[Prion diseases at the present stage and the investigations conducted at the M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences].

The review deals with the basic characteristics of prion diseases of man and animals. It details the studies of some little known aspects of the pathogenesis of prion diseases and their lifetime diagnosis, conducted at the M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, in the past decades.

[Some mechanisms of the action of oligonucleotides: stimulation of the immune system and decreased infection of the brain in tickborne encephalitis]. / Nekotorye mekhanizmy deistviia oligonukleotidov: stimuliatsiia immunnoi sistemy i umen'shenie porazhenii golovnogo mozga pri kleshchevom éntsefalite.

Morphological changes in the thymus, spleen, and brain are analyzed in white mice injected 16-component oligonucleotide (ON) pE16 complementary to the NS3 protein gene sequences of tickborne encephalitis (TBE) virus in doses of 1 to 0.001 nM. ON stimulated thymic and splenic cells. Besides the stimulating effect, injection of ON to mice infected with TBE enhanced the destruction of lymphocytes and boosted the macrophagal activity, which was paralleled by a decrease in the intensity of virus-specific injuries in the brain. Thus, the antiviral activity of ON may be due to not only the fact that it is complementary to the TBE virus genome, but to stimulation of the immune system, specifically, the thymus and T-related elements, as well.

[Experimental latency of scrapie]. / Eksperimental'naia latentsiia skrepi.

BALB/c mice infected with the scrapie agent without apparent symptoms of the disease for 12 to 14 months after inoculation were examined by virological and histological methods. Changes in the central nervous system characteristic of the pathohistological picture of scrapie were detected in two out of 66 mice. Intracerebral challenge of mice with the examined material from these animals did not result in disease. Scrapie superinfection of animals inoculated previously but not falling ill revealed a similar susceptibility to infection in these animals in comparison with 2-3-week-old intact mice. Basing on their findings and published data, the authors discuss the problem of latent infection in transmission spongiform encephalopathies and its possible contribution to the epidemic process.

[Lifetime diagnosis of prion transmissive encephalopathies]. / Prizhiznennaia diagnostika prionovykh transmissivnykh éntsefalopatii.

An original method for life-time diagnosis of Greutzfeldt-Jakob's disease, a neurodegenerative disease belonging to transmissive spongiform encephalopathies, is proposed. It consists in inoculation of the examined biological materials (blood serum and clot) into a continuous culture of the rat Gasser's node neurinoma, followed by passages and study of the inoculated culture by morphological methods and electron microscopy.

[The Gerstmann-Sträussler syndrome: new diagnostic possibilities]. / Sindroma Gerstmanna--Shtreusslera: novye vozmozhnosti diagnostiki.

On the basis of clinical picture of the disease, data of CT, MRT, psychological study, original laboratory investigation aimed at indication of changes in transposed neuroglia cells induced by the causal agent of subacute spongious transmissible encephalopathies, the diagnosis of patient K., 49 years old, was considered to be: syndrome of Gertsmann-Sträussler [correction of Herstmann Streussler]. Duration of the disease was 2 years. The case was sporadic. The history of the problem, modern views on etiology, pathogenesis of preventive measures are presented.

[Antiviral effect of various oligonucleotide derivatives, complementary to tick-born encephalitis virus RNA]. / Protivovirusnyi éffekt razlichnykh proizvodnykh oligonukleotidov, komplementarnykh RNK virusa kleshchevogo éntsefalita.

Antiviral effect of two nucleotides complementary to tick-borne encephalitis (TBE) virus genome and their derivatives was compared to that of noncomplementary oligonucleotides. All the tested reagents influenced TBE multiplication in cell culture, this manifesting by various degrees of suppression of the cytopathic effect of the virus. Intact oligonucleotides, both complementary and noncomplementary to TBE, reduced virus titer by 2-4 orders, whatever the concentration of oligonucleotide. In some experiments a higher virus-inhibiting effect of complementary oligonucleotides (by 3-4 orders) was observed vs. noncomplementary (by 1-2 orders). Moreover, different oligonucleotide derivatives suppressed virus multiplication in porcine embryo kidney cell culture. In parallel with investigation of virus-inhibitory effect of oligonucleotides in cell culture, their effects on the synthesis of virus-specific and cellular proteins was studied. Screening of oligonucleotide derivatives by capacity to suppress biosynthesis and multiplication of virus in cell culture showed the highest efficacy of reaction-capable and cholesterol derivatives.

[The antiviral action of medicinal plant extracts in experimental tick-borne encephalitis]. / Protivovirusnoe deistvie ékstraktov lekarstvennykh rastenii pri éksperimental'nom kleshchevom éntsefalite.

Some mechanisms of inducing resistance to experimental infection with tick-borne encephalitis virus were studied in experimental mice treated with aqueous extracts of berries of Vaccinium vitis-idaea, black currant, Vaccinium myrtillus, and of greater celandine grass. The condition of the immune system organs (spleen and thymus) after treatment with the extracts under study was analysed. A correlation was found between the degree of developing resistance to infection, virus accumulation in the brain, blood, spleen and thymus and changes in some parameters (spleen and thymus indices) of these immunocompetent organs. Possible mechanisms of induction of resistance to virus by herb extracts are discussed.

[The interrelationship of the causative agents of subacute transmissible spongiform encephalopathies]. / O vzaimosviazi vozbuditelei podostrykh transmissivnykh gubkoobraznykh éntsefalopatii.

Virological, histological, and electron microscopy methods were used to study the features of the infectious process in minks infected with scrapie agent as compared with that in minks infected with the agent of mink transmissive encephalopathy and in mice infected with scrapie. The results of the study showed the similarity in the clinical picture and the pattern of histological and ultramicroscopic lesions in minks infected with either of the agents. On the basis of the authors' own data and those from the literature, the relationship among the agents of the diseases comprising the group of subacute transmissive spongiform encephalopathies is discussed.

Development of antibodies to axonal neurofilaments in the progression of chronic tick-borne encephalitis.

We followed the presence of autoantibodies to neurofilaments (NF) in the sera of patients with acute tick-borne encephalitis (TBE), chronic TBE, amyotrophic lateral sclerosis (ALS), and other diseases of CNS. The diagnosis was made according to clinical signs and based on virus neutralizing antibodies. Autoantibodies to NF were found in the majority of chronic TBE patients during disease progression, but were neither present in acute TBE nor in chronic TBE cases during the stabilization phase. Autoantibodies to NF found in a patient with acute TBE showed subsequent progression to a prolonged course. The data are discussed in order to assess the mechanisms of the chronic TBE process and its role in impairing the slow axonal transport.

[Experimental phytotherapy of tick-borne encephalitis]. / Eksperimental'naia fitoterapiia kleshchevogo éntsefalita.

The virucidal effect of aqueous extracts of a number of plants was studied in tick-borne encephalitis (TBE) virus titration in SPEV cell culture in microplates, as well as their capacity to induce resistance in virus-infected mice. The aqueous extracts of ledum, motherwort, celandine, black currant, cowberry and bilberry inactivated TBE virus practically completely, and those of St. John's wort, pot marigold, tansy, chamomile, milfoil, and inula only partially. Studied in vivo, the extracts of motherwort, ledum, tansy and black currant induced resistance of mice to TBE virus infection assessed by the increased survival rate of the animals and significant prolongation of the average longevity. The degree of antiviral activity depended on the preparations used and the routes of their administration.

[Antibodies to the structural elements of the neuron in patients with amyotrophic lateral sclerosis and in their healthy relatives]. / Antitela k strukturnym élementam neirona u bol'nykh bokovym amiotroficheskim sklerozom i ikh zdorovykh rodstvennikov.

The results of determining antibodies to the structural elements of neuron in the serum and CSF of 100 patients with lateral amyotrophic sclerosis (LAS), in the serum of their relatives (n-67), and in biological fluids of 50 patients suffering from other neurologic diseases allowed the following conclusions to be made. The predominance of antibody demonstration in the CSF of LAS patients over that in the serum may attest to the immune response on the part of the CNS. The presence of antibodies in the relatives (not-blood ones for the most part) of LAS patients suggests an infectious nature of the disease.

Alterations of arginase activity in scrapie-infected mice and in amyotrophic lateral sclerosis.

We followed the dynamics of arginase activity, the ultrastructural changes, and accumulation of the scrapie agent in the CNS of scrapie-infected mice. The arginase activity has been shown to increase 5-fold within the first 3-4 months of the incubation period followed by subsequent fall at its end. The peak of increased arginase activity coincided with appearance of multilayer membranes, whereas the decrease of this activity was associated with the greatest development of status spongiosus, synaptic degeneration, accumulation of five-layer membranes as well as with maximal accumulation of the scrapie agent in the CNS. Examination of 100 patients with different forms of amyotrophic lateral sclerosis (ALS) revealed a 2-8-fold increase of arginase levels in the cerebrospinal fluid (CSF) as compared with the background levels in the comparative groups of control patients. Similar enzyme alterations in scrapie--and in ALS--are discussed in terms of possible resemblance of their pathogenesis.

[The effect of myelopeptides on the persistence of tick-borne encephalitis virus in monkeys]. / Vliianie mielopeptidov na persistentsiiu virusa kleshchevogo éntsefalita v organizme obez'ian.

Myelopeptides (MP), bioregulatory molecules of bone marrow origin, exert a protective effect in persistence of tick-borne encephalitis virus in cynomolgus monkeys (Macaca fascicularis). The experiments involved 32 monkeys. The effect of MP was observed after one or two subcutaneous injections in a dose of 1 mg within 1.5-2 months after virus infection. The effect consists in 25-fold reduction of the frequency of virus persistence, marked limitation of the zone of spread of the persisting virus, including the central nervous system (CNS), decrease in virulence of the persisting virus, and lack of morphological signs of progress of the pathological process in the CNS. The protective effect was also observed when the infected monkeys were treated with MP and inactivated concentrated TBE vaccine. At the same time, the vaccine alone exerted a much less marked effect on the persisting TBE virus producing only a 2-fold reduction in the frequency of persistence without limitation of the zones of virus spread. In acute TBE in BALB/c mice, the effect of MP is observed irregularly. The marked protective effect of MP in TBE virus persistence in monkeys is not associated with stimulation of humoral immunity but is mediated by other immunological mechanisms requiring further study.

[Cytomorphologic study of a line of hybrid somatic cells persistently infected with the scrapie agent]. / Tsitomorfologicheskoe issledovanie linii gibridnykh somaticheskikh kletok, persistentno infitsirovannykh agentom skrepi.

Virological, cytological and electron microscopic methods were used to study the peculiarities of the scrapie agent persistence in the tissue culture of the mouse and human hybrid cells. A long-term persistence of the scrapie agents in the cells (658 days) has been obtained. The fact of persistence is confirmed by the results of biotest and electron microscopic studies of the mouse CNS. The agent persistence promotes a decrease in the mitotic activity of the infected cells and development of the ultramicroscopic changes in cells similar to the picture of the specific changes in the CNS of mice inoculated by scrapie agent.

[Anti-neurofilament antibodies in slow infections of the nervous system]. / Antitela k neirofilamentam pri medlennykh infektsiiakh nervnoi sistemy.

Twenty-six patients including 12 with lateral amyotrophic sclerosis, 7 with multiple sclerosis, 5 with the Creutzfeld-Jakob disease and 2 with Alzheimer's disease were examined. Antibodies to neurofilaments in the blood serum were detected in all cases of the Creutzfeld-Jakob disease and Alzheimer's disease and in 8 patients with lateral amyotrophic sclerosis with clinical evidence of supranuclear structure involvement. A conclusion is drawn about a certain similarity of pathogenic mechanisms of these diseases, as well as about heterogeneity of the cytoskeleton of neurons in the brain and the spinal cord.

Persistence of the scrapie agent in glial cells from rat Gasserian ganglion.

Persistence of the scrapie agent in glial cell monolayers from rat Gasserian ganglion have been studied by electron microscopy, virologic and histologic methods. Under chosen experimental conditions the scrapie agent had been shown to persist in cells for over 2 years. The infected cells appeared to be infectious for BALB/c mice throughout. Persistence of the scrapie agent was associated with development of a marked proliferative effect with increasing mitotic index of the cells. Changes similar to those observed in the CNS in vivo were found by means of electron microscopy. The decreased number of oncovirus-containing cells seems to indicate the decreased proportion of such cells in the culture infected with scrapie agent.

Effect of hyperbaric oxygenation on experimental scrapie in mice.

The effect of hyperbaric oxygenation upon experimental infection of BALB/c mice with the scrapie agent was investigated by virological methods, histology and electron microscopy. A multiple exposure of scrapie-infected mice to hyberbaric oxygenation during the incubational period led to a certain aggravation of infection as evidenced by a greater accumulation of the agent in the central nervous system (CNS) and spleen, as well as by more pronounced ultramicroscopic changes in CNS. A single exposure to hypoxia failed to alter any manifestations of infection.

Influence of aminasine on experimental scrapie in mice.

The influence of long-term treatment with aminasine--an inhibitor of monoamine oxidase--on duration of the incubation period, morbidity and on accumulation of the agent in the brain was followed in experimental scrapie of mice. Aminasine administration after intracerebral (i.c.) but not after intraperitoneal (i.p.) inoculation of the agent markedly prolonged the incubation period and slightly reduced the morbidity. The accumulation of the scrapie agent and the degree of histological lesions in the CNS detected 6 months post-inoculation (p.i.) were equal in both groups compared. The significance of these results is discussed from the viewpoint of the role of biogenic monoamines in the pathogenesis of scrapie.