Cardiovascular disease and associated comorbid conditions as determinants of adverse perinatal outcomes in pregnancy - an analysis of the results of the register of pregnant BEREG.

AIM: the Aim of the BEREG Registry was to analyze the prevalence and structure of cardiovascular diseases, associated comorbid conditions and assess their effects on pregnancy and perinatal outcomes in real clinical practice. MATERIALS AND METHODS: In Tula city regional perinatal center the observation study named "Assessment of the clinical condition of the pregnant women with cardiovascular disease during gestation, at child delivery, at the early postpartum period and at twelve months after childbirth and assesment of perinatal outcomes, condition of the fetus and the newborn and the quality of treatment of these patients groups.  All eligibly pregnant women hospitalized in 2014 to "Tula regional perinatal center" have been recruited in the Registry. Clinical and demographic data at admission, obstetric history, laboratory and instrumental examination data, previous medical history have been investigated. The following endpoints were evaluated: maternal mortality, death of the fetus and newborn baby; preeclampsia or/and eclampsia, heart failure, arrhythmia, thromboembolism events.  Statistical processing of obtained data was carried out using the software package STATISTICA 10.0 (StatSoft, USA). RESULTS: The study included 3214 women delivered babies in the perinatal center in 2014, of which 691 (21,4%) were diagnosed with cardiovascular disease (CVD) in most cases (451 women, 65,9%) - these were different clinical variants of arterial hypertension (AH). Five women (0.7%) had acquired and 23 women ( 3.3%,) congenital heart defect, non-significant heart development abnormities were found in 80 subjects, (11.6%). and Cardiac arrhythmias and conductivity disturbance have been revealed in 116 and 16 cases (16.8% and 2.3%) correspondingly. Patients with CVD were significantly older than women without CVD and more often had a variety of disorders of carbohydrate metabolism, overweight, obesity and chronic varicose disease of the lower extremities. Pregnancy in women with CVD significantly more often was complicated by the threat of interruption, placental insufficiency, preterm and operative babies delivery. Arterial hypertension as well as obesity, placental insufficiency and threatened miscarriage became prognostically unfavorable conditions that contributed of premature birth and fetal death. Fetal death or newborn babies death took place in 1,3% of all the subjects enrolled. In this cohort antenatal death have been registered in 43,2%, intrapartum one in 2.3% and neonatal death in 54.5%. CONCLUSION: Negative prognostic factors for low birth-weight babies were: placental insufficiency, various clinical variants of AH, obesity and infectious diseases; less input had endocrine diseases and risk of abortion. Adverse factors for the fetus death or newborn death were different clinical variants of arterial hypertension and the risk of abortion in any trimestre of pregnancy.

Activity of Monoamine Oxidase in the Nigrostriatal System at Presymptomatic and Early Symptomatic Stages of Parkinsonism in Mice.

Activities of monoamine oxidases A and B were examined on the models of presymptomatic and early symptomatic stages of Parkinson's disease developed in mice treated with MPTP, a specific neurotoxin affecting dopaminergic neurons. Activity of monoamine oxidases A, the key enzyme of dopamine degradation, is increased in neuronal somas during the symptomatic stage, and it is augmented in the axons during both stages. Neuronal activity of monoamine oxidases A is higher during the symptomatic stage than that during the presymptomatic stage, which can explain depletion of intercellular dopamine and appearance of motor disturbances. Activity of monoamine oxidase B in the striatum is reduced during the presymptomatic stage, but returns to the control level during the symptomatic stage. Variation in monoamine oxidase activity seems to reflect the compensatory mechanisms triggered in degrading nigrostriatal dopaminergic system.

[The determination of amitriptyline and its metabolite, nortriptyline, in the biological objects of the corpse by the high-performance liquid chromatography technique].

Tricyclic antidepressants are among the preparations that most frequently cause intoxication in adults and children; moreover, poisoning with these substances not infrequently has a fatal outcome. Medications belonging to this group, such as amitriptyline, are extensively used to manage manifestations of depression, anxiety, migraine, neuropathic pain, and hyperactivity syndrome. Amitriptyline overdosage causes non-specific symptoms of intoxication, and its clinical picture does not allow to identify the nature of a psychotropic xenobiotic. Of primary importance in connection with this is to establish the cause of intoxication or death by the clinical toxicological and forensic medical methods based on the results of the fast identification and quantitation of amitriptyline in biological materials including blood, urine, hepatic tissues, etc. The authors describe the method for the determination of amitriptyline and its principal physiological metabolite nortriptyline in biological objects with the help of high performance liquid chromatography (HPLC).

Modeling of presymptomatic and symptomatic stages of parkinsonism in mice.

A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.

Experimental modeling of preclinical and clinical stages of Parkinson's disease.

Degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system is the key stage in the pathogenesis of Parkinson's disease. The first symptoms of this disease are observed after degeneration of 70-80% neurons, which occurs over 20-30 years. The clinical stage of Parkinson's disease begins after this period. Late diagnostics of Parkinson's disease contributes to low efficiency of therapy for this disorder. Detailed study of the pathogenesis and development of preclinical diagnostic methods for Parkinson's disease are the urgent problems. This work was designed to develop a new experimental model of the preclinical and clinical stages of the disease. Experimental modeling was performed on C57Bl/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This agent is converted into the MPP(+)-neurotoxin in brain DAergic neurons. We showed that MPTP in a dose of 4 mg/kg has no effect on the nigrostriatal DAergic system. MPTP in a dose of 8-16 mg/kg produced the toxic effect only on DAergic axons, which simulates the preclinical stage of Parkinson's disease. MPTP in a dose of 20-40 mg/kg had the toxic effect on neuronal axons and bodies, which simulates the clinical stage of Parkinson's disease. The data suggest that progressive degeneration of DAergic neurons is accompanied by activation of compensatory mechanisms for functional deficiency of these cells.

[Modeling of preclinical and early clinical stages of Parkinson's disease].

The first symptoms of Parkinson's disease manifest 20-30 years after the disease onset when the most dopaminergic neurons degenerated. Therefore, it is necessary to work out preclinical diagnostics and preventive treatment of this disease. Modeling of preclinical and early stages of Parkinson's disease was conducted in mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). The changes in motor behavior were not observed in mice by 14 day after MPTP injections in dose 12 mg/kg two times with interval of two hours. In the striatum, the region of dopaminergic axon projection, the content of dopamine and number of dopaminergic axons decreased by 57% and 59%, respectively, i.e. there were no changes in dopamine in single axons. In the substantia nigra, the region of dopamine neuron localization, the content of dopamine did not change though the total number of neurons decreased by 28%. However the dopamine content in remained neurons was higher by 77% compared to the control that indirectly indicated the compensatory enhancement of dopamine synthesis. After the MPTP injections in dose 4x12 mg/kg, there were changes in motor behavior of mice in the most sensitive tests. In the striatum, the dopamine content and number of dopaminergic axons decreased by 75% and 68%, respectively. In the substantia nigra, there were no changes in dopamine content but the number of dopaminergic neurons decreased by 43%. The intraneuronal dopamine content increased by more than 70%. In conclusion, we constructed the models of preclinical stage (two-time MPTP injections) and transition phase from presymptomatic to symptomatic stage (four times of MPTP injections) of Parkinson's disease.

[Experimental modeling of functional deficiency of the nigrostriatal dopaminergic system in mice].

The dopaminergic nigrostriatal system is a key component of regulation of the motor behaviour. Cell bodies of dopaminergic DA-ergic neurons are located in the compact zone of the substantia nigra, and their axons are projected along the nigrostriatal tract to the striatum. This study was aimed to develop an experimental model of the functional insufficiency of the DA-ergic neurons of the nigrostriatal system without any manifestation of movement disorders, i.e., a model of presymptomatic stage of parkinsonism. This model has been developed with a single subcutaneous injection of a low dose of MPTP (12 mg/kg) which is converted in the brain into the MPP+, a neurotoxin of DA-ergic neurons. It has been shown that the MPTP injection on the 14th day is followed by: (a) absence of any sign of movement disorders; (b) no change in the DA content and the number of DA-ergic neurons in the substantia nigra; (c) substantial loss of DA in the striatum as a result of the degeneration of about 50% of DA-ergic axons. The absence of movement disorders under the substantial DA depletion and degradation of DA-ergic axons in the striatum is supposed to be a consequence of the turning on of the compensatory processes in the brain. Thus, we have developed the experimental model of presymptomatic stage of parkinsonism which is characterized by the degeneration of DA-ergic axons in the striatum without degradation of the neuron cell bodes in the substantia nigra.