Treatment of the mucosa with local anaesthetics in ulcerative colitis

A new paradigm for the treatment of ulcerative colitis has recently been presented: Treatment of the mucosa with lidocaine (2%) enemas for prolonged periods. This therapy was introduced based on the hypothesis that hyperreactive autonomic nerves may play a pathogenetic role in the disease. One hundred consecutive patients have now been treated and the results presented. Theproctitis patients all responded to the treatment, despite previous therapeutic failures in more than two-thirds of the cases. They were treated for 3–12 weeks, but 68% had a relapse (observation period 20 months). Of the 49 patients withproctosigmoiditis, two-thirds had chronic symptoms resistant to previous therapy. One of these patients did not respond to lidocaine, but developed fulminant total colitis. The other patient had therapeutic failure with lidocaine but responded well to subsequent cortisone enemas. The patients were treated until the subsets of T-lymphocytes ( and ) disappeared from the mucosa. This occurred in parallel with symptomatic relief and eventual healing in 83% of the patients after treatment for 6–34 weeks. Of all the patients with proctosigmoiditis, 42% presented with recurrent symptoms (observation period 16 months). Of the 17 patients withleft-sided colitis, all went primarily into remission within 2–4 months, but 23% had a relapse (observation period 13 months). The 6 patients withtotal colitis had symptomatic relief and improvement of histology when treated over 3–8 months. One patient had recurrence after 12 months. Treatment with a local anaesthetic in ulcerative colitis is a new approach to mucosal inflammation. The beneficial effects may be due to blockade of certain neural effects, such as epithelial proliferation and shedding and congestion of the mucosal vasculature, with actions on cells of the immune system.This work was supported by grants from the Swedish MRC (2207, 5520), the Assar Gabrielsson Foundation, and the Ulf Widengren Foundation.     

Sensitivity of FL cells to polio- and adenoviruses

Summary Poliovirus plaque counts on the FL strain of human amnion cells were almost double the counts on rhesus monkey kidney for the same virus preparation, repeatedly assayed over more than six months. FL cells gave more consistent results in virus assay than monkey kidney cells. Plaque counts obtained with FL cells were 2 1/2 to 5 times higher than those obtained with HeLa, Chang's conjunctiva and Detroit-6 cells.Using the chick embryo-adapted MEF-1 strain of poliovirus, FL cells and primary human amnion cells reacted similarly in respect to plaque count and morphology, while no distinct plaques were seen on monkey kidney or HeLa monolayers under comparable conditions. For infectivity assays of adenovirus suspensions based on cytopathogenic effect, FL cells were found suitable, although no plaque formation was obtained.Aided by American Cancer Society Grant E-82 and a grant from the National Foundation.     

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.     

Blockade of Ca2+‐activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

Voltage- and Ca(2+)-dependent K(+) channels in the membrane of both T and B lymphocytes are important for the cellular immune response. In the current issue of the European Journal of Immunology, Reich et al. demonstrate that selective blockade of the intermediate-conductance Ca(2+)-activated K(+) channel (the IK channel encoded by the KCNN4 gene) prevents cytokine production in the spinal chord and ameliorates the development of EAE caused by injection of myelin oligodendrocyte glycoprotein (MOG)(35-55) in mice. These data renew the focus on the IK channel as a potential target for the development of new immune-suppressant drugs for the treatment of autoimmune diseases.     

Lack of FasL expression in cultured human retinal pigment epithelial cells

Retinal pigment epithelial (RPE) cells have been proposed to play a part in maintaining the eye as an immune privileged organ. However, our knowledge of the implicated mechanism is still sparse. Fas ligand (FasL) expression of RPE cells is generally recognized to be essential for the immune privilege of the eye, but due to contradictory published results, it is unclear whether RPE cells express this molecule. The purpose of this study was to investigate the expression of FasL in RPE cells in vitro and in vivo. Cultured human fetal and adult RPE cells were examined by flow cytometry, Western blotting, RT-PCR and RNase Protection assay for FasL expression. Additionally, sections of ocular tissue were stained for FasL by immunohistochemistry. None of the used methods indicated FasL expression in cultured fetal or adult RPE cells of various passages. However, RPE cells in vivo, as judged from tissue sections, were positive for FasL, indicating a discrepancy between RPE cells in vitro and in vivo with regard to this molecule.     

Transcription from the gene encoding the herpesvirus entry receptor nectin-1 (HveC) in nervous tissue of adult mouse

Hepatitis C virus core protein, in addition to being a component of the viral capsid, has a number of regulatory functions. Here we showed two bodies of evidence indicating that a fraction of the core protein species is a substrate of the ubiquitin (Ub)-proteasome pathway of targeted proteolysis. First, the core protein processing the C-terminal hydrophobic region is metabolically unstable, and incubation with a proteasome inhibitor led to a significant accumulation of the protein. Second, an in vivo ubiquitylation assay indicates conjugation of multi-Ub chain to the unstable core protein. In contrast, a stable form of core protein, p21, is also able to be ubiquitylated, but it links to a single or only a few Ub moiety. Therefore, processing event(s) at the C-terminal hydrophobic domain of HCV core protein may affect the ubiquitylation pathway, particularly the efficiency of the multi-Ub chain assembly, resulting in stable, matured core proteins.     

Distinct protein interaction domains and protein spreading in a complex centromere

Fission yeast (Schizosaccharomyces pombe) centromeres are composed of large (40-100 kb) inverted repeats that display heterochromatic features, thus providing a good model for higher eukaryotic centromeres. The association of three proteins that mediate region-specific silencing across centromere 1 has been mapped by quantitative chromatin immunoprecipitation. Swi6 and Chp1 are confined to the flanking outer repeats and Swi6 can spread across at least 3 kb of extraneous chromatin in cen1. In contrast, Mis6 coats the inner repeats and central core. tRNA genes demarcate this transition zone. These analyses clearly define two distinct domains within this complex centromere which interact with different proteins.