[Features of lung damage in baclofen poisoning]. / Osobennosti povrezhdeniya legkikh pri otravlenii baklofenom.

OBJECTIVE: To reveal pathological lung changes in baclofen poisoning and to assess their dynamics. MATERIAL AND METHODS: The experiment included 20 mature (at age 20 weeks) male rats of Wistar line weighing 290-350 gr. The animals were divided into 3 study groups (5 rats in each) depending on experiment's duration after 85 mg/kg baclofen administration: 3, 4.5 and 24 h in the 1st, 2nd and 3rd groups, respectively. Control group consisted of 5 animals without baclofen administration. RESULTS: A number of pathological reactions, including circulatory disorder (venular and capillary congestion, hemorrhage in interalveolar septa, alveoli, sludge) and the appearance of emphysema loci (interalveolar septa at emphysema loci are thinned), alternating with atelectases and dystelectases. The area taken up by vessels after 4.5 h. baclofen administration was statistically significantly higher than in control group, and after 24 h. - statistically significantly higher than in 4.5 h. The area with white blood cells and WBC/IAP ratio after 4.5 h of baclofen administration were statistically significantly higher than in control group after 3 and 24 h of administration. The number of white blood cells, giving PAS positive reaction, increases during baclofen administration. The complex of pathological lung changes, revealed by ourselves, has a certain dynamics. CONCLUSION: The data on morphological lung changes combined with results of chemical examination can be used to diagnose baclofen poisoning and to determine the time elapsed since this medicine administration.

The Effect of the Toxic Dose of Baclofen on Selected Parameters of the Cardiovascular and Respiratory Systems.

The effect of the toxic dose of the muscle relaxant baclofen on the parameters of the cardiovascular and respiratory systems was studied in adult male Wistar rats (n=20). Systolic and diastolic BP, HR, and respiratory rate were measured; histological changes in the lungs 3, 4.5, and 24 h after drug administration. Baclofen was administered orally in a sublethal toxic dose of 85 mg/kg under anesthesia. Cardiac activity was analyzed using RSM physiological indicators monitoring system with MouseMonitor S (Indus Instruments) software. Histological examination was performed by light microscopy. Baclofen significantly decreased the respiratory rate and increased HR and BP. Histological examination of the lungs revealed a complex of general pathological processes, such as local circulatory disorders (venular and capillary fullness, sludge), leukocyte infiltration of the interalveolar septa and their thickening due to edema. These findings can be used to estimate the time elapsed after baclofen treatment.

Association of BARD1 and BRIP1 Gene Polymorphisms with the Risk of Uveal Melanoma.

Considering the limited information about the role of hereditary predisposition to the development of uveal melanoma, we have performed an analysis of the frequencies of BARD1 (rs1048108, rs2229571, rs2070094) and BRIP1 (rs4986764) gene polymorphisms in patients with uveal melanoma and benign choroidal nevus in comparison with healthy volunteers (control). It has been found that the minor alleles of BRIP1 rs4986764 and BARD1 rs2070094 polymorphisms, as well as the homozygosity of T allele at the BARD1 rs1048108 locus are common genetic markers for the predisposition to uveal melanoma and benign choroidal nevus, while the homozygous genotype GG for the BARD1 rs2229571 polymorphism is a specific marker for the predisposition to uveal melanoma and progressive choroidal nevus. We have also found that the heterozygous genotype at BARD1 rs1048108 polymorphic locus is a specific marker for protection against uveal melanoma and progressive choroidal nevus. Thus, our results indicate the advisability of studying polymorphisms of the BARD1 gene (rs1048108, rs2229571, and rs2070094) and the BRIP1 gene (rs4986764) in patients with uveal melanoma and progressive choroidal nevus. The obtained findings can be used for forming risk groups, prevention of uveal melanoma, and differential diagnosis of intraocular neoplasms.

MTNR1A and MTNR1B Gene Variants of the Melatonin Receptor and Arterial Stiffness in Persons without Arterial Hypertension.

A comparative analysis of vascular stiffness indices and the results of blood test was carried out in 85 healthy donors aged 19-64 years, carriers of polymorphic variants of type 1 and type 2 melatonin receptor genes. The associations of polymorphic markers of type 1 MTNR1A (rs34532313) and type 2 MTNR1B (rs10830963) melatonin receptor genes with parameters of vascular stiffness and blood parameters in healthy patients were studied. Genotyping was performed using allele-specific PCR. In all patients, 24-h BP monitoring with assessment of arterial stiffness was performed. Allele C homozygotes of MTNR1A differed significantly from carriers of the major T allele by elevated triglyceride, LDL, and fibrinogen levels. The major allele C of the rs10830963 polymorphic variant of the MTNR1B gene is associated with elevated LDL and triglycerides, as well as with individual differences in the elastic properties of the vascular wall in the examined subjects.

Parameters of Hemodynamic Allostasis in Patients of Various Age Groups with Essential Arterial Hypertension.

We determined the criteria for the diagnosis of hemodynamic allostasis and compared it with the index of allostatic load in patients of different age group with essential arterial hypertension without metabolic syndrome. The study included 87 subjects divided into 3 groups: patients with essential arterial hypertension at the age ⩽60 years (n=31; group 1), patients with essential arterial hypertension above 60 years (n=41; group 2), and healthy volunteers (n=15; age 25-69 years, group 3). The data of 24-h BP monitoring were processed by methods of linear and nonlinear rhythm analysis. Based on the analysis, parameters were identified that allow determining the state of allostatic regulation of the 24-h dynamics of BP, as well as parameters that determine the allostatic hemodynamic load on the cardiovascular system. The data obtained were compared with the index of allostatic load in patients of both groups. Regulation of the hemodynamics in patients with essential hypertension without metabolic syndrome in both age groups remained within the limits of hemodynamic allostasis forming the allostatic load on the body, which does not depend on patient's age.

Baclofen (fun drug) and ethanol combined poisoning in humans: A histopathology and morphometry model.

BACKGROUND: - This study intends to address the scarcity of data regarding the pathogenesis of Baclofen poisoning in humans, which has seen a recent increase, worldwide, especially amongst the young people. Another reason for the conduction of this study was lack of the substantial data about the histo-pathological findings of lungs, in synergistic toxicity of Baclofen with Ethanol, in-spite of it being very common in humans, and both being respiratory depressant with similar mechanism of action. PURPOSE: - The authors aimed to understand the pathogenesis of fatal poisonings in humans due to Baclofen in combination with Ethanol via an animal research model. The enhancement of the overall scientific literature by extending research along the lines of the handful studies available in this regard was another adjunct goal of the study. MATERIAL AND METHODS: Fifteen Wistar rats were divided into control and test group of five and ten subjects respectively. The test group was further divided into two sub-groups of five each, with Baclofen administered to one, and it in conjunction with Ethanol to the other, in lowest dosages adjusted for the humans. Rats in both the groups were euthanized by dislocation of the cervical vertebrae for the histopathology examination. RESULTS: Capillary and venous plethora, hemorrhages in the inter-alveolar septi, hemorrhages into the alveoli and sludging was seen in the 1st sub-group. The plethora of venules, capillaries and arterioles, with sludging by the WBC (white blood corpuscle) infiltrates was seen in the 2nd sub-group. Desquamation of the ciliated epithelium and edematous thickening of the intra-alveolar septi, along with features suggestive of the peri-vascular edema was seen in the 2nd sub-group. The morphometric analysis of the micro vessels showed a significantly higher value of the arteriolar diameter in the 2nd sub-group, in comparison to 1st, but the venular diameter in the two sub-groups did not differ to any extent.

Expression of Bax and Bcl-2 Proteins in Left-Ventricular Cardiomyocytes in Wistar-Kyoto and SHR Rats with Insulin-Dependent Diabetes Mellitus.

Loss of cardiomyocytes due to apoptotic or necrotic death is an important component of the pathogenesis of heart failure. Initiation of apoptosis by the mitochondrial pathway depends on the balance between proapoptotic and antiapoptotic factors, in particular, Bax and Bcl-2. Cardiomyocyte apoptosis in essential hypertension is studied in sufficient details. At the same time, apoptotic processes in the myocardium in diabetes mellitus alone and in combination with essential hypertension remain poorly understood. Here we studied the expression of Bax and Bcl-2 in the left ventricular cardiomyocytes of 38-week-old male Wistar-Kyoto rats and 38- and 57-week-old SHR rats with essential hypertension, diabetes mellitus, and a combination of these pathologies. Insulin-dependent diabetes mellitus was modelled by a single parenteral administration of streptozotocin in a dose 65 mg/kg. Expression of Bax and Bcl-2 was assessed by the immunohistochemical method. In essential hypertension and diabetes mellitus, the apoptotic processes in the ventricular myocardium were enhanced, as is seen from the increase in the content of the proapoptotic factor Bax and a decrease in the expression of the antiapoptotic factor Bcl-2. However, in case of combined pathology, Bax content increased less markedly, while the expression of antiapoptotic Bcl-2 was significantly increased.

Association of Gene Polymorphisms of Some Endothelial Factors with Stent Reendothelization after Elective Coronary Artery Revascularization.

Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.

Beclin-1-Dependent Autophagy of Left Ventricular Cardiomyocytes in SHR and Wistar-Kyoto Rats with Type 1 Diabetes Mellitus.

Autophagy is considered as a mechanism of progression of heart failure, but under certain conditions, it can also act as an adaptation mechanism. Beclin-1 plays the key role in autophagy. We studied the features of Beclin-1 expression in cardiomyocytes of the left ventricle in arterial hypertension, type 1 diabetes mellitus, and their combination. The experiment was performed on male 38-week-old Wistar Kyoto rats and SHR rats aged 38 and 57 weeks. Type 1 diabetes mellitus was modeled by a single parenteral administration of streptozotocin. Expression of Beclin-1 in cardiomyocytes of the left ventricle was evaluated by immunohistochemical analysis. In arterial hypertension, a decrease in the intensity of Beclin-1-dependent autophagy of cardiomyocytes was seen, while in combined pathology, we observed an opposite effect manifested as a significant increase in the expression of protein Beclin-1.

Small Heat Shock Proteins HSP10 and HSP27 in the Left Ventricular Myocardium in Rats with Arterial Hypertension and Insulin-Dependent Diabetes Mellitus.

We studied the expression of small heat shock proteins HSP10 and HSP27 in left ventricular cardiomyocytes in animals with arterial hypertension, insulin-dependent diabetes mellitus, and their combination. The experiment was performed on 38-week-old male Wistar-Kyoto and 38-57-week-old SHR (spontaneously hypertensive) rats. Insulin-dependent diabetes mellitus was modeled by single parenteral injection of streptozotocin (65 mg/kg). Expression of HSP10 and HSP27 in left ventricular cardiomyocytes was evaluated by immunohistochemical assay. It was found that the content of HSP10 in the left ventricular cardiomyocytes decreased in comparison with the control in case of isolated diabetes mellitus and, on the contrary, increased in case of arterial hypertension combined with diabetes mellitus. The intensity of HSP27 expression decreased in case of 38-week arterial hypertension and a combination of arterial hypertension with diabetes mellitus. However, in case of 57-week arterial hypertension we observed an increase in the content of HSP27 in cardiomyocytes.

Heat Shock Protein HSP60 in Left Ventricular Cardiomyocytes of Hypertensive Rats with and without Insulin-Dependent Diabetes Mellitus.

In cardiomyocytes, high molecular ATP-dependent HSP70 and HSP90 play an important role in protecting the myocardium from abnormal proteins that appear, in particular, due to activation of oxidative stress. Molecular chaperone HSP60 is of particular importance for cardiomyocytes as it is responsible for assembly of mitochondrial matrix proteins. We studied the peculiarities of expression of HSP60 in left ventricular cardiomyocytes in hypertension, insulin-dependent diabetes mellitus, and their combination. The experiment was performed on 38-week-old male Wistar-Kyoto and SHR (spontaneously hypertensive) rats aged 38-57 weeks. Insulin-dependent diabetes mellitus was modeled by a single parenteral administration of 65 mg/kg streptozotocin. Expression of HSP60 in left ventricular cardiomyocytes was evaluated by immunohistochemical methods. It was found that hypertension, diabetes mellitus, and their combination are associated with a significant decrease in the content of HSP60 in left ventricular cardiomyocytes in comparison with the control. This finding can be considered as a pathogenetic mechanism of myocardial damage induced by hypertension and diabetes mellitus.

Bright Light Therapy Increases Blood Pressure and Changes the Structure of Circadian Rhythm of Melatonin Secretion in Spontaneously Hypertensive Rats.

Phototherapy (therapy with bright light) is widely used to treat seasonal affective disorders, different types of depression, sleep disorders, and other diseases; it has no significant contraindications, but its effects on functional state and biological rhythms of the cardiovascular system in hypertension are poorly studied. In experiments on Wistar-Kyoto and SHR (spontaneously hypertensive rats) rats, the effect of bright light therapy on the daily profile of BP, HR, and production of epiphyseal melatonin was investigated. Phototherapy was simulated by exposure to 9000-lux cold light at the level animal eyes over 1 h (from 10.00 to 11.00 h) with LED lamps. In freely moving rats (free access to food), daily profiles of BP and HR were studied by 24-h continuous telemetry monitoring. The production of epiphyseal melatonin was assessed by measuring urinary concentration of its stable metabolite 6-sulfatoxymelatonin (aMT6s) during the day and night. During phototherapy, systolic BP significantly increased in in animals of both lines and diastolic BP increased in SHR rats. This effect persisted after the end of phototherapy session. Bright light had no effect on HR. In Wistar-Kyoto rats, phototherapy induced a significant decrease in daily concentration of aMT6s, but its nocturnal level did not change. In SHR rats, bright light therapy significantly decreased nighttime concentration of aMT6s in the urine and had no effect on daytime concentration of this metabolite. As a result, the difference between the night and day levels of aMT6s in the urine was leveled. Phototherapy produced more pronounced and less favorable effect on animals with primary arterial hypertension.

Structure of Rhythms of Blood Pressure, Heart Rate, Excretion of Electrolytes, and Secretion of Melatonin in Normotensive and Spontaneously Hypertensive Rats Maintained under Conditions of Prolonged Daylight Duration.

We studied the structure of rhythms of BP, HR (by telemetric monitoring), electrolyte excretion (by capillary electrophoresis), and products of epiphyseal melatonin (by the urinary concentration of 6-sulfatoxymelatonin measured by ELISA) in normotensive Wistar-Kyoto rats and spontaneously hypertensive SHR rats maintained at 16/8 h and 20/4 h light-dark regimes. In Wister-Kyoto rats exposed to prolonged daylight, we observed changes in the amplitude, rhythm power (% of rhythm), and range of oscillations of systolic BP; HR mezor decreased. In SHR rats, mezor of HR also decreased, but other parameters of rhythms remained unchanged. Changes in electrolyte excretion were opposite in normo- and hypertensive rats. Under conditions of 20/4 h light-dark regime, daytime melatonin production tended to increase in normotensive rats and significantly increased in SHR rats. At the same time, nighttime melatonin production did not change in both normotensive and hypertensive animals. As the secretion of melatonin has similar features in animals of both lines, we can say that the epiphyseal component of the "biological clock" is not the only component of the functional system that determines the response of the studied rhythms to an increase in the duration of light exposure.

Association of DNMT3B and DNMN3L Gene Polymorphisms with Early Pregnancy Loss.

A total of 100 women with early pregnancy loss were recruited and further classified into two subgroups: sporadic pregnancy loss and recurrent pregnancy loss; each subgroup consisted of 50 women. The control group included 56 women with normal pregnancies. Genotyping was performed by PCR with restriction fragment length polymorphism analysis. A statistically significant increase in the frequencies of TT genotype and T allele for DNMT3B rs2424913 polymorphism was found in the total patient group and in both patient subgroups in comparison with the control. Moreover, homozygous TT genotype was associated with increased risk of early pregnancy loss (both sporadic and recurrent). DNMT3B rs2424913 gene polymorphism in women can be used a marker of predisposition to early pregnancy loss and recurrent pregnancy loss.

Distribution of Polymorphisms of the Renin-Angiotensin System Genes (ACE, AGT, and AGTR1), ITGB3, and FTO in Pregnant Patients with Hypertensive Disorders.

The study included pregnant women aged 23-41 years with preeclampsia and gestation-associated arterial hypertension at weeks 27-40 and patients with essential arterial hypertension developing under conditions of the metabolic syndrome and without it. Frequency analysis of polymorphisms of the renin-angiotensin system genes (ACE, AGT, and AGTR1), ITGB3, FTO and their associations confirmed the syndrome nature of hypertensive disorders in pregnancy. The presence allele T of AGT gene and/or allele C of AGTR1 gene in the genotype of patients with preeclampsia was associated with higher BP and pressure load over 24 h. Allele D of ACE gene was also essential for BP parameters (pressure load) in patients with preeclampsia and gestation-associated arterial hypertension. Due to high genetic heterogeneity of the preeclampsia syndrome and genetic differences in the incidence of the studied gene polymorphisms in preeclampsia and gestation-associated arterial hypertension, no direct associations between these gestation disorders and polymorphic markers of the renin-angiotensin system genes can be established. However, polymorphisms of the renin-angiotensin system genes are essential for the 24-h dynamics of BP and pressure load under conditions of hypertensive disorders in pregnancy.

24-Hour Profile of Blood Pressure, Heart Rate, Excretion of Electrolytes, and Locomotor Activity in Wistar-Kyoto and SHR Rats Under Conditions of Free-Run Rhythm.

We presented the results of our study of chronostructure of BP, HR, electrolyte excretion, and locomotor activity under conditions of "free-run rhythm" (light deprivation). In adult male Wistar-Kyoto (normotensive) and SHR (spontaneously hypertensive) rats, BP, biopotentials of the heart (ECG), and locomotor activity were recorded over 24 h by telemetric monitoring and the rate of excretion of electrolytes (Na+, K+, Ca2+, and Mg2+) during the nighttime and daytime hours was measured. It was found that under free-run rhythm, 24-h profiles of BP, HR, excretory function of the kidneys, and locomotor activity underwent more considerable changes in normotensive Wistar-Kyoto rats in comparison with hypertensive SHR rats. However, hypertensive rats demonstrated pronounced changes in rhythmic characteristics of HR, which can restrict adaptation reserves of the cardiovascular system.

Hemodynamic Allostasis of Pregnant Women against the Background of Preeclampsia.

We analyzed diurnal hemodynamic parameters (HR, systolic BP, and diastolic BP) recorded from two groups of edematous and preeclamptic pregnant women. The unidirectional character of changes in the control over the functional state of cardiovascular system was revealed except for the indices, which mark a pathological process: elevated diurnal BP in preeclampsia and diminished percentage of oscillation power in edematous patients. Uniformity of the regulatory changes in patients with and without arterial hypertension can be viewed as manifestation of allostasis developed by the cardiovascular system during pregnancy. In preeclampsia, the greater allostatic load was reflected by the changes in diurnal, daytime, and nighttime BP and in the circadian index calculated for HR, systolic BP, and diastolic BP. In edematous patients, elevation of allostatic load was indicated by the percentage of ultradian rhythms.

Specific Features of Electrolyte Excretion at the Early Stages of Arterial Hypertension in SHR Rats.

Daytime and nighttime systolic and diastolic BP was recorded in 23-week-old SHR and Wistar rats by telemetric monitoring. Urine concentrations of sodium, potassium, and calcium were determined in SHR rats during of light (07.00-19.00 h) and dark hours (19.00-07.00 h) at the age of 18, 19, 20, 21, 22, and 23 week; 23-week-old Wistar rats were used as the control. At early stages of the experiment, urine sodium concentration was elevated in SHR rats both at daytime and at night. Thereafter, this value declined and by 22-23 week was significantly lower than in normotensive Wistar rats, but only during daytime. Daytime potassium concentration significantly surpassed the control level during weeks 18-19 of the experiment, but later, a tendency to a decrease in this parameter was observed. Daytime calcium content in SHR rats did not significantly differ from the control throughout the experiment. At night, this value exceeded the control level by more than 2 times during weeks 18-19, but then returned to the level observed in normotensive animals.

Element Status of Students with Different Levels of Adaptation.

The element status was studied in students with different levels of adaptation determined by the parameters of cardiointervalography. The content of chemical elements in the hair was measured by atomic emission and mass spectrometry. In students whose autonomic status was characterized by sympathicotonia, the level of cobalt in the hair was significantly higher, while the levels of manganese and magnesium were lower than normal. The content of selenium in the hair was 2.3 times lower in the study group in comparison with the median level in Russia. The content of toxic elements did not exceed the normal. Significant positive correlations between hair content of magnesium and calcium and between potassium and sodium were revealed.

Influence of geomagnetic activity and earth weather changes on heart rate and blood pressure in young and healthy population.

There are many references in the literature related to connection between the space weather and the state of human organism. The search of external factors influence on humans is a multi-factor problem and it is well known that humans have a meteo-sensitivity. A direct problem of finding the earth weather conditions, under which the space weather manifests itself most strongly, is discussed in the present work for the first time in the helio-biology. From a formal point of view, this problem requires identification of subset (magnetobiotropic region) in three-dimensional earth's weather parameters such as pressure, temperature, and humidity, corresponding to the days when the human body is the most sensitive to changes in the geomagnetic field variations and when it reacts by statistically significant increase (or decrease) of a particular physiological parameter. This formulation defines the optimization of the problem, and the solution of the latter is not possible without the involvement of powerful metaheuristic methods of searching. Using the algorithm of differential evolution, we prove the existence of magnetobiotropic regions in the earth's weather parameters, which exhibit magneto-sensitivity of systolic, diastolic blood pressure, and heart rate of healthy young subjects for three weather areas (combinations of atmospheric temperature, pressure, and humidity). The maximum value of the correlation confidence for the measurements attributable to the days of the weather conditions that fall into each of three magnetobiotropic areas is an order of 0.006, that is almost 10 times less than the confidence, equal to 0.05, accepted in many helio-biological researches.