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PubMedDate not supplied

[Actual status of multiple sclerosis in Cuba. National cooperative group for the clinical trial "Recombinant interferon alpha-2b in multiple sclerosis"].

INTRODUCTION: Multiple sclerosis (MS) has been considered to be an uncommon disorder in Cuba. In recent years many Cuban investigators have worked hard studying MS in Cuba. DEVELOPMENT: We review the history, epidemiology, clinical characteristics, complementary investigations and clinical trials of recent studies published in national and international journals on the most important investigations done on MS in Cuba. There is an outstanding placebo-controlled, double blind, multicentric randomised clinical trial using recombinant alpha 2b-IFN in the relapsing-remitting clinical form in which the results obtained in the first 30 patients who completed 2 years treatment show a statistically significant reduction in the frequency of relapses and the number of patients free of relapses in patients who received alpha-IFN as compared with those given placebo treatment. CONCLUSIONS: There has been an increase in the number of studies made on MS in Cuba in the past two years. Numerous clinical, neuroepidemiological, neurophysiological, biochemical, immunological, imaging and neuropsychological investigations and clinical trials indicate a marked increase in understanding of MS. The results of all these studies indicated the need for the creation of a National Reference Centre for Patients with Multiple Sclerosis, due to the complexity of this type of patients and the need to offer improved medical attention from a specialist team and to integrate the investigations in Cuba and internationally so as to reach the level of more developed countries.

Adjuvants, Immunologic↗
PubMed2000

Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group.

A total of 754 consecutive patients with relapsing-remitting multiple sclerosis were investigated for interferon-beta (IFNbeta) antibodies by protein-G affinity chromatography and antiviral neutralization bioassay during 24 months on 6 MIU (22 microg) of subcutaneous IFNbeta-1a once weekly (n = 143) or three times weekly (n = 160), 6 MIU (30 microg) of intramuscular IFNbeta-1a once weekly (n = 140), or 8 MIU every other day of IFNbeta-1b (n = 311). The proportion of binding antibodies was higher in those receiving IFNbeta-1b compared with 6 MIU of IFNbeta-1a three times weekly (97 vs 89% at 12 months), and fewer became positive if 6 MIU of IFNbeta-1a was administered once weekly (58 vs 89%). Fewer patients on intramuscular than subcutaneous IFNbeta-1a became positive (33 vs 58%). The binding and neutralizing capacities were higher in the IFNbeta-1b group than in the IFNbeta-1a groups; these differences, however, were not significant after 12 months. The number of positive patients varied considerably and depended on the amount of IFN added to the bioassay; adding 10 LU/ml or more masked antibody detection. Antibodies induced by either preparation neutralized both IFNbeta species but not IFNalpha. In conclusion, IFNbeta-induced antibodies are frequently found in multiple sclerosis patients, and IFNbeta-1b is more immunogenic than IFNbeta-1a. The immunogenicity of IFNbeta-1a increases with the frequency of administration and if it is given subcutaneously.

Adolescent↗
PubMed1988

Double-masked trial of azathioprine in multiple sclerosis. British and Dutch Multiple Sclerosis Azathioprine Trial Group.

354 patients with multiple sclerosis were randomised to receive either azathioprine 2.5 mg/kg daily or placebo in a double-masked trial. During follow-up of at least 3 years only small differences emerged between the groups. After 3 years the mean deterioration in Kurtzke disability score was 0.62 in the azathioprine group and 0.80 in the placebo group, a difference of 0.18 (95% confidence intervals [CI] -0.15 to +0.52) and in the ambulation index it was 0.84 and 1.25, respectively, difference 0.41 (95% CI 0.03 to 0.80). After 3 years there had been slightly fewer relapses in the azathioprine group (average 2.2) than in the placebo group (average 2.5) but the difference of 0.3 (95% CI -0.2 to +0.9) was not significant. Although the results favour a small beneficial effect from azathioprine the benefit is so small that the use of azathioprine cannot be generally recommended for most patients with multiple sclerosis. Analysis of subgroups (by sex, age, severity, rate of progression, HLA status, relapsing or progressive course) has not revealed any that have shown clear clinical benefit.

Adolescent↗
PubMed1995

[Multiple sclerosis and prerequisites for driver's licence. A retrospective study of 33 patients with multiple sclerosis assessed at Sunnaas hospital].

There is increasing interest in assessing the prerequisites for a driver's licence among patients with traumatic brain injury, cerebrovascular accidents and other diseases of the central nervous system which cause cognitive impairments. In the present study, 33 patients with multiple sclerosis, 20 females and 13 males of mean age 43 years, were medically and neuropsychologically examined, and some were assessed in a practical driving test. In total, 19 patients were allowed to drive and 14 were refused. Regression analysis showed that, when deciding for or against driving, cognitive and emotional deficits were given more weight than duration of illness and degree of neurologic deficit. The authors discuss guidelines for assessing the prerequisites for a driver's licence among patients with multiple sclerosis, and indicators for when assessment is warranted.

Adult↗
PubMed1994

[Somatosensory evoked potentials in amyotrophic lateral sclerosis and primary lateral sclerosis].

Somatosensory evoked potentials (SEPs) were studied in 21 cases of amyotrophic lateral sclerosis (ALS) and 7 cases of primary lateral sclerosis (PLS). Despite the lack of clinical sensory abnormalities, SEPs showed abnormalities in both diseases: lack or delay of some components. In ALS these abnormalities indicate widespread sensory disturbance. In PLS only, the Brodmann area 4 seems to be affected.

Adult↗
PubMed1996

Motor evoked potentials (MEPs): evaluation of the different types of responses in amyotrophic lateral sclerosis and primary lateral sclerosis.

We studied different motor evoked potential parameters: cortical threshold (CT), primary response (PR) latency and amplitude and central conduction time (CCT) at rest and after maximal voluntary contraction of the target muscles, silent period (SP) and late muscular responses (LMR) in 21 normal subjects 42- to 75-years old and compared the results to those of 17 patients with motor disease (10 amyotrophic lateral sclerosis, ALS and 7 primary lateral sclerosis (PLS). We report for the first time in patients affected by motor diseases, LMRs were similar to controls. We found abnormalities in both ALS and PLS: enhanced cortical threshold, reduced PR amplitude during maximal voluntary contraction of target muscles compared to rest and shorter SP. CCT was slightly different: in ALS it was normal or undetermined (because of lack of the PR), while it was normal, enhanced or undetermined in PLS. We conclude that except for LMR, additional parameters would be useful for studying motor diseases: CT (reflecting excitability of the central cells), PR amplitudes and SP (disclosing inhibitory pathway disturbances in pyramidal tract diseases).

Adult↗
PubMed2004

Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis.

MSRV is a retroviral element previously isolated in cell cultures from patients with multiple sclerosis. It is part of a new multi-copy endogenous retrovirus family named HERV-W and displays pro-inflammatory properties both in vitro in human PBMC cultures and in vivo in a humanized SCID mice model. In the present study, we have evaluated potential links between the pro-inflammatory properties of MSRV envelope protein and MS disease. Thus, cytokine productions mediated by the surface unit of MSRV envelope protein were evaluated in PBMC of MS patients and compared with healthy controls. Divergent reactivity to ENV-SU between MS and control PBMC was observed and was reflected by a significant increase of IFN-gamma, IL-6 and IL-12p40 production by the tested MS population. Interestingly, the overproduction of IL-6 and IL-12p40 was found to correlate with disease severity (EDSS) in most patients. Altogether our data suggest that MSRV envelope protein may induce an abnormal cytokine secretion, thus contributing to the inflammatory process in MS.

Adult↗
PubMed2000

Transferrin in patients with multiple sclerosis: a comparison among various subgroups of multiple sclerosis patients.

OBJECTIVES: To compare cerebrospinal fluid (CSF) and serum transferrin (Tf) concentrations, transferrin quotient and index in various subgroups of MS patients. MATERIAL AND METHODS: CSF and serum transferrin concentrations, transferrin quotient QTf (i.e. CSF transferrin/serum transferrin x 10(3)) and index (QTf/Qalbumin) were determined in a group of 51 patients with clinically definite or probable multiple sclerosis (MS). Patients were subdivided according to the disease form (relapsing-remitting = RR, secondary progressive = SP, primary progressive = PP; patients with RR form were further subdivided into those in the attack and those in remission), disease severity (EDSS 0-5.5, EDSS 6.0-10.0), its treatment (non-treated - including patients treated with vitamins and/ or vasodilators only, treated - i.e. glucocorticoids and/or immunosuppressants and/or (exceptionally) beta-interferon), disease duration (0-2 years, >2-10 years, > 10 years) and sex. Correlation of transferrin values with age was also performed. RESULTS: Serum transferrin was somewhat lower and significantly more frequently subnormal in PP patients in comparison with the SP form and the RR form in remission. Transferrin index was significantly higher in the PP form than in the RR as well as the SP form. Transferrin quotient was significantly more frequently subnormal in patients in remission compared to those in the attack of the RR disease. CSF transferrin as well as transferrin quotient were more frequently subnormal in patients with short disease duration (0-2 years) than in patients with longer disease duration; these parameters, however, correlated also significantly with age. CSF transferrin and transferrin quotient were higher in male than in female patients. CONCLUSION: The authors conclude that evaluation of transferrin in MS patients - along with albumin - may help to differentiate among various MS subgroups, since there are significant differences among RR, SP and PP forms. For this purpose, however, other CSF protein fractions should be evaluated in parallel in order to obtain more complex information and to establish a panel of examinations enabling multiple statistical analyses. Transferrin evaluation in MS may also be of significant theoretical interest, since transferrin is known to be involved in the regulation of iron metabolism and it may have a protective role against the oxidative stress. Moreover, transferrin is a growth factor important for proliferation of activated T lymphocytes. By means of the use of transferrin quotient and especially transferrin index, it may be possible to estimate the proportion of intra-CNS-synthesized transferrin and/or rate of specific transferrin transport across the blood-CSF barrier. Further studies are, however, needed for such an evaluation.

Age Factors↗
PubMed2001

Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2.

Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1-2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC.

Adolescent↗
PubMed2006

Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes.

OBJECTIVE: To determine serum levels of BAFF, a potent B cell survival factor, in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc. METHODS: Serum BAFF levels in 83 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). In a longitudinal study, 131 serum samples obtained from 21 patients with SSc were analyzed. The expression of BAFF messenger RNA (mRNA) in the skin was quantified by real-time reverse transcription-polymerase chain reaction. The expression of BAFF receptor (BAFFR) on CD19+ B cells was assessed by flow cytometry. The production of IgG and interleukin-6 (IL-6) by isolated B cells was examined by ELISA. RESULTS: Serum BAFF levels were elevated in SSc patients compared with healthy controls and correlated positively with the extent of skin fibrosis. Among the 21 patients with SSc in the longitudinal study, 7 had decreased BAFF levels, 11 had levels that remained unchanged, and 3 patients had increased levels. Decreasing BAFF levels were accompanied by regression of skin sclerosis, whereas increasing levels of BAFF were associated with the new onset or worsening of organ involvement. BAFF mRNA expression was up-regulated in the affected skin of patients with early diffuse cutaneous SSc. BAFFR expression on B cells was increased in SSc patients relative to healthy controls. Furthermore, SSc B cells that were stimulated by BAFF exhibited an enhanced ability to produce IgG and IL-6. CONCLUSION: These results suggest that BAFF and its signaling in B cells contribute to B cell abnormalities and disease development in patients with SSc.

Adult↗
PubMed2002

Aortic valve sclerosis, mitral annular calcium, and aortic root sclerosis as markers of atherosclerosis in men.

Aortic valve sclerosis (AVS) and mitral annular calcium (MAC) as detected by transthoracic echocardiography have been associated with atherosclerosis. Aortic root sclerosis (ARS) may have a similar association, but has not been studied. This study evaluates, by transesophageal echocardiography, the association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. Multiplane transesophageal echocardiography with evaluation of AVS, MAC, ARS, and aortic atheromatous disease by 2 experienced observers unaware of clinical data was performed in 157 male patients > or =50 years old. The presence of cardiovascular disease, defined as coronary, carotid, or peripheral artery disease, was determined by specific criteria. The prevalence of AVS, MAC, ARS, and aortic atheromatous disease was 42%, 30%, 48%, and 71%, respectively. The presence of AVS, MAC, or ARS was highly associated with aortic atheromatous disease (odds ratio 4.9 to 12.0, confidence interval 1.4 to 35.8, p <0.001). ARS was also associated with cardiovascular disease (odds ratio 2.2, confidence interval 1.0 to 4.5, p = 0.038). The presence of AVS, MAC, or ARS had a sensitivity of 77%, specificity of 72%, a positive predictive value of 88%, and a negative predictive value of 55% for aortic atheromatous disease. We concluded that the prevalence of AVS, MAC, or ARS by transesophageal echocardiography in men is common, and their presence is highly associated with aortic atheromatous disease and coronary, carotid, or peripheral artery disease.

Aged↗
PubMed2004

[The methods for screening pulmonary hypertension related to systemic sclerosis in France. Descriptive survey of the French Research Group on Sclerosis].

CONTEXT AND OBJECTIVES: Pulmonary hypertension (PHT) represents one of the severest complications and is life-threatening for patients suffering from systemic sclerosis (SSc). In France, the modalities for screening and treating PHT related to SSc are not well codified and no consensus has been reached. We conducted a survey among physicians inscribed on the list of the French Research Group on Sclerosis (GRFS - Groupe de Recherche Francais sur la Sclerodermie) to gather information on the status of the management of PHT related to SSc. METHODS: In 2002, we sent a questionnaire to 160 physicians, members of the GRFS, to assess the epidemiology and clinical profile of SSc patients as well as the modalities of screening and management of PHT in these patients. RESULTS: Eighty-eight physicians in 71 centres replied to the questionnaire. Each centre followed-up a mean of 33 SSc patients, with a global distribution of 53% limited and 47% diffused SSc. These physicians saw a mean of 5 new cases of SSc per year. The patients had been referred by town practitioners (53%) or from the hospital (47%). The mean number of SSc patients with PHT was of 5.1 per physician (1.5 new SSc + PHT patients per year). Almost all the centres (65/67) who replied systematically screened for PHT in SSc patients using Doppler echocardiography a mean of every 1.3 years. For the management of the patients exhibiting PHT, the majority (41/63) of centres collaborated with a specialized unit. Around one third of the centres treated these patients with calcium channel inhibitors (82%) and/or prostacyclin (90%). All the patients were followed-up by Doppler echocardiography. The majority of the physicians (72%) were interested in a research protocol on the subject and each could have included 4 patients, i.e., a total of 160. CONCLUSION: Pulmonary hypertension, a severe complication of SSc is screened for by the physicians of the GRFS using echocardiography with a frequency similar to Who guidelines (1.3 versus once/year).

Diagnosis, Differential↗
PubMed1993

Connective tissue disease and autoantibodies in the kindreds of 63 patients with systemic sclerosis. The United Kingdom Systemic Sclerosis Study Group.

Systemic sclerosis (SSc) tends to occur in a sporadic fashion and familial occurrence of the disease is unusual. Nevertheless, reports of related connective tissue diseases (CTD), autoantibodies, or both in family members together with associations of certain HLA class II phenotypes with SSc suggest that genetic factors might play a part in susceptibility to the disease. Because of the relative rarity of SSc only a small number of family pedigrees have been studied previously. This report represents the largest study to date, to our knowledge, of family members of patients with scleroderma, and provides the opportunity to investigate the relative importance of genetic and environmental factors operating in the disease. The family pedigrees of 63 patients with systemic sclerosis were examined with respect to clinical, serologic, and immunogenetic features. Multiple cases of SSc were seen only in 1 family, in which the disease affected a father and daughter. Disease expression in these 2 individuals was very similar both clinically and serologically; relatives with other connective tissue diseases were found in 9 families, and nonspecific features of CTD such as Raynaud phenomenon, and arthralgia or arthritis, occurred commonly, especially in female relatives. Antinuclear antibodies (ANA) were also detected more frequently in relatives than in controls. However, antibodies previously demonstrated to have a high degree of specificity for SSc were confined to patients with this disease. Probands had an increase in the frequency of HLA-DR3, DR5, and C4AQO. Patients with diffuse scleroderma had an increased frequency of HLA-DR3, while those with the limited form of the disease had an increased frequency of HLA-DR5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2006

Serum levels of monocyte chemotactic protein-3/CCL7 are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis.

OBJECTIVE: To determine serum levels of monocyte chemotactic protein-3 (MCP-3) and its clinical associations in patients with systemic sclerosis (SSc). METHODS: Serum MCP-3 levels from 69 patients with SSc were examined by ELISA. RESULTS: Serum MCP-3 levels were raised in patients with SSc (n = 69) compared with healthy controls (n = 28). Patients with diffuse cutaneous SSc (n = 36) had higher levels of serum MCP-3 than those with limited cutaneous SSc (n = 33). Patients with raised MCP-3 levels had pulmonary fibrosis and decreased vital capacity (VC) more often than those with normal MCP-3 levels. MCP-3 levels correlated positively with the extent of skin fibrosis, and inversely with %VC and carbon monoxide transfer factor (Tlco) in patients with SSc. CONCLUSION: MCP-3 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that MCP-3 may have a role in the development of fibrosis in SSc.

Adolescent↗
PubMed2000

Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis.

OBJECTIVE: To determine the serum levels and clinical correlation of connective tissue growth factors (CTGF) in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (lSSc, n = 32), diffuse cutaneous SSc (dSSc, n = 28), systemic lupus erythematosus (SLE, n = 30), polymyositis/dermatomyositis (PM/DM, n = 20), and healthy control subjects (n = 30) were examined by ELISA for detection of CTGF. RESULTS: Serum CTGF levels in patients with SSc were significantly higher than those in patients with SLE or PM/DM, and in controls. CTGF levels in patients with dSSc were significantly higher than those in patients with lSSc. As for clinical correlation of CTGF, SSc patients with elevated CTGF had pulmonary fibrosis, decreased DLCO, and decreased vital capacity more frequently than those with normal CTGF levels. Further, DLCO and vital capacity were inversely and directly correlated with serum CTGF levels in patients with SSc. The dSSc patients with disease duration of 1-3 years had significantly elevated levels of CTGF compared with dSSc patients with duration < 1 year or more than 3 years. CONCLUSION: Serum CTGF levels were increased in patients with SSc, and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. In addition, it appears that production of CTGF is involved in the development or maintenance of fibrosis rather than in initiation of fibrosis in SSc. These data suggest that CTGF plays a critical role in the development of fibrosis in SSc.

Adolescent↗
PubMed1997

Role of the tuberous sclerosis gene-2 product in cell cycle control. Loss of the tuberous sclerosis gene-2 induces quiescent cells to enter S phase.

Tuberous sclerosis is an autosomal dominant disorder characterized by the development of benign growths in many tissues and organs. Linkage analysis revealed two disease-determining genes on chromosome 9 and chromosome 16. The TSC2 gene on chromosome 16 encodes a 1784-amino acid tumor suppressor protein, tuberin, that functions as a GTPase-activating protein for Rap1, a member of the superfamily of Ras-related proteins. By immunoblot analyses, we found TSC2 expression to be high in G0 as well as in early small G1 cells. Analyses after different cell synchronization procedures revealed that TSC2 mRNA and protein expression do not fluctuate throughout the cell cycle. Using inducible expression systems we further demonstrated that TSC2 expression is not affected by overexpression of the mitogenic transcription factor E2F-1 or c-Myc. Nevertheless, antisense inhibition of tuberin expression in logarithmically growing cells markedly decreased the percentage of cells in G1. Furthermore, we found that cells exposed to TSC2 antisense oligonucleotides did not undergo G0 arrest after serum withdrawal. Antisense inhibition of TSC2 expression also induced quiescent G0-arrested fibroblasts to reenter the cell cycle. Our data show for the first time that the absence of tuberin can both induce cells to pass through the G1/S transition of the eukaryotic cell cycle and prevent them from entering a quiescent state. These results have clear implications for the tumor suppressor function of TSC2. We further found that reentry into the cell cycle upon loss of TSC2 is dependent on the activity of the G1 cyclin-dependent kinases (CDKs), Cdk2 or Cdk4. Taken together with our finding that antisense inhibition of TSC2 causes up-regulation of cyclin D1 expression, these results provide the first evidence for a connection between tuberin/Rap1 and the G1 CDK-dependent regulation of the transition from G0/G1 to S phase.

Animals↗
PubMed2005

Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis.

Therapy-induced binding and neutralizing antibodies is a major problem in interferon (IFN)-beta treatment of multiple sclerosis. The objective of this study was to provide guidelines outlining the methods and clinical use of the measurements of binding and neutralizing antibodies. Systematic search of the Medline database for available publications on binding and neutralizing antibodies was undertaken. Appropriate publications were reviewed by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. Measurements of binding antibodies are recommended for IFN-beta antibody screening before performing a neutralizing antibody (NAB) assay (Level A recommendation). Measurement of NABs should be performed in specialized laboratories with a validated cytopathic effect assay or MxA production assay using serial dilution of the test sera. The NAB titre should be calculated using the Kawade formula (Level A recommendation). Tests for the presence of NABs should be performed in all patients at 12 and 24 months of therapy (Level A recommendation). In patients who remain NAB-negative during this period measurements of NABs can be discontinued (Level B recommendation). In patient with NABs, measurements should be repeated, and therapy with IFN-beta should be discontinued in patients with high titres of NABs sustained at repeated measurements with 3- to 6-month intervals (Level A recommendation).

Antibodies↗