[Liver damage in children and adolescents with newly diagnosed celiac disease: clinical and anamnestic, serological and morphological patterns].

Hypertransaminasemia is a common extra-intestinal manifestation of celiac disease. AIM: To analyze the frequency of hypertransaminasemia, clinical and anamnestic, serological and morphological picture in children in the active period of celiac disease. MATERIALS AND METHODS: The study included 272 children with celiac disease aged from 8 months to 17 years. The patients were divided into two groups: the first - children with hypertransaminasemia, the second - without hypertransaminasemia. RESULTS: Hypertransaminasemia was detected in 55.9% of children with celiac disease. The age of manifestation of the disease in the first group was 1.0 [0.5; 2.0] years, in the second group - 1.9 [0.5; 4.0] years (p=0.0004). Children of the first group were diagnosed at 2.5 [1.7; 4.9] years, the second group - at 4.9 [3.0; 10.8] years (p<0.001). The duration of the latency period in children of the first and second groups was 1.4 [0.6; 3.1] years and 2.4 [0.9; 4.3] years, respectively (p=0.002). The average values of IgA anti-tTG antibodies in children of the analyzed groups did not differ, and the indicators of IgG anti-tTG antibodies in the first group were 1.6 (p=0.04) times higher. The level of EMA in children with hypertransaminasemia was 2 times higher than in children without hypertransaminasemia. CONCLUSION: Hypertransaminasemia is more often detected in young children with early manifestation of the disease, increases with the deepening of atrophy in the mucous membrane of the small intestine. Higher titers of celiac-specific antibodies were detected in children with hypertransaminasemia.

[Paralytic poliomyelitis in Russian Federation in 1998-2005].

From 1998 through 2005 3,294 cases of acute flaccid paralysis (AFP) including 93 cases with clinical picture of poliomyelitis were registered in Russian Federation. From the latter cases 91 were classified as vaccine-associated paralytic poliomyelitis (VAPP): 66 were VAPP cases in oral poliomyelitis vaccine (OPV) recipients and 25--VAPP cases in contacts. VAPP rate was 1 case per 1.6 million of distributed OPV doses, 1 case per 2.2 million doses for OPV recipients, and 1 case per 186,000 doses for recipients of 1st OPV dose in children aged < 1 year. Majority of VAPP cases in recipients occurred after 1st dose (89.4%) and in contacts--in non-vaccinated children (76%). Mean interval between OPV administration and onset of VAPP in recipients was 21 days. Children aged < 1 year were predominant among VAPP cases (92.4% among recipient VAPP cases, and 80% among contact VAPP cases). Majority of the patients had unfavorable health status including defects of immunity. Most of poliovirus strains isolated from VAPP cases belonged to type 3 (52.9%) whereas to type 2 and 1--29.8% and 17.4% of strains respectively. All VAPP cases were associated with vaccine-derived polioviruses. A highly diverged poliovirus type 1 (2.65% of nucleotide substitutions in VP1 region) was isolated from patient with contact VAPP. Formation of poliovirus-neutralizing serum antibodies in children with VAPP including persons with immunodeficiency reflects the ability of the organism to produce specific antiviral immune response.

Spread of vaccine-derived poliovirus from a paralytic case in an immunodeficient child: an insight into the natural evolution of oral polio vaccine.

Sabin strains used in the manufacture of oral polio vaccine (OPV) replicate in the human organism and can give rise to vaccine-derived polioviruses. The increased neurovirulence of vaccine derivatives has been known since the beginning of OPV use, but their ability to establish circulation in communities has been recognized only recently during the latest stages of the polio eradication campaign. This important observation called for studies of their emergence and evolution as well as extensive surveillance to determine the scope of this phenomenon. Here, we present the results of a study of vaccine-derived isolates from an immunocompromised poliomyelitis patient, the contacts, and the local sewage. All isolates were identified as closely related and slightly evolved vaccine derivatives with a recombinant type 2/type 1 genome. The strains also shared several amino acid substitutions including a mutation in the VP1 protein that was previously shown to be associated with the loss of attenuation. Another mutation in the VP3 protein resulted in altered immunological properties of the isolates, possibly facilitating virus spread in immunized populations. The patterns and rates of the accumulation of synonymous mutations in isolates collected from the patient over the extended period of excretion suggest either a substantially nonuniform rate of mutagenesis throughout the genome, or, more likely, the strains may have been intratypic recombinants between coevolving derivatives with different degrees of divergence from the vaccine parent. This study provides insight into the early stages of the establishment of circulation by runaway vaccine strains.

Poliomyelitis in Russia in 1998-1999.

After introducing surveillance for poliomyelitis and AFP cases in the Russian Federation in 1998, 740 AFP cases have been registered in 1998-1999, and 18 of that number were considered as vaccine-associated paralytic poliomyelitis (VAPP). Of 18 cases 11 were classified as VAPP of vaccine recipients and confirmed by virus isolation; from two of the vaccine recipients virus was not isolated, and five were poliomyelitis cases in contact non-vaccinated children. In all the cases the disease was characterised with the typical clinical picture with residual pareses and paralyses. One case was fatal. Vaccine virus type 3 has been isolated from all the vaccine recipients. The MAPREC test has shown that the quality of monovaccine type 3 bulks used for vaccinating these children did not differ from the quality of other bulk vaccines produced by the Chumakov Institute of Poliomyelitis. Patients surveyed for gammaglobulin were positive. Polioviruses type 1 isolated from two of the contact cases had changed antigenic properties and were recombinants of types 1 and 2.

Outbreak of paralytic poliomyelitis in the Chechen Republic in 1995.

An outbreak of poliomyelitis with 146 cases among children of whom six died occurred in the Chechen Republic in 1995. Sporadic cases of poliomyelitis have been reported in the neighbouring Ingush Republic. The outbreak lasted for five months (from May to September) and the maximum number of cases was registered in July. The age of the patients did not exceed 11 years, and more than 90% of the patients were children aged from one month to four years. The overwhelming majority of the patients had not been vaccinated in the routine OPV immunization programme. The outbreak was due to wild poliovirus type 1 belonging to genotype T previously known to circulate in the territory of the former Soviet Union (FSU). Chechen and Ingush isolates were very closely related to each other and to isolates from Central Asia, Tajikistan, 1994. Only a very distant relatedness of the Chechen and Ingush isolates was found with the strains isolated at about the same time outside the FSU (China 1994, Pakistan 1995). The presence of high numbers of non-vaccinated/poorly vaccinated persons and the poor sanitary and hygienic conditions for civilians due to the military conflict were factors that had a role in the outbreak.

Some problems of molecular biology of poliovirus infection relevant to pathogenesis, viral spread and evolution.

Molecular mechanisms of poliovirus reproduction in the human gut remain largely unexplored. Nevertheless, there are grounds to believe that the virus spreads from cell to cell, like that from person to person during natural circulation, and involves a relatively small proportion of the highly heterogeneous viral population generated by the previous host. This mechanism of random sampling is responsible for the majority of fixed mutations, and contributes to the maintenance of a certain level of viral fitness (virulence). In the long term, random sampling may lead to the decrease in fitness and even to extinction of some viral evolutionary branches, explaining cases of self-limiting poliovirus infection in immunodeficient patients. A low propensity of the Sabin viruses for natural circulation may also be a related phenomenon. The trend to decrease in fitness may be interrupted by the appearance of rare, fitter (more virulent) variants, which may be responsible for poliomyelitis outbreaks caused by wild type virus, and for the development of paralytic disease in chronic carriers of the Sabin vaccine. All these evolutionary events are largely stochastic and hence are unpredictable in principle.

Evolution of circulating wild poliovirus and of vaccine-derived poliovirus in an immunodeficient patient: a unifying model.

We determined nucleotide sequences of the VP1 and 2AB genes and portions of the 2C and 3D genes of two evolving poliovirus lineages: circulating wild viruses of T geotype and Sabin vaccine-derived isolates from an immunodeficient patient. Different regions of the viral RNA were found to evolve nonsynchronously, and the rate of evolution of the 2AB region in the vaccine-derived population was not constant throughout its history. Synonymous replacements occurred not completely randomly, suggesting the need for conservation of certain rare codons (possibly to control translation elongation) and the existence of unidentified constraints in the viral RNA structure. Nevertheless the major contribution to the evolution of the two lineages came from linear accumulation of synonymous substitutions. Therefore, in agreement with current theories of viral evolution, we suggest that the majority of the mutations in both lineages were fixed as a result of successive sampling, from the heterogeneous populations, of random portions containing predominantly neutral and possibly adverse mutations. As a result of such a mode of evolution, the virus fitness may be maintained at a more or less constant level or may decrease unless more-fit variants are stochastically generated. The proposed unifying model of natural poliovirus evolution has important implications for the epidemiology of poliomyelitis.

[Geotyping of wild poliovirus strains on the territory of Russia and CIS countries in 1987-1995]. / Geotipirovanie dikikh shtammov virusa poliomielita, izolirovannykh na territorii Rossii i SNG v 1987-1995 gg.

33 wild poliovirus strains isolated on the territory of the former USSR were subjected to the comparative sequence analysis of the 150 bp genome fragment VP1/2A on the junction of the genome regions coding basic capsid protein VP1 and viral protease 2A. The dendrograms characterizing the similarity of nucleotide sequences revealed the existence of 3 geographical genotypes (geotypes) of wild poliovirus strains of type 1 (A, G, T) and broad geotype (C) of wild poliovirus strains of type 3. The comparison of the analyzed strains with strains circulating in the neighboring countries at the same period provided information on their genetic relationship. The data thus obtained made it possible to establish the pathways of the transmission of wild poliovirus strains in the common epidemic area of the Russia u CIS.

[Detection of poliomyelitis viral strains in natural isolates and identification of them by polymerase chain reaction]. / Obnaruzhenie shtammov virusa poliomielita v prirodnykh izoliatakh i ikh identifikatsiia s pomoshch'iu polimeraznoi tsepnoi reaktsii.

One hundred and fifty nucleotide-long VP1/2A junction regions were sequenced in the RNAs of 19 strains isolated in 1990-1991 from patients with paralytic poliomyelitis in different regions of the former USSR. On the basis of the alignments of these sequenced RNAs, four pairs of 19-25 base-long oligodeoxynucleotide PCR primers were designed capable of detecting polio RNAs in isolated strains and of discriminating between polio genotypes. PCR with 520 polio virus strains isolated from patients, normal subjects, and environmental objects showed 428 of these strains to be related to Sabin's vaccine strains, whereas the rest were referred to A (30), T (24), and G (1) genotypes of serotype 1 and to C-genotype (37) of serotype 3. The designed primers were highly specific and did not cross-react between themselves and with primers specific for Sabin's vaccine strains in PCR.