The mode of inheritance of Scheuermann's disease.

The mode of Scheuermann's disease inheritance and its phenotypic traits in probands and their relatives were studied in 90 pedigrees (90 probands and 385 relatives). The disorder was identified as a genetically related pathology inherited by autosomal dominant type, controlled by a mutant major gene, as a kyphotic deformity without signs of vertebral bodies' anomaly and torsion. Morphological and biochemical studies showed disturbance in the structure of vertebral growth plate anterior aspects at the level of deformity, defects in proliferation and differentiation of chondrocytes, and change in proteoglycan spectrum in cells and matrix. Twelve candidate genes were studied in chondrocytes isolated from vertebral growth plates of patients with Scheuermann's disease. The study results included disorder in the IHH gene expression and preservation of the expression of PAX1, two aggrecan isoforms, link protein, types I and II collagen, lumican, versican, growth hormone and growth factor receptor genes, and proliferation gene. Preservation of the SOX9 gene (transcription gene) probably indicates posttranscriptional genetic disorders. The study is under way.

[Redistribution of immune defence in male mice exposed by female scent].

Since scent marks of mice are harbored by parasites, their sniffing during olfactory search of the mating partner leads to increase of the infection risk. A hypothesis that sexual signals can induce, along with the reproductive behavior, non-specific immune defense against respiratory infections is tested in the present paper. It was found in the experiments on outbred ICR mice that the scent of soiled bedding from cages with mature females stimulated leukocyte intervention to the upper air-ways. Migration of the white blood cells to lung tissue was accompanied with a more prominent immune and endocrine responeses to intranasal application of the bacterial lipopolysacharide (LPS). In particular, LPS administration to male mice treated by female scent was resulted in much greater amount of leukocyte aggregations in the peribronchial areas than that was found in the males kept isolated from the female signals. The female scent also enhanced adrenocortical response to LPS administration, which was coincided with statistically significant increase of IL-1beta concentration in hypothalamus. So, chemical signals of the mature female induce travel of white blood cells to the upper air-waya in the scent treated male mice. It can increase resistance to respiratory infections, on the one hand, and aggravates stress response to inhalation of the bacterial compounds, on the other hand.

Glycosaminoglycans of the trabecular meshwork of the eye in primary juvenile glaucoma.

Significant changes in the qualitative and quantitative composition of glycosaminoglycans (decreased content of sulfated glycosaminoglycans and increased content of collagen-bound proteoglycanes) in the trabecular meshwork of the eye in primary juvenile glaucoma indicate fibrosis of the juxtacanalicular tissue, which was detected in pathomorphological examination of the operation material.

Aggrecan gene expression disorder as aetiologic factor of idiopathic scoliosis.

A pathogenetic mechanism of the idiopathic scoliosis (IS) has been established on the basis of in-depth morphological and biochemical investigations of structural components of the spine in patients with IS (surgical material). We have shown that IS develops on the basis of disturbance of proteoglycans (PG) synthesis and formation in vertebral growth plates. The found keratan sulphate-related fraction is likely a marker of genetic changes in PGs in IS. Long-term our studies demonstrated a major-gene effect in IS. The study has shown that aggrecan gene expression is significantly decreased in cultivated chondroblasts from patients with IS. The presence of keratan sulphate-related fraction and keratan sulphate increase are associated with lumnican increase.

Glycosaminoglycans of the vertebral body growth plate in patients with idiopathic scoliosis.

The concentrations of keratan sulfates and unmodified keratan sulfates increased in the vertebral body growth plate in patients with idiopathic scoliosis. Sulfation and acetylation of total glycosaminoglycans decreased by 50 and 30%, respectively. These changes reflect the decrease in biological activity of molecules that modulate function of the growth plate.

[Growth plate structure of the vertebral body in children of different age groups].

The purpose of this study was to investigate the regularities of formation and functioning of the structural components of the growth plate (GP) of the vertebral body in children during the postnatal period of ontogenesis: in newborns and in children aged 1, 3-5- 6-10- and 12-14-years. GP samples of were studied using histological, histochemical (demonstration of oxidation-reduction enzyme activity, polysaccharides, glycosaminoglycans) and electron microscopic methods with special reference to the age changes of the cells and matrix in different GP zones of the vertebral body. The process of chondrogenic differentiation is described, which includes the successive stages of cellular modifications starting from an undifferentiated chondroblast through a highly differentiated chondrocyte to a degrading and dying chondrocyte. The changes in synthetic activity of cartilage cells are noted as well as the nature of matrix components that are produced by them in the course of differentiation. Regular age-related changes of spatial distribution of mitotically active cells, forming cellular columns, and of isogenous groups are characterized in relation to the alterations of matrix quantity and chemical content in GP of the vertebral body.

[Analysis of polymorphism of the number of tandem repeats in the aggrecan gene exon G3 in the families with idiopathic scoliosis]. / Izuchenie polimorfizma chisla tandemnykh povtorov v ékzone G3 gena agrekana v sem'iakh s idiopaticheskim skoliozom.

In our previous study we showed that the inheritance of pronounced forms of idiopathic scoliosis was described by an autosomal-dominant major gene model assuming incomplete sex- and age-dependent penetrance. In the present study a search for the major gene was carried out by means of testing candidate genes. The aggrecan gene with known polymorphism of the number of tandem repeats in exon G3 was considered to be one of these candidate genes. Various alleles of this gene provide attachment of different number of chondroitin sulfate chains to a proteoglycan core protein, thereby changing functional properties of cartilage. Using the TDT analysis of 33 unrelated families consisting of a proband and his parents, we examined the existence of associations between the aggrecan alleles and the disease. Among nine alleles identified, three alleles with tandem repeats numbers of 25, 26, and 27 prevailed. We did not reveal preferable transmission of any of these alleles to the proband (TDT-statistics for different alleles varied from 0 to 0.71). There was also no correlation between the number of tandem repeats and the disease severity. Thus, either the polymorphism of the number of tandem repeats is not the direct reason for development of idiopathic scoliosis in the families tested, or its effect is too low to be detected using the samples examined.

Segregation analysis of Scheuermann disease in ninety families from Siberia.

Scheuermann disease [OMIM number 181440] is the most common cause of structural kyphosis in adolescence. Segregation analysis using a model with gender effects was applied to 90 pedigrees from Barnaul (West Siberia, Russia) ascertained through a proband with Scheuermann disease. The transmission probability model was used to detect major gene effect. A significant contribution of a major gene to the control of the pathology was established. Inheritance of the disease can be described within the framework of a dominant major gene diallele model. According to this model, Scheuermann disease should never occur in the absence of the mutant allele. All male carriers of the mutant allele develop the disease, while only a half of female carriers manifest it. We found a high frequency of idiopathic scoliosis in the families with Scheuermann disease (0.08 vs. 0.01-0.02 in general population). We also observed a succession of idiopathic scoliosis and Scheuermann disease in consecutive generations. The familial aggregation of these two spinal pathologies in the present sample may indicate a genetic unity of Scheuermann disease and idiopathic scoliosis.

[New models of inheritance of complex characteristics and their use in segregation analysis of idiopathic scoliosis]. / Novye modeli nasledovaniia slozhnykh priznakov i ikh ispol'zovanie pri segregatsionnom analize idiopaticheskogo skolioza.

New methods of segregation analysis of alternative traits have been developed. These methods make it possible to take into account the sex and age specificity of the disease manifestation. Hence, they extend the range of genetic hypotheses to be tested and ensure the correct analysis of inheritance of complex pathologies in humans. Segregation analysis of idiopathic scoliosis performed in this study demonstrates the possibilities of the new methods. Based on pedigrees of 93 probands, it has been demonstrated for the first time that the inheritance of severe (degrees II to IV) forms of this disease can be described by a model that assumes a dominant major gene with incomplete, sex- and age-dependent penetrances of all genotypes. According to this model, severe forms of idiopathic scoliosis do not develop if the mutant allele is absent (the penetrance of genotype A1A1 is zero). The probabilities of the disease for subjects with genotypes A1A2 and A2A2 are similar and approximately equal to 0.3 and 0.5 for males and females, respectively. Mild (degree I) forms of idiopathic scoliosis are heterogeneous. A progressive disease may be expected only in the patients that carry the mutant allele.

Segregation analysis of idiopathic scoliosis: demonstration of a major gene effect.

Segregation analysis using a model with age and gender effects was applied to 101 pedigrees ascertained through a proband with idiopathic scoliosis. The transmission probability model was used to detect major gene effect. When we analyzed the pedigrees where affected status was assigned to persons with a Cobb's angle of more than 5 degrees we did not detect a significant major gene effect. However, when the affected status was assigned to persons with pronounced forms of disease only (a curve of at least 11 degrees) a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex and age dependent penetrance of genotypes. According to this model, the pronounced forms of idiopathic scoliosis should never occur in the absence of the mutant allele. This indicates that only the carriers of the mutant allele develop pronounced forms of the disease. At the same time, only a fraction of the carriers of the mutant gene should manifest the disease (30% of males and 50% of females).

[The evolution of a contusion focus after the microsurgical autotransplantation of the omentum (an experimental study)]. / Evoliutsiia kontuzionnogo ochaga posle mikrokhirurgicheskoi autotransplantatsii sal'nika (éksperimental'noe issledovanie).

The purpose of treatment of head trauma cannot be limited by simple life saving, it also should be targeted at the improvement of the quality of life. Twenty dogs with graded local head trauma underwent microsurgical revascularization of the area adjacent to the contused brain with an autologous omental graft to provide functional improvement. The effectiveness of surgery was demonstrated in series of 5 experiments when the operation was performed on posttraumatic days 7-14, with the follow-up of as long as 180 days. After the procedure, no macroscopic signs of contusion could be demonstrated. Microscopically the contused area resembled a slit two times smaller than in controls. Microscopic and histochemical studies revealed both the morphologic recovery and an improvement in cellular enzyme activity. The data obtained adds some more information regarding clinical applications of microsurgical revascularization technique.

[Preliminary analysis of inheritance of scoliosis]. / Predvaritel'nyi analiz nasledovaniia skolioza.

90 pedigrees (283 individuals) were used for statistical and segregation analysis of scoliosis inheritance. It was shown that inheritance of scoliosis may be described by the monogenic model with incomplete penetrance of heterozygotes, the latter being lower in men than in women. The monogenic model allows to perform correct predictions, the probability of incorrect prediction being about 0.1.

[Hereditary galactosemia in rats: biochemical mechanisms of the disease]. / Nasledstvennaia galaktozemiia u krys: biokhimicheskie mekhanizmy razvitiia zabolevaniia.

A W/SSM rat strain with symptoms of inherited galactosemia (cataracts, hepatosplenomegaly, aminoaciduria) was previously developed by selection and inbreeding of Wistar rats highly susceptible to the galactosemic effect of galactose. Decreased activity of galactose-I-phosphate uridyl transferase (Gal-I-PUT) in liver and erythrocytes is the salient biochemical feature of the strain. The crossing experiments have shown that the decrease in Gal-I-PUT activity was not required for the expression of main galactosemia symptoms. The experiments excluded low galactokinase activity and high susceptibility of glucose-6-phosphate dehydrogenase and phosphoglucomutase to galactose-I-phosphate as probable reasons of galactosemia. It was shown that increased transport of 14C-galactose to the erythrocytes was characteristic of galactosemic rat strain. The intracellular accumulation of galactose concerned with its increased transport was assumed as a major reason for the development of galactosemia symptoms in W/SSM rats. Genetic analysis has shown that lens lesions in galactosemic rats were controlled by one dominant gene. It is suggested that this gene is responsible for the enhances transport of galactose into the rat cells and its accumulation in toxic concentrations. The main galactosemic symptoms including cataracts result obviously rom the pleiotropic effect of this gene; the decreased activity of Gal-I-PUT may be a consequence of its epistatic effect.

[Histochemical and electron-microscopic study of brain structures during the acute period of experimental craniocerebral injuries]. / Gistokhimicheskoe i élektronno-mikroskopicheskoe issledovanie struktur golovnogo mozga v ostrom periode cherepno-mozgovoi travmy v éksperimente.

Three stages of cerebral metabolism differing in tension were revealed in the acute period of closed craniocerebral trauma. In the mobilization stage (1 hour after trauma) enzymatic reactions reflecting the activity of aerobic and anaerobic glycolysis are sharply intensified. In the resistance stage (from 3 hours to 2 weeks after trauma) stable conversion to anaerobic glycolysis is noted, which leads to marked deficiency in macroergic compounds. Activation of alpha-glycerophosphate, pentose shunt by means of pharmacological agents in combination with hypothermia may be recommended in this stage. In the restoration stage (more than 2 weeks after the trauma) the metabolic processes are gradually normalized and therapy need not be so intensive.