Autoantibodies against complement components in systemic lupus erythematosus - role in the pathogenesis and clinical manifestations.

Many complement structures and a number of additional factors, i.e. autoantibodies, receptors, hormones and cytokines, are implicated in the complex pathogenesis of systemic lupus erythematosus. Genetic defects in the complement as well as functional deficiency due to antibodies against its components lead to different pathological conditions, usually clinically presented. Among them hypocomplementemic urticarial vasculitis, different types of glomerulonephritis as dense deposit disease, IgA nephropathy, atypical haemolytic uremic syndrome and lupus nephritis are very common. These antibodies cause conformational changes leading to pathological activation or inhibition of complement with organ damage and/or limited capacity of the immune system to clear immune complexes and apoptotic debris. Finally, we summarize the role of complement antibodies in the pathogenesis of systemic lupus erythematosus and discuss the mechanism of some related clinical conditions such as infections, thyroiditis, thrombosis, acquired von Willebrand disease, etc.

[FREQUENCIES OF FETAL CHROMOSOMAL ABERRATIONS DETECTED BY AMNIOCENTESIS: OUR 15-YEARS EXPERIENCE].

Amniocentesis is the most common and reliable prenatal diagnostic method for chromosomopathies. The purpose of the present study is to retrospectively evaluate our 15-year experience with prenatal cytogenetic diagnosis by amniocentesis, focusing on the indications and rates of chromosome abnormalities. The current study involve prenatal cytogenetic analysis from 564 amniocentesis performed at the Department of Medical Genetics, St. George University Hospital, Plovdiv between January 2000 and December 2014. Among clinical indications, abnormal maternal serum screening results (54.96%; 310/564) have been the most common indication for amniocentesis. Chromosomal abnormalities were detected in 5.5% (31/546) of cases. Structural rearrangements were the most common abnormality found (16/3 1;51,61%) with prevalence of balanced aberrations--11 cases. The highest detection rate of chromosome aberrations was in cases undergoing amniocentesis due to known family history of chromosomal abnormality (15.1%), followed by abnormal fetal ultrasound finding group (7.69%), increasing-risk maternal prenatal screening results (4.52%), and advanced maternal age (3.28%). This study provides important information for prenatal genetic counseling of families at risk with aim of prenatal care and prevention during pregnancies.

[CYTOGENETIC ANALYSIS OF PATIENTS WITH PRIMARY AMENORRHEA].

Primary amenorrhea is one of the common reproductive disorder affecting females. It leads to the absence of menarche in the reproductive age group in females and/or complete absence of reproductive organs. The physiology of menstruation and reproduction has a strong correlation with the expression of the X chromosome. Thus, the role of the clinical geneticists in terms of diagnosis, risk assessment, genetic counseling and management of patients with primary amenorrhea and their families is essential. The genetic contribution to amenorrhea is studied both at the cellular and molecular level aiming at chromosomal abnormalities and gene mutations. In the present study we aim to perform chromosomal analysis in 140 patients present with primary amenorrhea employing GTG banding technique. The resulting karyotype revealed 67.4% (n = 95) with normal chromosome composition and 32.6% (n = 46) showed chromosomal abnormalities. In patients with abnormal chromosome constituents, 20% (n = 9) exhibit numerical aberration, 22% (n = 10) showed structural abnormalities, 43% (n = 20) mosaic genotype and 15% (n = 7) of cases--male karyotype. Furthermore, the involvement of Y chromosome and the origin of marker chromosome was confirmed by applying fluorescent in situ hybridization (FISH) in four patients.

[PRENATAL DIAGNOSIS OF FOETAL TRISOMY 3Q WITH PATERNAL ORIGIN].

Balanced chromosomal translocations do not generally have phenotypic manifestation, but lead to increased risk of miscarriage and live-birth of chromosomally unbalanced offspring in carriers. Frequently prenatal diagnosis of an unbalanced translocation may incidentally detect a balanced translocation in the family. Here, we report a unique case of trisomy 3q (karyotype 46,XYder(3)t(3;21)(q11;p11)), detected prenatally due to abnormal findings of the fetus ascertained through ultrasound assessment like growth retardation, vermal agenesis, micrognathia, cystic hygroma of the neck, dextra position of arcus aortae, shorter for the gestational week long bones In order to determine the paternity of this chromosomal aberration, the cytogenetic analyses of the parents was performed. A balanced paternal translocation 46,XY,t(3;21)(q11;p11) wase identified. During the next pregnancy the same balanced translocation of paternal origin wase also identified. This case demonstrate the significance of prenatal ultrasound screening of the fetus; the necessity of cytogenetic analysis of a fetus with prenatal ultrasound abnormalities; genetic counseling of such families with aim of prenatal care and prevention during next pregnancies.

Investigation of fasciculation and elongation protein ζ-1 (FEZ1) in peripheral blood reveals differences in gene expression in patients with schizophrenia.

Schizophrenia (SZ) is a chronic neuropsychiatric disorder characterized by affective, neuromorphological and cognitive impairment, deteriorated social functioning and psychosis with underlying molecular abnormalities, including gene expression changes. Observations have suggested that fasciculation and elongation protein ζ-1 (FEZ1) may be implicated in the pathogenesis of schizophrenia. Nevertheless, our current knowledge of the expression of FEZ1 in peripheral blood of schizophrenia patients remains unclear. The purpose of this study was to identify the characteristic gene expression patterns of FEZ1 in peripheral blood samples from schizophrenia patients. We performed quantitative reverse-transcriptase (qRT-PCR) analysis using peripheral blood from drug-free schizophrenia patients (n = 29) and age and gender-matched general population controls (n = 24). For the identification of FEZ1 gene expression patterns, we applied a comparative threshold cycle (CT) method. A statistically significant difference of FEZ1 mRNA level was revealed in schizophrenia subjects compared to healthy controls (p = 0.0034). To the best of our knowledge, this study is the first describing a down-regulation of FEZ1 gene expression in peripheral blood of patients with schizophrenia. Our results suggested a possible functional role of FEZ1 in the pathogenesis of schizophrenia and confirmed the utility of peripheral blood samples for molecular profiling of psychiatric disorders including schizophrenia. The current study describes FEZ1 gene expression changes in peripheral blood of patients with schizophrenia with significantly down-regulation of FEZ1 mRNA. Thus, our results provide support for a model of SZ pathogenesis that includes the effects of FEZ1 expression.

Deletion analysis of Bulgarian SMA families.

All three types of autosomal recessive spinal muscular atrophy map to chromosome region 5q13. Recent reports suggest that they are associated with deletions of two adjacent genes: SMN and NAIP. Here we report the first deletion analysis of Bulgarian SMA families. Homozygous deletion of exons 7 and 8 of the SMN gene were found in 85% of our patients, but the NAIP gene (exons 5 and 6) was deleted in only 26% of patients. To our knowledge, these frequencies are some of the lowest reported so far. The NAIP gene was deleted predominantly in severely affected patients (type I), while in the group with milder types SMA only deletions of the SMN gene were detected. Our phenotype-genotype correlation study confirmed that larger deletions are associated with more severe clinical course. The Bulgarian data support the thesis that the telomeric SMN gene could play a major role in determining SMA, while the NAIP or the centromeric SMN copy have a modifying effect on the phenotype.

Alternative splicing of a previously unidentified CFTR exon introduces an in-frame stop codon 5' of the R region.

The cystic fibrosis transmembrane conductance regulator (CFTR) has been extensively characterized as the carrier of the basic defect in cystic fibrosis. CFTR is part of a growing family of proteins encoded by a single gene, the variant isoforms of which are generated by alternative splicing or RNA editing. We have analyzed the CFTR mRNA in the region of exons 10-11 in T84 cells and detected an alternatively spliced exon (10b) accounting for about 5% of the CFTR mRNA. The exon 10b found in both the human and mice genomes, introduces an in-frame stop codon. The resulting mRNA is translated into a truncated CFTR protein, identified in T84 cells by immunoprecipitation with the CFTR-specific monoclonal antibody MATG 1061. The insertion of a differentially spliced exon carrying an in-frame stop codon is a novel cellular mechanism for the production of a protein sharing common sequences with another, but having different properties and functions.

Effects of nootropic agents on the performing of active two-way avoidance tasks in young and old rats.

Experiments were made on 2- and 18-month-old male rats to test the effects on the acquisition and retention of piracetam, meclofenoxate and four newly-synthesized substances with assumed nootropic action: pyrrolidine derivatives with code names p-F, p-P and A-T, as well as the derivative of para-chlorophenoxypropionic acid, with code name 4-Cl-alpha PA. The method of two-way active avoidance was used, with punishment reinforcement during 5-day training and retention tests on the 14th day after the beginning of training. The agents studied were applied orally in doses of 30 and 150 mg/kg for 3 days (2 days before training and on the first day of training) and then again one hour before the retention testing. The older rats manifested a poorer learning capacity than the younger ones. Piracetam produced the best effect both on learning and on retention. Compounds with code names p-F, p-P and A-T induced an increase in the number of avoidances compared with the controls on isolated days only, according to the tests for acquisition. The favourable effects observed are not in close dependence either on the dose applied, or on the age of the experimental animal. No significant effects were observed under the effect of meclofenoxate and of its structural analogue 4-Cl-alpha PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the serotonin, dopamine and noradrenaline levels in the cerebral cortex of rats trained for active and passive avoidance.

Male Wistar rats were trained for active (shuttle-box) and passive (step-down) conditioned avoidance through negative reinforcement. The memory tests carried out on the 24th hour and on the 7th day after the training revealed that the rats trained for active avoidance demonstrated a considerably higher number of avoidance in both tests, compared with the avoidance shown during the training session. The memory tests on the 24th hour and on the 7th day after training for passive avoidance showed that the rats had mastered the task lastingly. The levels of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) in the frontal cortex were determined on the 24th hour and on the 7th day after the training, both for active and for passive avoidance. The 5-HT content was considerably increased on the 24th hour after both active and passive avoidance training, whereas on the 7th day its level was unchanged for both types of training. The DA content was slightly increased on the 24th hour and on the 7th day after active avoidance training, though it was considerably reduced on the 24th hour after passive training. The NA level was insignificantly raised on the 24th hour after active avoidance training, being considerably reduced after passive avoidance training. The observed changes in the cortical levels of 5-HT, DA and NA are probably caused to a certain extent by the different stressors used as unconditioned-reflex stimuli during the training for active or passive avoidance.

Memory effects of the combination of medazepam with nootropic agents.

Experiments were made on rats using step-through passive avoidance method to study the effect of the benzodiazepine medazepam (Mz) on the retention of the memory traces during tests on the 3rd hour, 24th hour and 7th day after training, as well as the influencing of this effect by the nootropic agents meclofenoxate (Mf), aniracetam (Anc) and Euclidan (Eucl.). All substances tested (Mz in a dose of 5 mg/kg weight, Mf - 100 mg/kg, Anc and Eucl - 50 mg/kg), applied both independently and in combination, were administered orally for six days prior to the training. Mz was found to impair the retention of the memory traces in all three tests. Meclofenoxate totally eliminated the memory-impairing effect of Mz. A marked antiamnestic effect of both Anc and Eucl was observed in similar experiments with scopolamine-induced (2 mg/kg i.p.) amnesia. Bearing in mind the results of other behavioural and biochemical studies, including radioligand tests, an attempt is made to justify the idea that the basic mechanism of the amnestic action of Mz is connected with the cerebral cholinergic neurotransmission. The results of the experiments using Opto-Varimex and Automex equipment for testing the effects of Mz, Mf, Anc and Eucl, and of the combination of Mz with the nootropic agents studied, on the spontaneous motor activity of the experimental rats, lead to the most general conclusion that Mz impedes the development of habituation, considered as a specific type of learning and memory process. To one degree or another, Mf, Anc and Eucl cancel this effect of Mz.(ABSTRACT TRUNCATED AT 250 WORDS)