Search

Aim: To elucidate genetically determined character of cardiovascular pathology with realization of its clinical manifestations at systemic, organ and tissue levels in patients with connective tissue dysplasia (CTD) at obstetric-gynecological setting., Materials and Methods: This study involved 614 women with classified and non-classified forms of CTD including 268 primigravidas, mean age 24.8 ± 3.46 yr (group 1) and 346 gynecological patients with genital prolapse, mean age 44.5 ± 10 yr (group 2). Each group was divided into subgroups 1A and 2A with predominant clinical manifestations on the part of the stromal-muscular component and 1B and 2B with the predominance of the vascular component. The methods used included laboratory analysis, ECG, ultrasound, echocardiographic , X-ray, combined urodynamic studies, MGT and laser flowmetry., Results: Prolapse of mitral valve (PMV) was diagnosed in 100 and 88.3% of the patients in groups 1 and 2 respectively with regurgitation in 1-2 valves in 140 (52.1%) and 143 (47.7%) ones, primary varicosis in 41 (15.2%) and 136 (39.5%), mixomatous degeneration in 65 (24.3%) and 107 (30.9%), predisposition to tissue hemorrhage in 37 (13.8%) and 64 (18.5%), vegetovascular dystonia in 50 and 60%. Patients of subgroup 1A with joint hypermobility and PMV exhibited a higher degree of uterine maturity (4.6 ± 1.75 scores). Rapid labor correlated with apical forms of genital prolapse (subgroups 1A, 2A); in the latter subgroup, they occurred in 83% ofthe patients, grade III rectocele occurred in 62.5%, protrusion and relaxation of pelvic floor in 50%. Pathology of the anorectal segment of pelvic diaphragm was diagnosed in more than 50% of the parous and nulliparous women (subgroups 1A and 2A). End diastolic volume was 102.7 ± 31.08 and 65.7 ± 59.48 ml in subgroups 2A and 2B respectively in association with a decrease of left ventricle mass to 135.6 ± 36.6 and 168.5 ± 86.97 g Hyperemic bloodflow prevailed in subgroup 1A while microcirculation index increased to 6.6 ± 1.84, perfusion coefficient to 2.2 ± 0.91, variation coefficient to 28.9 ± 5.46, relative HF amplitude to 21.9 ± 5.1 (control: 18.3 ± 1.29)., Conclusion: CTD is always realized at the level of cardiovascular system. Its form and the type of dysregulation of suprasegmental CNS regions are genetically determined and inter-related In combination with minor cardiac abnormalities, they determine the type of hemodynamics including microcirculation and the degree of dysmorphism in the form of disorders in pelvic organs and structures including changes in the stromal-vascular histion level. The type of hemodynamics (microcirculation) determines dysregulatory processes in cells and intercellular matrix with the development of pathomorphological changes in the form of rheologic disturbances, vasculitis, thickening and loosening of basal membrane, smooth cell dystrophy, swelling of collagen fibers, loss of their elasticity, and reduction of the collagenous network.

Aim: To estimate the role of different dysplastic syndromes and phenotypes in the development of sclerodegenerative lesions and calcific stenosis of the aortic valve (AV)., Subjects and Methods: One hundred and fifty patients (82 men and 68 women) aged 42 to 83 years were examined. A study group consisted of 89 patients (mean age 60.7 +/- 8.9 years) with clinical and echocardiographic signs of sclerodegenerative AV lesions (SDAVL). A control group included 61 patients (mean age 61.3 +/- 7.6 years) who had no clinical, physical, or echocardiographic signs of SDAVL. Twenty-five patients with critical calcific aortic stenosis (CAS) underwent histological examination of removed aortic semilunar valves after prosthetic AV replacement., Results: Persons with a Marfanoid habitus (18%) and mitral valve prolapse (10.7%) are most common in older age groups. An association has been found between the bone signs of dysmorphogenesis and the development of SDAVL and CAS., Conclusion: Three or more signs of bone dysmorphogenesis and the Marfanoid habitus should be viewed as a predictor of SDAVL.

The examination was applied to sampling of 238 patients of younger age with neurologic symptomatology under connective tissue dysplasia and 46 healthy persons. The venous cerebral angiodystonia was diagnosed in 153 (64.3%) patients with connective tissue dysplasia. The results are confirmed by duplex analysis of cerebral and vertebral vessels. The mutations of genes of blood coagulation system (FV Leiden, FII, MTHFR, FVII and PAI-1) are established. They include combined (61.4%) and independent (23.5%) groups of mutation. Alongside with it, in 23 (19.6%) patients disorders of hemostasis are presented as von Willebrand factor deficiency and in 105 (89.7%) patients as decrease of aggregation function of thrombocytes and disorders of final coagulation stage of blood coagulation. The results of study indicate the equally frequent risk of thrombotic and hemorrhagic complications in patients with connective tissue dysplasia.

Undifferentiated connective tissue dysplasia (UCTD) is one of most common diseases of the connective tissue. High frequency of UCTD in population along with the fact that it can provoke a number of other diseases make UCTD an important object of the modern biomedical research in the areas of cardiology, neurology, rheumatology and pulmonology. Modern diagnostics and determination of the predisposition to UCTD allow elaboration of personalized therapy. In particular, Mg-containing supplements and medications can be effectively used in the therapy of UCTD. In one of our previous works we have analyzed possible molecular mechanisms of UCTD etiology as well as therapeutic action of magnesium. The use of data on nucleotide polymorphisms as complementation of standard medical diagnostics is one of perspective trends of the post-genomic medical research. The present work suggest a number of nucleotide polymorphisms that can be used in genetic association analyses of the UCTD as of well as therapeutic efficiency of magnesium treatment. Selection and analysis of the polymorphisms was done on the base of molecular mechanisms we had proposed earlier, comprehensive analysis of published data and also with the use of an integral approach to analysis of the functional effects of the nucleotide polymorphisms and corresponding amino acid substitutions.

Connective tissue (CT) is a multifunctional universal structure of great importance to the human organism. Constituting about 50% of the body mass, CT forms a frame (skeleton) and outer cover (skin), as well as the inner medium, through which all structural elements receive nutrients and extract metabolic products. The great number of links, constituting the CT system, each of which is controlled genetically and is liable to genetic lesions, creates conditions for heterogeneity of malformations and diseases involving CT. Non-differentiated CT dysplasia (NDCTD) is a genetically heterogenous group, presenting a basis for various chronic diseases. NDCTD may present the cause of dysplastic changes in the CT of different organs and systems. Thanks to modern diagnostic techniques, NDCTD is revealed frequently. NDCTD is underlied by molecular-, onto-, and pathogenetic mechanisms, leading to structural and functional changes in CT. This CT "weakness" is manifested by the peculiarities of the structure of various organs and systems. Mesenchimal heart dysplasias are the most widespread visceral markers of the given CT pathology. CT dysplasias of the heart are often combined with varied manifestations of system CT anomaly. Mitral valve prolapse (MVP) is the most wide-spread and well-studied minor heart anomalies. Primary MVP is a hereditary or congenital pathology and is not connected with a particular disease. It is a genetic pathology--CT dysplasia with autosomal dominant inheritance. Patients with MVP have an increased expression of Bw35 antigen of HLA system, which causes dysmetabolism of collagen in the mitral cusps. It has been revealed that tissue deficiency of magnesium is associated with antigen expression and correlates with clinical symptoms in MVP. Exogenic factors influencing MVP have been described.

Aim: To examine relationships between genital prolapse and joint hypermobility (JHM), between GP severity and degree of JHM, to reveal causes of GP in JHM patients., Material and Methods: A total of 208 females with GP (mean age 38.9 years) entered the trial. They were divided into three groups by severity of connective tissue dysplasia (CTD): with mild CTD--16.3%, moderate CTD--35.6% and severe CTD--48.1%. The following methods of investigation were used: podometric Freedland's technique, ultrasonic investigation of the gall bladder, kidneys, echocardiography, morphological study of platelets, morphological and immunohistochemical study of the ligaments., Results: In GP patients JHM occurred in 41.8% patients. Hypermobility of large joints reaches 38.9%, large--20.7%. Such associated manifestations of CTD as flatfoot, JHM, deformation of the spine, varicosity, predisposition to vegetovascular dysfunctions, mitral prolapse, arrhythmia, impaired conduction, refraction, gastroptosis, nephroptosis, hernias were observed in 69.2, 46.1, 38, 53.8, 49, 43.3, 38, 19.2, 12, 6.7, 14.4%, respectively. The morphological changes are explained by 40 +/- 15% type 1-3 collagen loss in the interstitial substance. Severe forms of GP in patients with JHM were observed in 84%. 52.4% females with JHM developed severe GP within 3 years after delivery of a child. Most of the examinees carried undifferentiated congenital dysplasias., Conclusion: JHM is a criterion of CTD diagnosis.

An association between insertion/deletion polymorphism (IDP) of the Alu repeat in intron 16 of the angiotensin I-converting enzyme (ACE) gene and the serum free amino acid levels in the patients with connective tissue dysplasias was examined. Genotyping of 102 patients (25 II, 51 ID, and 26 DD) was performed using PCR. Serum free amino acids levels in these patients were determined by use of HPLC technique. A statistically significant increase of the leucine-isoleucine (P < 0.05) and phenylalanine (P < 0.01) levels in deletion homozygous patients (DD) relative insertion homozygous (II) patients was observed. The differences in respect of other amino acids were not detected. These findings point to the importance of registration of IDP in the ACE gene at dietary therapy of such patients, as well as in the individual choice of medical preparations containing the amino acids mentioned.

The anthropologic examination and exploration of phenotypic markers of connective tissue dysplasia (CTD) were conducted in 50 patients with renal anomaly verified by ultrasound investigations and excretory urography. It was established that CTD-associated renal anomalies occur primarily in asthenic and gynecomorphic constitutions. Phenotypic markers of the anomalies are scoliosis, distortion of the nasal septum and blue sclerotics. Thus, the anthropologic examination can provide initial information on possibility of renal developmental anomalies associated with CTD.

Phenotype was investigated in 86 patients with idiopathic prolapses of atrioventricular valves and in 21 patients with displaced chordae. 10 and 4 markers of connective tissue dysplasia were distinguished for patients with the prolapses and anomalous chordae, respectively. For patients with dysplasia of connective tissue of the heart a modified version of phenotypical length is proposed: norm-anomalous chordae--prolapse of the 1st degree--prolapse of the 2nd degree. For patients with 3 and more markers echo-CG registration is advisable to reject mitral and/or tricuspid valves.

The clinico-immunogenetic analysis of 47 patients with Marfan's syndrome and 83 patients with chest deformities combined with valvular prolapses and other connective tissues dysplasias elucidated a close relation of HLA-antigens allele variants with clinical dysplasia variants and specific immune alterations. The findings support the suggestion that clinical heterogeneity of connective tissue dysplasia forms results from their pathogenetic heterogeneity.

Ion-paired reversed-phase high performance liquid chromatography (HPLC) has been used for the analysis of the content of mature collagen crosslinks--hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) in biopsy specimens of human rib cartilage from healthy donors (n = 14) and patients with inherited diseases of the connective tissue complicated with funnel chest (n = 17). Analysis of normal tissues reveal the presence of LP (alongside with HP) in embryonal rib cartilage. LP has been found in the rib cartilage of 4 out of 6 patients with funnel chest (FC) associated with Ehlers-Danlos syndrome (EDS); with no signs of this pathology detected in individuals with isolated FC. In rib cartilage of 2 patients with recurrent isolated FC LP has been discovered alongside with the presence of type I collagen. A significant increase of LP content in rib cartilage in a child with clinical phenotype of EDS type VI has been discovered.

4 lethal cases of idiopathic arterial calcinosis (IAC) in three girls (1 month 10 days, 2 months and 3 months of age) and one 8-month-old boy are described. The authors' own material and literature data confirm the autosomal recessive character of the disease. The initial step in the IAC morphogenesis belongs to the genetically conditioned elastolysis with the participation of giant multinuclear cells with subsequent arterial calcinosis. Differential diagnosis of IAC with secondary arterial calcinosis is recommended.

Wolff-Parkinson-White syndrome (WPWS) was combined in a majority of patients with various syndromes of primary dysplasia of connective tissue determining phenotypic characteristics of patients. They are also of considerable diagnostic importance. During examination of 200 WPWS patients, asthenic constitution, dolichocephalism and arachnodactyly were revealed in most of them. The most frequent stigmata of dysembryogenesis were the high palate (76%) the 3rd type of the ear lobe (36.6%), and epicanthus (20.5%). The funnel chest and thoracic kyphosis in the sagittal plane were noted in 30% of WPWS patients. The syndrome of articular hypermobility was diagnosed in 51.6% of the patients with WPWS, of them 37% had extraarticular manifestations in the form of varicosis of the crural veins.

In this paper, information about the structure and function of collagen genes family coding the main proteins of connective tissue of higher organisms is summarized. The structure of collagen proteins, their precursors and the main properties of corresponding mRNA and cDNA are discussed. The data are presented on evolution of collagen genes and their association with the human hereditary diseases of connective tissue.