Beta interferons as immunotherapy in multiple sclerosis: a new outlook on a classic drug during the COVID-19 pandemic.

Beta interferons (IFN-ß) are pleiotropic cytokines with antiviral properties. They play important roles in the pathogenesis of multiple sclerosis (MS), an incurable immune-mediated disorder of the central nervous system. The clinical expression of MS is heterogeneous, with relapses of neuroinflammation and with disability accrual in considerable part unrelated to the attacks. The injectable recombinant IFN-ß preparations are the first approved disease-modifying treatments for MS. They have moderate efficacy in reducing the frequency of relapses, but good long-term cost-efficacy and safety profiles, so are still widely used. They have some tolerability and adherence issues, partly mitigated in recent years by the introduction of a PEGylated formulation and use of 'smart' autoinjector devices. Their general impact on long-term disability is modest but could be further improved by developing accurate tools for identifying the patient profile of best responders to IFN-ß. Here, we present the IFN-ß-based immunomodulatory therapeutic approaches in MS, highlighting their place in the current coronavirus disease (COVID-19) pandemic. The potential role of IFN-ß in the treatment of COVID-19 is also briefly discussed.

Tuning the coordination properties of phenothiazine by regioselective introduction of diphenylphosphanyl groups.

The palladium and platinum complexes of the newly synthesized 1-(diphenylphosphino)-10-methyl-10H-phenothiazine (1) and the previously reported 3-(diphenylphosphino)-10-alkyl-10H-phenothiazine [alkyl = Me (2), Et (3)] and 4-(diphenylphosphino)-10-ethyl-10H-phenothiazine (4) were prepared. Density functional calculations were carried out to explain the electronic properties of compounds 1, 3 and 4. Compounds 1, 3 and 4 can interact with DNA, as was observed in agarose gel electrophoresis experiments. In addition, the cytotoxicity of the platinum complexes of ligands 2 and 4 towards breast, colorectal and hepatocarcinoma cell lines was studied.

Single nucleotide polymorphism screening and association analysis--exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma.

BACKGROUND: The human genes coding for integrin beta 7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches. METHODS: All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose-response curve after bronchial challenge). RESULTS: Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non-coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study. CONCLUSIONS: These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level.

The heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice.

The stress response (SR) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-kappaB). As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG(35-55) peptide injection. The HSR reduced the incidence of EAE by 70%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon gamma (IFNgamma) in response to MOG(35-55), was also decreased by the HSR. The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-kappaB was also blocked by the HSR. The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases.

Temporal, regional, and cell-specific changes of iNOS expression after intrastriatal microinjection of interferon gamma and bacterial lipopolysaccharide.

Here we study expression of the inducible isoform of nitric oxide synthases after intrastriatal microinjection of interferon-gamma and bacterial lipopolysaccharide in the rat at different time points to detect time- and localisation-dependent changes of iNOS expression. Three different areas in the striatum and the corpus callosum were evaluated. Antibodies against the glial fibrillary acidic protein and the microglia/brain macrophage epitope ED1 were used to detect colocalization of inducible nitric oxide synthase with astrocytes or activated microglia/brain macrophages, respectively. Inducible nitric oxide synthase-positive cells occurred first in intravascular and perivascular cells at 4 h. Perivascular and parenchymal inducible nitric oxide synthase expression increased up to 24 h in the striatum, whereas in the corpus callosum inducible nitric oxide synthase expression was maximal after 16 h. Inducible nitric oxide synthase was still present in perivascular cells 7 days after immunostimulation. At all time points, inducible nitric oxide synthase was predominantly detected in ED1-positive microglia/brain. Nitrotyrosine immunohistochemistry was performed to detect NO-mediated nitration of proteins at all time points. Nitrotyrosine-positive neurons and microglial cells were detected from 24 h until 7 days after immunostimulation and were absent in controls. Detailed knowledge of the changes in the time course and cellular source of inducible nitric oxide synthase expression following brain immunostimulation provide a basis for establishing treatment strategies and windows of therapeutic intervention during neuroinflammation.

Intestinal absorption and permeability in human immunodeficiency virus-infected patients.

BACKGROUND: Impaired intestinal function could account for diarrhoea and weight loss, which are common features of advanced human immunodeficiency virus (HIV) infection. METHODS: We assessed intestinal permeability to lactulose and mannitol and absorption of D-xylose in 96 HIV-infected patients (group I: asymptomatic subjects (CDC-A); group II: symptomatic subjects (CDC-B or C) without body weight loss and/or diarrhoea; group III: 25 acquired immunodeficiency syndrome (AIDS) patients (CDC-C) with severe body weight loss and/or diarrhoea) and 10 healthy subjects as controls. RESULTS: An incremental decrease in urinary D-xylose recoveries was observed, with all groups statistically different from each other. Impaired intestinal permeability was only found in patients of group III (statistically different from all other groups). CONCLUSIONS: These findings suggest a loss of intestinal functional absorptive surface as HIV disease progresses. This process may be present at the early stage of infection. Impaired intestinal permeability is observed later in AIDS patients when digestive signs are present, particularly diarrhoea.

Decorin gene transfer-mediated suppression of TGF-beta synthesis abrogates experimental malignant glioma growth in vivo.

Cytokines such as transforming growth factor-beta (TGF-beta) are thought to mediate escape from immune surveillance in human malignant glioma. Here, we report that ectopic expression of the small TGF-beta-binding proteoglycan, decorin, inhibits not only TGF-beta bioactivity but also TGF-beta 1 and TGF-beta 2 mRNA transcription and TGF-beta protein synthesis by human LN-18, LN-229, T98G and rat C6 glioma cells in vitro. Ectopic expression of decorin in C6 rat glioma cells results in strong inhibition of tumor formation in vivo. Decorin-expressing C6 gliomas grow initially but regress to very small residual tumors at 12 weeks after implantation whereas all control animals die or have to be killed within 4 weeks. Decorin-expressing tumors show a four-fold increase of infiltration by activated T cells and a 1.6-fold increase in total B and T cells. Chronic steroid-mediated immunosuppression abrogates the inhibitory effects of decorin gene transfer. We conclude that decorin-induced inhibition of TGF-beta release by glioma cells significantly enhances antiglioma immune responses in vivo. Clinical evaluation of decorin gene therapy for human malignant gliomas may be warranted.

[Antibiograms in ambulatory medical practice. Results with a group of gram-negative bacilli strains isolated by uroculture]. / Antibiograma în practica medicala ambulatorie. Rezultate pe un lot de tulpini de bacili gramnegativi izolati prin urocultura.

During the April 1979--June 1978 period, 1161 tests were carried out on the sensitivity to antibiotics and chemotherapeutical agents of Gram-negative bacillus strains isolated from 7632 urocultures. Resistance was tested under qualitative control against 13 antimicrobial agents by the Kirby-Bauer diffusimetric method. The resistance sensitivity and the presence of intermediary strains is shown for E. coli Citrobacter, Enterobacter, Klebsiella, Proteus, Morganella, Providencia, and Pseudomonas. Attention is drawn to the fairly high proportion of intermediary strains. Their role from the therapeutical point of view is reduced, but epidemiologically, their role is important since their evolution towards resistance or sensitivity cannot be foreseen.

Comments on the aetiology of indirect traumatic thrombosis of the internal carotid (a study of 22 cases).

A group of 22 patients with internal carotid thrombosis following head injuries, admitted to hospital during the last decade is discussed, particularly as regards the relationship between trauma and thrombosis seen from the aetiological, diagnostic and medico-legal aspects.

Morphological and cytogenetical changes in HR-18 rat ascites cells after in vitro 3-[bis(2-chloroethyl)amino]-4-methylbenzoic acid (NSC-146171; IOB-82) administration.

A bifunctional alkylating agent, 3-[Bis(2-chloroethyl) amino]-4-methylbenzoic acid (NSC-146171; IOB-82) was administered in HR-18 rat ascites cell cultures (which presented 2 morphologic cellular types: A and B type cells, genetically, 2 cellular populations having 41-45 and 85-86 chromosomes and cells with high ploidy), and the morphological and cytogenetical effects were related to the compound concentration. Thus, 24 h after IOB-82 administration in small doses (3.62 X 10(-4) micron/ml), important morphological changes were observed: nuclear changes (denuded nuclei, pyknosis) and cytoplasmic alterations (breaks at the exoplasm level, followed by cytoplasmic extrusions in extracellular spaces, cytoplasmic vacuolization). In addition to these changes, other abnormalities were observed when IOB-82 was administered in large doses (3.62 X 10(-3) micron/ml), i.e., nuclear changes (nuclear residues, granulation of the nuclear material and spreading of the nuclear content into cytoplasm) and cytoplasmic alterations (cytoplasmic shades and accentuated cytoplasmic vacuolization). Generally, the large A-type cells were more affected. Twenty-four h after IOB-82 treatment (with small or large doses), the chromatid and chromosome aberrations (gaps, breaks, deletions, fragments) were also observed. These aberrations were more numerous when IOB-82 was administered in large doses. Both morphological and cytogenetical changes indicate that the effect of IOB-82 could be radiomimetic. Changes produced and their incidence appear to depend on the concentration of IOB-82 employed and the morphological type of ascites cells. These are expressed in terms of multiple abnormality production in these cells. IOB-82 treatment produced changes in chromosome numbers and especially the disappearance of polyploid cells and cell populations with 85-86 chromosomes. These results indicate a possible correlation between the increased sensitivity of HR-18 rat ascites cells and changes in ploidy.

The portals of entry of herpes simplex virus infections.

In the present paper different possible portals of entry into the body for Herpes simplex Virus are examined. The possibility to infect the cornea with HsV without a preceding scarification was established. Scanning microscopy clearly showed the lesions of the infected cornea and a parallelity between the concentration of the inoculum and the spread of lesions. The i.c., i.m. and i.p. portals of entry are compared as to their capacity to produce encephalitis. The titration of virus may also be realized in the animal experiment. The intragastric portal of entry could be clearly demonstrated. So it is possible to explain herpes encephalitis in human newborns from mothers infected with Herpes virus.

[Scanning electron-microscopic findings in orthoergically damaged skin surfaces of hairless mice (author's transl)]. / Rasterelektronenmikroskopische Befunde an der orthoergisch geschädigten Hautoberfläche haarloser Mäuse

Mechanic-chemically defined irritation of the skin surface of hairless mice regularly leads to macroscopically sub-visible changes of the horny layer. Scanning electron-microscopic analysis reveals extended regular horny layer dehiscences, as well as deeper dehiscence or trench formations in the area of irritation, as compared to normal skin. The damaged horny layer sample, presented respectively, depends-to a degree-upon type, intensity and duration of irritation. Hairless mice proved to be best suited at test animals for informative studies concerning cutaneous resistance to stress.