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PubMedDate not supplied

Serotonin induced platelet aggregation in systemic sclerosis.

We studied in vitro platelet aggregation response to serotonin in 19 patients with systemic sclerosis and 18 matched controls. Individuals with early systemic sclerosis had increased % platelet aggregation at 3 minutes over a wide range of serotonin concentrations when compared to individuals with late systemic sclerosis. Patients with generalized disease did not differ from those with limited disease. No significant differences in initial slope of platelet aggregation were detected in any patient subgroup. These data support previous studies suggesting platelet activation in systemic sclerosis and further suggest that future studies of platelet abnormalities in systemic sclerosis should consider the effects of disease duration.

Adult↗
PubMed1994

Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.

To determine the role of indoxyl sulfate in the progression of glomerular sclerosis, the serum level of indoxyl sulfate was measured in patients with uremia, and the effect of oral administration of indoxyl sulfate on renal function and renal histology was studied in subtotally nephrectomized uremic rats. Further, the effects of a low-protein diet and oral sorbent (AST-120) administration on the serum and urine levels of indoxyl sulfate were studied in different groups of subtotally nephrectomized uremic rats. We noted a marked elevation of serum level of indoxyl sulfate in the patients with uremia. The oral administration of indoxyl sulfate to the uremic rats increased the serum creatinine and blood urea nitrogen levels and decreased creatinine clearance, inulin clearance, and p-aminohippuric acid clearance. The glomerular sclerosis index in the indoxyl sulfate-administered uremic rats was higher than in the control uremic rats. A low-protein diet and AST-120 administration decreased the serum and urine levels of indoxyl sulfate, the blood urea nitrogen level, the urinary protein level, and the glomerular sclerosis index in the uremic rats as compared with those on a high-protein diet. Thus, indoxyl sulfate, a circulating uremic toxin, stimulated the progression of glomerular sclerosis in the uremic model. A low-protein diet and AST-120 reduced the serum and urine levels of indoxyl sulfate and suppressed the progression of glomerular sclerosis.

Aged↗
PubMedDate not supplied

Deconjugation ability of bacteria isolated from the jejunal fluid of patients with progressive systemic sclerosis and its gastric pH.

BACKGROUND/AIMS: Our goal was to demonstrate the role of bacteria in altered bile acid metabolism, which overgrow in the upper small intestine of patients with progressive systemic sclerosis. We identified the bacterial species, isolated from the jejunal fluid obtained from patients with progressive systemic sclerosis, who had previously shown an increase in 14CO2, specific activity on breath test, and normal controls. After which, we investigated the deconjugation ability of the isolated bacteria and the relationship between 14CO2, specific activity and gastric pH. METHODOLOGY: Bile acid breath tests were performed on 12 patients, and 19 normal controls using 5 microCi of oral glycine-1-(14)C-labeled glycocholate. Jejunal fluid was aspirated through a double lumen-tube with a rubber cover on the tip. Deconjugation ability was examined by thin-layer chromatography using conjugated bile acids in ox gall. RESULTS: The following species were identified in jejunal fluid samples obtained from patients: Bacteroides vulgatus, Eubacterium lentum, enterococcus, Lactobacillus bifidus, Escherichia (E) coli, Aerobacter (A) aerogenes. Except for E. coli and A. aerogenes, these species were capable of hydrolyzing conjugated bile acids in ox gall. The administration of chloramphenicol (1 g orally per day for 14 days in divided doses) significantly reduced the 14CO2, specific activity (p<0.05) in the patients with progressive systemic sclerosis. On the other hand, nineteen healthy control subjects demonstrated no increase in CO2 excretion, and 16 of the 19 had no bacteria isolated from jejunal fluid. The remaining healthy man showed an overgrowth of E. coli and Pseudomonas (P) aeruginosa, but the E. coli and P. aeruginosa did not have the ability of deconjugation. CO2 specific activity of expired breath samples in the patients with progressive systemic sclerosis was correlated with gastric pH (n=12, r=0.588, p<0.05). CONCLUSIONS: Our results demonstrated that some of the bacterial species that overgrow in the upper small intestine of patients with progressive systemic sclerosis can deconjugate bile acids, and that a shift to neutral pH in gastric juice, may promote the bacterial overgrowth related to their impaired peristaltic activity.

Adult↗
PubMed1994

Adrenal size is increased in multiple sclerosis.

OBJECTIVE: To determine if adrenal glands are enlarged in multiple sclerosis (MS). Patients with MS and major depression are insensitive to glucocorticoid feedback regulation. Depressed patients have excessively high glucocorticoid levels and enlarged adrenal glands. To our knowledge, this is the first study of adrenal size in MS. Chronic high levels of adrenal glucocorticoid in MS may downregulate responses to exogenous or endogenous steroids. DESIGN: Retrospective postmortem analysis compared adrenal size in MS with that in other neurologic and non-neurologic diseases. SETTING: Autopsy cases were obtained from the records of a tertiary care hospital. PATIENTS: Ten patients had definite MS; 13, amyotrophic lateral sclerosis; and 14, acute myocardial infarction. MAIN OUTCOME MEASURES: Adrenal and body weight at autopsy. RESULTS: At postmortem examination, the adrenal glands of patients with MS were enlarged in comparison with the adrenal glands of patients who died of acute myocardial infarction or amyotrophic lateral sclerosis. The adrenal glands of the patients with MS were 36% larger than those of the patients with amyotrophic lateral sclerosis who had comparable body weights. The adrenal-body weight ratio was 40% greater in patients with MS than in patients who died of acute myocardial infarction. CONCLUSIONS: The increased adrenal size in patients with MS may allow excessive glucocorticoid secretion in response to stress and affect immune regulation.

Adrenal Glands↗
PubMed2002

Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis.

The etiology of amyotrophic lateral sclerosis remains unknown in the majority of cases. Homozygous SMN1 (survival motor neuron) gene deletion causes spinal muscular atrophy, and SMN2 gene deletions are possible risk factors in lower motor neuron disease. We studied SMN1 and SMN2 genes copy numbers in 167 amyotrophic lateral sclerosis patients and in 167 matched controls. We noted that 16% of amyotrophic lateral sclerosis patients had an abnormal copy number of the SMN1 gene (1 or 3 copies), compared with 4% of controls. An abnormal SMN1 gene locus may be a susceptibility factor for amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed1999

A comparison of cell phenotypes in hemimegalencephaly and tuberous sclerosis.

Hemimegalencephaly, an uncommon sporadic nonfamilial congenital dysplastic abnormality of the central nervous system, constitutes a pathological spectrum of neuronal migration disorders, but consistently includes abnormal large neurons similar to those in the cortical tubers of tuberous sclerosis. Microscopically, there are also cells with homogeneous and weakly eosinophilic cytoplasm with a single eccentric nucleus, sometimes called balloon cells (likewise prominent in tuberous sclerosis). We looked for immunohistochemical and ultrastructural differences in the large neurons and balloon cells between hemimegalencephaly and tuberous sclerosis. Microtubule-associated protein 1B and 2, phosphorylated and non-phosphorylated neurofilament and synaptophysin identify the large neurons and distinguish them from balloon cells in both entities. Balloon cells in hemimegalencephaly showed no immunoreactivity for TSC2 gene product, tuberin, and vimentin, but similar cells in tuber tissue showed consistent immunoreactivity. Balloon cells in hemimegalencephaly showed no immunoreactivity for glial fibrillary acidic protein, but some cells in tubers showed such immunoreactivity. Ultrastructurally, balloon cells in hemimegalencephaly contained very few lysosomes, microfilaments, and microtubules, but abundant lipofuscin granules. Similar cells in tubers had prominent lysosomes, more microfilaments and microtubules, and very few lipofuscin granules. The resemblance between abnormal cells in hemimegalencephaly and tuberous sclerosis is superficial; their immunohistochemistry and electron microscopic profiles show distinct differences.

Adolescent↗
PubMed2004

Tuberous sclerosis and polycystic kidney disease in a 3-month-old infant.

Tuberous sclerosis (TSC) is an autosomal dominantly inherited multisystemic disease characterized by the development of hamartomas predominantly in brain and kidneys. The TSC2 gene for tuberous sclerosis is localized on chromosome 16p13.3 immediately adjacent to PKD1, the gene for autosomal dominant polycystic kidney disease (ADPKD). A TSC2-PKD1 contiguous gene syndrome caused by chromosomal microdeletions disrupting both the TSC2 and PKD1 genes has been identified in patients with TSC and early-onset severe ADPKD. We report a 3-month-old Caucasian girl of non-consanguineous parents with TSC and early manifestation of ADPKD. She presented with right-sided focal seizures, two small hypopigmented areas on the left flank, and elevated blood pressure requiring antihypertensive treatment. Brain magnetic resonance imaging revealed typical signs of tuberous sclerosis and abdominal ultrasonography showed bilaterally enlarged kidneys with multiple cysts resembling those seen in ADPKD. There was no family history of renal disease or of tuberous sclerosis. Findings were highly suspicious of TSC2-PKD1 contiguous gene syndrome. Using fluorescence in situ hybridization and plasmid probe CW23, which spans the adjacent 3' regions of TSC2 and PKD1 genes, we identified a submicroscopic deletion on only one of the chromosomes 16p13.3, thus permitting the diagnosis of the TSC2-PKD1 contiguous gene syndrome.

Brain↗
PubMed2006

Clinical relevance of antibodies against myelin oligodendrocyte glycoprotein in different clinical types of multiple sclerosis.

OBJECTIVE: Myelin oligodendrocyte glycoprotein (MOG) is a highly immunogenic minor component on the outside surface of CNS myelin which is believed to be one of the autoantigens in multiple sclerosis. The aim of this study was to evaluate the diagnostic potential of anti-MOG IgG antibody levels in cerebrospinal fluid (CSF) and serum of patients with relapsing-remitting multiple sclerosis (RRMS), primary progressive multiple sclerosis (PPMS) and non-inflammatory neurological diseases (NIND) as markers for the different clinical types of multiple sclerosis. PATIENTS AND METHODS: Consecutive serum and cerebrospinal fluid samples were taken from 21 patients with RRMS, 7 patients with PPMS and 19 patients with NIND. The antibody responses to MOG were determined in paired samples of these different clinical groups by enzyme-linked immunoassay using a recombinant human MOG protein. RESULTS: The performed analysis indicated that the differences in levels of anti-MOG IgG antibody in serum and cerebrospinal fluid from the patients with RRMS, PPMS or NIND were not statistically significant. CONCLUSION: The assay is not sensitive or specific enough to be used as a differential diagnostic tool for the clinical types of MS, nor for MS itself.

Adult↗
PubMed2003

Regulation of PCNA and CAF-1 expression by the two tuberous sclerosis gene products.

Tuberous sclerosis is an autosomal dominant tumor suppressor gene syndrome affecting about 1 in 6000 individuals. Two genes have been shown to be responsible for this disease: TSC1, encoding hamartin and TSC, encoding tuberin. A variety of tumors characteristically occur in different organs of tuberous sclerosis patients and are believed to result from defects in cell cycle/cell size control. In this study, we performed two-dimensional gel electrophoresis with subsequent mass spectrometrical identification of protein spots after overexpression of TSC1 or TSC2. We found expression of PCNA and the p48 subunit of CAF-1 to be regulated by two tuberous sclerosis gene products. CAF-1 and PCNA interact as major regulators of chromatin assembly during DNA repair. We suggest that deregulation of the control of chromatin assembly might contribute to development of tumors in tuberous sclerosis patients and provide important new insights into the molecular development, especially since deregulation of chromatin assembly and DNA repair results in genomic instability, a hallmark of tumor development.

Chromatin Assembly Factor-1↗
PubMed2001

Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy.

Primary cultures of murine cerebellar granule neurones were exposed to cerebrospinal fluid from patients with subtypes of multiple sclerosis or acute polyradiculoneuropathy (Guillain-Barré syndrome) for 2 days. Cells were then stained with Hoechst 33342 or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) to detect apoptotic bodies. The results were compared with control cultures exposed to cerebrospinal fluid from patients with no known neurological disease or deficit. There was no significant difference in the level of apoptosis induced between these controls and cultures not exposed to cerebrospinal fluid at all. Cultures exposed to cerebrospinal fluid samples from patients with relapsing-remitting multiple sclerosis did not have higher levels of apoptosis than cells exposed to controls, regardless of whether the sample was taken during relapse or remission. However, a significant increase in apoptosis was observed in cultures exposed to cerebrospinal fluid from patients with primary progressive multiple sclerosis, and apoptosis correlated with disease severity. This supports the existence of biochemical differences between subgroups of multiple sclerosis. A significant increase in apoptosis was also induced by cerebrospinal fluid samples from patients with acute polyradiculoneuropathy, suggesting the presence of neurotoxic factor(s) here also. The relevance to disease pathology is unclear.

Adult↗
PubMed1998

A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients.

The entire coding region of the TSC1 gene has been screened for mutations in 79 unrelated patients with tuberous sclerosis. Causative mutations have been found in 27 of these patients and five other variations in the gene have been identified. 26 of the mutations are predicted to cause premature truncation of the protein product of the gene and one mutation is in a splice site. The mutation screen has revealed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. We have also found that the only previously described case of non-penetrance can no longer be described as such, and that a single ungual fibroma is not necessarily diagnostic of tuberous sclerosis, important findings for the genetic counselling of tuberous sclerosis patients.

Blotting, Southern↗
PubMed2003

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Adult↗
PubMed2004

Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse.

The influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large prospective study which aimed to assess the possible influence of pregnancy and delivery on the clinical course of multiple sclerosis. We report here the 2-year post-partum follow-up and an analysis of clinical factors which might predict the likelihood of a relapse in the 3 months after delivery. The relapse rate in each trimester up to the end of the second year post-partum was compared with that in the pre-pregnancy year. Clinical predictors of the presence or absence of a post-partum relapse were analysed by logistic regression analysis. Using the best multivariate model, women were classified as having or not having a post-partum relapse predicted, and this was compared with the observed outcome. The results showed that, compared with the pre-pregnancy year, there was a reduction in the relapse rate during pregnancy, most marked in the third trimester, and a marked increase in the first 3 months after delivery. Thereafter, from the second trimester onwards and for the following 21 months, the annualized relapse rate fell slightly but did not differ significantly from the relapse rate recorded in the pre-pregnancy year. Despite the increased risk for the 3 months post-partum, 72% of the women did not experience any relapse during this period. Confirmed disability continued to progress steadily during the study period. Three indices, an increased relapse rate in the pre-pregnancy year, an increased relapse rate during pregnancy and a higher DSS (Kurtzke's Disability Status Scale) score at pregnancy onset, significantly correlated with the occurrence of a post-partum relapse. Neither epidural analgesia nor breast-feeding was predictive. When comparing the predicted and observed status, however, only 72% of the women were correctly classified by the multivariate model. In conclusion, the results for the second year post-partum confirm that the relapse rate remains similar to that of the pre-pregnancy year, after an increase in the first trimester following delivery. Women with greater disease activity in the year before pregnancy and during pregnancy have a higher risk of relapse in the post- partum 3 months. This is, however, not sufficient to identify in advance women with multiple sclerosis who are more likely to relapse, especially for planning therapeutic trials aiming to prevent post-partum relapses.

Adult↗
PubMed2005

Tissue preconditioning may explain concentric lesions in Baló's type of multiple sclerosis.

Lesions of Baló's concentric sclerosis are characterized by alternating layers of myelinated and demyelinated tissue. The reason for concentric demyelination in this variant of multiple sclerosis is unclear. In the present study we investigated the immunopathology in autopsy tissue of 14 patients with acute multiple sclerosis or fulminant exacerbations of chronic multiple sclerosis with Baló-type lesions in the CNS, focusing on the patterns of tissue injury in actively demyelinating lesions. We found that all active concentric lesions followed a pattern of demyelination that bears resemblances to hypoxia-like tissue injury. This was associated with high expression of inducible nitric oxide synthase in macrophages and microglia. At the edge of active lesions and, less consistently, in the outermost layer of preserved myelin, proteins involved in tissue preconditioning, such as hypoxia-inducible factor 1alpha and heat-shock protein 70, were expressed mainly in oligodendrocytes and to a lesser degree also in astrocytes and macrophages. Due to their neuroprotective effects, the rim of periplaque tissue, where these proteins are expressed, may be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue.

Adolescent↗
PubMed1998

Inducible nitric oxide synthase and nitrotyrosine are found in monocytes/macrophages and/or astrocytes in acute, but not in chronic, multiple sclerosis.

We have examined the localization of inducible nitric oxide synthase (iNOS) and nitrotyrosine (the product of nitration of tyrosine by peroxynitrite, a highly reactive derivative of nitric oxide [NO]) in demyelinating lesions from (i) two young adult patients with acute multiple sclerosis (MS), (ii) a child with MS (consistent with diffuse sclerosis), and (iii) five adult patients with chronic MS. Previous reports have suggested a possible correlation between iNOS, peroxynitrite, related nitrogen-derived oxidants, and the demyelinating processes in MS. We have demonstrated iNOS-immunoreactive cells in both acute-MS and diffuse-sclerosis-type lesions. In acute-MS lesions, iNOS was localized in both monocytes/macrophages and reactive astrocytes. However, foamy (myelin-laden) macrophages and the majority of reactive astrocytes were iNOS negative. In specimens from the childhood MS patient, iNOS protein was present only in a subpopulation of reactive or hypertrophic astrocytes. In contrast, no iNOS staining was detected in chronic-MS lesions. Immunohistochemical staining of acute-MS lesions with an antibody to nitrotyrosine revealed codistribution of iNOS- and nitrotyrosine-positive cells, although nitrotyrosine staining was more widespread in cells of the monocyte/macrophage lineage. In diffuse-sclerosis-type lesions, nitrotyrosine staining was present in hypertrophic astrocytes, whereas it was absent in chronic-MS lesions. These results suggest that NO and nitrogen-derived oxidants may play a role in the initiation of demyelination in acute-MS lesions but not in the later phase of the disease.

Acute Disease↗
PubMed2002

HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis.

BACKGROUND: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. METHODS: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. RESULTS: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. CONCLUSION: Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.

Adolescent↗
PubMed2001

Similar pro- and anti-inflammatory cytokine production in the different clinical forms of multiple sclerosis.

Cytokines play an important role in the initiation and maintenance of the inflammatory reaction in multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system. Magnetic resonance imaging evidence supports clinical divergence between forms of multiple sclerosis with relapses and the primary progressive form without relapses, which shows fewer and smaller inflammatory lesions. With the aim of understanding better the relative role of pro-inflammatory and/or anti-inflammatory cytokines in primary progressive multiple sclerosis in comparison to relapsing forms, we analysed in 65 patients (24 primary progressive, 20 relapsing-remitting and 21 secondary progressive) and 29 healthy controls, the production of cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10 and IL-12) by peripheral blood mononuclear cells after in vitro stimulation. We found a similar percentage of cytokines producing cells between healthy controls and the different clinical forms of multiple sclerosis patients.

Adult↗
PubMed1977

Computerised tomography findings in multiple sclerosis and Schilder's disease.

Computerised tomography of the brain was performed in 95 patients with multiple sclerosis and in a single patient with Schilder's disease. CT of the orbits was also carried out in 53 of these cases to examine the optic nerves. In 51% of the multiple sclerosis cases low density areas compatible with plaques of demyelination were found in the white matter of the cerebral hemispheres, and less frequently in the brain-stem. A much larger area of reduced intensity was found in the occipital white matter in the patient with Schilder's disease. Varying degrees of central and/or cortical cerebral atrophy were found in 45% of the multiple sclerosis patients, the more severe degrees being found in patients with long-standing disease. Serial observations in 15 patients who were examined on more than one occasion are also presented. Small low density areas were identified in one or both optic nerves in 52% of the multiple sclerosis cases. While these may represent demyelinating lesions their significance is uncertain.

Brain↗