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The membrane-associated Intercellular Adhesion Molecule 1 (mICAM 1) is fundamental for adhesion of leukocytes to endothelial cells. A soluble form of ICAM 1 (sICAM 1) exists in the human serum, and is seen as marker of disease activity in patients suffering from Multiple Sclerosis (MS). High levels of sICAM 1 have been detected in MS patients benefiting from interferon beta (IFNbeta) treatment, but little is known on the molecular origins of sICAM 1. This study investigated the interrelationship and the mechanisms of production of sICAM 1 and mICAM 1 in human endothelium (Human Umbilical Vein Endothelial Cells, HUVECs) and mononuclear leukocytes (MNL) upon stimulation with IFNbeta-1a and other inducers. We found that the expression of mICAM 1 and the release of sICAM 1 are differentially regulated in both these cytotypes. HUVECs and MNL express specific mRNA for both mICAM 1 and sICAM 1, and modification of the content of each of these transcripts results in regulation of both the ICAM 1 isoforms. We show that IFNbeta-1a is strong regulator of the ICAM 1 RNA splicing machinery. Effect of IFNbeta-1a over expression of the ICAM 1 isoforms might have a relevant immunomoregulatory role in Multiple Sclerosis.

Matrix metalloproteinase-9 (MMP-9) was detected by zymography and enzyme-linked immunosorbent assay (ELISA) in matched serum and cerebrospinal fluid (CSF) samples from patients with neurological diseases. Patients with relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels comparable to those from patients with inflammatory neurological diseases (INDs), but higher than patients with non-inflammatory neurological diseases (NINDs) and healthy donors (HDs). MMP-9 increased in active RR-MS in comparison with inactive RR-MS implying that MMP-9 in MS is related with clinical disease activity. A correlation between the CSF/serum albumin (Q(AIb)) and CSF/serum MMP-9 (Q(MMP-9)) was observed in IND and NIND but not in RR-MS patients, indicating that CSF MMP-9 levels in NIND and IND patents could be influenced by serum MMP-9 and blood-brain barrier (BBB) permeability properties. MS patients had higher values of Q(MMP-9):Q(Alb)(MMP-9 index) than IND and NIND patients suggesting that in MS the increase in CSF MMP-9 could be due to intrathecal synthesis of MMP-9. A significant inverse correlation was found between MMP-9 and its endogenous inhibitor TIMP-1 in RR-MS indicating that in MS patients both the increase in MMP-9 and the decrease in TIMP-1 serum levels could contribute to BBB disruption and T-lymphocyte entry into the CNS.

rIFN-beta reduces the frequency of the gadolinium-enhancing (Gd+) magnetic resonance imaging (MRI) lesions in relapsing remitting (RR) MS. Its mechanism of action on improving the integrity of the blood-brain barrier (BBB) remains unclear. We investigated the effect of rIFN-beta-1b on the soluble intercellular adhesion molecule-1 (sICAM-1) serum levels (ELISA) in 36 RR MS patients receiving treatment with rIFN-beta for 1 year, and also the TNF-alpha - induced membrane-bound ICAM-1 (mICAM-1) expression on cultured rat brain microvascular endothelial cells (BMECs). In vivo data showed that sICAM-1 serum levels at baseline significantly increased (P<0.01) in 12 months of rIFN-beta-1b treatment. The increase paralleled a clinical and MRI improvement. In the second semester of the treatment the integrated area under the curve of Expanded Disability Status Score normalised to entry baseline (DeltaEDSS AUC) was significantly (P<0.05) smaller than in the first semester. The percentage of patients with Gd+MRI decreased significantly (P<0.05) in the first (33%) and second (29%) semesters of treatment compared to baseline (62%). In vitro experiments showed that the incubation of BMEC monolayer with 100 u/ml of TNF-alpha for 24 h significantly (P<0.05) increased mICAM-1 expression, whereas 2000 u/ml of rIFN-beta-1b for 72 h did not modify the baseline levels. The incubation of BMEC with 2000 u/ml of rIFN-beta-1b for 48 h followed by combined IFN-beta-1b and TNF-alpha for 24 h significantly (P<0.05) downregulated TNF-alpha-induced mICAM-1 expression. These results suggest that the effect of rIFN-beta-1b on the BBB may be mediated by changes in both sICAM-1 serum levels and mICAM-1 BMEC expression.

The validity of serum sICAM-I levels to assess Multiple Sclerosis (MS) activity was evaluated in 49 untreated definite relapsing-remitting (RR) patients. sICAM-I levels were significantly (P = 0.0009) higher in the 'clinically active' group (No 22) than in the 'clinically inactive' (No 27), whereas no different values were found between patients with Gd-enhancing lesions at MRI (Gd-positive) (No 32) and patients without such lesions (Gd-negative) (No 17) independently of their clinical activity. Among the 'clinically active' MS, the Gd-positive (No 16) subgroup showed significant (P < 0.05) lower sICAM-I levels when compared to the Gd-negative (No 6) subgroup, but higher (P = 0.009) than those of the 'clinically inactive Gd-positive' (No 16) patients. The sICAM-I levels did not differ between the two 'clinically inactive' subgroups Gd-positive (No 16) and Gd-negative (No 11). Finally the clinically active Gd-negative (No 6) showed sICAM-I levels higher (P = 0.002) than the clinically inactive Gd-negative (No 11). The specificity of high serum sICAM-I levels (above M +/- 2 s.d. of control values) to assess the disease activity in MS resulted higher (100%) using clinical than Gd-MRI activity (76%) as gold standard. The changes induced by 1 year recombinant Interferon-beta-Ib (rIFN beta-Ib) treatment on sICAM-I serum levels were also longitudinally investigated in 36 of the 49 RR MS. sICAM-I levels at baseline significantly increased in the first 2 months (baseline vs 1st month P < 0.0001 and 1st vs 2nd month P = 0.02), persisted at high levels without any significant change after 3 months, showed a temporary decrease at 6 months, then significantly increased again at 9 and 12 months. Fourteen patients experienced relapses, with a total of 20 relapses, during the whole treatment duration. The mean relapse/rate and the frequency of patients with Gd-positive MRI scans resulted significantly higher in the first semester compared to the second semester of treatment. This study adds further insights into the validity of serum sICAM-I to assess disease activity in MS and on the immunomodulatory properties of rIFN beta-Ib.

Serum and cerebrospinal fluid (CSF) soluble intercellular adhesion molecule-I (ICAM-I) levels were evaluated (ELISA) in 22 untreated and 13 corticosteroid-treated active relapsing remitting (RR) Multiple Sclerosis (MS), in 10 untreated and 10 corticosteroid-treated Guillain-Barré syndrome (GBS) and in 17 non-inflammatory neurological diseases (NIND). Twenty-eight clinically inactive RR MS were assayed for serum sICAM-I before and after 3 months treatment of 8 MIU rIFN beta-Ib taken s.c. every other day. High sICAM-I serum levels above the NIND values were found in untreated clinically active MS and in untreated GBS (P < 0.05) but not in the untreated clinically inactive MS group. The active MS group showed significantly (P = 0.0001) higher sICAM-I serum levels if compared to the inactive group. Corticosteroid-treated active MS and GBS patients showed lower (P < 0.05) serum sICAM-I levels than the corresponding untreated groups. Serum sICAM-I levels after 3 months of rIFN beta-Ib treatment (P < 0.0001, paired t-test) resulted increased compared to pretreatment values in MS. The mean values of CSF/serum sICAM-I:CSF/serum Albumin ratios (sICAM-I Index) in active untreated MS patients were higher compared to NIND (P < 0.005) and to corticosteroid-treated MS group (P = 0.01). sICAM Index values in GBS did not differ from those in NIND. The results seem to suggest potential roles for serum sICAM-I in downregulating the ongoing inflammatory response at the blood-brain barrier level and for CSF sICAM-I in the maintenance of a central nervous system local immune response.

The authors report a case of cardiotoxicity secondary to 5-FU, the 67th in literature in a 46-year-old woman subjected to adjuvant therapy with a CMF protocol after surgical treatment for carcinoma of the breast, and presenting onset of clinical symptoms 16 hours after administration of the first dose. Analysis of previous cases reported in literature revealed no evidence of age or sex as risk factors. Doubts exist as to whether or not pre-existing heart disease and thoraco-mediastinic radiotherapy increase the risk. With regard to the causes of the syndrome, the authors are inclined to attribute its onset to an auto-immune mechanism. 5-FU-induced cardiotoxicity, though rare, should be borne in mind and the use of the drug should be discontinued at the first signs of cardiotoxicity.

A double blind test using famotidine and a placebo was conducted on 14 patients with hypersecretory, chronic bronchitis. No other drug treatment was given during the test or in the ten days preceding it. VC, FEV1, Sgaw and daily excrete volume were measured before the test and 7, 14 and 21 days after it began. The data collected indicate that H2 receptors have no influence on bronchial calibre or secretions.