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At least 577 records · Page 32Linked to original sources
PubMed2000

Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis.

We have used representational difference analysis (RDA) to identify up-regulated genes in skin fibroblasts from fibrotic lesions obtained from patients with systemic sclerosis (scleroderma). RDA of cDNA libraries derived from fibroblasts from involved and uninvolved skin detected several differentially expressed genes. One such gene consistently up-regulated in scleroderma cells coded for human connective tissue growth factor (CTGF). Other studies described here show that the CTGF protein is readily detected in cultures of systemic sclerosis fibroblasts but was not detected in comparable normal cells. High levels of CTGF are also evident in biological fluids from patients with systemic sclerosis. TGFbeta stimulates CTGF production in both normal and systemic sclerosis fibroblasts with the latter found to be higher producers. Moreover, an analysis of constitutive and TGFbeta-induced CTGF gene activation showed altered and elevated transcriptional responses in systemic sclerosis cells compared with controls. CTGF stimulated a two- to threefold increase in proalpha1(I) collagen and fibronectin synthesis by both dermal and lung fibroblasts in culture and promoted significant matrix remodeling of fibroblast-populated three-dimensional collagen lattices. A direct relation between the overexpression of CTGF and elevated collagen synthesis was suggested by the observation that transfection of a CMV-CTGF cDNA construct and protein expression in fibroblasts increased the transcription of a Col 1alpha2 promoter-reporter construct to levels seen in systemic sclerosis fibroblasts. Using Col 1alpha2 promoter deletion constructs the CTGF responsive element was localized to the first 379 bp upstream of the transcriptional start site. These data indicate that there is an overexpression of CTGF in the systemic sclerosis cells, probably due to increased gene transcription, and suggest that the dysregulation of CTGF production is an important factor in fibroblast activation and the excessive deposition of collagen in systemic sclerosis.

3T3 Cells↗
PubMed1995

The use of serologic markers for collagen synthesis and degradation in systemic sclerosis.

BACKGROUND: Systemic sclerosis is characterized by excessive accumulation of collagen in all involved organs. Serum markers of collagen synthesis and degradation, the aminoterminal propeptide of type III procollagen (PIIINP), the carboxyterminal propeptide of type I procollagen (PICP), and the crosslinked telopeptide of type I collagen (ICTP), can be measured. OBJECTIVE: Our purpose was to investigate these markers in different subgroups of untreated patients with systemic sclerosis and in patients before and after various types of therapy. PIIINP and PICP were also investigated in blister fluid from involved and uninvolved skin. METHODS: Sera from 97 patients and suction blister fluid from 13 patients were radioimmunoassayed. RESULTS: The highest levels of PIIINP and PICP were found in blister fluid from involved skin. Patients with systemic sclerosis had higher serum levels of PIIINP than control subjects. The highest levels were found in patients with diffuse cutaneous systemic (type III) sclerosis; increased serum PIIINP was also characteristic of type II limited cutaneous systemic sclerosis. Most patients with limited cutaneous type I systemic sclerosis had normal levels. Serum PICP was within normal limits in all three types of systemic sclerosis. Variations in ICTP type I collagen degradation in general followed PICP. Immunosuppressive drugs significantly reduced PIIINP, whereas no significant decrease was found after photopheresis. PICP and ICTP also diminished after treatment with D-penicillamine and cyclophosphamide given together with prednisone. CONCLUSION: PIIINP can be recommended for monitoring collagen synthesis in systemic sclerosis. Our data support the use of immunosuppressive therapy for this disease.

Biomarkers↗
PubMed1996

Circadian variations of plasma levels of blood coagulation/fibrinolysis molecular markers in progressive systemic sclerosis (PSS).

We measured plasma levels of the blood coagulation/fibrinolysis molecular markers, thrombin-antithrombin III complex (TAT), fibrinopeptide A (FPA), alpha 2-plasmin inhibitor plasmin complex (PIC), beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), at 6:00, 12:00, 18:00 and 24:00 in 10 female patients with progressive systemic sclerosis (PSS) (severe and mild sclerosis groups, each n = 5), 3 cases of dermatomyositis (DM) (M:F = 2:1) and 5 female healthy controls (HC). Corticosteroid (predonisolon; 20-25 mg/day) was administered orally in six patients with PSS and dermatomyositis longer than one month. Plasma levels of TAT increased more than 3 ng/ml in 8 out of 10 cases (80%) of PSS, while the levels increased in only 2 of 8 cases (25%) of the non-PSS groups (DM and HC). The severe sclerosis group of PSS showed a peak at 6:00 in the circadian variations of plasma levels of TAT and FPA, while the mild sclerosis group of PSS showed a peak at 12:00 or 24:00, and both DM and HC at 24:00. However, there was no significant peak in circadian variations of the plasma levels of PIC in the severe sclerosis group of PSS, although there was a peak at 24:00 in other diseases. The synchronized peaks of TAT and PIC were seen in 4 of 8 cases (50%) of the non-PSS group. On the other hand, this synchronization was only detected in 1 of 10 cases (10%) of PSS. The plasma levels of beta-TG and PF4 increased in 8 of 10 cases (80%) of PSS, but these levels did not increase in 8 non-PSS cases. Circadian variation of plasma levels of beta-TG showed a peak at 6:00 in the severe sclerosis group of PSS, while the mild sclerosis group of PSS, DM and HC revealed peaks at different times of 18:00, 24:00 and 12:00, respectively. Additionally, the plasma levels of beta-TG increased more than those of PF4 in the treated group with corticosteroid, although both beta-TG and PF4 revealed a statistically significant correlation in the non-treated group. These results may suggest abnormalities of not only platelet activity, but also of blood coagulation/fibrinolysis system in both severe and mild sclerosis groups of PSS.

Adult↗
PubMedDate not supplied

Defective vasculogenesis in systemic sclerosis.

BACKGROUND: Typical vascular features of systemic sclerosis include low capillary density and vascular obliteration. The formation and repair of blood vessels in adults involve vasculogenesis, which is mediated through the recruitment of bone-marrow-derived circulating endothelial precursors (CEP). We investigated whether vasculogenesis is impaired in patients with systemic sclerosis. METHODS: Peripheral blood was obtained from 11 patients with systemic sclerosis, 11 with rheumatoid arthritis, and 11 healthy controls. Factors potentially affecting the CEP number were matched among the three groups. CEP (identified as circulating cells positive for CD34, CD133, and the type 2 receptor for vascular endothelial growth factor) were quantified by cell sorting and three-colour flow cytometry. The circulating concentrations of angiogenic factors were measured by ELISA. The potential of CEP to differentiate into endothelial cells was assessed by the upregulation of von Willebrand factor after in-vitro maturation treatment. Findings The absolute number of CEP was much lower in patients with systemic sclerosis than in patients with rheumatoid arthritis or healthy controls (median 274 [IQR 178-395] vs 1154 [653-1524] and 1074 [713-1186] per 20 mL peripheral blood, respectively; p<0.0001 by Kruskal-Wallis test. Paradoxically, circulating concentrations of most angiogenic factors were significantly higher in patients with systemic sclerosis than in healthy controls. The proportion of CEP that differentiated into endothelial cells was significantly lower in patients with systemic sclerosis than in healthy controls (p<0.0001, Mann-Whitney test). INTERPRETATION: Insufficient vascular repair machinery due to defective vasculogenesis might contribute to vasculopathy in systemic sclerosis. RELEVANCE TO PRACTICE: As well as providing an important insight into the pathogenesis of this disorder, these findings suggest that dysregulated vasculogenesis might be important in other disorders with abnormalities in vascular formation, including those with excessive formation of new vessels such as cancer and those with deficient vessel formation such as atherosclerosis. Circulating endothelial precursors could be a novel target for therapeutic strategies for ischaemic complications in patients with systemic sclerosis.

AC133 Antigen↗
PubMed2005

Podocyte damage damages podocytes: autonomous vicious cycle that drives local spread of glomerular sclerosis.

PURPOSE OF REVIEW: For some time, the so-called vicious cycle has been believed to underlie progression of glomerular sclerosis. This mechanism describes a circumstance when loss of some glomeruli imposes injurious stress on the remnant glomeruli. Evidence from recent genetic approaches, however, has prompted revision of this classical view and now points toward a new direction of investigations. RECENT FINDINGS: Whereas experimental maneuvers that selectively injure mesangial cells have failed to induce glomerular sclerosis, genetic approaches that target visceral epithelial cells, or podocytes, in embryos and adult animals regularly produce glomerular sclerosis. Association between podocyte damage and glomerular sclerosis observed in many human diseases and animal models have identified podocyte injury as a common, if not universal, trigger leading to glomerular sclerosis. The process from podocyte injury to sclerosis is remarkably rapid, and the rate of progression depends upon the degree of initial podocyte injury. A single brief injurious stimulus on a podocyte activates a 'domino effect', whereby progressive damage of the initially hit podocyte spreads to involve cells that escaped the initial insult. SUMMARY: The mouse, a species highly useful for studying the function of specific gene products, is notoriously resistant to development of glomerular sclerosis in adulthood. However, recent genetic engineering in this species has overcome this disadvantage and brought about a new dimension to our understanding of the mechanisms involved in progressive glomerular sclerosis.

Animals↗
PubMed1999

Familial risk estimation in systemic sclerosis.

BACKGROUND: Familial systemic sclerosis has been rarely reported. Assumptions have therefore been made implying no familial disease aggregation. This study critically challenges the assumption using a methodical population-based epidemiological approach to quantify the prevalence and characteristics of familial systemic sclerosis. METHODS: In this retrospective cohort study the systemic sclerosis prevalence in first degree family members was compared between 715 systemic sclerosis patients (710 families) and 371 randomly ascertained age and gender group-matched general practice controls (371 families). These data, obtained by telephone questionnaire (living patients) or medical records review (deceased patients and untraceable patients of unknown living status), were validated, where necessary, and expressed in terms of relative risk, absolute risk and population point prevalence. RESULTS: Systemic sclerosis affecting first degree members was validated in ten of 710 families. Reporting of systemic disease in another four more distant family members, and the co-occurrence of systemic and localised disease in three families was also documented. Observed and expected disease subtype concordance was 80% (44-97%) and 68% respectively and the female predominance among familial cases was similar to that for non-familial disease. The risk of disease in a subsequent first degree relative was compared to the risk in an initial first degree family member. Its estimated magnitude was wide (11-158). However, use of population prevalence data to determine the expected number of systemic sclerosis patients in the negative cohorts' families suggests the higher estimate is more realistic. Despite the high magnitude, the absolute disease risk in first degree family members remained low--approximating 1%. The population prevalence of familial systemic sclerosis approximated 1.4/million. CONCLUSIONS: This study substantially increases the otherwise small list of documented instances of familial systemic sclerosis. More importantly, it quantifies the risk for the first time, ranking it as the disease's most powerful determinant identified to date.

Cohort Studies↗
PubMed2000

Male systemic sclerosis and occupational silica exposure-a population-based study.

BACKGROUND: The continuing uncertainty about the silica-systemic sclerosis relationship led to the investigation of its role as a disease determinant in a large population-based study of systemic sclerosis. AIMS: To compare the frequency, socioeconomic and educational status, age-specific prevalence and duration of occupational silica exposure in males with and without systemic sclerosis. To assess the temporal relationship between exposure and disease onset. To estimate disease latency. To compare disease characteristics between silica-exposed and non-silica-exposed male cases. METHODS: The study was case-control in design. The exposure variable was occupational silica exposure as assessed by an occupational health officer blinded to case/control status and the outcome variable was systemic sclerosis. The employed instrument comprised either a standardised telephone questionnaire (interviewed cases and controls) or medical records (deceased or living-status-unknown cases). RESULTS: Sixty of 160 cases (37.5%) and 11 of 83 (13.3%) controls had occupational silica exposure (OR=3.93; 1.84-8.54). Comparison of data between 64 interviewed cases and all controls demonstrated initial occupational silica exposure occurring before age 40, comparable educational status but significantly different cumulative socioeconomic status with cases being over-represented in semi-skilled and unskilled occupations. Cross-sectional 'current' occupational data underestimated cumulative silica exposure by more than 50%. Silica exposure uniformly preceded onset of second disease symptoms and disease diagnosis. In most, it also preceded onset of first disease symptoms. Disease latency approximated two decades. No disease features distinguished silica-associated systemic sclerosis from idiopathic systemic sclerosis. The duration of silica exposure in the interviewed silica-exposed cases did not significantly exceed that of silica-exposed controls. CONCLUSIONS: Male systemic sclerosis displays socioeconomic dependence. Silica is a disease determinant in male systemic sclerosis, with disease features including a long latency and clinical characteristics indistinguishable from idiopathic disease. Cross-sectional 'current' occupational data underestimate cumulative occupational silica exposure.

Adolescent↗
PubMed1991

Major histocompatibility complex class II genes and systemic sclerosis.

1. In no ethnic group is the overall association between systemic sclerosis and the MHC strong enough for direct clinical use. MHC associations do support the classification of the disease into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis. 2. Indications are that associations between specific subsets of patients with systemic sclerosis and genetic markers will assume greater importance both diagnostically and prognostically. The group with lung fibrosis look prime candidates, for example. 3. Genetic markers are useful means of relating chemically induced systemic sclerosis like disorders with the classical disease. Vinyl chloride disease provides an example. 4. Evidence is emerging of strong associations between certain genetic markers and autoantibody production; a similar story has emerged in systemic lupus erythematosus. We believe that, eventually, genetic tests will be used to influence treatment in at least a subset of patients with systemic sclerosis but that a dramatic breakthrough will not be made until we know how the genetics of the disease relate to the primary biochemical disease characteristic--that is, the overproduction of collagen. In this respect it has been suggested that the 5' flanking DNA of dermal collagen genes is particularly susceptible to the action of Scl-70 (topoisomerase I). A problem is how to tie this and the other observations discussed above together. The association of autoantibodies with topoisomerase I provides a tentative link between the MHC and collagen gene expression. Although the role and reason for anti-Scl-70 in systemic sclerosis is unknown, humoral autoimmunity, at least in systemic lupus erythematosus, seems to be strongly dependent on specific HLA genes. With an understanding of the function of MHC products at the molecular level, HLA and disease associations can now be analysed on a mechanistic level. For insulin dependent diabetes mellitus it has been shown that the MHC determined susceptibility to the disease is conferred by neutral residues (Val, Ser, Ala), at position 57 of the DQ beta chain, while Asp at this position correlates with resistance. A similar phenomenon has been described in rheumatoid arthritis. Although DR4 in general is associated with rheumatoid arthritis, it is heterogeneous, but a subtype of DR4 which is characterised by positively charged residues at positions 70 and 71 of the beta chains is not found in patients with rheumatoid arthritis (Wordsworth B P et al, unpublished data). A similar approach applied to the study of systemic sclerosis is likely to be similarly rewarding. The precise subtyping of the class II genes and the characterisation of their associated haplotypes is therefore required for a complete understanding of the contribution of the MHC to the disease. Additional genes linked to the MHC must not be overlooked, and are relevant to associations of haplotypes with the disease. Of particular interest are the recent reports of a new class of proteins, which are determined by genes in the MHC and which are considered to play a part in the assembly of the antigen peptide/MHC molecule complex.

Environmental Exposure↗
PubMed2002

Histometric data obtained by in vivo confocal laser scanning microscopy in patients with systemic sclerosis.

BACKGROUND: It would be a benefit if time-saving, non-invasive methods could give hints for diagnosing systemic sclerosis. To investigate the skin of patients with systemic sclerosis using confocal laser scanning microscopy in vivo and to develop histometric parameters to describe characteristic cutaneous changes of systemic sclerosis observed by this new technique, we conducted an exploratory study. MATERIALS AND METHODS: Fifteen patients with systemic sclerosis treated with extracorporal photopheresis were compared with 15 healthy volunteers and 10 patients with other disorders also treated with extracorporal photopheresis. All subjects were investigated using confocal laser scanning microscopy in vivo. RESULTS: Micromorphologic characteristics of skin of patients with systemic sclerosis and measuring parameters for melanisation, epidermal hypotrophy, and fibrosis for dislocation of capillaries by collagen deposits in the papillary dermis were evaluated. An interesting finding was an increased thickness of the tissue in the dermal papillae superior to the first dermal papilla vessel. It was also possible to reproduce characteristic histologic features by confocal laser scanning microscopy in vivo. Histometric parameters for fibrosis and vascular features developed in this study showed significant differences in patients with systemic sclerosis compared to controls. CONCLUSIONS: Although the predominant histopathological features in systemic sclerosis are findings of the reticular dermis and the subcutis, and in histopathological investigation the epidermis seems to remain unaffected by the disease, we have demonstrate some characteristic differences in the epidermis and papillary dermis by confocal laser scanning microscopy in vivo. Some of them have not been described so far. However, to use this technique as a tool for diagnosis and/or staging of systemic sclerosis, further studies are needed investigating the sensitivity and specificity of the histometric parameters developed in this study.

Adult↗
PubMed1996

Cardiorespiratory responses to incremental exercise in patients with systemic sclerosis.

Patients with systemic sclerosis are known to have histologic pulmonary abnormalities despite normal chest radiograph or conventional pulmonary function or both. In an attempt to detect early features of lung involvement in progressive systemic sclerosis, we investigated patients with systemic sclerosis using cardiopulmonary exercise testing. We have studied 78 patients who fulfilled the American Rheumatism Association criteria for the classification of systemic sclerosis, and according to the classification of LeRoy, 44 had limited cutaneous systemic sclerosis and 34 had diffuse cutaneous systemic sclerosis. A significantly decreased diffusing capacity (65 +/- 3% of that predicted) was present only in the group with diffuse cutaneous systemic sclerosis. The patients with lung involvement showed a significant reduction in exercise capacity (54 +/- 3% of that predicted) and in oxygen uptake (70 +/- 3% of that predicted). Additionally, we could demonstrate an increased functional dead space ventilation (0.34 +/- 0.02) and widened alveolar-arterial oxygen difference during exercise (44 +/- 3 mm Hg). By cardiopulmonary exercise testing, 12 of the 78 patients (15%) with normal single-breath diffusing capacity for carbon monoxide had increased dead space to tidal volume ratio. Our results suggest that occult pulmonary impairment may be present in patients with normal pulmonary function and that cardiopulmonary exercise testing enables detection of such impairment. Our study results show the limitations of resting data in predicting abnormalities during exercise in patients with systemic sclerosis.

Adult↗
PubMed1992

Percutaneous chemical gallbladder sclerosis after laser-induced cystic duct obliteration: results in an experimental model.

OBJECTIVE: Chemical gallbladder sclerosis has been attempted as a way to defunctionalize the gallbladder in patients who have undergone nonsurgical removal of gallstones and who are unable to undergo surgical/laparoscopic cholecystectomy. The purpose of this investigation was threefold: to study an animal model for chemical sclerosis of the gallbladder with 95% ethanol and 3% sodium tetradecyl sulfate, to attempt chemical sclerosis immediately after percutaneous cystic duct obliteration by laser thermocoagulation, and to assess histopathologic changes in the gallbladder after sclerosis. MATERIALS AND METHODS: Percutaneous cholecystostomy and laser thermocoagulation of the cystic duct was performed in 13 pigs. Eight pigs underwent immediate gallbladder sclerosis with 95% ethanol and 3% sodium tetradecyl sulfate while two pigs received 95% ethanol only. The remaining three pigs served as controls. The cholecystostomy catheter was removed immediately after the procedure. All animals were sacrificed 6 weeks after laser thermocoagulation. Multiple sections through the gallbladder, which included the adjacent liver, the cystic duct, and the common bile duct, were obtained for histologic examination. RESULTS: At autopsy, the gallbladder in all 10 animals who underwent gallbladder sclerosis was reduced in size compared with controls. In all treated animals, the gallbladder mucosa was denuded; however, in nine of 10 cases reepithelialization had occurred. Complete sclerosis without reepithelialization was achieved in one pig who received both ethanol and sodium tetradecyl sulfate. In the two animals who received ethanol only, the depth of wall necrosis around the gallbladder lumen was less than in those pigs who received both ethanol and sodium tetradecyl sulfate. No pigs showed signs of hepatic necrosis or injury to the common bile duct. CONCLUSION: Cystic duct laser thermocoagulation allows immediate gallbladder sclerotherapy without injury to the common bile duct. Sclerosis with ethanol and sodium tetradecyl sulfate results in denudation of the gallbladder mucosa. However, a single therapeutic session with immediate removal of the cholecystostomy catheter was inadequate for gallbladder ablation in this model because of reepithelialization.

Animals↗
PubMed2005

[Systemic sclerosis--clinical course and treatment possibilities].

Systemic sclerosis is an autoimmune disease, characterized by fibrosis of the skin and internal organs, such as esophagus, heart, lungs, and kidneys. Three main forms of systemic sclerosis are conspicuous: diffuse systemic sclerosis, limited systemic sclerosis and scleroderma sine sclerosis. Respective variants differ in skin sclerosis exacerbation, progress and prognosis; whereas organ involvement, osseous and articular alterations are comparable in all forms of the disease. Due to the fact that etiology of systemic sclerosis is not known, no specific therapy has been developed. The therapy is based on influencing main pathogenetic factors, such as peripheral circulation disturbances, abnormal immune activation and increase in collagen accumulation. An overview of clinical course of systemic sclerosis and new therapeutic modalities is provided.

Connective Tissue↗
PubMed2001

Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.

BACKGROUND: Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis. METHODS: Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections. FINDINGS: 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment. INTERPRETATION: Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.

Adolescent↗
PubMed2002

Genetic basis for clinical expression in multiple sclerosis.

Multiple sclerosis is a clinically heterogeneous demyelinating disease and an important cause of acquired neurological disability. An underlying complex genetic susceptibility plays an important role in multiple sclerosis aetiology; however, the role of genetic factors in determining clinical features of multiple sclerosis is unknown. We studied 184 stringently ascertained Caucasian multiple sclerosis families with multiple affected cases. A detailed evaluation of patient histories identified clinical variables including age of onset, initial clinical manifestations and disease severity. The concordance within families for continuous and categorical clinical variables was investigated using an intraclass correlation or Cohen's kappa coefficient, respectively. Genetic analyses included model-dependent, model-independent and association methodology. Linear and logistic regression models were used to evaluate the effect of human leucocyte antigen (HLA)-DR2 (DRB1*1501, DQB1*0602) on clinical outcome, taking account of correlation within families. Significant concordance for early clinical manifestations within families was observed for individuals with exclusive optic neuritis and/or spinal cord involvement as first and second multiple sclerosis attacks (P < 10(-6)). Linkage (LOD = 3.80, theta = 0.20) and association (P = 0.0002) to HLA-DR were present in the dataset; however, linkage was restricted to families in which the DR2 haplotype was present in at least one nuclear member. No evidence for linkage to HLA-DR in DR2-negative families was observed. When families were stratified by concordance of early clinical manifestations, a significant DR2 association was present in all subgroups. Concordance for early manifestations of multiple sclerosis was present in this familial dataset, but was not associated with HLA-DR2. The association of DR2 in families with different clinical presentations suggests that a common basis exists for susceptibility in multiple sclerosis. However, non-HLA genes or other epigenetic factors must modulate disease expression. Locus heterogeneity at the HLA region suggests a distinct immunopathogenesis in DR2 negative patients.

Adolescent↗
PubMed2003

Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study.

BACKGROUND: Beta(2) adrenoreceptor expression on peripheral blood mononuclear cells is increased in progressive multiple sclerosis. This increase has been correlated with disease activity in relapsing-remitting multiple sclerosis. OBJECTIVE: To determine the beta(2) adrenoreceptor expression in primary and secondary progressive multiple sclerosis in relation to findings on magnetic resonance imaging (MRI) and clinical disease activity. METHODS: 10 patients with multiple sclerosis were studied (five with primary progressive and five with secondary progressive forms of the disease) over a period of six months. Monthly clinical and MRI assessments of the brain and spinal cord were carried out. Beta(2) adrenoreceptor expression was assessed monthly using a ligand binding assay with [(125)I]iodocyanopindolol. Expression of beta(2) adrenoceptors on peripheral blood mononuclear cells was also assessed in five normal controls over a similar period. RESULTS: The mean (SEM) value of beta(2) adrenoreceptor density for the five normal controls was 1346 (183) sites/cell, with affinity Kd of 120 (40) pM. MRI disease activity in primary progressive multiple sclerosis was reported on two occasions and on those occasions the expression of beta(2) adrenoreceptors was increased in excess of 1900 sites/cell; in the remaining 28 observations beta(2) adrenoreceptor expression was within the normal range (800 to 1900 sites/cell). In patients with secondary progressive disease, MRI disease activity was observed on 16 occasions. In these patients expression of beta(2) adrenoreceptors was increased in excess of 2000 sites/cell in all measurements except in one subject who did not show MRI activity throughout the six months period of study. The affinity of the receptors was within the normal range in all cases. CONCLUSIONS: Increased expression of beta(2) adrenoreceptors was correlated with MRI disease activity in two patients with primary progressive multiple sclerosis. In secondary progressive multiple sclerosis, increased expression of beta(2) adrenoreceptors tended not to correlate with MRI disease activity. This may reflect a persistent Th1 immune reaction in the secondary progressive form of the disease.

Adult↗
PubMed2006

Mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis.

BACKGROUND: There are few treatment options for patients with secondary progressive and worsening relapsing-remitting multiple sclerosis. Mitoxantrone is an antineoplastic drug, recently approved for treatment of multiple sclerosis. Mitoxantrone is, however, associated with dose-related cardiotoxicity, which limits its use. OBJECTIVE: To investigate the possible cardiotoxicity of mitoxantrone in multiple sclerosis. METHODS: We studied 96 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis, to evaluate cardiotoxicity within one year of mitoxantrone therapy. This study was performed in the Multiple Sclerosis Clinic of Isfahan University of Medical Sciences from October 2003 through October 2004. Analysis of mitoxantrone therapy (12 mg/m2), in terms of cardiac toxicity, was conducted on patients who received at least 4 doses. Cardiac assessment was carried out every 6 months with electrocardiogram, as well as a spectral and color-flow Doppler echocardiographic examination at the time of enrollment and 6 and 12 months later. RESULTS: Ninety-six patients were assessed over 12 months. There was no evidence of clinically-significant cardiac dysfunction. Three patients had a left ventricular ejection fraction of <10% of the base-line value and three had <50%. CONCLUSION: Mitoxantrone (12 mg/m2) is effective and generally well tolerated by patients with worsening relapsing-remitting and secondary progressive multiple sclerosis. Our findings suggest that the risk for developing cardiotoxicity is low in patients with multiple sclerosis within one year of the treatment with mitoxantrone.

Adult↗
PubMed1993

Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events.

OBJECTIVE: A study was undertaken to determine whether cases of parainfectious-associated transverse myelitis (TM) and multiple sclerosis-associated TM could be distinguished on the basis of clinical criteria, radiologic features, or cerebrospinal fluid examination. A secondary objective was to determine the incidence of TM in a US population. DESIGN: A retrospective analysis of 33 cases was conducted. Cases were classified as being related to parainfectious multiple sclerosis, or spinal cord ischemia, or idiopathic. SETTING: All cases occurring in the Albuquerque, NM, area from 1960 through 1990 were reviewed. The population base was 500,000. OUTCOME MEASURES: Clinical presentation, radiologic features, cerebrospinal fluid, recovery of ambulation and bladder function, and recurrence rates were compared. RESULTS: Thirty-three patients satisfied study criteria, corresponding to an incidence of 4.6 per million per year. Forty-five percent of these cases were categorized as parainfectious, 21% as associated with multiple sclerosis, 12% as associated with spinal cord ischemia, and 21% as idiopathic. Patients with parainfectious TM suffered from spinal shock more frequently than did those with multiple sclerosis-associated TM. Patients with parainfectious TM showed evidence of spinal cord swelling, whereas patients with multiple sclerosis-associated TM had spinal cord plaques on magnetic resonance images but none showed swelling. Oligoclonal bands were absent in patients with parainfectious TM and present in three of five patients with multiple sclerosis-associated TM. CONCLUSIONS: Parainfectious TM may be distinguishable from that associated with multiple sclerosis on the basis of presentation, findings on imaging, and the presence of cerebrospinal fluid oligoclonal bands.

Adolescent↗
PubMed1981

Concurrence of multiple sclerosis and primary intracranial neoplasms.

The concurrence of multiple sclerosis and primary intracranial neoplasms is uncommon. The literature contains 20 cases of multiple sclerosis associated with gliomas and nine cases with non-gliomatous neoplasms. This report describes a protoplasmic astrocytoma and arteriovenous malformation found incidentally at autopsy of a 63-year-old woman with a 25-year history of multiple sclerosis. This is the first demonstrated association of multiple sclerosis with an arteriovenous malformation. Although neoplastic transformation of reactive glial cells in multiple sclerosis plaques has been proposed as the source of gliomas, the association of multiple sclerosis with astrocytoma and arteriovenous malformation in the present case is considered to be coincidental. Gliomas reported in association with multiple sclerosis are more frequently (30%) multicentric than are uncomplicated gliomas.

Astrocytoma↗