeneration may be worth evaluating in future clinical trials.     

Interleukin-10 is associated with resistance to febrile seizures: Genetic association and experimental animal studies

Purpose:   Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) β, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls.
Methods:   The promoter SNPs of four inflammatory cytokine genes ( IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs ( IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models.
Results:   The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10–administered rats was significantly higher than that in the saline-treated control ones (p = 0.027).
Conclusions:   The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1β, confers resistance to FS.     

Inflammation and atrophy in multiple sclerosis: MRI associations with disease course

Brain atrophy may be a useful surrogate marker of axonal loss and disease progression in multiple sclerosis (MS). Several studies have suggested that inflammatory disease activity is a risk factor for atrophy in the early stages of the disease, but may become less important later in the disease course. We aimed to investigate the relationships between atrophy and active inflammation at different stages of the disease course using brain volume measurements from magnetic resonance imaging (MRI) in patients with both relapsing-remitting (RR) (n=95) and secondary progressive (SP) (n=76) MS. Conventional dual echo and three-dimensional magnetization-prepared rapid-acquisition gradient echo imaging were performed in all patients and in 31 healthy controls. Supratentorial and infratentorial brain, and lateral ventricular volumes were determined using modern design stereology.Patients with SP MS had smaller supratentorial (p=0.003) and infratentorial brain volumes (p=0.0003), and larger lateral ventricles (p=0.02) than patients with RR MS. RR MS patients with T(1)-enhancing lesions had smaller supratentorial (p=0.02) and infratentorial (p=0.002) brain volumes and larger ventricles (p=0.002) than those without enhancing lesions. SP MS patients with enhancing lesions also had significantly larger lateral ventricles (p=0.03). Categorical analysis showed that more RR MS patients with enhancing lesions had smaller supratentorial brain (p=0.005), or larger lateral ventricular (p=0.028) volumes, and more SP MS patients with enhancing lesions had increased lateral ventricle volumes (p=0.013), than patients without enhancements. The number of enhancing lesions was significantly correlated with lateral ventricular volumes in both RR MS (r=0.39, p=0.0001) and SP MS (r=0.46, p<0.0001). Our data shows that the presence of active inflammation on a single MRI in the course of RR and SP MS, is associated with a higher risk and higher level of brain atrophy. These findings emphasise the important long-term relationship between inflammation and atrophy in MS and provide additional support for the strategy of early anti-inflammatory treatment to protect tissue integrity.     

SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population

BackgroundSignificant efforts have been focused on investigating the contribution of common variants to Parkinson disease (PD) risk. Several independent GWAS and metanalysis studies have shown a genome-wide significant association of single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) regions. Here we investigated the role of SNCA and MAPT as PD susceptibility genes in a large Italian population of 904 patients and 891 controls. An evaluation of gene–gene and gene-environment interactions in association with PD was also attempted.MethodsThe SNCA Rep1 microsatellite was genotyped by a fluorescent PCR assay, whereas the SNPlex genotyping system was used to genotype 12 additional markers across the SNCA gene, and 2 SNPs tagging the risk MAPT H1 haplotype.ResultsSingle-marker analysis demonstrated nominal evidence of association for: i) the 261-bp-long allele of Rep1; ii) 7 SNPs in the SNCA region (top SNP: rs356186, P = 3.08 × 10^?04, intron 4); iii) both SNPs identifying the MAPT H1 haplotype (P = 4.63 × 10^?04 and P = 4.23 × 10^?04 for rs1800547 and rs9468, respectively). Moreover, we found a highly significant protective haplotype spanning ～83 kb from intron 4 to the 3′ end of SNCA (P = 1.29 × 10^?05).ConclusionsOur findings strongly confirm SNCA and MAPT as major PD susceptibility genes for idiopathic PD in the Italian population. Interaction analyses did not evidence either epistatic effects between the two loci or gene-environment interactions.     

IP-10 and MCP-1 levels in CSF and serum from multiple sclerosis patients with different clinical subtypes of the disease

Interferon-gamma-inducible Protein-10 (IP-10) and Monocyte Chemotactic Protein-1 (MCP-1) levels were measured by enzyme-linked immunosorbent assay (ELISA) in the CSF and in the serum from 74 patients affected by different clinical forms of Multiple Sclerosis (MS), including 39 patients with Relapsing Remitting (RR) MS in an active phase, 14 patients in a stable phase of the disease, 12 patients with Secondary Progressive (SP) MS and 9 patients with Primary Progressive (PP) MS. IP-10 and MCP-1 levels were also determined in 19 subjects with no neurological diseases or major systemic disorders, 18 patients with non-inflammatory neurological diseases, as well as in 15 patients with other inflammatory neurological diseases.IP-10 levels were significantly elevated in CSF and serum from RR and SP, but not PP-MS patients. On the contrary, MCP-1 levels were decreased in CSF and serum of all MS patients. CSF concentrations of IP-10 and MCP-1 did not significantly correlate neither with each other, nor with CSF mononuclear cell count, albumin quotient or CSF IgG index. No correlation between disease duration, clinical course or EDSS score and chemokine levels was found.IP-10 and MCP-1 undergo modifications in different subtypes of the disease: IP-10 levels in CSF and serum samples are markedly increased when inflammation is prominent, and not in PP--MS patients, where inflammation is less evident. MCP-1 decrease in CSF and serum from MS patients could be related to the regulation of T-cell polarization.     

The relapse rate of multiple sclerosis changes during pregnancy: a cohort study

Objective – To evaluate the influence of pregnancy and puerperium on the relapse rate of multiple sclerosis (MS).
Methods – We determined retrospectively the yearly mean relapse rate (MRR) during pregnancies occurring in the course of relapsing–remitting MS. We compared the MRR of pregnancy-time with that of non-pregnancy time by paired t -test. Relative risk (RR) of relapses during the pregnancy-time was also compared with that of non-pregnancy time by χ ² analysis and 95% confidence intervals.
Results – From a population of 351 women affected by clinically definite MS, only 70 reported pregnancies during their relapsing–remitting phase of MS for a total of 98 pregnancies. Both MRR ( P  = 0.006) and RR (RR = 0.63, 95% CI = 0.40–0.94) decreased during the three trimesters of pregnancy. RR increased in the first 3 months of puerperium, although this was not statistically significant (RR = 1.36, 95% CI = 0.79–2.20).
Conclusion – Our study confirms that in MS the relapse rate decreases throughout pregnancy and increases during puerperium. This suggests a complex interplay between hormonal and immune factors.     

Mediators of apoptosis Fas and FasL predict disability progression in multiple sclerosis over a period of 10 years

TNF-alpha, IL-12p35, IL-12p40, IL-4, IL-10, TGF-beta1, CCR3, CXCR3, CCR5, Fas and FasL mRNA levels in PBMC of 25 multiple sclerosis (MS) patients were quantified at baseline by real-time PCR according to a post-hoc study design. The baseline values of the different markers were analysed with respect to their correlation with the increase in disability over a period of 10 years. High levels of Fas mRNA were associated with a favourable disease course in relapsing-remitting (RR) MS (R2 = 0.74, P = 0.0001, n = 13), as measured by the Expanded Disability Status Scale (EDSS); high levels of FasL mRNA were associated with relatively mild disease progression (R2 = 0.86, P = 0.0001, n =12) in secondary progressive (SP) MS. These findings suggest that Fas-mediated apoptosis plays a major role in the mechanism underlying long-term disease progression in MS.:     

Secondary progressive multiple sclerosis - clinical course and potential predictive factors

BACKGROUND AND PURPOSE: To characterize the course of secondary progressive multiple sclerosis (SPMS), with an attempt to assess the predictive value of early clinical variables. MATERIAL AND METHODS: Medical records of 100 patients with SPMS (40 men, 60 women, aged 34-73) were analyzed retrospectively. Age at onset of MS, first symptoms, annual exacerbation rate (AER), time to progressive phase (TTP), degree of disability at its beginning (Expanded Disability Status Scale; EDSS SP), and annual progression in disability in relapsing-remitting and progressive phases (APD RR and APD SP) were compared for the gender subgroups, and the relationships between them were analyzed. RESULTS: Time to progressive phase range was 2-29 years (mean 11.51) and EDSS SP 2-7.5 (mean 5.55). Time to progressive phase in women was longer and EDSS SP was lower than in men. Age at onset of MS, AER and ADP RR correlated positively with TTP. Optic neuritis was the most common first symptom (49%; motor deficit and cerebellar/brainstem involvement 26% and 21%, respectively). Time to progressive phase in the former subgroup was shorter than in the latter, but no differences in ADP SP were found. Annual progression in disability in relapsing-remitting was higher than APD SP. Degree of disability at its beginning (EDSS SP) correlated negatively with ADP SP. CONCLUSIONS: Older age at onset, male gender, frequent relapses and fast increase in disability in the relapsing-remitting phase are risk factors for conversion to SPMS. Increase in disability during the progressive phase is slower than in the relapsing-remitting phase and depends mainly on initial EDSS. Individual variability of the course of MS has to be considered.     

Effect of the treatment with methylprednisolone on the cerebrospinal fluid and serum levels of CCL2 and CXCL10 chemokines in patients with active multiple sclerosis

BACKGROUND: Several experimental and human studies suggest that the chemokines CCL2 and CXCL10 may play a role in the pathogenesis of multiple sclerosis (MS). Here, we evaluated the effect of intravenous methylprednisolone (IVMP) therapy on the levels of CCL2 and CXCL10 in the cerebrospinal fluid (CSF) and serum of patients with active MS. METHODS: Serum and CSF samples were obtained from 14 patients with active relapsing-remitting MS (age +/- SD years, 37.0 +/- 8.1; M/F, 6/8) and age- and gender-matched control subjects. All patients were submitted to IVMP treatment (500 mg daily for 5 days). Blood and CSF sampling were performed at admission, i.e. before treatment (day 0), at the end of the treatment (day 6) and 30 days after treatment (day 30). The clinical status of MS patients was also assessed. CCL2 and CXCL10 were measured by enzyme-linked immunosorbent assay. RESULTS: Multiple sclerosis patients had lower CCL2 and higher CXCL10 in CSF when compared with control subjetcs. After treatment with methylprednisolone, MS patients showed clinical improvement and the CSF concentrations of CCL2 and CXCL10 modified toward normal values. CONCLUSIONS: The clinical improvement of active MS following the treatment with methylprednisolone was associated with the modification of CSF levels of CCL2 and CXCL10, suggesting that these chemokines may be useful markers of response to treatment and relapses in MS patients.     

Serum and cerebrospinal fluid nitrite and nitrate levels in relapsing-remitting and secondary progressive multiple sclerosis patients

Nitric oxide (NO) has been implicated in immune mediated cellular cytotoxicity and inflammatory processes including multiple sclerosis (MS). We aimed to assess NO production in MS patients and to delineate its involvement in different stages. The stable end-products of NO; nitrite(NO₂⁻) and nitrate(NO₃⁻) were analysed both in serum and CSF (cerebrospinal fluid) of patients with MS and non-inflammatory neurological diseases. Nitrite levels were quantified by calorimetric assay based on the Griess reaction. Nitrate levels were examined spectrophotometrically. MS patients exhibited significantly increased serum and CSF levels of NO₂⁻+NO₃⁻ compared with the control subjects. CSF NO₂⁻+NO₃⁻ levels were raised significantly in MS patients with both relapsing remitting (RR) and secondary progressive (SP) course. There was no significant difference between RR and SP MS patients with regard to NO metabolites. No significant correlation was found between NO metabolites and disability score, disease progression index, MRI (magnetic resonance imaging) activity and development of cortical atrophy on MRI. This study provides further evidence for excessive NO production both in CSF and peripheral blood of MS patients. Excessive CSF NO₂⁻+NO₃⁻ levels being more increased than the levels in sera supports pathological inflammatory process within CNS (central nervous system) in both stages of MS. Another implication for the role of NO and INOS inhibitors in the treatment of MS patients with both RR and SP courses was also suggested.