Epidemiology of Viliuisk encephalomyelitis in Eastern Siberia.

BACKGROUND: Viliuisk encephalomyelitis is a disorder that starts, in most cases, as an acute meningoencephalitis. Survivors of the acute phase develop a slowly progressing neurologic syndrome characterized by dementia, dysarthria, and spasticity. An epidemic of this disease has been spreading throughout the Yakut Republic of the Russian Federation. Although clinical, neuropathologic, and epidemiologic data suggest infectious etiology, multiple attempts at pathogen isolation have been unsuccessful. METHODS: Detailed clinical, pathologic, laboratory, and epidemiologic studies have identified 414 patients with definite Viliuisk encephalomyelitis in 15 of 33 administrative regions of the Yakut Republic between 1940 and 1999. All data are documented in a Registry. RESULTS: The average annual Viliuisk encephalomyelitis incidence rate at the height of the epidemic reached 8.8 per 100,000 population and affected predominantly young adults. The initial outbreak occurred in a remote isolated area of the middle reaches of Viliui River; the disease spread to adjacent areas and further in the direction of more densely populated regions. The results suggest that intensified human migration from endemic villages led to the emergence of this disease in new communities. Recent social and demographic changes have presumably contributed to a subsequent decline in disease incidence. CONCLUSIONS: Based on the largest known set of diagnostically verified Viliuisk encephalomyelitis cases, we demonstrate how a previously little-known disease that was endemic in a small indigenous population subsequently reached densely populated areas and produced an epidemic involving hundreds of persons.

A proposal for new criteria for the classification of hantaviruses, based on S and M segment protein sequences.

Hantaviruses, members of the family Bunyaviridae, are the causative agents of hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome. Hantaviruses are currently demarcated into species based on the guidelines provided by the International Committee on Taxonomy of Viruses (ICTV). These guidelines however, are often ignored by the descriptors of novel hantaviruses. With this study we attempted to refine the second ICTV guideline for hantavirus species demarcation by phylogenetically analyzing all in Genbank available complete sequences derived from the S, M or L segments of hantaviruses. S and M segment amino acid sequence comparison allowed clear and unequivocal distinction between different hantavirus species, and lead us to propose additional criteria for the demarcation of hantavirus species (S segment amino acid distance >10% or M segment amino acid distance >12%) and hantavirus groups (S segment amino distance >24% or M segment amino acid distance >32%). With this study, we propose to adjust the second rule of the ICTV classification guidelines ("a 7% difference in amino acid identity when comparing the complete S segment and M segment sequences") to a more appropriate rule, "a 10% difference in S segment similarity and a 12% difference in M segment similarity based on complete amino acid sequences" in accordance with the current situation in the hantavirus field.

Review. Kuru and its contribution to medicine.

The solution of kuru led us to the solution of Creutzfeldt-Jakob disease and to the elucidation, in humans and other species, of previously unknown mechanisms of infection. These require very close three-dimensional matching, which determines infectious nucleant or prion activity. Evidence for nucleation processes is found widely in the organic and inorganic worlds and in the interactions between them: in the formation of amyloid fibrils; in the biochemistry of silicon; in cave formations deep in the Earth; and in outer space. Kuru in its location in Papua New Guinea has also led to an understanding of the cultural achievements of the Palaeo-Melanesians, with deep roots in human history.

Family clustering of Viliuisk encephalomyelitis in traditional and new geographic regions.

Viliuisk encephalomyelitis is an acute, often fatal, meningoencephalitis that tends to develop into a prolonged chronically progressive panencephalitis. Clinical, neuropathologic, and epidemiologic data argue for an infectious cause, although multiple attempts at pathogen isolation have been unsuccessful. To assess mechanisms of disease transmission and spread, we studied 6 multiplex families. Secondary cases occurred among genetically related and unrelated persons in a setting of prolonged intrahousehold contact with a patient manifesting the disease. Transmission to unrelated persons was documented in a densely populated region around the city of Yakutsk in which Viliuisk encephalomyelitis had not been previously known. Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.

Infectivity studies of both ash and air emissions from simulated incineration of scrapie-contaminated tissues.

We investigated the effectiveness of 15 min exposures to 600 and 1000 degrees C in continuous flow normal and starved-air incineration-like conditions to inactivate samples of pooled brain macerates from hamsters infected with the 263K strain of hamster-adapted scrapie with an infectivity titer in excess of 10(9) mean lethal doses (LD50) per g. Bioassays of the ash, outflow tubing residues, and vented emissions from heating 1 g of tissue samples yielded a total of two transmissions among 21 inoculated animals from the ash of a single specimen burned in normal air at 600 degrees C. No other ash, residue, or emission from samples heated at either 600 or 1000 degrees C, under either normal or starved-air conditions, transmitted disease. We conclude that at temperatures approaching 1000 degrees C under the air conditions and combustion times used in these experiments, contaminated tissues can be completely inactivated, with no release of infectivity into the environment from emissions. The extent to which this result can be realized in actual incinerators and other combustion devices will depend on equipment design and operating conditions during the heating process.

Neuronal cell death in transmissible spongiform encephalopathies (prion diseases) revisited: from apoptosis to autophagy.

Neuronal autophagy, like apoptosis, is one of the mechanisms of the programmed cell death (PCD). In this review, we summarize the presence of autophagic vacuoles in experimentally induced scrapie, Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Initially, a part of the neuronal cytoplasm was sequestrated by concentric arrays of double membranes; the enclosed cytoplasm appeared relatively normal except that its density was often increased. Next, electron density of the central area dramatically increased. The membranes then proliferated within the cytoplasm in a labyrinth-like manner and the area sequestrated by these membranes enlarged into a more complex structure consisting of vacuoles, electron-dense areas and areas of normally-looking cytoplasm connected by convoluted membranes. Of note, autophagic vacuoles form not only in neuronal perikarya but also in neurites and synapses. Finally, a large area of the cytoplasm was transformed into a collection of autophagic vacuoles of different sizes. On a basis of ultrastructural studies, we suggest that autophagy plays a major role in transmissible spongiform encephalopathies (TSEs) and may even participate in a formation of spongiform change.

Viliuisk encephalomyelitis: intrathecal synthesis of oligoclonal IgG.

Viliuisk encephalomyelitis (VE) is a neurodegenerative disorder expressed as subacute meningo-encephalitis progressing to a more prolonged pan-encephalitic syndrome with a fatal outcome within 1 to 10 years. Some patients survive to a steady state of global dementia and severe spasticity that may last for over 20 years. Multiple micronecrotic foci surrounded by inflammatory infiltrates are observed throughout the cerebral cortex and other gray matter areas. Infectious etiology of VE is strongly suspected, but the causative agent has not been identified. We conducted a search for assays that might be helpful for VE diagnosis and established for the first time that the majority of patients with definite VE show evidence for intrathecal IgG synthesis correlating with the clinical manifestations of the disease. This indicates that the detection of oligoclonal IgG banding in the cerebrospinal fluid is a valuable diagnostic assay for VE. Implications of these findings for a possible etiology of VE are discussed.

Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in hamsters. I. Alterations of myelinated axons.

Classical and ultrastructural neuropathology of prion diseases are generally well described. Here we report that alterations of myelinated fibres in hamsters infected either with polioencephalopathic strains of scrapie or panencephalopathic strains of CJD (Echigo-1) are virtually identical and differ only quantitatively. In contrast, mice infected with the panencephalopathic Fujisaki strain of CJD exhibited much more elaborate changes of myelinated fibres.

How do neurons degenerate in prion diseases or transmissible spongiform encephalopathies (TSEs): neuronal autophagy revisited.

As in other neurodegenerative diseases such as Alzheimer's disease, neurons in prion diseases or transmissible spongiform encephalopathies (TSEs) die via programmed cell death of which the apoptotic process is relatively well characterized. A subcellular alteration linked to apoptosis is the formation of autophagic vacuoles, which we and others demonstrated in CJD- and scrapie-affected rodent brains. Autophagy may co-exist with apoptosis or may precede it and the process may be induced by apoptotic stimuli. Here, we extend these observations using different model of scrapie and CJD. Both scrapie models (the 263K and 22C-H) demonstrated autophagic vacuoles with the same frequency; hence, they will be described together. While the following changes had been observed simultaneously in different areas of the same sample, this description is organised as if it followed a sequence of events. First, a part of the neuronal cytoplasm was sequestrated by concentric arrays of membrane; that part of the cytoplasm closed by membranes appeared relatively normal but its density often appeared increased. Next, electron density of the central dramatically increased. Then, membranes proliferated within the cytoplasm in a labyrinth-like manner and an area sequestrated by these membranes enlarged and became more complex structure consisting of vacuoles, electron-dense area and areas of normally-looking cytoplasm connected with convoluted membranes. Finally, a large area of the cytoplasm was transformed into a collection of autophagic vacuoles of different sizes. Virtually identical alterations, albeit with much lower frequency, were seen in terminally ill CJD-affected hamsters.

Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in hamsters. II. Astrocytic and macrophage reaction towards axonal destruction.

We report here the microglial (macrophage) and astrocytic reaction in several models of transmissible spongiform encephalopathies (TSEs) or prion diseases. With the low power electron microscopy it was readily apparent that myelinated vacuoles were surrounded by cells and their processes. The latter belonged either to hyperplastic reactive astrocytes or to macrophages. Typically, reactive astrocytes exhibited cytoplasm filled with innumerable glial filaments and, occasionally, other organelles (like cilia) and abundant tortuous intercellular junctions of adhesive plaque junction type. Desmosome-like junctions connecting astrocytic elements were also seen. As described earlier, astrocytic processes were occasionally interdigitated with oligodendroglial cells and their processes. Two types of macrophages were readily described. The majority of them exhibited electron-dense cytoplasm and numerous "empty" vacuoles (digestive chambers) containing cellular debris. Occasional vacuoles were surrounded by a thin collar reminiscent of "lyre-like inclusions" of the second type of macrophages. Several mylinated fibres were clearly engulfed by the cytoplasm of a macrophage containing unusual annulate lamellae.

Raymond Pearl memorial lecture, 1989: Cultural practices as determinants of clinical pathology and epidemiology of venereal infections: Implications for predictions about the AIDS epidemic.

Sexually transmitted diseases newly introduced into diverse primitive and isolated populations have behaved differently in clinical severity and seriousness of the epidemics they have caused, because of culturally different sexual practices. Epidemic interstitial plasma cell pneumonia in the 1930s-1950s in eastern and northern Europe, caused by Pneumocystis carinii and accompanied by cytomegalovirus infection, was an unexpected AIDS-like epidemic which spread slowly, then quickly and inexplicably disappeared. Newly recognized endemic HTLV-I and epidemic HIV human retrovirus infections are behaving in a fashion similarly difficult to anticipate and predict.